EUROPEAN RESPIRATORY MONOGRAPH

Volume 10
Monograph 32, September 2005

Sarcoidosis

Edited by
M. Drent and U. Costabel

EUROPEAN
RESPIRATORY
SOCIETY
Mon 32 page i.qxd 09/08/2005 17:06 Page 1

Sarcoidosis
Mon 32 page ii.qxd 09/08/2005 17:07 Page 1

European Respiratory Monograph 32

September 2005

Editor in Chief
E.F.M. Wouters

This book is one in a series of European Respiratory Monographs. Each individual issue provides a
comprehensive overview of one specific clinical area of respiratory health, communicating infor-
mation about the most advanced techniques and systems needed to investigate it. It provides factual
and useful scientific detail, drawing on specific case studies and looking into the diagnosis and
management of individual patients. Previously published titles in this series are listed at the back of
this book with details of how they can be purchased.
Mon 32 page iii.qxd 09/08/2005 17:07 Page 1

Sarcoidosis

Edited by
M. Drent
U. Costabel
Mon 32 page iv.qxd 09/08/2005 17:08 Page 1

Published by European Respiratory Society Journals Ltd 2005

September 2005
Hardback ISBN: 1-904097-37-5
Paperback ISBN: 1-904097-41-3
ISSN: 1025-448x
Printed by The Charlesworth Group, Wakefield, UK

Business matters (enquiries, advertisement bookings) should be addressed to: European Respiratory
Society Journals Ltd, Publications Office, Suite 2.4, Hutton's Building, 146 West Street, Sheffield,
S1 4ES, UK. Fax: 44 114 2780501.

All material is copyright to European Respiratory Society Journals Ltd. It may not be reproduced
in any way including electronic means without the express permission of the company.

Statements in the volume reflect the views of the authors, and not necessarily those of the
European Respiratory Society, editors or publishers.
Contents MON 32.qxd 18/08/2005 16:39 Page 1

The European Respiratory Monograph

Number 32 September 2005

CONTENTS
The Guest Editors vii

Preface viii

Introduction ix

1. Definition and history of sarcoidosis 1

O.P. Sharma

2. Epidemiology of Sarcoidosis 13
M. Thomeer, M. Demedts, W. Wuyts

3. Aetiologies of sarcoidosis 23
L.S. Newman

4. Immunology and pathophysiology 49

G. Semenzato, M. Bortoli, E. Brunetta, C. Agostini

5. Genetics 64
R.M. du Bois, P.A. Beirne, S.E. Anevlavis

6. Pathology 82
V. Poletti, G. Casoni, M. Chilosi

7. Fatigue, quality of life and health status in sarcoidosis 92

J. De Vries, R.M. Wirnsberger

8. Pulmonary sarcoidosis 105

J.P. Lynch 3rd, E.S. White

9. Cardiac involvement in sarcoidosis 130

W. Schulte, D. Kirsten, M. Drent, U. Costabel

10. Skin manifestation in sarcoidosis 150

A. Eklund, G. Rizzato

11. Neurosarcoidosis 164

E. Hoitsma, O.P. Sharma

12. Clinical aspects of ocular sarcoidosis 188

K. Ohara, M.A. Judson, R.P. Baughman

13. Sarcoidosis: joint, muscle and bone involvement 210

T.L.Th.A. Jansen, P.P.M.M. Geusens
Contents MON 32.qxd 18/08/2005 16:39 Page 2

14. Renal sarcoidosis and hypercalcaemia 220

O.P. Sharma

15. Rare manifestations of sarcoidosis 233

D.R. Moller

16. Sarcoidosis in children 251

A. Clement, R. Epaud, B. Fauroux

17. Diagnostic approach to sarcoidosis 259

U. Costabel, J. Guzman, M. Drent

18. Sarcoidosis: imaging features 265

J.A. Verschakelen

19. Clinical usefulness of nuclear imaging techniques in sarcoidosis 284

J. Ma, M. Van Kroonenburgh

20. Therapy for sarcoidosis 301

R.P. Baughman, E.E. Lower

21. Rehabilitation programmes in sarcoidosis: a multidisciplinary approach 316

M.A. Spruit, E.F.M. Wouters, R. Gosselink

22. Transplantation for sarcoidosis 327

I. Saleem, S.O. Beirne, J.J. Egan

23. History of the WASOG and current activities 335

G. Rizzato

24. Sarcoidosis patient groups 337

P.Y. Polite

Appendix: Websites of national and international sarcoidosis patient societies 340

monograph list.qxd 09/08/2005 17:10 Page 1

Previously published in the European Respiratory

Monograph Series:
Lung Function Testing, Monograph 31 Lung Cancer, Monograph 17
Edited by R. Gosselink, H. Stam (2005) Edited by S G Spiro (2001)
Imaging, Monograph 30 Noninvasive Mechanical Ventilation,
Edited by A. Bankier, P.A. Gevenosis (2004) Monograph 16
Surgery for Non-Neoplastic Disorders of the Edited by J-F Muir, N Ambrosino, A K Simonds
Chest: a Clinical Update, Monograph 29 (2001)
Edited by G.M. Verleden, D. Van Raemdonck, Interstitial Lung Diseases, Monograph 14
T. Lerut, M. Demedts (2004) Edited by D Olivieri, R M du Bois (2000)
Antibiotics and the Lung, Monograph 28 Pulmonary Rehabilitation, Monograph 13
Edited by M. Cazzola, F. Blasi, S. Ewig (2004) Edited by C F Donner, M Decramer (2000)
Pulmonary Vascular Pathology: A Clinical Respiratory Mechanics, Monograph 12
Update, Monograph 27 Edited by J Milic-Emili (1999)
Edited by M. Demedts, M. Delcroix,
Occupational Lung Disorders, Monograph 11
R. Verhaeghe, G.M. Verleden (2004)
Edited by C E Mapp (1999)
Lung Transplantation, Monograph 26
Respiratory Disorders During Sleep,
Edited by J Boe, M Estenne, W Weder (2003)
Monograph 10
Respiratory Diseases in Women, Monograph 25 Edited by W T McNicholas (1998)
Edited by C Mapp, S Buist (2003)
Pulmonary Endoscopy, Monograph 9
Nutrition and Metabolism in Respiratory Edited by J Strausz (1998)
Disease, Monograph 24
Edited by J Boe, M Estenne, W Weder (2003) Mechanical Ventilation from Intensive Care to
Home Care, Monograph 8
Asthma, Monograph 23 Edited by C Roussos (1998)
Edited by F Chung, L M Fabbri (2003)
Management of COPD, Monograph 7
Pleural Diseases, Monograph 22 Edited by D S Postma, N M Siafakas (1998)
Edited by R Loddenkemper, V B Antony (2002)
Clinical Exercise Testing, Monograph 6
The Impact of Air Pollution on Respiratory Edited by J Roca, B J Whipp (1997)
Health, Monograph 21
Edited by G D'Amato, S T Holgate (2002) New Diagnostic Techniques in Paediatric
Respiratory Medicine, Monograph 5
ARDS, Monograph 20
Edited by M Zach, K H Carlsen, J O Warner,
Edited by T W Evans, M J D Griffiths, B F Keogh
F H Sennhauser (1997)
(2002)
Growing up with Lung Disease: The Lung in Tuberculosis, Monograph 4
Transition to Adult Life, Monograph 19 Edited by R Wilson (1997)
Edited by A Bush, K-H Carlsen, M S Zach Pneumonia, Monograph 3, 1997
(2002) Edited by A Torres, M Woodhead (1997)
The Nose and Lung Diseases, Monograph 18 Carcinoma of the Lung, Monograph 1
Edited by B Wallart, P Chanex, P Godard (2001) Edited by S G Spiro (1995)
Monographs may be purchased from:
Publications Sales Department, Maney Publishing, Hudson Road, Leeds LS9 7DL, UK.
Tel: 44 (0)113 2497481; Fax: 44 (0)113 2486983; E-mail: books@maney.co.uk
Customers in the Americas should contact: Old City Publishing Inc., 628 North 2nd Street, Philadelphia
PA 19123, USA. Tel: 1 215 925 4390; Fax: 1 215 925 4371; E-mail: info@oldcitypublishing.com
PREFACE Preface

A wide range of acute and chronic pulmonary disorders are capable of diffusely
affecting the lung parenchyma with variable amounts of inflammation and fibrosis. A
variety of agents and clinical conditions have been associated with interstitial lung
disorders. Sarcoidosis is one of the most common causes of idiopathic interstitial lung
disease. Clinical presentation can range from asymptomatic to severe respiratory
symptoms.
Sarcoidosis is considered as a multisystemic disease and chest physicians are frequently
involved in the evaluation and management of this disease. The treatment of sarcoidosis
ranges from nothing to complex immunosuppressive agents. Given the range of effective
therapies for sarcoidosis, appropriate treatment is important.
This issue of the European Respiratory Monograph provides the reader with the current
status of our understanding of sarcoidosis. Different aspects of the multisystem
involvement of this disease condition are discussed by experts in the field of sarcoidosis.
Their contributions offer the reader new insights, ideas and perspectives in the
management of sarcoidosis. As Editor in Chief of the European Respiratory Monograph,
I am most grateful to all the authors for gladly contributing and I am deeply indebted to
Urich Costabel and Marjolein Drent, the guest editors of this issue, for their cooperation.

E.F.M. Wouters
Editor in Chief

Eur Respir Mon, 2005, 32, viii. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
viii
INTRODUCTION

M. Drent #, U. Costabel }
#
Sarcoidosis Management Centre, Dept of Respiratory Medicine, University Hospital Maastricht,
Maastricht, The Netherlands. Fax: 31 842234007; E-mail: m.drent@lung.azm.nl; www.pul.unimaas.nl
}
Dept of Pneumology/Allergy, Ruhrlandklinik Essen, Essen, Germany. Fax: 49 2014334029; E-mail:
erj.costabel@t-online.de

More than a century ago, J. Hutchinson, a surgeon/dermatologist, identified the first

case of sarcoidosis in London, UK. In the decades around the turn of the 19th century
several independent observations were made on manifestations of a disease that is now
regarded to be sarcoidosis. The cause or causes of this multiorgan disease remain
unknown. The disorder is characterised by an abundant immunological T-helper cell
type 1 response as the initial event, which leads to granuloma formation. More than 60%
of sarcoidosis patients experience resolution during the following 25 yrs; in the others,
the disease runs a chronic course. In some patients, it may lead to end-stage lung fibrosis
with signs of permanent respiratory functional impairment. It is emphasised that
clinicians may face difficulties when trying to categorise sarcoidosis in an individual case.
One of the most important clinical issues is to identify those cases that deteriorate and
eventually develop fibrosis or other manifestations of chronic sarcoidosis. These patients
should be monitored more closely and receive appropriate and timely treatment in order to
avoid the development of unnecessary damage. In general, the state of a disease can be
classified either by activity and/or severity. Unlike other disorders, activity in sarcoidosis
does not necessarily indicate a progressive course, a fatal prognosis, or the need for medical
treatment. Moreover, there is much discussion about the definitions of both, as it is difficult
to make a clear distinction between activity and severity. In addition, there is overlap
between the two. Inconsistency also exists on how to define severity. The course of
sarcoidosis is mainly monitored by assessing clinical features and using auxiliary diagnostic
procedures. Clinical parameters used to depict respiratory involvement include laboratory
parameters, lung function tests, bronchoalveolar lavage and imaging procedures.
Recently, insight has been provided into the genetic risk for sarcoidosis and how the
genetic make-up of a patient (genotype) determines the clinical presentation and outcome
(phenotype). Genetically, sarcoidosis is a complex disease whose genetic predisposition is
not determined by a single gene. Genetic associations can only be studied if the
phenotypes of sarcoidosis are properly defined and categorised.
Patients with sarcoidosis most often suffer from symptoms related to the lungs, but
may also suffer from a wide spectrum of other symptoms. The complicated
multidimensional nature and wide range of symptoms of sarcoidosis underlines the
need of a multidisciplinary approach and management. This includes the cooperation
between clinicians and basic scientists to get better insight into this whimsical disorder.
The patients need care from pulmonary physicians as well as other medical care
representatives. Attention should be paid to the somatic as well as the psychosocial
aspects of a disease that is a riddle to all patients and many doctors.
The current issue of the European Respiratory Monograph aims to offer clinicians
guidelines for the management of their sarcoidosis patients, with special attention to
extrathoracic and rare manifestations. The therapeutic approach to the various organ
manifestations is reviewed. This includes the role of alternative drugs to reduce steroid-
related side-effects. Currently, biological agents targeted at the selective inhibition of
tumour necrosis factor-a, the major cytokine in the induction of granuloma formation,
are under investigation.
Eur Respir Mon, 2005, 32, ix. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
ix
CHAPTER 1

Definition and history of sarcoidosis

O.P. Sharma

Correspondence: O.P. Sharma, Room 11-900, Los Angeles County-University of Southern California
Medical Center, 1200 North State Street, Los Angeles, CA 90033, USA. Fax: 1 3232262738; E-mail:
osharma@usc.edu

Sarcoidosis, a commonplace inflammatory disease, is characterised by the formation

of noncaseating granulomas. The granuloma is a battle fought on a genetically
vulnerable terrain between an unrecognised antigen(s) and a highly organised team of
lymphocytes and macrophages. The disease occurs worldwide; no race, sex or age is
immune from it. Its chameleon-like multisystemic presentation can involve any organ in
the body. Owing to its diverse presentation, the disease easily crosses the artificial
boundaries of medical specialities, and appears in the offices and clinics of practitioners
of different disciplines. The fresh, innovative and individual approach of international
investigators, scientists and specialists of different disciplines have constructed an
engrossing historical saga of sarcoidosis (table 1).

Definition
It is hard to provide a concise definition of a disease whose cause is yet to be
discovered. Scadding and Mitchell [3] recommended the following: "Sarcoidosis is a

Table 1. Sarcoidosis milestones

Event
1869 J. Hutchinson: first account of skin lesions
1888 E. Besnier: coined term lupus pernio
1892 M. Tenneson: defined histology
1897 C. Boeck: described a policeman with skin lesions
1902 R. Kienbock/K. Kreibich/O. Jungling: described bone changes
1906 DarierRoussy syndrome: subcutaneous nodules described
19091910 H. Schumacher/Christian Heerfordt/F. Bering: recognised uveitis
1915 J. Schaumann: emphasised multisystemic disorder
1915 E. Kuznitsky: classified skin lesions
1915 A. Bittorf: described lung lesions
1937 W. Bruins-Slot/L-M. Pautrier/W.T. Longcope/J. Pierson/ J. Costa Waldenstrom: uveoparotid fever
1941 A. Kveim: introduced Kveim test
S. Lofgren: described Lofgrens syndrome
1958 K. Wurm: first proposal for radiographic staging
1958 1st International Conference on Sarcoidosis: London, UK
1961 1st USA conference: Washington, DC, USA
19671981 H. Reynolds, G. Hunninghake, R Crystal: bronchoalveolar lavage
1976 Commemorative publication dedicated to L. Siltzbach: Mount Sinai Journal of Medicine, New York [1]
1984 G. Rizzato: starts journal Sarcoidosis (now called Sarcoidosis, Vasculitis and Diffuse Lung Diseases)
1987 G. Rizzato: founds World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG);
D.G. James elected the first president
1987 Commemorative publication dedicated to D.G. James: Sarcoidosis [2]

Eur Respir Mon, 2005, 32, 112. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
1
 O. P. SHARMA

disease characterised by the formation in all of several affected tissues of epithelioid-cell

tubercles without caseation though fibrinoid necrosis may be present at the centre of a
few, proceeding either to resolution or to conversion into hyaline fibrous tissue". This
definition emphasises only the histological features of the illness. Knowledge of the
disease is now so expansive that not only the clinical but also the radiological,
immunological, biochemical and genetic aspects of the illness need to be included. A brief
definition of sarcoidosis is not possible because of ignorance of its cause. The following
descriptive definition is provided in the American Thoracic Society/European
Respiratory Society/World Association of Sarcoidosis and Other Granulomatous
Disorders (WASOG) statement on sarcoidosis of 1999 [4]: "Sarcoidosis is a multisystemic
disorder of unknown cause. It commonly affects young and middle-aged adults and
frequently presents with bilateral hilar adenopathy, pulmonary infiltration, ocular and
skin lesions. The liver, spleen, lymph nodes, salivary glands, heart, nervous system,
muscles, bones and other organs may also be involved. The diagnosis is established when
clinico-radiographic findings are supported by histological evidence of noncaseating
epithelioid cell granulomas. Granulomas of unknown causes and local sarcoid reactions
must be excluded. Frequently observed immunological features are depression of
cutaneous delayed type-hypersensitivity and a heightened Th-1 [T-helper cell type-1]
immune response at sites of disease. Circulating immune-complexes along with signs of
B-cell hyperactivity may also be found. The course and prognosis may correlate with the
mode of the onset, and the extent of the disease. An acute onset with erythema nodosum
or asymptomatic bilateral hilar adenopathy usually heralds a self-limiting course,
whereas an insidious onset, especially with multiple extrapulmonary lesions, may be
followed by relentless, progressive fibrosis of the lungs and other organs."

History
The London school
J. Hutchinson is a convenient starting point for tracing the history of sarcoidosis.
Hutchinson was born on July 23, 1828 in Selby (UK) to a Quaker family. After
graduating from St Bartholomews Hospital (London, UK), he became the best known
medical consultant in London because of his wide range of interests. He was
dermatologist at the Blackfriars Hospital for Diseases of the Skin, ophthalmologist to
the Royal London Ophthalmic Hospital, venereologist to the Lock Hospital, physician
to the City of London Chest Hospital, and a general surgeon to the London and
Metropolitan Hospitals (all London, UK). He became president of the Royal College of
Surgeons (1889), the Pathological Society of London (1879), the Ophthalmological
Society of the United Kingdom (1883), the Neurological Society (1887), the Medical
Society of London (1892), the Royal Medical and Chirurgical Society (18941896), and
the International Dermatology Congress (1896) (fig. 1).
In January 1869, a 58-yr-old coal-wharf worker, visited Hutchinson complaining of
purple symmetrical skin plaques on his legs and hands that had developed gradually over
the preceding 2 yrs. The lesions were neither tender nor painful. In 1877, Hutchinson [5]
described the lesion as livid papillary psoriasis and considered that it was in some way
related to the patients gout. In a later publication, Hutchinson [6] described additional
cases and described the lesion as a "form of skin disease which has hitherto escaped
special recognition". In Hutchinsons time, sarcoidosis was a dermatological curiosity.
Hutchinsons contemporary, A.C. Doyle, the creator of Sherlock Holmes, made a skin
disease, most probably cutaneous sarcoidosis, a basic ingredient of the plot of The

2
 DEFINITION AND HISTORY OF SARCOIDOSIS

a) b)

Fig. 1. a) J. Hutchinson and b) his patient showing typical chronic sarcoidosis lesions.

Adventure of the Blanched Soldier [7]. Whether or not A.C. Doyle ever discussed patients
with J. Hutchinson remains unclear, but it can be surmised that A.C. Doyle and J.
Hutchinson must have met and exchanged ideas during one of the many London Medical
Society meetings. J. Hutchinson was a member and regular discussant at the meetings,
whereas A.C. Doyle practised at 2 Devonshire Street (London, UK), just a few steps
away from 10 Chandos Street, home of the Medical Society of London.
From those early days, there have been other British pioneers of sarcoidosis, but none
more influential and erudite than J.G. Scadding, who was stimulated to take up
sarcoidosis by I. Snapper, Professor of Clinical Medicine at the University of Amsterdam
(Amsterdam, The Netherlands). In the early 1940s, at the Hammersmith Hospital
(London, UK), J.G. Scadding collaborated with S. Sherlock on a study of aspiration
liver biopsy in sarcoidosis (fig. 2). This test became the most valuable tool for diagnosing
sarcoidosis, and remained so for decades before being replaced by bronchoscopy. J.C.
Scadding consolidated his vast personal experience of the disease, gathered at the
Hammersmith Hospital and Brompton Chest Hospital, now the Royal Brompton
(London, UK), in the widely acclaimed book Sarcoidosis, first published in 1967 by Eyre
and Spottiswoode, London, UK. The credit for making sarcoidosis a household word,
however, goes to the ebullient internist and medical historian D.G. James, who, in 1953,
started the renowned sarcoidosis clinic in a small North London hospital. The clinic, in
its heyday, attracted sarcoidologists from all over the world. The Royal Northern
Sarcoidosis Clinic, as it was called, became a sarcoidosis Mecca. H. Israel, C. Johns,
J.G. Scadding, S. Lofgren, Y. Hosoda, L. Sitzbach, L. Levinsky, E. Kendig, J. Chretien,
N. Bethlem, T. Izumi, W. Jones Williams, R. Crystal, O.P. Sharma, G. Rizzato, S. Gupta,

3
 O. P. SHARMA

Fig. 2. D.G. James, S. Sherlock and S. Lofgren (from left to right, respectively).

D. Mitchell, U. Costabel, J. Costa Waldenstrom, F. Wegener, R. DeRemee, S. Sherlock,

M. Turner-Warwick, O. Selroos, B. Djuric and many others lectured and actively
participated in sarcoidosis meetings, conferences and group discussions at the Royal
Northern Hospital. Neither the clinic nor the hospital exists any longer [8].
The 1st International Conference on Sarcoidosis, organised by D.G. James, was held
in London in 1958, with a handful of physicians in attendance. The second international
gathering on British soil was the 7th International Conference on Sarcoidosis, held in the
historic city of Cardiff. W. Jones Williams was the host. R. Dubois staged the 15th
WASOG Conference in London, UK, in 1995.

The Scandinavian school

In the summer of 1869, J. Hutchinson visited Christiania (now Oslo) University (Oslo,
Norway), where W. Bidenkap showed him a collection of pathological drawings in the
university museum. Among these was one of a patient of C.W. Boeck. The patient, a
healthy Swedish sailor, had skin lesions similar to those of the 58-yr-old coal-wharf
worker who had visited Hutchinson earlier, but did not suffer from gout. C.W. Boeck
was an uncle of C. Boeck, who was later to make valuable contributions to the study of
sarcoidosis. He coined the term "sarkoid" because the lesion resembled sarcoma, but was
benign. Just before his death, C. Boeck published an extensive study of 24 cases of
"benign miliary lupoids"; some of the cases showed involvement of the lungs,
conjunctiva, bone, lymph nodes, spleen and nasal mucous membrane [9]. Thus, the
malady that started as a curious skin ailment in London, UK, became a multisystemic
disease in Oslo, Norway.
J. Schaumann was born in Soustad (Malmohus, Sweden) and studied medicine in
nearby Lund, Sweden. He became a dermatologist at Saint Gorans Hospital and the
Finsen Institute in Stockholm (Sweden). He provided a common pathological basis for
diverse clinical aspects; he was the first to propose a clinico-pathological synthesis of
multisystemic sarcoidosis. He called it lymphogranulomatosis benigna in order to
distinguish it from Hodgkins malignant granuloma. This he described in an admirable

4
 DEFINITION AND HISTORY OF SARCOIDOSIS

Zambaco-prize-winning essay written in 1914. The article was not published until 1936
[10].
S. Lofgren was born in Stockholm, Sweden. He received his medical training there and
married a Swedish physician. His medical life revolved around Saint Gorans Hospital,
where he came under the scientific influence of A.V. Westergren and J. Schaumann. His
elegant studies brought the mysterious disease of sarcoidosis out of the shadows and into
the limelight as a common disorder with a good prognosis. Although erythema nodosum
was first described by R. Willan (fig. 3) in his classic work On Cutaneous Disorders [11],
published in parts between 1798 and 1808, it was S. Lofgren who, by obtaining tissue
biopsy specimens, linked erythema nodosum and bilateral hilar adenopathy as
manifestations of acute sarcoidosis [12, 13]. The combination of erythema nodosum
and hilar adenopathy is now known as Lofgrens syndrome. When S. Lofgren attended
the 1st International Conference on Sarcoidosis in London, UK, in 1958, he was strongly

Fig. 3. R. Willan, known as the father of modern dermatology, is immortalised by his picture on every issue
of the British Journal of Dermatology.

5
 O. P. SHARMA

of the opinion that sarcoidosis was unlike and unrelated to tuberculosis and favoured a
viral cause. At the London conference, he also described renal sarcoidosis, with kidney
biopsy evidence of granulomas and associated abnormal calcium metabolism.
A. Kveim was born in Gjerstad, Norway, and became a dermatologist in the
department of N. Danbolt at the Rikshospitalet in Oslo (Norway) during the period
19361945. He made the important observation that sarcoid lymph node tissue
inoculated intradermally gave rise to papules of sarcoid tissue in l2 out of l3 of his
sarcoidosis patients (fig. 4). Since the reaction did not occur in normal subjects or in one
patient with lupus vulgaris, he concluded that the papule was the specific lesion caused by
an unknown agent and that the test might serve to differentiate sarcoidosis from
tuberculosis [14].
N. Svanborg, a prominent pulmonary physiologist, was born in Umea, Sweden on
February 5, 1920 and lived until the same month in 1997. He published the first and
perhaps only authoritative monograph describing pulmonary function abnormalities in
sarcoidosis in great detail [15].
C. Heerfordt, son of a local doctor, was born in Terndtrup, Denmark. He eventually
became an ophthalmologist and drew attention to "febris uveoparotidea subchronica", a

a) c)

b)

Fig. 4. a) Kveim-Siltzbach test: a nodule appears at the site of inoculation in y46 weeks and b) close up.
c) The biopsy specimen shows a noncaseating granuloma.

6
 DEFINITION AND HISTORY OF SARCOIDOSIS

combination of uveitis and enlargement of the parotid glands [16]. He noted that the
condition was chronic and frequently complicated by cranial nerve palsies, especially of
the seventh nerve, and pleocytosis of the cerebrospinal fluid. C. Heerfordt was keen to see
Scandinavia and Europe form a single community and had written two books, A New
Europe I and II, during the years 19241926.
A. Hanngren, Professor and Head of Thoracic Medicine at the Karolinska Institute
(Stockholm, Sweden), was an ardent student of both tuberculosis and sarcoidosis. He
regularly attended national as well as international sarcoidosis conferences. A. Hanngren
enjoyed discussing the aetiology of sarcoidosis because he had definite views about the
topic. He believed strongly that clinical medicine and experimental research should work
together amicably. His philosophy helped to create excellent research opportunities for
young Swedish doctors interested in chest disease.
Scandinavia had the distinct honour of holding the first WASOG Conference of the
twenty-first century, held in June 2002 in Stockholm, Sweden. It was organised by O.
Selroos, A. Eklund and J. Grunewald. The conference will be remembered for its in-
depth exposition of the cytokine network leading to granuloma formation and discourse
about the role of genetic make-up in predisposing to various phenotypes of sarcoidosis.

The French school

In 1889, E. Besnier described a patient with violaceous swellings of the nose, ears and
fingers, for which he coined the term lupus pernio [17]. He referred to J. Hutchinsons
patient (the 58-yr-old coal-wharf worker), but the distribution of the lesions was
sufficiently dissimilar to justify his opinion that the two conditions were not identical
[17]. In 1892, M. Tenneson reported another example of lupus pernio and described its
essential histology of a "predominance of epithelioid cells and a variety of giant cells" in
the skin lesions [18]. In the reports published by Besnier [17] and Tenneson [18], cases
were not illustrated and wax models of the appearance of their patients were used instead
to illustrate skin lesions.
The father of L-M. Pautrier was from Aix-en-Provence and his mother from Arles
(both France); he was born in Marseilles (France) on August 2, 1876. He studied there
and in Paris, France, where he became a dermatologist with L. Brocq at the Saint Louis
Hospital. His doctorate was an imposing 350-page document on "Atypical cutaneous
tuberculosis". During the First World War, he was in an artillery regiment and was
awarded the French cross of the Legion of Honour, knight class. He became professor of
dermatology at the University of Strasbourg (Strasbourg, France) and the University of
Lausanne (Lausanne, Switzerland). In his 1939 textbook on sarcoidosis, he opposed the
tuberculous theory and regarded the disease as a reticuloendotheliosis.
J. Turiaf was born in Martinique, into a family of seven brothers and sisters; their
father was a French senator. Turiaf qualified in Paris in 1943 and eventually joined the
Bichat Hospital (Paris) in 1954, where he remained for the remainder of his life. A chair
of respiratory pathology was created for him. The 4th International Conference on
Sarcoidosis was held on September 1215, 1966, under the genial presidency of J. Turiaf.
The proceedings contain voluminous information crammed into 782 pages.
J. Chretien was editor of the French Thoracic Society journal and elected an honorary
fellow of the Royal College of Physicians (London, UK). Monoclonal antibodies first
featured in sarcoidosis in the 1981 International Conference on Sarcoidosis organised by
J. Chretien in Paris. F. Basset was the leading lady of the French sarcoidosis school. She
also studied and wrote about eosinophilic granuloma, now called Langerhans cell
granulomatosis.

7
 O. P. SHARMA

The Italian school

Italy has contributed more to the process of gathering information on sarcoidosis than
any other country. G. Rizzato organised an International Conference on Sarcoidosis in
Milan in 1987, and, at the same time, took the opportunity to found the WASOG. This
infrastructure enables sarcoidologists worldwide to exchange information. In 1984, G.
Rizzato founded a journal devoted to sarcoidosis; this is now a flourishing scientific
document that appears four times each year under the editorship of G. Semenzato, an
expert immunologist. The Italian sarcoidosis movement is also blessed with the
contributions of A. Blasi, C. Grassi, C. Agostini, D. Olivieri, P. Rottoli, L. Allegra and
other active members of the Italian school.

The USA school

In the last quarter of the nineteenth and earlier decades of the twentieth century,
sarcoidosis was not a significant illness in the USA. Its existence was shrouded by
tuberculosis. It was not uncommon for sarcoidosis patients to end up in tuberculosis
sanatoria in the belief that they had pulmonary tuberculosis. Conversely, patients with
sarcoid skin lesions were often incarcerated in leprosaria because the skin lesions of
sarcoidosis were frequently misdiagnosed as lesions of lepromatous leprosy. Sarcoidosis
did not appear in W. Oslers famous text, The Principle and Practice of Medicine [19].
Osler did not recognise the disease, but his 11-yr-old patient, who had bilateral parotid
and lachrymal gland enlargement, splenomegaly, and a thickened and ulcerated nasal
septum, was most probably the first example of sarcoidosis in a child [20].
W.T. Longcope was Professor of Medicine at Johns Hopkins Hospital, Baltimore, MD,
from 19221946. He graduated from the medical school of Johns Hopkins University in
1901, was a student of W. Osler and a profound scholar of disease in the Oslerian tradition.
His papers on sarcoidosis, which began to appear in 1936, did more than any other
publications to create interest in the disease in the USA. He described all manifestations of
the disease and established it as a distinct multisystemic clinical entity [21].
L. Siltzbach, M. Cummings, H. Israel and M. Sones were the four distinguished
American sarcoidologists at the 1st International Conference on Sarcoidosis held in
London, UK in June 1958. Later, to this list of adult sarcoidologists was added the name
of E. Kendig Jr., who, from his home base in Richmond (VA, USA), spread the message
that sarcoidosis effected, albeit rarely, children.
The London conference was followed by a second conference, held in Washington DC,
USA, in June 1960. M. Cummings, who for a brief period believed that sarcoidosis was
caused by pine pollens, masterminded it. The conferences became a model for all
subsequent conferences. It was fruitful for it produced a working definition and
exemplary proceedings. Participants also included the pioneers J. Chapman, C. Nelson
and M. Michael Jr. During the 7th International Conference on Sarcoidosis, organised
by L. Siltzbach, immunological aberrations associated with sarcoidosis were defined and
serum angiotensin-converting enzyme was first recognised as a possible biochemical
marker of active sarcoidosis. L. Siltzbach was a world leader in the sarcoidosis
movement; he spread the sarcoidosis word around the world. L. Siltzbach popularised
the Kveim test and affirmed its specificity in a large international study. The test is now
called the KveimSiltzbach test. D.G. James edited a commemorative publication
dedicated to L. Siltzbach while the latter was still alive, well and able to enjoy it [1].
C.J. Johns, an internationally recognised clinician and teacher, organised the 10th
International Conference on Sarcoidosis in Baltimore in 1984. V. McKusick delivered a
memorable opening lecture, "Sarcoidosis: a case study in nosology" [22]. The concept of

8
 DEFINITION AND HISTORY OF SARCOIDOSIS

activity of sarcoidosis was extensively discussed in the context of the then recently
developed techniques of gallium scanning and bronchoalveolar lavage fluid analysis. The
proceedings of this highly scientific conference were edited by C.J. Johns and published in a
massive 750-page document. C.J. Johns was an untiring advocate of the womens cause and
was elected to the Johns Hopkins Womens Medical Alumnae Associations Hall of Fame.
H. Israel was a popular clinician and teacher. He diagnosed, treated, taught and wrote
about a number of illnesses, including tuberculosis, Wegeners granulomatosis,
pulmonary embolism, histoplasmosis, aspergillosis and, of course, sarcoidosis. In
1951, he recommended corticosteroids for the treatment of sarcoidosis.
E.L. Kendig Jr. was Professor of Paediatrics at the University of Virginia, Richmond
(VA, USA). He wrote extensively about childhood sarcoidosis. He was the only member
of the WASOG who was recognised for his expertise in the field of childhood sarcoidosis.

The Japanese school

Japan has been a prolific contributor on granulomatous disorders, with significant
contributions on clinical features, epidemiology, microbiology and immunology. It has
hosted three International/WASOG Conferences on Sarcoidosis and has a splendid
Japanese Sarcoidosis Association. Y. Hosoda is its worldwide ambassador, and has
made important contributions as a general chest physician, an occupational/environ-
mental expert and an epidemiologist. Y. Hosoda organised the 6th International
Conference on Sarcoidosis in 1972 in Tokyo, with 300 delegates representing 22
countries. Recently, in order to understand the relationship between sarcoidosis and
tuberculosis, Hosoda et al. [23] analysed a series of health surveillance data in a Japanese
work population of 460,000 employees. This population underwent annual radiography
and tuberculin testing. The authors found no causal relationship between tuberculosis
and sarcoidosis. This study represents a landmark in the curious history of tuberculosis
and sarcoidosis. The Japanese school has been a leader in investigating the role of
Propionibacterium acnes in the causation and pathogenesis of sarcoidosis.
T. Izumi, Professor of Medicine at Kyoto University (Kyoto, Japan), organised,
together with S. Nagai, the 1991 WASOG Conference in Kyoto jointly with the XI
Annual Meeting of the Japan Society of Sarcoidosis. He edited the 681-page proceedings
as a special issue of the journal Sarcoidosis. M. Ando hosted the 7th WASOG
Conference in Kumamoto in 1999.

Germany
The German pioneers in the field include A. Bittorf, E. Kuznitsky, P. Langerhans, T.
Langhans, E. Uehlinger, F. Wegener, H. Eule, J. Meier-Sydow and K. Wurm. In 1958,
K. Wurm developed the radiological staging of pulmonary sarcoidosis that was adopted
by clinical investigators all over the world. In 1997, U. Costabel hosted a superb and
memorable conference in Essen (Germany).

Czechoslovakia
K. Kreibich was born on May 20, 1869 in Prague (Czechoslovakia) and graduated in
1894 in the German Medical Faculty in Prague. His extensive postgraduate training in
Vienna (Austria) included 6 yrs with M. Kaposi in the Dermatology Department.
In 1909, he succeeded F.J. Pick as Professor of Dermatology and later became Dean
(1913) and Rector (1923) of the German University in Prague. He died in Prague on

9
 O. P. SHARMA

December 30, 1932. Three of his 200 scientific papers were on lupus pernio. In one of his
patients, he noted lattice-like rarefactions of the terminal phalanges; this was the first
description of bone cysts in sarcoidosis [24].
L. Levinsky, recently deceased, was a retired chest physician in Prague. Delegates from
37 countries attended his International Conference on Sarcoidosis (1969), from which he
produced a wide-ranging 653-page transaction. Recently, under the leadership of V.
Kolek, the nerve centre of Czech sarcoidosis activity has shifted to Olomouc (Czech
Republic).

Portugal
T.G. Villar was a man of Lisbon (Portugal). He was born, educated, practised
medicine and died there. After postgraduate studies in Jersey City (NJ, USA), he
returned to Lisbon, where he became Professor of Lung Disease and president of
Portugals Respiratory Pathology Society in 1974. He was truly international, being
elected honorary fellow of the British Thoracic Society in 1977 and representing the
American College of Chest Physicians as Fellow (1973), Governor (1974) and Regent
(1978). He funded two Portuguese medical reviews, Pneumologia and Medicina
Thoracalis; became vice-president of the International Association of Bronchopneumol-
ogy in 1973; and pursued active research on hypersensitivity pneumonitis, particularly
suberosis. In 1976, he co-authored, with R. Avila, an international text on pulmonary
granulomatoses due to inhaled particles. M. Freitas e Costa was Professor of Respiratory
Disease at the University Medical School, Lisbon. In 1989, he organised a sarcoidosis
conference that attracted 322 delegates; there were 76 oral presentations and 76 posters.
The transactions formed a special issue of the journal Sarcoidosis.

Yugoslavia
For almost 30 yrs, O. and B. Djuric (a brother and sister team) kept the sarcoidosis
candle burning by conducting clinical research and participating in various international
conferences. In 2000, V. Vucinic formed the Yugoslav Association of Sarcoidosis, which
now holds a sarcoidosis conference every year.

India
Although a short review of sarcoidosis with a case report was published as early as
1957 in the Indian Journal of Dermatology [25], the disease remained hidden under the
menace of widespread tuberculosis for a long time. The late S. Gupta shared his
experience on clinical aspects of sarcoidosis in India at various national and international
conferences. In his hometown, Kolkata (previously known as Calcutta), India, on
February 22, 2003, the Indian Association of Sarcoidosis and other Granulomatous
Disorders (IASOG) was inaugurated. The first annual meeting of the IASOG was held
on January 12, 2004 and was organised by A. Shah. The events came too late for S.
Gupta, a pioneer in sarcoidosis and tuberculosis, who had passed away earlier on
September 9, 2002.

Brazil
N. Bethlem was Titular Professor of Physiology and Pneumology at the Federal
University of Rio de Janeiro (Rio de Janeiro, Brazil) from 19641986. He taught about

10
 DEFINITION AND HISTORY OF SARCOIDOSIS

sarcoidosis, wrote about it, and was a frequent participant at various national and
international meetings. After his death in 1998, his son E.P. Bethlem inherited his fathers
love for and dedication to sarcoidosis. He continues to be WASOG ambassador in South
America.

The future
The cause of sarcoidosis and related symptoms remains a mystery [26, 27]. The most
recent WASOG Conference was held in 2005 (June 1215) in Denver (CO, USA), under
the leadership of R. Baughman and L. Newman. More than 400 delegates from all over
the world were in attendance. Once again, there was intense scrutiny and research
concentrated on finding out the cause and genetic predisposition of sarcoidosis.
Moreover, young investigators were challenged to try to explore the many remaining
questions.

Key points
1. Sarcoidosis, a multisystemic granulomatous disease, has a long and distinguished
medical history that stretches over all the continents and covers the last 150 yrs.
2. Since the 1950s, there has been rapid progress in the understanding of the clinical,
radiological, physiological, biochemical and immunological aspects of the granuloma-
tous process.
3. Advances in the field of medical genomics and proteomics may hold the key to the
aetiology of sarcoidosis.

Summary
More than a century ago, J. Hutchinson, a surgeon-dermatologist, identified the first
case of sarcoidosis at Kings College Hospital (London, UK). In the decades before
and following the turn of the nineteenth century, several publications independently
drew attention to what is now regarded as sarcoidosis. This trend gained a significant
momentum in the latter part of the twentieth century and has continued relentlessly
into the nascent years of the twenty-first century. This brief account provides a
working definition of the disease and outlines the countries, institutions and
individuals that have participated in the historical journey of sarcoidosis to the
present.

Keywords: Granuloma, J. Hutchinson, Kveim test, Lofgrens syndrome, sarcoidosis,

World Association of Sarcoidosis and Other Granulomatous Disorders.
Editors note. O. Sharma, the author of this chapter and current World Association of
Sarcoidosis and Other Granulomatous Disorders (WASOG) president, is himself a
distinguished member of the USA school. As a master clinician in the field, he has made
significant contributions to the management of extrathoracic manifestations of sarcoidosis and
the mechanism leading to hypercalcaemia. In 1993, he was a perfect host of the memorable
3rd WASOG meeting in Los Angeles (CA, USA) and edited the 474-page proceedings as a
special issue of the journal Sarcoidosis.

11
 O. P. SHARMA

References
1. James DG. Sarcoidosis and respiratory disorders: festschrift in honour of Louis E. Siltzbach MD.
Mt Sinai J Med 1977; 44: 683879.
2. Anon. Festschrift in honor of Geraint D. James. Sarcoidosis 1987; 4: Suppl. 1, 146.
3. Scadding JG, Mitchell D. Sarcoidosis, 2nd Edn. London, Chapman and Hall, 1985; pp. 3642.
4. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
5. Hutchinson J. Anomalous diseases of skin and fingers: case of livid papillary psoriasis? In:
Illustrations of Clinical Surgery. London, J and A Churchill, 1877; pp. 4243.
6. Hutchinson J. Mortimers malady: a form of lupus pernio. Arch Surg (London) 1898; 9: 307315.
7. Doyle AC. The Adventure of the Blanched Soldier. In: The Complete Sherlock Holmes. New
York, NY, Doubleday and Co., Inc, 1930; pp. 10001012.
8. Sharma O. A memorable period. A small United Nations. BMJ 1999; 319: 1468.
9. Boeck C. Multiple benign sarcoid of the skin. Norsk Mag Laegevid 1899; 14: 13211345.
10. Schaumann J. Lymphogranuloma benigna in the light of prolonged clinical observations and
autopsy findings. Br J Dermatol 1936; 48: 399346.
11. Willan R. On Cutaneous Disorders. London, J. Johnson, 1805.
12. Sharma O. Robert Willan remembered. J Am Acad Dermatol 1983; 9: 971976.
13. Lofgren S. Primary pulmonary sarcoidosis. I. Early signs and symptoms. Acta Med Scand 1953;
145: 424431.
14. Kveim A. On a new and specific cutaneous reaction in Boecks sarcoid: a preliminary report. Nord
Med 1941; 9: 169172.
15. Svanborg N. Studies on the cardiopulmonary function in sarcoidosis. Acta Med Scand 1961;
170: Suppl., 366.
16. Heerfordt CF. On febris uveo-parotidea subchronica localized in the parotid gland and uvea of the
eye, frequently complicated by paralysis of the cerebrospinal nerves. Graefes Arch Ophthal 1909;
70: 254258.
17. Besnier E. Lupus pernio de la face. [Lupus pernio of the face]. Ann Dermatol Syphiligr (Paris)
1889; 10: 3336.
18. Tenneson H. Lupus pernio. Ann Dermatol Syphiligr (Paris) 1889; 10: 333336.
19. Osler W. The Principle and Practice of Medicine. New York, NY, D. Appleton and Company,
1892.
20. Osler W. On chronic symmetrical enlargement of the salivary and lachrymal glands. Am J Med Sci
1898; 11: 14.
21. Longcope WT. The generalized form of Boecks sarcoid. Trans Assoc Am Physicians 1936; 51: 94
102.
22. McKusick VA. Sarcoidosis: a case study in nosology. Ann N Y Acad Sci 1986; 465: 12.
23. Hosoda Y, Sasagawa S, Yamaguchi T. Sarcoidosis and tuberculosis: epidemiological similarities
and dissimilarities. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 8593.
24. Kreibich K. Ueber lupus pernio. [On Lupus Pernio]. Arch Derm Syph (Wien) 1904; 71: 312.
25. Rajam R, Vishwanathan G, Rangiar P. Sarcoidosis. a short review with a case report. Indian J
Dermatol 1957; 23: 913.
26. Newman L, Rose C, Maier L. Sarcoidosis. N Engl J Med 1997; 336: 12241234.
27. Baughman R, Lower E, du Bois R. Sarcoidosis. Lancet 2003; 361: 111118.

12
CHAPTER 2

Epidemiology of sarcoidosis

M. Thomeer*,#, M. Demedts#, W. Wuyts#

*Dienst Longziekten, Ziekenhuis Oost-Limburg, Genk, and #Afdeling Longziekten, Universitaire Zieken-
huizen, Katholieke Universiteit Leuven, Leuven, Belgium.

Correspondence: M. Thomeer, Dienst Longziekten, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600

Genk, Belgium. Fax: 32 22564890; E-mail: michiel.thomeer@zol.be

Sarcoidosis is a systemic granulomatous disorder of unknown cause characterised by

frequent pulmonary involvement. The disease occurs throughout the world, affecting
both sexes, and all races and ages. The incidence and prevalence have been extensively
studied, but difficulties arise when ascertaining the real extent of sarcoidosis in a
community [1]. First, descriptions of sarcoidosis differ widely among various populations
in the world and are usually based on data from different studies without standardisation
of the diagnostic criteria [2]. Secondly, the clinical presentation of sarcoidosis is highly
variable. Involvement of the lungs or intrathoracic lymph nodes becomes clinically
evident in 90% of symptomatic patients during their disease and up to 30% have
spontaneous remission [3]. However, a large percentage of sarcoidosis-affected
individuals may never manifest clinical disease. In a historical cohort of w1 million
USA Navy recruits screened with chest radiographs, of the 134 cases of sarcoidosis
detected, 48.5% were asymptomatic on examination [4]. Thirdly, studies use different
methods of case detection in different selected population cohorts, possibly resulting in
selection bias (e.g. community-based radiographic screening programmes versus
retrospective reviews of histologically proven sarcoidosis cases in a tertiary hospital
setting), lack sensitive and specific diagnostic tests to detect the disease, resulting in
under-recognition and misdiagnosis of the disease, and lack systematic epidemiological
investigations of the cause [5]. The aim of this review is to present the available data of
the global incidence and prevalence, the possible risk factors and prognosis, and the
survival of subjects with sarcoidosis.

Search strategy, definitions and conditions for study design

Search strategy
To identify the published data on epidemiology of sarcoidosis, a search was carried out
in PubMed from 1966 to December 1, 2004 and articles were selected that included the
combination of keywords "sarcoidosis", "epidemiology", "incidence" and "prevalence".
The search was restricted to articles in English, Dutch, German, French, Italian and
Spanish and included review articles and original research publications. Recent reviews
found by this strategy were also used to identify additional articles. Letters to the editor,
commentaries, and case reports were excluded. Publications from nonpeer-reviewed
sources and personal correspondence were not included.

Eur Respir Mon, 2005, 32, 1322. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
13
 M. THOMEER ET AL.

Definitions
The term epidemiology is used to define the distribution of disease, factors that cause
disease, and the attributes of disease in defined populations. It also includes incidence,
frequency, prevalence, endemic and epidemic outbreaks. Moreover, it incorporates
surveys and estimates of morbidity in geographical areas and in specified populations.
The term incidence is defined as the number of new cases of a given disease during a given
period of time in a specified population. It is differentiated from prevalence, which refers
to all cases, new or old, in the population at a given period of time.

Conditions for study design

One of the best ways to ascertain the incidence and natural history of a disease is the
cohort study design. This type of study can be carried out by going ahead in time from
the present (prospective cohort study) or, alternatively, by going back in time to comprise
the cohorts and following them up to the present (retrospective cohort study). A survival
analysis is a variation in the design (i.e. time-to-event cohort study) and is useful when
lengths of follow-up vary substantially or when participants enter a study at different
times. Selection bias and bias by lost to follow-up are important limitations, and are a
challenge for the presentation of incidence and prevalence indices [6]. As sarcoidosis is a
rare disease, selection bias is one of the most important issues to manage.
Case-control study design is a statistical method to identify risk groups and risk factors
in sarcoidosis. Unlike cohort studies, case-control studies cannot yield incidence rates.
Instead they provide an odds ratio (OR), derived from the proportion of individuals
exposed in each of the cases and control groups. When the incidence rate of a particular
outcome in the population of interest is low (usually v5% in both the exposed and
unexposed groups), the OR from a case-control study is a good estimate of relative risk
(RR) [7]. Epidemiologists often praise case-control studies as the most efficient design in
terms of time, money and effort, but many methodological issues affect the validity of the
results of case-control studies, and two factors, i.e. choosing a control group and
obtaining exposure history, can greatly affect a studys vulnerability to bias [7]. Most of
the research in defining risk factors for sarcoidosis is still in the early stages; only few
robust case-control studies exist, of which the ACCESS study (A Case Control Etiologic
Study of Sarcoidosis) attracted the most attention [8].

Global incidence and prevalence

Incidence and prevalence
Several studies tried to calculate the incidence and prevalence of sarcoidosis in
different settings and by different study designs and, therefore, are at risk for possible
bias. A population-based study that was conducted among residents of Rochester,
Minnesota, USA from 19351984 found that occurrence of asymptomatic sarcoidosis
was elevated in immigrants and health professionals because of more routine use of
screening chest radiographs or access to chest radiographs. They concluded that the
selection of the population by diagnostic access include a possible bias [9], which is
intrinsic to cohort studies [6]. The incidence and/or prevalence of sarcoidosis will be
discussed by the method of population selection, including: 1) mass chest radiography
screening; 2) use of national registries or databases; 3) use of (nationwide) surveys or
questionnaires; and 4) reviewing data from autopsy registries.

14
 EPIDEMIOLOGY OF SARCOIDOSIS

Mass chest radiography for screening purposes is one of the first methods used to
ascertain the occurrence of sarcoidosis, taking into account that up to 90% of the
clinically detected cases have chest radiograph abnormalities [10]. In these studies the
prevalence of sarcoidosis varied from 0.2 in Portugal to 64 per 100,000 screened
individuals in Sweden. In Finland, a prevalence of sarcoidosis was found of 28.2 per
100,000 inhabitants, with an incidence of 11.4 per 100,000 [11].
Another method is the use of national registries or databases to identify sarcoidosis
cases. Using a database of a large health maintenance organisation (19671987), the
incidence of clinically identified sarcoidosis (i.e. ascertained either because of symptoms
or an incidental chest radiograph) in a northwest USA population was calculated to be
4.8 per 100,000 (95% confidence interval (CI)=1.77.9) [12]. A Danish study identified
patients with sarcoidosis by using the Danish National Patient Registry (19801994),
which contained information about presence of disease, sex, age and residence [13]. The
overall incidence was 7.2 per 100,000, but decreased over a period of time with an
incidence of 8.1 per 100,000 in 19801984 to 6.4 per 100,000 in 19901994. Furthermore,
they reported a difference in incidence from the eastern region compared with the
western region, with an incidence increasing from 5.7 to 8.4 per 100,000, respectively [13].
Three studies in Flanders (Belgium) [14], Japan [15], and Korea [16] used a
standardised questionnaire, with specific diagnostic criteria for sarcoidosis sent to the
(respiratory) physicians in their country. The Belgian study was intended to evaluate the
occurrence of different forms of interstitial lung diseases and was compared with two
other European registries of interstitial lung diseases [17]. In Flanders (Belgium), a
prevalence of 1.33 per 100,000 and an incidence of 0.17 per 100,000 for sarcoidosis was
found. Yamaguchi et al. [15] conducted their survey in 1972 and 1984, and compared the
trends over time in prevalence and incidence. They found a prevalence of 3.0 per 100,000
population in 1972 and 3.8 in 1984 in males, and of 3.3 and 5.6 in females, respectively. In
contrast, the incidence of 1.2 per 100,000 in males and 1.4 in females had not changed.
The nationwide survey ofw80-bed size hospitals in Korea found an incidence of 0.03 per
100,000 in 1993 and of 0.13 per 100,000 in 1998 [16]. Interestingly, they reported that not
a single case of sarcoidosis was detected among a population of 190,029 that participated
in a screening for tuberculosis with mass chest radiography in 19801995.
The use of registries of serial autopsy reports of a specific population is another
method to report the occurrence of sarcoidosis. In 1964, HAgerstrand and Linell [18]
described 43 cases of sarcoidosis among 6,706 autopsies (i.e. 60% of the population who
died) in 19571962 in Malmo (Sweden), and calculated a prevalence of 640 per 100,000.
A review of 9,324 adult autopsy files from Cuyahoga County (USA) over a period of
7 yrs revealed that 31 cases had sarcoidosis and calculated a prevalence of 320 per
100,000 [19].

Age and sex variations

The study by Byg et al. [13], which used the Danish National Patient Registry, found a
difference in sex and age at diagnosis with a peak incidence in males aged 3034 yrs of
14.8 per 100,000. Females displayed two peak incidences at 2529 yrs of age (10.5 per
100,000) and at 6569 yrs of age (11.0 per 100,000). The median age in males was 38 yrs
and in females it was 45 yrs, with an overall male to female ratio of 1.06 [13].
The ACCESS study, a USA based, multicentre case-control study on the aetiology of
sarcoidosis, determined organ involvement for the whole group of 736 patients with
sarcoidosis within 6 months and differentiated them into subgroups by sex, race, and age
(v40 yrs or i40 yrs). The study population was heterogeneous in terms of race (53%
White, 44% Black), sex (64% female, 36% male), and age (46% v40 yrs). Females were

15
 M. THOMEER ET AL.

more likely to have eye and neurological involvement (Chi-squared test=4.74 (pv0.05)
and 4.60 (pv0.05), respectively), erythema nodosum (7.28; pv0.01), and more often were
i40 yrs (6.07; pv0.02), whereas males were more often suffering from hypercalceamia
(7.38; pv0.01). The ACCESS investigators concluded that the initial presentation of
sarcoidosis was related to sex, race and age [2].

Sarcoidosis in children
Sarcoidosis is uncommon in children, although little epidemiological data exist. A
Danish study describes the incidence of sarcoidosis in children 15 yrs of age from data
obtained from a nationwide patient registry from 19791994. They found an incidence of
0.29 per 100,000 person-yrs. The incidence was 0.06 in children aged 4 yrs and
increased gradually with age to 1.02 in children aged 1415 yrs. General malaise, fever,
weight loss, abdominal discomfort, respiratory symptoms, lymphadenopathy and central
nervous system symptoms were common; a total of 31% of patients had erythema
nodosum, 12.5% had sarcoid skin lesions, 25% had uveitis/iridocyclitis and 4.2% had
sarcoid arthritis [20]. The same authors confirmed the incidence in another Copenhagen-
based registry and calculated that the approximate incidence of clinically recognised
sarcoidosis in Danish children aged v15 yrs was 0.220.27 per 100,000 children per yr,
corresponding to approximately three new cases in Denmark each year. In children aged
v5 yrs, the disease is characterised by involvement of the skin, eyes and joints, whereas
in older children involvement of lungs, lymph nodes and eyes predominate. The long-
term prognosis is not well established, but it seems to be poorer in children aged v5 yrs.
Older children appear to have a prognosis as favourable as in young adults [21].

Prognosis and risk of death

Sarcoidosis is a benign disorder. A substantial percentage of sarcoidosis-affected
individuals may never manifest clinical disease and up to 30% have spontaneous
remission [3]. A chronic course occurs in 1030% of patients, at times resulting in
significant impairment of lung function [22]. Mortality rates of 16% have been reported
[2325]. The presence of fibrosis on chest radiograph and a vital capacity ofv1.5 L seems
predictive for dying from respiratory failure because of their sarcoidosis [26, 27].
Comparing the mortality of different forms of interstitial lung disease in a tertiary
hospital setting, sarcoidosis had the best prognosis with a 5-yr survival of 91.6% in
sarcoidosis compared with 85.5% in idiopathic interstitial pneumonia (nonspecific
interstitial pneumonia, desquamative interstitial pneumonia), 84.1% in hypersensitivity
pneumonitis, 69.7% in lung fibrosis due to connective tissue disease, 69.5% in undefined
forms of lung fibrosis, and 35.4% in idiopathic pulmonary fibrosis [27]. Patients with
advanced sarcoidosis awaiting lung transplantation have a high mortality rate with a
median survival ofv2 yrs [22]. The survival rate of listed patients was 66% at 1 yr, 40% at
2 yrs, and 31% at 3 yrs. Survival after transplantation was 62% at both 1 and 2 yrs, and
50% at 3 yrs. Shorr et al. [28] calculated that patients with sarcoidosis are at as high a
risk for mortality as patients with idiopathic pulmonary fibrosis while awaiting
transplantation. They also found in another study that race, pulmonary hypertension
and oxygen use are important factors indicative of mortality in sarcoidosis patients on
the waiting list for lung transplantation [29].
Only one case-control study suggests a possible increased risk of malignant
lymphomas, lung cancer as well as cancer, in other organs frequently involved in
sarcoidosis [30]. Two groups of 474 patients from an incidence study (19661980) and
8,541 patients identified in the Swedish Inpatient Register (19641994) were tested. They

16
 EPIDEMIOLOGY OF SARCOIDOSIS

found an elevated RR for cancer in both cohorts, (RR 1.3; 95% CI 1.21.4). An elevated
risks were found for melanoma (RR=1.6; 95% CI=1.02.3) and nonmelanoma skin cancer
(RR=2.8; 95% CI=2.03.8). An increased risk was also found for liver cancer (RR=1.4;
95% CI=0.82.2). However, this study was not confirmed by a long-term follow-up study
of 555 Danish sarcoidosis patients. No increased risk of lung cancer or malignant
lymphoma (OR=0.23, 95% CI=0.001.25 and OR=1.25, 95% CI=0.026.95, respectively)
was found. Neither age at diagnosis of sarcoidosis nor clinical sarcoidosis features were
indicators of later occurrence of malignancy [31].
Prognosis is linked to sarcoidosis severity [26]. Rabin et al. [32] examined the
socioeconomic and insurance characteristics of Black and White patients in municipal
and private hospital sarcoidosis clinics and their relationship to severity, and the diseases
functional and social significance. They concluded that: 1) sarcoidosis severity is
associated with socioeconomic status and insurance indicators; 2) no/public insurance
and low income are associated with functional limitations; and 3) the lack of private
insurance may inhibit the use of medical care, contributing to disease severity and
impairment [32].

Risk factors
Environmental and occupational risk factors
An epidemiological investigation using a cluster analysis on the Isle of Man, UK in
1987 found a timespace association with sarcoidosis incidence. This case-control study
of residents of the Isle of Man observed that 39.6% of sarcoidosis cases reported prior
contact with a person known to have the disease, compared with 12% of controls. These
contacts included members of the same household, colleagues at work, and close friends.
A possible bias may have been introduced as patients would inevitably be more aware of
the disease and be more likely to mention previous contact than the controls.
Nevertheless, the evidence is considered to support the view that sarcoidosis is a
communicable disease [33] through the presence of a shared environmental or infectious
exposure. However, this has never been proved.
Some studies have observed a seasonal clustering of sarcoidosis cases in winter and
early spring [34]. The peak incidence appeared to be between March and May in London,
March to April in Athens, January to June in Finland [35], and between May and August
in Japan [34]. Yamaguchi et al. [15] found that the prevalence of sarcoidosis was higher
in the Northern part of Japan with cold winters and cool summers, in contrast with the
Southern part characterised by mild winters and warm summers.
Geographical and spatial clusters of disease have also been described, although
problems with disease misclassification, with differences in racial distributions in these
regions and with study design, hamper interpretation. In the 1940s an increased disease
prevalence in the rural south-eastern and middle Atlantic USA led to studies that
examined potential aetiological factors in meteorology and soil, beryllium in clay, plants,
pine, pollen, proximity to forests, water supply, use of firewood, proximity to lumbering
and wood milling, and exposure to farm animals and pets. Neither animal experiments
nor human studies have yet proven these hypotheses [3]. Also intriguing is the inverse
relationship between the presence of sarcoidosis and smoking tobacco. This relationship
has never been thoroughly examined, and is possibly biased by the fact patients
discontinue smoking on onset of symptoms [3].
The most robust study that investigated the association between environmental and
occupational exposures and sarcoidosis is the ACCESS study [8]. In this study 10 centres

17
 M. THOMEER ET AL.

recruited 706 newly diagnosed patients with sarcoidosis and an equal number of age-,
race-, and sex-matched control subjects. Interviewers administered questionnaires
containing questions regarding occupational and nonoccupational exposures. They
observed positive associations between sarcoidosis and specific occupations (e.g.
agricultural employment, OR=1.46, 95% CI=1.131.89), exposures (e.g. insecticides at
work, OR=1.52, 95% CI=1.142.04, and work environments with mould and mildew
exposures (environments with possible exposures to microbial bioaerosols), OR=1.61,
95% CI=1.132.31). A history of ever-smoking cigarettes was less frequent among cases
than control subjects (OR=0.62, 95% CI=0.500.77). In multivariable modelling, an
elevated OR for work in areas with musty odours (OR=1.62, 95% CI=1.242.11) and with
occupational exposure to insecticides (OR=1.61, 95% CI=1.132.28), and a decreased OR
related to ever-smoking cigarettes (OR=0.65, 95% CI=0.510.82) were observed. The
study did not identify a single, predominant cause of sarcoidosis.
Occupational clusters, with presumptive toxic or infectious exposures, have been
reported for sarcoidosis in healthcare workers [33, 36, 37], USA Navy enlisted males
serving on aircraft carriers, lumbar or wood millers, post office workers and mechanics
[3], and fire fighters [38]. Perhaps this increased incidence is only reflecting increased
detection rates arising from more frequent use of routine chest radiographs in these
occupations [3, 38]. This argument is probably not true for fire fighters, an occupation
more at risk for toxic exposures. A case-control study was performed in the New York
City Fire Department, New York, NY, USA with w11,000 fire fighters as cases and
nearly 3,000 emergency medical services healthcare workers as the controls. The
investigators found an annual incidence of biopsy-proven sarcoidosis in fire fighters
ranging from 043.6 per 100,000, and averaged 12.9 per 100,000. This study, although
being a case-control design, did not calculate the OR of the risk factor (being a fire fighter
of the New York City Fire Department), probably because controls are not selected in
the same time period as for the case group and, therefore, are not comparable.
A case-control study performed among 10,161 USA military personnel suggests the
association between sarcoidosis-like disease and environmental factors. They found,
after adjusting for age, ship assignment and length of service, a decreased risk for
sarcoidosis diagnoses among males who worked only on "clean ships" (OR=0.37, 95%
CI=0.130.84) [39]. They calculated that being Black (OR=8.6, 95% CI=7.510.0), entered
in the USA Navy before 1985 (OR=4.7, 95% CI=3.66.3), length of service (OR per
yr=1.1, 95% CI=1.11.1) and age at entry (OR=1.4, 95% CI=1.31.7) were increased risk
factors. In the study, they could not assign which single factor was attributable to the
decreased risk.

Infectious agents as risk factor

Environmental exposures to infectious agents have been from time to time appointed
as the (exclusive) causative agent for sarcoidosis. The characteristic lesion of sarcoid
granulomas is a discrete, compact, noncaseating epithelioid cell granuloma and can only
be differentiated with an infectious cause by microbiological studies and cultures [5].
Also, the granulomatous nature of inflammatory response in sarcoidosis suggests that
infection may play a possible role in the pathogenesis of this disease [3].
Mycobacteria have, since the search of the aetiology of sarcoidosis, always be one of
the most important suspects. Several studies identified DNA of mycobacteria by PCR
[40, 41]. The study of Saboor et al. [41] included 104 patients (62 referred for possible
tuberculosis and 20 for possible sarcoidosis, and 22 control patients) and analysed
bronchial washings, and tissue specimens (one from each patient) underwent assay by
PCR. They found Mycobacterium tuberculosis DNA was found in half the sarcoidosis

18
 EPIDEMIOLOGY OF SARCOIDOSIS

patients, and nontuberculosis mycobacterial DNA in a further 20%, suggesting that

M. tuberculosis complex may play an aetiological role in sarcoidosis [41]. However,
isolation or culture of mycobacteria in the specimens has until now never been shown,
which is an important criteria for establishing an infectious agent as a cause of
sarcoidosis.
On April 11, 2002 the Swedish newspaper "Aftonbladet" printed on its front-page
"Bakterien finns hos var sjatte fasting", as if the cause of sarcoidosis was defined. Many
sarcoidosis patients and their representative support groups were informed, as they had
to be treated by antibiotics and many physicians had to temper their thoughts. This news
was derived from an article published by Nilsson et al. [42]. They found genetic material
from Rickettsia helvetica by PCR in samples obtained from autopsy of two patients with
sarcoidosis. However, in a recent study, sera from 20 well-characterised sarcoidosis
patients did not display detectable titres of anti-rickettsia immunoglobulin G antibodies.
Therefore, the association between Rickettsia and sarcoidosis could not be confirmed
[43].

Genetic risk factors

The familial predisposition dates back to 1920s when the first cases of acute sarcoidosis
in siblings were reported. There have been a number of reports of the prevalence of
familial clustering in sarcoidosis, ranging from 1.7% (UK), 4.3% (Japan), 4.7% (Finland),
9.6% (Ireland) to 17% (African-Americans) [44].
The ACCESS study estimated sarcoidosis familial RR using data on disease
occurrence in 10,862 first- and 17,047 second-degree relatives of 706 age-, sex-, race-
and geographically-matched cases and controls. They concluded that a significant
elevated risk of sarcoidosis was observed among first- and second-degree relatives of
sarcoidosis cases compared with relatives of matched control subjects. Siblings had the
highest RR (OR=5.8, 95% CI=2.115.9), followed by avuncular relationships (OR=5.7,
95% CI=1.620.7), grandparents (OR=5.2, 95% CI=1.518.0), and then parents (OR=3.8,
95% CI=1.211.3). In a multivariate model fit to the parents and siblings data, the
familial relative risk adjusted for age, sex, relative class, and shared environment was 4.7
(95% CI=2.39.7). White cases had a markedly higher familial RR compared with
African-American cases (18.0 versus 2.8; p=0.098) [45]. Another study, in which 179
African-American families were ascertained through an index sarcoidosis case diagnosed
at Henry Ford Hospital in Detroit, Michigan, USA, found that in African Americans,
siblings and parents of sarcoidosis cases have about a 2.5-fold increased risk for
sarcoidosis [46].
A study performed in the UK in 2000, based on a questionnaire and answered by 268
sarcoidosis patients, revealed that 5.91% were found to have at least one other relative
(first, second or third degree) with biopsy-proven sarcoidosis. They calculated that the
prevalence of sarcoidosis in siblings of an affected person/population prevalence for the
disease (i.e. RR ratio to siblings of sarcoidosis) was 3873 (95% CI=21145) [44].
Interestingly, they found an absence of a significant difference in ethnic distribution
between familial and index sarcoidosis patients, which is in contrast to the findings of
Rybicki et al. [46].

Conclusion
The global incidence and prevalence of sarcoidosis have been extensively studied, but
difficulties arise when ascertaining the real extent of sarcoidosis in a community. In the

19
 M. THOMEER ET AL.

different studies presented, the prevalence varies between 0.03640 per 100,000. The lack
of standardisation of the diagnostic criteria, the different methods of case detection in
different selected population cohorts used and the lack of sensitive and specific diagnostic
tests to detect the disease are different causes of this variation in prevalence. The
prognosis of sarcoidosis is favourable. A large percentage of affected individuals may
never manifest clinical disease and up to 30% have spontaneous remission. A chronic
course occurs in 1030% of the patients, at times resulting in significant impairment of
lung function. Mortality rates of 16% have been reported. Studies that defined possible
environmental, occupational and genetic risk factors as cause of sarcoidosis are
promising, but most of the research in defining risk factors for sarcoidosis is still in the
early stage. These case-control studies, together with recent advances in molecular
genotyping, will hopefully help to define in the future the genetic factors that predispose
to sarcoidosis and to the variability in the phenotype of sarcoidosis.

Summary
The global incidence and prevalence of sarcoidosis varies between studies, mostly
because of selection bias when ascertaining the actual extent of sarcoidosis in a given
community. The prevalence of sarcoidosis varies between 0.03640 per 100,000 in
various studies.
In general, the prognosis of sarcoidosis is favourable. A large percentage of affected
individuals may never manifest clinical disease and up to 30% have spontaneous
remission. A chronic course occurs in 1030% of patients, at times resulting in a
significant impairment of lung function. Mortality rates of 16% have been reported.
Studies that defined possible environmental, occupational and genetic risk factors as a
cause of sarcoidosis are promising. Most of the research in defining risk factors for
sarcoidosis are still in the early stages and only a few robust case-control studies exist,
of which A Case Control Etiologic Study of Sarcoidosis (ACCESS) attracted the most
attention.

Keywords: Epidemiology, incidence, prevalence, prognosis, risk factors, sarcoidosis.

References
1. Kitaichi M. Prevalence of sarcoidosis around the world. Sarcoidosis Vasc Diffuse Lung Dis 1998;
15: 1618.
2. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control
study of sarcoidosis. Am J Respir Crit Care Med 2001; 164: 18851889.
3. Rybicki BA, Maliarik MJ, Major M, et al. Epidemiology, demographics, and genetics of
sarcoidosis. Semin Respir Infect 1998; 13: 166173.
4. Sartwell PE, Edwards LB. Epidemiology of sarcoidosis in the U.S. Navy. Am J Epidemiol 1974;
99: 250257.
5. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
6. Grimes DA, Schulz KF. Cohort studies: marching towards outcomes. Lancet 2002; 359: 341345.
7. Schulz KF, Grimes DA. Case-control studies: research in reverse. Lancet 2002; 359: 431434.

20
 EPIDEMIOLOGY OF SARCOIDOSIS

8. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis:
environmental and occupational risk factors. Am J Respir Crit Care Med 2004; 170: 13241330.
9. Hennessy TW, Ballard DJ, DeRemee RA, et al. The influence of diagnostic access bias on the
epidemiology of sarcoidosis: a population-based study in Rochester, Minnesota, 19351984. J Clin
Epidemiol 1988; 41: 565570.
10. Siltzbach LE, James DG, Neville E, et al. Course and prognosis of sarcoidosis around the world.
Am J Med 1974; 57: 847852.
11. Pietinalho A, Hiraga Y, Hosoda Y, et al. The frequency of sarcoidosis in Finland and Hokkaido,
Japan. A comparative epidemiological study. Sarcoidosis 1995; 12: 6167.
12. Reich JM, Johnson RE. Incidence of clinically identified sarcoidosis in a northwest United States
population. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13: 173177.
13. Byg KE, Milman N, Hansen S. Sarcoidosis in Denmark 19801994. A registry-based incidence
study comprising 5536 patients. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 4652.
14. Thomeer M, Demedts M, Vandeurzen K. Registration of interstitial lung diseases by 20 centres of
respiratory medicine in Flanders. Acta Clin Belg 2001; 56: 163172.
15. Yamaguchi M, Hosoda Y, Sasaki R, et al. Epidemiological study on sarcoidosis in Japan. Recent
trends in incidence and prevalence rates and changes in epidemiological features. Sarcoidosis 1989;
6: 138146.
16. Kim DS. Sarcoidosis in Korea: report of the Second Nationwide Survey. Sarcoidosis Vasc Diffuse
Lung Dis 2001; 18: 176180.
17. Thomeer MJ, Costabel U, Rizzato G, et al. Comparison of registries of interstitial lung diseases in
three European countries. Eur Respir J 2001; 18: Suppl. 32, 114s118s.
18. Hagerstrand I, Linell F. The prevalence of sarcoidosis in the autopsy material from a Swedish
town. Acta Med Scand 1964; 425: Suppl., 171174.
19. Reid JD. Sarcoidosis in coroners autopsies: a critical evaluation of diagnosis and prevalence from
Cuyahoga County, Ohio. Sarcoidosis Vasc Diffuse Lung Dis 1998; 15: 4451.
20. Hoffmann AL, Milman N, Byg KE. Childhood sarcoidosis in Denmark 19791994: incidence,
clinical features and laboratory results at presentation in 48 children. Acta Paediatr 2004; 93: 30
36.
21. Milman N, Hoffmann AL, Byg KE. Sarcoidosis in children. Epidemiology in Danes, clinical
features, diagnosis, treatment and prognosis. Acta Paediatr 1998; 87: 871878.
22. Arcasoy SM, Christie JD, Pochettino A, et al. Characteristics and outcomes of patients with
sarcoidosis listed for lung transplantation. Chest 2001; 120: 873880.
23. Hillerdal G, Nou E, Osterman K, et al. Sarcoidosis: epidemiology and prognosis. A 15-year
European study. Am Rev Respir Dis 1984; 130: 2932.
24. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an
analysis of 818 patients. Q J Med 1983; 52: 525533.
25. Chappell AG, Cheung WY, Hutchings HA. Sarcoidosis: a long-term follow up study. Sarcoidosis
Vasc Diffuse Lung Dis 2000; 17: 167173.
26. Baughman RP, Winget DB, Bowen EH, et al. Predicting respiratory failure in sarcoidosis patients.
Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: 154158.
27. Thomeer MJ, Vansteenkiste J, Verbeken EK, et al. Interstitial lung diseases: characteristics at
diagnosis and mortality risk assessment. Respir Med 2004; 98: 567573.
28. Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung
transplantation. Chest 2002; 122: 233238.
29. Shorr AF, Helman DL, Davies DB, et al. Sarcoidosis, race, and short-term outcomes following
lung transplantation. Chest 2004; 125: 990996.
30. Askling J, Grunewald J, Eklund A, et al. Increased risk for cancer following sarcoidosis. Am J
Respir Crit Care Med 1999; 160: 16681672.
31. Romer FK, Hommelgaard P, Schou G. Sarcoidosis and cancer revisited: a long-term follow-up
study of 555 Danish sarcoidosis patients. Eur Respir J 1998; 12: 906912.

21
 M. THOMEER ET AL.

32. Rabin DL, Richardson MS, Stein SR, et al. Sarcoidosis severity and socioeconomic status. Eur
Respir J 2001; 18: 499506.
33. Parkes SA, Baker SB, Bourdillon RE, et al. Epidemiology of sarcoidosis in the Isle of Man-1: A
case controlled study. Thorax 1987; 42: 420426.
34. Hosoda Y, Yamaguchi M, Hiraga Y. Global epidemiology of sarcoidosis. What story do
prevalence and incidence tell us? Clin Chest Med 1997; 18: 681694.
35. Pietinalho A, Ohmichi M, Hirasawa M, et al. Familial sarcoidosis in Finland and Hokkaido,
Japan-a comparative study. Respir Med 1999; 93: 408412.
36. Bresnitz EA, Stolley PD, Israel HL, et al. Possible risk factors for sarcoidosis. A case-control
study. Ann N Y Acad Sci 1986; 465: 632642.
37. Edmondstone WM. Sarcoidosis in nurses: is there an association? Thorax 1988; 43: 342343.
38. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in
New York City firefighters. Chest 1999; 116: 11831193.
39. Jajosky P. Sarcoidosis diagnoses among U.S. military personnel: trends and ship assignment
associations. Am J Prev Med 1998; 14: 176183.
40. Bocart D, Lecossier D, De Lassence A, et al. A search for mycobacterial DNA : in granulomatous
tissues from patients with sarcoidosis using the polymerase chain reaction. Am Rev Respir Dis
1992; 145: 11421148.
41. Saboor SA, Johnson NM, McFadden J. Detection of mycobacterial DNA in sarcoidosis and
tuberculosis with polymerase chain reaction. Lancet 1992; 339: 10121015.
42. Nilsson K, Pahlson C, Lukinius A, et al. Presence of Rickettsia helvetica in granulomatous tissue
from patients with sarcoidosis. J Infect Dis 2002; 185: 11281138.
43. Planck A, Eklund A, Grunewald J, et al. No serological evidence of Rickettsia helvetica infection in
Scandinavian sarcoidosis patients. Eur Respir J 2004; 24: 811813.
44. McGrath DS, Daniil Z, Foley P, et al. Epidemiology of familial sarcoidosis in the UK. Thorax
2000; 55: 751754.
45. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-
control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001; 164: 2085
2091.
46. Rybicki BA, Kirkey KL, Major M, et al. Familial risk ratio of sarcoidosis in African-American
sibs and parents. Am J Epidemiol 2001; 153: 188193.

22
CHAPTER 3

Aetiologies of sarcoidosis

L.S. Newman

Correspondence: L.S. Newman, Division of Environmental and Occupational Health Sciences, Dept of
Medicine, National Jewish Medical and Research Center, 1400 Jackson St, Room G212, Denver,
Colorado 80206, USA. Fax: 1 3033981983; E-mail: newmanl@njc.org

Why is the aetiology of sarcoidosis unknown?

One would think that in the nearly 130 yrs since its initial description, someone would
have uncovered the root cause of sarcoidosis. This failure speaks to the probable
complexity of the problem from both an exposure and genetic perspective, as discussed
later. Since its earliest descriptions, sarcoidosis has been suspected to be an infectious
disease and yet, to date, while many different microbes have been indicated, none has
been convincingly proven to be causative. Interestingly, in the same century, the causes of
many idiopathic disorders have been revealed, most of which were due to infectious
agents. These include, among others, swamp fever (Plasmodium falciparum), anthrax
(Bacillus anthracis), consumption (Mycobacterium tuberculosis), gastric ulcers (Helico-
bacter pylori) and Whipples disease (Tropheryma whippelii). In most of these other cases,
Henle-Koch postulates could be fulfilled (table 1). Several generations of sarcoidosis
researchers have learned that fulfilment of these postulates is not an easy matter. This is
because not all organisms can be isolated or cultivated, ignorance remains of the true
spectrum of both pathogenic and nonpathogenic microbes, some microbes may be
endogenous to the host, and some colonised microbes may cause pathology through their
antigenic or adjuvant properties, not because of infection, per se. Hence, despite many
attempts to discover a microbial pathogen, it has been difficult to fulfil Kochs postulates.
Lingering concerns are left that either the right conditions have not been used to find and
culture the organism, that the cause is not microbial, or the disease called "sarcoidosis" is
made up of more than one disorder, each of which may have a different cause [1, 2].
There may be other reasons why the aetiology of sarcoidosis remains obscure. 1) Case
definition: a careful review of the medical literature demonstrates that researchers have
used highly variable, imprecise and inconsistent case definitions [4]. This may improve
through the application of recent guidelines for defining sarcoidosis [5]. A more
systematic and rigorous methodology will be needed in sarcoidosis in clinical research. 2)
Case ascertainment: differences in how study subjects are recruited and enrolled
introduce bias and make it difficult to draw comparisons among groups of patients and
among published studies. 3) Disease heterogeneity: the wide range of clinical patterns
seen in sarcoidosis [6] raises the possibility that sarcoidosis a) might not be one disease,
b) might be triggered by more than one aetiologic agent, or c) that a single agent
produces different effects based on host factors, such as genetics. 4) Indefinite time of
disease onset: epidemiology is at its best when the onset of disease can be defined
precisely. As discussed later, even though there appears to be time-dependent clustering
of sarcoidosis in some studies, the latency between exposure to an inciting agent and the
onset of disease is unknown. This makes it difficult to determine if, or when, a previous
exposure triggered illness. 5) Absence of sensitive and specific diagnostic tests: the
diagnosis of sarcoidosis is dependent on a constellation of clinical findings and the
Eur Respir Mon, 2005, 32, 2348. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
23
 L.S. NEWMAN

Table 1. Paradigms for establishing causation versus association

Paradigm Elements Comments and limitations

Henle-Koch postulates Isolation of pathogen from disease host Limited ability to isolate known organisms
Many unknown organisms
Growth of organism in pure culture Growth conditions uncertain for many microbes.
Reproduce characteristics of disease Organism might cause granulomatous disease
by inoculating susceptible host because of microbial antigenicity, not infection.
Causative organisms can be "endogenous" in
genetically susceptible individual.
Bradford HILL [3] Strength of association Greater relative risk favours causation
criteria Cause-and-effect not fully excluded just
because association is weak.
Also consider how often exposures occur and
do not produce disease
Consistency Repeated observation of association between
exposure and disease: by different researchers,
in different places, circumstances and times
Best when similar results reached in different
ways (e.g. prospectively and retrospectively)
Specificity Show that the exposure is associated with a
limited group of individuals, in particular
environment, with particular clinical phenotypes
of disease and that there is no association
between that exposure and other diseases.
Certain agents do cause more than one disease
Diseases may have more than one cause. In
fact, multicausation may be more common
than single causation
Temporal relationship Show that exposure occurs prior to onset of
disease
Problematic for "slow" diseases in which it is
not known when the disease began
Biological gradient Dose-response curve for exposure-disease
Difficult to quantitatively measure environment
Implies knowledge of intensity and duration of
exposure
Dose-response in sarcoidosis might not be a
linear relationship because of genetic
susceptibility or because response is
immunological
Plausibility Biologically plausible that agent can cause
granulomas
Not essential, but helpful for making the case
for causation.
Presumes that the mechanism is understood
and that the biological effect of a particular
exposure is known
Coherence The data should not seriously conflict with
generally known facts of the natural history
and biology of the disease
Experiment If an intervention prevents disease, it
strengthens the case for causation (e.g. if
removal of exposure prevents or reduces
frequency of illness, or if a treatment cures
illness)
Analogy Suspected exposure is similar to other agents
known to cause granulomatous disease
(e.g. a metal, a mycobacterium)

24
 AETIOLOGIES OF SARCOIDOSIS

exclusion of known causes of diseases that imitate it [5]. There are no diagnostic tests of
high sensitivity or specificity for sarcoidosis. Even the Kveim-Siltzbach test, which
possesses granuloma-causing attributes, is negative in a sizeable fraction of cases. The
consequence is under-recognition, misdiagnosis, and misclassification of disease. Even
though most current case definitions require the presence of noncaseating granulomas, this
pathological finding is not pathognomonic. 6) Surrendering to the "idiopathic": when
clinicians and researchers see sarcoidosis patients, their mindset is to consider the case to be
idiopathic. As a result, they often do not aggressively pursue the causes of granulomatous
diseases beyond routine cultures and stains for infectious diseases. 7) Limited tools for
detecting relevant exposures: apart from available culture methods, mineral analysis of
tissue, in situ staining for microbes or microbial antigens, and a few immunological assays
that help separate sarcoidosis from other diseases like chronic beryllium disease (CBD),
hypersensitivity pneumonitis and infection, the repertoire of tools for identifying prior
environmental exposures is limited. In-roads are being made in the use of proteomics to
identify microbial antigens in sarcoidosis patients, but this is still in its infancy and will need
to be linked with other techniques to establish aetiology [79]. Epidemiological methods
may help to identify environmental risk factors, as discussed later, but have thus far only
helped narrow the search for a cause. Immunological studies suggest that antigens are
important in pathogenesis, but the complexities of identifying antigen in disease by
immunological and biochemical methods is as daunting as the epidemiology and
microbiology. 8) Genetic and other host factor complexity: it is clear that people differ in
their susceptibility to sarcoidosis. Genetic factors are associated with particular patterns of
disease (clinical phenotype), disease risk, and with disease severity and progression [1016].
Host factors, such as tobacco use, modify disease risk as well [17]. As a consequence, even if
a specific environmental factor could be identified, it is probable that it will be confounded
or interact with the individuals genetics and their habits in conferring risk. There are good
reasons for hypothesising that sarcoidosis is caused by environmental antigens in
genetically susceptible individuals. Both the lungs and skin, two common target organs for
sarcoidosis, are regularly in contact with environmental antigens; studies of sarcoidosis
immunopathogenesis strongly suggest that the disease is an overexuberant response to
antigens, as discussed elsewhere in this Monograph [1824]. There are many potential
environmental antigens that can induce sensitisation, an adoptive, cell-mediated immune
response responsible for the development of granulomas [2527]. As summarised in
table 2, such environmental factors cause a variety of granulomatous diseases that mimic
sarcoidosis, including: CBD due to inhalation of and sensitisation by beryllium, and other
metal-induced granulomatous lung diseases (aluminum, titanium, zirconium) [28];
hypersensitivity pneumonitis due to organic and inorganic antigens; and infections,
such as tuberculosis, atypical mycobacteria, and fungi, amongst others [2, 5]. Inorganic
dusts and fibres, such as talc, silica, glass fibres, and man-made mineral fibres can be
considered another subclass of environmental exposures that induce sarcoidosis-like
illness, possibly by inducing a less specific, innate immune response which might promote
adoptive immune responses to available antigens [2932]. The list of agents capable of
inducing granulomatous responses in experimental animals is even longer, including
mycobacteria, avian proteins, fungal spores, acanthamoeba, schistosome eggs, propino-
bacterium, carrageenan, brucella, and leishmania, amongst others [27].

Implications of epidemiologic studies of sarcoidosis aetiology

A number of epidemiological studies of sarcoidosis have been conducted over the past
50 yrs in efforts to narrow the field of possible aetiological agents. An increasingly

25
 L.S. NEWMAN

Table 2. Granuloma-forming disorders and potential aetiologies for sarcoidosis

Category Subcategory Examples

Infections Fungi Histoplasma spp., Aspergillus spp., Coccidioides spp.
Protozoa Toxoplasma, Leishmania
Metazoa Schistosoma
Spirochetes Treponema pallidum
Mycobacteria Mycobacterium tuberculosis, M. leprae, NTM
Bacteria Yersinia spp., Brucella spp., Borrelia spp., Propionibacteria
Viruses Epstein-Barr virus, Herpes, Rubella, Measles,
Cytomegalovirus, Coxsackie B virus,
Neoplasms Carcinoma, Sarcoma Malignant nasal granuloma.
Malignancy associated granulomas
Metals Beryllium, aluminium, titanium, zirconium
Inorganic dust Silica, talc, man-made mineral fibres, starch, silicone
Organic dust Hypersensitivity pneumonitis Farmers lung, bird fanciers lung, suberosis, bagassosis,
hot tub lung
Hypothesised Pine tree pollen, Clay
Immune disorders Idiopathic Sarcoidosis, Crohns disease, primary biliary cirrhosis,
giant cell arteritis, hypogammaglobulinaemia, idiopathic
hepatic granulomas, common variable immune deficiency
Vasculitides Idiopathic Wegeners granulomatosis, Churg-Strauss, Lymphomatoid
granulomatosis, Bronchocentric granulomatosis,
polyarteritis nodosa
Other Leukocyte oxidase deficiency Chronic granulomatous disease of childhood
Blaus syndrome
NTM: nontuberculous Mycobacteria.

coherent picture starts to emerge when these studies are taken in aggregate. Whilst no
one study proves the cause, several conclusions can be drawn that help point the way to
specific hypotheses meriting further investigation. The prevailing view from these studies
is that sarcoidosis occurs as a consequence of exposure to one or more environmental
agents interacting with genetic factors [2, 5, 3335]. The challenge will be to identify and
link such environmental factors with genetic susceptibility.
Clustering of disease has been well described in sarcoidosis, and should ultimately help
guide us toward aetiology. At very least, any newly suspected causative agent must
plausibly explain why some forms of clustering occur.

Age-specific clustering
There is a marked predilection for disease to develop in early adulthood, with the
disease being notably rare in children and early teens [36] and rare in the elderly beyond
the age of 70 yrs [3739]. This observation might suggest that exposure to the aetiological
agent(s), whether they are antigenic or infectious, may first occur about the time that
individuals reach working age, raising speculation about the contribution of
occupational exposures.

Race-specific clustering
This disease appears to occur more commonly among African Americans than among
Caucasians [3841]. Paradoxically, clustering also occurs among individuals of northern
European descent, especially with acute forms of disease, such as Lofgrens syndrome.
Data suggest that disease severity and prognosis also varies by race and ethnicity. Studies
of the genetics of acute sarcoidosis have begun to suggest a strong genetic determinant in
the latter group that may account for some of these differences [4244]. However,

26
 AETIOLOGIES OF SARCOIDOSIS

consideration should be given to differences in host factors and environmental factors

that may impact on exposures and gene expression as well.

Sex-specific clustering
Although studies vary in their findings with regard to male/female rates of sarcoidosis,
most suggest a slightly higher rate in females. In the only population-based incidence
study of sarcoidosis in the USA, Henke et al. [45] observed similar age-adjusted
incidences in the two groups (5.9/100,000 person-yrs for males and 6.3/100,000 person-
yrs for females). However, interestingly, they also noted an increase in incidence between
1946 and 1975 for females. Henke et al. [45] hypothesised that this increase in sarcoidosis
among females may have been due to earlier less aggressive case finding for females
compared with males. An alternative hypothesis is that large numbers of females entered
the workforce over this time period, where they may have encountered environmental
antigens that induce sensitisation and disease.

Seasonal clustering
Numerous studies, have observed a predilection for sarcoidosis to become clinically
apparent in winter and early spring, peaking in spring months [4652]. If it is assumed
that the latency between exposure to the causative agent and development of sarcoidosis-
related symptoms is in the order of a few weeks to a few months, as is the case in animal
models [27], it seems likely that exposure may first occur in many cases in the late fall to
early spring. It is attractive to speculate that increased contact with the aetiological agent,
whether the agent is infectious or antigenic, occurs when people spend more time in
closed, confined spaces at work or at home during winter months. One might speculate
that sarcoidosis is a type of building-related illness, resulting from sensitisation to
airborne antigens or an infectious agent(s) (so-called bioaerosols), much like the
building-related illnesses hypersensitivity pneumonitis, humidifier fever, Pontiac fever,
and legionellosis [35, 53, 54].

Geographic clustering
Not all studies of the geographic clustering of sarcoidosis agree [41, 5557]. Despite the
discrepancies, methodological problems, case and control selection biases, diagnostic
access biases, and reporting biases in these studies, the preponderance of published data
suggests that this disease occurs more commonly in geographically distinct regions [41,
5961]. This geographic distribution has promoted much speculation and a large number
of studies that examined factors in the meteorology and soil [40, 56, 6266], plants, pine
pollen, and proximity to forests [61, 6370], water supply [40], use of firewood [40, 63
66], and exposure to farm animals and pets [40, 6366], amongst others. Past studies have
noted a clustering in parts of the country where there is more lumbering activity [67, 71].
In particular, a study by Dunner and Williams [71] suggested that sarcoidosis cases
occurred twice as often where lumbering and wood milling was a principal industry.
More recently, Kajdasz et al. [72] confirmed that geography is associated with
sarcoidosis risk as in the example of Atlantic coast clustering in South Carolina,
Charleston, USA. Resurrecting the pine pollen hypothesis, Gripenback et al. [73] in
Sweden have recently reported increased accumulation of lung T-lymphocytes and
eosinophils after pinewood dust exposure. A Case Control Etiologic Study of Sarcoidosis
(ACCESS) [35] found no association with lumber or wood dust exposures, wood use in

27
 L.S. NEWMAN

the home or at work, in a study of 706 sarcoidosis cases and matched controls; however,
that study recruited controls on the basis of telephone number prefix or, in some cases,
zip code of the cases, thus matching for geography and possibly for regional
environmental factors, such as forests and wood use as well. Taken in aggregate,
most of the studies that have tried to use the geographical distribution of disease as a
means of unearthing the cause of sarcoidosis have either not been confirmed by
subsequent investigations, or have lacked biological plausibility and not been pursued
further. Most have not considered antigens that are commonly associated with firewood,
lumber and wood milling that are known to cause granulatomous disease in the form of
hypersensitivity pneumonitis. These include thermophilic bacteria and fungi, such as
Merulium lacrymans, Aspergillus spp., Penicillium spp., and Trichosporon cutaneum. For
example, an interesting analogy can be drawn between sarcoidosis and "summer-type
hypersensitivity pneumonitis" in Japan [74]. In that granulomatous disease, recurrent
seasonal respiratory and systemic symptoms occur with familial clustering, and with the
onset coinciding with occupancy of homes containing damp and decayed wood and
woven straw mats contaminated with T. cutaneum [7476]. Thus, from a hypothesis
generating standpoint, the past sarcoidosis literature should be considered carefully for
the possibility that the associations with forests, lumbering, wood milling and wood
burning are surrogates for the sensitising antigens they harbour.

Rural clustering
A number of past studies have associated sarcoidosis with rural residence, birthplace,
or time spent in rural regions [37, 41, 56, 67, 68, 77, 78]. In 1961, Buck et al. [6366], for
example, conducted an extensive case-control study of the rural hypothesis. Cases, as
compared with controls, were more likely to have been born in rural areas, than to have
lived at any time in rural areas prior to diagnosis, and to have spent more cumulative
time in a rural residence. Unfortunately, this investigation used a relatively small study
population, lacked precision in its definition of disease, took one-third of its control
subjects from an urban venereal disease, and was subject to survivor, recall, and
reporting bias. More recently, Kajdasz and co-workers [59, 72] have confirmed the rural
risk and have investigated aspects of rural life that play a role, including exposure to
wood stoves and fireplaces. In aggregate, these investigations suggest that sarcoidosis
occurs more frequently in rural rather than urban areas. In the ACCESS study, the
present author observed an elevated odds ratio (OR) among individuals who worked in
agriculture and with having lived in a small town (v50,000 population) in childhood [35].
Thus, the rural risk is of interest, although inner city populations clearly develop disease
as well [38].

Spatial clustering
Apart from geographic clustering, a number of studies have examined the tendency for
sarcoidosis to occur in individuals who have close physical contact to one another or to a
common location within a community. For example, Parkes et al. [60] and Hills et al.
[79], in their 1987 case-control study of residents on the Isle of Man, UK, observed that
40% of the 96 sarcoidosis cases reported prior contact with a person known to have
sarcoidosis, compared with 12% of controls. Of these contact-pairs, 14 occurred in the
same household, only nine of which were blood relatives. A total of 19 pairs came in
contact with one another at work, two were next-door neighbours, and 14 were
noncohabitating friends [60, 79]. From an infectious disease perspective, these studies of
space- and time-clustering of sarcoidosis may suggest that sarcoidosis is a communicable

28
 AETIOLOGIES OF SARCOIDOSIS

disease [60, 79]. The same data, when viewed from an occupational/environmental
medicine perspective, suggest that these cases might have shared a common environ-
mental exposure in the home or work that induced a hypersensitivity response.
Unfortunately, these Isle of Man studies examined only a very limited list of
occupational titles and gave limited consideration to the home environment.
Intriguingly, they did observe that 18.8% of the sarcoidosis cases were healthcare
workers (especially nurses), a rate significantly higher than for controls (4.2%) [60]. This
particular finding has raised concern that such studies may be subject to a diagnostic
access bias, i.e. those with better access to healthcare may be more likely to be diagnosed,
and thus counted in research studies, than those less connected to the healthcare system
[80, 81]. Other reports of husband-wife occurrences of sarcoidosis fuel the hypothesis that
shared environment may hold the key to finding aetiologies of sarcoidosis [82, 83]. In the
future, prospective studies are needed to examine the frequency with which sarcoidosis
clusters occur among individuals with shared work and home environments, and include
more detail characterisation of these environments.

Familial clustering
Numerous studies have focused on the propensity of sarcoidosis to occur in families,
amongst same-sex parent-child pairs, mother-child pairs, same-sex siblings and in
monozygotic twins [39, 6366, 82, 8486]. One recent study suggests that familial
clustering of sarcoidosis is more common among African Americans than Caucasians
[87]. It is interesting to note that in the ACCESS study, Rybicki et al. [39] estimated
familial relative risk (RR) in 10,862 first- and 17,047 second-degree relatives of 706
sarcoidosis cases. Siblings had the highest risk (OR=5.8; confidence interval=2.115.9),
with other significant elevations of avuncular, grandparental and parental risk. White
cases had a markedly higher familial RR than African Americans (OR=18.0 versus 2.8;
p=0.098). McGrath et al. [88] have reported a sibling RR in a primarily White
population of between 36 and 73. Although a more sophisticated genetic linkage analysis
is underway, using variable number of tandem repeat DNA markers and PCR [89], the
past genetic analyses of families with several affected members suggest that the heritable
risk is complex and polygenic [13, 9099]. Even if there proves to be genetic risk factors
for sarcoidosis, it is likely that development of disease will also be contingent upon
exposure to appropriate environmental antigens [18, 33]. Interestingly, the family studies
have almost exclusively focused on genetic explanations, with little attention given to the
families members shared environment. A notable exception is the recent study by
Kucera et al. [34], in which occupational data were collected from 921 African
Americans in 273 sibships identified through a sarcoidosis case. The findings of that
study are discussed later.

Industry and Occupational Associations

Some of the studies discussed above suggest the possibility of shared exposure to
granuloma-inducing antigens at work [55, 60, 6567, 71]. Until recently, very few studies had
systematically investigated the occupational and environmental exposures of sarcoidosis
patients. As with the other epidemiological studies described earlier, research addressing the
possible role of industry or occupation are subject to recall, referral and selection biases,
often have used imprecise case definitions, lacked controls or used inappropriate controls,
and employed survey methodology that was incomplete or inadequate for defining
coexisting or pre-morbid work-related risk factors [33]. Additionally, most of such studies
have focused only on the occupations and industries held at the time of diagnosis rather than

29
 L.S. NEWMAN

systematically examining occupational history for the entire period preceding diagnosis.
Nonetheless, three recent papers that were derived from the ACCESS study [100, 101], plus
a study conducted in South Carolina [72] and one that examined occupational risk factors in
African-American families [34] have helped advance the notion that occupational and
environmental factors contribute to sarcoidosis risk.
Historically, in 1959, Cummings et al. [67] examined the case records of 1,194 of a total
of 1,700 patients seen in USA veterans hospitals who were diagnosed between 1949 and
1954. In this large case series, there was no indication of case definition, no validation of
diagnosis by review of radiographs or histopathology, and no control group. The
geographic distribution was determined by identifying the county of birth. Cummings
et al. [67] observed a clustering of cases in 50 communities in the USA. In 40 out of the 50
communities, lumbering or wood milling were listed as the principal local industry. The
authors concluded that this may be a "lead worth following".
Two other studies of USA veterans collected occupational exposure data retro-
spectively from discharge records in veterans hospitals [6366, 71]. In the study by
Dunner and Williams [71], a single occupation was obtained by reviewing the medical
records of 500 sarcoidosis patients. The job titles were compared with those of a control
group of hospitalised veterans without sarcoidosis. Without presenting any actual data,
Dunner and Williams [71] indicated that there were more post office workers and
mechanics among the veterans with sarcoidosis than in the control group. Keller [55]
performed a retrospective review of charts from 420 USA male veterans from 19601964.
The study matched 420 cases for age, sex, race, and the veterans hospital from which
they were diagnosed. Details of the method by which an occupation title was assigned
were not provided, and no work histories were obtained apart from the job title found in
the chart. Despite these shortcomings, Keller [55] observed three statistically significant
differences: 8.3% of sarcoidosis cases were professionals compared with 3.8% controls;
3.8% were sales workers, compared with 1.2% of controls, and sarcoidosis occurred at
lower frequency among labourers (17.1% in sarcoidosis cases versus 28.6% for controls in
the African-American veteran subgroup; 14.3% versus 21.4% overall). These data
suggested and that certain occupations may confer increased risk and others reduced risk
for sarcoidosis. It is intriguing to note, for example, that labourers, who often perform
outdoor work and work at multiple different sites, had lower risk of being diagnosed with
sarcoidosis (OR=0.5), again fuelling speculation about the association of indoor
environments and sarcoidosis. In the case-control study by Buck and co-workers [63
66], the authors collected data on work in lumbering and farming industries, finding no
differences between 62 cases and controls. In addition to the studies by Parkes et al. [60]
and Hills et al. [79], showing an increased frequency of nurses and healthcare
professionals with sarcoidosis, Edmondstone [102] observed that 24 out of 156 cases of
sarcoidosis from a London hospital (UK) were hospital workers (15.4%), including 16
nurses. The rate was compared to population census figures from 1981 showing that only
1.6% of the relevant population were nurses.
The ACCESS study [35] recruited 706 newly diagnosed, pathology-proven cases of
sarcoidosis and age-, raced- and sex-matched controls from 10 USA academic centres.
Interviewers administered questionnaires containing questions regarding occupational
and nonoccupational exposures, including a full chronology of jobs and industries for
each individual that were held for 6 months or longer at any time prior to diagnosis.
Subjects reported history of an exposure, as well as where the exposure had occurred
(home, work, or both) and duration of exposure (v or w1 yr). The ACCESS study [35]
observed positive associations between sarcoidosis and specific occupations, including
agricultural employment, jobs raising birds, jobs in automotive manufacturing, middle/
secondary school teaching, and physicians. A review of cases suggested that the bird
exposure cases were not typical of hypersensitivity pneumonitis. The finding of physician

30
 AETIOLOGIES OF SARCOIDOSIS

risk was suspected to be spurious, driven by the possibility that physicians without
sarcoidosis would have been more likely to not agree to be control subjects. Exposures
that were positively associated with sarcoidosis risk included insecticide use at work, and
work environments with mould/mildew exposures, which the ACCESS study authors
[35] speculated would have represented environments with possible exposures to
microbial bioaerosols. Multivariable modelling observed statistically elevated ORs
for work in areas with musty odours, with occupational exposure to insecticides, and
a decreased OR for those who ever smoked cigarettes. This study notably did not find
a single, predominant risk factor for sarcoidosis. While the ORs were elevated for a
number of factors, in general these associations were weak [35].
In a more comprehensive analysis of the standardised industry codes (SIC) and
standardised occupational codes (SOC) for each job held by the ACCESS cases and
controls, Barnard et al. [100] reported positive associations including employment in
retail industries selling building materials, hardware, garden supplies, and mobile homes
(by SIC). Study subjects who worked in these industries were three times more likely to
be a sarcoidosis case than a control. Subjects who reported work in industries with
exposure to industrial organic dusts (by SIC), including work in an industry producing
aerosolised plant material in its raw (e.g. wood) or manufactured (textiles, paper,
agricultural chemicals) form, were likewise more likely to be cases than controls. Work in
both elementary and secondary school settings (by SIC) and as an educator (SOC
combination) were positively associated with sarcoidosis. Interestingly, several industries
and occupations were negatively associated with sarcoidosis status. Occupations in
personal service (e.g. baggage porters and bellhops, welfare service aides, childcare
workers (except in private households), and personal service occupations) were
negatively associated with sarcoidosis (by SOC). Subjects reporting employment in
industries manufacturing electrical energy (SIC), providing social and rehabilitation
services (SIC), as well as a combination variable of work in childcare provision (SIC)
were less likely to be sarcoidosis cases than controls. The ACCESS SIC/SOC data
analysis also suggests that there may be differences in risk factors for sarcoidosis by race
and exposure. For example, Caucasian sarcoidosis cases were more likely than African
Americans with sarcoidosis to have worked in industries with exposures to metal dust/
fumes or with exposure to industrial organic dust [100].
A somewhat different task was taken by the ACCESS research group in the study by
Kreider et al. [101], in which the sarcoidosis cases were subdivided by clinical phenotype.
Hypothesising that different sarcoidosis clinical phenotypes may be associated with
different exposure risks, Kreider et al. [101] categorised 716 sarcoidosis cases into two
groups: 1) pulmonary-only disease (311 cases, 43%) and 2) systemic disease (with or
without pulmonary involvement; 407 cases, 57%). Of the systemic cases, 376 (92.3%) had
lung involvement in addition to at least one other organ. For their analysis, location/
duration variables were created for each exposure that incorporated both location (e.g.
metal dusts at home, work or both) and duration of exposure (e.g. metal dusts for v or
w1 yr). The location/duration exposures were created because of concerns about
exposure misclassification, potentially diluting the ability to detect real associations
because of inclusion in the same category of subjects with relatively trivial exposures with
those strong and long exposures. All information on exposures was collected and
categorised prior to the determination of organ involvement, thus avoiding potential
information bias. Logistic regression was used to examine associations of candidate
exposures with clinical phenotype [101].
The study by Kreider et al. [101] demonstrated that exposures to wood burning,
agricultural organic dust, or military service are associated with sarcoidosis, in which
disease is present in the lungs only. The number of subjects in the military service category
was small and, thus, may be an unstable estimate of risk. Methodologically, this paper is

31
 L.S. NEWMAN

conceptually important, because it strongly suggests that differentiation of sarcoidosis

subjects on the basis of clinical phenotypes will demonstrate that these subgroups may have
unique environmental exposure associations. Self-defined race may also play a role in the
determination of the effect of certain exposures on disease phenotypes [101].
Using a questionnaire instrument that was highly derivative of the ACCESS
questionnaire, Kucera et al. [34] found positive associations between sarcoidosis
cases and certain occupations and industries for African Americans with sarcoidosis as
compared with unaffected siblings. Although the number of cases per exposure category
was small, these investigators observed that individuals who worked in occupations with
potential metal exposures or in workplaces with high humidity, water damage or musty
odours (again suggestive of a microbial-rich environment) may be at increased risk for
sarcoidosis. Kucera et al. [34] appropriately noted that the complexity of occupationally
related exposures makes it difficult to identify specific agents based on job titles alone, a
critique that applies to most of the environmental epidemiological research to date.
Also, using a questionnaire instrument and study design that was similar to that
employed in ACCESS, Kajdasz et al. [59] followed up on an earlier observation of
geographic risk for sarcoidosis hospitalizations among African Americans from South
Carolina, USA. A number of exposures were found by univariable analysis to be associated
with sarcoidosis risk, including use of wood stoves, fireplaces, nonpublic water supplies
(e.g. wells), and living or working on a farm. Dose-response gradients were found for
exposure to wood stoves and use of fireplaces in both univariable and multivariable logistic
regression models. The article suggested less emphasis for agricultural occupation, and
greater importance of wood use in explaining the rural association in South Carolina [59].
Notably, when this rural-based study is taken in context with the other investigations
described above, the data suggest that local environmental conditions may lead us to
appreciate different aetiological triggers for sarcoidosis.

Occupational case clusters that suggest environmental aetiology

for sarcoidosis
A number of investigators have identified clusters of sarcoidosis cases that suggest a
possible occupational association. Stewart and Davidson [103] reported on a cluster of
sarcoidosis cases occurring in two sisters and two unrelated social contacts, including one
sisters employer. However, this study did not address any occupational or environ-
mental hypotheses. Kern et al. [104] reported on the occurrence of a cluster of three
sarcoidosis cases among 57 fire-fighters who had previously apprenticed together in
Rhode Island, USA. Other examples of environmental or occupational clustering of
recent note include a study of New York City (NY, USA) fire-fighters [105] and an excess
incidence among Navy enlisted males from 19711993 [106, 107]. It is not known with
what frequency occupational clusters of sarcoidosis are missed due to insufficient clinical
investigation of the work-relatedness of patient symptoms, but such clusters have
historically offered important insights into the aetiology of idiopathic diseases [108110].
A number of studies are illustrative of two important concepts: 1) in some instances
sarcoidosis is really a misdiagnosed case of another environmental antigen-induced
disorder; and 2) environmental exposures can cause sarcoidosis.

Example 1
An outbreak of cases of sarcoidosis was identified in an automotive manufacturing
plant in which metal parts where being machined using a semi-synthetic oil coolant

32
 AETIOLOGIES OF SARCOIDOSIS

called a metal working fluid [39, 111]. Clinically and pathologically indistinguishable
from sarcoidosis, these cases were all linked to workplace exposure. Such metalworking
fluids become contaminated with a variety of bacteria, including mycobacteria and
endotoxin [112, 113]. Analogously, mycobacterially-contaminated water sources can
create aerosols that, when inhaled, produced sarcoidosis-like illness [114116].
Clinically, the patients respond to removal from exposure and corticosteroids, not to
antimicrobial therapy.

Example 2
In 1979, an African-American male employee of a nuclear weapons facility developed
hilar adenopathy, diffuse nodular interstitial infiltrates on chest radiograph, hepatic
enzyme elevations, and had noncaseating granulomas on lung biopsy. Clinically and
histologically, he was diagnosed with sarcoidosis. After a period of 5 yrs, through the use
of blood and bronchoalveolar lavage (BAL) beryllium lymphocyte proliferation testing,
the patient was recognised as a sentinel case of CBD in a company that manufactured
nuclear weapons parts. This led to the systematic investigation of the plant and
workforce, and the discovery of endemic sarcoidosis-like disease due to beryllium among
the current and retired workforce that helped produce nuclear weapons [117123]. Some
of the CBD cases first carried the diagnosis of sarcoidosis, given the strong similarities
between the two conditions [124126]. In hindsight, the initial mistake of calling this
nuclear weapons workers disease "sarcoidosis" is not surprising, and continues to occur
in many industries [127]. For example, Fireman et al. [126] in Israel asked patients in
their sarcoidosis clinic if they had been exposed to metals. Those who said "yes" were
offered blood beryllium lymphocyte proliferation tests. Approximately 6% of
"sarcoidosis" patients were found to have CBD [126].

Example 3
In March 1989, a 24-yr-old lifeguard developed persistent cough, chest tightness,
progressive dyspnoea on exertion, eye irritation and headache without fever. Symptoms
worsened toward the end of his work shift, persisted through the evening, resolved by the
next morning, but recurred. The patient developed hypoxaemia and a chest radiograph
showing diffuse interstitial opacities consistent with Scadding stage III sarcoidosis. BAL
showed marked T-helper cell (CD4z)-predominant lymphocytosis. Transbronchial
biopsies showed multiple noncaseating granulomas read by the pathologist as consistent
with sarcoidosis. This patient became the index case for an epidemic of sarcoidosis-like
illnesses related to inhalation of bioaerosols at an indoor swimming pool [128]. The pool
had many water spray features that generated a six-fold increase in airborne respirable
particles and an eight-fold increase in endotoxin levels in the air, raising the hypothesis
that the sprays may have disseminated an antigenic bioaerosol [128]. From two
sequential investigations, a total of 33 symptomatic lifeguards had biopsy- or lavage-
proven granulomatous lung disease. Gram-negative bacterial colonisation was found in
the water sprays, predominately Pseudomonas spp., although there remains uncertainty
about the actual causative agent in this particular environment. This investigation
demonstrates that illnesses, which are clinically and pathologically indistinguishable
from sarcoidosis, can occur in clusters with a common environmental exposure in both
space and time. Similar stories have been described in relation to mycobacterially-
contaminated hot tubs as discussed earlier.

33
 L.S. NEWMAN

Example 4
A patient with occupational exposure to glass fibres developed a sarcoidosis-like illness
[31]. This case led Drent et al. [32] to review records of 50 sarcoidosis cases seen from 1996
1999. In 14 cases, patients had reported an occupational history of exposure to either glass
fibres or both. In six of the 12 biopsies, Drent et al. [32] were able to review by electron
microscopy with energy dispersive x-ray microanalysis, a number of minerals were
detected, including silica, aluminum, and magnesium, which are all elements of man-made
mineral fibres. Fibre deposits were found to be associated with granulomas, leading the
authors to conclude that these fibres elicit a sarcoidosis-like granulomatous response.
Notably, in each of these four examples, the patients (index cases) initially carried the
diagnosis of sarcoidosis based on both the pathologists readings of lung or lymph node
histology, and clinical assessment of experienced physicians caring for these individuals.
These cases met current definitional criteria for sarcoidosis [5], including aetiology
unknown, until investigators were able to identify an aetiologic agent or a common point
source of exposure. Such cases suggest that when sarcoidosis cases are suspected by
clinicians, evaluation must include careful consideration of the home and workplace,
possibly including a combination of environmental sampling, epidemiologic assessment
of other exposed individuals, biological monitoring, and careful case series description.
With this sentinel health event follow-back model [129], the confusion about sarcoidosis
aetiology may be reduced by identifying an already known cause of granulomatous
disease cases in that environment or at least identifying common exposure circumstances
that can lead to further hypotheses about possible new aetiological agents for sarcoidosis
(fig. 1).

Exclude known causes of

granulomatous disease

All sarcoidosis Infection

Subdivide sarcoidosis on
basis of genotype and Inorganic
clinical phenotype and organic
antigens

Seek new environmental triggers

in genotypic/phenotypic subsets
of disease

Lfgrens, uveitis, cardiac

Sarcoidosis of
unknown
aetiology

Fig. 1. Proposed schema for approaching the aetiologies of sarcoidosis.

34
 AETIOLOGIES OF SARCOIDOSIS

In order to address the cause or causes of sarcoidosis, first consideration should be

given to distinguishing between granulomatous disorders of known aetiology from those
that are idiopathic. At present, some cases of so-called "sarcoidosis" are due to known
environmental agents. Using available clinical and research tools, it is important to
thoroughly exclude known infectious agents (such as mycobacteria), organic antigens
(such as thermophiles and fungi that produce granulomatous pneumonitis) and
inorganic antigens (such as beryllium and other metals). If sarcoidosis has more than
one cause because the disorder itself is a heterogeneous collection of disorders, the next
step will be to refine the phenotypes. It is possible to capitalise on what is now known
both clinically and genetically to separate subsets of "sarcoidosis". For example, there is
now ample evidence to suggest that Lofgrens syndrome is a separate disease, based on its
genetics, immunology, clinical phenotype and behaviour. The same might be said for
sarcoidosis that predominantly presents with uveitis, as seen in Japan, and possibly
cardiac sarcoidosis. By purifying the clinical phenotype and genotype, thus reducing
sarcoidosis heterogeneity, it will be easier to then examine the possible environmental
causes of each of those separate conditions, be they microbial or not (fig. 1).

Evidence for a microbial cause

For a century, microbial pathogens have been leading suspects as the cause of
sarcoidosis. The search continues because, although no infectious agent has been
consistently cultured from sarcoidosis specimens or even consistently detected using
ribosomal RNA markers, there are clinical and epidemiological features of sarcoidosis
that suggest an infectious origin. For example, there is evidence for transmissibility of
sarcoidosis. "Donor-acquired sarcoidosis", in which sarcoidosis develops in naive
transplant recipients who have received tissues or organs from donors who were known
or suspected to have active sarcoidosis has been documented [130, 131]. Inversely,
sarcoidosis has recurred in nonaffected allografts after lung transplantation [132].
Sarcoidosis-like granulomas develop in animals that have received tissue from
sarcoidosis patients [133136]. When human tissue containing sarcoidal granulomas
was homogenised and then injected into mice, granulomas formed 15 months later [137].
In that study the effect was destroyed by autoclaving, by freezing at -20uC, and by
radiation exposure.
Kveim antigen, which is a protein extract from the lymph node or spleen of sarcoidosis
patients, elicits an oligoclonal T-cell response in patients with sarcoidosis and produces
granuloma-like infiltration of skin [138]. A further study has shown that nonviable BAL
cells harvested from patients with sarcoidosis and carefully filtered cause granuloma
formation when injected intracutaneously into these patients [139]. Although the active
agent in the Kveim antigen has not been identified and Kveim antigen has not been
shown to contain bacterial DNA [140], a recent study by Song et al. [7] has detected
mycobacterial antigens (mKatG) in sarcoidosis tissues, as well as their antibodies in some
cases, fuelling new speculation of a mycobacterial aetiology.
Sarcoidosis granulomas have been examined for evidence of foreign matter and
especially for structures that resemble microbial elements. Structures resembling
leptospiral organisms have been identified by microscopy from the BAL fluid of
patients with sarcoidosis [141]. Similar structures have been seen in epithelioid cells
within granulomas in sarcoidosis and in familial granulomatous disease [142, 143],
although they also bear strong resemblance to altered platelets and have not been proven
to be infectious organisms [144]. Abnormal structures by electron microscope
examination seen in white cells associated with sarcoidosis granulomas have been

35
 L.S. NEWMAN

identified as possible mycoplasma [145]. Recent immunohistochemical and electron

microscopic examinations by Eishi et al. [9] has suggested propoiniobacterium antigen-
specific antibody staining as well. Thus, the book remains open on the nature of the
unusual ultrastructural elements found in some sarcoidosis granulomas.
Additional logic for an infectious cause stems from the fact that other granulomatous
diseases are often induced by infectious organisms (table 2). These include mycobacteria,
herpes viruses, histoplasmosis, treponematosis, sporotrichosis, coccidiomycosis, schis-
tosomiasis, listeria, Rhodococcus spp., Cladophialophora spp., and the agent of Whipples
disease [146151]. Epidemiological lines of evidence include the reports suggesting that
sarcoidosis can occur through close interpersonal contact [60, 152] and in "clusters", such
as that described by Kern et al. [153] among previously cohabitating fire-fighters. As
discussed earlier, the epidemiological findings of ACCESS results suggest that
environments favourable to the production of bioaerosols are associated with elevated
sarcoidosis risk [35]. In that study, it was hypothesised that the environments favourable
to the production of bioaerosols, whether infectious or antigenic, would be associated
with sarcoidosis. Occupational exposures to musty odours were associated with
sarcoidosis risk in the multiple logistic regression model. Most fungi exude volatile
organic compounds during active growth, causing the "musty" or "mouldy" odour
associated with fungal contamination [75, 154], and may reflect microorganism presence
even when there is no visible growth [155, 156]. Additionally, ACCESS observed that
sarcoidosis cases were more likely to report central air conditioner use in the home.
Several studies have found symptoms to be associated with central air conditioning with
or without humidification [75, 157, 158]. The ACCESS results, taken in context with
several previous studies, add to mounting epidemiological evidence linking microbial
bioaerosols to sarcoidosis risk. Many of the microbes that have been suggested as
possible causes of sarcoidosis, or of diseases mimicking sarcoidosis, grow readily in
standing water. Opportunities to aerosolise particulate antigen and/or infectious agents
may result in the inhalation, pulmonary deposition, and immune response to such
particles. In a recent study [59], sarcoidosis-related hospitalisations were concentrated in
proximity to the South Carolina coastline. Previous studies have shown a predilection for
sarcoidosis in coastal states [41, 56, 57]. In a study by Rose et al. [128], the lifeguards who
developed granulomatous pneumonitis were exposed to bioaerosols in an indoor leisure
swimming centre. In a study of African-American siblings, Kucera et al. [34] observed
that siblings with sarcoidosis were more likely to report indoor exposures to high
humidity, water damage, or musty odours than were their unaffected siblings.
Additionally, clusters of granulomatous pneumonitis mimicking sarcoidosis have been
described in relation to occupational exposure to microbially-contaminated metal
working fluids in the automotive/metal machining industry [159]. The study by Kucera
et al. [34] similarly reported elevated sarcoidosis risk associated with metal machining
and metalworking.
Proposed microbial candidates have included mycobacteria, human herpes virus,
retroviruses, Chlamydia pneumoniae, Borrelia burgdorferi, and Rickettsia Helvetica,
amongst others. However, none of these agents has yet been proven to be the pathogenic
cause of sarcoidosis. Kochs postulates have not been fulfilled, despite major efforts to
prove microbial cause, and especially the intense pursuit of mycobacteria [8, 160].
Culture and histiological staining of sarcoidosis tissues does not reveal mycobacteria,
although two recent studies that have detected mycobacterial antigens. Drake et al. [8]
detected mycobacterial rRNA or rpoB sequences in 60% of sarcoidosis tissues, but not in
controls [8]. Consistent with this finding, Song et al. [7] identified mycobacterial catalase-
peroxidase mKatG and mycobacterium tuberculosis 16S rRNA DNA in a subset of
sarcoidosis tissues using in situ hybridisation. Although such studies have found 16s
rRNA for mycobacteria in pathologic tissue, the studies to date, when taken in

36
 AETIOLOGIES OF SARCOIDOSIS

composite, are inconclusive, in part because of design limitations, such as definition of

cases, selection of controls, details of experimental methodology, and lack of
reproducibility of results in other laboratories using similar methods. Some investigators
have been unable to demonstrate mycobacterial DNA in sarcoidosis lesions [160166],
whereas others have amplified mycobacterial DNA of various species [167173].
Propionibacterium spp. have been implicated by Eishi et al. [9]. The original
observation was that Propionibacterium acnes could be frequently isolated from patients
with sarcoidosis [174]. Ishige et al. [175] reported that 15 out of 15 sarcoidosis tissue
samples were positive for propionibacterial (P. acnes or P. granulosum) rRNA by PCR
analysis, compared with only three patients positive for mycobacterial DNA; conversely,
two out of 15 tissue samples from patients with tuberculosis were positive for
propionibacteria and 15 out of 15 positive for mycobacteria. These results were extended
in a study involving 259 patients from five centres from Japan, Italy, Germany and
England. Propionibacterial DNA was detected in all but two of 108 sarcoidosis lymph
node samples compared with M. tuberculosis DNA that was found in 09% of these
samples. Propionibacterial DNA was detected in 060% of M. tuberculosis or control
samples [9]. Using in situ hybridisation, Yamada et al. [176] localised Proprionibacterium
16S rRNA primarily to areas outside of granuloma formation in sarcoidosis and
tuberculosis tissues. These results will require and await confirmation by other
investigators in independent studies. As exciting as these studies have been, the majority
of the work has been conducted in a single centre; moreover, there have been limitations
in the selection, blinding and matching of controls and the organisms appear to be rather
ubiquitous, challenging the theory of causation. In sum, to date, while traditional and
PCR-based methods have been attempted in the search for microbial cause, there
remains insufficient proof. Genetic analysis serves as an alternative means of identifying
a putative infectious agent when histology and culture fail. Despite being inconclusive to
date, PCR-based approaches, in principle, still hold great promise for detecting infectious
agents in sarcoidosis tissue specimens. PCR was used to identify the aetiological agents of
bacillary angiomatosis (Bartonella henselae) [177], Whipples disease (Tropheryma
whippelii) [178] and to demonstrate that the agent of severe acute respiratory syndrome is
a novel coronavirus [179]. PCR has the advantage of circumventing the need for
culturing an organism, with sensitivity that theoretically can approach one genome copy.
An excellent example of the advantage of genetic analysis of pathologic tissue involves
Tropheryma whippelii, the agent of Whipples disease. Histological examination of
specimens from patients with Whipples disease revealed small gram-positive rods that
appear as diastase-resistant intracytoplasmic inclusions on periodic acid-Schiff staining
[180]. Cultures were unable to isolate this organism. PCR analysis was performed on
patients with Whipples disease [178], using broad-range bacterial primers to identify the
proposed causative agent of Whipples disease. The diagnosis of Whipples disease was
confirmed in peripheral blood by a genetic assay [181], and by 2000, this organism was
cultured from the aortic valve of a patient with endocarditis due to Tropheryma whippelii
[182]. In principle, this same approach should still be pursued in the microbial search for
the sarcoidosis "holy grail".

Conceptual framework: from Henle-Koch to Bradford Hill

As described earlier, emerging technologies, such as genetic probes and immunological
assays, offer great potential for helping to discovering the causes of sarcoidosis.
However, despite the potential, there remain several nagging concerns and obstacles to
establishing causation.

37
 L.S. NEWMAN

First, there are persuasive clinical, immunological and genetic reasons to think that
sarcoidosis is not one disease, but rather a family of diseases. One of the most compelling
examples is the acute form of Lofgrens syndrome, in which the clinical phenotype,
patient demographics, T-cell immunological and human lymphocyte antigen (HLA)
genetic polymorphism data all strongly suggest that this is a separate disease, distinct
from other more chronic forms of sarcoidosis. It may share a common pathologic
consequence (granulomas), but is otherwise quite unique. If sarcoidosis is a
heterogeneous "family" of granulomatous disorders, efforts to find a single cause will
prove fruitless, until investigators focus their aetiological investigations on carefully
defined clinical/immunological/genetic subsets of patients.
Secondly, even if the cause were microbial, the mechanism leading to granuloma
formation might not depend on a single organism, but rather require the interaction of
more than one immunopathogenic moiety, such as the presence of factors that promote
innate immunity (adjuvant properties) plus the presence of an antigen, which itself might
or might not be microbial in origin. There is ample evidence in the immunology literature
to suggest that "two hits", both innate and adoptive immunity, are at play in sarcoidosis
[18]. As such, it is conceivable that more than one organism, or possibly an organism plus
an environmental or endogenous source of adjuvant, is required for pathogenicity.
Thirdly, science is regularly humbled by the diversity of microbial species and by the
relative ignorance of their number, name, and potential health effects. In other words, if
the cause of sarcoidosis is microbial, there is a strong possibility that it could be an as-yet
undiscovered and unnamed organism. Even more likely, there is a strong possibility that
more than one organism may be able to cause sarcoidosis. By way of example, the
literature on nontuberculous mycobacteria regularly discovers new mycobacteria, some
of which: 1) have been shown to cause forms of granulomatous disease producing a
sarcoidosis-like illness in workers exposed to contaminated metal working fluids; or
which 2) have not yet been found to cause disease but which may, in time, be linked to
idiopathic disease. Here, help may come from the work of those who laboriously probe
the environment and human tissues for markers of new organisms.
Fourthly, detection of a genetic or immunological "fingerprint" does not, in and of
itself, necessarily prove causation. If Henle-Koch postulates are strictly relied upon, then
genetic analyses, including 16s ribosomal RNA or various in situ labelling of granulomas,
will fall short of proving causation. Kochs postulates stipulate that the organism must be
isolated from diseased hosts, grown in pure culture, and reproduce characteristics of
disease when introduced into susceptible hosts. The postulates only apply if one is
looking for an infectious agent. Science can and will continue to use the tools of
immunology and genetics to narrow the list of microbial "suspects" and to then focus its
attention on how to fulfill Kochs postulates. For example, in Whipples disease, results
of 16s rRNA PCR guided investigators to delve deeper into specific techniques for
culturing and immunologically marking actinomycetes in tissue and blood of affected
individuals. This may yet prove fruitful in sarcoidosis, but for the time being, sarcoidosis
researchers will continue to work with the nagging concerns that not all organisms are
known, not all can be isolated or cultivated, that the growth and proliferation of
microbes might not always be necessary for them to be antigenic and induce granuloma
formation, and that the cause might not be microbial.
If sarcoidosis is not caused by an infection, how can investigators hope to establish
the causal link between an environmental factor or factors and disease? Clearly, one
must employ a different paradigm for establishing causation, one that does not assume
that all disease has infectious cause and that does not attempt to fulfil Kochs
postulates. In the field of occupational and environmental medicine, this question is
addressed routinely. A wide range of environmental toxins, from tobacco smoke to
beryllium dust, has been established as the causes of disease, without the benefit of

38
 AETIOLOGIES OF SARCOIDOSIS

Kochs postulates. Sarcoidosis researchers may benefit from using this more
epidemiologic conceptual framework, maybe by merging the tools of epidemiology
with those of immunology and genetics.
The conceptual framework for establishing causation due to noninfectious,
environmental agents was most eloquently and clearly outlined 40 yrs ago by Bradford
Hill [3], in an address entitled "The environment and disease: association or causation".
As summarised in table 1, A. Bradford Hill, then a Professor Emeritus of Medical
Statistics at University of London (London, UK), described nine "viewpoints" from
which to study association "before we cry causation". Bradford Hill [3] was quick to
point out that although the nine viewpoints summarised in table 1 may each contribute
to the ability to establish cause and effect, "none can be required as a sine qua non". What
they can do, with greater or lesser strength, is to help us to make up our minds on the
fundamental question: is there any other way of explaining the set of facts before us, is
there any other answer equally, or more likely than cause and effect? It was his belief that
researchers cannot "usefully lay down some hard-and-fast rules of evidence that must be
obeyed before we accept cause and effect", but that the use of these nine criteria would
help to clarify thinking about cause.
Several of the Bradford Hill [3] criteria bear special comment in the context of
sarcoidosis research, to help illustrate the challenges faced in proving, epidemiologically,
the cause of sarcoidosis. 1) Specificity of the association presents a particular challenge,
because most forms of pathology, be it cancer, fibrosis, or granuloma, are more likely to
have more than one cause. 2) Demonstrating that a temporal relationship exists between
exposure to a factor prior to the onset of illness is problematic for sarcoidosis research
because it can only be guessed at when the disease process started in an individual or
group. Sarcoidosis can present insidiously or dramatically, however, in either case,
precise knowledge of when the disease started is lacking. Likewise, many exposures that
are capable of producing granulomatous disease range widely in the latency between
when the individual was first exposed and when they manifested their illness. For
example, the range in time between first exposure to beryllium and the development of
CBD stretches from 2 months to w40 years. By analogy, if there is an environmental
cause of sarcoidosis, prior exposure could have occurred at almost any time prior to
illness. 3) Bradford Hills [3] criterion of biological gradient is also problematic for an
illness such as sarcoidosis. Even if one were to know the cause of sarcoidosis, it is likely to
be difficult to measure the dose of prior exposure that resulted in disease. It is likely to be
modified by genetic susceptibility of the host and to require immunological sensitisation
to occur in a step that precedes onset of disease. The dose-response curves for antigen
sensitisation and for immune-mediated diseases are likely to be nonlinear. Thus,
epidemiological studies of exposure6disease risk in sarcoidosis will face greater
challenges than for those diseases in which the exposure obeys a linear cause-and-
effect model. Fortunately, the immunological properties of any agent that causes
sarcoidosis will allow investigators to use Bradford Hills [3] criteria of experimental
evidence to great advantage. Unlike many environmentally caused disorders, in
sarcoidosis it should be possible, in fact required, to experimentally test a putative
exposure for its ability to induce a disease-specific antigenic response. In the same way
that the beryllium lymphocyte proliferation test is used to prove granulomatous disease is
CBD and not sarcoidosis, any agent that is thought to cause sarcoidosis should lend itself
to one or more demonstration of antigen-specific, disease-specific response, such as the
antigen-specific humoral response, antigen-specific lymphocyte proliferation, cytokine
production, or skin test reactivity. Experiments that test the antigenicity of microbial
peptides or of self, found in the HLA binding-groove of sarcoidosis antigen-presenting
cells, are being conducted in several laboratories in an effort to help make this causal link
experimentally. As suggested by Bradford Hill [3], such experiments will need to be

39
 L.S. NEWMAN

integrated with the other eight criteria as part of the set of evidence for causation for this
perplexing illness.

Summary
The cause or causes of sarcoidosis remain unknown. This chapter addresses some of
the reasons for the collective ignorance, discusses clues that can be derived from past
research literature, reviews the strengths and weaknesses of the prevailing candidates,
including microbes, and proposes a conceptual framework for addressing causation.
With increasing numbers of studies supporting a putative role for biological agents in
sarcoidosis pathogenesis, this review critically examines the body of evidence toward
the goal of making reviews, such as this one, someday seem quaint and obsolete.

Keywords: Aetiology, environment, occupational, sarcoidosis.

References
1. du Bois RM, Goh N, McGrath D, Cullinan P. Is there a role for microorganisms in the
pathogenesis of sarcoidosis? J Intern Med 2003; 253: 417.
2. Newman LS, Rose CS, Maier LA. Medical progress: Sarcoidosis. N Engl J Med 1997; 336: 1224
1234.
3. Bradford Hill A. The environment and Disease: association or causation? Proc R Soc Med 1965;
58: 295300.
4. Yamamoto M, Sharma OP, Hosoda Y. Special Report: The 1991 descriptive definition of
sarcoidosis. Sarcoidosis 1992; 9: Suppl. 1, 3334.
5. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European
Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous
Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive
Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736755.
6. James DG. Clinical picture of sarcoidosis. In: Schwartz M, King TE Jr, eds. Interstitial Lung
Disease, 2nd Edn. St. Louis, Mosby Year Book, 1993; pp. 159178.
7. Song Z, Marzilli L, Greenlee BM, et al. Mycobacterial catalase-peroxidase is a tissue antigen and
target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005; 201: 755767.
8. Drake WP, Pei Z, Pride DT, Collins RD, Cover TL, Blaser MJ. Molecular analysis of sarcoidosis
tissues for mycobacterium species DNA. Emerg Infect Dis 2002; 8: 13341341.
9. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial
DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 2002;
40: 198204.
10. Foley PJ, Lympany PA, Puscinska E, Zielinski J, Welsh KI, du Bois RM. Analysis of MHC
encoded antigen-processing genes TAP1 and TAP2 polymorphisms in sarcoidosis. Am J Respir
Crit Care Med 1999; 160: 10091014.
11. Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA. Sarcoidosis susceptibility and resistance
HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med 2003; 167: 12251231.
12. Rossman MD, Thompson B, Frederick M, et al. HLA-DRB1*1101: a significant risk factor for
sarcoidosis in blacks and whites. Am J Hum Genet 2003; 73: 720735.
13. Schurmann M, Reichel P, Muller-Myhsok B, Schlaak M, Muller-Quernheim J, Schwinger E.

40
 AETIOLOGIES OF SARCOIDOSIS

Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care
Med 2001; 164: 840846.
14. Rybicki BA, Maliarik MJ, Poisson LM, et al. The major histocompatibility complex gene region
and sarcoidosis susceptibility in African Americans. Am J Respir Crit Care Med 2003; 167: 444
449.
15. Foley PJ, McGrath DS, Puscinska E, et al. Human leukocyte antigen-DRB1 position 11 residues
are a common protective marker for sarcoidosis. Am J Respir Cell Mol Biol 2001; 25: 272277.
16. Grutters JC, Sato H, Pantelidis P, et al. Increased frequency of the uncommon tumor necrosis
factor -857T allele in British and Dutch patients with sarcoidosis. Am J Respir Crit Care Med 2002;
165: 11191124.
17. Maier LA. Is smoking beneficial for granulomatous lung diseases? Am J Respir Crit Care Med
2004; 169: 893895.
18. Moller DR, Chen ES. Genetic basis of remitting sarcoidosis: triumph of the trimolecular complex?
Am J Respir Cell Mol Biol 2002; 27: 391395.
19. Moller DR. Involvement of T cells and alterations in T cell receptors in sarcoidosis. Semin Respir
Infect 1998; 13: 174183.
20. Grunewald J, Janson CH, Eklund A, et al. Restricted V alpha 2.3 gene usage by CD4z T
lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3.
Eur J Immunol 1992; 22: 129135.
21. Forman JD, Klein JT, Silver RF, Liu MC, Greenlee BM, Moller DR. Selective activation and
accumulation of oligoclonal V beta-specific T cells in active pulmonary sarcoidosis. J Clin Invest
1994; 94: 15331542.
22. Forrester JM, Wang Y, Ricalton N, et al. TCR expression of activated T cell clones in the lungs of
patients with pulmonary sarcoidosis. J Immunol 1994; 153: 42914301.
23. Klein JT, Horn TD, Forman JD, Silver RF, Teirstein AS, Moller DR. Selection of oligoclonal V
beta-specific T cells in the intradermal response to Kveim-Siltzbach reagent in individuals with
sarcoidosis. J Immunol 1995; 154: 14501460.
24. Moller DR. Cells and cytokines involved in the pathogenesis of sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 1999; 16: 2431.
25. Semenzato G, Agostini C. Immunology in sarcoidosis. In: Schwarz MI, King TE Jr, eds.
Interstitial Lung Disease, 2nd Edn. St. Louis, Mosby Year Book, 1993; pp. 127158.
26. OConnor CM, FitzGerald MX. Speculations on sarcoidosis. Respir Med 1992; 86: 277282.
27. Boros DL. Mechanisms of granuloma formation in the lung. In: Daniele RP, ed. Immunology and
immunologic diseases of the lung. Boston, Blackwell Scientific Publications, 1988; pp. 263287.
28. Newman LS. Metals that cause sarcoidosis. Semin Respir Infect 1998; 13: 212220.
29. Schauble TL, Rich EA. Lymphocytic alveolitis in a crematorium worker. Chest 1994; 105: 617
619.
30. Gysbrechts C, Michiels E, Verbeken E, et al. Interstitial lung disease more than 40 years after a 5
year occupational exposure to talc. Eur Respir J 1998; 11: 14121415.
31. Drent M, Kessels BL, Bomans PH, Wagenaar SjSc, Henderson RF. Sarcoid-like lung
granulomatosis induced by glass fibre exposure. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17:
8687.
32. Drent M, Bomans PH, Van Suylen RJ, Lamers RJ, Bast A, Wouters EF. Association of man-
made mineral fibre exposure and sarcoid-like granulomas. Respir Med 2000; 94: 815820.
33. Bresnitz EA, Strom BL. Epidemiology of sarcoidosis. Epidemiol Rev 1983; 5: 124156.
34. Kucera GP, Rybicki B, Kirkey KL, et al. Occupational Risk Factors for Sarcoidosis in African-
American Siblings. Chest 2003; 123: 15271535.
35. Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis:
environmental and occupational risk factors. Am J Respir Crit Care Med 2004; 170: 13241330.
36. Gordis L. Sarcoidosis. In: Epidemiology of chronic lung diseases in children. Baltimore, The Johns
Hopkins University Press, 1973; pp. 5378.

41
 L.S. NEWMAN

37. Cooch JW. Sarcoidosis in the United States Army, 1952 through 1956. Am Rev Respir Dis 1961;
84: Suppl., 103108.
38. Rybicki BA, Major M, Popovich JJ, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis
incidence: A 5-year study in a health maintenance organization. Am J Epidemiol 1997; 145: 234
241.
39. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-
control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001; 164: 2085
2091.
40. Terris M, Chaves AD. An epidemiologic study of sarcoidosis. Am Rev Respir Dis 1966; 94: 5055.
41. Sartwell PE, Edwards LB. Epidemiology of sarcoidosis in the U.S. Navy. Am J Epidemiol 1974;
99: 250257.
42. Spagnolo P, Renzoni EA, Wells AU, et al. C-C chemokine receptor 2 and sarcoidosis: association
with Lofgrens syndrome. Am J Respir Crit Care Med 2003; 168: 11621166.
43. Grunewald J, Wahlstrom J, Berlin M, Wigzell H, Eklund A, Olerup O. Lung restricted T cell
receptor AV2S3z CD4z T cell expansions in sarcoidosis patients with a shared HLA-DRbeta
chain conformation. Thorax 2002; 57: 348352.
44. Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in
Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 1997; 156: 1601
1605.
45. Henke CE, Henke G, Elveback LR, Beard CM, Ballard DJ, Kurland LT. The epidemiology of
sarcoidosis in Rochester, Minnesota: A population-based study of incidence and survival. Am J
Epidemiol 1986; 123: 840845.
46. Putkonen T, Hannuksela M, Mustakallio KK. Cold season prevalence in the clinical onset of
sarcoidosis. Arch Environ Health 1966; 12: 564568.
47. Poukkula A, Huhti E, Lilja M, Saloheimo M. Incidence and clinical picture of sarcoidosis in a
circumscribed geographical area. Br J Dis Chest 1986; 80: 138147.
48. James GD. Erythema nodosum. BMJ 1961; 1: 853857.
49. Selroos O. The frequency, clinical picture and prognosis of pulmonary sarcoidosis in Finland. Acta
Med Scand 1969; 503: Suppl., 373.
50. Badrinas F, Morera J, Fite E, Plasencia A. Seasonal clustering of sarcoidosis. Lancet 1989; 2: 455
456.
51. Panayeas S, Theodorakopoulos P, Bouras A, Constantopoulos S. Seasonal occurrence of
sarcoidosis in Greece. Lancet 1991; 338: 510511.
52. Wilsher ML. Seasonal clustering of sarcoidosis presenting with erythema nodosum. Eur Respir J
1998; 12: 11971199.
53. Kreiss K. The epidemiology of building-related complaints and illness. In: Cone JE, Hodgson MJ,
eds. State of the Art Reviews: Problem Buildings: Building-Associated Illness and the Sick
Building Syndrome. Philadelphia, Hanley and Belfus, Inc., 1989; pp. 575592.
54. Burge HA. Indoor air and infectious disease. In: Cone JE, Hodgson MJ, eds. State of the Art
Reviews: Problem Buildings: Building-Associated Illness and the Sick Building Syndrome.
Philadelphia, Hanley and Belfus, Inc., 1989; pp. 713721.
55. Keller AZ. Hospital, age, racial, occupational, geographical, clinical, and survivorship
characteristics in the epidemiology of sarcoidosis. Am J Epidemiol 1971; 94: 222230.
56. Gentry JT, Nitowsky HM, Michael JM. Studies on the epidemiology of sarcoidosis in the United
States: The relationship to soil areas and to urban-rural residence. J Clin Invest 1955; 34: 1839
1856.
57. Israel H. Influence of race and geographical origin on sarcoidosis. Arch Environ Health 1970;
20: 608609.
58. Michael M Jr, Cole RM, Beeson PB, Olson BJ. Sarcoidosis: preliminary report on a study of 350
cases with special reference to epidemiology. Am Rev Tuberc 1950; 62: 403407.
59. Kajdasz DK, Lackland DT, Mohr LC, Judson MA. current assessment of A rurally linked
exposures as potential risk factors for sarcoidosis. Ann Epidemiol 2001; 11: 111117.

42
 AETIOLOGIES OF SARCOIDOSIS

60. Parkes SA, Baker SBdC, Bourdillon RE, Murray CRH, Rakshit M. Epidemiology of sarcoidosis
in the Isle of Man1: A case controlled study. Thorax 1987; 42: 420426.
61. Horwitz O. Geographic epidemiology of sarcoidosis in Denmark. Am Rev Respir Dis 1961;
84: Suppl., 130134.
62. Comstock GW, Keltz H, Sencer DJ. Clay Eating and Sarcoidosis: A controlled study in the state
of Georgia. Am Rev Respir Dis 1961; 84: Suppl., 130134.
63. Buck AA, Sartwell PE. Epidemiologic investigations of sarcoidosis: II. Skin sensitivity and
environmental factors. Am J Hyg 1961; 74: 152173.
64. Buck AA. Epidemiologic investigations of sarcoidosis: I. Introduction; material and methods. Am
J Hyg 1961; 74: 137151.
65. Buck AA, McKusick VA. Epidemiologic investigations of sarcoidosis: III. Serum proteins;
syphilis; association with tuberculosis; familial aggregation. Am J Hyg 1961; 74: 174188.
66. Buck AA. Epidemiologic investigations of sarcoidosis: IV. Discussion and summary. Am J Hyg
1961; 74: 189202.
67. Cummings MM, Dunner E, Williams JH Jr. Epidemiologic and clinical observations in
sarcoidosis. Ann Intern Med 1959; 50: 879890.
68. Douglas AC. Sarcoidosis in Scotland. Am Rev Respir Dis 1961; 84: Suppl. 5 Pt 2, 143147.
69. Nobechi K. Sarcoidosis in Japan. Am Rev Respir Dis 1961; 84: Suppl. 5 Pt 2, 148152.
70. Uehlinger EA. Epidemiology of sarcoidosis in Switzerland. Am Rev Respir Dis 1961; 84: Suppl. 5
Pt 2, 153.
71. Dunner E, Williams JH Jr. Epidemiology of sarcoidosis in the United States. Am Rev Respir Dis
1961; 84: Suppl. 5 Pt 2, 163168.
72. Kajdasz DK, Judson MA, Mohr LC Jr, Lackland DT. Geographic variation in sarcoidosis in
South Carolina: its relation to socioeconomic status and health care indicators. Am J Epidemiol
1999; 150: 271278.
73. Gripenback S, Lundgren L, Eklund A, et al. Accumulation of eosinophils and T-lymphocytes in
the lungs after exposure to pinewood dust. Eur Respir J 2005; 25: 118124.
74. Kawai T, Tamura M, Murao M. Summer-type hypersensitivity pneumonitis: A unique disease in
Japan. Chest 1984; 85: 311317.
75. Rose C. Hypersensitivity pneumonitis. In: Rosenstock L, Cullen MR, eds. Textbook of Clinical
Occupational and Environmental Medicine. Philadelphia, W.B. Saunders Co., 1994; pp. 242248.
76. Rose CS, Newman LS. Hypersensitivity pneumonitis and chronic beryllium disease. In: Schwarz
MI, King TE Jr., eds. Interstitial Lung Disease, 2nd Edition. St. Louis, Mosby Year Book, 1993;
pp. 231253.
77. Whitehead HG. Sarcoidosis: A manifestation of tuberculosis without allergy. Bull Am Acad
Tuberc Physicians 1940; 4: 117.
78. Gundelfinger BF, Britten SA. Sarcoidosis in the United States Navy. Am Rev Respir Dis 1961;
84: 109115.
79. Hills SE, Parkes SA, Baker SBdC. Epidemiology of sarcoidosis in the Isle of Man2: Evidence for
space-time clustering. Thorax 1987; 42: 427430.
80. Newman AN, Taylor P. Cullinan, Sarcoidosis: in search of the cause. Am J Respir Crit Care Med
2004; 170: 12681269.
81. Hennessy TW, Ballard DJ, DeRemee RA, Chu CP, Melton LJ 3rd. The influence of diagnostic
access bias on the epidemiology of sarcoidosis: a population-based study in Rochester, Minnesota,
19351984. J Clin Epidemiol 1988; 41: 565570.
82. Scadding JG, Chappell AG, Sutherland I. Familial association in sarcoidosis: British Thoracic and
Tuberculosis Association. Tubercle 1973; 54: 8798.
83. Hosoda Y, Iwai K, Hiraga Y. Recent epidemiologic features of sarcoidosis in Japan. In: Williams
WJ, Davies BH, eds. Eighth International Conference on Sarcoidosis and Other Granulomatous
Diseases. Cardiff, Alpha Omega Publishing, Ltd., 1980; pp. 519521.
84. Headings VE, Weston D, Young RC Jr, Hackney RL Jr. Familial sarcoidosis with multiple

43
 L.S. NEWMAN

occurrences in eleven families: a possible mechanism of inheritance. Ann NY Acad Sci 1976;
278: 377385.
85. Sharma OP, Neville E, Walker AN, James DG. Familial sarcoidosis: a possible genetic influence.
Ann NY Acad Sci 1976; 278: 386400.
86. Nassif X, Valeyre D, Loiseau A, Battesti JP. Familial sarcoidosis: apropos of 22 families. Ann Med
Interne 1985; 136: 611614.
87. Harrington D, Major M, Popovich J, Maliarik M, Iannuzzi M. Familial sarcoidosis: analysis of 61
families. Am Rev Respir Dis 1993; 147: A91.
88. McGrath D, Daniil Z, Foley P, et al. Epidemiology of familial sarcoidosis in the UK. Thorax 2000;
55: 751754.
89. Maliarik M, Kost J, Harrington D, et al. Genetic analysis of T cell receptor genes in familial
sarcoidosis. Am J Respir Crit Care Med 1994; 149: A266.
90. Brackertz D, Kueppers F, Schwarb B. Histocompatibility (HL-A) antigens in sarcoidosis. In: Iwai
K, Hosoda Y, eds. Proceedings of the Sixth International Conference on Sarcoidosis. Baltimore,
University Park Press, 1972; pp. 235238.
91. Hedfors E, Moller E. HL-A antigens in sarcoidosis. Tissue Antigens 1973; 3: 9598.
92. Persson I, Ryder LP, Nielson LS. The LH-A7 histocompatibility antigen in sarcoidosis in relation
to tuberculin sensitivity. Tissue Antigens 1975; 6: 5053.
93. McIntyre JA, McKee KT, Loadholt CB, Mercurio S, Lin I. Increased HLA-B7 antigen frequency
in South Carolina blacks in association with sarcoidosis. Transplant Proc 1977; 9: 173176.
94. Turton CWG, Turner-Warwick M, Morris L. HLA in familial sarcoidosis. In: Williams WJ,
Davies BH, eds. Eighth International Conference on Sarcoidosis and Other Granulomatous
Diseases. Cardiff, Alpha Omega Publishing, Ltd., 1980; pp. 195200.
95. Al-Arif L, Goldstein RA, Affronti LF. HLA antigens and sarcoidosis in a North American Black
population. In: Williams WJ, Davies BH, eds. Proceedings of the Eighth International Conference
on Sarcoidosis and Other Granulomatous Diseases. Cardiff, Alpha Omega Publishing, Ltd., 1980;
pp. 206212.
96. Newill CA, Johns CJ, Cohen BH. Sarcoidosis, HLA and immunoglobulin markers in
Baltimore blacks. In: Chretien J, Marsac J, Saltiel JC, eds. Proceedings of the Ninth
International Conference on Sarcoidosis and Other Granulomatous Disorders. Paris, Pergamon
Press, 1983; pp. 253256.
97. Nowack D, Goebel KM. Genetic aspects of sarcoidosis: class II histocompatibility antigens and a
family study. Arch Intern Med 1987; 147: 481483.
98. Lenhart K, Kolek V, Bartova A. antigens associated with HLA sarcoidosis. Dis Markers 1990;
8: 2329.
99. Luisetti M, Maartinatti M, Cuccia M, et al. HLA markers in sarcoidosis. Sarcoidosis 1991; 8: 177.
100. Barnard J, Rose C, Newman L, et al. Job and industry classification associated with sarcoidosis in
a case control etiologic study of sarcoidosis. J Occ Env Med 2005; 47: 226234.
101. Kreider ME, Christie JD, Thompson B, et al. Environmental exposures and the clinical phenotype
of sarcoidosis. Clin Chest Med 2004; (In press).
102. Edmondstone WM. Sarcoidosis in nurses: is there an association? Thorax 1988; 43: 342343.
103. Stewart IC, Davidson NM. Clustering of sarcoidosis. Thorax 1982; 37: 398399.
104. Kern DG, Sherman CB, Neill MA, Wrenn DS. Serum neopterin elevations in firefighters. Am J
Respir Crit Care Med 1994; 149: A408.
105. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in
New York City firefighters. Chest 1999; 116: 11831193.
106. U.S. Sarcoidosis among Navy enlisted men, 19651993. Morb Mortal Wkly Rep 1997;
46: 539543.
107. Jajosky P. Sarcoidosis diagnoses among U.S. military personnel: trends and ship assignment
associations. Am J Prev Med 1998; 14: 176183.
108. Fleming LE, Ducatman AM, Shalat SL. Disease clusters: A central and ongoing role in
occupational health. J Occup Med 1991; 33: 818825.

44
 AETIOLOGIES OF SARCOIDOSIS

109. Figueroa WG, Raszowski R, Weiss W. Lung cancer of chloromethylether workers. N Engl J Med
1973; 28: 10961099.
110. Creech JL Jr, Johnson MN. Angiosarcoma of the liver in the manufacture of polyvinyl chloride.
J Occup Med 1974; 16: 150151.
111. Rose CS, Robins T, Harkaway P. Biopsy-confirmed hypersensitivity pneumonitis associated with
exposure to metal-working fluids. Morb Mortal Wkly Rep 1996; 45: 606609.
112. Shelton BG, Flanders WD, Morris GK. Mycobacterium sp. as a possible cause of hypersensitivity
pneumonitis in machine workers. Emerg Infect Dis 1999; 5: 270273.
113. Gordon T. Metalworking fluid the toxicity of a complex mixture. J Toxicol Environ Health A
2004; 67: 209219.
114. Embil J, Warren P, Yakrus M, et al. Pulmonary illness associated with exposure to
Mycobacterium-avium complex in hot tub water. Hypersensitivity pneumonitis or infection?
Chest 1997; 111: 813816.
115. Khoor A, Leslie KO, Tazelaar HD, Helmers RA, Colby TV. Diffuse pulmonary disease caused by
nontuberculous mycobacteria in immunocompetent people (hot tub lung). Am J Clin Pathol 2001;
115: 755762.
116. Marras TK, Wallace RJ Jr, Koth LL, Stulbarg MS, Cowl CT, Daley CL. Hypersensitivity
pneumonitis reaction to Mycobacterium avium in household water. Chest 2005; 127: 664671.
117. Kreiss K, Mroz MM, Zhen B, Martyny J, Newman LS. Epidemiology of beryllium sensitization
and disease in nuclear workers. Am Rev Respir Dis 1993; 148: 985991.
118. Kreiss K, Wasserman S, Mroz MM, Newman LS. Beryllium disease screening in the ceramics
industry. Blood lymphocyte test performance and exposure-disease relations. J Occup Med 1993;
35: 267274.
119. Newman LS, Kreiss K, King TE Jr. Pathologic and immunologic alterations in early stages of
beryllium disease. Am Rev Respir Dis 1989; 139: 14791486.
120. Mroz MM, Kreiss K, Lezotte DC, Campbell PA, Newman LS. Reexamination of the blood
lymphocyte transformation test in the diagnosis of chronic beryllium disease. J Allergy Clin
Immunol 1991; 88: 5460.
121. Stange AW, Furman FJ, Hilmas DE. Rocky Flats beryllium health surveillance. Env Health
Perspect 1996; 104: 981986.
122. Stange AW, Hilmas DE, Furman FJ. Possible health risks from low level exposure to beryllium.
Toxicology 1996; 111: 213224.
123. Stange AW, Hilmas DE, Furman FJ, Gatliffe TR. Beryllium sensitization and chronic beryllium
disease at a former nuclear weapons facility. Appl Occup Environ Hyg 2001; 16: 405417.
124. Newman LS, Kreiss K. Non-occupational chronic beryllium disease masquerading as sarcoidosis:
Identification by blood lymphocyte proliferative response to beryllium. Am Rev Respir Dis 1992;
145: 12121214.
125. Newman LS. Beryllium disease and sarcoidosis: Clinical and laboratory links. Sarcoidosis 1995;
12: 719.
126. Fireman E, Haimsky E, Noiderfer M, Priel I, Lerman Y. Misdiagnosis of sarcoidosis in patients
with chronic beryllium disease. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 144148.
127. Infante PF, Newman LS. Beryllium exposure and chronic beryllium disease. Lancet 2004; 363:
415416.
128. Rose CS, Martyny JW, Newman LS, et al. "Lifeguard lung": endemic granulomatous pneumonitis
in an indoor swimming pool. Am J Public Health 1998; 88: 17951800.
129. Rutstein DD, Mullan RJ, Frazier TM, Halperin WE, Melius JM, Sestito JP. Sentinel health events
(occupational): A basis for physician recognition and public health surveillance. Am J Public
Health 1983; 73: 10541062.
130. Padilla ML, Schilero GJ, Teirstein AS. Donor-acquired sarcoidosis. Sarcoidosis Vasc Diffuse Lung
Dis 2002; 19: 1824.
131. Heyll A, Meckenstock G, Aul C, et al. Possible transmission of sarcoidosis via allogeneic bone
marrow transplantation. Bone Marrow Transplant 1994; 14: 161164.

45
 L.S. NEWMAN

132. Muller CBJ. Sarcoidosis recurrence following lung transplantation. Transplantation 1996; 16: 1117
1119.
133. Ikonomopoulos JA, Gorgoulis VG, Kastrinakis NG, Galanos AA, Karameris A, Kittas C.
Experimental inoculation of laboratory animals with samples collected from sarcoidal patients and
molecular diagnostic evaluation of the results. In vivo 2000; 14: 761765.
134. Mitchell IC, Turk JL. Observations on the Kveim reaction using an animal model of
granulomatous bowel disease. Gut 1991; 32: 159162.
135. Kataria YP, Park HK, Mountain LD. Enhanced inflammatory response with histiocytes and
epithelioid cells in rabbits to the intradermal injection of supernatants of cultured cutaneous
sarcoidal granulomas. Ann N Y Acad Sci 1986; 465: 176182.
136. Kooy R, Ruitenberg EJ, Sirks JL. Experience with a Dutch Kveim suspension in men and guinea
pigs. Ann N Y Acad Sci 1976; 278: 717721.
137. Teirstein AS. The Kveim-Siltzbach test. Clin Dermatol 1986; 4: 154164.
138. Richter E, Kataria YP, Zissel G, Homolka J, Schlaak M, Muller-Quernheim J. Analysis of
the Kveim-Siltzbach test reagent for bacterial DNA. Am J Respir Crit Care Med 1999; 159: 1981
1984.
139. Chemical and physical characteristics of the active principle of Kviem suspensions. In: V
International Congress on Sarcoidosis, 1971. Prague, Czechoslovakia, Univ Karlova, 1971.
140. Ewer K, Deeks J, Alvarez L, et al. Comparison of T-cell-based assay with tuberculin skin test for
diagnosis of Mycobacterium tuberculosis infection in a school tuberculosis outbreak. Lancet 2003;
361: 11681173.
141. Williams WR, Davies BH. Pseudo-leptospires in bronchoalveolar lavage fluid and blood cell
cultures. Br J Exp Pathol 1986; 67: 167170.
142. Wang N, Schraufnagel DE, Sampson MG. The tadpole-shaped structures in human non-
necrotising granulomas. Am Rev Respir Dis 1981; 123: 560564.
143. de Chadarevian JP, Raphael SA, Murphy GF. Histologic, ultrastructural, and
immunocytochemical features of the granulomas seen in a child with the syndrome of familial
granulomatous arthritis, uveitis, and rash. Arch Pathol Lab Med 1993; 117: 10501052.
144. Lawrence HJ, Greenberg BR. Autoimmune thrombocytopenia in sarcoidosis. Am J Med 1985;
79: 761764.
145. Johnson LA, Edsall JR, Austin JH, Ellis K. Pulmonary sarcoidosis: could mycoplasma-like
organisms be a cause? Sarcoidosis Vasc Diffuse Lung Dis 1996; 13: 3842.
146. Bisaccia E, Scarborough DA, Carr RD. Cutaneous sarcoid granuloma formation in herpes zoster
scars. Arch Dermatol 1983; 119: 788789.
147. Su WP, Kuechle MK, Peters MS, Muller SA. Palisading granulomas caused by infectious diseases.
Am J Dermatopathol 1992; 14: 211215.
148. Ehlers S, Mielke ME, Hahn H. The mRNA-phenotype of granuloma formation: CD4z T cell-
associated cytokine gene expression during primary murine listeriosis. Immunobiology 1994;
191: 432440.
149. Cho C, Linscheer WG, Hirschkorn MA, Ashutosh K. Sarcoid-like granulomas as an early
manifestation of Whipples disease. Gastroenterology 1984; 87: 941947.
150. Southern JF, Moscicki RA, Magro C, Dickersin GR, Fallon JT, Bloch KJ. Lymphedema,
lymphocytic myocarditis, and sarcoid-like granulomatosis. Manifestations of Whipples disease.
JAMA 1989; 261: 14671470.
151. Tintelnot K, von Hunnius P, de Hoog GS, Polak-Wyss A, Gueho E, Masclaux F. Systemic
mycosis caused by a new Cladophialophora species. J Med Vet Mycol 1995; 33: 349354.
152. Parkes SA, Baker SBdC, Bourdillon RE, et al. Incidence of sarcoidosis in the Isle of Man. Thorax
1985; 40: 284287.
153. Kern DG, Neill MA, Wrenn DS, Varone JC. Investigation of a unique time-space cluster of
sarcoidosis in firefighters. Am Rev Respir Dis 1993; 148: 4 Pt 1, 974980.
154. Favata EA, Neill HM, Yang CS. Emerging microbial diseases of the indoor environment. In:

46
 AETIOLOGIES OF SARCOIDOSIS

Couturier AJ, ed. Occupational and environmental infectious diseases. Beverly Farms, MA, USA,
OEM Press, 2000; pp. 697716.
155. Andersson MA, Nikulin M, Koljalg U, et al. Bacteria, molds, and toxins in water-damaged
building materials. Appl Environ Microbiol 1997; 63: 387393.
156. Verhoeff AP, van Wijnen JH, Brunekreef B, Fischer P, van Reenen-Hoekstra ES, Samson RA.
Presence of viable mould propagules in indoor air in relation to house damp and outdoor air.
Allergy 1992; 47: Suppl. 2 Pt 1, 8391.
157. Finnegan MJ, Pickering C, Burge PS. The sick building syndrome: Prevalence studies. BMJ 1984;
289: 15731575.
158. Mendell MJ, Smith AH. Consistent pattern of elevated symptoms in air-conditioned
office buildings: a reanalysis of epidemiologic studies. Am J Public Health 1990; 80: 1193
1199.
159. Rose C, Robins T, Harkaway P. Biopsy-confirmed hypersensitivity pneumonitis in automobile
production workers exposed to metal working fluids-Michigan, 19941995. Morb Mortal Wkly
Rep 1996: 606609.
160. Mangiapan G, Hance AJ. Mycobacteria and sarcoidosis: an overview and summary of recent
molecular biological data. Sarcoidosis 1995; 12: 2037.
161. Richter E, Greinert U, Kirsten D, et al. Assessment of mycobacterial DNA in cells and tissues of
mycobacterial and sarcoid lesions. Am J Respir Crit Care Med 1996; 153: 375380.
162. Bocart D, Lecossier D, De Lassence A, Valeyre D, Battesti J-P, Hance AJ. A search for
mycobacterial DNA in granulomatous tissues from patients with sarcoidosis using the polymerase
chain reaction. Am Rev Respir Dis 1992; 145: 11421148.
163. Ghossein RA, Ross DG, Salomon RN, Rabson AR. Search for mycobacterial A DNA in
sarcoidosis using the polymerase chain reaction. Am J Clin Pathol 1994; 101: 733737.
164. Wilsher ML, Menzies RE, Croxson MC. Mycobacterium tuberculosis DNA in tissues affected by
sarcoidosis. Thorax 1998; 53: 871874.
165. Chao SC, Yan JJ, Lee JY. Cutaneous sarcoidosis among Taiwanese. J Formos Med Assoc 2000; 99:
317323.
166. Vokurka M, Lecossier D, du Bois RM, et al. Absence of DNA from mycobacteria of the M.
tuberculosis complex in sarcoidosis. Am J Respir Crit Care Med 1997; 156: Suppl. 3 Pt 1, 1000
1003.
167. Popper HH, Klemen H, Hoefler G, Winter E. Presence of mycobacterial DNA in sarcoidosis. Hum
Pathol 1997; 28: 796800.
168. Li N, Bajoghli A, Kubba A, Bhawan J. Identification of mycobacterial DNA in cutaneous lesions
of sarcoidosis. J Cutan Pathol 1999; 26: 271278.
169. Ikonomopoulos JA, Gorgoulis VG, Kastrinakis NG, et al. Sensitive differential detection of
genetically related mycobacterial pathogens in archival material. Am J Clin Pathol 2000; 114: 940
950.
170. Klemen H, Husain AN, Cagle PT, Garrity ER, Popper HH. Mycobacterial DNA in recurrent
sarcoidosis in the transplanted lung a PCR-based study on four cases. Virchows Arch 2000; 436:
365369.
171. Almenoff PL, Johnson A, Lesser M, Mattman LH. Growth of acid fast L forms from the blood of
patients with sarcoidosis. Thorax 1996; 51: 530533.
172. El-Zaatari FA, Naser SA, Markesich DC, Kalter DC, Engstand L, Graham DY. Identification of
Mycobacterium avium complex in sarcoidosis. J Clin Microbiol 1996; 34: 22402245.
173. Moller DR. Identification of potential etiologic antigens in sarcoidosis. J Clin Microbiol 2001; 163:
A214.
174. Homma JY, Abe C, Chosa H, et al. Bacteriological investigation on biopsy specimens from
patients with sarcoidosis. Jpn J Exp Med 1978; 48: 251255.
175. Ishige I, Usui Y, Takemura T, Eishi Y. Quantitative PCR of mycobacterial and propionibacterial
DNA in lymph nodes of Japanese patients with sarcoidosis. Lancet 1999; 354: 120123.
176. Yamada T, Eishi Y, Ikeda S, et al. In situ localization of Propionibacterium acnes DNA in lymph

47
 L.S. NEWMAN

nodes from sarcoidosis patients by signal amplification with catalysed reporter deposition. J
Pathol 2002; 198: 541547.
177. Relman DA, Loutit JS, Schmidt TM, Falkow S, Tompkins LS. The agent of bacillary
angiomatosis. An approach to the identification of uncultured pathogens. N Engl J Med 1990; 323:
15731580.
178. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of
Whipples disease. N Engl J Med 1992; 327: 293301.
179. Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute
respiratory syndrome. N Engl J Med 2003; 348: 19531966.
180. Fleming JL, Wiesner RH, Shorter RG. Whipples disease: clinical, biochemical, and
histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988; 63:
539551.
181. Lowsky R, Archer GL, Fyles G, et al. Brief report: diagnosis of Whipples disease by molecular
analysis of peripheral blood. N Engl J Med 1994; 331: 13431346.
182. Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipples disease. N Engl J
Med 2000; 342: 620625.

48
CHAPTER 4

Immunology and pathophysiology

G. Semenzato, M. Bortoli, E. Brunetta, C. Agostini

Dept of Clinical and Experimental Medicine, Padua University School of Medicine, Padua, Italy.

Correspondence: G. Semenzato, Universita` di Padova, Dipartimento di Medicina Clinica e Sperimentale,

Immunologia Clinica, Via Giustiniani 2, 35128 Padova, Italy. Fax: 39 0498754179; E-mail: g.semenzato
@unipd.it

Sarcoidosis is considered the archetype of immune granulomatous disorders, since

immunoregulatory mechanisms that play a part in the development of the sarcoid
granuloma may modulate pathogenetic events leading to granuloma development in
other granulomatous diseases [1]. Remarkable advances have been made in under-
standing general immunological and molecular aspects of the mechanisms leading to
granuloma formation and the development of fibrosis in sarcoidosis. In particular, the
sarcoid granuloma is considered to be the consequence of a crippled immunological
response against an unidentifed antigen that has persisted at sites of disease involvement,
perhaps because of its low solubility and degradability. Indeed, although hypersensitivity
reactions commonly resolve, the balance between events that mediate resolution or
perpetuation of inflammatory responses may be altered in patients with chronic
sarcoidosis. The persistence of the aetiological agents and/or an imbalance of
mechanisms for the removal of inflammatory cells and their by-products ultimately
lead to an ongoing inflammatory response. As a result, cytokines with pro-inflammatory
destructive biological functions are locally produced; overall, these cytokines set the
stage for the development of irreversible remodelling of lung tissue, progression toward
pulmonary granuloma formation, and, in some individuals, irreversible development of
pulmonary fibrosis.
The aim of the present chapter is to provide an overview of the available knowledge
concerning the mechanisms leading to the inflammatory processes that occur at common
sites of involvement in sarcoidosis. A detailed description of the cellular interactions that
govern the dynamics of granuloma formation is also included.

The infiltration of inflammatory cells in the formation of

sarcoid granulomas
Mechanisms leading to T-cell infiltration at sites of disease activity
The infiltration of CD4z activated T-cells represents the immunological hallmark of
sarcoidosis (table 1). Although lung parenchyma normally contains only a few lymphoid
elements, lymphocyte populations are strikingly compartmentalised in sarcoidosis air
spaces and interstitium. The equivalent of 256106 T-cells can be recovered from the
bronchoalveolar lavage fluid (BALF) of patients with active pulmonary sarcoidosis,
most probably in response to unknown exogenous or endogenous antigen(s). Sarcoid T-
cells are predominantly CD4z, CD45R0 T-cells, coexpressing the ab T-cell receptor,
mainly producing interferon gamma (IFN)-c or interleukin (IL)-2 and, thus, belonging
Eur Respir Mon, 2005, 32, 4963. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
49
 G. SEMENZATO ET AL.

Table 1. Immunological features that have been observed in patients with sarcoidosis

Feature
T-cells Infiltration of CD4z cells showing a Th1 cytokine profile with a marked increase in
CD4:CD8 ratio at sites of disease activity.
Expansion of T-cells bearing a restricted Vb and Va TCR repertoire in involved tissues.
This pattern is consistent with TCR oligoclonality.
Increased expression of members of TNF receptor superfamilies and molecules which
regulate cell survival and death of sarcoid T-cells. This suggests that dysregulation of T-cell
apoptotic mechanisms may explain the absence of apoptosis in the granuloma and the
persistence of inflammation.
Increased expression of chemokine receptors involved in the recruitment of activated Th1 cells
(CXCR3, CCR6, CXCR6).
Macrophages Tissue accumulation of macrophages expressing increased levels of activation markers,
adhesion molecules (CD49a, CD54, CD102) and costimulatory molecules (CD80 and CD86,
CD40 and CD72).
Pulmonary macrophages showing increased antigen-presenting capacity
Production of macrophage-derived cytokines (IL-1, IL-6, IL-15, TNF-a, GM-CSF) that favour
tissue damage and granuloma assembly.
Release of macrophage-derived chemokines that favour granuloma assembly (CCL5, CCL20,
CXCL9, CXCL10, CXCL16)
Production of macrophage-derived fibrogenetic cytokines (TGF-b and related cytokines, PDGF,
IGF-I) involved in progression towards fibrosis.
Th: T-helper cell; V: variable region; TCR: T-cell receptor; TNF: tumour necrosis factor; CXCR: CXC chemokine
receptor; CCR: CC chemokine receptor; IL: interleukin; GM-CSF: granulocyte-macrophage colony-stimulating
factor; CCL: CC chemokine ligand; CXCL: CXC chemokine ligand; TGF: transforming growth factor; PDGF:
platelet-derived growth factor; IGF-I: insulin-like growth factor-I.

to the T-helper (Th) cell type-1 subset. The marked accumulation of CD4z lymphocytes
can be observed in all tissues affected by the sarcoid immuno-inflammatory process [2, 3],
where the CD4:CD8 ratio is extremely high (usually w10).
T-cells expanding at sites of disease activity bear a restricted variable region (V)b and
Va T-cell receptor (TCR) repertoire, a pattern which is consistent with TCR
oligoclonality. Different mechanisms could account for the limited usage of the TCR
repertoire in sarcoidosis. One hypothesis is that the putative antigen(s) drives oligoclonal
expansion of T-cells using particular Va or Vb regions. In addition, the in situ release of
cytokines probably plays a role in this phenomenon. After in vitro growth in IL-2-
supplemented media, T-cells from sarcoid patients show selective expansion of particular
Vb-expressing subsets. Junctional region sequencing indicates that the IL-2-stimulated
T-cells are strikingly oligoclonal and derive from T-cell clones already selectively
expanded in vivo. Thus, it is thought that the antigen(s) that triggers the development of
the granulomatous lesions favours the progressive accumulation and activation of a
limited number of Th1 clones. When a sufficient amount of tissue is involved by
inflammatory Th1 cells, clinical signs of disease activity appear, and are sensed by the
individual, for instance, as dyspnoea when the respiratory tract is involved.
T-cell homeostasis is strictly controlled by soluble factors and membrane receptors
that activate proliferative and apoptotic processes (fig. 1). It has been known since the
1980s that the in situ proliferation of Th1 represents a putative mechanism responsible
for CD4 accumulation in sarcoid inflamed tissues (see later). A number of data also
suggest that the binding of death-signal-transmitting receptors or modulators of T-cell
apoptosis may have undesirable pathogenetic effects in subjects with progressive
sarcoidosis. As has recently been shown, sarcoid T-lymphocytes exhibit resistance to
apoptosis [4], which might contribute to the accumulation of inflammatory cells in the
lungs, persistence of inflammation, and the development and maintenance of
granulomas. Interestingly, the percentage of T-regulatory cells (Tr), defined as CD4z,

50
 IMMUNOLOGY OF SARCOIDOSIS

IL-12, IL-18 IL-12, IL-18

IFN-g AM IFN-g

Th1
Th1 Chemokines IL-15

Recruitment Proliferation

Alveolitis

Fig. 1. Following recognition of the unknown antigen(s) causing sarcoidosis, alveolar macrophages (AMs) are
triggered to produce interleukin (IL)-12 and IL-18. Both cytokines enable the activation of macrophages. This
favours the release of macrophage-derived chemokines (CXC chemokine 10/interferon (IFN)-c-inducible protein
10) and cytokines (IL-15) involved in T-helper (Th) cell type-1 recruitment. In turn, newly recruited Th1 cells
release IFN-c which stimulates a further autocrine loop. The net effect is the development of T-cell alveolitis.

CD25z(bright) lymphocytes, is increased in the lungs of patients with active disease who
show spontaneous clinical resolution, suggesting that an increased number of Tr in active
sarcoidosis may favour the downregulation of cell-mediated immune responses [5].
Tumour necrosis factor (TNF)-a may also play conflicting roles in modulating the
activities of sarcoid T-cells at sites of inflammation. There are data suggesting that the
chronic overexpression of TNF-a and IFN-c sets the stage for the persistence and
progression of inflammatory events in patients with chronic sarcoidosis; in some
circumstances, alteration of the TNF receptor/ligand balance leads to the chronic
recruitment of inflammatory cells, which, once in the inflamed tissue, assemble new
granulomatous structures. Conversely, there are data from animal models indicating that
TNF-a is required for Th1 recruitment, granuloma assembly [6] and antigen clearance,
and, thus, for recovery from granulomatous disorders. Both effects are likely to be
possible. TNF-a may be essential or have little impact on the control of apoptotic
mechanisms within the granulomatous structure depending on a combination of genetic
factors, previous environmental exposure and local alterations in immunocompetence.
p21, a member of the Cip/Kip family, regulates cell survival and death, implying that it
is a master regulator of cell fate. Specifically, activation of macrophages in vitro by IFN-c
or their adhesion to extracellular matrix decorin leads to suppression of apoptosis [7, 8];
this anti-apoptotic effect is mediated by the expression of p21 (Waf1). From recent
studies, high levels of p21 have been demonstrated in sarcoid lung, and it has been

51
 G. SEMENZATO ET AL.

hypothesised that the hyperexpression of p21 could explain the absence of apoptosis in
the granuloma and the persistence of inflammation [9].
Another system that is involved in the regulation of T-cell inflammatory processes is
the Fas/Fas ligand (FasL) system. Fas, which is expressed at high levels by chronically
stimulated T-cells, limits the expansion of antigen-reactive T-cells after ligation with a
specific ligand belonging to the TNF ligand superfamily (FasL), thus preventing
excessive accumulation of antigen-activated lymphocytes [10]. Both of these systems have
been evaluated in sarcoidosis [11]. Fas molecules are expressed at higher levels on sarcoid
T-lymphocytes than in normal T-cell subpopulations [12]. Furthermore, high
concentrations of the soluble form of FasL, which is associated with downregulation
of cytotoxicity, are detected in the BALF and serum of patients with sarcoidosis but not
in normal subjects [13]. Programmed T-cell death is also inhibited by oncogene products.
The oncogene encoding B-cell leukaemia/lymphoma 2 gene product (Bcl-2) (BCL2), in
particular, belongs to a family of apoptosis-regulatory products that may be either death
antagonists or agonists. Overexpression of some family members (e.g. BCL2 and the gene
encoding Bcl-2-like 1 (BCLXL)) protects lymphoid cells from programmed cell death
when certain growth factors, such as IL-2, are withdrawn, whereas overexpression of
others (e.g. the genes encoding the apoptotic protein BAD (BAD), Bcl-2-associated X-
protein (BAX) and BH3-interacting domain death agonist (BID)) overrides the incoming
signals from the cytokine receptor and induces apoptosis. Like Fas, BCL2 is highly
expressed by T-lymphocytes surrounding the granulomatous lesions of patients with
sarcoidosis [14]. Applying high-density human gene chip probe arrays for RNA
expression profiling, it has been shown that a number of apoptosis-related gene products,
including growth factors and the BCL2 family of genes, are upregulated in patients with
sarcoidosis, consistent with a pro-survival profile [15]. Furthermore, patients with
progressive disease show upregulation of nuclear factor (NF)-kB and a lack of
downregulation of inhibitors of apoptosis [15].
It has also been shown that interaction with fibroblasts can inhibit the apoptosis of
cytokine-deprived activated T-cells by a selective effect on BCLXL: this phenomenon is
probably mediated by a soluble factor released by fibroblasts that upregulates
glutathione synthesis and maintains high BCLXL levels, helping to maintain the
granulomatous process. Therefore, it is possible that overexpression of this inhibitor of
apoptosis may prevent the clearance of activated T-cells.

Th1 cell-derived molecules influence inflammatory events in sarcoidosis

Data on the pattern of lymphokine production during sarcoidosis may be summarised
in the context of the Th1/Th2 paradigm. The idea is that alterations in Th1/Th2 balance
play an important role in determining the organisation of the sarcoid granuloma and the
progression of the disease. The cytokines released mainly by T-cells, and those released
by macrophages that regulate Th1/Th2 subsets, are discussed in the following section.

Th1 cell-derived cytokines. IFN-c is the key factor that triggers all inflammatory
processes in sarcoidosis (fig. 1). IFN-c is typically expressed by Th1 cells infiltrating the
sarcoid tissue and favours the development of the typical hypersensitivity reaction, and, in
general terms, inhibition of fibrogenetic processes. As a confirmation of the role of this
cytokine, levels of IFN-c are significantly high in the fluid component of the BALF of
patients with active sarcoidosis [16].
Through its pleiotropic effects on cytokine production, IFN-c upregulates the
expression of the costimulatory molecules on accessory cells, including CD80 and CD86
[17]. IFN-c also has crucial antifibrotic effects, since it inhibits the proliferation of

52
 IMMUNOLOGY OF SARCOIDOSIS

endothelial cells and the synthesis of collagens by fibroblasts. As previously reported,

there is also a significant correlation between increased expression of IFN-c and
expression of the cdk inhibitor p21/Waf1 (an anti-apoptotic molecule) in sarcoid lung [9],
suggesting that the high levels of IFN-c-induced p21 may explain the absence of
apoptosis in the granuloma and the persistence of inflammation.
However, by inducing non-ERL chemokines (monokine induced by IFN-c (MIG)/CXC
chemokine ligand (CXCL)9, IFN-c-inducible protein (IP)-10/CXCL10, IFN-c-inducible
T-cell a chemoattractant (ITAC)/CXCL11), IFN-c plays a major role in the recruitment
and activation of sarcoid CXC chemokine receptor (CXCR)3zT-cells in inflamed tissues
(fig. 1). Indeed, there are a high number of CD4z T-cells expressing CXCR3, CC
chemokine receptor (CCR)5, IL-12 receptor (IL-12R) and IL-18R in the lung of patients
with sarcoidosis, whereas the Th2-associated chemokine receptors CXCR4 and CCR4 are
expressed by a low percentage of pulmonary sarcoid CD4z T-cells [18].
IL-2 is also actively released at sites of disease activity during sarcoidosis, where it acts
as a local growth factor for T-lymphocytes infiltrating involved tissues [1921]. The
presence of binding sites for IL-2 has also been demonstrated on human lung fibroblasts.
Addition of IL-2 to fibroblasts leads to enhanced expression of the gene encoding
monocyte chemoattractant protein (MCP)-1/CC chemokine ligand (CCL)2, a chemokine
which is involved in fibrosis through the regulation of profibrotic cytokine generation
and matrix. IL-2 may, thus, serve to integrate fibroblasts and sarcoid macrophages into a
coordinated response of the connective tissue initiated by Th1 lymphocytes at sites of
disease activity.

Th2 cell-derived cytokines. A switch to Th2 may occur in patients with progressive
sarcoidosis. In these subjects, T-cells release Th2 cytokines, including IL-4, which is a
cofactor for the proliferation of multiple cell lineages, including fibroblasts (see later) [22
24]. Activated Th2 cells also represent a source of IL-10, a molecule which has anti-
inflammatory and immunoregulatory properties: it inhibits pro-inflammatory cytokine
and chemokine production in addition to blocking T-cell responses to specific antigens. It
has been proposed that the local secretion of IL-10 may represent a down-modulating
mechanism involved in the spontaneous resolution of alveolitis in sarcoidosis [25]. In this
regard, recent data suggest that the low macrophagic production of IL-22, a member of
the human type-I IFN family, which includes IL-10, may play a role in the pathogenesis of
sarcoidosis [26]. IL-22 has the potential to interact with IL-10 because it binds to the IL-
10R2c chain with IL-22R1 in its receptor complex. Its role in the pathogenesis of
sarcoidosis remains to be established. Finally, IL-13, a Th2 cytokine which is expressed by
CD4z T-cells and has been shown to suppress TNF-a in human blood monocytes is
actively released in the lung of some patient with sarcoidosis [27]. However, alveolar
macrophages rather than Th2 cells seem to be the cellular source of this pro-Th2 cytokine
in sarcoid lung. In any case, the overproduction of IL-13 might have an anti-inflammatory
effect on the surrounding microenvironment by acting on TNF-a release.

Monocyte/macrophage-derived molecules
The interaction between IFN-c and its receptor triggers macrophages to become
primed from the early phases of the sarcoid inflammatory process (fig. 1). This activation
state of sarcoid macrophages is indicated by enhanced secretion of immunomodulatory
molecules (table 1), as specified in the following section.

Pro-inflammatory cytokines. Sarcoid macrophages are capable of producing detectable

amounts of IL-1, which regulates the development of alveolar inflammation in

53
 G. SEMENZATO ET AL.

sarcoidosis. Moreover, IL-1 per se may stimulate granuloma formation and fibrosis
development by inducing fibroblast proliferation and increasing collagen production.
As previously discussed, TNF-a is another pro-inflammatory cytokine actively
produced by sarcoid macrophages. It plays a critical role in pulmonary injury and the
regulation of fibroblast growth via induction of IL-6. Furthermore, TNF-a stimulates
and regulates the synthesis and release of other lymphokines (IL-1, granulocyte-
macrophage colony-stimulating factor (GM-CSF), platelet-activating factor and IL-6)
and increases prostaglandin (prostaglandin E2) production. There are data suggesting
that the chronic overexpression of TNF-a and IFN-c sets the stage for the persistence
and progression of inflammatory events and tissue damage during sarcoidosis [12, 28
30]. This suggests the importance of anti-TNF strategies in the treatment of sarcoidosis.

Cytokines involved in the regulation of Th1/Th2 cells. IL-12, the main macrophage-
derived molecule involved in initiating Th1 immune responses, has been extensively
evaluated in sarcoid lung. Its involvement in the development of lung granulomas,
including sarcoidosis, has been clearly demonstrated [3134]. IL-12 stimulates the
proliferation of activated sarcoid T-cells. In synergy with IL-15, IL-12 favours contact
between activated T-cells and sarcoid macrophages and induces the expression of
chemokine receptors by Th1 cells (fig. 1). This cytokine acts by interacting with specific
receptors (IL-12Rb) expressed by lymphocytes accumulating at sites of disease activity
during sarcoidosis [35].
IL-27, a newly described member of the IL-12 family, has been recently implicated in
the pathogenesis of granulomas [36]. This cytokine synergises with IL-12 and is
composed of two subunits, p28 and EpsteinBarr virus-induced gene 3 (EBI3).
Immunohistochemical studies in granulomatous tissues have shown that EBI3 and
p28 coexpression can be detected in epithelioid and multinucleate giant cells of sarcoid
granulomas. In addition, sinus or tissue macrophages, endothelial cells and plasma cells
coexpress EBI3 and p28. Taken together, these data suggest that IL-27 may play some
role in granuloma pathogenesis, although the molecular mechanisms through which IL-
27 participates in the assembly of the central macrophagic core of the granuloma remains
to be defined.
Another macrophage-derived pro-Th1 cytokine which cooperates with IL-12 is IL-18
(fig. 1). Mainly produced by monocytes and macrophages, IL-18 induces expression of
IFN-c and GM-CSF, whereas it inhibits the production of IL-10. IL-18 and IL-12 act
synergistically on sarcoid Th1 cells in the development and organisation of the Th1-type
immune response [3740]. However, it has been shown that IL-18, via activation of
activation protein 1 and NF-kB, leads to enhanced IL-2 gene expression and production
in sarcoid lung [37].
In confirmation of the local effects of IL-18, it has been shown that patients with active
disease show upregulation of the NF-kB family of transcription factors [41]. Recent
findings suggest that the local hyperexpression of these critical regulators of immediate
transcriptional responses may be, to some extent, genetically regulated in sarcoidosis [42,
43]. Some molecular mechanisms that favour the upregulation of NF-kB on sarcoid
macrophages begin to be clarified. The ligand-activated transcription factor peroxisome
proliferator-activated receptor (PPAR)-c has crucial effects in modulating the Th1 immune
response, partly by down-regulating the production of inflammatory cytokines. Sarcoid
macrophages exhibit activation of NF-kB and deficiency of PPAR-c, suggesting that
insufficient PPAR-c activity contributes to ongoing inflammation in pulmonary sarcoi-
dosis by failing to suppress pro-inflammatory transcription factors, such as NF-kB [44].
Sarcoid macrophages also release IL-15, a cytokine which supports the growth,
survival and chemotaxis of sarcoid T-cells, favouring the development of Th1 infiltration

54
 IMMUNOLOGY OF SARCOIDOSIS

[45, 46]. It also behaves as a costimulatory factor for the production of other cytokines
and chemokines (IL-17, CXCL8/IL-8, CCL2/MCP-1, GM-CSF, IFN-c and TNF-a),
and for the expression of molecules involved in the antigen-presenting capability of
resident accessory cells (CD80/CD86). Furthermore, the finding that IL-15 down-
modulates the apoptotic rate of lung T-cells indicates IL-15 as a possible inhibitor of
physiological apoptotic stimuli that favour the persistence of inflammatory processes at
sites of disease activity.

Colony-stimulating factors. Colony-stimulating factors, and in particular GM-CSF, are

actively produced by sarcoid macrophages. In particular, GM-CSF is able to induce the
growth and differentiation of sarcoid macrophages, facilitating the development of the
macrophage-derived core of the sarcoid granuloma [47, 48]. Furthermore, GM-CSF
modulates cytokine production and enhances the antigen-presenting capacity of sarcoid
macrophages [49].

Chemokines
The trafficking and accumulation of immunocompetent cells are essential components
in the pathophysiology of the inflammatory processes taking place in the lung of patients
with sarcoidosis. A number of data suggest that most of these events are regulated by
chemokines, which are highly expressed in the lung of patients with sarcoidosis (table 2).
Monocyte inflammatory protein (MIP)-3b/CCL19 has been implicated in T-lymphocyte
recruitment in sarcoidosis, is associated with disease progression and is down-regulated
by drugs used for sarcoidosis treatment [50]. However, production of high levels of MCP-
1/CCL2, MIP-1a/CCL3, MIP-1b/CCL4 and regulated on activation, normal T-cell
expressed and secreted (RANTES)/CCL5 cooperate to immobilise several leukocyte
subpopulations in perivascular foci of inflammation. MCP-1/CCL2 and RANTES/
CCL5, interacting with CCR1/CCR2 or CCR1/CCR3/CCR5, respectively, may be
Table 2. Chemokines and chemokine receptors that have been implicated in the pathogenesis of sarcoidosis

Chemokine Human ligand Receptor

CC Chemokines
CCL2 MCP-1, MCAF CCR2
CCL3 MIP-1a, LD78a, LD78b, AT464.1, AT464.2, CCR1, CCR5
GOS19-1, GOS19-2
CCL4 MIP-1b, AT744.1, AT744.2, Act-2, G-26, CCR5
HC21, H400, LAG-1
CCL5 RANTES CCR1, CCR3, CCR5
CCL19 MIP-3b/exodus-3 CCR7
CCL20 MIP-3a/exodus-1 CCR6
CXC chemokines
CXCL8 IL-8, MDNCF, NAP-1, NCF CXCR1, CXCR2
CXCL9 MIG, HuMIG CXCR3
CXCL10 IP-10 CXCR3
CXCL11 ITAC, H174, b-R1 CXCR3
CXCL16 SR-PSOX CXCR6
CCL: CC chemokine ligand; CXCL: CXC chemokine ligand; MCP-1: monocyte chemoattractant protein-1; MCAF:
monocyte chemotactic and activating factor; CCR: CC chemokine receptor; MIP: monocyte inflammatory protein;
RANTES: regulated on activation, normal T-cell expressed and secreted; IL: interleukin; MDNCF: monocyte-
derived neutrophil chemotactic factor; NAP-1: neutrophil-activating protein 1; NCF: neutrophil chemotactic factor;
CXCR: CXC chemokine receptor; MIG: monokine induced by IFN-c; HuMIG: human MIG; IP: interferon-gamma
(IFN-c)-inducible protein; ITAC: IFN-c-inducible T-cell a chemoattractant; SR-PSOX: scavenger receptor that
binds phosphatidylserine and oxidised lipoprotein.

55
 G. SEMENZATO ET AL.

chemoattractant for different cell targets that characterise this different phase of the
sarcoid inflammatory process, including macrophages and T-lymphocytes.
Three lymphocyte-specific CXC chemokines, which are produced in response to IFN-c
(i.e. CXCL10, MIG/CXCL9 and ITAC/CXCL11) [51], play an important role in the
recruitment of activated T-cells into the pulmonary microenvironment during
sarcoidoisis. Sarcoid macrophages are the main cell source for these molecules; they
release large amounts of CXCL10 and CXCL9 that, by interacting with specific receptors
expressed by Th1 cells (CXCR3), allow for the accumulation of pulmonary T-
lymphocytes and contribute to granuloma formation [52]. Activated bronchial
epithelium is another important source of CXCL9, CXCL10 and CXCL11.
The present authors have recently evaluated whether or not CXCR3 is coexpressed with
other Th1-associated chemokine receptors. The preliminary data indicate that two other
typical Th1 chemokine receptors, CCR6 and Bonzo/CXCR6, are highly expressed by
sarcoid Th1 cells. In particular, it has been shown that, whereas CXCR3 is expressed early
by sarcoid T-cells, CXCR6 expression is the result of prolonged exposure in the pulmonary
microenvironment to IFN-c and macrophage-derived cytokines, primarily IL-15.
IL-8/CXCL8, a chemokine that favours T-cell and neutrophil recruitment, is actively
released in the airways during sarcoidosis, and its release is associated with lung damage.
Immunolocalisation of IL-8 has demonstrated that the pulmonary fibroblast is the
predominant cellular source of IL-8, even if there are data suggesting that macrophages
may release this chemokine. Interestingly, pulmonary fibrosis may be associated with
increased release of IL-8/CXCL8 and dysregulation of CXCL10 production, suggesting
that the balance of chemokine production is an important factor in the regulation of local
angiogenesis and fibrogenesis.
Collectively, these data emphasise the role of chemokines and chemotactic molecules
in the development of sarcoid inflammation. It is also likely that cell-to-cell and cell-to-
matrix interactions modulate local chemokine expression, contributing to the
pathological progression toward fibrosis of inflammatory lesions. As recently reviewed
[29], a number of antagonists of chemokine receptors are being developed by different
pharmaceutical companies. Specific chemokine antagonists are now approaching their
first clinical trials. The therapeutic use of molecules selective for chemokine receptors
appears to have great potential for sarcoidosis and other T-cell mediated diffuse lung
diseases.

Macrophage/T-cell interactions are key factors in granuloma

formation
The central core of the typical sarcoid granuloma is made up of a number of
monocytes/macrophages at various states of activation and differentiation, as well as
epithelioid cells and multinucleate giant cells. Chemotactic and activating factors for
leukocytes, which are actively secreted in tissues involved by sarcoidosis, are then capable
of recruiting blood monocytes to the local milieu, favouring the development of the
central structure of the granuloma.
Histopathological data have demonstrated the presence of macrophage and
macrophage-derived interdigitating professional antigen-presenting cells (APCs) in the
T-cell areas [53]. These cells, even when assembled into the mature components of the
granuloma, maintain APC features as well as the ability to synthesise an array of
cytokines. T-cell/macrophage interaction depends on the presence of a number of
costimulatory molecules on lung macrophages, including members of the B7 family
(CD80 and CD86), some molecules of the TNF receptor superfamily (CD40 and CD27)

56
 IMMUNOLOGY OF SARCOIDOSIS

and the CD5 co-ligand CD72. The pattern of CD80 and CD86 expression shown by
pulmonary macrophages of patients with sarcoidosis is consistent with that of
conventional APCs [17, 54, 55]. Indeed, sarcoid macrophages increase their expression
of molecules which endow macrophages with accessory functions for T-cell activation
and proliferation, including CD80 and CD86, and CD40 and CD72. Furthermore, it has
been shown that mature dendritic cells can be found in the central core of sarcoid
granulomas of patients with sarcoidosis, suggesting that blood dendritic cell subsets may
migrate into the affected tissues, contributing to the formation of the granuloma [56].
The expression of cytokine genes, which ultimately accounts for the accumulation of
immunocompetent cells inside granulomas, was recently investigated in sarcoid lymph
nodes using in situ hybridisation techniques and immunohistological studies. IL-1b, IFN-
c, CXCL16 and CXCL10, and CCL20 and CCL5 are preferentially expressed by cells
inside the granuloma [29, 57, 58], whereas cells containing TNF-a, IL-1a, IL-6 and IL-2
mRNA are scattered and randomly distributed. These findings suggest that the
development of the new granuloma is due to molecules with chemotactic properties
which cooperate to attract monocytes and lymphocytes in the perivascular foci of
inflammation (fig. 2). It is probable that IFN-c release by CD4 cells is essential to the
assembly of the granuloma since it is not possible to induce the formation of granulomas
in mice in which the IFN-c gene has been disrupted [59]. IFN-c-induced chemokines
have also been implicated in the assembly of the granuloma structure. Indeed,
immunohistological analysis of tissues displaying abundant sarcoid granulomas has
revealed that cells bearing CXCL10 and CXCL16 are mainly epithelioid cells and CD68z
macrophages located inside the granulomatous areas (fig. 2). Both chemokines are
functionally active. Indeed, by interacting with specific receptors expressed on Th1 cells
(CXCR6 and CXCR3), the two chemokines are able to favour the migration and
accumulation of the sarcoid T-lymphocytes that surround the central macrophagic core.

Fibrosis in sarcoidosis
Although the granuloma structure is aimed at containing the dissemination of inciting
agents in hypersensitivity reactions, it is to be expected that the inflammatory response
will spontaneously clear once the aetiological factors are isolated. This paradigm is not
supported in the case of refractory sarcoidosis. Iny60% of patients with sarcoidosis, the
course of the disease is self-limiting with spontaneous resolution of the granuloma,
whereas patients with progressive sarcoidosis show massive development of granulomas
and do not recover even if strong immunosuppressive therapy is used. The uncontrolled
development of granulomas results in fibrosis.
Although the reversible phases of initial alveolar injury in the sarcoid process are
mediated by Th1 lymphocytes, the fibrotic changes that follow the sarcoid Th1 immune
response are modulated by macrophages, neutrophils, eosinophils and mast cells [60, 61],
which, via overproduction of the superoxide anion, oxygen radicals and proteases, can
cause local injury, disruption of the epithelial basement membrane, alteration of
epithelial permeability and consequent derangement of the normal architecture of lung
parenchyma [62]. In confirmation of the role of polymorphonuclear cells in lung damage,
an increased number of BALF neutrophils has been related to a more severe course of the
sarcoid process [63].
By releasing a number of molecules, including transforming growth factor (TGF)-b
and the family of TGF-related cytokines, platelet-derived growth factor and insulin-like
growth factor I, sarcoid macrophages may, in theory, mediate fibrosis. These growth
factors for fibroblasts and epithelial cells and their receptors are abundantly expressed in

57
 G. SEMENZATO ET AL.

CXCL16
CXCL10

l ll
l l l
ll ll l l l
l l
l l ll l ll ll l l
lll CXCR3
l
ll ll CXCR6
l ll ll ll
l
ll l l l l
l lll lll
l ll
lll l l ll
l l
l lll lll ll
l
llll l l llll l
llll
ll l
l
ll l l
ll

l l l lll
llllllll ll
l
ll
ll l l ll llll
ll llll ll
llll ll
l l l
ll l l l l
lll l
ll l
l lllllll
lll lll lll
lllll ll llll
ll
lll llllll
l
Fig. 2. Molecules with chemotactic properties cooperate to attract monocytes in perivascular foci of sarcoid
inflammation (see section on Chemokines). However, cells bearing CXC chemokine ligand (CXCL)10 and
CXCL16 are located mainly inside granulomas. Indeed, epithelioid cells and CD68z macrophages of the central
core of the granuloma are CXCL10z/CXCL16z, whereas lymphocytes surrounding the granuloma core are
CXC chemokine receptor (CXCR)3z/CXCR6z T-cells, suggesting that interaction between chemokine receptors
and their ligands are crucial to the mechanisms leading to granuloma assembly.

fibrotic lung. They cooperate with the TGF family in promoting fibroblast growth and
deposition of collagen fibrils. Furthermore, macrophage-derived cytokines which are
overexpressed at sites of granuloma formation (including IL-1, IL-6, IFN-c, TNF-a and
GM-CSF) [6466] and immunoglobulin G immune complexes may upregulate the
expression of the inducible form of nitric oxide synthase and nitric oxide production in
granuloma cells [67], thus contributing to the injury and consequent reparative processes.
In general terms, the recruitment of fibroblasts and the subsequent increased
production of matrix macromolecules are crucial to the fibrotic process. In particular,
migration of fibroblasts and epithelial cells from the interstitium to the alveolar spaces
and adhesive interactions of fibroblasts with the surrounding interstitial matrix are the
major factors contributing to the development of fibrosis. The migratory process of
fibroblasts reflects the local release of a variety of molecules which can act as
chemoattractant factors for fibroblasts, such as chemokines, products of coagulation and

58
 IMMUNOLOGY OF SARCOIDOSIS

the fibrinolytic cascade, as well as matrix proteins (collagen peptides, laminin, fibronectin
and elastin-derived peptides) [6871]. Most of these are actively produced in sarcoid lung.
Molecules secreted by sarcoid inflammatory cells are also able to prime fibroblasts to
enter the G1 phase of the growth cycle, and thus to proliferate. Indeed, an increased
proportion of fibroblasts isolated from patients with pulmonary fibrosis demonstrate
unexpected growth capability and a higher rate of cell division than fibroblasts isolated
from normal lung. Furthermore, they show increased migratory capability [72].

Conclusions
Since 2000, much has been learnt regarding the pathogenesis of sarcoidosis, and
improved therapies are being developed based on these findings. Currently, most interest
in soluble cytokine and chemokine inhibitors, genetically engineered antagonists, and
single or combinations of anti-inflammatory cytokines has focused on the possibility that
they may become standard pharmacological agents for controlling and modulating the
sequelae of the immunological events that lead to granuloma formation and fibrosis
development. For example, molecules capable of neutralising TNF-a have been used in
the clinical setting of patients with sarcoidosis [29, 73]. Not unexpectedly, these data
suggest the real possibility of using anti-TNF strategies to treat refractory sarcoidosis.
These data are preliminary and clinical trials are in progress to confirm both the efficacy
and tolerability of anti-TNF agents when used in patients with sarcoidosis. Blockades of
other inflammatory cytokines are also expected to be therapeutic in sarcoidosis and other
T-cell-mediated diffuse lung diseases. In particular, therapies directed at neutralising
chemokines and other molecules which control the trafficking and accumulation of
immunocompetent cells are potentially more selective and attractive but require a priori
knowledge of the precise pathways regulating the inflammation state involving the
alveolar and interstitial structures.

Summary
By influencing many of the physiological properties of immunocompetent cells,
including proliferation, differentiation, activation and chemotaxis, chemokines and
cytokines act as critical mediators of cell function and cell-to-cell communication in
sarcoidosis. In fact, it is well established that the release of a cascade of interacting
extracellular signalling proteins orchestrates the trafficking of immune cells during
sarcoid inflammatory process. Cytokines regulate the expression of adhesion
molecules on the lung vascular endothelium within and around the site of
inflammation by combining with relevant receptors on neighbouring cells. This in
turn favours the entrance and activation of type-1 T-helper (Th) cells, and modulates
the local survival and proliferation of different types of immune cells, including
macrophages, which in turn release pro-inflammatory cytokines. As a result, cytokines
with pro-inflammatory destructive biological functions set the stage for the
development of irreversible remodelling of the lung tissue, the evolution toward
pulmonary granuloma formation, and, in some sarcoid individuals, the development
of fibrosis.

Keywords: Cytokines, immunopathogenesis, sarcoidosis, T-cell alveolitis.

59
 G. SEMENZATO ET AL.

References
1. Semenzato G, Adami F, Maschio N, Agostini C. Immune mechanisms in interstitial lung diseases.
Allergy 2000; 55: 11031120.
2. Semenzato G, Bortolin M, Facco M, Tassinari C, Sancetta R, Agostini C. Lung lymphocytes:
origin, biological functions, and laboratory techniques for their study in immune-mediated
pulmonary disorders. Crit Rev Clin Lab Sci 1996; 33: 423455.
3. Semenzato G, Pezzutto A, Agostini C, Gasparotto G, Cipriani A. Immunoregulation in
sarcoidosis. Clin Immunol Immunopathol 1981; 19: 416427.
4. Stridh H, Planck A, Gigliotti D, Eklund A, Grunewald J. Apoptosis resistant bronchoalveolar
lavage (BAL) fluid lymphocytes in sarcoidosis. Thorax 2002; 57: 897901.
5. Planck A, Katchar K, Eklund A, Gripenback S, Grunewald J. T-lymphocyte activity in HLA-
DR17 positive patients with active and clinically recovered sarcoidosis. Sarcoidosis Vasc Diffuse
Lung Dis 2003; 20: 110117.
6. Lukacs NW, Chensue SW, Strieter RM, Warmington K, Kunkel SL. Inflammatory granuloma
formation is mediated by TNF-a-inducible intercellular adhesion molecule-1. J Immunol 1994;
152: 58835889.
7. Xaus J, Cardo M, Valledor AF, Soler C, Lloberas J, Celada A. Interferon gamma induces the
expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis.
Immunity 1999; 11: 103113.
8. Xaus J, Comalada M, Cardo M, Valledor AF, Celada A. Decorin inhibits macrophage colony-
stimulating factor proliferation of macrophages and enhances cell survival through induction of
p27 (Kip1) and p21 (Waf1). Blood 2001; 98: 21242133.
9. Xaus J, Besalduch N, Comalada M, et al. High expression of p21 Waf1 in sarcoid granulomas: a
putative role for long-lasting inflammation. J Leukoc Biol 2003; 74: 295301.
10. Alderson MR, Tough TW, Davis-Smith T, et al. Fas ligand mediates activation-induced cell death
in human T lymphocytes. J Exp Med 1995; 181: 7177.
11. Kunitake R, Kuwano K, Miyazaki H, Hagimoto N, Nomoto Y, Hara N. Apoptosis in the course
of granulomatous inflammation in pulmonary sarcoidosis. Eur Respir J 1999; 13: 13291337.
12. Agostini C, Zambello R, Sancetta R, et al. Expression of tumor necrosis factor-receptor
superfamily members by lung T lymphocytes in interstitial lung disease. Am J Respir Crit Care
Med 1996; 153: 13591367.
13. Shikuwa C, Kadota J, Mukae H, et al. High concentrations of soluble Fas ligand in
bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis. Respiration 2002; 69: 242
246.
14. Agostini C, Perin A, Semenzato G. Cell apoptosis and granulomatous lung diseases. Curr Opin
Pulm Med 1998; 4: 261266.
15. Rutherford RM, Kehren J, Staedtler F, et al. Functional genomics in sarcoidosis reduced or
increased apoptosis? Swiss Med Wkly 2001; 131: 459470.
16. Meloni F, Caporali R, Marone Bianco A, et al. BAL cytokine profile in different interstitial lung
diseases: a focus on systemic sclerosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 111118.
17. Agostini C, Trentin L, Perin A, et al. Regulation of alveolar macrophageT cell interactions during
Th1-type sarcoid inflammatory process. Am J Physiol 1999; 277: Suppl. 2 Pt 1, L240L250.
18. Katchar K, Eklund A, Grunewald J. Expression of Th1 markers by lung accumulated T cells in
pulmonary sarcoidosis. J Intern Med 2003; 254: 564571.
19. Hunninghake GW, Bedell GN, Zavala DC, Monick M, Brady M. Role of interleukin-2 release by
lung T-cells in active pulmonary sarcoidosis. Am Rev Respir Dis 1983; 128: 634638.
20. Pinkston P, Bitterman PB, Crystal RG. Spontaneous release of interleukin-2 by lung T
lymphocytes in active pulmonary sarcoidosis. N Engl J Med 1983; 308: 793800.
21. Muller-Quernheim J, Pfeifer S, Kienast K, Zissel G. Spontaneous interleukin 2 release of broncho-
alveolar lavage cells in sarcoidosis is a codeterminator of prognosis. Lung 1996; 174: 243253.

60
 IMMUNOLOGY OF SARCOIDOSIS

22. Wallace WA, Howie SE. Immunoreactive interleukin 4 and interferon-c expression by type II
alveolar epithelial cells in interstitial lung disease. J Pathol 1999; 187: 475480.
23. Moller DR. Cells and cytokines involved in the pathogenesis of sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 1999; 16: 2431.
24. Lukacs NW, Hogaboam C, Chensue SW, Blease K, Kunkel SL. Type 1/type 2 cytokine paradigm
and the progression of pulmonary fibrosis. Chest 2001; 120: Suppl. 1, 5S8S.
25. Bingisser R, Speich R, Zollinger A, Russi E, Frei K. Interleukin-10 secretion by alveolar
macrophages and monocytes in sarcoidosis. Respiration 2000; 67: 280286.
26. Whittington HA, Armstrong L, Uppington KM, Millar AB. Interleukin-22: a potential
immunomodulatory molecule in the lung. Am J Respir Cell Mol Biol 2004; 31: 220226.
27. Hauber HP, Gholami D, Meyer A, Pforte A. Increased interleukin-13 expression in patients with
sarcoidosis. Thorax 2003; 58: 519524.
28. Wahlstrom J, Katchar K, Wigzell H, Olerup O, Eklund A, Grunewald J. Analysis of intracellular
cytokines in CD4z and CD8z lung and blood T cells in sarcoidosis. Am J Respir Crit Care Med
2001; 163: 115121.
29. Agostini C. Cytokine and chemokine blockade as immunointervention strategy for the treatment
of diffuse lung diseases. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18: 1822.
30. Baughman RP, Strohofer SA, Buchsbaum J, Lower EE. Release of tumor necrosis factor by
alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990; 115: 3642.
31. Shigehara K, Shijubo N, Ohmichi M, et al. Enhanced mRNA expression of Th1 cytokines
and IL-12 in active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17: 151
157.
32. Minshall EM, Tsicopoulos A, Yasruel Z, et al. Cytokine mRNA gene expression in active and
nonactive pulmonary sarcoidosis. Eur Respir J 1997; 10: 20342039.
33. Moller DR, Forman JD, Liu MC, et al. Enhanced expression of IL-12 associated with Th1
cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996; 156: 49524960.
34. Taha RA, Minshall EM, Olivenstein R, et al. Increased expression of IL-12 receptor mRNA
in active pulmonary tuberculosis and sarcoidosis. Am J Respir Crit Care Med 1999; 160: 1119
1123.
35. Rogge L, Papi A, Presky DH, et al. Antibodies to the IL-12 receptor b2 chain mark human Th1
but not Th2 cells in vitro and in vivo. J Immunol 1999; 162: 39263932.
36. Larousserie F, Pflanz S, Coulomb-LHermine A, Brousse N, Kastelein R, Devergne O. Expression
of IL-27 in human Th1-associated granulomatous diseases. J Pathol 2004; 202: 164171.
37. Greene CM, Meachery G, Taggart CC, et al. Role of IL-18 in CD4z T lymphocyte activation in
sarcoidosis. J Immunol 2000; 165: 47184724.
38. Fukami T, Miyazaki E, Matsumoto T, Kumamoto T, Tsuda T. Elevated expression of interleukin-
18 in the granulomatous lesions of muscular sarcoidosis. Clin Immunol 2001; 101: 1220.
39. Shigehara K, Shijubo N, Ohmichi M, et al. IL-12 and IL-18 are increased and stimulate IFN-c
production in sarcoid lungs. J Immunol 2001; 166: 642649.
40. Shigehara K, Shijubo N, Ohmichi M, et al. Am J Respir Crit Care Med 2000; 162: 19791982.
41. Drent M, van den Berg R, Haenen GR, van den Berg H, Wouters EF, Bast A. NF-kB activation in
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18: 5056.
42. Abdallah A, Sato H, Grutters JC, et al. Inhibitor kappa B-alpha (IkB-a) promoter polymorphisms
in UK and Dutch sarcoidosis. Genes Immun 2003; 4: 450454.
43. Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with
constitutive nuclear factor-kB activation: common genetic etiology with Blau syndrome. Blood
2004; 105: 11951197.
44. Culver DA, Barna BP, Raychaudhuri B, et al. Peroxisome proliferator-activated receptor c
activity is deficient in alveolar macrophages in pulmonary sarcoidosis. Am J Respir Cell Mol Biol
2004; 30: 15.
45. Agostini C, Trentin L, Facco M, et al. Role of IL-15, IL-2, and their receptors in the development
of T cell alveolitis in pulmonary sarcoidosis. J Immunol 1996; 157: 910918.

61
 G. SEMENZATO ET AL.

46. Zissel G, Baumer I, Schlaak M, Muller-Quernheim J. In vitro release of interleukin-15 by broncho-

alveolar lavage cells and peripheral blood mononuclear cells from patients with different lung
diseases. Eur Cytokine Netw 2000; 11: 105112.
47. Itoh A, Yamaguchi E, Kuzumaki N, et al. Expression of granulocyte-macrophage colony-
stimulating factor mRNA by inflammatory cells in the sarcoid lung. Am J Respir Cell Mol Biol
1990; 3: 245249.
48. Kreipe H, Radzun HJ, Heidorn K, et al. Proliferation, macrophage colony-stimulating factor, and
macrophage colony-stimulating factor-receptor expression of alveolar macrophages in active
sarcoidosis. Lab Invest 1990; 62: 697703.
49. Enthammer C, Zambello R, Trentin L, et al. Synthesis and release of granulocyte-macrophage
colony-stimulating factor by alveolar macrophages of patients with sarcoidosis. Sarcoidosis 1993;
10: 147148.
50. Gibejova A, Mrazek F, Subrtova D, et al. Expression of macrophage inflammatory protein-3b/
CCL19 in pulmonary sarcoidosis. Am J Respir Crit Care Med 2003; 167: 16951703.
51. Farber JM. Mig and IP-10: CXC chemokines that target lymphocytes. J Leukoc Biol 1997; 61:
246257.
52. Agostini C, Adami F, Semenzato G. New pathogenetic insights into the sarcoid granuloma. Curr
Opin Rheumatol 2000; 12: 7176.
53. Menestrina F, Lestani M, Mombello A, et al. Transbronchial biopsy in sarcoidosis: the role of
immunohistochemical analysis for granuloma detection. Sarcoidosis 1992; 9: 95100.
54. Kaneko Y, Kuwano K, Kunitake R, et al. Immunohistochemical localization of B7 costimulating
molecules and major histocompatibility complex class II antigen in pulmonary sarcoidosis.
Respiration 1999; 66: 343348.
55. Nicod LP, Isler P. Alveolar macrophages in sarcoidosis coexpress high levels of CD86 (B7.2),
CD40, and CD30L. Am J Respir Cell Mol Biol 1997; 17: 9196.
56. Ota M, Amakawa R, Uehira K, et al. Involvement of dendritic cells in sarcoidosis. Thorax 2004;
59: 408413.
57. Lipscomb MF, Bice DE, Lyons CR, Schuyler MR, Wilkes D. The regulation of pulmonary
immunity. Adv Immunol 1995; 59: 369455.
58. Huang H, Meyer KC, Kubai L, Auerbach R. An immune model of beryllium-induced pulmonary
granulomata in mice. Histopathology, immune reactivity, and flow-cytometric analysis of
bronchoalveolar lavage-derived cells. Lab Invest 1992; 67: 138146.
59. Gudmundsson G, Hunninghake GW. Interferon-c is necessary for the expression of
hypersensitivity pneumonitis. J Clin Invest 1997; 99: 23862390.
60. Bjermer L, Engstrom-Laurent A, Thunell M, Hallgren R. The mast cell and signs of pulmonary
fibroblast activation in sarcoidosis. Int Arch Allergy Appl Immunol 1987; 82: 298301.
61. Inoue Y, King TE Jr, Tinkle SS, Dockstader K, Newman LS. Human mast cell basic fibroblast
growth factor in pulmonary fibrotic disorders. Am J Pathol 1996; 149: 20372054.
62. Agostini C, Semenzato G. Cytokines in sarcoidosis. Semin Respir Infect 1998; 13: 184196.
63. Drent M, Jacobs JA, de Vries J, Lamers RJ, Liem IH, Wouters EF. Does the cellular broncho-
alveolar lavage fluid profile reflect the severity of sarcoidosis? Eur Respir J 1999; 13: 13381344.
64. Ishioka S, Saito T, Hiyama K, et al. Increased expression of tumor necrosis factor-a, interleukin-6,
platelet-derived growth factor-B and granulocyte-macrophage colony-stimulating factor mRNA
in cells of bronchoalveolar lavage fluids from patients with sarcoidosis. Sarcoidosis Vasc Diffuse
Lung Dis 1996; 13: 139145.
65. Homma S, Nagaoka I, Abe H, et al. Localization of platelet-derived growth factor and insulin-like
growth factor I in the fibrotic lung. Am J Respir Crit Care Med 1995; 152: 20842089.
66. Bost TW, Riches DW, Schumacher B, et al. Alveolar macrophages from patients with beryllium
disease and sarcoidosis express increased levels of mRNA for tumor necrosis factor-a and
interleukin-6 but not interleukin-1b. Am J Respir Cell Mol Biol 1994; 10: 506513.
67. Facchetti F, Vermi W, Fiorentini S, et al. Expression of inducible nitric oxide synthase in human
granulomas and histiocytic reactions. Am J Pathol 1999; 154: 145152.

62
 IMMUNOLOGY OF SARCOIDOSIS

68. Shigehara K, Shijubo N, Hirasawa M, Abe S, Uede T. Immunolocalization of extracellular matrix

proteins and integrins in sarcoid lymph nodes. Virchows Arch 1998; 433: 5561.
69. Probst-Cousin S, Poremba C, Rickert CH, Bocker W, Gullotta F. Factor XIIIa expression in
granulomatous lesions due to sarcoidosis or mycobacterial infection. Pathol Res Pract 1997; 193:
741745.
70. Marshall BG, Wangoo A, Cook HT, Shaw RJ. Increased inflammatory cytokines and new
collagen formation in cutaneous tuberculosis and sarcoidosis. Thorax 1996; 51: 12531261.
71. Roman J, Jeon YJ, Gal A, Perez RL. Distribution of extracellular matrices, matrix receptors, and
transforming growth factor-b1 in human and experimental lung granulomatous inflammation. Am
J Med Sci 1995; 309: 124133.
72. Suganuma H, Sato A, Tamura R, Chida K. Enhanced migration of fibroblasts derived from lungs
with fibrotic lesions. Thorax 1995; 50: 984989.
73. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
2001; 18: 7074.

63
CHAPTER 5

Genetics

R.M. du Bois*, P.A. Beirne*, S.E. Anevlavis#

*Interstitial Lung Disease Unit, Dept of Occupational and Environmental Medicine, National Heart and
Lung Institute, Imperial College of Science, Technology and Medicine, London, UK. #Dept of
Pulmonology, Dimokritio University of Thrace, Medical School, University Hospital of Alexandroupolis,
Alexandroupolis, Greece.

Correspondence: R.M. du Bois, Interstitial Lung Disease Unit, Dept of Occupational and Environmental
Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine,
London, SW3 6LR, UK. Fax: 44 2073518336; E-mail: r.dubois@rbht.nhs.uk

There is compelling evidence that sarcoidosis is the product of environmental triggers

operating in an immunogenetically susceptible host that results in the formation of
immune-mediated granulomas at disease sites. There is also support for the concept that
immunogenetic predisposition determines the pattern of organ involvement in sarcoidosis.
Two approaches have been taken to determine the genetics of sarcoidosis: familial
studies and case-control studies of sporadic disease. In familial studies, linkage or target
gene association approaches are taken to the association of genotype with disease. In
linkage studies, a series of linkage markers that span the whole genome are used to track
marker pattern with disease. The area of possible association can then be mapped more
finely with a second set of markers to target the specific area of interest.

Familial sarcoidosis
The first indication that sarcoidosis may be of genetic predisposition came from the
recognition of familial clustering of disease in several populations. The first record of
disease in two German sisters appeared in 1923 [1]. Familial disease has also been
confirmed in northern Sweden and central Hokkaido in Japan [2]. Pietinahlo et al. [3]
identified familial sarcoidosis with a prevalence of 3.6% in Finnish and 4.3% in Japanese
patients. An increased prevalence of sarcoidosis has also been described in the Furano
district of northern Japan, with some evidence of familial clustering [4]. Table 1 shows
the familial clustering of sarcoidsis in several populations worldwide.
In a study by Headings et al. [5] involving African-American patients a sibling disease
prevalence of 10% was reported. Rybicki et al. [6] studied 488 parents and siblings of 179
African-American sarcoidosis cases and found a 2.5-fold increased risk of history of
sarcoidosis in case relatives over that in the general population. In the UK, McGrath
et al. [7] reported a sarcoidosis risk ratio for siblings of 3673, indicating significant
familial clustering of the disease. The population studied was mainly Caucasian (62.5%).
The highest frequency of sarcoidosis among the immediate family of patients was found
in an Irish population of 114 patients attending a specialist clinic; 9.6% of the patients
were found to have one or more siblings with the same disease [8]. A Case-Control
Etiologic Study of Sarcoidosis (ACCESS) is the largest prospective study that set out to
investigate, among other things, the familial aggregation of sarcoidosis [9]. It is a large
case-control study consisting of 10,862 first-degree and 17,047 second-degree relatives
identified by 706 sarcoidosis case-control pairs. The familial relative risk (RR) to siblings
Eur Respir Mon, 2005, 32, 6481. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
64
 GENETICS

Table 1. Familial sarcoidosis

Ethnicity Familial aggregation Reference

Finland 3.6% PIETINALHO [3]
Japan 4.3% PIETINALHO [3]
African Americans 10% HEADINGS [5]
African Americans (siblings and parents) 2.5-fold increase in the disease risk RYBICKI [6]
UK Caucasians RR 3673 MCGRATH [7]
Irish 9.6% BRENNAN [8]
African Americans (parents and siblings) RR 3.1 RYBICKI [9]
USA Whites (parents and siblings) RR 16.6 RYBICKI [9]
USA Blacks 19% HARRINGTON [10]
USA Whites 5% HARRINGTON [10]
RR: relative risk.

was larger than in parents (odds ratio (OR)=5.8 versus 3.8). For African-Americans, the
familial RR for a sarcoidosis case was 2.8, whereas the familial RR for Whites was
markedly higher at 16.6. In summary, in the ACCESS study, cases were almost five times
more likely than controls to report a sibling or a parent with a history of sarcoidosis.

Familial genetic studies

Sarcoidosis in all its clinical phenotypes is a genetically complex disease, i.e. the disease
and, more specifically, subsets of disease are the product(s) of more than one gene
interacting with one or more triggers to produce the end phenotype.
Few linkage studies have been performed in sarcoidosis, largely due to the difficulties
in gathering large numbers of familial cases. SchUrmann et al. [11] have completed two
studies using microsatellite markers and multipoint nonparametric linkage (NPL)
analysis. In the first study, they genotyped 122 affected siblings from 55 families for seven
DNA polymorphisms in the major histocompatability complex (MHC) region [11]. NPL
analysis showed linkage for the entire MHC region, with the peak score identified at a
marker locus in the Class III region (D6S1666). They subsequently suggested that the
susceptibility region was nearer the class II MHC loci. A follow-up, genome-wide study
using 225 microsatellite markers in 63 families with 138 affected siblings also found the
most prominent peak at the MHC (p=0.001), including the D6S1666 marker identified in
the first study [12]. However, six additional minor peaks (pv0.05) were found on
chromosomes 1, 3 (close to the chemokine receptor genes CCR2 and CCR5), 7 (two
peaks, one close to the T-cell receptor B gene), 9 (close to the gene for transforming
growth factor-b receptor 1), and the X chromosome (close to the gene coding for the
interleukin (IL)-2 receptor gamma chain). The authors of that study did warn that, with
225 markers, 11 similar minor peaks would be expected by chance alone. They also noted
the lack of association with markers near other candidate genes, such as angiotensin-
converting enzyme (ACE) and NRAMP1, but again warned that for genes with minor
effects on susceptibility, a greater marker density and a much larger sample of affected
sibling pairs would be required. More linkage studies in different ethnic groups,
employing larger samples and more microsatellite markers, are required to allow
identification of other candidate genes exerting minor effects on susceptibility.
More recently, Valentonyte et al. [13] utilised a three-stage single-nucleotide
polymorphism (SNP) analysis approach to fine focus the region of interest on
chromosome 6 in families and sporadic case-control samples of individuals with
sarcoidosis. They identified a 15 kb disease-associated segment of the butyrophilin-like 2
(BTNL2) gene. BTNL2 is a member of the immunoglobulin superfamily and
demonstrates homology to B7-1. It has thus been implicated as a costimulatory

65
 R.M. DU BOIS ET AL.

molecule involved in T-cell activation. The G to A variant results in a truncated protein

that is presumed to have aberrant function. Valentonyte et al. [13] concluded that the
BTNL2 association is class II MHC independent, although there is almost complete
linkage disequilibrium with HLA-DRB1; this requires further resolution.

Association studies
Major histocompatibility complex
Human leukocyte antigen class I. Some of the first studies of the genetics of sarcoidosis
explored human leukocyte antigen (HLA) class I typing using serological techniques; a
summary of these studies is presented in table 2.
The earliest such study in 1974 failed to detect any association between sarcoidosis in
132 German patients and HLA locus A [22]. Subsequent studies reported associations
with HLA-B8 in Caucasian patients [1416], but not in Black patients [23]. One of these
studies in Czech patients also found an association with HLA-B13, and B8 B13
heterozygotes had a RR of 8.5 for sarcoidosis [16]. When these results were compared
with 127 Italian patients, the association with HLA-B8 was confirmed, as well as an
association with HLA-A1 [17]. HLA-B8 has been associated with disease of acute onset
and short duration [18]. One study of 114 Japanese patients failed to find any association
with class I antigens that could not be better explained by linkage disequilibrium with
class II antigens, although they did find a reduction in HLA-B7 in patients compared
with controls [19]. This is of interest because HLA-B7 has been found in increased
frequency in African-American patients (a population with high disease prevalence) [20].
On the basis of these studies, it can be concluded that the association with HLA-B8 seems
to be most commonly reported across racial boundaries, but it has not been found in all
studies and other reported associations are even weaker. In any case, the immunology of
sarcoidosis would suggest that HLA class II molecules are more likely to be involved in
antigen presentation; any reported disease associations with class I genes may merely
represent linkage with more relevant class II genes. However, in this regard a more recent
study of Scandinavian patients found that both HLA-B*07 and HLA-B*08
independently increased the risk of sarcoidosis [21]. Other class I associations were
secondary to their linkages to class II alleles. The common allele combination A*03,

Table 2. Human leukocyte antigen class I associations

Ethnicity Sample size Susceptibility Protection Phenotype Reference(s)

patients/controls associations associations associations
UK 65 patients B8 BREWERTON [14]
American 174/97 B8 OLENCHOCK [15]
Caucasians
Czech 123/500 A1 LENHART [16]
B8 and MARTINETTI [17]
B13
Italian 107/510 B8 MARTINETTI [17]
UK 37 resolved disease/ B8 acute self-limiting SMITH [18]
50 fibrosed disease/ disease
164 healthy
Japanese 114/478 B7 INA [19]
African American 28/80 B7 MCINTYRE [20]
Scandinavian 166/210 B*07 A*03, B*07, DRB1*15 GRUNEWALD [21]
B*08 Haplotype and
chronic disease

66
 GENETICS

B*07, DRB1*15 was most strongly associated with persistent disease and was found in
25.3% of such patients against 7.1% of healthy controls. The authors concluded that
HLA class I alleles may have more influence on disease susceptibility and prognosis than
has been recently thought.

Human leukocyte antigen class II. More contemporary studies have used molecular
(usually SNP) methodology to determine associations with MHC class II alleles (table 3)
[17, 19, 21, 24, 2530, 31, 32, 33, 34]. The most compelling of these studies show
associations that cross ethnic boundaries.
HLA-DR-associated antigens have attracted most attention recently. In Japanese
patients, HLA-DR5, -DR6 and -DR8 [24, 35] and -DR8 and -DR9 [25] have been
associated with disease. In Germans, HLA-DR5 has been linked with chronic disease
[25], but HLA-DR3 with acute disease [26]. This pattern of differential linkage in acute
and chronic disease has been confirmed in Scandinavia; certain alleles have been
associated with chronic disease (HLA-DR14 and -DR15), while others have been
associated with acute self-limiting disease (DR17 (3)) [27]. HLA-DR14 was also
associated with chronic disease in a recent study of Asian Indians [28]. HLA-DR9 has
been associated with disease risk in Japanese patients, but with disease protection in
Scandinavians.
Some attempt has been made to arrive at a consensus from this confused picture.
HLA-DR1 and -DR4 have been found to be protective in Scandinavians, Japanese,
Italians, and in a study of UK, Polish and Czech patients [29]. This study showed
position 11 of the HLA-DRB1 amino acid sequence to be the most variable, with three
susceptibility alleles all coding for small hydrophilic amino acids, and two protective
alleles coding for amino acids with bulky, hydrophobic, aliphatic side chains. As the
position 11 amino acid is located at a crucial interface between the HLA-DR a and b
chains, it is easy to imagine how these different alleles could affect HLA-DR heterodimer
conformation and antigen binding.
A recent study reported high-resolution typing for the HLA-DPB1, HLA-DQB1,
HLA-DRB1 and HLA-DRB3 loci in the first 474 ACCESS patients and case-matched
controls [30]. A significant association was found between HLA-DRB1 alleles and
disease in both Blacks and Whites. The HLA-DRB1*1101 allele was associated with
sarcoidosis in both Blacks and Whites, with a population attributable risk of 16% in
Blacks and 9% in Whites. The only class II allele differentially distributed between Blacks
and Whites with respect to disease was HLA-DRB1*1501, being associated with controls
in Blacks and with sarcoidosis in Whites. This caused Rossman et al. [30] to speculate
that broadly similar HLA class II alleles may be associated with sarcoidosis in both
populations, and that the increased risk in Blacks could be due to increased prevalence of
susceptibility alleles in the Black population.
The HLA-DP locus has attracted considerable interest due to the finding that chronic
beryllium disease (a chronic multisystem granulomatous disease with many immuno-
pathological similarities to sarcoidosis) is associated strongly with the presence of a
glutamic acid residue at position 69 of the HLA-DP beta chain. However, this
association has not been found in two studies in sarcoidosis [36, 37], although the latter
study in African Americans did find an increased risk of disease associated with Val36z
and Asp55z alleles. In this regard, in the ACCESS study, the HLA-DPB1 locus also
contributed towards susceptibility, but with the HLA-DPB1*0101 allele conveying most
of the risk [30].
In another recent study in African Americans, 225 sarcoidosis patients with
family members as controls were genotyped for six microsatellite markers covering the
MHC region [38]. An association was observed between disease and the marker closest to

67
 Table 3. Human leukocyte antigen class II associations

Ethnicity Sample size Susceptibility associations Protection associations Phenotype associations Reference
patients/controls
Asian Indians 56/275 DRB1*11 DRB1*07 DRB1*14 severe disease SHARMA [28]
DRB1*14 DQB1*0201
American Caucasians 268/268 DRB1*1101 DQB1*0602 DRB1*0401 ROSSMAN [30]
DRB1*1501 Eye
DRB1*1401 DPB1*0101 hypercalcaemia
DRB1*0402
American Blacks 193/193 DRB1*1101 DRB1*0401 parotid/salivary glands ROSSMAN [30]
DRB1*1201
DPB1*0101
DQB1*0502 DRB3 bone marrow
225/479 first-degree DQB1*0602 DQB1*0201 DQB1*0602 severe disease IANNUZZI [31]

68
relatives
Scandinavians 122/250 DR17(3) DR17(3) acute disease BERLIN [27]
DR14, DR15 chronic disease
Japanese 75/150 DRB1*11 (DR5) DRB1*0101 GRUNEWALD [21]
R.M. DU BOIS ET AL.

DRB1*14 (DR6) DQB1*0501

DRB1*08 (DR8) DPB*0402
40/110 DRB1*12 ISHIHARA [24]
DRB1*14
DRB1*08
26/247 DQB1*0601 cardiac NARUSE [33]
114/478 DRw5 DR5 mild disease INA [19]
DRw8
DRw52 DR8 chronic disease
 Table 3. Continued

Ethnicity Sample size Susceptibility associations Protection associations Phenotype associations Reference
patients/controls
UK and Dutch Caucasians 235/568 DQB1*0201 mild disease, SATO [32]
including Lofgrens
DQB1*0602 severe disease
Dutch Caucasians 37 Lofgrens/88 DQB1*0201-DRB1*03(01) DQB1*0201-DRB1*03(01) Lofgrens ROSSMAN [30]
and Lofgrens
Czech and Italian 233/1010 DR3 DR4 DR3 mild disease MARTINETTI [17]
Caucasians
German 78/50 DR4 severe disease SWIDER [26]
DR3 Lofgrens
73/199 DR5 chronic disease NOWACK [25]

69
UK Caucasians 189/288 DRB1*12 DRB1*01 FOLEY [29]
DRB1*14 DRB1*04
GENETICS

DRB1*15 DQB1*06039
DQB1*0602
DQB1*0301/4
Polish 87/133 DRB1*15 DRB1*01 FOLEY [29]
DQB1*0602 DQB1*05
DQB1*06039
Czech 69/158 DRB1*14 DR7 FOLEY [29]
DQB1*02
DQB1*04
Dutch Caucasian 149/418 DRB1*150101/DQB1*0602 Severe disease VOORTER [34]
 R.M. DU BOIS ET AL.

HLA-DQB1; further analysis of other markers at this locus confirmed that in this African-
American cohort, it is HLA-DQB1 and not HLA-DRB1 that confers susceptibility to
sarcoidosis. A follow-up study found that HLA-DQB1*0201 was transmitted to affected
offspring only half as often as expected, whereas DQB1*0602 was transmitted to affected
offspring y20% more than expected, and was associated with radiographic disease
progression [31]. This contrasts with the study on ACCESS patients, in which the major
association was with HLA-DRB1; however, that paper did also report an association of
disease in blacks with HLA-DQB1*0502, albeit a weaker association than with HLA-
DRB1 [30]. In a recent study in a population of 149 Dutch Caucasian sarcoidosis patients,
an association was found between severe disease and the haplotype DRB1*150101/
DQB1*0602; due to the tight linkage disequilibrium of the alleles in the Caucasian
population, it is not possible to assign the primary association [39].
These DQB1 associations are consistent with a European study of the HLA-DQB1
locus in 235 Dutch and UK patients. DQB1*0201 was found to be strongly protective
against severe sarcoidosis (i.e. it was associated with stage I disease) whereas the
DQB1*0602 allele tended to have the opposite effect [32]. Furthermore, the patient group
included 15 patients with Lofgrens syndrome and 23 patients with erythema nodosum
(EN); carriage of the DQB1*0201 allele was greatly increased in these subgroups. In a
follow-up study based on this finding and the previously reported associations between
Lofgrens and the DRB1*0301 allele and the A allele at position -307 of the tumour
necrosis factor (TNF)-a gene (TNF2) [26], 37 Dutch Lofgrens patients were genotyped
for all three alleles [40]. The associations were confirmed, being strongest for DQB1*0201
(OR=8.6 versus 6.7 and 6.8 for DRB1*03 and TNF2, respectively). In addition, there was
100% linkage disequilibrium between DQB1*0201 and DRB1*03, and 70% LD between
these alleles and TNF2. This article, therefore, identified the DQB1*0201-DRB1*03(01)-
TNF2 haplotype as an extended MHC haplotype that was present in 76% of Lofgrens
patients (versus 24% of controls) and conferred the risk for Lofgrens syndrome in Dutch
Caucasians (OR=9.9).
Lofgrens syndrome is extremely rare in Japanese patients; this fits well with the above
study, as the Japanese do not have the HLA-DR3 allele. However, cardiac sarcoidosis is
more common than in Caucasians. Takashige et al. [41] reported an association between
cardiac sarcoidosis and the TNFA2 allele. Further studies by Naruse et al. [33]
concluded that the strongest association was in fact with the HLA-DQB1*0601 allele,
with homozygosity for this allele conferring a RR of 29.5 compared with healthy
controls. The TNFA2 allele was not in linkage disequilibrium with the class II allele, so
the authors of that study suggested that this allele might confer an additional genetic risk
for cardiac sarcoidosis. Small fibre neuropathy has recently been identified as a relatively
common problem in a cohort of Dutch chronic sarcoidosis patients. Sarcoidosis patients
suffering from small fibre neuropathy showed an increased prevalence of DQB1*0602,
suggesting a possible genetic relationship [34].
These studies all demonstrate one of the most taxing issues, that of primary association
or association through linkage disequilibrium. Tight phenotyping of different ethnic
groups with different linkage profiles, in concert with extended haplotyping and sequence
data across the whole MHC region, will assist clarification of this issue.

Infection susceptibility genes

The histopathological and immunological similarities between sarcoidosis and
infectious granulomatous diseases, such as tuberculosis, have led to several studies
attempting to associate sarcoidosis with allelic variations in genes necessary for innate
immunity (table 4).

70
 Table 4. Non-human leukocyte antigen class I/II associations

Gene Population Sample size Susceptibility Protection Phenotype associations Reference

patients/controls associations associations
TNF-a 101/216 TNFA2 (-308A) Lofgrens SEITZER [42]
UK and Dutch 196/576 -857T TNFA2 Lofgrens GRUTTERS [43]
UK and Dutch 228 (46 Lofgrens) TNFA2 Lofgrens GRUTTERS [44]
-857T severe disease
TNF-b Japanese 110/161 TNFB*1 prolonged disease YAMAGUCHI [45]
IL-1a Czech 95/199 -889C/C homozygotes HUTYROVA [46]#
IL-18 Japanese 119/130 -607C TAKADA [47]
MIF Spanish 28 with EN/122 -173C EN AMOLI [48]
IkB-a UK and Dutch 205/201 -297T -826T mild disease ABDALLAH [49]
CCR2 Japanese 100/122 V64I HIZAWA [50]#

71
Dutch 137 (47 Lofgrens)/167 Haplotype 2 (-6752A, 3000A, SPAGNOLO [51]
3547T, 4385T) Lofgrens
GENETICS

CCR5 Czech 66/386 CCR5D32 CCR5D32 severe disease PETREK [52]

RANTES Japanese 114/136 -403A/A homozygotes severe TAKADA [53]
disease
VDR Japanese B allele intron 8 NIIMI [54]
NRAMP African Americans 157/111 59(CA)n 120bp allele MALIARIK [55]
TAP2 UK 117/290 565T FOLEY [56]#
665A
Polish 87/158 379V FOLEY [56]#
CR1 Italian 91/94 5507G/G homozygotes ZORZETTO [57]
ACE African Americans 183/111 Deletion polymorphism MALIARIK [58]#
intron 16
TNF: Tumour necrosis factor; IL: interleukin; MIF: macrophage migration inhibitory factor; IkB: inhibitor protein kappa B; CCR: CC chemokine receptor; RANTES: regulated
on activation, normal T-cell expressed and secreted; VDR: vitamin D receptor; NRAMP: natural resistance-assisted macrophage protein; TAP: transporter associated with
antigen processing; CR: complement receptor; ACE: angiotensin-coverting enzyme; EN: erythema nodosum. #: not replicated in subsequent studies.
 R.M. DU BOIS ET AL.

Mannose binding lectin. Mannose binding lectin (MBL) is a serum protein that binds
oligosaccharides on the surface of pathogens, and triggers complement activation. Foley
et al. [59] studied the MBL gene promoter and exon 1 variants known to decrease serum
levels of MBL and increase susceptibility to infection. No associations were found in 167
British patients and 164 controls between these MBL gene variants and susceptibility to
sarcoidosis, age of disease onset, or severity of disease.

Vitamin D receptor. 1,25-dihydroxycholecalciferal (1,25-DHCC) binds the nuclear

vitamin D receptor (VDR). As well as its role in calcium homeostasis, it has an
immunoregulatory effect, and polymorphisms within the VDR gene on chromosome 12
have been linked to susceptibility to infections, such as tuberculosis and leprosy [60]. 1,25-
DHCC is known to inhibit Mycobacterium tuberculosis growth in human macrophages
and monocytes. Pulmonary macrophages from sarcoidosis patients show an increased
capacity to synthesise 1,25-DHCC, and it then acts on other macrophages, inducing
intracellular adhesion molecule (ICAM)-1 expression, and reducing TNF-a release [61]. It
is known that 1,25-DHCC is produced at sites of granulomatous inflammation in
sarcoidosis and that this is responsible for the hypercalcaemia seen in 10% of patients. A
biallelic polymorphism in intron 8 accounts for three genotypes, bb, bB, and BB. The
more common bb genotype is associated with reduced VDR mRNA expression. One
Japanese study has found an association between susceptibility to sarcoidosis, and the
presence of the bB genotype and B allele [54]. However, this study found no correlation of
genotype with severity or spread of the disease.

Natural resistance-associated macrophage protein

The gene encoding for natural resistance-assisted macrophage protein (NRAMP) was
first identified in a murine model resistant to infection by the intracellular parasites
leishmania, salmonella and mycobacteria. A single nonconservative amino acid
substitution of aspartate for glycine at position 169 (within the second predicted
transmembrane domain) confers susceptibility to infection, and Nramp1 gene-disrupted
mice are susceptible to all three pathogens [6264]. Resistance is restored in transgenic
mice when the Nramp1G169 allele is transferred, proving that Nramp1 is vital in mice to
protect against mycobacteria and other intracellular pathogens [65].
NRAMP1 (solute carrier family 11 (proton-coupled divalent metal ion transporters),
member 1 (SLC11A1)) is the human equivalent of this gene. It has been mapped to
human chromosome 2q35 [66, 67]. The function of the NRAMP1 gene product remains
uncertain, but the gene is expressed only in reticuloendothelial cells. The NRAMP family
is conserved from prokaryotes to eukaryotes. It has been suggested that it has a role in
controlling the phagolysosomal environment, possibly by regulating the concentration of
divalent cations, such as iron or manganese.
Bellamy et al. [68] typed NRAMP1 polymorphisms in 410 patients with smear-
positive pulmonary tuberculosis and 417 controls in West Africa. They found
associations between smear-positive tuberculosis and heterozygosity for two
NRAMP1 polymorphisms in intron 4 and the 39 untranslated region.
The putative role of NRAMP1 in macrophage activation, and the association of
genetic polymorphisms with susceptibility to tuberculosis in humans, makes it an
attractive candidate gene in sarcoidosis. Maliarik et al. [55] analysed several NRAMP1
gene polymorphisms in 157 African Americans with sarcoidosis and 111 ethnically
matched controls. They identified a statistically significant difference in allele frequency
distribution of 59(CA)n alleles between patients and controls. The commonest 120-bp
allele was over-represented in the sarcoidosis patients, suggesting that the polymorphism

72
 GENETICS

at this site is protective against sarcoidosis. Interestingly, the two variants that were
associated with susceptibility to tuberculosis did not affect susceptibility to sarcoidosis in
this study. Its role in sarcoidosis susceptibility is uncertain.

Transporter associated with antigen processing. Transporter associated with antigen

processing (TAP)1 and TAP2 genes, located in the Class II MHC region, encode subunits of
a heterodimeric complex that function in the endogenous antigen-processing pathway. TAP
is inserted into the membrane of the endoplasmic reticulum, and facilitates the transport of
proteosome-generated antigenic peptide fragments from the cytosol into the lumen of the
endoplasmic reticulum, for subsequent presentation of the peptides in association with
MHC class I molecules [69]. One study examined two SNPs in TAP1 and three SNPs in
TAP2, in 117 UK Caucasions with 290 UK controls and in 87 Polish-Slavonic patients with
158 Polish controls [56]. They found different associations with different TAP2 variants in
the two ethnically diverse populations studied. In the UK population, a threonine variant at
position 565 and an alanine variant at position 665 were found to be significantly under-
represented in the patient groups. By contrast, they failed to find these differences in the
Polish population; in this group the valine variant at position 379 was under-represented.
The location of these genes in the MHC class II region suggests that these associations could
be due to linkage disequilibrium, but significant linkage disequilibrium was not found either
between the TAP1 and TAP2 loci or between TAP variants and HLA-DPB1 variants.
However, in Japanese patients no associations were found between TAP1 or TAP2
polymorphisms and disease susceptibility [70].

Complement receptor 1. Complement receptor (CR)1 is a membrane protein expressed on

erythrocytes, phagocytes, lymphocytes and dendritic cells that plays a number of roles in the
complement system. CR1 on erythrocytes mediates the transport of immune complexes
through the bloodstream to phagocytes in the liver and spleen. As sarcoidosis is
accompanied by a polyclonal hypergammaglobulinaemia, it could be hypothesised that
interaction with the sarcoid antigen could lead to immune complex formation that may be
involved in the pathogenesis of the disease and immune complexes have been shown to be
present in this disease. The CR1 gene on chromosome 17 is known to contain a number of
SNPs that can be correlated with high or low expression of CR1 on erythrocytes. A study of
91 Italian sarcoidosis patients compared with ethnically matched controls demonstrated a
significant association between the GG genotype at the C5507G polymorphism and
sarcoidosis [57]. This association was even stronger when the female subgroup was analysed
separately. This allele is known to be associated with low CR1 expression on erythrocytes,
and Zorzetto et al. [57] postulated that reduced clearance of immune complexes could lead
to deposition outside the reticuloendothelial system with the consequent granulomatous
inflammation characteristic of sarcoidosis. However, these findings have not been found in
other studies (the present authors unpublished observations).

Angiotensin-converting enzyme
Concentrations of serum angiotensin-converting enzyme (ACE) are above normal in
onlyy60% of patients with sarcoidosis. A 287-bp insertion/deletion (I/D) polymorphism
in intron 16 of the ACE gene has been reported to account for 47% of the phenotypic
variation in serum ACE levels; the DD genotype is associated with the highest serum
levels in patients and controls and the II genotype with the lowest [71]. However, no
consistent correlation between ACE I/D polymorphisms and disease prevalence or
severity have been demonstrated. In the most recent study, McGrath et al. [72]
summarise the previous studies in this area. They also genotyped 118 UK and 56 Czech

73
 R.M. DU BOIS ET AL.

patients with sarcoidosis, and attempted to correlate ACE I/D polymorphisms with
disease susceptibility and pulmonary disease severity or progression at 2 and 4 yrs from
presentation. They found no such associations and concluded that this ACE gene
polymorphism has no effect on disease susceptibility or progression in European Whites.
By contrast, in an African-American population, an excess of D alleles was found in
183 cases compared with 111 controls, and a gene dosage effect was seen causing an
increased risk of sarcoidosis in DD homozygotes that was higher than the increased risk
in ID heterozygotes [58]. ACE genotype did not appear to influence disease severity or
progression. This same study showed no difference in allele distribution between 60
Caucasian cases and 48 controls. In summary, there is little strong evidence to relate this
particular polymorphism with either disease presence or severity.

Cytokines
Cytokines are appealing candidate genes, alleles that may affect cytokine levels, may
modify disease pathogenesis and, therefore, susceptibility to disease, and/or the clinical
course [73]. Many case-control studies have picked a candidate gene and speculatively
genotyped for allelic variations; table 4 details the positive reports to date.

Tumour necrosis factor. The TNF gene complex is located within the MHC complex,
and includes the TNF-a and TNF-b (lymphotoxin a) genes. TNF is an early cytokine in
the pathogenetic cascade in sarcoidosis, and the many studies linking sarcoidosis to the
MHC complex have aroused much interest in the genes of the TNF gene complex as
further candidate susceptibility genes.
Early studies explored two biallelic markers in the TNF-a gene (G to A at position -308,
known as TNFA) and the TNF-b gene (in the first intron, known as TNFB). Both have
been shown to affect cytokine production and the former has been linked to granulomatous
disease caused by beryllium [74]. The less common TNFA2 allele (-308A), associated with
high TNF-a production, was first linked with Lofgrens syndrome in a study of 101 patients
with pulmonary sarcoidosis (including 16 Lofgrens patients) compared with 216 healthy
controls [42]. This same study found no association of either polymorphism with the
sarcoidosis group as a whole. A survey of 110 Japanese patients (in whom Lofgrens
syndrome is extremely rare) and 161 controls also found no associations between either of
these polymorphisms and susceptibility to sarcoidosis as a whole [45]. However, this study
did find the TNFB1 allele to be correlated with a prolonged clinical course, with carriage of
this allele significantly prolonging the time to spontaneous disease resolution. Prolonged
disease must be distinguished from severe disease; this association was present in patients
who did not require corticosteroid therapy for severe symptoms or organ-threatening
disease despite a prolonged disease course. Yamaguchi et al. [45] noted that TNFB1 has
been associated with increased production of both TNF-b and TNF-a, so this
polymorphism could have a functional role in sarcoidosis.
The association between Lofgrens syndrome and TNFA2 has been confirmed in a
more recent study of 196 British and Dutch patients and 576 controls [43]. This study
looked at five bi-allelic TNF promoter polymorphisms, including the G to A allele at
position -308 (now renumbered as position -307). This less common TNFA2 allele was
not associated with sarcoidosis susceptibility overall, but was significantly associated
with the Lofgrens subgroup (n=15). However, a highly significant increase in the TNF-a
-857T allele was found in the sarcoidosis patient group overall. Of the sarcoid patients,
25.5% carried the TNF -857T allele compared with 14.1% of controls; allele frequency
was 13.5% in cases versus 7.3% in controls. This allele has been associated with higher
transcriptional promoter activity.

74
 GENETICS

Interestingly, this allele was not associated with Lofgrens patients; in fact there was a
trend towards it being under-represented in this subgroup. In a follow-up study of 228
sarcoidosis patients including 46 Lofgrens, six haplotypes were constructed across the
five polymorphisms studied in the TNF-a promoter [44]. The -307A allele associated with
Lofgrens syndrome occurred exclusively in haplotype 2. The -857T allele associated with
sarcoidosis susceptibility, but under-represented in the Lofgrens group, occurred
exclusively in haplotype 4. There was a very strong association between haplotype 2 and
stage I disease with EN, including Lofgrens patients (p=6.6610-11) and with favourable
radiological evolution over 4 yrs. By contrast, haplotype 4 was strongly associated with
stages IIIV disease (pcv0.01) and with unfavourable radiological evolution over 4 yrs.
An association between cardiac sarcoidosis and the TNFA2 allele in Japanese was
found to be due to linkage disequilibrium with the HLA-DQB1*0601 allele [33, 41]. It
remains unclear whether TNF associations are functional polymorphisms, or whether
one or both are in linkage disequilibrium with another site elsewhere in the MHC region.

Interleukin-1. Rybicki et al. [75] studied six polymorphic markers that are closely linked
to certain candidate cytokine genes in African-Americans and identified two alleles that
may be associated with sarcoidosis. If both the IL-1a*137 and F13A*188 alleles were
present, there was a six-fold increased risk of sarcoidosis, rising to a 15-fold increase in
patients with a family history of sarcoidosis. The F13A marker is close to the gene for
IRF-4 (a member of the interferon (IFN) regulatory factor family, a transcription factor).
The importance of IL-1 in granulomatous inflammation is well known; less is known
about the role of IRF-4.
A Czech case-control study investigated polymorphisms within the IL-1 gene cluster
on chromosome 2q1321 [46]. They studied bi-allelic polymorphisms in the IL-1a and
IL-1b genes, and an 86-bp variable number tandem repeat polymorphism in intron 2 of
the IL-1 receptor antagonist (IL-1RN). They found an increase in the IL-1a -889 1.1
genotype (C/C homozygotes) in 95 patients with sarcoidosis compared with 199 controls
(60.0% versus 44.2%, p=0.012). There was a corresponding fall in the number of IL-1a
-889 1.2 (C/T) heterozygotes (32.6% versus 47.7%, p=0.015). The RR of disease for IL-1a
-889 1.1 homozygotes compared with 1.2 heterozygotes or 2.2 homozygotes was 1.9. This
finding was consistent with the study by Rybicki et al. [75] in African-Americans.
However, a study of this same polymorphism in 147 UK patients with 101 UK controls
and 102 Dutch patients with 166 controls failed to reproduce this association in either
population [76]. This led Rybicki et al. [75] to surmise that the previously reported
associations may have been due to linkage disequilibrium within the IL-1 gene cluster
between the IL-1a -889C allele and the unidentified locus that actually confers the risk of
sarcoidosis. Population-dependent differences in linkage could explain the failure to
reproduce this finding in UK and Dutch populations.

Interleukin-18. IL-18 is known to act synergistically with IL-12 to induce IFN-c

production from T-helper type 1 cells. It is constitutively expressed in healthy airway
epithelium and this expression is increased in sarcoidosis tissue. Serum and
bronchoalveolar lavage (BAL) levels of IL-18 are high in sarcoidosis patients.
Therefore, it is an attractive candidate.
One Japanese study genotyped 119 patients with sarcoidosis and 130 controls for two
polymorphisms in the gene promoter known to affect promoter activity after stimulation
[47]. They found a significant increase in the percentage of patients carrying the C allele
at position -607. This position may be a binding site for the cAMP-responsive element
binding protein (CREB), and it is postulated that the A allele at this position may

75
 R.M. DU BOIS ET AL.

interfere with CREB binding, leading to a reduction in responsiveness with subsequent

reduced IL-18 expression.

Macrophage migration inhibitory factor. Macrophage migration inhibitory factor is

known to stimulate T-cells and drive the delayed type hypersensitivity reaction;
polymorphisms in this gene have been investigated in a cohort of Spanish patients with
EN [48]. A SNP at position -173 (G to C) was genotyped in 28 patients with sarcoidosis-
associated EN, 70 patients with EN of other aetiologies, and 122 healthy controls. The C
mutant allele was significantly over-represented in the sarcoidosis EN group compared
with the nonsarcoid EN group and with controls. Patients with EN carrying this allele
were at increased risk of having sarcoidosis compared with EN patients without this allele.
This G to C transition in the 59-flanking region of the gene creates an AP-4 binding site
and may, therefore, be of functional significance in controlling transcription.

Inhibitor kappa B-alpha. Nuclear factor (NF)-kB transcription is one of several factors
that influence cytokine gene expression. Activation of this signalling pathway occurs in
several of the components of the sarcoidosis pathogenetic process. In the resting cell, NF-
kB is retained in the cell cytoplasm by the bound inhibitor (I)kB. This inhibitor protein
degrades upon phosphorylation, unmasking the nuclear localisation sequence of NFk-B,
allowing nuclear localisation and initiation of transcription. IkB-a, a IkB protein that is
essential for normal termination of the NF-kB response, has three single nucleotide
polymorphisms in the promoter region of its gene on chromosome 14. A total of 205 UK
and Dutch sarcoidosis patients were genotyped for these polymorphisms and compared
with 201 controls [49]. The T allele at position -297 was strongly associated with disease
susceptibility (p=0.008). By contrast, this allele was not associated with disease severity as
measured by radiographic staging and pulmonary function test indices. However, the
frequency of the T allele at position -826 progressively decreased across the chest
radiographic stages of sarcoidosis IIIV, suggesting that it could be protective against
fibrotic disease. The functional effects of these polymorphisms are not known.

Chemokines
A number of chemokines (and their receptors) play a role in the pathogenesis of
sarcoidosis. These include regulated on activation, normal T-lymphocyte expressed and
secreted (RANTES), monocyte chemoattractant protein (MCP)-1 and macrophage
inflammatory protein (MIP)-1a; all are known to be released by alveolar macrophages
and increased levels may correlate with disease severity (table 4).

C-C chemokine receptor 2. C-C chemokine receptor (CCR) 2 is a receptor for the MCP
family. This receptor also acts as a co-receptor for HIV infection. A SNP in the CCR2
gene at position 64 substitutes isoleucine for valine (V64I). This polymorphism has a
protective effect against progression of HIV infection to AIDS. It was first studied in
sarcoidosis in a Japanese population, and the V64I allele was found to be associated with a
lower risk of sarcoidosis in 100 patients compared with 122 controls (pv0.0017) [50]. This
same polymorphism was studied in 65 Czech patients and 80 controls [52]. The allelic
frequency of the polymorphism was again reduced in patients compared with controls,
but did not reach statistical significance (6.9% versus 11.9%; p=0.17).
Spagnolo et al. [51] investigated the CCR2 gene in more detail, genotyping 304 Dutch
individuals (90 non-Lofgrens sarcoid, 47 Lofgrens syndrome, 167 controls) for eight
SNPs (including V64I) across the whole gene. When analysing all sarcoidosis patients
together, no statistically significant differences in any of the allele frequencies were

76
 GENETICS

found. However, analysing the Lofgrens syndrome patients separately, strongly

significant associations were found with five of these alleles when compared both with
the healthy controls and also when compared with the non-Lofgrens sarcoidosis
patients. The V64I polymorphism was not one of the alleles showing association with
Lofgrens syndrome. They were able to construct nine haplotypes from the eight
polymorphisms. In patients with Lofgrens syndrome, a strongly significant increase in
the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide
position -6752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with
control subjects (74% versus 38%, respectively; pv0.0001), whereas no difference was
found between non-Lofgrens sarcoidosis and control subjects (both 38%). The
association remained strong after correcting for two other known associations with
Lofgrens syndrome, female sex and carriage of HLA haplotype DRB1*0301-
DQB1*0201. It remains unclear how this association should be interpreted; it is not
yet known which of the polymorphisms has a functional effect that could explain the
association, or whether the functional effect is due to an as yet unidentified
polymorphism in the CCR2 gene or a neighbouring gene that is in linkage disequilibrium
with this CCR2 gene haplotype. It also remains unclear whether this CCR2 haplotype
predisposes to Lofgrens in all carriers, or only in those positive for HLA DRB1*0301-
DQB1*0201. In Lofgrens patients negative for HLA DRB1*0301-DQB1*0201, the
CCR2 haplotype did not appear to be more common but the number of subjects in this
subgroup was too small for definitive statistical conclusions to be drawn.

C-C chemokine receptor 5. CCR5 acts as a receptor for the chemokines RANTES and
MIP-1a. A 32-bp deletion in the gene (CCR5D32) renders the surface receptor molecule
nonfunctional. In a study of 66 Czech sarcoidosis patients and 386 controls, this allele was
significantly more common in patients [52]. Furthermore, this allele was associated with
clinically more apparent disease; it was present in 39.1% of patients requiring
corticosteroids but in only 16.7% of patients who needed no treatment. This study
implicates the CCR5 gene as affecting both disease susceptibility and severity.

RANTES (C-C chemokine ligand 5). RANTES, a member of the C-C chemokine
family, is produced at sites of granulomatous reaction and is a potent chemoattractant for
lymphocytes, monocytes and eosinophils. A Japanese study genotyped 114 sarcoidosis
patients and 136 healthy controls for an A/G SNP at position -403 in the promoter of the
RANTES gene [53]. Although finding no association between alleles and disease, they did
find the less common AA genotype was associated with disease in three or more organs.
They also found that this genotype was associated with a higher CD4z/CD8zT-cell ratio
in BAL cells than the GA or GG genotypes. They postulate that homozygosity for the A
allele may be a risk factor for more extensive disease in Japanese patients.

Conclusion
In summary, the strongest associations between genotype and phenotype in
sarcoidosis are found in the MHC complex region of chromosome 6. Other candidate
loci are less appealing and most associations have either not been reproducible or
validated functionally. The future will demand very precise phenotyping as part of a
trans-ethnic approach to this disease that will allow subtle differences in linkage in
different ethnic cohorts to be determined, which will help tease out prime associations
from those that are secondary. Familial and case-control studies will provide important
complementary approaches.

77
 R.M. DU BOIS ET AL.

Summary
Although sarcoidosis is described in almost all populations around the world, there
are wide variations in the incidence and prevalence of the different clinical phenotypes,
suggesting genetic influence on disease susceptibility and phenotype. It has emerged
from multiple family and case-control studies that sarcoidosis does indeed have a
significant genetic susceptibility. This review sets out to outline the genetic studies to
date and to highlight key genetic targets and the importance of precise phenotyping.
Despite the study of many logical (and occasionally illogical) loci, the overwhelming
consensus is that the Class II major histocompatability complex (MHC) region of
chromosome 6 is the major association hot spot. In this regard, Lofgrens syndrome
has been strongly associated with an extended MHC haplotype encompassing alleles
in human leukocyte antigen (HLA)-DQ, HLA-DR and tumour necrosis factor,
suggesting that other clinical subtypes and phenotypes might be associated with
different susceptibility genes. In more global sarcoidosis, there is a consistency
evolving from studies around the world that there is a small set of susceptibility HLA-
DR alleles and other alleles that confer protection, possibly in association with an
independent effect from the butyrophilin-like 2 gene.
Other case-control studies using the candidate gene approach have reported some,
generally less convincing, associations with genes encoding for cytokines, chemokines
and infection susceptibility genes. Of these, the chemokine receptor associations are
most promising.
The development of tighter definitions of clinical phenotypes and the emergence of
larger cohort studies of sarcoidosis, including familial sarcoidosis, should combine
with new technological advances to build a clearer picture of the genetics of
sarcoidosis susceptibility and phenotypes in the future.

Keywords: Familial, genetics, human leukocyte antigen, polymorphisms, sarcoidosis.

References
1. Martenstein H. Knochveranderungen bei Lupus pernio. Zentralb Haut Geschlechtskrankh 1923;
7: 308.
2. Hiraga Y. An epidemiological study of clustering of sarcoidosis cases. Nippon Rinsho 1994;
52: 14381442.
3. Pietinalho A, Ohmichi M, Hirasawa M, et al. Familial sarcoidosis in Finland and Hokkaido,
Japan- a comparative study. Respir Med 1999; 93: 408412.
4. Hiraga Y, Hosoda Y, Zenda I. A local outbreak of sarcoidosis in Northern Japan. Z Erkr
Atmungsorgane 1977; 149: 3843.
5. Headings VE, Weston D, Young RC Jr, Hackney RL Jr. Familial sarcoidosis with multiple
occurrences in eleven families: a possible mechanism of inheritance. Ann N Y Acad Sci 1976;
278: 377385.
6. Rybicki BA, Kirkey KL, Major M, et al. Familial risk ratio of sarcoidosis in African-American
sibs and parents. Am J Epidemiol 2001; 153: 188193.
7. McGrath DS, Daniil Z, Foley P, et al. Epidemiology of familial sarcoidosis in the UK. Thorax
2000; 55: 751754.
8. Brennan NJ, Crean P, Long JP, Fitzgerald MX. High prevalence of familial sarcoidosis in an Irish
population. Thorax 1984; 39: 1418.

78
 GENETICS

9. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-
control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001; 164: 2085
2091.
10. Harrington AC, Major M, Rybicki BA, et al. Familial sarcoidosis: analysis of 91 families.
Sarcoidosis 1994; 11: 240243.
11. Schurmann M, Lympany P, Reichel P, et al. Familial sarcoidosis is linked to the major
histocompatibility complex region. Am J Respir Crit Care Med 2000; 162: 861864.
12. Schurmann M, Reichel P, Muller-Myhsok B, et al. Results from a genome-wide search for
predisposing genes in sarcoidosis. Am J Respir Crit Care Med 2001; 164: 840846.
13. Valentonyte R, Hampe J, Huse K, et al. Sarcoidosis is associated with a truncating splice site
mutation in BTNL2. Nat Genet 2005; 27; (In press).
14. Brewerton D, Cockburn C, James D, et al. HLA antigens in sarcoidosis. Clin Exp Immunol 1977;
27: 227229.
15. Olenchock S, Heise E, Marz J, et al. HLA-B8 in sarcoidosis. Ann Allergy 1981; 47: 151153.
16. Lenhart K, Kolek V, Bartova A. HLA antigens associated with sarcoidosis. Dis Markers 1990;
8: 2329.
17. Martinetti M, Tinelli C, Kolek V, et al. "The sarcoidosis map": a joint survey of clinical and
immunogenetic findings in two European countries. Am J Respir Crit Care Med 1995; 152: 557
564.
18. Smith M, Turton C, Mitchell D, et al. Association of HLA-B8 with spontaneous resolution in
sarcoidosis. Thorax 1981; 36: 296298.
19. Ina Y, Takada K, Yamamoto M, et al. HLA and sarcoidosis in the Japanese. Chest 1989;
95: 12571261.
20. McIntyre J, McKee K, Loadholt C, et al. Increased HLA-B7 antigen frequency in South Carolina
blacks in association with sarcoidosis. Transplant Proc 1977; 9: 173176.
21. Grunewald J, Eklund A, Olerup O. Human leukocyte antigen class I alleles and the disease course
in sarcoidosis patients. Am J Respir Crit Care Med 2004; 169: 696702.
22. Kueppers F, Mueller-Eckhardt C, Heinrich D, et al. HL-A antigens of patients with sarcoidosis.
Tissue Antigens 1974; 4: 5658.
23. Eisenberg H, Terasaki P, Sharma O, Mickey M. HLA association studies in black sarcoidosis
patients. Tissue Antigens 1978; 11: 484486.
24. Ishihara M, Inoko H, Suzuki K, et al. HLA class II genotyping of sarcoidosis patients in
Hokkaido by PCR-RFLP. Jpn J Ophthalmol 1996; 40: 540543.
25. Nowack D, Goebel KM. Genetic aspects of sarcoidosis. Class II histocompatibility antigens and a
family study. Arch Intern Med 1987; 147: 481483.
26. Swider C, Schnittger L, Bogunia-Kubik K, et al. TNF-alpha and HLA-DR genotyping as
potential prognostic markers in pulmonary sarcoidosis. Eur Cytokine Netw 1999; 10: 143146.
27. Berlin M, Fogdell-Hahn A, Olerup O, et al. HLA-DR predicts the prognosis in Scandinavian
patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 1997; 156: 16011605.
28. Sharma SK, Balamurugan A, Pandey RM, et al. Human leukocyte antigen-DR alleles influence
the clinical course of pulmonary sarcoidosis in Asian Indians. Am J Respir Cell Mol Biol 2003;
29: 225231.
29. Foley P, McGrath D, Petrek M, et al. HLA-DRB1 position 11 residues are a common protective
marker for sarcoidosis. Am J Respir Crit Care Med 2000; 161: A826.
30. Rossman MD, Thompson B, Frederick M, et al. HLA-DRB1*1101: a significant risk factor for
sarcoidosis in blacks and whites. Am J Hum Genet 2003; 73: 720735.
31. Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA. Sarcoidosis susceptibility and resistance
HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med 2003; 167: 12251231.
32. Sato H, Grutters JC, Pantelidis P, et al. HLA-DQB1*0201: a marker for good prognosis in British
and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol 2002; 27: 406412.
33. Naruse TK, Matsuzawa Y, Ota M, et al. HLA-DQB1*0601 is primarily associated with the
susceptibility to cardiac sarcoidosis. Tissue Antigens 2000; 56: 5257.

79
 R.M. DU BOIS ET AL.

34. Voorter CEM, Drent M, Hoitsma E, Faber CG, van den Berg-Loonen PM. Association of HLA
DQB1 in sarcoidosis patients with small fiber neuropathy. Sarcoidosis Vasc Diffuse Lung Dis 2005;
22: 129133.
35. Ishihara M, Ishida T, Inoko H, et al. HLA serological and class II genotyping in sarcoidosis
patients in Japan. Jpn J Ophthalmol 1996; 40: 8694.
36. Foley PJ, Lympany P, Puscinska E, et al. HLA-DPB1 and TAP1 polymorphisms in sarcoidosis.
Chest 1997; 111: Suppl. 6, 73S.
37. Maliarik MJ, Chen KM, Major ML, et al. Analysis of HLA-DPB1 polymorphisms in African-
Americans with sarcoidosis. Am J Respir Crit Care Med 1998; 158: 111114.
38. Rybicki BA, Maliarik MJ, Poisson LM, et al. The major histocompatibility complex gene region
and sarcoidosis susceptibility in African Americans. Am J Respir Crit Care Med 2003; 167: 444
449.
39. Voorter CEM, Drent M, van den Berg-Loonen PM. Severe sarcoidosis is strongly associated with
the haplotype HLA-DQB1*0602 - DQB1*150101. Hum Immunol 2005; (In press).
40. Grutters JC, Ruven HJT, Sato H, et al. MHC haplotype analysis in Dutch sarcoidosis patients
presenting with Lofgrens syndrome. In: Grutters JC, ed. Genetic polymorphisms and phenotypes
in sarcoidosis. Utrecht, Thesis University Utrecht, 2003: pp. 8596.
41. Takashige N, Naruse TK, Matsumori A, et al. Genetic polymorphisms at the tumour necrosis
factor loci (TNFA and TNFB) in cardiac sarcoidosis. Tissue Antigens 1999; 54: 191193.
42. Seitzer U, Swider C, Stuber F, et al. Tumour necrosis factor alpha promoter gene polymorphism in
sarcoidosis. Cytokine 1997; 9: 787790.
43. Grutters JC, Sato H, Pantelidis P, et al. Increased frequency of the uncommon tumor necrosis
factor -857T allele in British and Dutch patients with sarcoidosis. Am J Respir Crit Care Med 2002;
165: 11191124.
44. Grutters JC, Ruven HJT, Sato H, et al. TNF promoter haplotypes associate with clinical
phenotypes and prognosis in sarcoidosis. In: Grutters JC, ed. Genetic polymorphisms and
phenotypes in sarcoidosis. Utrecht, Thesis University Utrecht, 2003: pp. 4966.
45. Yamaguchi E, Itoh A, Hizawa N, Kawakami Y. The gene polymorphism of tumor necrosis factor-
beta, but not that of tumor necrosis factor-alpha, is associated with the prognosis of sarcoidosis.
Chest 2001; 119: 753761.
46. Hutyrova B, Pantelidis P, Drabek J, et al. Interleukin-1 gene cluster polymorphisms in sarcoidosis
and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2002; 165: 148151.
47. Takada T, Suzuki E, Morohash K, Gejyo F. Association of single nucleotide polymorphisms in
the IL-18 gene with sarcoidosis in a Japanese population. Tissue Antigens 2002; 60: 3642.
48. Amoli MM, Donn RP, Thomson W, et al. Macrophage migration inhibitory factor gene
polymorphism is associated with sarcoidosis in biopsy proven erythema nodosum. J Rheumatol
2002; 29: 16711673.
49. Abdallah A, Sato H, Grutters JC, et al. Inhibitor kappa B-alpha (IkappaB-alpha) promoter
polymorphisms in UK and Dutch sarcoidosis. Genes Immunol 2003; 4: 450454.
50. Hizawa N, Yamaguchi E, Furuya K, et al. The role of the C-C chemokine receptor 2 gene
polymorphism V64I (CCR2-64I) in sarcoidosis in a Japanese population. Am J Respir Crit Care
Med 1999; 159: 20212023.
51. Spagnolo P, Renzoni EA, Wells AU, et al. C-C chemokine receptor 2 and sarcoidosis: association
with Lofgrens syndrome. Am J Respir Crit Care Med 2003; 168: 11621166.
52. Petrek M, Drabek J, Kolek V, et al. CC chemokine receptor gene polymorphisms in Czech patients
with pulmonary sarcoidosis. Am J Respir Crit Care Med 2000; 162: 10001003.
53. Takada T, Suzuki E, Ishida T, et al. Polymorphism in RANTES chemokine promoter affects
extent of sarcoidosis in a Japanese population. Tissue Antigens 2001; 58: 293298.
54. Niimi T, Tomita H, Sato S, et al. Vitamin D receptor gene polymorphism in patients with
sarcoidosis. Am J Respir Crit Care Med 1999; 160: 11071109.
55. Maliarik MJ, Chen KM, Sheffer RG, et al. The natural resistance-associated macrophage protein
gene in African Americans with sarcoidosis. Am J Respir Cell Mol Biol 2000; 22: 672675.

80
 GENETICS

56. Foley PJ, Lympany PA, Puscinska E, et al. Analysis of MHC encoded antigen-processing genes
TAP1 and TAP2 polymorphisms in sarcoidosis. Am J Respir Crit Care Med 1999; 160: 10091014.
57. Zorzetto M, Bombieri C, Ferrarotti I, et al. Complement receptor 1 gene polymorphisms in
sarcoidosis. Am J Respir Cell Mol Biol 2002; 27: 1723.
58. Maliarik MJ, Rybicki BA, Malvitz E, et al. Angiotensin-converting enzyme gene polymorphism
and risk of sarcoidosis. Am J Respir Crit Care Med 1998; 158: 15661570.
59. Foley P, Mullighan C, McGrath D, et al. Mannose-binding lectin promoter and structural gene
variants in sarcoidosis. Eur J Clin Invest 2000; 30: 549552.
60. Fraser D. Vitamin D. Lancet 1995; 345: 104107.
61. Braun J, Dinkelacker C, Bohnet S, et al. 1,25-dihydroxycholecalciferol stimulates ICAM-1
expression of human alveolar macrophages in healthy controls and patients with sarcoidosis. Lung
1999; 177: 139149.
62. Vidal S, Malo D, Vogan K, et al. Natural resistance to infection with intracellular parasites:
isolation of a candidate for Bcg. Cell 1993; 73: 469485.
63. Malo D, Vogan K, Vidal S, et al. Haplotype mapping and sequence analysis of the mouse Nramp
gene predict susceptibility to infection with intracellular parasites. Genomics 1994; 23: 5161.
64. Vidal S, Tremblay M, Govoni G, et al. The Ity/Lsh/Bcg locus: natural resistance to infection with
intracellular parasites is abrogated by disruption of the Nramp1 gene. J Exp Med 1995; 182: 655
666.
65. Govoni G, Vidal S, Gauthier S, et al. The Bcg/Ity/Lsh locus: genetic transfer of resistance to
infections in C57BL/6J mice transgenic for the Nramp1Gly169 allele. Infect Immun 1996; 64: 2923
2929.
66. Cellier M, Govoni G, Vidal S, et al. Human natural resistance-associated macrophage protein:
cDNA cloning, chromosomal mapping, genomic organisation, and tissue-specific expression. J
Exp Med 1994; 180: 17411752.
67. Blackwell J, Barton C, White J, et al. Genomic organisation and sequence of the human NRAMP
gene: identification and mapping of a promoter region polymorphism. Mol Med 1995; 1: 194205.
68. Bellamy R, Ruwende C, Corrah T, et al. Variations in the NRAMP1 gene and susceptibility to
tuberculosis in West Africans. N Engl J Med 1998; 338: 640644.
69. Kelly A, Powis SH, Kerr LA, et al. Assembly and function of the two ABC transporter proteins
encoded in the Human Major Histocompatibility Complex. Nature 1992; 335: 641644.
70. Ishihara M, Ohno S, Mizuki N, et al. Genetic polymorphisms of the major histocompatibility
complex-encoded antigen-processing genes TAP and LMP in sarcoidosis. Hum Immunol 1996;
45: 105110.
71. Arbustini E, Grasso M, Leo G, et al. Polymorphism of angiotensin-converting enzyme gene in
sarcoidosis. Am J Respir Crit Care Med 1996; 153: 851854.
72. McGrath DS, Foley PJ, Petrek M, et al. Ace gene I/D polymorphism and sarcoidosis pulmonary
disease severity. Am J Respir Crit Care Med 2001; 164: 197201.
73. Luisetti M, Beretta A, Casali L. Genetic aspects in sarcoidosis. Eur Respir J 2000; 16: 768780.
74. Somoskovi A, Zissel G, Seitzer U, et al. Polymorphisms at position -308 in the promoter region of
the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and
lipopolysaccharide-induced TNF-alpha release in sarcoidosis. Cytokine 1999; 11: 882887.
75. Rybicki B, Maliarik M, Malvitz E, et al. The influence of T cell receptor and cytokine genes on
sarcoidosis susceptibility in African Americans. Hum Immunol 1999; 60: 867874.
76. Grutters JC, Sato H, Pantelidis P, et al. Analysis of IL6 and IL1A gene polymorphisms in UK and
Dutch patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 2027.

81
CHAPTER 6

Pathology

V. Poletti*, G. Casoni*, M. Chilosi#

#
*Dept of Diseases of the Thorax, Ospedale GB Morgagni, Forli, and Dept of Anatomic Pathology,
Universita` di Verona, Verona, Italy.

Correspondence: V. Poletti, Dept of Diseases of the Thorax, U.O. di Pneumologia Interventistica,

Ospedale GB Morgagni, Via Forlanini 34, 47100 Forli, Italy. Fax: 39 0543735882; E-mail: vepolet@tin.it

From the pathological point of view, sarcoidosis is characterised by the formation of

small, granular inflammatory lesions (granulomas). The word "granuloma" comes from
the Latin word "granum," meaning grain or seed. This characteristic lesion of sarcoidosis
is a discrete, compact, noncaseating epithelioid cell granuloma (fig. 1a and b).
The epithelioid cell granulomas consist of highly differentiated mononuclear
phagocytes (epithelioid cells and giant cells) and lymphocytes (fig. 2a). The central
portion of the granuloma consists predominantly of CD4zlymphocytes, whereas CD8z
lymphocytes are mainly located in the peripheral zone [13]. A proportion of these CD4z
lymphocytes exhibit a "memory" phenotype, as defined by the expression of CD45RO, as
well as proliferation and activation markers (Ki67, CD25) [3, 4]. Sarcoid granulomas
may develop fibrotic changes that usually begin at the periphery and travel centrally,
ending with complete fibrosis and/or hyalinisation. Granulomas may occasionally exhibit
focal coagulative necrosis [1]. It has been suggested that necrotising sarcoid
granulomatosis may be a variant of sarcoidosis [2]. On electron microscopy, well
developed epithelioid cells show numerous cytoplasmic projections with frequent
interdigitations. The morphology suggests a secretory function [1, 5]. These cytoplasmic
inclusions, including basophilic calcifications (Schaumanns bodies) and lucent,
birefringent calcium oxalate crystals, can be valued using polarising microscopy.
The morphological diagnosis of pulmonary sarcoidosis relies on three main findings:
1) the presence of tight, well-formed granulomas and a rim of lymphocytes and fibro-
blasts in the outer margin of granulomas; 2) perilymphatic interstitial distribution of

a) b)

Fig. 1. Pulmonary sarcoidosis: numerous large epithelioid granulomas are present, mainly located along
lymphatic routes (a and b). Haematoxylin and eosin staining. b) Scale bar=10 mm.

Eur Respir Mon, 2005, 32, 8291. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
82
 PATHOLOGY

a) b)

c) d)

Fig. 2. a) The morphology of granuloma is evidenciated at higher magnification, including numerous

epithelioid macrophages, a giant cell and a minority of lymphocytes. b) The location of a granuloma near a
lymphatic vessel is evidenciated by immunostaining for podoplanin (a marker of lymphatic endothelium). c) All
lymphocytes associated to macrophages within a granuloma all T-cells, as defined by their expression of CD3.
d) CD68 expression in epithelioid and giant cells.

granulomas (which allows transbronchial biopsies to be used as sensitive diagnostic

tools; fig. 2b and c); and 3) exclusion of an alternate cause [67]. The granulomas are
distributed along the pulmonary lymphatics, in the pleura and septa and along
pulmonary arteries, veins, and bronchi. This distribution along lymphatic routes is one of
the most helpful features in recognising sarcoidosis and in distinguishing it from other
forms of granulomatous pulmonary disease. Small foci of fibrinoid necrosis may be seen
in the granulomas. The extent of granulomas identified histologically often correlate with
the changes on chest radiograph, but do not necessarily correlate with pulmonary
function tests [5]. Lung tissue from patients with sarcoidosis demonstrated at an
extrapulmonary site and normal chest radiographs often show scattered granulomas,
either singly or as small confluent masses along lymphatic routes, too small to be
radiographically visible, especially on conventional chest radiographs. More than half
the cases of pulmonary sarcoidosis show histological involvement of pulmonary arteries
or veins or both [1, 4, 8]. However, pulmonary hypertension caused by extensive vascular
involvement in sarcoidosis is extremely rare [911]. More often, pulmonary hypertension
in sarcoidosis is related to massive lung fibrosis and honeycombing, with loss of more
than half the capillary bed. Small and large airways can also be involved by granulomas,
and measurable airflow obstruction occurs in a small percentage of cases [12, 13], with
segmental bronchial stenoses being a frequent cause. Granulomas in the mucosa and the

83
 V. POLETTI ET AL.

submucosa of large airways may be visible as multiple small nodules at bronchoscopy.

The presence of granulomas in the pleura of patients with sarcoidosis is relatively
common, although clinical evidence of pleural disease is quite unusual [14]. Fewer than
10% of patients have evidence of a pleural effusion, which may be small, asymptomatic,
and transient, or massive and associated with significant symptoms [15]. Kanada et al.
[16] described a case of sarcoidosis in which there was massive pleural thickening by
granulomas and severe respiratory compromise.
Various other diseases can cause the formation of granulomas. In tuberculosis, the
centres of the granulomas become so isolated that the cells probably die for a variety of
causes, including oxygen shortage and accumulation of toxic substances produced by the
macrophages and leukocytes that make up the granuloma (e.g. tumour necrosis factor).
The dead tissue resembles a soft, cheesy substance, so the process is called caseation. In
contrast, sarcoid granuloma is never caseating, although small foci of fibrinoid necrosis
can occasionally be observed. Regional lymph nodes draining carcinomas can
occasionally show the presence of noncaseating epithelioid cell granulomas (sarcoid
reactions) with an average frequency of 4.4% [1718]. In seminoma/disgerminoma,
sarcoid-like granulomas can be present in the primary tumours in a significant number of
cases, and can represent a diagnostic challenge in small mediastinal biopsies.
Epithelioid granulomas can be observed in Hodgkins and non-Hodgkins lymphomas.
Biopsy specimens of liver and spleen obtained at laparotomy for the staging of Hodgkins
disease and non-Hodgkins lymphomas show granulomas with an average frequency of
13.8% and 7.3% respectively [1718]. A total of 1520% of biopsy samples with
granulomatous lesions have an undetermined aetiology. These patients have a disease
process that has been named GLUS syndrome (granulomatous lesions of unknown
significance) [19]. Immunohistologically, GLUS syndrome granulomas are B-cell
positive, as are tumour-related sarcoid reactions and toxoplasmosis. However,
granulomas in sarcoidosis and mycobacterial infection are B-cell negative [20].
Granulomas may or may not be found in the rare cases that progress to honeycombing
[21]. In cases with marked airway involvement, bronchiectasis may develop that can
represent a dominant feature of the honeycombing. Aspergilloma may be a late
complication in patients with bronchiectasis and honeycombing [22]. If untreated, these
lesions can become scarred.

Diagnostic approaches
The diagnosis of sarcoidosis needs a compatible clinical picture, histological
demonstration of noncaseating granulomas and exclusion of other diseases capable of
producing a similar histological or clinical picture. The presence of noncaseating
granulomas in a single organ, such as skin, does not establish a diagnosis of sarcoidosis.

Radiology
The chest radiographic findings vary to a great extent: 510% of patients have normal
chest radiographs despite the fact that granulomas in the lungs are identified
histologically. One-third of all patients (40% of Black patients) have both pulmonary
infiltrates and bilateral hilar lymph node enlargement. Another one-third have hilar or
lymph node enlargement alone, which is unilateral in 5%. Pulmonary infiltrates may be
reticular, reticulonodular, alveolar [23], or show a ground-glass appearance and are not
necessarily bilateral [24]. Peripheral pulmonary infiltrates, similar to those of chronic
eosinophilic pneumonia, can be occasionally observed in sarcoidosis [25]. Radiological

84
 PATHOLOGY

staging systems have been in use for many years and are still of value in pulmonary
sarcoidosis. The chest radiographic evaluation of sarcoidosis was vastly improved by
conventional and high-resolution computed tomography (CT) of the chest. CT allows
identification of pathological changes not seen on conventional chest radiographs. These
techniques show remarkably good correlation with gross and microscopic changes. There
is a distribution of small nodules and irregular linear opacities along lymphatic routes,
particularly bronchovascular bundles [26, 27].

Bronchoalveolar lavage
This technique was first used to evaluate patients with sarcoidosis in the mid 1970s.
The initial results suggested a poorer prognosis for patients who had w28% lymphocytes
in their bronchoalveolar lavage (BAL) cell differential. Subsequent studies have not
confirmed these early results, and some results suggest that patients with a high
lymphocyte count actually have a more favourable course. In BAL fluid, there is
generally a moderate increase in the total number of cells, and an increased percentage
(y1560%) of CD4z T-lymphocytes. As a consequence, the CD4z:CD8z ratio will be
high. There are also reports on alveolitis in sarcoidosis dominated by CD8z cells [28],
and neutrophils may accumulate in more advanced fibrosing cases [29]. If T-cell
subpopulations are analysed, typically the CD4z:CD8z ratio is w1.5, usually ranging
from 3:1 to as high as 10:1. There may be prognostic significance to an elevated
CD4z:CD8zratio in BAL fluid, but again the results of studies addressing this issue are
conflicting. Several suggest that pulmonary function values and prognosis are inversely
related to the ratio, whereas others suggest that radiographic improvement in pulmonary
infiltrates is greater with a high CD4z:CD8z ratio. These discrepancies may be due to
inclusion of patients with acute onset disease, i.e. Lofgrens Syndrome, who typically
have an elevated CD4z:CD8z and a favourable prognosis. Subjects with more chronic
disease may also have an elevated CD4z:CD8zratio but overall their prognosis is not as
good as those with the acute onset of disease [29]. For now, the role of BAL in the
management of sarcoidosis remains ill-defined. Although it cannot reliably diagnose this
disease, it is helpful in assessing the presence of infection and other immunological
diseases of the lung, such as chronic hypersensitivity pneumonitis, where the
CD4z:CD8z ratio is typically inverted. If there is an experienced BAL laboratory
available to analyse the fluid, doing a BAL as part of the initial workup of a patient with
suspected sarcoidosis is justified.

Transbronchial needle aspiration

Transbronchial needle aspiration (TBNA) is a minimally invasive bronchoscopic
procedure that allows sampling of hilar and mediastinal lymph nodes in close contact
with the airways. In a recent study, the authors assessed the value of TBNA in the
diagnosis of sarcoidosis manifesting with intrathoracic lymphadenopathies (stages I
and II), and compared its yield with that of transbronchial biopsy (TBB) [30]. The
conclusions of this study suggest that a diagnostic approach combining TBNA and TBB
is safe and effective in the setting of stage I and II sarcoidosis. It also confirmed the value
of TBNA, with excellent diagnostic yields, especially in stage I of the disease. In
particular, the combination of the two methods was associated with the highest
diagnostic yield (93.7% overall sensitivity), and allowed significantly better results over
both TBNA alone (93.7% versus 65.6%; p=0.011) and TBB alone (93.7% versus 62.5%;
p=0.005).

85
 V. POLETTI ET AL.

Biopsy
Although the clinical and radiological features in some cases are so typical that a
presumptive diagnosis of sarcoidosis can be made without histological confirmation, it is
generally agreed that histological confirmation should be obtained before institution of
steroid therapy [14]. TBB is the recommended procedure in most cases. Its diagnostic
yield depends largely on the experience of the operator, ranging 4090% when four to five
lung biopsies are carried out [3132]. TBBs show features compatible with the diagnosis
of sarcoidosis in 6580% of cases, with the highest positive rate in patients with both hilar
lymphadenopathy and pulmonary infiltrates [33]. In one study it was found that four or
more TBB specimens yielded a diagnostic rate of 90% [31]. TBB may yield positive results
even in patients with normal chest radiographs. The use of a restricted panel of
monoclonal antibodies, such as CD68z and CD45RO, can significantly increase the
sensitivity of histological recognition of sarcoid lesions in small, occasionally crunched,
TBBs (fig. 2d) [34].
In the absence of the typical clinical circumstances, a diagnosis of sarcoidosis based
solely on TBB alone is very risky, particularly if poorly formed or only a few granulomas
are present. TBNA has been used to confirm the presence of granulomatous tissue in the
sampled nodes and to complement TBB but it has the same limitations that apply to TBB
alone. Bronchial mucosal biopsy may be performed during the same procedure; it is
positive for noncaseating granuloma in 4157% of patients with sarcoidosis [3537]. A
careful examination of the patient may disclose other possible sites for biopsy, such as
skin, lips, or superficial lymph nodes. A granulomatous scar (a fresh granulomatous
reaction on the site of an old scar) may be a very useful site for biopsy. It is not useful to
biopsy erythema nodosum lesions since they will not show granulomas. Liver biopsy is
rarely indicated, even if there is biochemical or clinical evidence of liver involvement.
Finally, the diagnostic yield of biopsy by mediastinoscopy or video-assisted thoraco-
scopic (VTLB) or open lung biopsy [38] is reported to bew90%. VTLB has the advantage
of permitting biopsy of both the lung and lymph nodes.
In conclusion, to provide histological confirmation of the disease, the bronchial
mucosal biopsy should also be taken, since the histological demonstration of granuloma
is possible in 4060% of cases, even when the bronchial mucosa is grossly normal. When
gross endoscopic findings, such as mucosal nodularity, oedema or hypervascularity are
present, the yield of endobronchial biopsies may exceed 90% [39]. TBB through a
fibreoptic bronchoscope is the recommended procedure in most cases [33]. The diagnostic
yield is high, reaching 8090% if i45 adequate samples are obtained [31]. Even in stage
I disease, the yield may be 7080% [40]. These bronchoscopic biopsy procedures may be
combined with BAL and studies of lymphocyte subpopulations. Three independent
groups have shown very similar values for the sensitivity and specificity of BAL
CD4z:CD8z ratios [4143]. A ratio of w3.5 or 4.0 has a sensitivity of 5259% and a
specificity of 9496%. These three studies reached a similar conclusion: in patients with a
clinical picture typical of sarcoidosis, an elevated CD4z:CD8z ratio in BAL may
confirm the diagnosis and obviate the need for confirmation by additional biopsy [44]. It
is important to note that in the study of Winterbauer et al. [42], TBB had a specificity of
89% for the distinction between sarcoidosis and other forms of diffuse lung disease, and
was, therefore, no better than the CD4z:CD8z ratio in this regard.

Differential diagnosis of various granulomatous disorders

Noninfectious environmental agents. It is assumed that sarcoidosis is caused by

inhalation of airborne agents in susceptible persons triggering the inflammatory reaction.

86
 PATHOLOGY

The noninfectious environmental agents can elicit a granulomatous response with many
features that are similar to sarcoidosis, e.g. beryllium (Be), aluminium dusts and
zirconium (Zr) [4547]. In particular, Berylliosis is an environmental chronic
inflammatory disorder of the lung caused by inhalation of insoluble Be dusts and
characterised by the accumulation of CD4z T-cells and macrophages in the lower
respiratory tract. In response to Be inhalation, noncaseating granuloma form and,
eventually, fibrosis occurs. The immunopathogenic process is maintained by Be-specific
lung CD4z T-lymphocytes. Consistent with the disease immunopathology, these Be-
specific T-cells have a T-helper type-1 phenotype producing interleukin-2 and interferon-
gamma, the macrophage-activating cytokine driving the granulomatous reaction [48, 49].
However, De Vuyst et al. [45] in a case report suggests that also aluminium may cause
granulomatous lung disease accompanied by a helper T-lymphocyte alveolitis, similar to
that of berylliosis. Furthermore, it has been suggested in some subjects a special
susceptibility responsible for the development of a granulomatous disease after Zr
exposure occurs. In any case, Zr must be considered as another metal, besides Be, which
can cause pulmonary and generalised granulomatosis [50]. Finally, Drent et al. [51]
observed the association of sarcoid-like granulomatous reaction and occupational history
of glass fibre exposure and that, in susceptible people, exposure to other man-made
mineral fibres, such as rock wool, might be related to a chronic granulomatous disease
similar to chronic Be disease. Histologically similar granulomatous disease has been
associated with a variety of other metals including barium, cobalt, copper, gold, rare earth
metals (lanthanides) and titanium [52].
Therefore, the accurate diagnosis of sarcoidosis depends on a stringent inquiry of
potential exposures to both organic and inorganic antigens. Finally, the host itself has
been considered a potential source of autoreactive granuloma-inducing antigens,
although the possibility that sarcoidosis is an autoimmune disorder is not supported by
any evidence. As granulomatous inflammation is the histological hallmark of sarcoidosis,
investigators continue to improve and apply modern diagnostic tools in search for
infectious agents, such as mycobacteria, which are known to induce a host
granulomatous response [53]. To date, there is no evidence that sarcoidosis is caused
by an infectious agent.

Infectious environmental agents. Infections are the commonest causes of disseminated

granulomatous disease. For instance, cat scratch disease is due to Bartonella henselae and
Whipples disease due to Tropheryma whippeli. Infective causes are suspected but not yet
established for sarcoidosis, Crohns disease, primary biliary cirrhosis, Kikuchis disease,
Langerhans granulomatosis, and chronic granulomatous disease of childhood.
Granulomatous fungal infections mimic sarcoidosis worldwide. It is important to
recognise or exclude fungi localised to one system or disseminated; in particular,
granulomatous fungal meningitis needs to be distinguished from sarcoidosis by all
available techniques.
Whipples Disease is also a chronic multisystemic granulomatous disorder. There may
be hepatosplenomegaly and generalised lymphadenopathy, but there is evidence for
Whipples disease also presenting with large pulmonary nodules and endobronchial
lesions and for the absence of gastrointestinal features [54]. Furthermore, a case of
systemic Whipples disease with pericardial and pleural effusions and severe pulmonary
hypertension has been described, where 3 months of antibiotic treatment produced a
complete resolution, not only of the symptoms known to be associated with Whipples
disease (diarrhoea, arthralgia, pericardial and pleural effusions), but also of pulmonary
hypertension [55]. Biopsy of lymph node, liver, or small intestine reveals foci of periodic
acid-schiff (PAS) staining foamy macrophages in all sites. The PAS-positive material

87
 V. POLETTI ET AL.

within these histiocytes corresponds with lysosomes containing bacilliform bodies.

Electron microscopy reveals rod shaped bacilli, termed Whipple bacilli or T. whippelii or
Whipple-associated bacterial organisms [56]. The resulting PCR product from the
bacterial 16S ribosomal DNA showed that Whipple bacilli were most likely to belong to
the family of gram-positive bacteria of the rhodococcus, streptomyces and arthrobacter
genera, and more weakly related to mycobacteria. PCR primers for T. whippeli now
provide a helpful diagnostic technique.

Other causes of granulomatous inflammation. The family of vasculitic granulomatoses

comprise Wegeners granulomatosis, necrotising sarcoidal granulomatosis, Churg-
Strauss syndrome, lymphomatoid granulomatosis, polyarteritis nodosa, broncho-
centric granulomatosis, giant cell arteritis, and systemic lupus erythematosus. They
may occasionally be confused with sarcoidosis and hypersensitivity pneumonitis (extrinsic
allergic alveolitis), so a careful clinico-pathological synthesis is essential
Finally, the commonest cause of granulomatous inflammation in the gastrointestinal
tract is Crohns disease. This reaction seems to centre on the blood vessels of the
intestinal wall causing multifocal gastrointestinal infarction. There may be associated
lung changes, including pulmonary vasculitis, granulomatous interstitial lymphocytic
infiltration, alveolitis, and interstitial fibrosis. Alveolar macrophages may show an
increased spontaneous superoxide anion production. An increase in CD4zcells is found
in BAL fluid and even in sputum. Serum antibody increases include anti-reticulin
antibody, anti-saccharomyces cerevisiae antibody (ASCA), and p-anti-neutrophil
cytoplasmic antibody (ANCA). There is concordance between ASCA and ANCA.
ASCA occurs in up to 60% of patients, particularly with familial Crohns disease, and
ASCA is evident in 20% of first-degree relatives [57, 58].

Summary
Sarcoidosis is a chronic, multisystemic disorder of unknown cause characterised in
involved organs by an accumulation of activated CD4z T-cells and macrophages,
noncaseating epithelioid cell granuloma, and tissue injury. The diagnosis is established
when clinico-radiological findings are supported by histological evidence of
noncaseating epithelioid cell granulomas. Granulomas of known causes and local
sarcoid reactions must be excluded.

Keywords: Bronchoalveolar lavage, CD4z lymphocytes, hilar lymph node enlarge-

ment, noncaseating granuloma, sarcoidosis, transbronchial needle aspiration.

References
1. Rosen Y. Sarcoidosis. In: Dail DH, Hammer SP, eds. Pulmonary Pathology, 2nd Edn. New York,
Springer-Verlag, 1994; pp. 13645.
2. Colby TV. Interstitial lung diseases. In: Thurlbeck W, Churg A, eds. Pathology of the Lung, 2nd
Edn. New York, Thieme Medical Publishers, 1995; pp. 589737.
3. Semenzato G, Chilosi M, Agostini C. Sarcoidosis: Immunology and immunohistology. In:
Sarcoidosis and other granulomatous disorders. James DG, ed. Lung Biology in Health and
Disease. Vol 73. New York, Marcel Dekker, 1994; pp. 153179.

88
 PATHOLOGY

4. Chilosi M, Menestrina F, Capelli P, et al. Immunohistochemical analysis of sarcoid granulomas.

Evaluation of Ki67z and interleukin-1z cells. Am J Pathol 1988; 131: 191198.
5. Sheffield EA, Williams WJ. Pathology. In: James DG, ed. Sarcoidosis and Other Granulomatous
Disorders. New York, Marcel Dekker, 1994; pp. 4567.
6. Tuder RM. A pattologists approach to interstitial lung disease. Curr Opin Pulm Med 1996; 2: 357
363.
7. Freiman DG, Hardy HL. Beryllium disease. The relation of pulmonary pathology to clinical
course and prognosis based on a study of 130 cases from the U.S. beryllium case registry. Hum
Pathol 1970; 1: 2544.
8. Rosen Y, Moon S, Huang C-T, Gourin A, Lyons HA. Granulomatous pulmonary angiitis in
sarcoidosis. Arch Pathol Lab Med 1977; 101: 170174.
9. Levine BW, Saldana M, Hutter AM. Pulmonary hypertension in sarcoidosis: A case report of a
rare but potentially treatable cause. Am Rev Respir Dis 1971; 103: 413417.
10. Schachter EN, Smith GW, Cohen GS, Lee SH, Lasser A, Gee BL. Pulmonary granulomas in a
patient with pulmonary venoocclusive disease. Chest 1975; 7: 487489.
11. Smith L, Lawrence B, Katzenstein M. Vascular sarcoidosis: A rare cause of pulmonary
hypertension. Am Med Sci 1983; 285: 3844.
12. Dines DE, Stubbs SE, McDougall C. Obstructive disease of the airways associated with stage I
sarcoidosis. Mayo Clin Proc 1978; 53: 788791.
13. Stjernberg N, Thunell M. Pulmonary function in patients with endobronchial sarcoidosis. Acta
Med Scand 1984; 215: 121126.
14. Harkleroad LE, Young RL, Savage P, Jenkins DW, Lordon RE. Pulmonary sarcoidosis: Long-
term follow-up of the effects of steroid therapy. Chest 1982; 82: 8487.
15. Nicholls A, Friend AR, Legge S. Sarcoid pleural effusion: Three cases and review of the literature.
Thorax 1980; 35: 277281.
16. Kanada D, Scott D, Sharma OP. Unusual presentations of pleural sarcoidosis. Br Dis Chest 1980;
74: 203205.
17. Brincker H. Sarcoid reactions in malignant tumors. Cancer Treat Rev 1986; 13: 147156.
18. Romer F. Sarcoidosis and Cancer. In: James DG, ed. Sarcoidosis and Other Granulomatous
Disorders. New York, Marcel Dekker, 1994; pp. 401415.
19. Brincker H.: Granulomatous lesions of unknown significance: the GLUS syndrome. In: James D,
ed. Sarcoidosis and Other Granulomatous Disorders. New York, Marcel Dekker, 1994; pp. 6986.
20. Brincker H, Pedersen NT. Immunohistologic separation of B-cell-positive granulomas from B-cell-
negative granulomas in paraffin-embedded tissues with special reference to tumor-related sarcoid
reactions. Apmis 1999; 199: 282290.
21. Huang CT, Heurich AE, Sutton AL, Lyons HA. Mortality in sarcoidosis: A changing pattern of
the causes of death. Eur Respir Dis 1981; 62: 231238.
22. Wollschlager C, Khan F. Aspergillomas complicating sarcoidosis: A prospective study in 100
patients. Chest 1984; 86: 585588.
23. Battesti P, Saumon G, Valeyre D, et al. Pulmonary sarcoidosis with an alveolar radiographic
pattern. Thorax 1982; 37: 448452.
24. Demicco WA, Fanburg BL. Sarcoidosis presenting as a lobar or unilateral lung infiltrate. Clin
Radiol 1982; 33: 663669.
25. Glazer HS, Levitt RG, Shackelford GD. peripheral pulmonary infiltrates in sarcoidosis. Chest
1984; 86: 741744.
26. Oberstein A, von Zitzewitz H, Schweden F, Muller-Quernheim. Non invasive evaluation of the
inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc
Diffuse Lung Dis 1997; 14: 6572.
27. Drent M, De Vries J, Lenters M, et al. Sarcoidosis: assessment of disease severity using HRCT.
Eur Radiol 2003; 13: 24622471.
28. Agostini C, Trentin L, Zambello R, et al. CD8 alveolitis in sarcoidosis: incidence, phenotypic
characteristics, and clinical features. Am J Med 1993; 95: 466472.

89
 V. POLETTI ET AL.

29. Lin YH, Haslam PL, Turner-Warwick M. Chronic pulmonary sarcoidosis: relationship between
lung lavage cell counts, chest radiograph, and results of standard lung function tests. Thorax 1985;
40: 501507.
30. Trisolini R, Lazzari Agli L, Cancellieri A, et al. Transbronchial needle aspiration improves the
diagnostic yield of bronchoscopy in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 147
151.
31. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis. An approach to determine the
optimal number of biopsies. Am Rev Respir Dis 1980; 122: 721724.
32. Poletti V, Patelli M, Spiga L, Ferracini R, Manetto V. Transbronchial lung biopsy in pulmonary
sarcoidosis. Is it an evaluable method in detection of disease activity? Chest 1986; 89: 361365.
33. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
34. Menestrina F, Lestani M, Mombello A, et al. Transbronchial biopsy in sarcoidosis: the role of
immunohistochemical analysis for granuloma detection. Sarcoidosis. 1992; 9: 95100.
35. Bjermer L, Thunell M, Rosenhall L, Stjernberg N. Endobronchial biopsy positive sarcoidosis:
relation to broochoalveolar lavage and course of disease. Respir Med 1991; 85: 229234.
36. Stjernberg N, Bjomstad-Pettersen H, Truedsson H. Flexible fiberoptic bronchoscopy in
sarcoidosis. Acta Med Scand 1980; 208: 397399.
37. Armstrong JR, Radke JR, Kvale PA, Eichenhorn MS, Popovich J Jr. Endoscopic findings in
sarcoidosis. Characteristics and correlations with radiographic staging and bronchial mucosal
biopsy yield. Ann Otol Rhinol Laryngol 1981; 90: 339343.
38. Gossot D, Toledo L, Fritsch S, Celerier M. Mediastinoscopy versus thoracoscopy for mediastinal
biopsy. Results of a prospective nonrandomized study. Chest 1996; 110: 13281331.
39. Armstrong JR, Radke JR, Kvale PA, et al. Endoscopic findings in sarcoidosis. Ann Otol 1981;
90: 339434.
40. Kopp C, Perruchoud A, Heitz M, Dalquen P, Herzog H. Transbronchiale Lungenbiopsie bei
Sarkoidose. [Transbronchial lung biopsy in Sarcoidosis]. Klin Wschr 1983; 61: 451454.
41. Costabel U, Zaiss AW, Guzman J. Sensitivity and specificity of BAL findings in sarcoidosis.
Sarcoidosis 1992; 9: Suppl. 1, 211214.
42. Winterbauer RH, Lammert J, Selland M, Wu R, Springmeyer CD. Bronchoalveolar lavage cell
populations in the diagnosis of sarcoidosis. Chest 1993; 104: 352361.
43. Thomeer M, Demedts M. Predictive value of CD4/CD8 ratio in bronchoalveolar lavage in the
diagnosis of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: Suppl. 1, 36.
44. Costabel U. CD4/CD8 ratios in bronchoalveolar lavage fluid: of value for diagnosing sarcoidosis?
Eur Respir J 1997; 10: 26992700.
45. De Vuyst P, Dumortier P, Schandene L, Estenne M, Verhest A, Yemault JC. Sarcoidlike lung
granulomatosis induced by aluminum dusts. Am Rev Respir Dis 1987; 135: 493497.
46. Skelton HG 3rd, Smith KJ, Johnson FB, Cooper CR, Tyler WF, Lupton GP. Zirconium
granuloma resulting from an aluminum zirconium complex: a previously unrecognized agent in the
development of hypersensitivity granulomas. J Am Acad Dermatol 1993; 28: 874876.
47. Newman LS. Beryllium disease and sarcoidosis: clinical and laboratory links. Sarcoidosis 1995;
12: 719.
48. Saltini C, Amicosante M. Beryllium disease. Am J Med Sci 2001; 321: 8998.
49. Infante PF, Newman LS. Beryllium exposure and chronic beryllium disease. Lancet 2004;
363: 4156.
50. Werfel U, Schneider J, Rodelsperger K, et al. Sarcoid granulomatosis after zirconium exposure
with multiple organ involvement. Eur Respir J 1998; 12: 750.
51. Drent M, Bomans PH, Van Suylen RJ, Lamers RJ, Bast A, Wouters EF. Association of man-
made mineral fibre exposure and sarcoidlike granulomas. Respir Med 2000; 94: 815820.
52. Newman LS. Metals that cause sarcoidosis. Semin Respir Infect 1998; 13: 212220.

90
 PATHOLOGY

53. Mangiapan G, Hance AJ. Mycobacteria and sarcoidosis: an overview and summary of recent
molecular biological data. Sarcoidosis 1995; 12: 2037.
54. Kelly CA, Egan M, Rawlinson J. Whipples disease presenting with lung involvement. Thorax
1996; 51: 343344.
55. Riemer H, Hainz R, Stain C, et al. Severe pulmonary hypertension reversed by antibiotics in a
patient with Whipples disease. Thorax 1997; 52: 10141015.
56. Spapen HDM, Segers O, DeWit N. Electron microscopic detection of Whipples bacillus in
sarcoidlike periodic acid-Schiff-negative granulomas. Dig Dis Sci 1989; 34: 640643.
57. Vermeire S, Peeters M, Joossens S, et al. The value of anti-saccharomyces cerevisial antibodies
(ASCA) as clinical marker in Crohns disease (CD). Gastroenterology 1999; 116: 3647.
58. James DG, Jones Williams W. Sarcoidosis and other granulomatous disorders. Philadelphia, WB
Saunders, 1985.

91
CHAPTER 7

Fatigue, quality of life and health status in

sarcoidosis

J. De Vries*,#,}, R.M. Wirnsbergerz

*Dept of Psychology and Health, Medical Psychology, Tilburg University, and #St. Elisabeth Hospital
Tilburg, Tilburg, and }Research Institute for Psychology and Health and zAsthma Centre Heideheuvel,
Hilversum, The Netherlands.

Correspondence: J. De Vries, Tilburg University, Medical Psychology, Dept of Psychology and Health,
P.O. Box 90153, 5000 LE Tilburg, The Netherlands. Fax: 31 134772370; E-mail: j.devries@uvt.nl

Although fatigue is a well-known symptom in sarcoidosis, it still seems an

underestimated problem in clinical practice. A recent study showed that even physicians
experienced in the treatment of sarcoidosis showed poor chance-corrected agreement
with patients on the presence of symptoms attributable to sarcoidosis [1]. It was
suggested that physicians probably rely more on chest radiographs and lung function and
laboratory test results. They may, therefore, underestimate symptoms important to the
patient, such as pain, stress, and fatigue, which cannot be assessed using laboratory tests
[1]. Previously, only poor relations of objective disease parameters, such as lung function
tests and health status [13], as well as quality of life (QoL) [4], have been shown in
sarcoidosis patients. Presumably, objective clinical parameters do not reflect a patients
perceived well-being.
Sarcoidosis is a young persons disease with a peak at 2040 yrs [5, 6]. At this age, it
may be more difficult to cope with a symptomatic multi-organ disease of unknown
origin and unpredictable course than at older age. A chronic disease at a young age
may result in working and social problems, especially when the patient looks healthy.
When disabling fatigue remains the only symptom, procedures concerning working
disability with the employer or the insurance company may be difficult because there is
no method of establishing objectively that the patient suffers from serious loss of
working capacity.
A number of studies have shown that fatigue is a prominent feature of sarcoidosis and
that the health status, as well as QoL, of this patient group is impaired [1, 2, 4, 7].
Different aspects of fatigue, QoL and health status in sarcoidosis are discussed in the
present chapter.

Fatigue
Fatigue is a common symptom in a large number of medical conditions. It can be
present in autoimmune disorders, such as rheumatoid arthritis, in malignant disease
and in viral infections [8]. Recent studies have shown that fatigue is also a prominent
problem in sarcoidosis [2, 4, 7, 9]. A substantial number of sarcoidosis patients suffer
from persistent fatigue [4, 7]. In a selected group of 1,046 patients (all members of the
Dutch Sarcoidosis Society (DSS)), mainly chronic sarcoidosis patients, fatigue was the
most frequently reported symptom [7]. In a study among 64 sarcoidosis patients from
eight Dutch hospitals [2], 73% of the symptomatic sarcoidosis patients (n=37) reported
Eur Respir Mon, 2005, 32, 92104. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
92
 FATIGUE IN SARCOIDOSIS

persistent fatigue. In this study, fatigue was by far the most frequent symptom,
compared to dyspnoea, cough, arthralgia and thoracic pain. The mean disease
duration was 5 yrs. A similar percentage of fatigue was found in another sample of
outpatients who had suffered from sarcoidosis for 2 yrs [10]. In contrast, in a group
of 715 newly detected sarcoidosis patients from 19 pulmonary hospitals throughout
former West Germany and Switzerland, only 18% reported constitutional symptoms
such as fatigue, together with weight loss and night sweats [5]. In the American
Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and
Other Granulomatous Disorders statement on sarcoidosis, constitutional symptoms,
such as fever, weight loss, fatigue and malaise, were mentioned as being present in
approximately one-third of patients [11].
With regard to sex, results are inconsistent. In a group of patient members of the DSS,
females indicated more often that they suffered from fatigue [12]. However, a study
among chronic outpatients showed higher scores for fatigue in males [13]. Another study
did not find sex differences with respect to fatigue [10].
Sharma [9] postulated three different types of fatigue in sarcoidosis, i.e. early morning
fatigue, intermittent fatigue and afternoon fatigue. Patients with early morning fatigue
awake unrefreshed. They have difficulty getting out of bed, partly because of joint
stiffness and/or muscle pain. Moreover, sleeping disorders (see later) may play a role in
this type of fatigue. Patients with intermittent fatigue awake fit, but feel exhausted after a
few hours of activity. Rest resolves this type of fatigue and patients can pick-up their
activity for a few hours, after which they again become tired. Afternoon fatigue is present
in patients who are fit in the morning but completely exhausted in the afternoon. Patients
with this type of fatigue may feel as though they have influenza and wish only to go to
bed. Although this classification seems plausible, studies examining these different types
of fatigue in sarcoidosis are lacking.

Causes of fatigue in sarcoidosis

Some attempts have been made to examine the underlying causes of fatigue in
sarcoidosis. The general inflammation and metabolic derangement have been discussed
[14]. In a recent study, none of the variables tested, including lung function, metabolic
measures, laboratory parameters of inflammation, T-cell activation and granuloma
formation, were useful in predicting fatigue in sarcoidosis patients [10]. However, these
were cross-sectional studies.
Other factors that may contribute to fatigue in sarcoidosis are myopathy and sleeping
disorders, such as obstructive sleep apnoea [15, 16], which is frequent in sarcoidosis, and
sleep disturbances associated with periodic leg movements [17]. The prevalence of
obstructive sleep apnoea syndrome in the studied sarcoidosis population with clinically
significant sarcoidosis was 17%, which was significantly higher than in a control group
(3.3%) and the general population (24%) [15]. Moreover, patients with lupus pernio
were 8.1 times more likely to exhibit sleep apnoea than those without.
In sarcoidosis, pain also appears to be related to fatigue. In a study among a large
group of sarcoidosis patients without comorbid conditions, fatigue was associated with
the presence of pain and specific types of pain, such as muscle pain, chest pain, arthralgia,
abdominal pain and headache [18]. A feeling of general weakness is common in
sarcoidosis [7]. It is also possible that lack of exercise contributes to fatigue in sarcoidosis.
Fatigue has been examined in relation to psychological factors. In a recent study, a
considerable number of sarcoidosis patients were diagnosed with depression, a major
symptom of which is fatigue [1, 19]. In a Dutch study, patients appeared to score highly
for perceived stress, which was related to fatigue, even after the role of depression was

93
 J. DE VRIES, R.M. WIRNSBERGER

partialled out [20]. In accordance with this, in a group of USA sarcoidosis patients, a
high prevalence of stress was reported [1]. Moreover, the development of fatigue and
depressive symptoms might be attributed to involvement of the central nervous system
[21].
Recently, it was shown that small fibre neuropathy (SFN) is common among
sarcoidosis patients [22, 23]. Since patients with SFN report a range of nonspecific
symptoms, such as fatigue, the relationship between SFN and fatigue was examined.
Sarcoidosis patients with SFN reported higher fatigue scores (Fatigue Assessment Scale
(FAS); see below) than those without SFN [24]. Accordingly, fatigue in sarcoidosis may
be caused, at least in part, by autonomic dysfunction. Further studies are needed to
examine the pathways between fatigue and SFN.

Assessment
There is no objective parameter for assessing fatigue in sarcoidosis [10]. When features
of disease activity, such as the chest radiograph and lung function test results, as well as
laboratory test results, have become normal, either spontaneously or after treatment,
fatigue may persist [10]. Fatigue is a state that is not necessarily related to the subjective
experience of fatigue [25, 26]. A common way of assessing perceived fatigue is by means
of questionnaires. In sarcoidosis, fatigue has been assessed using the energy and fatigue
facet of the 100-item World Health Organization Quality of Life instrument (WHOQOL-
100) [27], the FAS [28] and once with the Multidimensional Fatigue Inventory [29]. The
energy and fatigue facet of the WHOQOL-100 physical health domain consists of four
questions: "How easily do you get tired?", "How much are you bothered by fatigue?",
"Do you have enough energy for everyday life?", and "How satisfied are you with the
energy you have?" [4]. In a group of 64 sarcoidosis patients, this facet appeared to
differentiate between symptomatic and asymptomatic patients, as well as patients versus
matched healthy controls [4]. In another study, sarcoidosis patients also reported
significantly more fatigue than controls (fig. 1) [18].

18
WHOQOL-100 score

12

0
Energy & fatigue Overall QoL
Facet

Fig. 1. Mean 100-item World Health Organization Quality of Life instrument (WHOQOL-100) energy and
fatigue facet and overall quality-of-life (QoL) scores in two groups of sarcoidosis patients (&: [4]; &: [18]) and
a control group (%: [18]). Patients reported having significantly less energy (pv0.05) than the control group. No
differences emerged concerning overall QoL.

94
 FATIGUE IN SARCOIDOSIS

The FAS is a promising measure for assessing fatigue in sarcoidosis patients [13]. One
study showed that the majority (80%) of a general population sample scored below the
cut-off score on the FAS, whereas 80% of sarcoidosis patients scored above that score
[13]. Since fatigue has a major impact on QoL in sarcoidosis, establishing the extent of
fatigue will provide valuable insight regarding patients QoL. Thus, in order to find out
how the patient feels, measuring fatigue with the FAS would provide such information.
Fatigue, measured with a single yes/no question, appears to be related to inflammation,
as indicated by an acute phase response [14]. However, single-item measurements are not
preferred since the reliability of such instruments is low.

Treatment
As mentioned above, there exists no effective treatment for fatigue in sarcoidosis. In a
study examining fatigue in two groups of sarcoidosis patients, it appeared that, in the
group of patient members of the DSS, patients using prednisone exhibited higher fatigue
scores than patients not using prednisone. In the outpatient group, fatigue was unrelated
to prednisone use [10, 13]. Several case reports of sarcoidosis patients treated with anti-
tumour necrosis factor (TNF)-a showed a dramatic reduction in fatigue [3032]. The
positive effect of anti-TNF-a on fatigue has also been demonstrated in other diseases,
such as Crohns disease and rheumatoid arthritis [33, 34]. For obvious reasons, however,
this kind of drug cannot be given to patients who are suffering exclusively from fatigue
without other evidence of disease activity.
When fatigue has a (partly) psychological cause, various treatments are available.
Patients with clinical depression can be prescribed antidepressants. Cognitive therapy
can be offered to treat coping problems or stress perception. Furthermore, physical
training programmes might also improve patients exercise tolerance. These programmes
appear to work in the management of chronic fatigue syndrome [35], and increase
exercise tolerance in patients with left ventricular dysfunction [36], who also report severe
fatigue.

Quality of life and health status

QoL and health status (often referred to as "health-related quality of life") are
increasingly being recognised as important measures of disease impact and therapeutic
outcome. Both concepts consist of a physical, psychological and social domain. Since the
mid-1980s, QoL and health status have been studied in a considerable number of chronic
diseases. Although most of the studies indicate measurement of QoL, it is health status
that has been assessed. QoL and health status are two different but complementary
concepts. Health status refers to the impact of disease on patients physical,
psychological and social functioning. QoL refers to patients perception or evaluation
of their functioning [37, 38], i.e. how satisfied or bothered they are with their functioning
[39].

Differences between quality of life and health status

The differences between the types of questions and meanings of the scores from QoL
and health status measures are explained below. First, health status may indicate whether
or not there are limitations, whereas QoL also reflects to what extent patients experience
these limitations as a problem in daily life. Individual expectations regarding health, the
ability to cope with limitations and the threshold of tolerance of discomfort modulate

95
 J. DE VRIES, R.M. WIRNSBERGER

objective health status facts into subjective values, which represent QoL [40].
Consequently, two persons with identical restrictions in functioning (health status)
may evaluate these restrictions (QoL) differently. Similarly, a low health status score can
coincide with a high score on the corresponding domain of a QoL measure within the
same person. Thus using a health status measure to assess QoL can provide misleading
conclusions [38]. This can be illustrated using the social domain. Health status measures
focus on how often and to what extent physical health and emotional problems have
interfered with (unspecified) social activities. Consequently, patients with few social
contacts have a low score and are thus expected to have an unsatisfactory social life. A
QoL measure enquires about patients satisfaction with their social contacts. Since this is
not related to the size of their social network, few social contacts may reflect a patients
preference.
Secondly, health status and QoL measures differ in their level of differentiation. In
general, QoL questionnaires assess more aspects of life than health status measures, in
such a way that they provide more detailed information on patients lives. For example,
the psychological domain of health status measures incorporates a wide spectrum of
questions, such as the frequency of feeling nervous, down, calm and quiet, depressed, and
happy. However, since these questions are aggregated into one score, this does not permit
identification of the feelings that are affected. In contrast, a QoL questionnaire assesses a
broader range of separate aspects of the domain, e.g. negative feelings, positive feelings
and self-esteem.
Thirdly, health status measures only aspects that are directly related to health, whereas
QoL instruments measure a broader range of aspects of patients lives. Measuring a
wider scope of aspects is important because patients may feel that aspects that are not
directly health-related are very relevant to them and determine their QoL [41]. An
example is financial resources, which are often influenced by disease, e.g. because patients
have to reduce their number of working hours. Fourthly, health status measures are
characterised by the tendency to assess infirmity or disability, rather than health [39].
Questions focus on the negative consequences of disease and disregard the positive
aspects of life, which are part of QoL measures.
The choice of a QoL or health status measure depends on the aim. In general, if
information is wanted about what patients can and cannot do (functioning), a health
status measure must be used. However, if the interest is in how patients feel about various
aspects of their lives, a QoL measure is indicated. Using the right type of questionnaire
for achieving the desired aim is of the utmost importance, since QoL and health status
measures may provide conflicting results. Using a combination of health status and QoL
measures has been suggested by several researchers.

Quality of life and health status measures used in sarcoidosis

To date, only one QoL measure has been employed in sarcoidosis, the WHOQOL-100
[27, 42]. This questionnaire is applicable in chronically ill persons, individuals living
under stress and healthy persons. It was originally developed in 15 collaborative centres
throughout the world (e.g. in the UK, the USA, The Netherlands, France and Russia).
The WHOQOL-100 consists of 100 items, assessing 24 facets of QoL within six domains
(physical health, psychological health, level of independence, social relationships,
environment and spirituality/religion/personal beliefs) and a general evaluative facet of
overall quality of life and general health. The response scale is a five-point Likert scale.
The psychometric properties, including sensitivity to change, are good [43, 44]. Studies
among sarcoidosis patients have shown that the questionnaire is reliable and valid
(table 1) [45].

96
 FATIGUE IN SARCOIDOSIS

Table 1. Quality of life (QoL) and health status (HS) questionnaires used or examined in sarcoidosis

QoL/HS Items n Time required min Quality in sarcoidosis

CRQ HS 20 2030 Not good#
SF-36 HS 36 10 Good#
SGRQ HS 76 1520 Good#
SHQ HS 29 10 Good
SIP HS 136 2030 Unknown
WHOQOL-100 QoL 100 1520 Good
CRQ: Chronic Respiratory Disease Questionnaire; SF-36: 36-item Short-Form Health Survey; SGRQ: St
Georges Respiratory Questionnaire; SHQ: Sarcoidosis Health Questionnaire; SIP: Sickness Impact Profile;
WHOQOL-100: 100-item World Health Organization Quality of Life instrument. #: validated in interstitial lung
disease sample including 10 sarcoidosis patients.

With regard to health status, five different measures have been used in sarcoidosis
studies (table 1). The Chronic Respiratory Disease Questionnaire (CRQ) [46] is a
respiratory-specific health status measure that was originally developed for chronic
obstructive pulmonary disease (COPD) patients. It measures four aspects of health
status: dyspnoea, fatigue, emotional function, and mastery. The questionnaire allows
patients to rate the severity of dyspnoea associated with individually identified activities.
Scores can range 0100, with higher scores indicating a better health status. Contrary to
the other questionnaires used in sarcoidosis, the CRQ is an interviewer-assisted
questionnaire. It appears to be a reliable and valid instrument for COPD and asthma
patients [4648]. Chang et al. [49] have used the CRQ in a validation study among
patients with interstitial lung disease (ILD), which included 10 sarcoidosis patients (20%
of the total ILD group). They concluded that the CRQ was not a good measure for use in
ILD.
The 36-item Short-Form Health Survey (SF-36) [50] is a 36-item generic health status
measure that assesses health in eight dimensions: physical functioning, social
functioning, limitations in usual role activities due to physical problems (role physical),
limitations in usual role activities due to emotional problems (role emotional), mental
health, vitality, bodily pain, and general health perception. In addition, health changes
over the last year may be assessed. Besides scores for each subscale, the testing yields a
composite health status score on a scale of 0100, where a high score indicates good
health status. The SF-36 has been widely used and has good psychometric properties [51].
The reliability and validity have been shown to be good in a sample of patients with ILD
that included some sarcoidosis patients [49].
The Sarcoidosis Health Questionnaire (SHQ) [3] is a sarcoidosis-specific health status
measure that consists of 29 questions covering three domains: daily functioning, physical
functioning, and emotional functioning. The response scales range 1 (all of the time)7
(none of the time). The reliability and validity of this questionnaire appear good [3], but
further testing is needed. Unfortunately, fatigue, a major symptom of sarcoidosis, is only
represented by one question, which forms part of a domain. Specific information on this
symptom cannot be derived from the SHQ. In order to assess fatigue, another specific
fatigue measure needs to be used.
The Sickness Impact Profile (SIP) [52] is designed to assess sickness-related
behavioural dysfunction in 12 categories: alertness behaviour, ambulation, body care
and movement, communication, eating, emotional behaviour, home management,
mobility, recreation and pastimes, sleep and rest, social interaction, and employment. It
also provides summary scores for physical, psychosocial and overall behavioural
dysfunction. The scores are expressed as percentages of the maximal possible score
of dysfunction. The scores range 0100, with higher scores reflecting greater impact of

97
 J. DE VRIES, R.M. WIRNSBERGER

disease on patients lives. The SIP has been used in many studies among a wide range
of patient populations and its reliability and validity appear to be good [51, 52]. This
questionnaire has not been validated for use in sarcoidosis.
The final questionnaire that has been used in sarcoidosis is the St Georges Respiratory
Questionnaire (SGRQ) [53], a measure developed for COPD patients. It contains 76
items with weighted responses covering three components: symptoms, activity, and
impacts. The latter two relate to the patients current state of health. All component
items can be aggregated into a total SGRQ score. Scores can range 0100, with higher
scores indicating poorer health status. The SGRQ appears to have good reliability and
validity in COPD and asthma patients [5456]. Moreover, this final questionnaire was
considered a good respiratory-specific measure useful in ILD patients, including 10
sarcoidosis patients [49].

Quality of life in sarcoidosis

QoL research has a short history in sarcoidosis. The first QoL study, using the
WHOQOL-100, was published in 1998 [4].
Concerning QoL, nonspecific symptoms, such as fatigue and pain, have an important
impact on the QoL of sarcoidosis patients [12, 18, 57]. In one study [4], 64 sarcoidosis
patients completed the WHOQOL-100 and a symptom checklist. The patients were
divided into two groups: patients with symptoms, such as dyspnoea, cough, chest pain,
arthralgia and fatigue, and those who were asymptomatic. The WHOQOL-100 revealed
a number of areas in which sarcoidosis patients, especially those with current symptoms,
experienced problems. Both patient groups exhibited sleeping problems and impaired
general QoL compared with healthy controls. Beside the physical problems mentioned
above, patients with current symptoms suffered from impaired QoL, mainly in their level
of independence. This area includes problems with mobility, working capacity and
activities of daily living. Sarcoidosis has a considerable impact on the QoL of patients,
especially in those with current symptoms, but also, to a lesser extent, in patients with a
relatively mild respiratory functional impairment [4]. This conclusion was affirmed in
three other QoL studies [12, 57, 58].
In one of these studies, the QoL of sarcoidosis patients (n=37) was compared with
that of healthy controls and a group of rheumatoid arthritis patients. In comparison to
the QoL of the healthy controls, the QoL of both patient groups was impaired.
Fatigue, sleep, activities of daily living and working capacity were major problems in
sarcoidosis, as well as rheumatoid arthritis, patients. As might be expected,
rheumatoid arthritis patients demonstrated more problems related to pain and
mobility [57]. In another study, sex differences were examined with regard to QoL and
symptoms [12]. Male and female patients with symptoms differed from each other in
pain, sleep, positive feelings, appearance, mobility and activities of daily living. Except
for positive feelings, female patients exhibited a lower QoL [12]. The patients in this
study were all recruited through the DSS. Possible explanations for the sex differences
could not be evaluated because relevant medical data about the patients were lacking.
A group of outpatients, a group of DSS members matched to the outpatients on the
basis of age and sex, and a group of DSS members matched to the outpatients on the
basis of age, sex and current symptoms were studied [58]. The outpatient group was,
on average, more satisfied with their physical health. They indicated being less
bothered by pain and fatigue than the DSS members. Another study showed that
patients with SFN had a worse QoL than patients without SFN [24]. No other QoL
studies have been conducted in sarcoidosis patients.

98
 FATIGUE IN SARCOIDOSIS

Health status in sarcoidosis

Research on health status in sarcoidosis is also relatively recent. The relationship
between health status and sarcoidosis was first examined in 1997 [59]. Compared with
controls, the sarcoidosis patients scored more highly in the SIP categories alertness
behaviour, home management, recreation and pastimes, sleep and rest, social interaction,
and employment. In addition, they scored more highly on the summary scores for
psychosocial and overall behavioural dysfunction. Correlations were found between
respiratory muscle endurance time and the SIP categories mobility and body care and
movement. Radiographic stage was related to the SIP categories alertness behaviour,
emotional behaviour, home management and social interaction [59].
Drent et al. [2] found an association between SIP scores and depressive symptoms in
sarcoidosis patients. With regard to the summary dysfunction scores, patients scored
more highly on all three scores, i.e. physical, psychosocial and total score. The differences
between the sarcoidosis patients and the control group were caused by patients with
symptoms. With regard to depressive symptoms, patients with current symptoms also
scored more highly in the component cognitive depressive symptoms compared to
patients without current symptoms. This latter group experienced more positive effect,
whereas no differences were found between the two sarcoidosis subgroups concerning
negative effect. Health status, especially the category sleep and rest, was associated with
depressive symptoms in general, and depressive cognitions in particular [2].
In two USA studies, the prevalence of depression was high, i.e. 60 and 66% [1, 19].
Increased dyspnoea score and number of systems involved were among the risk factors
for depression [19]. Cox et al. [1] found that higher scores for depressive symptoms and
perceived stress were related to lower health status scores. In accordance with this study,
a Dutch study found that depressive symptoms and perceived stress were substantially
related in sarcoidosis patients, and that sarcoidosis patients scored highly for perceived
stress [20].
In another sarcoidosis study, the relationship between socioeconomic status and health
status was assessed. Patients were asked about activity limitations and social limitations
due to physical or emotional disability. Activity limitations due to physical disability were
mainly related to insurance status. Patients who reported limitations were more frequently
without insurance or had public insurance. Nearly all patients with a high income reported
that they were not limited in activity by emotional disability. Furthermore, patients with
private health insurance were more likely to report no limitations, while, at the same time,
they more often indicated that they were limited in particular kinds of activity. With regard
to social limitations, patients with private insurance were again more likely to report no
limitations [60]. Thus, in general, patients with a high socioeconomic status reported a
better health status. The same conclusion was drawn using data from A CaseControl
Etiologic Study of Sarcoidosis (ACCESS) [61].
Health status was also evaluated among lung transplant recipients (n=31), including
three sarcoidosis patients [62]. Compared to transplant candidates, the SGRQ and all
SF-36 subscale scores, except bodily pain, showed a better score for transplant recipients,
indicating a considerable improvement in most dimensions of health status in patients
who survived lung transplantation. Finally, a study by Baughman et al. [63] examining
the usefulness of fluticasone in patients with acute symptomatic pulmonary sarcoidosis
asked patients to complete the SF-36. All patients were on an initial dose of oral
corticosteroids prior to enrolment in a randomised double-blind trial of inhaled
fluticasone. The results of the SF-36 showed no difference between the fluticasone and
the placebo group. However, oral corticosteroids appeared to be associated with
significant complaints, whereas inhaled corticosteroids were well tolerated [63].

99
 J. DE VRIES, R.M. WIRNSBERGER

Clinical implications
Fatigue has a substantial impact on patients QoL and health status. However, the
assessment of QoL and health status in the follow-up of sarcoidosis patients in clinical
practice seems not to be feasible. For clinical studies in sarcoidosis patients, however, the
use of a health status measure as well as a genuine QoL measure seems essential to be able
to evaluate, for example, the effect of an intervention not only on patients functioning
but also on their subjective QoL and well-being.
Although fatigue is not reflected in lung function test results or other clinical
parameters, in the follow-up of sarcoidosis patients in daily practice, it is important to
take this symptom seriously. One way of assessing fatigue in the clinical setting may be
completion of the FAS in regular terms. The FAS is available digitally. When patients
complete this questionnaire, a score profile appears on screen. This measure provides the
physician with more detailed information about the nature and extent of the patients
fatigue. Although no medication is available for improving this symptom, results from
this questionnaire make fatigue a topic of discussion between patient and physician. This
may improve patient-physician communication because the patient feels that fatigue is
being taken seriously.

Conclusions
In conclusion, fatigue in sarcoidosis is a frequent symptom, although it is still
underestimated in clinical practice, especially when lung function test results, chest
radiographs and laboratory parameters are normalised. Physicians treating sarcoidosis
patients should take fatigue seriously even in the absence of any objective marker of it
and when they have no treatment to offer. Absence of evidence does not mean evidence
of absence. In particular, QoL is low, especially in symptomatic sarcoidosis patients, with
respect to mobility, working capacity and activities of daily living. The health status of
sarcoidosis patients is also impaired.
Patients with fatigue may suffer from SFN. Other possible causes are underlying
depression or neurosarcoidosis, which should also be taken into consideration. A
number of case reports of patients with severe disease treated with anti-TNF-a have
indicated a decrease in fatigue in addition to a general improvement in sarcoidosis.
However, there is no specific treatment for fatigue in sarcoidosis. Some patients may
require help in improving coping and self-management of their disease in general and this
symptom in particular. In some cases, cognitive therapy may be indicated.
Physiotherapists can advise patients on how to improve their exercise tolerance and
physical fitness, taking into consideration their fatigue. Rehabilitation programmes
should be developed in order to guide patients properly. Beside physical problems,
sarcoidosis has a substantial impact on QoL. It is very important to guide persons
involved in the follow-up of patients with sarcoidosis. Moreover, it is important to
educate employers and assurance physicians that the absence of objective parameters
does not always guarantee that persons are healthy. Since taxability is clearly decreased,
activities should be adapted accordingly.

100
 FATIGUE IN SARCOIDOSIS

Summary
Fatigue still seems an underestimated problem in sarcoidosis. Objective clinical
parameters are not related to fatigue. General inflammation and metabolic
derangement, pain, sleeping disorders, small fibre neuropathy and depression have
been postulated as possible causes. Since fatigue cannot be assessed using objective
measures, validated questionnaires, such as the Fatigue Assessment Scale, are
recommended for establishing the extent of fatigue. No effective treatment for fatigue
in sarcoidosis is known. Case reports have shown a positive effect of anti-tumour
necrosis factor-a on fatigue.
Nonspecific symptoms, such as fatigue, have a negative impact on the quality of life
and health status of sarcoidosis patients. Quality of life is particularly impaired with
respect to mobility, working capacity and the activities of daily living. As long as there
is no effective treatment for fatigue in sarcoidosis, rehabilitation for improvement of
physical fitness, coping and self-management should be considered for some patients.
Finally, it must be stressed that fatigue should be taken seriously in the management of
sarcoidosis patients.

Keywords: Fatigue, Fatigue Assessment Scale, health status, 100-item World Health
Organization Quality of Life instrument, quality of life, sarcoidosis.

References
1. Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. Health-related quality of life of
persons with sarcoidosis. Chest 2004; 125: 9971004.
2. Drent M, Wirnsberger RM, Breteler MHM, Kock LMM, De Vries J, Wouters EFM. Quality of
life and depressive symptoms in patients suffering from sarcoidosis. Sarcoidosis Vasc Diffuse Lung
Dis 1998; 15: 5966.
3. Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. The Sarcoidosis Health
Questionnaire: a new measure of health-related quality of life. Am J Respir Crit Care Med
2003; 168: 323329.
4. Wirnsberger RM, De Vries J, Breteler MHM, Van Heck GL, Wouters EFM, Drent M. Evaluation
of quality of life in sarcoidosis patients. Respir Med 1998; 92: 750756.
5. Loddenkemper R, Kloppenborg A, Schoenfeld N, Grosser H, Cosatabel U, for the WATL Study
Group. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis results of a
cooperative study in former West Germany and Switzerland. Sarcoidosis Vasc Diffuse Lung Dis
1998; 15: 178182.
6. Klonoff EA, Kleinhenz ME. Psychological factors in sarcoidosis. The relationship between life
stress and pulmonary function. Sarcoidosis 1993; 10: 118124.
7. Wirnsberger RM, De Vries J, Wouters EFM, Drent M. Clinical presentation of sarcoidosis in the
Netherlands. An epidemiological study. Neth J Med 1998; 53: 5360.
8. Lewis G, Wessely S. The epidemiology of fatigue. More questions than answers. J Epidemiol
Community Health 1992; 46: 9297.
9. Sharma OP. Fatigue and sarcoidosis. Eur Respir J 1999; 13: 713714.
10. De Vries J, Rothkrantz-Kos S, Van Dieijen-Visser MP, Drent M. The relationship between fatigue
and clinical parameters in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 127
136.
11. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory

101
 J. DE VRIES, R.M. WIRNSBERGER

Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on

sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
12. De Vries J, Van Heck GL, Drent M. Gender differences in sarcoidosis: symptoms, quality of life,
and medical consumption. Women Health 1999; 30: 99114.
13. De Vries J, Michielsen H, Van Heck GL, Drent M. Measuring fatigue in sarcoidosis: the Fatigue
Assessment Scale (FAS). Br J Health Psychol 2004; 9: 279291.
14. Drent M, Wirnsberger RM, De Vries J, Van Dieijen-Visser MP, Wouters EFM, Schols AMWJ.
Association of fatigue with an acute phase response in sarcoidosis. Eur Respir J 1999; 13: 718722.
15. Turner GA, Lower EE, Corser BC, Gunther KL, Baughman RP. Sleep apnea in sarcoidosis.
Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: 6164.
16. Drent M, Verbraecken J, Van der Grinten CP, Wouters EFM. Fatigue associated with obstructive
sleep apnea in a patient with sarcoidosis. Respiration 2000; 67: 337340.
17. Verbraecken J, Hoitsma E, Van der Grinten CPM, Cobben NAM, Wouter EFM, Drent M. Sleep
disturbances associated with periodic leg movements in chronic sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2004; 21: 137146.
18. Hoitsma E, De Vries J, Van Santen-Hoeufft M, Faber CG, Drent M. Impact of pain in a Dutch
sarcoidosis patient population. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 3339.
19. Chang B, Steimel J, Moller DR, et al. Depression in sarcoidosis. Am J Respir Crit Care Med 2001;
163: 329334.
20. De Vries J, Drent M. Relationship between perceived stress and sarcoidosis in a Dutch patient
population. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 5763.
21. Hoitsma E, Faber CG, Drent M, Sharma OP. Neurosarcoidosis: a clinical dilemma. Lancet Neurol
2004; 3: 397407.
22. Hoitsma E, Marziniak M, Faber CG, et al. Small fibre neuropathy in sarcoidosis. Lancet 2002;
359: 20852086.
23. Hoitsma E, Drent M, Verstraete E, et al. Abnormal warm and cold sensation thresholds suggestive
of small fibre neuropathy in sarcoidosis. Clin Neurophysiol 2003; 114: 23262333.
24. De Vries J, Jonkers GJ, Hoitsma E, Faber CG, Drent M. Relationship of fatigue and small fiber
neuropathy (SFN) in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005; (In press).
25. Aldasheva AA, Chernook TB, Glushkova MY, Kurmanalieva RD. Dependence of working
capacity and fatigue on the nervous and mental state of workers doing long stints in the
mountains. Hum Physiol 1992; 18: 371374.
26. Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res
1993; 37: 147153.
27. World Health Organization Quality of Life Group. Field Trial WHOQOL-100 February 1995:
Facet Definitions and Questions. MNH/PSF/95.1.B. Geneva, World Health Organization, 1995.
28. Michielsen HJ, De Vries J, Van Heck GL. Psychometric qualities of a brief self-rated fatigue
measure: the Fatigue Assessment Scale (FAS). J Psychosom Res 2003; 54: 345352.
29. Smets EMA. Fatigue in cancer patients undergoing radiotherapy. PhD thesis. Amsterdam,
University of Amsterdam, 1997.
30. Fouchier SM, Moller GM, Van Santen-Hoeufft M, Faber CG, Smeenk FWJM, Drent M.
Succesvolle behandeling met infliximab van een patient met therapieresistente sarcodose.
[Successful treatment with infliximab of a patient with refractory sarcoidosis]. Ned Tijdschr
Geneeskd 2004; 148: 24462450.
31. Hoitsma E. Small fiber neuropathy. A novel finding in sarcoidosis. PhD thesis. Maastricht,
Maastricht University, 2005.
32. De Vries J, Drent M. Quality of Life and Health Status in Sarcoidosis. In: Baughman RP, ed.
Sarcoidosis. New York, NY, Marcel Dekker, 2005; (In press).
33. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with
Crohns disease. N Engl J Med 1999; 340: 13981405.
34. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor a

102
 FATIGUE IN SARCOIDOSIS

monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant

methotrexate: a randomised phase III trial. Lancet 1999; 354: 19321939.
35. Sharpe M, Chalder T, Palmer I, Wessely S. Chronic fatigue syndrome. A practical guide to
assessment and management. Gen Hosp Psychiatry 1997; 19: 185199.
36. Toda G, Shibata S, Nakamizo R, Seto S, Yano K. Effect of physical exercise training on health-
related quality of life and exercise tolerance in patients with left ventricular dysfunction. J Cardiol
2004; 44: 179187.
37. Curtis JR, Patrick DL. The assessment of health status among patients with COPD. Eur Respir J
2003; 21: Suppl. 41, 36s45s.
38. Bradley C. Importance of differentiating health status from quality of life. Lancet 2001; 357: 7
8.
39. De Vries J. Quality of life assessment. In: Vingerhoets AJJM, ed. Assessment in Behavioral
Medicine. Hove, Brunner-Routledge, 2001; pp. 353370.
40. Testa MA. Methods and applications of quality-of-life measurement during antihypertensive
therapy. Curr Hypertens Rep 2000; 2: 530537.
41. Montazeri A, Milroy R, Gillis CR, McEwen J. Quality of life: perception of lung cancer patients.
Eur J Cancer 1996; 32A: 22842289.
42. World Health Organization Quality of Life Group. The World Health Organization quality of life
assessment (WHOQOL): position paper from the World Health Organization. Soc Sci Med 1995;
41: 14031409.
43. OCarroll RE, Cossar JA, Couston MC, Hayes PC. Sensitivity to change following liver
transplantation: a comparison of three instruments that measure quality of life. J Health Psychol
2000; 5: 6974.
44. World Health Organization Quality of Life Group. The World Health Organisation quality of life
assessment (WHOQOL): development and general psychometric properties. Soc Sci Med 1998; 46:
15691585.
45. De Vries J. Beyond health status: construction and validation of the Dutch WHO Quality of Life
Instrument. PhD thesis. Tilburg, Tilburg University, 1996.
46. Guyatt GH, Berman LB, Townsend M, Pugsley SO, Chambers LW. A measure of quality of life
for clinical trials in chronic lung disease. Thorax 1987; 42: 773778.
47. Guyatt GH, Townsend M, Keller J, Singer J, Nogradi S. Measuring functional status in chronic
lung disease: conclusions from a randomised control trial. Respir Med 1989; 83: 293297.
48. Wijkstra PJ, Ten Vergert EM, Van Altena R, et al. Reliability and validity of the Chronic
Respiratory Questionnaire (CRQ). Thorax 1994; 49: 465467.
49. Chang JA, Curtis JR, Patrick DL, Raghu G. Assessment of health-related quality of life in patients
with interstitial lung disease. Chest 1999; 116: 11751182.
50. Ware JE Jr, Snow KK, Gandek B. SF-36 Health Survey. Manual and Interpretation Guide.
Boston, The Health Institute, New England Medical Center, 1993.
51. Bowling A. Measuring Disease: A Review of Disease-Specific Quality of Life Measurement Scales.
Buckingham, Open University Press, 1995.
52. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile: development and
final revision of a health-status measure. Med Care 1981; 19: 787805.
53. Jones PW, Quirk FH, Baveystock CM. The St Georges Respiratory Questionnaire. Respir Med
1991; 85: 2531.
54. Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J
Respir Crit Care Med 1997; 155: 12831289.
55. Jones PW, Nedocromil Sodium Quality of Life Study Group. Quality of life, symptoms and
pulmonary function in asthma: long-term treatment with nedocromil sodium examined in a
controlled multicentre trial. Eur Respir J 1994; 7: 5562.
56. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for
chronic airflow limitation: the St Georges Respiratory Questionnaire. Am Rev Respir Dis 1992;
145: 13211327.

103
 J. DE VRIES, R.M. WIRNSBERGER

57. Wirnsberger RM, De Vries J, Jansen TL, Van Heck GL, Wouters EF, Drent M. Impairment of
quality of life: rheumatoid arthritis versus sarcoidosis. Neth J Med 1999; 54: 8695.
58. De Vries J, Drent M, Van Heck GL, Wouters EFM. Quality of life in sarcoidosis: a comparison
between members of a patient organization and a random sample. Sarcoidosis Vasc Diffuse Lung
Dis 1998; 15: 183188.
59. Wirnsberger RM, Drent M, Hekelaar N, et al. Relationship between respiratory muscle function
and quality of life in sarcoidosis. Eur Respir J 1997; 10: 14501455.
60. Rabin DL, Richardson MSA, Stein SR, Yeager H Jr. Sarcoidosis severity and socioeconomic
status. Eur Respir J 2001; 18: 499506.
61. Rabin DL, Thompson B, Brown KM, et al. Sarcoidosis: social predictors of severity at
presentation. Eur Respir J 2004; 24: 601608.
62. Stavem K, Bjrtuft , Lund MB, Kongshaug K, Geiran O, Boe J. Health-related quality of life in
lung transplant candidates and recipients. Respiration 2000; 67: 159165.
63. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 198204.

104
CHAPTER 8

Pulmonary sarcoidosis

J.P. Lynch 3rd*, E.S. White#

*Division of Pulmonary, Critical Care Medicine and Hospitalists, Dept of Internal Medicine, The David
Geffen School of Medicine, University of California, Los Angeles, CA, and #Division of Pulmonary and
Critical Care Medicine, Dept of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI,
USA.

Correspondence: J.P. Lynch 3rd, The David Geffen School of Medicine at the University of California,
Division of Pulmonary, Critical Care Medicine, and Hospitalists, 10833 Le Conte Ave, 37-131 CHS, Los
Angeles, CA 90095, USA. Fax: 1 3102068622; E-mail: jplynch@mednet.ucla.edu

Sarcoidosis can affect any organ system [1], but pulmonary manifestations typically
dominate [2]. Abnormalities on chest radiographs are detected in 8595% of patients [2
7]. However, 3060% of patients with sarcoidosis are asymptomatic, with incidental
findings on chest radiographs [2, 6, 8, 9]. The clinical course is heterogeneous;
spontaneous remissions occur in nearly two-thirds of patients, but the course is chronic
in 1030% [37, 10]. Chronic, progressive pulmonary sarcoidosis may result in severe
respiratory failure [11]. Fatality rates ascribed to sarcoidosis range from 25% [35, 12
14], but rates are lower (v1%) in nonreferral settings [69]. In the USA, 87% of deaths
attributed to sarcoidosis were secondary to pulmonary complications [15]. In contrast, in
Japan, 77% of deaths resulted from cardiac involvement.

Clinical features of pulmonary sarcoidosis

Nonproductive cough, dyspnoea and chest pain are the most common features of
pulmonary sarcoidosis, occurring in 3050% of patients [16]. These features may be more
prominent in patients with significant endobronchial or pulmonary parenchymal
involvement [2, 17]. In contrast to idiopathic pulmonary fibrosis (IPF), physical findings
are usually minimal or absent in pulmonary sarcoidosis. Crackles are present inv20% of
patients with sarcoidosis, even when radiographic infiltrates are extensive [2]. Clubbing,
which is observed in 2550% of patients with IPF [18], is rarely observed in sarcoidosis
[2]. Fatigue [19] and impaired quality of life (QoL) [20] are far more common among
patients with sarcoidosis compared with healthy controls. In one study, the extent of
fatigue correlated inversely with the carbon monoxide diffusing capacity of the lung
(DL,CO), but not with forced expiratory volume in one second (FEV1), forced vital
capacity (FVC), radiographic stage or serological parameters [19].

Chest radiographic features in sarcoidosis

Chest radiographs are abnormal in w85% of patients with sarcoidosis [27]. The most
characteristic finding (present in 5085% of cases) is bilateral hilar lymphadenopathy
(BHL), often with concomitant enlargement of the right paratracheal lymph nodes [2].
Lymph node involvement at other intrathoracic sites is often present by computed
tomography (CT) scans [21, 22]. Unilateral hilar lymphadenopathy on CT is uncommon,
Eur Respir Mon, 2005, 32, 105129. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
105
 J.P. LYNCH, E.S. WHITE

occurring in v10% of cases [23]. Pulmonary parenchymal infiltrates (with or without

BHL) are present in 2550% of patients with sarcoidosis, and preferentially involve the
central (rather than peripheral) regions and upper lobes [2, 6]. Large bullae [24, 25], cystic
bronchiectasis, or enlarged pulmonary arteries (attributable to secondary pulmonary
arterial hypertension (PAH)) may complicate advanced stage III or IV sarcoidosis [26].
Rare features (occurring in 13% of patients) include pleural effusions [27], unilateral
segmental infiltrates or mass lesions, unilateral hilar adenopathy, large nodular opacities
simulating metastases [28, 29], cavitation [30, 31], and diffuse ground-glass opacities [2,
32]. The radiographic features of sarcoidosis are discussed in detail in chapter 18 of this
monograph, and will not be reiterated here.

Radiographic classification schema

The radiographic staging system for pulmonary sarcoidosis was developed more than
four decades ago [5]. This classification schema defines the following stages: stage 0
(normal); stage I (BHL without pulmonary infiltrates; fig. 1); stage II (BHL plus
pulmonary infiltrates; fig. 2); stage III (parenchymal infiltrates without BHL; fig. 3).
Stage IV (not universally adopted) refers to extensive fibrosis with distortion or bullae [6,
33] (table 1).
Although individual exceptions exist, the prognosis is best with stage I, intermediate
with stage II, and worst with stage III or IV. Spontaneous remissions occur in 6090% of
patients with stage I disease, 4070% with stage II, 1020% with stage III, and 0% with
stage IV [36, 14, 34, 35].
The long-term prognosis is often dictated by the evolution of the disease within the first
23 yrs. Several series cited improvement or stability in chest radiographs in w70% of
sarcoidosis patients within 23 yrs of follow-up. Furthermore, several studies noted that
spontaneous remission predicted a low rate (v10%) of late relapse [3537].
In a study from New South Wales (Australia), chest radiographs normalised in 112 out
of 150 (75%) patients presenting with stage I or II sarcoidosis [38]. In a cohort of

a) b)

Fig. 1. a) Posteroanterior and b) lateral chest radiographs of a patient with stage I sarcoidosis. Notice the
prominence of the hilae on the posteroanterior radiograph. White arrows on the lateral radiograph point to
enlarged mediastinal lymph nodes.

106
 PULMONARY SARCOIDOSIS

a) b)

Fig. 2. a) Posteroanterior and b) lateral chest radiographs of a patient with stage II pulmonary sarcoidosis.
Note the prominence of the hilae and enlarged mediastinal lymph nodes. Also seen are increased upper-lobe
predominant parenchymal infiltrates.

a) b)

Fig. 3. a) Posteroanterior and b) lateral chest radiographs of a patient with stage III/IV sarcoidosis. Note the
hilar retraction due to thick fibrous bands in the mid-lung fields. No significantly enlarged hilar or mediastinal
lymph nodes are seen.

Japanese patients with sarcoidosis, chest radiographs cleared within 3 yrs in 68% [39]. A
study of 193 Spanish sarcoidosis patients detected persistent abnormalities on chest
radiographs in only 22%, 2 yrs after diagnosis [40]. Failure to remit within 2 yrs
predicted a chronic or persistent course [40]. A subsequent Danish study showed that
85% of spontaneous remissions occurred within 2 yrs of presentation [4]. Further, among
patients who remained in stage II after 2 yrs of observation, chest radiographs eventually

107
 J.P. LYNCH, E.S. WHITE

Table 1. Radiographic staging of sarcoidosis

Stage Radiographic Finding

Stage 0 Normal chest radiograph
Stage I Bilateral hilar/mediastinal lymphadenopathy
Stage II Bilateral hilar/mediastinal lymphadenopathy plus interstitial infiltrates
Stage III Interstitial infiltrates without evidence of hilar/mediastinal lymphadenopathy
Stage IV# Dense fibrosis, bullae formation, architectural distortion
Adapted from SCADDING et al. [5]. #: not included in the original staging schema, and not
universally accepted.

normalised in only 12% [4]. A recent prospective study in the USA followed 215
sarcoidosis patients for 2 yrs [10]. In most patients, pulmonary function, radiographic
stage, and dyspnoea scale did not change during the 2-yr period. Spirometry worsened in
12%. Only 11 out of 176 (6%) with stage 0, I, or II disease progressed to stage III or IV
over the 2-yr follow-up period. A total of 50 patients (23%) developed one or more new
organ involvement during that time frame [10].
Differing prognoses between studies may reflect ethnic, geographic, or referral biases
[41]. A large cohort of 437 Finnish and 457 Japanese patients were followed for 5 yrs [41].
Chest radiographs normalised within 1 yr in 46% of Japanese but only 16% of Finnish
patients. After 5-yrs follow-up, the rates were 73% and 40%, respectively (pv0.001).
During the 5-yr period, 28 out of 142 (20%) Finnish patients and 43 out of 309 (14%)
Japanese patients with initial stage I lesions developed parenchymal infiltrates. At 5 yrs,
among patients with initial stage II disease, chest radiographs were normal in 73% of
Japanese and 36% of Finnish patients. Among patients with initial stage III disease, chest
radiographs had normalised in 35% and 24% of Japanese and Finnish patients,
respectively [41].

Additional prognostic factors

Besides the radiographic stages, other clinical factors have prognostic value. The
presence of acute inflammatory manifestations (i.e., erythema nodosum, polyarthritis
and fever) portend an excellent prognosis, with high rates (w85%) of spontaneous
remission [3, 10, 35, 42]. In contrast, factors associated with a poor prognosis and a
chronic or relapsing course include: Black race [10, 4345]; age of onset w40 yrs [3, 40];
hypercalcaemia [3]; extrathoracic disease [3, 43]; lupus pernio [3]; splenomegaly [40];
pulmonary infiltrates on chest radiograph [3, 40]; chronic uveitis, cystic bone lesions,
nasal mucosal sarcoidosis [3]; central nervous system and cardiac involvement; and lower
annual family income [10].

CT scans
CT scans are superior to conventional chest radiographs in delineating parenchymal,
mediastinal, and hilar structures [21, 26, 46, 47]. Characteristic features of sarcoidosis on
CT include mediastinal and/or hilar lymphadenopathy, nodular opacities and
micronodules along bronchovascular bundles, predilection for mid and upper lung
zones, an axial distribution, pleural or subpleural nodules, septal and nonseptal lines,
confluent nodular opacities with air-bronchograms (i.e., consolidation), and ground-
glass opacities [26, 48] (fig. 4). With advanced disease, architectural distortion, hilar
retraction, fibrous bands, bronchiectasis, cystic radiolucencies, bullae, and enlarged

108
 PULMONARY SARCOIDOSIS

Fig. 4. High-resolution computed tomography of the chest in a patient with sarcoidosis. Innumerable nodules
are seen throughout the parenchyma, involving both upper and lower lobes. Hilar lymph nodes (white arrows)
are mildly enlarged.

pulmonary arteries may be observed [22, 26, 49, 50]. Despite the enhanced accuracy of
CT, routine CT is not necessary or cost-effective in the management of sarcoidosis [51].
Chest CT scans may be helpful in the following circumstances: atypical clinical or chest
radiographic findings [16, 26], or to detect specific complications in the lung (e.g.,
bronchiectasis, aspergilloma, pulmonary fibrosis, superimposed infection or malig-
nancy). In a study by Remy-Jardin et al. [52], no correlation was found between CT
features and bronchoalveolar lavage (BAL) or other parameters of disease activity, either
at presentation or at follow-up [52]. Furthermore, findings on initial CT scan have
limited prognostic value, since the disease has potential to evolve over time. Despite these
limitations, high-resolution thin-section CT (HRCT) may be helpful in selected patients
with stage II or III disease to discriminate active inflammation from fibrosis. Nodules,
ground-glass opacities, consolidation, or alveolar opacities suggest granulomatous
inflammation, which may reverse with therapy [53, 54]. In contrast, honeycomb change,
cysts, coarse broad bands, distortion, or traction bronchiectasis indicate irreversible
fibrosis [49, 55]. The salient features and role of CT in the management of sarcoidosis are
addressed in chapter 18 of this monograph.

Pulmonary function tests in sarcoidosis

Aberrations in pulmonary function tests (PFTs) are present in y20% of patients with
radiographic stage I sarcoidosis, but in 4080% of patients with parenchymal infiltrates
(stages II, III, or IV) [24, 33, 56, 57]. Reductions in lung volumes (e.g., vital capacity
(VC) and total lung capacity (TLC)) are characteristic; the DL,CO is often reduced, but is
less pronounced in sarcoidosis than in IPF [2, 58]. Even in the setting of a normal chest
radiograph (stage 0), reductions in FVC or DL,CO occur in 1525% and 2550% of
patients, respectively [56, 59]. Oxygenation is usually preserved until late in the course
of sarcoidosis [2].
Airflow obstruction (e.g., reduced FEV1 and expiratory flow rates) and bronchial
hyperreactivity occur in 3050% of sarcoid patients with pulmonary parenchymal
involvement [57, 5961]. In one study of 107 patients with newly diagnosed sarcoidosis,

109
 J.P. LYNCH, E.S. WHITE

the FEV1/FVC ratio was reduced in 61 patients (57%), reductions in DL,CO were noted in
29 (27%), but only seven (6%) manifested restriction [59]. Airflow obstruction was more
frequent with worsening radiographic stage. In another study of 18 patients with
sarcoidosis, all of whom had reduced lung volumes or DL,CO, concomitant airways
obstruction was present in all 18 when sensitive tests were employed (e.g., frequency
dependence of compliance, airway resistance, closing volumes) [62]. Airflow obstruction
may be suggested on CT when bronchial mural thickening, small airway narrowing, or
patchy air trapping is present [6365]. Patients with advanced pulmonary sarcoidosis
(radiographic stages III or IV) may exhibit severe decrements in FEV1/FVC [57]. Viskum
and Vestbo [66] noted a higher mortality risk (OR=1.9) among sarcoid patients with a
percentage of predicted (% pred) FEV1/FVC ratio v70% compared with patients with
w70% pred. Airflow obstruction may reflect narrowing of bronchial walls (via
granulomatous lesions or fibrotic scarring) [6769]; peribronchiolar fibrosis [70];
compression by enlarged lymph nodes [2]; airway distortion caused by pulmonary
fibrosis [57, 71]; small airways disease [59, 62, 72]; or bronchial hyperreactivity [17].
Increased airway hyperreactivity in response to methacholine has been noted in patients
with sarcoidosis [73, 74]. In one study, 50% of patients with stage I or II sarcoidosis
exhibited bronchial hyperreactivity following methacholine challenge [17]. Clinically, this
may manifest as chronic, hacking cough. The mechanism of this bronchial
hyperreactivity has not been elucidated, but likely reflects granulomatous inflammation
involving the bronchial mucosa [67]. Clinical bronchiectasis is a rare complication of
stage IV sarcoidosis [75].
Impaired inspiration muscle endurance (IME) was noted in sarcoid patients with
normal lung function compared with healthy controls [76]. Recently, Brancaleone et al.
[77] corroborated reductions in IME in a cohort of sarcoid patients that correlated with
impairments in health-related QoL.
Alterations in cardiopulmonary exercise tests (CPETs) have been noted in 2847% of
patients with sarcoidosis [71, 7880]. Typical aberrations include ventilatory limitation,
increased dead space/tidal volume (VT) or widened alveolar-arterial O2 gradient with
exercise [71, 78]. CPETs may be abnormal when static PFTs are normal [71, 75]. In one
study of 30 sarcoidosis patients with normal spirometry, ventilatory abnormalities were
noted during maximal exercise testing in 14 (47%) [71]. A prospective study of 19 sarcoid
patients with normal PFTs (including DL,CO) and normal echocardiograms noted
reductions in maximal workload, maximal oxygen consumption (V9O2,max), VT and heart
rate compared with age- and sex-matched healthy sedentary controls [75]. Exercise
limitation in sarcoidosis patients without pulmonary impairment could reflect an
impaired heart rate response to exercise.
Exercise-induced desaturation usually correlates with reductions in DL,CO [71, 79, 81,
82]. Karetzky and McDonough [79] found that DL,COv55% had a high sensitivity
(85%) and specificity (91%) in predicting a fall in arterial oxygen tension (Pa,O2) with
exercise in patients with pulmonary sarcoidosis [79]. Arterial desaturation and DL,CO
correlate with the extent and severity of sarcoidosis as assessed by CT [81]. In a recent
study, alveolar membrane diffusing capacity and DL,CO were the strongest predictors of
gas exchange abnormalities during exercise [83]. In contrast, neither lung volumes nor
expiratory flow rates correlated with exercise gas exchange parameters [83]. Arterial
desaturation with exercise is rare in patients with radiographic stage I disease or
preserved DL,CO [82].
One study of patients with mild pulmonary sarcoidosis noted abnormalities on CPETs
in nine out of 20 patients (45%) [78]. Reduced V9O2,max at the anaerobic threshold was
low, and/or the rate of increase of V9O2,max was abnormal relative to work rate or heart
rate, suggesting a defect in cardiac circulatory function. Resting and exercise
echocardiography revealed normal left ventricular function in all patients, but right

110
 PULMONARY SARCOIDOSIS

ventricular dysfunction or hypertrophy was evident in five. Abnormal response of

V9O2,max during exercise may reflect subclinical right heart dysfunction.
Although CPETs is more sensitive than static PFTs in predicting work and exercise
capacity, the practical value of CPETs is limited. Spirometry and oximetry are usually
adequate to follow the course of the disease. For patients with more severe disease, a
noninvasive 6-minute walk test provides additional quantitative data.
Physiological aberrations correlate only roughly with histological severity of the
disease [70, 8487]. Three quantitative morphometric studies of 162 open lung biopsies
from patients with sarcoidosis found that no physiological parameter predicted the
histologic severity of the disease [70, 85, 86]. Mean values of physiological parameters
were lower among patients with advanced fibrosis and least deranged with mild disease,
but the degree of overlap was considerable. Importantly, none of the physiological
parameters discriminate alveolitis (which might be amenable to therapy) from
irreversible fibrosis [86, 87].
The extent of pulmonary physiological impairment correlates with severity of disease
by chest radiographs [8891] or CT scanning [21, 22, 52, 90], but correlations are
imprecise. The extent of disease on CT scans correlates only modestly with functional
impairment [22, 52, 90]. Correlations between physiological parameters and HRCT are
improved when semi-quantitative scoring systems are applied [52, 90, 92, 93]. Semi-
quantitative scores from CT scans correlated inversely with FVC (r=-0.81) and to a lesser
extent, with DL,CO (r=-0.49) [21]. Hansell et al. [94] confirmed inverse correlations
between a reticular pattern on HRCT scan and several physiological parameters (i.e.,
FVC, FEV1, FEV1/FVC, and DL,CO [94]. Muers et al. [92] noted that reticular and
fibrotic abnormalities on HRCT scan correlated modestly with physiological aberra-
tions, but mass lesions or confluence did not. The pattern of CT may reflect underlying
pathology. A honeycomb pattern is most often associated with restriction and low DL,CO,
whereas bronchial distortion is usually associated with lower expiratory flow rates [50]. A
linear pattern was associated with the least functional impairment [50]. More recently,
Drent et al. [95] found that HRCT correlated with several physiological parameters (i.e.,
FEV1, FVC, DL,CO, maximum Pa,O2), and was more sensitive than chest radiographs in
detecting pulmonary disability or abnormal gas exchange [95]. In the study by Drent
et al. [95], specific findings on CT (e.g., thickening or irregularity of bronchovascular
bundles, intra-parenchymal nodules, septal and nonseptal lines, and focal pleural
thickening) correlated with pulmonary functional impairment, whereas other features
(e.g., focal consolidations, ground-glass opacities, or enlarged lymph nodes) were of
minor importance [95]. One recent study examined initial and follow-up HRCT scans in
40 patients with pulmonary sarcoidosis [96]. Predominantly nodular or multiple large
nodules disappeared of decreased in size at follow-up. A conglomeration pattern shrank
and evolved into bronchial distortion and a decline in FEV1/FVC ratio [96].
Interestingly, ground-glass opacities and consolidation evolved into honeycombing,
and were associated with a decline in FVC [96]. Given the imprecise correlations between
CT and physiological parameters, direct measurement of PFTs is critical to assess the
extent and degree of pulmonary functional impairment.

Influence of pulmonary function on prognosis

Although physiological parameters at the onset do not predict long-term outcome in
patients with sarcoidosis [56, 9799], mortality is higher among patients with severe
physiological impairment [11]. Sequential studies are important to follow the course of
the disease and assess response to therapy. Several studies have shown that VC improves

111
 J.P. LYNCH, E.S. WHITE

more frequently than DL,CO [56, 100, 101], TLC [102], or arterial oxygenation [87].
Importantly, changes in VC and DL,CO are usually concordant (in the same direction);
discordant (opposite direction) changes occur in v5% of patients [10, 87]. A recent
prospective study in the USA found excellent concordance between changes in FVC and
FEV1 in a cohort of 193 sarcoidosis patients [10]. Changes in FVC and FEV1 were
concordant in 155 patients (80.3%) but were never discordant. Measurement of oxygen
saturation at rest or during exercise is no more sensitive than VC or DL,CO [87]. Given the
variability of DL,CO [56], and the expense of obtaining lung volumes, spirometry and
flow-volume loops are the most useful and cost-effective parameters to follow the course
of the disease. Additional studies, such as DL,CO, TLC, or gas exchange have a role in
selected patients.
Criteria for assessing "response" or improvement have not been validated. Most
investigators define a change in FVC w1015% or DL,CO w20% as significant [87, 103].
Responses to therapy are usually evident within 612 weeks of initiation of therapy [56, 104].

Laboratory features
Serum angiotensin converting enzyme (ACE) is increased in 3080% of patients with
sarcoidosis, and may be a surrogate marker of total granuloma burden [2, 105]. False
positives are noted in v20% of patients with other pulmonary disorders. However, ACE
may be normal in patients with active disease. The present authors believe ACE provides
ancillary information when the activity of sarcoidosis is uncertain on clinical grounds.
However, ACE should never be used in isolation to dictate therapeutic interventions.
More recently, Rothkrantz-Kos et al. [106] found that serum levels of soluble
interleukin (IL)-2 receptor (sIL-2R) appeared to be more useful for monitoring disease
severity in sarcoidosis. Moreover, others have demonstrated that extrapulmonary
manifestations of sarcoidosis are accompanied by increases in sIL-2R, suggesting that
sIL-2R may serve as a marker of disease activity [107].
Historically, the Kveim-Siltzbach skin test was used to diagnose sarcoidosis [108]. The
current authors see no current clinical role for the Kveim-Siltzbach skin test [109].

BAL in sarcoidosis
Interaction between alveolar macrophages and T-helper (Th) CD4z cells leads to a
Th1-skewed cytokine profile that drives the granulomatous process [109]. Lung T-cells
from patients with sarcoidosis spontaneously release Th1 cytokines, such as interferon
(IFN)-c [110] and IL-2 [111].
Clinical manifestations of pulmonary sarcoidosis depend on the intensity of alveolar
inflammation. In some cases, the alveolitis remains subclinical, whereas others present
with cough, dyspnoea, or chest pain. Alveolitis in sarcoidosis reflects a local expression of
a disseminated immunological reaction. Interestingly, in cases of extrathoracic
sarcoidosis where pulmonary symptoms are clinically lacking, features of an alveolitis
suspicious for sarcoidosis can be found, and, therefore, BAL fluid analysis may be of
additional diagnostic value [112]. Typically, BAL fluid in pulmonary sarcoidosis reveals
lymphocytosis, low or normal granulocytes, and an increased CD4z/CD8z ratio [113
115]. These features are not specific, as there is overlap between other interstitial lung
disorders [113, 115]. However, BAL fluid cell profiles may narrow the differential
diagnosis [113, 115]. BAL has provided invaluable insight into the pathogenesis of
sarcoidosis [109]. Recently, it was demonstrated that the number of polymorphonuclear

112
 PULMONARY SARCOIDOSIS

neutrophils in BAL fluid is useful to distinguish sarcoidosis patients with a more

favourable outcome from those having a more severe course [116, 117]. Furthermore,
increased numbers of mast cells in BAL fluid [73, 118] were associated with a worse
prognosis in some studies, but significant variability exists.
Most studies have found no significant correlations between initial BAL CD4z/CD8z
ratios and subsequent outcome or response to therapy. In fact, intense alveolitis is
characteristic of Lofgrens syndrome, which spontaneously remits in w85% of patients
[114, 119, 120]. Provided its limitations are kept in mind and considered in the context of
information gained from conventional ancillary diagnostic tests, together with a
thorough clinical evaluation, there appears to be a place for BAL in the diagnostic work-
up of pulmonary inflammation, including sarcoidosis.

Radionuclide techniques
Radionuclide techniques (e.g., 67gallium (Ga) citrate [121, 122]), scintigraphy with
somatostatic analogues (111In-pentreotide [123] or 99mtechnetium-labelled depreotide
[124]) or fluoro-2-deoxyglucose positron emission tomography scans [125127] have been
employed to diagnose or stage sarcoidosis. The role of these techniques is reviewed in
depth in chapter 19 of this monograph.

Diagnosis of pulmonary sarcoidosis

Flexible fiberoptic bronchoscopy with transbronchial lung biopsy (TBLB) achieves
diagnostic yields of 6090%, even among patients with radiographic stage I disease [128,
129]. Transbronchial needle aspiration biopsies (TBNA) with Wang 18-, 19- or 22-gauge
cytology needles are diagnostic in 6390% of patients with mediastinal and/or hilar
adenopathy on chest CT [23, 130135]. The combination of TBNA and TBLB may have
a higher yield than either procedure alone [136]. Diagnostic cytological criteria for
sarcoidosis by TBNA include: the presence of epithelioid cell granulomas, lymphocytes,
clusters or palisading epithelioid histiocytes, multinucleated giant cells with no or
minimal necrosis; and negative stains for fungi and acid-fast bacteria [23, 134]. Damage
to the bronchoscope may complicate TBNA, particularly when performed by individuals
with limited experience [137]. One study suggested that fine-needle aspiration (FNA) is
underutilised to diagnose sarcoidosis and is cost-effective [138].

Mediastinal lymph node biopsies

CT-guided transthoracic FNA, with or without core needle biopsy, may be useful to
diagnose malignant or benign lesions involving mediastinal or subcarinal lymph nodes
(yields up to 78%) [139]. Complications of transthoracic FNA include pneumothoraces
(1060%) and haemoptysis (510%) [139]. Severe bleeding is rare, but has been described
with core biopsy. Endoscopic ultrasound (EUS)-guided FNA has been used to diagnose
mediastinal masses, primarily in patients with suspected malignancy [140], but experience
is limited in patients with sarcoidosis [141]. EUS gives an excellent overview of
mediastinal structures, including the paraoesophageal space, aortopulmonary window,
subcarinal region [142].
Surgical procedures to access mediastinal nodes include: 1) cervical mediastinoscopy
[143145]; the Chamberlain procedure (a parasternal mini-thoracotomy to biopsy

113
 J.P. LYNCH, E.S. WHITE

aortopulmonary window or para-aortic nodes), and video-assisted thoracoscopic

surgical biopsy (VATS). Currently, VATS can be performed safely in an outpatient
setting [146, 147] and is preferred over traditional thoracotomy.

Specific complications of intrathoracic sarcoidosis

Necrotising sarcoid angiitis
Necrotising sarcoid angiitis and granulomatosis, initially described by Liebow in 1973
[148], is a variant of sarcoidosis characterised by pulmonary vasculitis, granulomas, and
pulmonary nodules on chest radiographs [149153]. Histological features include: 1) a
granulomatous vasculitis involving arteries and veins; 2) confluent non-necrotising
granulomata involving the bronchi, bronchioles, and lung; 3) variable degrees of fibrosis;
and 4) extensive parenchymal necrosis [149, 152]. Systemic vasculitis does not occur.
Clinical and radiographic features of necrotising sarcoid angiitis and granulomatosis are
similar to "nodular sarcoid" [28, 154156]. Cardinal histological features of nodular
sarcoidosis are focal nodules composed of masses of granulomas and hyalinised
connective tissue [154]. The present authors believe that necrotising sarcoid angiitis and
nodular sarcoid are simply variants of sarcoidosis. Prognosis of these entities is generally
excellent. The disease resolves (either spontaneously or in response to therapy) in most
patients.

Bronchostenosis
Stenosis or compression of bronchi may result from granulomatous inflammation of
the bronchial wall, extrinsic compression from enlarged hilar nodes, or distortion of
major bronchi caused by end-stage parenchymal sarcoidosis [68, 69, 157159]. Atelectasis
of involved lobes or segments (particularly the right middle lobe) may result [157, 158,
160162]. Bronchostenosis was detected in 226% of patients with sarcoidosis
undergoing bronchoscopy in two studies [68, 159]. One retrospective study of 2,500
patients with sarcoidosis identified 18 patients with w50% stenosis of proximal bronchi
[69]. Three bronchoscopic patterns were observed, including single focal stenosis,
multiple focal stenoses and diffuse narrowing of the bronchial tree [69]. The bronchial
mucosa appeared oedematous and inflamed at the site of stenosis in all cases.
Endobronchial biopsies showed noncaseating granulomata in 77% of patients [69].
Typical clinical features of proximal endobronchial stenosis include dyspnoea, cough,
wheezing and extrapulmonary manifestations [68, 69]. Wheezing, high-pitched
inspiratory "squeaks", or stridor may be evident on chest auscultation in patients with
symptomatic bronchostenosis [68]. Helical CT scans are useful to determine the extent
and nature of stenotic lesions in the lower respiratory tract [63], but false positive results
were noted in 8% [63] and 14% [163] of cases in two series. Early initiation of
corticosteroid therapy may be efficacious in ameliorating symptoms and pulmonary
dysfunction. Conversely, delay in therapy may result in acquired fixed stenoses and
persistent ventilatory defects [69]. Dilatation of endobronchial stenoses may provide
relief in patients who are refractory to medical therapy [164].

Mycetomas
Mycetomas (typically due to Aspergillus spp.) may develop in cystic spaces (typically
in the upper lobes) in patients with advanced (radiographic stage III or IV) sarcoidosis

114
 PULMONARY SARCOIDOSIS

[165167]. Ipsilateral pleural thickening usually antedates the fungus ball or air-crescent
sign [168]. Mycetomas are often asymptomatic, but fatal haemorrhage can occur when
Aspergillus invades vessel walls [161, 166, 169]. Surgical resection is advised for localised
lesions in patients able to tolerate surgery [165167]. However, surgery may be
contraindicated in patients with severe parenchymal disease or extensive pleural adhesions
[166, 167]. In such cases, topical or intracavitary therapy has been tried, with anecdotal
successes, but experience is limited [170, 171]. Systemic antifungal therapy is of unproven
value. Bronchial embolisation has been successful to control intractable bleeding [165].

Pleural involvement in sarcoidosis

Clinically-significant pleural manifestations (e.g., pneumothorax, pleural effusions,
chylothorax, or pleural thickening) occur in 24% of patients with sarcoidosis [27, 172
174]. Sarcoid pleural effusions may be either transudative or exudative; lymphocytosis
occurs in two-thirds of cases [27, 172]. Pneumothorax may complicate advanced
fibrocystic sarcoidosis [173]. Chylothorax is a rare complication of sarcoidosis (only a
few cases have been described) [2, 175177].

Pulmonary vascular involvement in sarcoidosis

As sarcoid granulomatous lesions follow pulmonary vessels, incidental histological
involvement is common, noted in 4289% of open lung biopsies from patients with
pulmonary sarcoidosis [70, 178]. However, clinically significant pulmonary vascular
involvement is uncommon. PAH has been noted in 15% of patients with sarcoidosis
[179183]. The incidence is considerably higher among patients with advanced fibrocystic
sarcoidosis [184187]. Mechanism(s) responsible for PAH in sarcoidosis probably
include: 1) hypoxic vasoconstriction [180]; 2) infiltration and/or obliteration of the
pulmonary vasculature by the granulomatous, fibrotic response [188]; and/or 3) extrinsic
compression of major pulmonary arteries by enlarged lymph nodes [179]. In one study of
patients with stage III sarcoidosis, pulmonary artery (PA) pressures were elevated in 50%
of patients at rest and 100% during exercise [184]. Chest CT scans may be useful to
predict the presence of PAH in patients with parenchymal lung disease [189]. CT features
which suggest PAH include: main PA diameter w29 mm; segmental artery-to-bronchus
ratiow1:1 in three out of four lobes [189]; ratio of the diameter of the main PA and of the
ascending aortaw1 [190]. Two recent studies evaluated PA pressures in patients with end-
stage pulmonary sarcoidosis awaiting lung transplantation (LT) [185187]. Pulmonary
hypertension was an independent predictor of mortality among patients with sarcoidosis
listed for LT [185, 187]. The role of vasodilators in sarcoidosis-associated PAH has not
been elucidated, but short- and long-term responses were noted in case reports [180] or
small series [188, 191].
Other rare vascular complications of sarcoidosis (limited to a few case reports) include:
pulmonary arterial stenoses from granulomatous involvement of the vessels [192, 193];
extrinsic compression of pulmonary arteries by enlarged hilar lymph nodes [194, 195] or
fibrosing mediastinitis [2]; and pulmonary veno-occlusive disease (resulting from
obstruction of interlobular septa veins by graulomata or perivascular fibrosis) [196, 197].

Superior vena cava syndrome

Rarely, extensive fibrosis of mediastinal or vascular structures results in narrowing or
obstruction of innominate veins [198], superior vena cava (SVC) [199], or bronchi [200] in

115
 J.P. LYNCH, E.S. WHITE

patients with sarcoidosis. The current authors are aware of only six published cases of
SVC syndrome complicating sarcoidosis [193, 199, 201204]. Extensive mediastinal
lymphadenopathy compressing the SVC was a universal feature.

Pulmonary embolism
Sarcoidosis involving the lung has been linked to pro-coagulant activity in BAL fluid
[205], and published case reports have described patients with sarcoidosis and vascular
thrombosis in the absence of known risk factors [206, 207], thus, raising the question of
an association between sarcoidosis and venous thromboembolic disease. To the best of
the present authors knowledge, no reports defining such an association have been
published. However, the presentation of sarcoidosis is known to mimic acute pulmonary
embolism. Numerous case reports have described patients presenting with acute onset
chest pain and dyspnoea accompanied by ventilation-perfusion studies, suggestive of
pulmonary embolism [208212]. Subsequent evaluation (with either pulmonary
angiogram or 67Ga scanning) demonstrated evidence of pulmonary (and, in some
cases, extrapulmonary) sarcoidosis with compression of lobar or segmental pulmonary
arteries by enlarged lymph nodes. Furthermore, serological testing for D-dimer in
suspected pulmonary embolism may potentially confound the diagnosis of sarcoidosis.
In one study of 28 patients with newly diagnosed sarcoidosis, Shorr and Hnatiuk [213]
observed elevated D-dimer titres (as assessed by latex agglutination) in 11 (39.3%)
subjects. These investigators also noted a positive correlation among elevated D-dimer
titres (defined as w1:2), interstitial involvement with sarcoidosis, lower DL,CO, elevated
serum ACE levels, and presence of dyspnoea [213]. Hence, these data suggest that
sarcoidosis should be considered in the differential diagnosis of acute pulmonary
embolism.

Sarcoidosis in HIV-infected patients

Sarcoidosis (pulmonary or extrapulmonary) may rarely complicate HIV infection
[214217]. Chest radiographic [214] and histological [218] findings are similar to
sarcoidosis in non-HIV infected patients. Most cases of sarcoidosis in HIV-infected
patients developed after beginning highly active antiretroviral therapy (HAART) [214,
217220], but sarcoidosis can occur prior to institution of HAART [214, 221]. Intense
CD4z alveolitis on BAL fluid analysis was noted in two HIV-infected patients receiving
HAART [218], whereas earlier reports of sarcoidosis complicating HIV cited CD8z
alveolitis [222]. A retrospective study of seven patients with sarcoidosis and HIV
infection noted that CD4z lymphocyte counts exceeded 200 cells?mL-1 in all patients
[223], suggesting that CD4z lymphocytes were instrumental to the granulomatous
process.

Sarcoidosis complicating type-1 interferon therapy

Type 1 IFNs (e.g., IFN-a or IFN-b), used to treat viral hepatitis, multiple sclerosis,
and diverse autoimmune and malignant disorders, may evoke a Th1 lymphocyte bias and
thereby amplify granulomatous inflammation [224, 225]. Although uncommon, new-
onset or recurrent sarcoidosis may complicate IFN-a or IFN-b therapy [224230]. Most
cases remit with IFN withdrawal or dose reduction, but corticosteroids are required in
some patients [225, 231].

116
 PULMONARY SARCOIDOSIS

Treatment of sarcoidosis
Treatment of sarcoidosis remains controversial. Corticosteroids (CS) are the
cornerstone of therapy for severe or progressive sarcoidosis (pulmonary or extra-
pulmonary), and often produce dramatic resolution of the disease [33, 232]. The long-
term benefit of CS therapy is less clear, as relapses may occur upon taper or cessation of
therapy [44, 45, 233]. A few prospective, randomised studies found no long-term benefit
with CS among patients with pulmonary sarcoidosis [103, 234238]. However, these
studies included patients with normal or near normal pulmonary function, and the rates
of spontaneous remissions were high. Patients with severe or progressive disease were
excluded from these studies. Interpretation of efficacy of therapy is confounded by
heterogeneous patient populations, a high rate of spontaneous remissions, differing doses
and duration of therapy, inability to discriminate the effects of therapy from the natural
history of the disease, and lack of validated standards for disease activity. A multicentre,
prospective, randomised trial sponsored by the British Thoracic Society supports the use
of CS for patients with chronic persistent radiographic infiltrates [36]. In the study by
Gibson et al. [36], patients with stage II or III sarcoidosis and persistent radiographic
infiltrates after 6 months of observation were randomised to prednisolone or no therapy.
At long-term follow-up, PFTs improved in the CS-treated cohort. Thus, CS may
attenuate loss of pulmonary function, even in asymptomatic patients. Extensive clinical
experience suggests that CS are efficacious in patients with active, symptomatic disease
involving lungs or extrapulmonary organs [1, 33, 44]. The decision to treat requires a
careful assessment of acuity and severity of disease, likelihood of spontaneous remission,
and risks associated with therapy. Treatment should be circumscribed and focused.
Treatment is rarely appropriate for stage I disease, but a trial of CS is reasonable in
symptomatic patients with progressive or persistent pulmonary infiltrates or significant
physiological dysfunction. Alternative therapeutic modalities are reserved for patients
failing or experiencing adverse effects from CS [1, 232, 239245]. Medical treatment of
sarcoidosis is discussed in detail in chapter 20 of this monograph.

Lung transplantation for sarcoidosis

LT (either single or bilateral) is a viable option for patients with end-stage pulmonary
sarcoidosis refractory to medical therapy [186]. Registry data from the International
Society for Heart and Lung Transplantation (ISHLT) noted that sarcoidosis was the
indication for lung transplantation in 287 patients (2.6% of all lung transplants
performed from 1995 to June 2003) [246]. Mortality rates among sarcoidosis patients
awaiting transplantation are high (2753%) [185, 187]. Arcasoy et al. [185] analysed 43
patients with sarcoidosis awaiting LT. Mean PA pressure was an independent predictor
of death. Further, right atrial pressure w15 mmHg conferred a 5.2-fold increase in
mortality [185]. In one study of sarcoid patients listed for transplant, Black race and
increased severity of illness were independent predictors of 30-day mortality [186]. In a
subsequent retrospective study of all patients in the USA listed for LT, the following
parameters were independently associated with increased mortality: Black race, the
amount of supplemental oxygen used and mean PA pressures [187]. Surprisingly, PFTs
did not correlate with mortality. These investigators correctly noted that data predicting
mortality for other types of interstitial lung diseases may not apply to sarcoidosis [187].
Short- and late-term mortality rates following LT for sarcoidosis were higher compared
with lung transplants performed for other diseases [186, 246]. Data from the ISHLT cited
1-, 3-, and 5-yr survival rates of 67%, 53% and 45%, respectively, among sarcoidosis

117
 J.P. LYNCH, E.S. WHITE

patients undergoing LT [246]. In a retrospective review of experience in the USA from

19952000, 30-day survival post-lung transplant was 83% among 133 patients with
sarcoidosis compared with 91% among LT recipients for other conditions (p=0.002)
[247]. Others authors cited worse outcomes among African Americans receiving kidney
[248] or liver transplants [249]; this may reflect greater major histocompatibility
polymorphisms or immunological hyperreponsiveness among African Americans.
Recurrent non-necrotising granulomas have been noted in the transplanted allografts
in up to 35% of patients [250252], but are not usually associated with symptoms [252].
Although data are sparse, the presence of mycetomas was associated with a worse
prognosis post-transplant [253], and is considered by many centres to be a contra-
indication to performing LT.

Summary
Sarcoidosis is a multi-systemic inflammatory disorder, but affects the lungs iny90% of
cases. Nonproductive cough, dyspnoea and chest pain are the most common features
of pulmonary sarcoidosis.
The diagnosis of pulmonary sarcoidosis is suggested by bilateral hilar lymphadeno-
pathy, with or without parenchymal changes, on chest radiographs, and is supported
by noncaseating granulomata in tissue biopsies. Radiographic staging of pulmonary
sarcoidosis, as well as clinical and laboratory findings can be prognostic.
Treatment of pulmonary sarcoidosis typically includes corticosteroids, but other
therapeutic agents may have benefit, and treatment needs to be individualised. Lung
transplantation remains a viable therapeutic alternative for patients who do not
respond to pharmaceutical agents.

Keywords: Corticosteroids, interstitial lung disease, lung transplantation, lymphade-

nopathy, transbronchial lung biopsy.

References
1. Lynch 3rd J, Baughman R, Sharma O. Extrapulmonary sarcoidosis. Semin Respir Infect 1998;
13: 229254.
2. Lynch 3rd JP, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. Clin Chest Med 1997; 18: 755785.
3. Neville E, Walker A, James DG. Prognostic factors predicting the outcome of sarcoidosis: An
analysis of 818 patients. Q J Med 1983; 208: 525533.
4. Romer FK. Presentation of sarcoidosis and outcome of pulmonary changes. Dan Med Bull 1982;
29: 2732.
5. Scadding J. Prognosis of intrathoracic sarcoidosis in England: a review of 136 cases after five years
observation. BMJ 1961; 2: 11651172.
6. Hillerdal G, Nou E, Osterman K, Schmekel B. Sarcoidosis: epidemiology and prognosis. A 15-
year European study. Am Rev Respir Dis 1984; 130: 2932.
7. Henke CE, Henke G, Elveback LR, Beard CM, Ballard DJ, Kurland LT. The epidemiology of
sarcoidosis in Rochester, Minnesota: a population-based study of incidence and survival. Am J
Epidemiol 1986; 123: 840845.
8. Reich JM, Johnson RE. Course and prognosis of sarcoidosis in a nonreferral setting. Analysis of
86 patients observed for 10 years. Am J Med 1985; 78: 6167.

118
 PULMONARY SARCOIDOSIS

9. Reich JM. Mortality of intrathoracic sarcoidosis in referral vs population-based settings: influence

of stage, ethnicity, and corticosteroid therapy. Chest 2002; 121: 3239.
10. Judson MA, Baughman RP, Thompson BW, et al. Two year prognosis of sarcoidosis: the
ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 204211.
11. Baughman RP, Winget DB, Bowen EH, Lower EE. Predicting respiratory failure in sarcoidosis
patients. Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: 154158.
12. Huang CT, Heurich AE, Sutton AL, Lyons HA. Mortality in sarcoidosis. A changing pattern of
the causes of death. Eur J Respir Dis 1981; 62: 231238.
13. Perry A, Vuitch F. Causes of death in patients with sarcoidosis. A morphologic study of 38
autopsies with clinicopathologic correlations. Arch Pathol Lab Med 1995; 119: 167172.
14. Siltzbach LE, James DG, Neville E, et al. Course and prognosis of sarcoidosis around the world.
Am J Med 1974; 57: 847852.
15. Gideon NM, Mannino DM. Sarcoidosis mortality in the United States 19791991: an analysis of
multiple-cause mortality data. Am J Med 1996; 100: 423427.
16. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European
Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous
Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive
Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736755.
17. Bechtel JJ, Starr T 3rd, Dantzker DR, Bower JS. Airway hyperreactivity in patients with
sarcoidosis. Am Rev Respir Dis 1981; 124: 759761.
18. Lynch 3rd JP, Wurfel M, Flaherty K, et al. Usual interstitial pneumonia. Semin Resp Crit Care
Med 2001; 22: 357387.
19. De Vries J, Rothkrantz-Kos S, van Dieijen-Visser MP, Drent M. The relationship between fatigue
and clinical parameters in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 127
136.
20. Wirnsberger RM, De Vries J, Breteler MH, van Heck GL, Wouters EF, Drent M. Evaluation of
quality of life in sarcoidosis patients. Respir Med 1998; 92: 750756.
21. Bergin CJ, Bell DY, Coblentz CL, et al. Sarcoidosis: correlation of pulmonary parenchymal
pattern at CT with results of pulmonary function tests. Radiology 1989; 171: 619624.
22. Brauner MW, Grenier P, Mompoint D, Lenoir S, de Cremoux H. Pulmonary sarcoidosis:
evaluation with high-resolution CT. Radiology 1989; 172: 467471.
23. Cetinkaya E, Yildiz P, Altin S, Yilmaz V. Diagnostic value of transbronchial needle aspiration by
Wang 22-gauge cytology needle in intrathoracic lymphadenopathy. Chest 2004; 125: 527531.
24. Packe GE, Ayres JG, Citron KM, Stableforth DE. Large lung bullae in sarcoidosis. Thorax 1986;
41: 792797.
25. Zar HJ, Cole RP. Bullous emphysema occurring in pulmonary sarcoidosis. Respiration 1995;
62: 290293.
26. Lynch 3rd JP. Computed tomographic scanning in sarcoidosis. Semin Resp Crit Care Med 2003;
24: 393418.
27. Sharma OP, Gordonson J. Pleural effusion in sarcoidosis: a report of six cases. Thorax 1975;
30: 95101.
28. Rose RM, Lee RG, Costello P. Solitary nodular sarcoidosis. Clin Radiol 1985; 36: 589592.
29. Sharma OP, Hewlett R, Gordonson J. Nodular sarcoidosis: an unusual radiographic appearance.
Chest 1973; 64: 189192.
30. Biem J, Hoffstein V. Aggressive cavitary pulmonary sarcoidosis. Am Rev Respir Dis 1991;
143: 428430.
31. Ichikawa Y, Fujimoto K, Shiraishi T, Oizumi K. Primary cavitary sarcoidosis: high-resolution CT
findings. Am J Roentgenol 1994; 163: 745.
32. Tazi A, Desfemmes-Baleyte T, Soler P, Valeyre D, Hance AJ, Battesti JP. Pulmonary sarcoidosis
with a diffuse ground glass pattern on the chest radiograph. Thorax 1994; 49: 793797.
33. Sharma OP. Pulmonary sarcoidosis and corticosteroids. Am Rev Respir Dis 1993; 147: Suppl. 6 Pt
1, 15981600.

119
 J.P. LYNCH, E.S. WHITE

34. Siltzbach LE. Sarcoidosis: clinical features and management. Med Clin North Am 1967; 51: 483502.
35. Mana J, Gomez-Vaquero C, Montero A, et al. Lofgrens syndrome revisited: a study of 186
patients. Am J Med 1999; 107: 240245.
36. Gibson GJ, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of
long term corticosteroid treatment. Thorax 1996; 51: 238247.
37. Hunninghake GW, Gilbert S, Pueringer R, et al. Outcome of the treatment for sarcoidosis. Am J
Respir Crit Care Med 1994; 149: Suppl. 4 Pt 1, 893898.
38. Chappell AG, Cheung WY, Hutchings HA. Sarcoidosis: a long-term follow up study. Sarcoidosis
Vasc Diffuse Lung Dis 2000; 17: 167173.
39. Nagai S, Shigematsu M, Hamada K, Izumi T. Clinical courses and prognoses of pulmonary
sarcoidosis. Curr Opin Pulm Med 1999; 5: 293298.
40. Mana J, Salazar A, Manresa F. Clinical factors predicting persistence of activity in sarcoidosis: a
multivariate analysis of 193 cases. Respiration 1994; 61: 219225.
41. Pietinalho A, Ohmichi M, Lofroos AB, Hiraga Y, Selroos O. The prognosis of pulmonary
sarcoidosis in Finland and Hokkaido, Japan. A comparative five-year study of biopsy-proven
cases. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17: 158166.
42. Gran JT, Bohmer E. Acute sarcoid arthritis: a favourable outcome? A retrospective survey of 49
patients with review of the literature. Scand J Rheumatol 1996; 25: 7073.
43. Israel HL, Karlin P, Menduke H, DeLisser OG. Factors affecting outcome of sarcoidosis.
Influence of race, extrathoracic involvement, and initial radiologic lung lesions. Ann N Y Acad Sci
1986; 465: 609618.
44. Johns CJ, Michele TM. The clinical management of sarcoidosis. A 50-year experience at the Johns
Hopkins Hospital. Medicine (Baltimore) 1999; 78: 65111.
45. Gottlieb JE, Israel HL, Steiner RM, Triolo J, Patrick H. Outcome in sarcoidosis. The relationship
of relapse to corticosteroid therapy. Chest 1997; 111: 623631.
46. Sider L, Horton ES Jr. Hilar and mediastinal adenopathy in sarcoidosis as detected by computed
tomography. J Thorac Imaging 1990; 5: 7780.
47. Hennebicque AS, Nunes H, Brillet PY, Moulahi H, Valeyre D, Brauner MW. CT findings in severe
thoracic sarcoidosis. Eur Radiol 2005; 15: 2330.
48. Nishimura K, Itoh H, Kitaichi M, Nagai S, Izumi T. CT and pathological correlation of
pulmonary sarcoidosis. Semin Ultrasound CT MR 1995; 16: 36170.
49. Brauner MW, Lenoir S, Grenier P, Cluzel P, Battesti JP, Valeyre D. Pulmonary sarcoidosis: CT
assessment of lesion reversibility. Radiology 1992; 182: 349354.
50. Abehsera M, Valeyre D, Grenier P, Jaillet H, Battesti JP, Brauner MW. Sarcoidosis with
pulmonary fibrosis: CT patterns and correlation with pulmonary function. Am J Roentgenol 2000;
174: 17511757.
51. Mana J, Teirstein AS, Mendelson DS, Padilla ML, DePalo LR. Excessive thoracic computed
tomographic scanning in sarcoidosis. Thorax 1995; 50: 12641266.
52. Remy-Jardin M, Giraud F, Remy J, Wattinne L, Wallaert B, Duhamel A. Pulmonary sarcoidosis:
role of CT in the evaluation of disease activity and functional impairment and in prognosis
assessment. Radiology 1994; 191: 675680.
53. Muller NL, Miller RR. Ground-glass attenuation, nodules, alveolitis, and sarcoid granulomas.
Radiology 1993; 189: 3132.
54. Remy-Jardin M, Giraud F, Remy J, Copin MC, Gosselin B, Duhamel A. Importance of ground-
glass attenuation in chronic diffuse infiltrative lung disease: pathologic-CT correlation. Radiology
1993; 189: 693698.
55. Murdoch J, Muller NL. Pulmonary sarcoidosis: changes on follow-up CT examination. Am J
Roentgenol 1992; 159: 473477.
56. Alhamad EH, Lynch JP 3rd, Martinez FJ. Pulmonary function tests in interstitial lung disease:
what role do they have?. Clin Chest Med 2001; 22: 715750, ix.
57. Sharma OP, Johnson R. Airway obstruction in sarcoidosis. A study of 123 nonsmoking black
American patients with sarcoidosis. Chest 1988; 94: 343346.

120
 PULMONARY SARCOIDOSIS

58. Dunn TL, Watters LC, Hendrix C, Cherniack RM, Schwarz MI, King TE Jr. Gas exchange at a
given degree of volume restriction is different in sarcoidosis and idiopathic pulmonary fibrosis. Am
J Med 1988; 85: 221224.
59. Harrison BD, Shaylor JM, Stokes TC, Wilkes AR. Airflow limitation in sarcoidosisa study
of pulmonary function in 107 patients with newly diagnosed disease. Respir Med 1991; 85: 59
64.
60. McCann BG, Harrison BD. Bronchiolar narrowing and occlusion in sarcoidosiscorrelation of
pathology with physiology. Respir Med 1991; 85: 6567.
61. Stjernberg N, Thunell M. Pulmonary function in patients with endobronchial sarcoidosis. Acta
Med Scand 1984; 215: 121126.
62. Levinson RS, Metzger LF, Stanley NN, et al. Airway function in sarcoidosis. Am J Med 1977; 62:
5159.
63. Lenique F, Brauner MW, Grenier P, Battesti JP, Loiseau A, Valeyre D. CT assessment of bronchi
in sarcoidosis: endoscopic and pathologic correlations. Radiology 1995; 194: 419423.
64. Lavergne F, Clerici C, Sadoun D, Brauner M, Battesti JP, Valeyre D. Airway obstruction in
bronchial sarcoidosis: outcome with treatment. Chest 1999; 116: 11941199.
65. Gleeson FV, Traill ZC, Hansell DM. Evidence of expiratory CT scans of small-airway obstruction
in sarcoidosis. Am J Roentgenol 1996; 166: 10521054.
66. Viskum K, Vestbo J. Vital prognosis in intrathoracic sarcoidosis with special reference to
pulmonary function and radiological stage. Eur Respir J 1993; 6: 349353.
67. Benatar SR, Clark TJ. Pulmonary function in a case of endobronchial sarcoidosis. Am Rev Respir
Dis 1974; 110: 490496.
68. Udwadia ZF, Pilling JR, Jenkins PF, Harrison BD. Bronchoscopic and bronchographic findings
in 12 patients with sarcoidosis and severe or progressive airways obstruction. Thorax 1990;
45: 272275.
69. Chambellan A, Turbie P, Nunes H, Brauner M, Battesti JP, Valeyre D. Endoluminal stenosis
of proximal bronchi in sarcoidosis: bronchoscopy, function, and evolution. Chest 2005; 127: 472
481.
70. Carrington CB. Structure and function in sarcoidosis. Ann N Y Acad Sci 1976; 278: 265283.
71. Miller A, Brown LK, Sloane MF, Bhuptani A, Teirstein AS. Cardiorespiratory responses to
incremental exercise in sarcoidosis patients with normal spirometry. Chest 1995; 107: 323329.
72. Radwan L, Grebska E, Koziorowski A. Small airways function in pulmonary sarcoidosis. Scand J
Respir Dis 1978; 59: 3743.
73. Ohrn MB, Skold CM, van Hage-Hamsten M, Sigurdardottir O, Zetterstrom O, Eklund A.
Sarcoidosis patients have bronchial hyperreactivity and signs of mast cell activation in their
bronchoalveolar lavage. Respiration 1995; 62: 136142.
74. Manresa Presas F, Romero Colomer P, Rodriguez Sanchon B. Bronchial hyperreactivity in fresh
stage I sarcoidosis. Ann N Y Acad Sci 1986; 465: 523529.
75. Delobbe A, Perrault H, Maitre J, et al. Impaired exercise response in sarcoid patients with normal
pulmonary function. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 148153.
76. Wirnsberger RM, Drent M, Hekelaar N, et al. Relationship between respiratory muscle function
and quality of life in sarcoidosis. Eur Respir J 1997; 10: 14501455.
77. Brancaleone P, Perez T, Robin S, Neviere R, Wallaert B. Clinical impact of inspiratory muscle
impairment in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 219227.
78. Sietsema KE, Kraft M, Ginzton L, Sharma OP. Abnormal oxygen uptake responses to exercise in
patients with mild pulmonary sarcoidosis. Chest 1992; 102: 838845.
79. Karetzky M, McDonough M. Exercise and resting pulmonary function in sarcoidosis. Sarcoidosis
Vasc Diffuse Lung Dis 1996; 13: 4349.
80. Bradvik I, Wollmer P, Blom-Bulow B, Albrechtsson U, Jonson B. Lung mechanics and gas
exchange during exercise in pulmonary sarcoidosis. Chest 1991; 99: 572578.
81. Medinger AE, Khouri S, Rohatgi PK. Sarcoidosis: the value of exercise testing. Chest 2001;
120: 93101.

121
 J.P. LYNCH, E.S. WHITE

82. Barros WG, Neder JA, Pereira CA, Nery LE. Clinical, radiographic and functional predictors of
pulmonary gas exchange impairment at moderate exercise in patients with sarcoidosis. Respiration
2004; 71: 367373.
83. Lamberto C, Nunes H, Le Toumelin P, Duperron F, Valeyre D, Clerici C. Membrane and
capillary blood components of diffusion capacity of the lung for carbon monoxide in pulmonary
sarcoidosis: relation to exercise gas exchange. Chest 2004; 125: 20612068.
84. Young RL, Lordon RE, Krumholz RA, Harkleroad LE, Branam GE, Weg JG. Pulmonary
sarcoidosis. 1. Pathophysiologic correlations. Am Rev Respir Dis 1968; 97: 9971008.
85. Young RC Jr, Carr C, Shelton TG, et al. Sarcoidosis: relationship between changes in lung
structure and function. Am Rev Respir Dis 1967; 95: 224238.
86. Huang CT, Heurich AE, Rosen Y, Moon S, Lyons HA. Pulmonary sarcoidosis: roentgenographic,
functional, and pathologic correlations. Respiration 1979; 37: 337345.
87. Winterbauer RH, Hutchinson JF. Use of pulmonary function tests in the management of
sarcoidosis. Chest 1980; 78: 640647.
88. McLoud TC, Epler GR, Gaensler EA, Burke GW, Carrington CB. A radiographic classification
for sarcoidosis: physiologic correlation. Invest Radiol 1982; 17: 129138.
89. Lin YH, Haslam PL, Turner-Warwick M. Chronic pulmonary sarcoidosis: relationship between
lung lavage cell counts, chest radiograph, and results of standard lung function tests. Thorax 1985;
40: 501507.
90. Muller NL, Mawson JB, Mathieson JR, Abboud R, Ostrow DN, Champion P. Sarcoidosis:
correlation of extent of disease at CT with clinical, functional, and radiographic findings.
Radiology 1989; 171: 613618.
91. Nugent KM, Peterson MW, Jolles H, Monick MM, Hunninghake GW. Correlation of chest
roentgenograms with pulmonary function and bronchoalveolar lavage in interstitial lung disease.
Chest 1989; 96: 12241227.
92. Muers MF, Middleton WG, Gibson GJ, et al. A simple radiographic scoring method for
monitoring pulmonary sarcoidosis: relations between radiographic scores, dyspnoea grade and
respiratory function in the British Thoracic Society Study of Long-Term Corticosteroid
Treatment. Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: 4656.
93. Oberstein A, von Zitzewitz H, Schweden F, Muller-Quernheim J. Non invasive evaluation of the
inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc
Diffuse Lung Dis 1997; 14: 6572.
94. Hansell DM, Milne DG, Wilsher ML, Wells AU. Pulmonary sarcoidosis: morphologic
associations of airflow obstruction at thin-section CT. Radiology 1998; 209: 697704.
95. Drent M, De Vries J, Lenters M, et al. Sarcoidosis: assessment of disease severity using HRCT.
Eur Radiol 2003; 13: 24622471.
96. Akira M, Kozuka T, Inoue Y, Sakatani M. Long-term follow-up CT scan evaluation in patients
with pulmonary sarcoidosis. Chest 2005; 127: 185191.
97. Finkel R, Teirstein AS, Levine R, Brown LK, Miller A. Pulmonary function tests, serum
angiotensin-converting enzyme levels, and clinical findings as prognostic indicators in sarcoidosis.
Ann N Y Acad Sci 1986; 465: 665671.
98. Keogh BA, Hunninghake GW, Line BR, Crystal RG. The alveolitis of pulmonary sarcoidosis.
Evaluation of natural history and alveolitis-dependent changes in lung function. Am Rev Respir
Dis 1983; 128: 256265.
99. Lieberman J, Schleissner LA, Nosal A, Sastre A, Mishkin FS. Clinical correlations of serum
angiotensin-converting enzyme (ACE) in sarcoidosis. A longitudinal study of serum ACE,
67gallium scans, chest roentgenograms, and pulmonary function. Chest 1983; 84: 522528.
100. Johns CJ, Macgregor MI, Zachary JB, Ball WC. Extended experience in the long-term
corticosteroid treatment of pulmonary sarcoidosis. Ann N Y Acad Sci 1976; 278: 722731.
101. Odlum CM, FitzGerald MX. Evidence that steroids alter the natural history of previously
untreated progressive pulmonary sarcoidosis. Sarcoidosis 1986; 3: 4046.
102. Bradvik I, Wollmer P, Blom-Bulow B, Albrechtsson U, Jonson B. Lung mechanics and gas

122
 PULMONARY SARCOIDOSIS

exchange in steroid treated pulmonary sarcoidosis. A seven year follow-up. Sarcoidosis 1991;
8: 105114.
103. Zaki M, Lyons H, Leilop L, Huang C. Corticosteroid therapy in sarcoidosis. A five-year,
controlled follow-up study. NY State J Med 1987; 87: 496499.
104. Goldstein DS, Williams MH. Rate of improvement of pulmonary function in sarcoidosis during
treatment with corticosteroids. Thorax 1986; 41: 473474.
105. Muller-Quernheim J, Pfeifer S, Strausz J, Ferlinz R. Correlation of clinical and immunologic
parameters of the inflammatory activity of pulmonary sarcoidosis. Am Rev Respir Dis 1991; 144:
13221329.
106. Rothkrantz-Kos S, van Dieijen-Visser MP, Mulder PG, Drent M. Potential usefulness of
inflammatory markers to monitor respiratory functional impairment in sarcoidosis. Clin Chem
2003; 49: 15101517.
107. Grutters JC, Fellrath JM, Mulder L, Janssen R, van den Bosch JM, van Velzen-Blad H. Serum
soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation.
Chest 2003; 124: 186195.
108. Siltzbach LE. The Kveim test in sarcoidosis. A study of 750 patients. JAMA 1961; 178: 476
482.
109. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336: 12241234.
110. Robinson BW, McLemore TL, Crystal RG. Gamma interferon is spontaneously released by
alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin
Invest 1985; 75: 14881495.
111. Pinkston P, Bitterman PB, Crystal RG. Spontaneous release of interleukin-2 by lung T
lymphocytes in active pulmonary sarcoidosis. N Engl J Med 1983; 308: 793800.
112. Drent M, Jacobs JA, Cobben NA, Costabel U, Wouters EF, Mulder PG. Computer program
supporting the diagnostic accuracy of cellular BALF analysis: a new release. Respir Med 2001;
95: 781786.
113. Welker L, Jorres RA, Costabel U, Magnussen H. Predictive value of BAL cell differentials in the
diagnosis of interstitial lung diseases. Eur Respir J 2004; 24: 10001006.
114. Drent M, van Velzen-Blad H, Diamant M, Hoogsteden HC, van den Bosch JM. Relationship
between presentation of sarcoidosis and T lymphocyte profile. A study in bronchoalveolar lavage
fluid. Chest 1993; 104: 795800.
115. Drent M, Mulder PG, Wagenaar SjSc, Hoogsteden HC, van Velzen-Blad H, van den Bosch JM.
Differences in BAL fluid variables in interstitial lung diseases evaluated by discriminant analysis.
Eur Respir J 1993; 6: 803810.
116. Ziegenhagen MW, Rothe ME, Schlaak M, Muller-Quernheim J. Bronchoalveolar and serological
parameters reflecting the severity of sarcoidosis. Eur Respir J 2003; 21: 407413.
117. Drent M, Jacobs JA, De Vries J, Lamers RJ, Liem IH, Wouters EF. Does the cellular
bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis? Eur Respir J 1999; 13: 1338
1344.
118. Bjermer L, Rosenhall L, Angstrom T, Hallgren R. Predictive value of bronchoalveolar lavage cell
analysis in sarcoidosis. Thorax 1988; 43: 284288.
119. Ward K, OConnor C, Odlum C, Fitzgerald MX. Prognostic value of bronchoalveolar lavage in
sarcoidosis: the critical influence of disease presentation. Thorax 1989; 44: 612.
120. Valeyre D, Saumon G, Georges R, et al. The relationship between disease duration and
noninvasive pulmonary explorations in sarcoidosis with erythema nodosum. Am Rev Respir Dis
1984; 129: 938942.
121. Mana J. Nuclear imaging. 67Gallium, 201thallium, 18F-labeled fluoro-2-deoxy-D-glucose
positron emission tomography. Clin Chest Med 1997; 18: 799811.
122. Schuster DM, Alazraki N. Gallium and other agents in diseases of the lung. Semin Nucl Med 2002;
32: 193211.
123. Kwekkeboom DJ, Krenning EP, Kho GS, Breeman WA, Van Hagen PM. Somatostatin receptor
imaging in patients with sarcoidosis. Eur J Nucl Med 1998; 25: 12841292.

123
 J.P. LYNCH, E.S. WHITE

124. Shorr AF, Helman DL, Lettieri CJ, Montilla JL, Bridwell RS. Depreotide scanning in sarcoidosis:
a pilot study. Chest 2004; 126: 13371343.
125. El-Haddad G, Zhuang H, Gupta N, Alavi A. Evolving role of positron emission tomography in
the management of patients with inflammatory and other benign disorders. Semin Nucl Med 2004;
34: 313329.
126. Alavi A, Gupta N, Alberini JL, et al. Positron emission tomography imaging in nonmalignant
thoracic disorders. Semin Nucl Med 2002; 32: 293321.
127. Halter G, Buck AK, Schirrmeister H, et al. [18F] 3-deoxy-39-fluorothymidine positron emission
tomography: alternative or diagnostic adjunct to 2-[18f]-fluoro-2-deoxy-D-glucose positron
emission tomography in the workup of suspicious central focal lesions? J Thorac Cardiovasc Surg
2004; 127: 10931099.
128. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis. An approach to determine the
optimal number of biopsies. Am Rev Respir Dis 1980; 122: 721724.
129. Poe RH, Israel RH, Utell MJ, Hall WJ. Probability of a positive transbronchial lung biopsy result
in sarcoidosis. Arch Intern Med 1979; 139: 761763.
130. Wang KP, Fuenning C, Johns CJ, Terry PB. Flexible transbronchial needle aspiration for the
diagnosis of sarcoidosis. Ann Otol Rhinol Laryngol 1989; 98: Suppl. 4 Pt 1, 298300.
131. Leonard C, Tormey V, Lennon A, Burke CM. Utility of Wang transbronchial needle biopsy in
sarcoidosis. Ir J Med Sci 1997; 166: 4143.
132. Cetinkaya E, Yildiz P, Kadakal F, et al. Transbronchial needle aspiration in the diagnosis of
intrathoracic lymphadenopathy. Respiration 2002; 69: 335338.
133. Sharafkhaneh A, Baaklini W, Gorin AB, Green L. Yield of transbronchial needle aspiration in
diagnosis of mediastinal lesions. Chest 2003; 124: 213135.
134. Trisolini R, Agli LL, Cancellieri A, et al. The value of flexible transbronchial needle aspiration
in the diagnosis of stage I sarcoidosis. Chest 2003; 124: 21262130.
135. Morales CF, Patefield AJ, Strollo PJ Jr, Schenk DA. Flexible transbronchial needle aspiration in
the diagnosis of sarcoidosis. Chest 1994; 106: 709711.
136. Trisolini R, Lazzari Agli L, Cancellieri A, et al. Transbronchial needle aspiration improves the
diagnostic yield of bronchoscopy in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 147
151.
137. Prakash UB, Offord KP, Stubbs SE. Bronchoscopy in North America: the ACCP survey. Chest
1991; 100: 16681675.
138. Tambouret R, Geisinger KR, Powers CN, et al. The clinical application and cost analysis of fine-
needle aspiration biopsy in the diagnosis of mass lesions in sarcoidosis. Chest 2000; 117: 1004
1011.
139. Zwischenberger JB, Savage C, Alpard SK, Anderson CM, Marroquin S, Goodacre BW.
Mediastinal transthoracic needle and core lymph node biopsy: should it replace mediastinoscopy?
Chest 2002; 121: 11651170.
140. Pedersen BH, Vilmann P, Folke K, et al. Endoscopic ultrasonography and real-time guided fine-
needle aspiration biopsy of solid lesions of the mediastinum suspected of malignancy. Chest 1996;
110: 539544.
141. Larsen SS, Krasnik M, Vilmann P, et al. Endoscopic ultrasound guided biopsy of mediastinal
lesions has a major impact on patient management. Thorax 2002; 57: 98103.
142. Wiersema MJ, Vazquez-Sequeiros E, Wiersema LM. Evaluation of mediastinal lymphadenopathy
with endoscopic US-guided fine-needle aspiration biopsy. Radiology 2001; 219: 252257.
143. Hammoud ZT, Anderson RC, Meyers BF, et al. The current role of mediastinoscopy in the
evaluation of thoracic disease. J Thorac Cardiovasc Surg 1999; 118: 894899.
144. Kirschner PA. Cervical mediastinoscopy. Chest Surg Clin N Am 1996; 6: 120.
145. Venissac N, Alifano M, Mouroux J. Video-assisted mediastinoscopy: experience from 240
consecutive cases. Ann Thorac Surg 2003; 76: 208212.
146. Blewett CJ, Bennett WF, Miller JD, Urschel JD. Open lung biopsy as an outpatient procedure.
Ann Thorac Surg 2001; 71: 11131115.

124
 PULMONARY SARCOIDOSIS

147. Chang AC, Yee J, Orringer MB, Iannettoni MD. Diagnostic thoracoscopic lung biopsy: an
outpatient experience. Ann Thorac Surg 2002; 74: 19426; discussion 19461947.
148. Liebow AA. The J. Burns Amberson lecture--pulmonary angiitis and granulomatosis. Am Rev
Respir Dis 1973; 108: 118.
149. Churg A. Pulmonary angiitis and granulomatosis revisited. Hum Pathol 1983; 14: 868883.
150. Chittock DR, Joseph MG, Paterson NA, McFadden RG. Necrotizing sarcoid granulomatosis
with pleural involvement. Clinical and radiographic features. Chest 1994; 106: 672676.
151. Niimi H, Hartman TE, Muller NL. Necrotizing sarcoid granulomatosis: computed tomography
and pathologic findings. J Comput Assist Tomogr 1995; 19: 920923.
152. Koss MN, Hochholzer L, Feigin DS, Garancis JC, Ward PA. Necrotizing sarcoid-like
granulomatosis: clinical, pathologic, and immunopathologic findings. Hum Pathol 1980;
11: Suppl. 5, 510519.
153. Churg A, Carrington CB, Gupta R. Necrotizing sarcoid granulomatosis. Chest 1979; 76: 406
413.
154. Onal E, Lopata M, Lourenco RV. Nodular pulmonary sarcoidosis. Clinical, roentgenographic,
and physiologic course in five patients. Chest 1977; 72: 296300.
155. Romer FK. Sarcoidosis with large nodular lesions simulating pulmonary metastases. An analysis
of 126 cases of intrathoracic sarcoidosis. Scand J Respir Dis 1977; 58: 1116.
156. Tellis CJ, Putnam JS. Cavitation in large multinodular pulmonary disease a rare manifestation of
sarcoidosis. Chest 1977; 71: 792793.
157. Olsson T, Bjornstad-Pettersen H, Stjernberg NL. Bronchostenosis due to sarcoidosis: a cause of
atelectasis and airway obstruction simulating pulmonary neoplasm and chronic obstructive
pulmonary disease. Chest 1979; 75: 663666.
158. Mendelson DS, Norton K, Cohen BA, Brown LK, Rabinowitz JG. Bronchial compression: an
unusual manifestation of sarcoidosis. J Comput Assist Tomogr 1983; 7: 892894.
159. Armstrong JR, Radke JR, Kvale PA, Eichenhorn MS, Popovich J Jr. Endoscopic findings in
sarcoidosis. Characteristics and correlations with radiographic staging and bronchial mucosal
biopsy yield. Ann Otol Rhinol Laryngol 1981; 90: Suppl. 4 Pt 1, 339343.
160. Munt PW. Middle lobe atelectasis in sarcoidois. Report of a case with prompt resolution
concomitant with corticosteroid administration. Am Rev Respir Dis 1973; 108: 357360.
161. Rockoff SD, Rohatgi PK. Unusual manifestations of thoracic sarcoidosis. Am J Roentgenol 1985;
144: 513528.
162. Aye M, Campbell AP, Greenstone MA. An unusual case of lobar collapse. Chest 2002; 122: 1465
1466.
163. Naidich DP, Lee JJ, Garay SM, McCauley DI, Aranda CP, Boyd AD. Comparison of CT
and fiberoptic bronchoscopy in the evaluation of bronchial disease. Am J Roentgenol 1987; 148: 1
7.
164. Fouty BW, Pomeranz M, Thigpen TP, Martin RJ. Dilatation of bronchial stenoses due to
sarcoidosis using a flexible fiberoptic bronchoscope. Chest 1994; 106: 677680.
165. Tomlinson JR, Sahn SA. Aspergilloma in sarcoid and tuberculosis. Chest 1987; 92: 505508.
166. Wollschlager C, Khan F. Aspergillomas complicating sarcoidosis. A prospective study in 100
patients. Chest 1984; 86: 585588.
167. Israel HL, Lenchner GS, Atkinson GW. Sarcoidosis and aspergilloma. The role of surgery. Chest
1982; 82: 430432.
168. Libshitz HI, Atkinson GW, Israel HL. Pleural thickening as a manifestation of aspergillus
superinfection. Am J Roentgenol Radium Ther Nucl Med 1974; 120: 883886.
169. Fujimura M, Ishiura Y, Kasahara K, et al. Necrotizing bronchial aspergillosis as a cause of
hemoptysis in sarcoidosis. Am J Med Sci 1998; 315: 5658.
170. Shapiro MJ, Albelda SM, Mayock RL, McLean GK. Severe hemoptysis associated with
pulmonary aspergilloma. Percutaneous intracavitary treatment. Chest 1988; 94: 12251231.
171. Rumbak M, Kohler G, Eastrige C, Winer-Muram H, Gavant M. Topical treatment of life
threatening haemoptysis from aspergillomas. Thorax 1996; 51: 253255.

125
 J.P. LYNCH, E.S. WHITE

172. Nicholls AJ, Friend JA, Legge JS. Sarcoid pleural effusion: three cases and review of the literature.
Thorax 1980; 35: 277281.
173. Soskel N, Sharma OP. Pleural involvement in sarcoidosis. Case presentation and detailed review of
the literature. Semin Resp Med 1992; 13: 492514.
174. Warshawsky ME, Shanies HM, Rozo A. Sarcoidosis involving the thyroid and pleura. Sarcoidosis
Vasc Diffuse Lung Dis 1997; 14: 165168.
175. Aberg H, Bah M, Waters AW. Sarcoidosis: complicated by chylothorax. Minn Med 1966;
49: 10651070.
176. Cappell MS, Friedman D, Mikhail N. Chyloperitoneum associated with chronic severe
sarcoidosis. Am J Gastroenterol 1993; 88: 99101.
177. Jarman PR, Whyte MK, Sabroe I, Hughes JM. Sarcoidosis presenting with chylothorax. Thorax
1995; 50: 13241325.
178. Rosen Y, Moon S, Huang CT, Gourin A, Lyons HA. Granulomatous pulmonary angiitis in
sarcoidosis. Arch Pathol Lab Med 1977; 101: 170174.
179. Smith LJ, Lawrence JB, Katzenstein AA. Vascular sarcoidosis: a rare cause of pulmonary
hypertension. Am J Med Sci 1983; 285: 3844.
180. Barst RJ, Ratner SJ. Sarcoidosis and reactive pulmonary hypertension. Arch Intern Med 1985;
145: 21122114.
181. Gluskowski J, Hawrylkiewicz I, Zych D, Zielinski J. Effects of corticosteroid treatment on
pulmonary haemodynamics in patients with sarcoidosis. Eur Respir J 1990; 3: 403407.
182. Battesti JP, Georges R, Basset F, Saumon G. Chronic cor pulmonale in pulmonary sarcoidosis.
Thorax 1978; 33: 7684.
183. Emirgil C, Sobol BJ, Herbert WH, Trout K. The lesser circulation in pulmonary fibrosis secondary
to sarcoidosis and its relationship to respiratory function. Chest 1971; 60: 371378.
184. Gluskowski J, Hawrylkiewicz I, Zych D, Wojtczak A, Zielinski J. Pulmonary haemodynamics at
rest and during exercise in patients with sarcoidosis. Respiration 1984; 46: 2632.
185. Arcasoy SM, Christie JD, Pochettino A, et al. Characteristics and outcomes of patients with
sarcoidosis listed for lung transplantation. Chest 2001; 120: 873880.
186. Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung
transplantation. Chest 2002; 122: 233238.
187. Shorr AF, Davies DB, Nathan SD. Predicting mortality in patients with sarcoidosis awaiting lung
transplantation. Chest 2003; 124: 922928.
188. Preston IR, Klinger JR, Landzberg MJ, Houtchens J, Nelson D, Hill NS. Vasoresponsiveness of
sarcoidosis-associated pulmonary hypertension. Chest 2001; 120: 866782.
189. Tan RT, Kuzo R, Goodman LR, Siegel R, Haasler GB, Presberg KW. Utility of CT scan
evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease.
Medical College of Wisconsin Lung Transplant Group. Chest 1998; 113: 12501256.
190. Ng CS, Wells AU, Padley SP. A CT sign of chronic pulmonary arterial hypertension: the ratio of
main pulmonary artery to aortic diameter. J Thorac Imaging 1999; 14: 270278.
191. Jones K, Higenbottam T, Wallwork J. Pulmonary vasodilation with prostacyclin in primary and
secondary pulmonary hypertension. Chest 1989; 96: 784789.
192. Damuth TE, Bower JS, Cho K, Dantzker DR. Major pulmonary artery stenosis causing
pulmonary hypertension in sarcoidosis. Chest 1980; 78: 888891.
193. Hamper UM, Fishman EK, Khouri NF, Johns CJ, Wang KP, Siegelman SS. Typical and
atypical CT manifestations of pulmonary sarcoidosis. J Comput Assist Tomogr 1986; 10: 928
936.
194. Hietala SO, Stinnett RG, Faunce HF 3rd, Sharpe AR Jr, Scoggins WG, Smith RH. Pulmonary
artery narrowing in sarcoidosis. JAMA 1977; 237: 572573.
195. Westcott JL, DeGraff AC Jr. Sarcoidosis, hilar adenopathy, and pulmonary artery narrowing.
Radiology 1973; 108: 585586.
196. Hoffstein V, Ranganathan N, Mullen JB. Sarcoidosis simulating pulmonary veno-occlusive
disease. Am Rev Respir Dis 1986; 134: 809811.

126
 PULMONARY SARCOIDOSIS

197. Schachter EN, Smith GJ, Cohen GS, Lee SH, Laser A, Gee JB. Pulmonary granulomas in a
patient with pulmonary veno-occlusive disease. Chest 1975; 67: 487489.
198. Javaheri S, Hales CA. Sarcoidosis: a cause of innominate vein obstruction and massive pleural
effusion. Lung 1980; 157: 8185.
199. Gordonson J, Trachtenberg S, Sargent EN. Superior vena cava obstruction due to sarcoidosis.
Chest 1973; 63: 292293.
200. Westcott JL, Noehren TH. Bronchial stenosis in chronic sarcoidosis. Chest 1973; 63: 893897.
201. Brandstetter RD, Hansen DE, Jarowski CI, King T, Barletta A. Superior vena cava syndrome as
the initial clinical manifestation of sarcoidosis. Heart Lung 1981; 10: 101104.
202. Radke JR, Kaplan H, Conway WA. The significance of superior vena cava syndrome developing
in a patient with sarcoidosis. Radiology 1980; 134: 311312.
203. Kinney EL, Murthy R, Ascunce G, Guntapalli KK, Zelis R. Sarcoidosis: rare cause of superior
vena caval obstruction. Pa Med 1980; 83: 31.
204. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case
11-1984. Long-standing sarcoidosis with the recent onset of the superior-vena-cava syndrome. N
Engl J Med 1984; 310: 708716.
205. Hasday JD, Bachwich PR, Lynch JP 3rd, Sitrin RG. Procoagulant and plasminogen activator
activities of bronchoalveolar fluid in patients with pulmonary sarcoidosis. Exp Lung Res 1988;
14: 261278.
206. Chapelon-Abric C, Evrard S, Buthiau D, Wechsler B, Bousser MG. [Cerebral thrombophlebitis in
sarcoidosis]. Rev Med Interne 1994; 15: 216217.
207. Raherison C, Nocent C, Tunon De Lara JM, Latrabe V, Laurent F, Taytard A. [Mediastinal
sarcoidosis and vascular thrombosis: a fortuitous association?]. Rev Mal Respir 2001; 18: 63
65.
208. Morello FA, Ali SA, Cesani F. Sarcoid: an unusual mimicker of classic pulmonary embolus. Clin
Nucl Med 1998; 23: 654656.
209. Finestone H, Colp C, Rackson M, Shams J, Gallagher R. Ventilation-perfusion imaging in
sarcoidosis: potential for nonembolic segmental mismatch. J Nucl Med 1994; 35: 476478.
210. Velchik MG, Tobin M, McCarthy K. Nonthromboembolic causes of high-probability lung scans.
Am J Physiol Imaging 1989; 4: 3238.
211. Cassling RJ, Lois JF, Gomes AS. Unusual pulmonary angiographic findings in suspected
pulmonary embolism. Am J Roentgenol 1985; 145: 995999.
212. Stanley DC, Cho SR, Tisnado J, Vines FS, Coyne SS. Pulmonary arteriography in patients with
hilar or mediastinal masses and lung scans suggesting pulmonary embolism. South Med J 1981;
74: 960964, 967.
213. Shorr AF, Hnatiuk OW. Circulating D dimer in patients with sarcoidosis. Chest 2000; 117: 1012
1016.
214. Haramati LB, Lee G, Singh A, Molina PL, White CS. Newly diagnosed pulmonary sarcoidosis in
HIV-infected patients. Radiology 2001; 218: 242246.
215. Newman TG, Minkowitz S, Hanna A, Sikand R, Fuleihan F. Coexistent sarcoidosis and HIV
infection. A comparison of bronchoalveolar and peripheral blood lymphocytes. Chest 1992;
102: 18991901.
216. Gomez V, Smith PR, Burack J, Daley R, Rosa U. Sarcoidosis after antiretroviral therapy in a
patient with acquired immunodeficiency syndrome. Clin Infect Dis 2000; 31: 12781280.
217. Foulon G, Wislez M, Naccache JM, et al. Sarcoidosis in HIV-infected patients in the era of highly
active antiretroviral therapy. Clin Infect Dis 2004; 38: 418425.
218. Naccache JM, Antoine M, Wislez M, et al. Sarcoid-like pulmonary disorder in human
immunodeficiency virus-infected patients receiving antiretroviral therapy. Am J Respir Crit Care
Med 1999; 159: 20092013.
219. Mirmirani P, Maurer TA, Herndier B, McGrath M, Weinstein MD, Berger TG. Sarcoidosis in a
patient with AIDS: a manifestation of immune restoration syndrome. J Am Acad Dermatol 1999;
41: Suppl. 2 Pt 2, 285286.

127
 J.P. LYNCH, E.S. WHITE

220. Lenner R, Bregman Z, Teirstein AS, DePalo L. Recurrent pulmonary sarcoidosis in HIV-infected
patients receiving highly active antiretroviral therapy. Chest 2001; 119: 978981.
221. Granieri J, Wisnieski JJ, Graham RC, Smith H, Gogate P, Aucott JN. Sarcoid myopathy in a
patient with human immunodeficiency virus infection. South Med J 1995; 88: 591595.
222. Mayaud CM, Cadranel J. HIV in the lung: guilty or not guilty? Thorax 1993; 48: 11911195.
223. Morris DG, Jasmer RM, Huang L, Gotway MB, Nishimura S, King TE Jr. Sarcoidosis following
HIV infection: evidence for CD4z lymphocyte dependence. Chest 2003; 124: 929935.
224. Charlier C, Nunes H, Trinchet JC, et al. Evolution of previous sarcoidosis under type 1 interferons
given for severe associated disease. Eur Respir J 2005; 25: 570573.
225. Leclerc S, Myers RP, Moussalli J, Herson S, Poynard T, Benveniste O. Sarcoidosis and interferon
therapy: report of five cases and review of the literature. Eur J Intern Med 2003; 14: 237243.
226. Menon Y, Cucurull E, Reisin E, Espinoza LR. Interferon-alpha-associated sarcoidosis responsive
to infliximab therapy. Am J Med Sci 2004; 328: 173175.
227. Ravenel JG, McAdams HP, Plankeel JF, Butnor KJ, Sporn TA. Sarcoidosis induced by interferon
therapy. Am J Roentgenol 2001; 177: 199201.
228. Pietropaoli A, Modrak J, Utell M. Interferon-alpha therapy associated with the development of
sarcoidosis. Chest 1999; 116: 569572.
229. Rubinowitz AN, Naidich DP, Alinsonorin C. Interferon-induced sarcoidosis. J Comput Assist
Tomogr 2003; 27: 279283.
230. Husa P, Klusakova J, Jancikova J, Husova L, Horalek F. Sarcoidosis associated with interferon-
alpha therapy for chronic hepatitis B. Eur J Intern Med 2002; 13: 129131.
231. Nawras A, Alsolaiman MM, Mehboob S, Bartholomew C, Maliakkal B. Systemic sarcoidosis
presenting as a granulomatous tattoo reaction secondary to interferon-alpha treatment for chronic
hepatitis C and review of the literature. Dig Dis Sci 2002; 47: 16271631.
232. Baughman RP, Sharma OP, Lynch JP 3rd. Sarcoidosis: is therapy effective? Semin Respir Infect
1998; 13: 255273.
233. Johns CJ, Schonfeld SA, Scott PP, Zachary JB, MacGregor MI. Longitudinal study of chronic
sarcoidosis with low-dose maintenance corticosteroid therapy. Outcome and complications. Ann N
Y Acad Sci 1986; 465: 702712.
234. Eule H, Weinecke A, Roth I, Wuthe H. The possible influence of corticosteroid therapy on the
natural course of pulmonary sarcoidosis. Late results of a continuing clinical study. Ann N Y Acad
Sci 1986; 465: 695701.
235. Young RL, Harkleroad LE, Lordon RE, Weg JG. Pulmonary sarcoidosis: a prospective
evaluation of glucocorticoid therapy. Ann Intern Med 1970; 73: 207212.
236. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am
Rev Respir Dis 1973; 107: 609614.
237. Yamamoto M, Saito N, Tachibana T. Effects of an 18 month corticosteroid therapy to stage I and
stage II sarcoidosis patients (control trial). In: Chretien J, Marsac J, Saltiel JC, eds. Sarcoidosis
and other granulomatous disorders. Paris, Pergamon Press, 1980; pp. 470474.
238. Selroos O, Sellergren T. Corticosteroid therapy of pulmonary sarcoidosis. A prospective
evaluation of alternate day and daily dosage in stage II disease. Scand J Respir Dis 1979; 60: 215
221.
239. OLeary TJ, Jones G, Yip A, Lohnes D, Cohanim M, Yendt ER. The effects of chloroquine on
serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis. N Engl J Med 1986;
315: 727730.
240. Muller-Quernheim J, Kienast K, Held M, Pfeifer S, Costabel U. Treatment of chronic sarcoidosis
with an azathioprine/prednisolone regimen. Eur Respir J 1999; 14: 11171122.
241. Lewis SJ, Ainslie GM, Bateman ED. Efficacy of azathioprine as second-line treatment in
pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 8792.
242. Baltzan M, Mehta S, Kirkham TH, Cosio MG. Randomized trial of prolonged
chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med 1999;
160: 192197.

128
 PULMONARY SARCOIDOSIS

243. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
2001; 18: 7074.
244. Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive
pulmonary sarcoidosis. Chest 2003; 124: 177185.
245. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
2004; 21: 4348.
246. Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. The registry of the
International Society for Heat and Lung Transplantation: twenty-first official adult heart
transplant report2004. J Heart Lung Transplant 2004; 23: 804815.
247. Shorr AF, Helman DL, Davies DB, Nathan SD. Sarcoidosis, race, and short-term outcomes
following lung transplantation. Chest 2004; 125: 990996.
248. Young CJ, Gaston RS. African Americans and renal transplantation: disproportionate need,
limited access, and impaired outcomes. Am J Med Sci 2002; 323: 9499.
249. Nair S, Eustace J, Thuluvath PJ. Effect of race on outcome of orthotopic liver transplantation: a
cohort study. Lancet 2002; 359: 287293.
250. Nunley DR, Hattler B, Keenan RJ, et al. Lung transplantation for end-stage pulmonary
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 93100.
251. Walker S, Mikhail G, Banner N, et al. Medium term results of lung transplantation for end stage
pulmonary sarcoidosis. Thorax 1998; 53: 281284.
252. Collins J, Hartman MJ, Warner TF, et al. Frequency and CT findings of recurrent disease after
lung transplantation. Radiology 2001; 219: 503509.
253. Hadjiliadis D, Sporn PA, Perfect JR, Tapson VF, Davis RD, Palmer SM. Outcome of lung
transplantation in patients with mycetomas. Chest 2002; 121: 128134.

129
CHAPTER 9

Cardiac involvement in sarcoidosis

W. Schulte*, D. Kirsten#, M. Drent}, U. Costabelz

*Dept of Pneumology and Cardiology, Malteser-Krankenhaus, Bonn, #Dept of Pneumology,

Krankenhaus, Grohansdorf, and zDept of Pneumology/Allergy, Ruhrlandklinik Essen, Essen, Germany.
}
Sarcoidosis Management Centre, Dept of Respiratory Medicine, University Hospital Maastricht,
Maastricht, The Netherlands.

Correspondence: U. Costabel, Dept of Pneumology/Allergy, Tuschener Weg 40, Ruhrlandklinik, D-45239

Essen, Germany. Fax: 49 2014334029; E-mail: erj.costabel@t-online.de

Sarcoidosis is a systemic disease of unknown aetiology characterised by the formation

of noncaseating epitheloid cell granulomas, which can occur in virtually any organ.
Cardiac involvement is of critical importance, due to the poor prognosis if this organ
manifestation is left undiagnosed and untreated. Early initiation of therapy seems to be
associated with a good prognosis; therefore, the diagnosis of cardiac sarcoidosis should
be made before irreversible damage has occurred. Nevertheless, the diagnosis of cardiac
sarcoidosis still remains "an imperfect science, a hesitant art" [1].

Epidemiology
Cardiac sarcoidosis was first described by Bernstein et al. [2] in an autopsy case. A
period of 4 yrs later, Schaumann [3] demonstrated cardiac involvement in two further
autopsy cases. In 1937, Gentzen [4] reported about giant cell granulomas in two patients
with endomyocardial fibrosis, which was the first publication of death due to cardiac
sarcoidosis. Until 1980, literature reports were limited to mainly anecdotal descriptions
of single or small numbers of patients. Clinically apparent cardiac involvement has since
been noted in 210% of patients with proven sarcoidosis [1, 518]. Prior to the
introduction of echocardiography, the distinction from cor pulmonale was probably
imprecise. Since modern diagnostic tools, such as echocardiography, nuclear scan or
magnetic resonance imaging (MRI), have become available, higher rates of patients with
cardiac sarcoidosis have been reported. Nevertheless, the rate still remains influenced by
the selection of the patients and the differences in the local health system [10, 12, 1928].
The highest rates of cardiac involvement (from 2078%) are found in necropsy series
[6, 7, 22, 2937]. In 1978, Silverman et al. [30] analysed 84 consecutive autopsies in
patients who died due to sarcoidosis at John Hopkins Hospital (Baltimore, MD, USA)
between 1899 and 1977. They detected granulomas in the heart of 27% of the patients
[30]. Similar frequencies of 20% and 19.5% were reported by Longscope and Freiman
[32] and Sharma et al. [6] in a series of 92 and 123 autopsied cases, respectively.
Apparently, there are differences in the presentation of the disease between patients
from Europe and America and those from Japan. Japanese pathologists reported much
higher rates of cardiac involvement, reaching as much as 5078% [3135, 3840].
Whereas in the USA 1350% of all sarcoidosis deaths have been attributed to cardiac
involvement [33, 35], in Japan up to 85% of all deaths have been related to heart
involvement [31, 40]. A retrospective clinical study from Haifa, Israel showed that only
two out of 120 patients with sarcoidosis died due to cardiac involvement [20].
Eur Respir Mon, 2005, 32, 130149. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
130
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

A questionnaire sent to 651 sarcoidosis-affected members of the German Sarcoidosis

Patients Union (Deutsche Sarkoidose Vereinigung; see Appendix) revealed cardiac
sarcoidosis in only 8% [11]. In this survey, the latency between the first symptoms, or first
abnormal medical findings, and the ultimate diagnosis amounted for up to 7 yrs [11].
The involvement of the heart often remains subclinical, especially in patients with
sudden cardiac death, as the changes in the heart are often just detected post mortem [1, 8,
22, 2931, 33, 36, 37]. Cardiac sarcoidosis seems to be more frequent in younger patients
and can also affect adolescents [19, 3436].
The course of the cardiac and thoracic manifestations of sarcoidosis may not
necessarily be concomitant. Cardiac sarcoidosis may occur at any point in time during
the course of sarcoidosis, may occur in the absence of pulmonary or other organ
involvement, or may be the initial presentation. In the follow-up of 52 patients with
cardiac sarcoidosis from Bad Berka, the central sarcoidosis clinic of former Eastern
Germany, in one-third of the cases the cardiac involvement became apparent only after
the pulmonary changes had normalised [21]. Cardiac sarcoidosis should also be
presumed in young individuals with unclear cardiac arrhythmias or dysfunction where it
may be the first and only disease manifestation.

Cardiac sites of involvement

In principle, all cardiac structures can be involved (table 1) [2954]. Most often the
changes affect the conduction system and the myocardium [29] (figs 1 and 2). A valvular
dysfunction mainly presents as mitral insufficiency and is usually the result of a
granulomatous infiltration of the corresponding papillary muscle or a change in the
ventricular architecture [46]. Direct involvement of the mitral valve is very rare, and of
the other valves even more uncommon (v3%) [8, 13, 29].
Circumscribed myocardial involvement mostly presents as local hypertrophy or
dyskinesia of the myocardium. In the further course, myocardial scaring and remodelling
replaces the active granuloma, resulting in dilatation of the left ventricle, local
hypokinesia or aneurysms (in 810%) [6, 7]. Diffuse involvement of the myocardium
results in dilated cardiomyopathy, global hypokinesia, and left ventricular failure [6, 14,
41, 42, 45]. Cardiac sarcoidosis can also mimic right ventricular dysplasia [55, 56]. The
myocardial lesions are occasionally associated with an active granulomatous arteritis of
the coronary arteries [7].
Involvement of the conducting system or the septum results in bradycardic
arrhythmias or conduction disturbances, such as variable degrees of atrioventricular
(AV) block or bundle brunch block [7, 8, 29]. Clinically, completely healed scars still
Table 1. Manifestations of cardiac sarcoidosis

Clinical manifestation Histology

Asymptomatic granulomas Incidental granulomas in the myocardium
Conduction defects (e.g. bundle Granulomatous or fibrotic involvement of the conduction system
brunch block)
Atrial arrhythmias Ventricular dysfunction, pulmonary arterial hypertension, myocardium
or nerve involvement
Mitral insufficiency Papillary muscle dysfunction
Ventricular aneurysms Myocardial fibrosis
Ventricular tachyarrhythmias Granulomas or scars in the myocardium
Congestive heart failure Remodelling of the heart by inflammatory or fibrotic processes.
Pericardial effusions or fibrosis Inflammation, fibrosis and/or fluid in the pericardium
Adapted from [18].

131
 W. SCHULTE ET AL.

Fig. 1. Macroscopic view of a left ventricle with cardiac sarcoidosis.

a)

b)

Fig. 2. Microscopic view of myocardial granulomas in sarcoidosis. a) low power; b) high power view.

represent an arrhythmogenic substrate that can promote arrhythmias by micro-re-entry.

Granulomas are most often found in the septum and the free wall of the left ventricle,
and rarely seen in the myocardium of the atrium or right ventricle due to the minor
amount of muscle [29]. Therefore, supraventricular arrhythmias most likely result from

132
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

atrial dilatation, secondary to ventricular dysfunction, than from granulomatous

infiltration of the atrial myocardium [8, 29].
Infiltration of the pericardium may lead to pericardial effusions and fibrosis [29, 53
54]. Constrictive pericarditis has also been described [44]. Pericardial effusions can be
detected by echocardiography in 1021% of patients with pulmonary or systemic
sarcoidosis, even in the absence of cardiac symptoms [54, 57].

Diagnostic approach
Many diagnostic tests can be performed in the assessment of patients suspected of
suffering from cardiac sarcoidosis. They all have their own advantages and
disadvantages. The present authors propose a stepwise diagnostic approach, starting
with easy and widely accessible tests and ending with the more expensive and invasive
procedures (table 2).

ECG
Numao et al. [47] observed pathological findings in the 12-lead ECG in 22% of 963
Japanese patients with sarcoidosis, but also in 17% of a control group of healthy persons
with the same distribution of age and sex. Chapelon-Abric et al. [58] found ECG
abnormalities in 22% of 41 patients with cardiac sarcoidosis compared with 77% who had
abnormal echocardiographies. The study by Fleming et al. [7] of 300 patients with
cardiac sarcoidosis in England revealed ventricular arrhythmias in 45%, conduction
disturbances in 38%, supraventricular arrhythmias in 28%, and sudden cardiac death in
16%.
The prevalence of ECG changes seems to be related to the severity of the disease.
Silverman et al. [30] compared clinical data with autopsy findings. Only 15% of the
patients without cardiac involvement at autopsy had ECG abnormalities. This
proportion increased to 42% in patients with mild cardiac involvement (visible only
on microscopy), and to 75% in patients with severe involvement (gross evidence of
granulomas or infiltration). A comparison between Swedish and Japanese patients did
not show significant differences in the frequency and type of ECG changes [51]. Taken
from these series, y2040% of patients with sarcoidosis have detectable ECG
Table 2. Diagnostic approach in the evaluation of cardiac sarcoidosis
Step 1 ECG
Routine procedure in each patient with sarcoidosis
In case of no abnormality and no complaints stop
Step 2 Holter monitor and echocardiography
In case of i1 abnormalities, perform i1 of the following dependent on the
availability in the clinical setting
Step 3 MRI: useful in detecting granulomas and/or fibrosis
Thallium or other nuclear scans: useful in assessing ischaemia, necrosis
or granulomas
MIBG scan: useful in detecting autonomic dysfunction
PET scan: useful in detecting granulomas
Coronary angiography: useful in excluding coronary artery disease
Step 4 Endomyocardial biopsy
In the case of no other histological confirmation of sarcoidosis and of no clinical
picture compatible with sarcoidosis. If there is already biopsy confirmation of
sarcoidosis in any other tissue of the body, there is no indication for a biopsy of the heart
MRI: magnetic resonance imaging; MIBG: I-123 meta-iodobenzylguanidine; PET: positron emission tomography.

133
 W. SCHULTE ET AL.

abnormalities. More sophisticated ECG measurements, such as late potentials or heart

rate variability, are nonspecific and do not play a role in the diagnostic or prognostic
assessment.
Exercise ECG and exercise testing (spiroergometry) seem to be more sensitive than the
resting ECG, and are more helpful in discriminating a myocardial ischaemia or to
differentiate between cardiovascular and pulmonary limitations [6, 4851]. A reduced
increase of the heart rate with exercise has been reported [52]. Often exercise performance
and peak oxygen uptake are much better than expected from the ejection fraction (EF) of
the left ventricle. This is already explained by the fact that the myocardium is not
damaged diffusely and there is still healthy muscle around the granulomas in all parts of
the ventricular wall. The present authors perform an exercise test in all patients with
severely reduced left ventricular function. The result enables us to recommend the
amount of physical activity to the patients and estimate the necessity of listing for heart
transplantation. Furthermore, exercise testing allows a reliable measurement of the
therapeutic effects (table 3).
24-h Holter monitoring is important for the diagnosis and for risk estimation. In a
prospective study of 38 patients with sarcoidosis referred to a cardiology clinic, 67% of
the 12 patients with confirmed cardiac involvement had w100 extra ventricular
beats?day-1 versus only 8% of the 26 patients without cardiac sarcoidosis and only 5%
of a control group of 58 healthy individuals [49]. The Holter ECG plays a crucial role in
defining the indications for an antibradycardic pacemaker, as well as the implantation of
an internal defibrillator. Any abnormality on Holter monitoring or ECG should be
further evaluated by echocardiography and/or other studies.

Echocardiography
Echocardiography is a useful noninvasive method to demonstrate morphological as
well as functional changes of the heart (figs 3 and 4). Due to low costs and high
availability, it is particularly well suited for follow-up examinations. The sensitivity can
further be improved by performing a stress-echocardiography, tissue Doppler technique
or using pulmonary capillaries passing contrast fluid [59]. Echocardiography has been
reported to show pathological findings in 1477% of the patients with sarcoidosis, and
also in patients with a normal ECG [24, 26, 27, 5359]. Many of the older studies on this
topic have been published in the 1980s, when the available ultrasound equipment was far
Table 3. Results of exercise testing and echocardiography in a 45-yr-old female with proven cardiac
sarcoidosis, normal lung function tests and no other disease#

Before After 9 months of treatment with 1040 mg

treatment prednisolone and biventricular pacemaker
Ejection fraction % 20 45
Diameter LV mm 77 54
Diameter RV mm 32 27
VO2 peak mL?kg-1?min-1 980 1170
VO2 peak?kg-1 16.1 19.5
Maximum load W 88 100
Maximum HR 1?min-1 145 105
RQ 1.3 1.4
TL,CO 75 80
LV: left ventricle; RV: right ventricle; VO2: maximal oxygen uptake; HR: heart rate; RQ: respiratory quotient; TL,CO:
transfer factor of the lung for carbon monoxide. #: VO2 in the first test was much better than expected from
echocardiography; the improvement in the second test only minor compared with the marked improvement of the
ejection fraction, partly explained by an abnormally low increase of the HR under exercise.

134
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

Fig. 3. Echocardiography in proven cardiac sarcoidosis. Dilated left ventricle. The septum is thinned and
shows echo-dense dots like pearls on a string, interpreted as local scaring. Arrows point to, from top to bottom,
the left ventricle, septum, mitral valve and left atrium, respectively.

a) b)

Fig. 4. Echocardiography of the posterior wall of the left ventricle, showing a very circumscribed akinesia of
y1 cm. In a) diastole, the arrow points to the bulged wall of the left ventricle, postero-basal, and in b) systole,
the arrow points to circumscribed akinesia at the upper end of the bulged area, stimulating an aneurysm of
1 cm diameter.

135
 W. SCHULTE ET AL.

less sophisticated and of less optimal resolution than today. In the opinion of the current
authors, echocardiography should be one of the basic examinations in the evaluation and
follow-up of patients with sarcoidosis.
Yazaki et al. [60] compared 15 patients with cardiac sarcoidosis and 30 patients with
idiopathic dilated cardiomyopathy (DCM). A total of 73% of the patients with
sarcoidosis had circumscribed thinning or thickening of the wall of the left ventricle,
usually of the septum. An involvement of the septum was always accompanied by an AV
conduction disturbance or block. In the patients with DCM, just 17% showed a
circumscribed widening of the wall, but never a regional hypertrophy. Many other
diseases, such as valve dysfunction, cor pulmonale, hypertrophic cardiomyopathy or
amyloidosis can usually be well differentiated by ultrasound scan due to typical or
pathognomonic features. In patients with proven cardiac sarcoidosis, a diastolic
dysfunction is reported for approximately half of all patients in studies with
echocardiography, as well as with MRI of the heart [61].

Radionuclide imaging
Myocardial imaging with 201Thallium (201Tl) has been most frequently used and
investigated in patients with suspected sarcoidosis. This radionuclide is absorbed by the
living heart muscle cell. Areas with scars, necrosis, ischaemia or inflammation
accumulate less 201Tl and appear as cold spots. In cardiac sarcoidosis, the segmental
defects detected at rest are reversible or decrease in size on delayed scans or with exercise,
dipyridamole or adenosine. This phenomenon, called "reverse distribution", differs from
ischaemic changes in coronary artery disease, in which defects at rest worsen or fail to
improve with exercise, dipyridamole or adenosine. However, patchy thallium perfusion
defects are nonspecific for sarcoidosis even in the presence of normal coronary arteries.
Unfortunately, they also occur in other causes of myocardial infiltration, inflammation
or cardiomyopathy. In addition, just a minor portion of all patients with sarcoidosis
develop relevant cardiac involvement and the method is associated with a high radiation
burden. Pathological results have been found in 1375% of all examined patients
depending on the size and composition of the study group [6, 24, 25, 28, 6174].
The 67gallium (67Ga) scan seems to have a lower sensitivity than the 201Tl scintigraphy
[68, 7381]. Patients with a positive result in the 67Ga scan nearly always demonstrate
pathological changes in the 201Tl scan. It was hoped that an improvement in the
diagnostic approach or the estimation of the further course of the disease would
occur when both tools were combined, but this was not proven until now [73, 74, 7678].
The myocardial infiltration in sarcoidosis can also be detected with 99Technetium-
pyrophosphate scans, but no comparative studies with 201Tl have been done [81]. The
99m
Tc-sesta-methoxy-isobutyl-isonotrile (99mTc-mibi) single-photon emission computed
tomography scan seems to be superior to 201Tl scanning, but only a limited number of
studies are available [71, 8283].
Iodine-123 meta-iodobenzylguanidine, an analoque of norepinephrine, is a tracer for
the functioning of sympathetic neurons. This allows visualisation of the sympathetic
innervation of the heart and a quantitative assessment of pre-synaptic sympathetic nerve
terminal disturbances. An imbalance of the sympathetic tone is considered to increase the
propensity to develop ventricular arrhythmias in various cardiac diseases and conditions,
and also in sarcoidosis [84].
In summary, in the absence of cardiac symptoms radionuclide imaging should not be
used as routine screening for cardiac involvement in patients with sarcoidosis, and should
not be repeated very frequently in the follow-up in patients with a positive test result due
to the high radiation burden and the availability of less harmful tests. However, in the

136
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

presence of normal coronary arteries, the perfusion defects on 201Tl imaging in patients
with known systemic sarcoidosis strongly suggest cardiac involvement.

Magnetic resonance imaging

Gated cardiac MRI imaging, as a noninvasive method of investigation, is very
promising and is being more frequently used in cardiac sarcoidosis. Apart from case
reports dating back to 1988 [79], there are increasing numbers of small studies becoming
available [61, 70, 72, 8589]. Shimada et al. [70] demonstrated localised enhancements on
gadolinium-enhanced cardiac MRI in eight out of 16 patients with suspected cardiac
sarcoidosis, indicative of interstitial oedema, inflammation or scaring; 201Tl scanning was
abnormal in seven patients, and the ECG in only two patients. Under corticosteroid
therapy, these changes improved or vanished in a follow-up examination after 1 month.
The pictures of MRI are accurate in their detail and are able to demonstrate structural
and functional abnormalities, which can usually be well differentiated from ischaemic
lesions by the different shape and distribution of the abnormal area. Due to this
advantage and the lack of radioactivity, the method is well suited for follow-up
investigations in patients with positive findings, but limited by availability and costs [72,
85, 86]. In a small series by the present authors, characteristic, unambiguous
abnormalities in untreated patients with newly diagnosed cardiac sarcoidosis were
found (figs 57). In contrast, all the patients with proven cardiac sarcoidosis and long-
term steroid therapy only presented nonspecific changes, such as enlargement of the
ventricle or hypokinesia, but not the typical regional changes in the myocardium itself.

Fig. 5. Cardiac magnetic resonance imaging scan of a patient with histologically-proven cardiac sarcoidosis.
Involved areas are seen in white, which corresponds to enrichment of contrast (gadolinum) in acutely involved
myocardium near the basis of the papillary muscles of the left ventricle. Normal myocardium and coronary
arteries present in dark stain (two-chamber view of the left ventricle, long axis, 1.5 Tesla, T1-weighting, fast-spin
echo, contrast gadolinum, inversion recovery sequence). Arrows point to, going clock wise, contrast-enriched
myocardium (white), normal myocardium (dark), filling (blood) of the left ventricle (grey) and the coronary
arteries, respectively.

137
 W. SCHULTE ET AL.

Fig. 6. Cardiac magnetic resonance imaging scan of a patient presenting with atrioventricular block 2nd to 3rd
degree: typical thickening and contrast enrichment of the basal septum in the four-chamber view. Arrows point
to, from top to bottom, the right ventricle, left ventricle, thickened basal septum with inhomogeneous contrast
enrichment due to sarcoidosis, and left atrium, respectively.

Fig. 7. Cardiac magnetic resonance imaging scan: diffuse involvement of the heart in histologically-proven
cardiac sarcoidosis. The focal and nodular differences in the contrast enrichment and the local thickening of the
myocardium are well visible (same view as in figure 2, but different T1/T2-weighting)

138
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

These unpublished data are in agreement with a recent publication by Skold et al. [61].
They studied 18 consecutive patients with sarcoidosis. They observed regional
myocardial contrast enhancement on MRI in only two patients despite abnormalities
on ECG and/or echocardography in the majority of patients [61]. MRI imaging is not
possible in patients with implanted pacemakers [70, 71, 79, 8592]. Cardiac MRI still
needs further investigation in myocardial sarcoidosis before it can be considered as the
diagnostic test of choice.

Positron-emission tomography
To date, there are only case reports and a few small studies available [9396].
Yamagishi et al. [93] examined 17 patients with cardiac sarcoidosis by (13)N-NH(3)/
(18)F-fluoro-2-deox-d-glucose (FDG) positron-emission tomography (PET) and identi-
fied a myocardial (13)N-NH(3)-defect in 13 patients and an increased (18)F-FDG uptake
in 14 patients. Only six of these patients had a positive 201Tl scan and only three patients
a positive 67Ga scan in the heart [93]. Ishimaru et al. [94] found in 10 out of 32 patients
with sarcoidosis, but in none of a control group of 30 subjects, a focal pattern in the
myocardium. None of the patients exhibited abnormal findings on 67Ga scan and only
four on 99mTc-Mibi scan [94]. Thus, PET imaging seems promising, being more sensitive
than 201Tl and 67Ga scanning, but it is expensive and further studies are needed to clarify
its role in the management of cardiac sarcoidosis in the future.

Invasive examinations
Cardiac catheterisation with coronary angiography is done in the majority of patients
with suspected cardiac sarcoidosis in order to exclude coronary artery disease.
Endomyocardial biopsies, introduced in 1962, are nearly always taken from the right
ventricle, whereas sarcoid granulomas are more commonly located in the parts of the
heart with larger muscle masses, predominantly in the left ventricle. The smaller and
more circumscribed the lesions are, the lower the likelihood to hit them in the biopsy.
Thus, the degree of sampling error is high, and as expected, the reported success rate of
endomyocardial biopsy is generally v25% [38, 39, 47, 97100]. Therefore, the present
authors do not recommend the routine use of biopsy to confirm myocardial
involvement if the diagnosis of cardiac sarcoidosis can be substantiated by other
techniques.

Clinical criteria for diagnosis

In the experience of the current authors, the criteria of the Japanese Ministry of
Health and Welfare from 1993 [70] to diagnose cardiac sarcoidosis are useful and
reliable (table 4). These criteria distinguish between histologically-proven and
clinically-based diagnosis of cardiac sarcoidosis. In the clinically-based diagnosis,
the cardiac involvement by sarcoidosis must be proven histologically at an
extracardiac site. In addition, characteristic ECG abnormalities (i.e. bundle brunch
block, AV-dissociation or complex ventricular arrhythmias) as well as structural or
functional abnormalities of the myocardium must be present. Excluded are patients in
whom these changes are already explained by other diseases, such as myocardial
infarction or cor pulmonale.

139
 W. SCHULTE ET AL.

Table 4. Guidelines for diagnosing cardiac sarcoidosis#

Histological diagnosis Cardiac sarcoidosis is confirmed when histological analysis of operative or endomyocardial
group biopsy specimens demonstrates epithelioid granuloma without caseating granuloma
Clinical diagnosis In patients with a histological diagnosis of extracardiac sarcoidosis, cardiac sarcoidosis is
group suspected when item a) and i1 of items be) are present:
a) Complete right bundle brunch block, left axis deviation, AV block, ventricular
tachycardia, premature ventricular contraction} or abnormal Q or ST-T change
on the ECG
b) Abnormal wall motion, regional wall thinning or dilatation of the left ventricle on the
echocardiography
c) Perfusion defect by 201TI-myocardial scintigraphy or abnormal accumulation by
67
Ga-citrate or 99mTc-PYP myocardial scintigraphy
d) Abnormal intracardiac pressure, low cardiac output, abnormal wall motion or
depressed ejection fraction of the left ventricle on cardiac catheter examination
e) Interstitial fibrosis or cellular infiltration over moderate grade in myocardial biopsy
even if the findings are nonspecific
Taken from [70]. AV: atrioventricular; Tl: thallium; Ga: gallium; PYP: pyrophosphate. #: Japanese Ministry of
Health and Welfare, 1993; }: over grade 2 in Lowns classification of premature ventricular tachycardia.

Management and prognosis

The specific treatment of cardiac sarcoidosis is similar to the treatment of other organ
involvement. Standard therapy is the administration of systemic corticosteroids (CS) [6
8, 14, 58, 70, 97, 98, 101108]. Recommendations are based on case reports and
retrospective studies. Prospective or randomised trials for cardiac sarcoidosis have not
been performed. Whereas good short-term responses have been reported, data
concerning long-term efficacy or criteria for dosage, duration, or potential cessation
of CS therapy are scarce. Cardiac-specific treatment of cardiac dysfunction or
arrhythmias is guided by theoretical and empirical considerations based on the
experience with other cardiomyopathies in which treatment has been validated in large
multi-centre trials. Treatment of cardiac sarcoidosis is difficult and requires careful
monitoring of efficacy and safety of therapeutic agents [18].

Antiarrhythmic therapy
The indication to implant an antibradycardic pacemaker is easy to decide. Today
biventricular pacemakers are available to improve the systolic function and diastolic filling.
This is achieved by resynchronising the contraction of the left ventricle and prolonging the
diastolic filling time when wide QRS complexes lead to an asynchrony and asynergy of the
work of the left ventricle. Biventricular pacing seems to be associated with a higher survival
rate over time in other cardiomyopathies with wide QRS complexes [109, 110].
Many questions remain to be answered regarding antitachycardic systems, such as the
automatic implantable cardioverter defibrillator (AICD), or combined systems. In patients
with sustained or recurrent ventricular tachyarrhythmias, in combination with a syncope
or a resuscitation event, who are at high risk for sudden death, the AICD is surely
mandatory. In view of the high rate of sudden deaths in cardiac sarcoidosis, not only a
secondary but preferably a primary protection would be desirable. However, the question
of prophylactic AICD implantation is difficult to decide. The prognostic importance of
complex ventricular tachyarrhythmias can only be assessed in combination with other
factors, such as the left ventricular function. This function can remarkably improve with
CS therapy, but a myocardial scar, as residual of sarcoid granulomas or inflammation, still
represents an arrhythmogenic substrate. In contrast, the implantation of an AICD is very
expensive, demands the change of the aggregate every few years and can be frightening to

140
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

the patients in case of accidental shocks. Therefore, the decision to implant an AICD, with
the right timing, is at present bound to the individual case [102, 109118]. Nevertheless,
many authors believe that the current data are sufficient to justify the prophylactic
implantation of an AICD in patients at risk. Along these lines, Winter et al. [101]
investigated seven patients with cardiac sarcoidosis who all had documented sustained
ventricular tachyarrhythmia. Despite antiarrhythmic and CS medication, two patients died
due to sudden cardiac death, and four patients had recurrent ventricular tachyarrhythmias.
All four patients who received an AICD experienced at least one adequate shock, which
obviously saved them from sudden death [101].
Antiarrhythmic drug therapy is empirical. Amiodarone is the preferred drug, but
appears to be less effective than in other cardiomyopathies. Often bradycardic and
tachycardic arrhythmias can be found simultaneously, restricting the use of
antiarrhythmic drugs in the absence of a pacemaker. The value of invasive
electrophysiological examinations for a differentiated antiarrhythmic therapy or for
estimating the probability of cardiac events seems to be very limited [111117].

Corticosteroids
A study by Yazaki et al. [42] strongly supports the early and long-term administration
of corticosteroids in order to improve the grim prognosis of cardiac sarcoidosis. Yazaki
et al. [42] retrospectively reviewed the course of the disease in 95 patients who were
diagnosed with cardiac sarcoidosis from 19841996. Overall survival rates were 85% at
1 yr, 72% at 3 yrs, 60% at 5 yrs, and 44% at 10 yrs. During a mean follow-up of 68
months, 29 patients (30%) died of congestive heart failure and 11 (12%) experienced
sudden death. A multivariate analysis identified the New York Heart Association
(NYHA) functional class (hazard ratio=7.7 per NYHA class increase; p=0.0008), the left
ventricle end-diastolic diameter (hazard ratio=2.6 per 10 mm increase; p=0.02) and
sustained ventricular tachycardia (hazard ratio=7.2; p=0.03) as independent predictors of
mortality. Prognosis was excellent in those patients who were treated with CS early,
before systolic dysfunction developed. The 5-yr survival rate was 75% for all steroid-
treated patients. In those with a left ventricular EF of i50% before treatment, the 10-yr
survival rate was 89%, compared with only 27% in those with an EF ofv50%. There was
no difference in survival curves between patients with high initial dose (i40mg) and low
initial dose (v30 mg) of prednisone. A total of 20 out of the 95 patients had autopsy-
proven cardiac sarcoidosis and had never been treated, and they had a poor 5-yr survival
rate of only 10%. In summary, this study shows that starting CS before the occurrence of
severe systolic dysfunction results in an excellent clinical outcome, and that a high initial
dose of prednisone may not be essential for cardiac sarcoidosis.
Kato et al. [106] reported similar results in 20 patients, all with AV block and normal
cardiac function initially. During a mean follow-up period of 79 months, the seven
patients receiving CS experienced no decline in the EF and none of them died. AV-block
regression was seen in four of these seven patients receiving CS. The 13 untreated patients
developed a decline in the mean EF from 60.56.4% to 37.617.3%, and two (15%) of
them died. Ventricular tachycardia occurred in 62% of the untreated, but in only 14% of
the treated patients.
Shimada et al. [70] studied eight patients with cardiac sarcoidosis and abnormalities on
contrast-enhanced MRI. After one month of higher doses of prednisolone (30
40 mg?day-1), the localised high-intensity signals markedly diminished in all eight
patients. Vigneaux et al. [72] followed 12 patients with cardiac sarcoidosis by MRI. All
six patients receiving higher doses of CS were scored as cleared or improved at the 12

141
 W. SCHULTE ET AL.

months follow-up MRI. One patient on low dose prednisone of 10 mg?day-1 was stable,
the five patients not receiving any CS therapy were scored as stable or worsening [72].
Chiu et al. [105] studied 43 patients with cardiac sarcoidosis by echocardiography
before and after CS therapy. In patients with initial left ventricular EF w55%, long-term
steroid treatment (mean follow-up time at 88 months) showed preventive effects on left
ventricular remodelling and left ventricular function. Patients with left ventricular EF
between 30% and 54% showed significant reductions in left ventricular volume and
improvements in left ventricular EF. However, in patients with left ventricular EFv30%,
neither left ventricular volume reductions nor left ventricular EF improvements were
observed. This study underlines previous observations [42] that CS therapy may not be as
effective in the late stage of cardiac sarcoidosis with severe left ventricular dysfunction.
Recently, Chapelon-Abric et al. [58] reported promising long-term follow-up data.
They observed an improvement in 87% of 41 patients with cardiac sarcoidosis after an
average follow-up of 58 months, and 54% were regarded as cured. Two patients
worsened, but they received very late or no treatment. There was no case of sudden death
in this series. These patients were treated early with CS (n=39), and another
immunosuppressant was added (n=13) in case there was an insufficient response to
CS. Treatment was stopped in 13 patients who were apparently cured, after a mean
duration of CS of 34 months (range 9109 months). Relapses occurred in three out of
these 13 patients during a 36-month follow-up (range 492 months), affecting the heart in
two cases.
In summary, despite the lack of large prospective and randomised studies there is no
doubt about the effectiveness of CS therapy. Questions still remain about the right dose
and the duration of therapy. According to the experience of the present authors and the
above mentioned studies, a relapse/death can occur after reducing the dose to v10 mg
prednisone, despite prior stable course of the disease. The present authors advise that CS
administration should be long-term (i2 yrs), if not lifelong.

Other immunosuppressants
There are many case reports and small, uncontrolled studies on additional therapeutic
agents administered in sarcoidosis including methotrexate, azathioprine, hydroxychlor-
oqine, chloroquine, cyclophosphamide, cyclosporine A, thalidomide, pentoxyphylline,
infliximab (anti-tumour necrosis factor), but experience with cardiac sarcoidosis is
limited [18, 103, 119139]. Nevertheless, the current authors believe that there is a place
for combining CS with either azathioprine, hydroxychloroquine or methotrexate to
achieve a CS-sparing effect and reduce CS toxicity in patients with cardiac sarcoidosis
who may need lifelong therapy.

Heart transplantation
Heart transplantation should be considered in patients with severe heart failure
refractory to medical therapy [8, 101, 107]. Recurrence of sarcoidosis in the transplanted
heart is possible and may respond to intensified CS therapy [140142]. The right moment
for listing a patient for heart transplantation is still an individual decision of the
responsible doctor/health centre. Alongside the current functional status, the course and
complications of the disease have to be considered. However, medical treatment should
always be attempted before listing a patient for transplantation. In some patients with
severe heart failure and previously undiagnosed sarcoidosis, transplantation can be
avoided by treating the disease successfully with CS.

142
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

Summary
Clinically evident cardiac sarcoidosis is noted in 210% of patients, although occult
involvement is much higher. The involvement of the heart is an important prognostic
factor in sarcoidosis. Early treatment, predominantly with corticosteroids, prevents
irreversible damage of the heart and seems to be associated with good prognosis.
Technical progress has led to improvements and new diagnostic techniques that allow
a better assessment of the structure and function of the heart. However, for early
diagnosis there is still no single diagnostic tool with acceptable reliability. A
histological confirmation is rarely obtained, and the diagnosis is, therefore, a challenge
and dependent on clinical rules. The most decisive approach is to suspect the disease
and to introduce, in good time, further investigations according to the clinical
presentation, e.g. cardiac arrhythmias in young patients.
Specific therapy is long term, often lifelong, and is based on corticosteroids with or
without immunosuppressants. The symptomatic treatment of cardiac arrhythmias and
dysfunction corresponds to experience with dilated cardiomyopathy.
The indication and timing of implantable defibrillators and transplantation still raises
many questions.

Keywords: Cardiac involvement, diagnosis, heart, sarcoidosis, treatment.

References
1. Sharma OP. Diagnosis of cardiac sarcoidosis: an imperfect science, a hesitant art. Chest 2003; 123:
1819.
2. Bernstein M, Konzelman FW, Sidlick DM. Boecks sarcoid: report of a case with visceral
involvement. Arch Intern Med 1929; 4: 721734.
3. Schaumann J. Etude anatomo-pathologique et histologique sur les localisationes viscerales de la
lymphogranulomatose benigne. Bull Soc Franc Dermat Syph 1933; 40: 11671171.
4. Gentzen G. U ber Riesenzellgranulome bei zwei Fallen von Endokardfibrose. Beitr Pathol Anat
1937; 98: 375.
5. Gozo EG, Cosnow I, Cohen HC, et al. The heart in sarcoidosis. Chest 1971; 60: 379388.
6. Sharma OP, Maheshwari A, Thaker K. Myocardial sarcoidosis. Chest 1993; 103: 253258.
7. Fleming H. Cardiac Sarcoidosis. In: James D, ed. Sarcoidosis and other granulomatous disorders.
New York, Marcel Dekker, 1994; pp. 323334.
8. Shammas RL, Movahed A. Sarcoidosis of the heart. Clin Cardiol 1993; 16: 462472.
9. Kirsten D, Schaedel H. Herzbeteiligung bei Lungensarkoidose. [Heart involvement in lung
sarcoidosis]. Z Erkrank Atm Org 1984; 162: 99107.
10. Kirsten D, Schaedel H, Kessler G. Retrospektive Auswertung des Sarkoidosekrankengutes der
Jahrgange 19701979 der Zentralklinik fur Herz- und Lungenkrankheiten in Bad Berka zur
Auffindung moglicher Herzbeteiligung. [Retrospective evaluation of sarcoidosis patients 1970
1979 at the Bad Berka Central Clinic for Heart and Lung Diseases for the detection of possible
heart involvement]. Z Erkrank Atm Org 1984; 162: 108117.
11. Kirsten D. Sarkoidose in Deutschland. [Sarcoidosis in Germany]. Pneumologie 1995; 49: 378382.
12. Kirsten D. Herzsarkoidose. [Sarcoidosis of the heart]. Pneumologie 1994; 48: 737743.
13. Fleming HA. Sarcoid heart disease. Br Heart J 1974; 36: 5468.
14. Johns CJ, Michele TM. The clinical management of sarcoidosis: a 50 year experience at the John
Hopkins Hospital. Medicine 1999; 78: 65111.

143
 W. SCHULTE ET AL.

15. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336: 12241234.
16. Scadding JG. Sarcoidosis. London, Eyre and Spottiswoode, 1967; p. 291.
17. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European
Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous
Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive
Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736755.
18. Deng JC, Baughman RP, Lynch JP. Cardiac involvement in sarcoidosis. Semin Respir Crit Care
Med 2002; 23: 513527.
19. Duke C, Rosenthal E. Sudden death caused by cardiac sarcoidosis in childhood. J Cardiovasc
Electrophysiol 2002; 13: 939942.
20. Yigla M, Badarna-Abu-Ria N, Tov N, et al. Sarcoidosis in northern Israel: clinical characteristics
of 120 patients. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 220226.
21. Schaedel H, Kirsten D, Schmidt H, et al. Sarcoid heart disease results of follow up investigations.
Eur Heart J 1991; 12: Suppl D, 2627.
22. Uemura A, Morimoto S. Cardiac sarcoidosis. Nippon Rinsho 2002; 60: 17941800.
23. Arunabh S, Verma N, Brady TM. Massive pericardial effusion in sarcoidosis. Am Fam Physician
1998; 58: 660662.
24. Kinney EL, Jackson GL, Reeves WC, et al. Thallium scan myocardial defects and
echocardiographic abnormalities in patients with sarcoidosis without clinical cardiac
dysfunction: an analysis of 44 patients. Am J Med 1980; 68: 497503.
25. Tellier P, Paycha F, Antony I, et al. Reversibility by dipyridamole of thallium -201 myocardial
scan defects in patients with sarcoidosis. Am J Med 1988; 85: 189193.
26. Fahy GJ, Marwick T, McCreery CJ, et al. Doppler echocardiographic detection of the left
ventricular diastolic dysfunction in patients with pulmonary sarcoidosis. Chest 1996; 109: 6266.
27. Burstow DJ, Tajik AJ, Bailey KR, et al. Two-dimensional echocardiographic findings in systemic
sarcoidosis. Am J Cardiol 1989; 63: 478482.
28. Buckley BH, Rouleau JR, Whitaker JQ, et al. The use of thallium for myocardial perfusion
imaging in sarcoid heart disease. Chest 1977; 72: 2732.
29. Roberts WC, McAllister HA Jr, Ferrans VJ. Sarcoidosis of the heart: a clinicopathologic study of
35 necropsy patients (group 1) and review of 78 previously described necropsy patients (group 2).
Am J Med 1977; 63: 86108.
30. Silverman KJ, Hutchins GM, Buckley BH. Cardiac Sarcoid: a clinicopathologic study of 84
unselected patients with systemic sarcoidosis. Circulation 1978; 58: 12041211.
31. Matsui Y, Iwai K, Tachibana T, et al. Clinicopathological study on fatal myocardial sarcoidosis.
Ann NY Acad Sci 1976; 278: 455469.
32. Longscope WT, Freiman DG. A study of sarcoidosis: based on a combined investigation on 160
cases, including 30 autopsies from John Hopkins Hospital and Massachusetts General Hospital.
Medicine 1952; 3: 1152.
33. Perry A, Vuitch F. Causes of death in patients with sarcoidosis: a morphologic study of 38
autopsies with clinicopathologic correlations. Arch Pathol Lab Med 1995; 119: 167172.
34. Iwai K, Skiguchi M, Hosoda, et al. Racial differences in cardiac sarcoidosis noted at autopsy.
Sarcoidosis 1994; 11: 248251.
35. Gideon NM, Mannino DM. Sarcoidosis mortality in the United States 19791991: an analysis of
multiple cause mortality data. Am J Med 1996; 100: 423427.
36. Virmani R, Bures JC, Roberts WC. Cardiac sarcoidosis: a major cause of sudden death in young
individuals. Chest 1980; 77: 423428.
37. Fleming HA. Sarcoid heart disease. BMJ 1973; 1: 174175.
38. Sekiguchi M, Numao Y, Imai M, et al. Clinical and histopathological profile of sarcoidosis of the
heart and acute idiopathic myocarditis. Concepts through a study employing endomyocardial
biopsy. I. Sarcoidosis. Jpn Circ J 1980; 44: 249263.
39. Sekiguchi M, Yazaki Y, Isobe M, et al. Cardiac sarcoidosis: diagnostic, prognostic and therapeutic
considerations. Cardiovasc Drugs Ther 1996; 10: 495510.

144
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

40. Tachibana T, Ohmori F, Ueda E. Clinical study on cardiac sarcoidosis. Ann NY Acad Sci 1986;
465: 530542.
41. Stewart RE, Graham DM, Godfrey GW, et al. Rapidly progressive heart failure resulting from
cardiac sarcoidosis. Am Heart J 1988; 115: 13241326.
42. Yazaki Y, Isobe M, Hiroe M, et al. Prognostic determinants of long term survival in Japanese
patients with cardiac sarcoidosis treated with prednisolone. Am J Cardiol 2001; 88: 1006
1010.
43. Israel RH, Poe RH. Massive pericardial effusion in sarcoidosis. Respiration 1994; 61: 176180.
44. Garret J, ONeill H, Blake S. Constrictive pericarditis associated with sarcoidosis. Am Heart J
1984; 107: 394.
45. Yazaki Y, Hongo M, Hiroyochi Y, et al. Cardiac sarcoidosis in Japan: treatment and prognosis.
In: Sekiguchi M, Richardson PJ, eds. Prognosis and treatment of cardiomyopathy and
myocarditis. Tokyo, University of Tokyo Press, 1994; 351353.
46. Zoneraich S, Gupta MP, Metha J, et al. Myocardial sarcoidosis presenting as acute mitral
insufficiency. Chest 1974; 66: 452454.
47. Numao Y, Sekiguchi M, Fruie T, et al. A study of cardiac involvement in 963 cases of sarcoidosis
by ECG and endomyocardial biopsy. Ann NY Acad Sci 1976; 76: 607614.
48. Gibbons WJ, Levy RD, Nava S, et al. Subclinical cardiac dysfunction in sarcoidosis. Chest 1991;
100: 4450.
49. Suzuki T, Kanda T, Kubota S, et al. Holter monitoring as a noninvasive indicator of cardiac
involvement in sarcoidosis. Chest 1994; 106: 10211024.
50. Thunell M, Bjerle P, Karp K, et al. Exercise test in patients with sarcoidosis: the importance of
repolarization disturbances. Acta Med Scand 1988; 223: 6973.
51. Larsen F, Pehrsson SK, Hammar N, et al. ECG-abnormalities in Japanese and Swedish patients
with sarcoidosis. A Comparison. Sarcoidosis Vasc diffuse Lung Dis 2001; 18: 284288.
52. Delobbe A, Perault H, Maitre J, et al. Impaired exercise response in sarcoid patients with normal
pulmonary function. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 148153.
53. Kinney E, Murthy R, Ascunce G, et al. Pericardial effusions in sarcoidosis. Chest 1979; 76: 476
478.
54. Angomachalelis N, Hourzamanis A, Salem N, et al. Pericardial effusion concomitant with specific
heart musle disease in systemic sarcoidosis. Postgrad Med J 1994; 70: Suppl. 1, S8S12.
55. Ott P, Marcus FI, Sobonya RE, et al. Cardiac sarcoidosis masquerading as right ventricular
dysplasia. Pacing Clin Electrophysiol 2003; 26: 14981503.
56. Shiraishi J, Tatsumi T, Shimoo K, et al. Cardiac sarcoidosis mimicking right ventricular dysplasia.
Circ J 2003; 67: 169171.
57. Gregor P, Widimsky P, Sladkova T, et al. Echocardiography in sarcoidosis. Jpn Heart J 1984;
25: 499508.
58. Chapelon-Abric C, de Zuttere D, Duhaut P, et al. Cardiac sarcoidosis: a retrospective study of 41
cases. Medicine (Baltimore) 2004; 83: 315334.
59. Hyodo E, Hozumi T, Takemoto Y, et al. Early detection of cardiac involvement in patients with
sarcoidosis by a non-invasive method with ultrasonic tissue characterisation. Heart 2004; 90: 1275
1280.
60. Yazaki Y, Isobe M, Hiramitsu S, et al. Comparison of clinical features and prognosis of cardiac
sarcoidosis and idiopathic dilated cardiomyopathy. Am J Cardiol 1998; 82: 537540.
61. Skold CM, Larsen FF, Rasmussen E, et al. Determination of cardiac involvement in sarcoidosis
by magnetic resonance imaging and Doppler echocardiography. J Intern Med 2002; 252: 5: 465
471.
62. Tellier P, Valeyre D, Nitenberg A, et al. Cardiac sarcoidosis: reversion of myocardial perfusion
abnormalities by dipyridamole. Eur J Nucl Med 1985; 11: 201204.
63. Yamamoto N, Gotoh K, Yagi Y, et al. Thallium-201-myocardial SPECT findings at rest in
sarcoidosis. Ann Nucl Med 1993; 7: 97103.
64. Valeyre D, Marsac J, Gambini G, et al. Assessment of sarcoid heart disease : a study of 37 patients

145
 W. SCHULTE ET AL.

with thoracic sarcoidosis. In: Chretien J, Marsac J, Saltiel JC, eds. Sarcoidosis and other
granulomatous diseases. Oxford, Pergamon 1983; 296300.
65. Haywood LJ, Sharma OP, Siegel ME, et al. Detection of myocardial sarcoidosis by thallium201
imaging. J Natl Med Assoc 1982; 74: 959964.
66. Fields CL, Ossorio MA, Roy TM, et al. Thallium-201 scintigraphy in the diagnosis and
management of myocardial sarcoidosis. South Med J 1990; 83: 339342.
67. Okayama K, Kurata C, Tawarahara K, et al. Diagnostic and prognostic Value of myocardial
scintigraphy with thallium-201 and gallium-67 in cardiac sarcoidosis. Chest 1995; 107: 330334.
68. Mana J. Nuclear imaging: 67Gallium, 201thallium, 18F-labelled fluoro- 2-deoxy-D-glucose
positron emission tomography. Clin Chest Med 1997; 18: 799811.
69. Nitenberg A, Foult JM, Blanchet F, et al. Multifactorial determinants of reduced coronary flow
reserve in after dipyridamole in dilated cardiomyopathy. Am J Cardiol 1985; 55: 748754.
70. Shimada T, Shimada K, Sakane T, et al. Diagnosis of cardiac sarcoidosis and the evaluation of the
effect of steroid therapy by Gadolinium DTPA-enhanced magnetic resonance imaging. Am J
Med 2001; 110: 520527.
71. Le Guludec D, Menad F, Faraggi M, et al. Myocardial sarcoidosis: clinical value of technetium-
99m-sestamibi tomo-scintigraphy. Chest 1994; 106: 16751682.
72. Vignaux O, Dhote R, Duboc D, et al. Clinical significance of myocardial magnetic resonance
abnormalities in patients with sarcoidosis: a 1-year follow up study. Chest 2002; 122: 18951901.
73. Tajima T, Naito T, Dohi Y, et al. Ga-67 and TI-201 imaging in sarcoidosis involving myocardium.
Clin Nucl Med 1981; 6: 120121.
74. Nagatomo Y, Imamura T, Koiwaya Y, et al. Thallium-201 and gallium-67 myocardial
scintigraphy for the evaluation of sarcoid involvement. Clin Nucl Med 1987; 12: 335336.
75. Hirose Y, Ishida Y, Hayashida K, et al. Myocardial involvement in patients with sarcoidosis: an
analysis of 75 patients. Clin Nucl Med 1994; 19: 522526.
76. Kurata C, Sakata K, Taguchi T, et al. SPECT imaging with TI-201 and Ga-67 in myocardial
sarcoidosis. Clin Nucl Med 1990; 15: 408411.
77. Taki J, Nakajima K, Bunko H, et al. Cardiac sarcoidosis demonstrated by TI-201 and Ga-67
SPECT imaging. Clin Nucl Med 1990; 15: 636639.
78. Tawarahara K, Kurata C, Okayama K, et al. Thallium-201 and gallium- 67 single photon emission
computed tomographic imaging in cardiac sarcoidosis. Am Heart J 1992; 124: 13831384.
79. Riedy K, Fisher MR, Belic N, et al. MR imaging of myocardial sarcoidosis. Am J Roentgenol 1988;
151: 915916.
80. OConnell JB, Henkin RE, Robinson JA, et al. Gallium-67 imaging in patients with dilated
cardiomyopathy and biopsy-proven myocarditis. Circulation 1984; 70: 5862.
81. Forman MB, Sandler MP, Sacks GA, et al. Radionuclide imaging in myocardial sarcoidosis:
demonstration of myocardial uptake of technetium 99m pyrophosphate and gallium. Chest 1983;
83: 578580.
82. Eguchi M, Tsuchihashi K, Hotta D, et al. Technetium 99m sestamibi/tetrofosmin myocardial
perfusion scanning in cardiac and noncardiac sarcoidosis. Cardiology 2000; 94: 193199.
83. Nishijima K, Miyahara Y, Furukawa K, et al. Simultaneous assessment of right ventricular
function and hypertrophy by Tc-99m MIBI. Clin Nucl Med 1999; 24: 151155.
84. Hoitsma E, Faber CG, van Kroonenburgh MJPG, et al. Cardiac sympathetic dysfunction and
small fiber neuropathy: a common problem in sarcoidosis? Sarcoidosis Vasc Diffuse Lung Dis 2005;
22: 4350.
85. Doherty MJ, Kumar SK, Nicholson AA, et al. Cardiac sarcoidosis: the value of magnetic
resonance imaging in diagnosis and assessment of response to treatment. Respir Med 1998;
92: 697699.
86. Eliasch H, Juhlin-Dannfelt A, Sjogren I, et al. Magnetic resonance imaging as an aid to the
diagnosis and treatment evaluation of suspected myocardial sarcoidosis in a fighter pilot. Aviat
Space Environ Med 1995; 66: 10101013.
87. Matsuki M, Matsuo M. MR findings of myocardial sarcoidosis. Clin Radiol 2000; 55: 323325.

146
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

88. Dupis JM, Victor J, Furber A, et al. Magnetic resonance imaging in cardiac sarcoidosis: a case
report. Arch Mal Coeur 1994; 87: 105110.
89. Chandra M, Silverman ME, Oshinski J, et al. Diagnosis of cardiac sarcoidosis aided by MRI.
Chest 1996; 110: 562565.
90. Bajaj AK, Kopelman HA, Echt DS. Cardiac sarcoidosis with sudden death: treatment with the
automatic implantable cardioverter defibrillator. Am Heart J 1988; 116: 557560.
91. Danias PG. Gadolinium-enhanced cardiac magnetic resonance imaging: expanding the spectrum
of clinical applications. Am J Med 2001; 110: 591592.
92. Vignaux O, Dhote R, Duboc D, et al. Detection of myocardial involvement in patients with
sarcoidosis applying T2-weighted, contrast-enhanced, and cine magnetic resonance imaging: initial
results of a prospective study. J Comput Assist Tomogr 2002; 26: 762767.
93. Yamagishi H, Shirai N, Takagi M, Yoshiyama M, Akioka K, Yoshikawa J. Identification of
cardiac sarcoidosis with (13)N-NH(3)/(18)F-FDG PET. J Nucl Med 2003; 44: 10301036.
94. Ishimaru S, Tsujino I, Takei T, et al. Focal uptake on 18F-fluoro-2-deoxyglucose positron
emission tomography images indicates cardiac involvement of sarcoidosis. Eur Heart J 2005;
(Epub ahead of print).
95. Takeda N, Yokoyama I, Hiroe Y, et al. Positron emission tomography predicted recovery of
complete A-V nodal dysfunction in a patient with cardiac sarcoidosis. Circulation 2002; 105: 1144
1145.
96. Okumura W, Iwasaki T, Toyama T, et al. Usefulness of 18F-FDG PET in identification of cardiac
sarcoidosis. J Nucl Med 2004; 45: 19891998.
97. Ishikawa T, Kondoh H, Nakagawa S, et al. Steroid therapy in cardiac sarcoidosis: increased left
ventricular contractility concomitant with electrocardiographic improvement after prednisolone.
Chest 1984; 85: 445447.
98. Lorell B, Alderman EL, Mason JW. Cardiac sarcoidosis: diagnosis with endomyocardial biopsy
and treatment with corticosteroids. Am J Cardiol 1978; 42: 143146.
99. Uemura A, Morimoto S, Hiramitsu S, et al. Histologic diagnostic rate of cardiac sarcoidosis.
Evaluation of endomyocardial biopsies. Am Heart J 1999; 138: 299302.
100. Ratner SJ, Fenoglio JJ, Ursel P. Utility of endomyocardial biopsy in the diagnosis of cardiac
sarcoidosis. Chest 1986; 90: 528533.
101. Winter SL, Cohen M, Grennberg S, et al. Sustained ventricular tachycardia associated with
sarcoidosis: assessment of the underlying cardiac anatomy and the prospective utility of
programmed ventricular stimulation, drug therapy and implantable anti-tachycardia device. J Am
Coll Cardial 1997; 18: 937943.
102. Takada K, Ina Y, Yamamoto M, et al. Prognosis after pacemaker implantation in cardiac
sarcoidosis in Japan: clinical evaluation of corticosteroid therapy. Sarcoidosis 1994; 11: 113117.
103. Baughman RP, Sharma OP, Lynch JP III. Sarcoidosis: is therapy effective? Semin Respir Infect
1998; 13: 255273.
104. Hiyama K. Corticosteroid therapy for sarcoidosis. Nippon Rinsho 2002; 60: 18271833.
105. Chiu CZ, Nakatani S, Zhang G, et al. Prevention of left ventricular remodeling by long-term
corticosteroid therapy in patients with cardiac sarcoidosis. Am J Cardiol 2005; 95: 143146.
106. Kato Y, Morimoto S, Uemura A, Hiramitsu S, Ito T, Hishida H. Efficiacy of corticosteroids
in sarcoidosis presenting with atrioventricular block. Sarcoidosis Vasc Diffuse Lung Dis 2003;
20: 133137.
107. Valantine HA, Tazelaar HD, Macoviak J, et al. Cardiac sarcoidosis: response to steroids and
transplantation. J Heart Transplant 1987; 6: 244250.
108. Berhouet M, Casset-Senon D, Machet MC, et al. Conduction defects as the presenting feature of
sarcoidosis, observed during the course of the disease: regression with corticoid steroid therapy.
Arch Mal Coeur Vaiss 2003; 96: 677682.
109. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with and without
an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350: 21402150.
110. Cleland JGF, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L, for

147
 W. SCHULTE ET AL.

the cardiac resynchronizationheart failure (CARE-HF) study investigators. The effect of cardiac
resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352: 15391549.
111. Mezaki T, Chinushi M, Washizuka T, et al. Discrepancy between inducibility of ventricular
tachycardia and activity of cardiac sarcoidosis: requirement of defibrillator implantation for the
inactive stage of cardiac sarcoidosis. Intern Med 2001; 40: 731735.
112. Huang PL, Brooks R, Carpenter C, et al. Anti-arrhythmic therapy guided by programmed
electrical stimulation in cardiac sarcoidosis with ventricular tachycardia. Am Heart J 1991;
121: 599601.
113. Kowey PR, Waxman HL, Greenspon A, et al. Value of electro physiologic testing in patients with
previous myocardial infarction and nonsustained ventricular tachycardia. Philadelphia
Arrhythmia Group. Am J Cardiol 1990; 65: 594598.
114. Poll DS, Marchlinski FE, Buxton AE, et al. Usefullness of programmed stimulation in idiopathic
dilated cardiomyopathy. Am J Cardiol 1986; 58: 992997.
115. Hsia HH, Marchlinski FE. Electrophysiology studies in patients with dilated cardiomyopathy.
Card Electrophysiol Rev 2002; 6: 472481.
116. Huikuri HV, Castellanos A, Myersburg RJ. Sudden death due to cardiac arrhythmias. N Engl J
Med 2001; 345: 14731482.
117. Paz HL, McCormick DJ, Kutalek SP, et al. The automated implantable cardiac defibrillator:
prophylaxis in cardiac sarcoidosis. Chest 1994; 106: 16031607.
118. Furushima H, Chinushi M, Sugiura H, et al. Ventricular tachyarrhythmia associated with cardiac
sarcoidosis . its mechanism and outcome. Clin Cardiol 2004; 27: 217222.
119. Baughman RP, Ohmichi M, Lower EE. Combination therapy for sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2001; 18: 133137.
120. Lynch JP, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary
disorders. Am J Respir Crit Care Med 1997; 155: 395420.
121. Zic JA, Horowitz DH, Arzubiaga C, et al. Treatment of cutaneous sarcoidosis with chloroquine:
review of the literature. Arch Dermatol 1991; 127: 10341040.
122. Baltzan M, Mehta S, Kirkham TH, et al. Randomized trial of prolonged chloroquine therapy in
advanced pulmonary sarcoidosis. Am J Respir Crit Care Med 1999; 160: 192197.
123. Adams JS, Diz MM, Sharma OP. Effective reduction in the serum 1,25- dihydroxyvitamine D and
Calcium concentration in sarcoidosis- associated hypercalcemia with short course chloroquine
therapy. Ann Intern Med 1989; 111: 437438.
124. Sharma OP. Neurosarcoidosis: a personal perspective based on the study of 38 patients. Chest
1997; 112: 220228.
125. Kaye O, Pallazo E, Grossin M, et al. Low dose methotrexate: an effective corticosteroid sparing-
sparing agent in the musculoskeletal manifestations of sarcoidosis. Br J Rheumatol 1995; 34: 642
644.
126. Webster GF, Razsi LK, Sanchez M, et al. Weekly low-dose methotrexate therapy for cutaneous
sarcoidosis. J Am Acad Dermatol 1991; 24: 451454.
127. Baughman RP, Lower EE. A clinical approach to the use of methotrexate for sarcoidosis. Thorax
1999; 54: 742746.
128. Muller-Quernheim J, Kienast K, Held M, et al. Treatment of chronic sarcoidosis with an
azathioprine/prednisolone regimen. Eur Respir J 1999; 14: 11171122.
129. Agbogu BN, Stern BJ, Sewell C, et al. Therapeutic considerations in patients with refractory
neurosarcoidosis. Arch Neurol 1995; 52: 875879.
130. Lower EE, Broderick JP, Brott TG, et al. Diagnosis and management of neurological sarcoidosis.
Arch Intern Med 1997; 157: 18641868.
131. Demeter SL. Myocardial sarcoidosis unresponsive to steroids: treatment with cyclophosphamide.
Chest 1988; 94: 202203.
132. Stern BJ, Schonfeld SA, Sewell C, et al. The treatment of neurosarcoidosis with cyclosporine. Arch
Neurol 1992; 49: 10651072.
133. Martinet Y, Pinkston P, Saltini C, et al. Evaluation of the in vitro and in vivo effects of cyclosporine

148
 CARDIAC INVOLVEMENT IN SARCOIDOSIS

on the lung T-lymphocyte alveolitis on active pulmonary sarcoidosis. Am Rev Respir Dis 1988;
138: 12421248.
134. Wyser CP, van Schalkwyk EM, Alheit B, et al. Treatment of progressive pulmonary sarcoidosis with
cyclosporin A: a randomized controlled trial. Am J Respir Crit Care Med 1997; 156: 13711376.
135. Carlesimo M, Giustini S, Rossi A, et al. Treatment of cutaneous and pulmonary sarcoidosis with
thalidomide. J Am Acad Dermatol 1995; 32: 866869.
136. Baughman RP, Judson MA, Teirstein AS, et al. Thalidomide for chronic sarcoidosis. Chest 2002;
122: 227232.
137. Zabel P, Entzian P, Dalhoff K, et al. Pentoxifylline in the treatment of sarcoidosis. Am J Respir
Crit Care Med 1997; 155: 16651669.
138. Baughman RP. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;
18: 7074.
139. Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis
factor-alpha therapy. Ann Intern Med 2001; 135: 2731.
140. Oni AA, Hershberger RE, Norman DJ, et al. Recurrence of sarcoidosis in a cardiac allograft:
control with augmented corticosteroids. J Heart Lung Transplant 1992; 11: 367369.
141. Martinez FJ, Orens JB, Deeb M, et al. Recurrence of sarcoidosis following bilateral allogenic lung
transplantation. Chest 1994; 106: 15971599.
142. Meyer A, Schafer H, Doring V, et al. Heart transplantation in myocardial sarcoidosis. Studies on
the explanted heart. Dtsch Med Wochenschr 1999; 124: 11311134.

149
CHAPTER 10

Skin manifestations in sarcoidosis

A. Eklund*, G. Rizzato#

*Dept of Medicine, Division of Respiratory Medicine and Allergology, Karolinska University Hospital,
Stockholm, Sweden. #Ambulatorio della Sarcoidosi, Vergani Dept, Niguarda Hospital, Milano, Italy.

Correspondence: A. Eklund, Dept of Respiratory Medicine and Allergology, Karolinska University

Hospital, SE-171 76 Stockholm, Sweden. Fax: 46 8312705; E-mail: anders.eklund@karolinska.se

Almost a century ago, the relationship of sarcoid infiltrations of the skin and
granulomatous changes in other organs was recognised. Schaumann, in 1914, proposed
that lupus pernio (fig. 1ac) could be a manifestation of a generalised disease. Later on, a
variety of skin manifestations have been described to occur more or less frequently. Lupus
pernio indicates an unfavourable prognosis, whereas in the case of erythema nodosum
(EN) (fig. 2), disease remission generally occurs within months or a few years [14]. The
histopathological characteristics of the two findings are totally different, reflecting the
variable clinical picture and outcome in this inflammatory disorder where the antigen(s)
still are unknown [5, 6]. Beside these two extremes, there are a number of other more or less
common skin lesions having either a maculopapular, subcutaneous, cicatricial or plaque
character. In this chapter, a sharp distinction will be made between nonspecific lesions, i.e.
erythema nodosum, and specific skin manifestations, e.g. lupus pernio.
The frequency of skin lesions in sarcoidosis varies depending on the intensity by which
they are looked for [7, 8], as well as on the ethnic background of the patients [5, 6]. In
Scandinavia, about one-third of the patients born there will present with EN as part of
Lofgrens syndrome [2]. However, in Japanese patients, this syndrome is less common. In
contrast, lupus pernio is very infrequent in Scandinavia, but more common among
African Americans in the USA [5, 6]. On an average, y25% of sarcoidosis cases have
cutaneous involvement, which may appear at any stage of the disease [5, 9, 10]. More
recently, Yanardag et al. [7] reported a higher percentage (almost 33%) of skin
manifestations among w500 Turkish patients. Roughly, 20% of them had EN. The
frequency of reported specific cutaneous involvement in sarcoidosis ranges from 1040%.

Systemic sarcoidosis and skin lesions

When sarcoidosis presents with EN, there will be mostly concomitant chest
radiographic changes showing bilateral hilar lymphoma (stage I) and, frequently, also
fever and sometimes signs of ankle arthritis, or just arthralgia. The bilateral hilar
syndrome has previously been described in 1952 by LOfgren and LundbAck [11]. Later
on, it was designated Lofgrens syndrome. Furthermore, according to MaNA et al. [12], in
sarcoidosis patients with a more insidious onset, cutaneous manifestations are also rather
frequently observed at an early stage of the disorder. MaNA et al. [12] reported the
presence of cutaneous lesions at the beginning of the disease inw70% of their patients. In
addition, the majority of patients had other systemic manifestations at this time as well.
Nonetheless, almost one-third of patients present with only skin lesions, without any
other sign of sarcoidosis. However, they are prone to the development of other organ
Eur Respir Mon, 2005, 32, 150163. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
150
 SKIN LESIONS IN SARCOIDOSIS

a) b)

c)

Fig. 1. a) Possibly the first ever case of lupus pernio to be described (Pollaiolo, Galleria degli Uffizi, Florence,
Italy). b) Lupus pernio with typical advanced changes on the cheeks and nose in a middle-aged Caucasian
female with sarcoidosis, and c) a less pronounced manifestation in a somewhat younger female.

151
 A. EKLUND, G. RIZZATO

Fig. 2. Erythema nodosum on the lower limbs of a female patient.

involvement months to years later, calling for a close follow-up by the physician in
charge for signs of systemic disease. Finally, some patients with systemic sarcoidosis may
develop their skin manifestations later in the disease course.
In their study population consisting of y200 Caucasians diagnosed with cutaneous
sarcoidosis, Veien et al. [13] reported that the majority had infiltrative lesions. Moreover,
they found no relationship between the extent of cutaneous manifestations and the extent
of systemic disease. Many of the infiltrative lesions appeared to be of a chronic nature
and were commonly associated with pulmonary changes, such as mottling and fibrosis.
In patients with skin lesions, other than EN, Olive and Kataria [14] found
splenomegaly, hepatomegaly and lymphadenopathy in approximately one-third of
these. In general, skin manifestations are associated with less delay in diagnosis than
other manifestations of sarcoidosis [15].
Although not primarily skin lesions, in the conventional way of thinking, the recent
and very interesting findings by Hoitsma et al. [16] of altered thermal threshold for warm
and cold sensation in the feet and hands reflect small fibre neuropathy. This may cause all
kinds of symptoms, including burns of the skin and other more or less traumatic signs
referred to the skin.

152
 SKIN LESIONS IN SARCOIDOSIS

Diagnostic tools
The most important way to discover skin lesions in sarcoidosis is of course by a
thorough clinical investigation. Mostly, when the patient presents with EN changes on
the lower limbs, the skin lesions are very obvious. In contrast, there may be an insidious
onset of discrete non-itching lesions on other parts of the body, which only the observant
doctor will notice. The clinical appearance may differ depending on the degree of
commonly existing epidermal changes. Thus, there may be ichthyosiform manifestations,
verrucous plaques, psoriasiform lesions, ulcers and hypo- or hyperpigmentation [17]. In
general, skin lesions are easy to get access to and the diagnosis can be confirmed by
obtaining a biopsy in most cases. However, EN is an exception.
Noncaseating epithelioid cell granulomas are mostly observed in the dermis, and
sometimes in the subcutaneous tissue. To exclude other causes of skin lesions, signs of
bacteria, mycobacteria and fungi should be looked for. Examination with polarised light
enables identification of foreign material.
When searching for other extrathoracic manifestations by scintigraphic techniques
[18], skin lesions may be registered and documented as well (fig. 3). However, there is no
clinical relevance in detecting cutaneous manifestations in this way.
The differential diagnoses include, depending on the character of the lesion and what
part of the world the patient comes from, disorders such as cutaneous tuberculosis,
syphilis, discoid lupus erythematosus and lepromatous leprosy.

Nonspecific skin manifestation: erythema nodosum

EN is the most common nonspecific skin lesion in sarcoidosis. The entity EN was
introduced over two centuries ago by Robert Willan who described the initially occurring
red, rounded patches, which become elevated and painful within days. After w1 week
they get more bluish and this appearance subsequently becomes less pronounced and
subsides within weeks or months (fig. 2). EN associated with bilateral hilar lymphoma,
fever and often arthralgia is most commonly present on the lower limbs below the knees
of young females [1]. It may, however, also occur in other localisations and is
occasionally noticed in males. James [1], in the late 1950s, studied 170 patients with EN,
and y75% of them were female. A total of 60% of them had polyarthralgia,

Fig. 3. Octreoscan scintigraphy, using a long-lived radiolabelled somatostatin analogue, displaying granuloma-
tous skin lesions on the forearms of a patient diagnosed with sarcoidosis.

153
 A. EKLUND, G. RIZZATO

predominantly in ankles and knees. The majority of this latter population consisted of
patients diagnosed with sarcoidosis. Interestingly, James [1] noticed that, although EN
may occur at every season of the year, there is a clear predominance in Europe for late
winter and early spring. The reversed phenomenon has been reported from the southern
hemisphere of the globe [19].
A negative tuberculin reaction in cases with EN does not support one of the alternative
diagnoses, tuberculosis. A conversion to a positive from a negative reaction strongly
favours primary tuberculosis. Another fairly common cause of EN is a streptococcal
infection.
The diagnosis of EN is made after physical examination, and punch biopsies should
not be taken to look for noncaseating epithelioid granulomas as they are rarely present in
EN. Disease onset with Lofgrens syndrome is strongly indicative of a good prognosis,
but there are some cases which are not human leukocyte antigen (HLA)-DRB1*03
(DR17) positive that may have a more protracted disease course [4]. The HLA class I
type may modify the class II-related disease course and the most favourable outcome
seems to be in sarcoidosis patients having the deduced haplotype: A*01, B*08, DRB1*03
[20]. Once the EN changes have disappeared, they will very seldom recur after the first
year has elapsed.

Specific skin manifestations

Lupus pernio
This is an indolent, red-purple or violaceous, indurated skin lesion (fig. 1ac) that may
affect cheeks, nose, lips and ears mostly in females aged w40 yrs. The lesions can range
widely from small rounded manifestations to exuberant plaques covering cheeks and
nose, becoming very disfiguring. Scaly desquamation may be observed, and erosions can
occur. The lesions can erode into cartilage and bone and are regarded as ominous signs
reflecting chronicity and poor prognosis. Lupus pernio is more often seen in Blacks than
in Caucasians [5, 6, 21]. Frequently, there is concomitant involvement of the upper
respiratory tract and, in aggressive cases, ulcerations in the nasal mucosa and even
perforation of the septum may occur. Concomitant fibrosing changes in the lungs and
bone cysts have been reported. The skin overlying bone manifestations may show similar
changes, e.g. in the phalanxes of toes and fingers, which may be swollen. If the facial
manifestations resolve there may be discrete telangiectatic scars [13].

Plaque formation
One of the most frequently encountered specific skin manifestations [12] in sarcoidosis
is plaque formation (fig. 4ac). Often the plaques are rounded or oval in shape. Their size
may vary from some millimetres to several centimetres in diameter. They are usually red-
brownish, indurate, and not itchy (fig. 5). They may extend in a centrifugal way leaving a
centre which looks somewhat atrophic, and presents as a slightly elevated and marked
margin. The process often tends to proceed over months to years and may leave
disfiguring areas behind or eventually heal with remarkably little scarring. In atrophic
areas, telangiectasis can be observed. Plaques have a predilection for the limbs, back,
face, and scalp.

154
 SKIN LESIONS IN SARCOIDOSIS

a) b)

c)

Fig. 4. a) Brownish, rounded granulomatous plaque formations on the back of a middle-aged Caucasian
female. b) The indurated, elevated character of the lesions is seen on a close up, whereas c) the depressed
central part and somewhat raised rim is seen at resolution a few years later.

Maculopapular eruptions
Maculopapular lesions (fig. 6) have been reported to be the most common cutaneous
manifestation of granulomatous involvement in sarcoidosis [9]. The papules are
commonly red-brown to purple, slightly infiltrated and measure less than 10 mm. In
contrast to lupus pernio or plaques, they are more often associated with a favourable

Fig. 5. Plaque formation on the lower back in a male with stage I disease.

155
 A. EKLUND, G. RIZZATO

Fig. 6. Maculopapular lesions on a knee.

outcome and can resolve in rather a short time. They may even herald the disease and can
be observed almost anywhere, often in groups. In a study by MaNA et al. [12], skin
eruptions were accompanied by chest radiographic changes corresponding to stage I
disease in w50% of the cases. These findings were supported by a report by Yanardag
et al. [7]. However, papules and nodules may also be seen in subacute and occasionally
chronic phases of sarcoidosis.

Subcutaneous nodules
Similar to maculopapular lesions, subcutaneous nodules also frequently occur;
according to some authors, they are most often seen in patients with stage I disease [7].
In contrast, others have found them to be less frequent and often accompanied by
more systemic disease [14, 22]. The reported differences may reflect genetic
heterogeneity between the investigated populations. The lesions are usually painless,
firm and mobile.

156
 SKIN LESIONS IN SARCOIDOSIS

Cicatricial and foreign body manifestations

Reactivation of old scar tissue has been reported in a small percentage of sarcoidosis
patients [7, 23]. This may occur in scars from previous wounds (fig. 7a and b), as well as at
sites of tattoos [24], sites of ritual scarification, etc. Skin lesions have also been reported
after carbon dioxide laser resurfacing of the skin [25]. The changes may be solitary or just a
manifestation of systemic disease. Reactivation of old scars, often seen as red-brownish
infiltrations, seems to be a rather unique occurrence in sarcoidosis and should always call
for a work-up with regard to the disease. In this context, it is important to emphasise that in
a considerable part (y2050%) of biopsies from cutaneous lesions, foreign bodies may be
observed [2628]. This is particularly common in biopsies taken from sites that are easily
exposed to trauma, such as elbows and knees. Cutaneous sarcoid-like lesions without signs
of systemic disease may be regarded as local-sarcoid tissue reactions. There will be cases
with sarcoidal reactions in the skin despite no known trauma. In addition, lesions will be
seen with signs of foreign material, but with or without demonstrable systemic disease. All
patients with sarcoid-type granulomatous dermatitis should be investigated for presence of
generalised granulomatous disease [29]. Diagnosis depends, on the one hand, if there are
signs of granulomas at other sites, and, on the other hand, if possible causes for a local
reaction can be proven [30, 31]. Cicatricial lesions may reflect the activity of the systemic
disease and be used as one of several markers to monitor the disorder. Commonly scar
lesions will persist more than 2 yrs after diagnosis [13].
Recently, it has been reported that highly active antiretroviral therapy in HIV patients
may activate granulomatous reactions in tattoos and scar tissue as the immune system is
restituted [32].

Alopecia due to sarcoidosis

There are rare reports on sarcoidosis of the scalp (fig. 8) causing local alopecia [33]. In
patients with sarcoidosis getting patchy hair loss, it should be taken into consideration
that there may be a relationship with the granulomatous disease.

Psoriasiform sarcoidosis
Scaly follicular skin lesions are occasionally observed in patients with histologically
confirmed sarcoidosis. The skin changes can resemble those seen in psoriasis (fig. 9a and
b). In addition, coexistence of sarcoidosis and psoriasis may occur [34].

a) b)

Fig. 7. a) Granulomatous infiltration in an old scar after appendectomy in a sarcoidosis patient with multiple
skin lesions. b) The scar resolved after the disease some years later. Reprinted with permission from [31].

157
 A. EKLUND, G. RIZZATO

Fig. 8. Alopecia caused by sarcoidosis.

Granuloma annulare and sarcoidosis

Annular cutaneous lesions have been reported to occur in sarcoidosis, but granuloma
annulare may also coexist with sarcoidosis, i.e. two granulomatous entities present in the
same patient. In 1977, Umbert and Winkelmann [35] described five cases with coexisting
disorders.

Other types of skin lesions

A number of other seldom occurring types of skin manifestations in sarcoidosis have
been reported. These are partly listed in a review by English et al. [9]. One of the
manifestations is an ichthyosiform kind of the disease [36].
Another possible cause of cutaneous and pulmonary sarcoidosis was reported by
Chang et al. [37] who found granulomatous formation in papular skin lesions, superficial
lymph nodes and in transbronchial biopsies in a middle-aged Chinese females who had
silicone breast augmentation a few years earlier. They speculate that silicone elastomer
from the implants may have leaked and caused the granulomatous reaction. Remission
of sarcoidosis has been reported following removal of silicone gel breast implants [38].
There are several recent reports on cutaneous as well as systemic manifestations of

a) b)

Fig. 9. Psoriasiform skin manifestations on a) the elbow in a patient with stage I sarcoidosis, and b) scaly
follicular lesions localised close to the elbow.

158
 SKIN LESIONS IN SARCOIDOSIS

sarcoidosis following interferon-a (IFN) alone or in combination with ribavarin and/or

amantadine, mostly in the treatment of hepatitis C [39]. IFN is regarded to increase the
T-helper cell type 1 response, which is considered to be so important in granulomatous
disease. It seems that patients suffering from IFN-induced skin lesions will mostly do well
despite continuation of the medication that induced it.
The possibility that papular, nodular and granulomatous skin lesions in patients with
suspected sarcoidosis may be manifestations of various forms of cutaneous vasculitis
should also be considered [40].

Vitiligo
An association between sarcoidosis and autoimmune diseases is well-recognised. The
presence of autoimmune diseases and involvement of subcutaneous fat in the sarcoid
inflammation has been reported in one case but appears to represent a most unusual
clinicopathological combination [41]. Vitiligo was one of the features in this reported
case, and it is seen occasionally in patients with sarcoidosis (fig. 10).

Treatment
In general in systemic sarcoidosis with skin manifestations, the decision to treat will
depend on associated organ involvement. Sometimes, however, especially when the
cutaneous lesions are progressive and disfiguring, attempts to treat them will be made.
Treatment with oral steroids given in sufficient dosage over a considerable period of time
in most cases will to some extent suppress skin manifestations of a more chronic
character. Such treatment will, however, also cause serious side-effects in some patients.
If therapy with oral steroids is started to test the sensitivity to the drug in a specific
patient, it should be kept in mind that therapy is likely to be required for a long time.

Erythema nodosum
Most patients will do well without any treatment or with just anti-inflammatory drugs
given for a few weeks. In some cases, general malaise and inflammatory changes adjacent
to or involving the joints in the lower limbs will call for a short course of oral steroids,

Fig. 10. Vitiligo in a patient with sarcoidosis.

159
 A. EKLUND, G. RIZZATO

given just for a few weeks or, as an alternative, steroids could be injected in the ankles. As
James [1] has already pointed out, steroids may interfere with some important immune
mechanisms, of which medicine was (at that time) and is presently fairly ignorant about.

Other skin lesions

No treatment. As there is no known cure as yet for sarcoidosis, treatment of harmless
skin lesions or ones that are not too disfiguring, especially on limbs and the trunk, should
be avoided. The manifestations seldom itch and ulcerations are fairly uncommon.

Drug treatment. Topical treatment with corticosteroids is often ineffective but some
improvement may follow if complete occlusive dressings covered in clobetasol propionate
lotion are used on a weekly basis to increase absorption [42]. It will take some weeks until
remission occurs but the dressings seem to reduce the need for topical corticosteroids.
Monthly intralesional injections of triamcinolone can be effective in treating small
papules and plaques [5].
When oral steroids are prescribed, it can be in a dose which corresponds to that given
for pulmonary changes (see Chapter 20 of this monograph).
As many of the facial lesions, in particular lupus pernio, are of a chronic character, the
therapy, if showing a substantial beneficial effect, will have to go on for many months or
even years. Hydroxychloroquine (fig. 11a and b) is an alternative to oral corticosteroids,
as are methotrexate and azathioprine given in doses recommended for pulmonary
changes . There are also reports on positive effects of thalidomide [4347].
Anti-tumour necrosis factor (TNF)-a therapy is a very promising therapeutic
approach of severe and therapy-resistant lesions of sarcoidosis. There is an ongoing
multinational study on the efficacy of infliximab treatment in pulmonary sarcoidosis and
on some extrapulmonary manifestations, such as skin lesions. The drug is a chimeric
monoclonal antibody against TNF, which is thought to be a crucial player in granuloma
formation. There are reports from smaller studies so far indicating that it may be an
attractive treatment, acting fairly rapidly in carefully selected patients [47, 48].
The immunomodulating properties of antibiotics, beside their anti-infectious effects,
have gained some interest. As no really efficient therapy of cutaneous manifestations in
sarcoidosis has been reported, Bachelez et al. [49] conducted an open trial giving 12
patients minocycline (200 mg?day-1) for a median duration of 12 months. Complete
response was reported in eight patients, and partial in two subjects. Relapse was noticed
in three patients after withdrawal. They then received doxycycline, which was followed

a) b)

Fig. 11. Lupus pernio a) before and b) two months after chloroquine therapy.

160
 SKIN LESIONS IN SARCOIDOSIS

by remission. Bachelez et al. [49] state that randomised controlled studies to evaluate
the effects are warranted.

Other therapeutic approaches. Laser. A few case reports focus on laser treatment of
skin lesions in sarcoidosis. Different modalities have been used, such as the Q-switched
ruby laser, pulsed dye laser and carbon dioxide (CO2) laser [50, 51], but, at present, no
definitive recommendations can be given. It should also be considered that CO2 laser
therapy has been associated with the occurrence of granulomatous reactions [24].
Therefore, this method does not seem to be clinically relevant.

Ultraviolet phototherapy. There are sporadic case reports on the effect of ultraviolet
(UV) A1 phototherapy in sarcoidosis skin lesions arguing that some immunomodulating
effects have been shown by UVA1 administration [52]. However, long-term risks, such as
carcinogenic ones, have to be taken into account. In general, this therapy is not
recommended.

Conclusion
Cutaneous lesions are present iny25% of sarcoidosis patients. Sometimes these lesions
appear to be the first manifestation and, therefore, may guide an appropriate diagnosis.
The skin lesions could have specific aspects (papules, plaques, nodules, alopecia or purple
scars) or can be more or less nonspecific. In general, the therapeutic approach is similar
to the treatment of sarcoidosis affecting other organs, such as the lungs. It varies from
none to a combination of cytotoxic agents. Therapeutic protocols are increasingly
composed of multiple agents, rather than relying on a single drug.

Summary
Noncaseating epithelioid cell granulomas characterising sarcoidosis may affect most
organs, including the skin. Skin lesions may be the only manifestations, or just one of
several other organ involvements. Roughly 25% of all sarcoidosis patients may suffer
from skin lesions during the course of their disease.
Erythema nodosum, which usually occurs at acute onset of the disease, is not
characterised by granulomas and normally spontaneously resolves within weeks or
months. In contrast, other skin manifestations may signal a protracted disease course.
Particularly, lupus pernio may result in disfiguring lesions in the face with destruction
of underlying cartilage and bone. In between these two extremes, several other types of
lesions have been reported, such as red-brownish plaque formations, maculopapular
eruptions, subcutaneous nodules and cicatricial manifestations. There is also a
psoriasiform and an ichthyosiform of the disease.
The therapeutic approach is similar to other manifestations of sarcoidosis. The choice
of drugs depends on the severity and prognosis of the lesion and whether there is any
accompanying organ involvement(s).

Keywords: Cutaneous lesions, erythema nodosum, lupus pernio, sarcoidosis, skin

manifestations.

161
 A. EKLUND, G. RIZZATO

References
1. James DG. Erythema nodosum. BMJ 1961; 1: 853857.
2. Hillerdal G, Nou E, Osterman K, Schmekel B. Sarcoidosis: epidemiology and prognosis. A 15-
year European study. Am Rev Respir Dis 1984; 130: 2932.
3. Eklund A. Lofgrens syndrome. In: Sarcoidosis and other granulomatous disorders. James DG,
ed. New York, Marcel Dekker, Inc., 1994; pp. 267273.
4. Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in
Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 1997; 156: 1601
1605.
5. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Eng J Med 1997; 336: 12241234.
6. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and other Granulomatous Disorders: statement on
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
7. Yanardag Y, Pamuk ON, Karayel T. Cutaneous involvement in sarcoidosis: analysis of the feature
in 170 patients. Respir Med 2003; 97: 978982.
8. Rizzato G, Palmieri G, Agrati AM, Zanuzzi C. The organ-specific extrapulmonary presentation of
sarcoidosis: a frequent occurence but a challenge to an early diagnosis. A 3 year-long prospective
observational study. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 119126.
9. English JC 3rd, Purvisha JP, Patel PJ, Greer KE. Sarcoidosis. J Am Acad Dermatol 2001; 44: 725
743.
10. Wilson NJ, King CM. Cutaneous sarcoidosis. Postgrad Med J 1998; 74: 649652.
11. Lofgren S, Lundback H. The bilateral hilar lymphoma syndrome. A study of the relation to age
and sex in 212 cases. Acta Med Scand 1952; 142: 259264.
12. Mana J, Marcoval J, Graells J, Salazar A, Peyri J, Pujol R. Cutaneous involvement in sarcoidosis.
Relationship to systemic disease. Arch Dermatol 1997; 133: 882888.
13. Veien NK, Stahl D, Brodthagen H. Cutaneous sarcoidosis in Caucasians. J Am Acad Dermatol
1987; 16: 534540.
14. Olive KE, Kataria YP. Cutaneous manifestations of sarcoidosis: relationship to other organ
system involvement, abnormal laboratory measurements, and disease course. Arch Intern Med
1985; 145: 18111814.
15. Judson MA, Thompson BW, Rabin DL, et al. The diagnostic pathway to sarcoidosis. Chest 2003;
123: 406412.
16. Hoitsma E, Drent M, Verstraete E, et al. Abnormal warm and cold sensation thresholds suggestive
of small-fibre neuropathy in sarcoidosis. Clin Neurophysiol 2003; 114: 23262333.
17. Okamoto H. Epidermal changes in cutaneous lesions of sarcoidosis. Am J Dermatopathol 1999;
21: 229233.
18. Eklund A, Jacobsson H, Larsson SA, Skold CM. Detection of extrathoracic manifestations
in sarcoidosis with somatostatin analogue scintigraphy. Sarcoidosis Vasc Diff Lung Dis 1997;
14: 146151.
19. Wilsher ML. Seasonal clustering of sarcoidosis presenting with erythema nodosum. Eur Respir J
1998; 12: 11971199.
20. Grunewald J, Eklund A, Olerup O. Human leukocyte antigen class I alleles and the disease course
in sarcoidosis patients. Am J Respir Crit Care Med 2004; 169: 696702.
21. Spiteri MA, Matthey F, Gordon T, et al. Lupus pernio: a clinico-radiological study of thirty-five
cases. Br J Dermatol 1985; 112: 315322.
22. Kalb RE, Epstein W, Grossman ME. Sarcoidosis with subcutaneous nodules. Am J Med 1988;
85: 731736.
23. Sorabjee JS, Garje R. Reactivation of old scars: inevitably sarcoid. Postgrad Med J 2005; 81: 6061.
24. Landers MC, Skokan M, Law S, Storrs FJ. Cutaneous and pulmonary sarcoidosis in association
with tattoos. Cutis 2005; 75: 4448.

162
 SKIN LESIONS IN SARCOIDOSIS

25. Kormeili T, Neel V, Roy RL. Cutaneous sarcoidosis at sites of previous laser surgery. Cutis 2004;
73: 5355.
26. Marcoval J, Mana J, Moreno A, Gallego I, Fortuno Y, Peyri J. Foreign bodies in granulomatous
lesions of patients with systemic sarcoidosis. Arch Dermatol 2001; 137: 427430.
27. Marcoval J, Moreno A, Mana J. Foreign bodies in cutaneous sarcoidosis. J Cut Pathol 2004; 31: 516.
28. Ball NJ, Kho GT, Martinka M. The histologic spectrum of cutaneous sarcoidosis: a study of
twenty-eight cases. J Cutan Pathol 2004; 31: 160168.
29. Callen JP. The presence of foreign antibodies does not exclude the diagnosis of sarcoidosis. Arch
Dermatol 2001; 137: 485486.
30. Mitchell DN, Scadding JG, Heard BE, Hinson KFW. Sarcoidosis: histopathological definition
and clinical diagnosis. J Clin Pathol 1977; 30: 395408.
31. Eklund A and Grunewald J. Sarcoidoisis. In: Respiratory Medicine, Vol. 2. Elsevier, 2003; p. 1610.
32. Pascual JC, Belinchon I, Silvestre JF, et al. Sarcoidosis after highly active antiretroviral therapy in
a patient with AIDS. Clin Exp Dermatol 2004; 29: 156158.
33. Douri T, Chawaf AZ, Alrefaee BA. Cicatricial alopecia due to sarcoidosis. Dermatol Online J
2003; 9: 16.
34. Burgoyne JS, Wood MG. Psoriasiform sarcoidosis. Arch Dermatol 1972; 106: 896898.
35. Umbert P, Winkelmann RK. Granuloma annulare and sarcoidosis. Br J Dermatol 1977; 97: 481
486.
36. Kauh YC, Goody HE, Luscombe HA. Ichthyosiform sarcoidosis. Arch Dermatol 1978; 114: 100
101.
37. Chang K-C, Chan K-T, Chong L-Y, et al. Cutaneous and pulmonary sarcoidosis in a Hong Kong
Chinese woman with silicone breast protheses. Respirology 2003; 8: 379382.
38. Teuber SS, Howell LP, Yoshida SH, Gershwin ME. Remission of sarcoidosis following removal of
silicone gel breast implants. Int Arch Allergy Immunol 1994; 105: 404407.
39. Marzouk K, Saleh S, Kannass M, Sharma OP. Interferon-induced granulomatous lung disease.
Curr Opin Pulm Med 2004; 10: 435440.
40. Crowson AN, Mihm MC Jr, Magro CM. Cutaneous vasculitis: a review. J Cutan Pathol 2003;
30: 161173.
41. Barnadas MA, Rodriguez-Arias JM, Alomar A. Subcutaneous sarcoidosis associated with vitiligo,
pernicious anaemia and autoimmune disease. Clin Exp Dermatol 2000; 25: 5556.
42. Volden G. Successful treatment of chronic skin diseases with clobetasol proprionate and a
hydrocolloid occlusive dressing. Acta Derm Venerol 1992; 72: 6971.
43. Baughman RP, Lynch JP Jr. Difficult treatment issues in sarcoidosis. J Intern Med 2003; 253: 4145.
44. Carlesimo M, Giustini S, Rossi A, et al. Treatment of cutaneous and pulmonary sarcoidosis with
thalidomide. J Am Acad Dermatol 1995; 32: 866869.
45. Nguyen YT, Dupuy A, Cordoliani F, et al. Treatment of cutaneous sarcoidosis with thalidomide.
J Am Acad Dermatol 2004; 50: 235241.
46. Baughman RP, Judson MA, Teirstein A, Moller DR, Lower EE. Thalidomide for chronic
sarcoidosis. Chest 2002; 122: 227232.
47. Baughman RP, Lower EE. Newer therapies for cutaneous sarcoidosis: the role of thalidomide and
other agents. Am J Clin Dermatol 2004; 5: 385394.
48. Haley H, Cantrell W, Smith K. Infliximab therapy for sarcoidosis (lupus pernio). Br J Dermatol
2004; 50: 235241.
49. Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L. The use of tetracyclines for the
treatment of sarcoidosis. Arch Dermatol 2001; 137: 6973.
50. Grema H, Greve B, Raulin C. Scar-sarcoidosis treatment with the Q-switched ruby laser. Lasers
Surg Med 2002; 30: 398400.
51. Young HS, Chalmers RJ, Griffiths CE, August PJ. CO2 laser vaporization for disfiguring lupus
pernio. J Crosmet Ther 2002; 4: 8790.
52. Mahnke N, Medve-Koenigs K, Berneburg M, Ruzicka T, Neumann NJ. Cutaneous sarcoidosis
treated with medium dose UVA1. J Am Acad Dermatol 2004; 50: 978979.

163
CHAPTER 11

Neurosarcoidosis

E. Hoitsma*,#, O.P. Sharma}

*Dept of Neurology and #Sarcoidosis Management Centre, University Hospital Maastricht, Maastricht,
The Netherlands, and }Dept of Pulmonary and Critical Care Medicine, Keck School of Medicine,
University of Southern California, Los Angeles, CA, USA.

Correspondence: O.P. Sharma, Room 11-900, LACzUSC Medical Center, 1200 North State Street, Los
Angeles, CA 90033, USA. Fax: 1 3232262728; E-mail: osharma@usc.edu

Sarcoidosis is an inflammatory multisystemic disorder. Its cause is not known. The

disease may involve any part of the nervous system. The incidence of clinical involvement
of the nervous system in a sarcoidosis population is estimated to be y515% [1, 2].
However, the incidence of subclinical neurosarcoidosis may be much higher [3, 4].
Necropsy studies suggest that ante mortem diagnosis is made in only 50% of patients with
nervous system involvement [5]. As neurosarcoidosis may manifest itself in many
different ways, diagnosis may be complicated [2, 3, 610]. It may appear in an acute
explosive fashion or as a slow chronic illness. Furthermore, any part of the nervous
system can be attacked by sarcoidosis, but the cranial nerves, hypothalamus and
pituitary gland are more commonly involved [1]. Sarcoid granulomas can affect the
meninges, parenchyma of the brain, hypothalamus, brainstem, subependymal layer of
the ventricular system, choroid plexuses and peripheral nerves, and also the blood vessels
supplying the nervous structures [11, 12]. One-third of neurosarcoidosis patients show
multiple neurological lesions. If neurological syndromes develop in a patient with biopsy-
proven active systemic sarcoidosis, the diagnosis is usually easy. However, without
biopsy evidence of sarcoidosis at other sites, nervous system sarcoidosis remains a
difficult diagnosis [13]. Neurological symptoms may also arise in patients with inactive
sarcoidosis. In such situations, neurosarcoidosis may occupy a high place in the list of
differential diagnoses, but histological evidence of granulomatous involvement of the
neurological apparatus is still required in these cases. Furthermore, in a smaller number
of patients, sarcoidosis may selectively involve the nervous system [14, 15]. In such cases,
it is important not to confuse the nonspecific local sarcoid reaction with multisystemic
sarcoidosis [16]. Neurosarcoidosis is rare; most articles report small numbers of patients
or case reports, and prospective studies on neurosarcoidosis are scarce [17].
Consequently, evidence-based recommendations are lacking.

Neurological manifestations of sarcoidosis

Cranial neuropathy
Cranial neuropathy is the most frequent neurological complication of sarcoidosis
(table 1) [1]. Cranial nerve palsy may be due to nerve granulomas, increased intracranial
pressure or granulomatous basal meningitis. A peripheral seventh nerve palsy (Bells
palsy) is the single most common cranial nerve lesion [1], and is, indeed, the most
Eur Respir Mon, 2005, 32, 164187. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
164
 NEUROSARCOIDOSIS

Table 1. Manifestation of cranial neuropathies in neurosarcoidosis

Cranial nerve Manifestation

#
I: olfactory [18, 19] Anosmia
II: optic [20, 21] Diminished visual acuity, papilloedema
III: oculomotor [22] Ophtalmoplegia, diplopia, ptosis
IV: trochlear [22] Ophtalmoplegia, diplopia
V: trigeminal [23] Hypoaesthesia, neuralgia
VI: abducent [22] Ophtalmoplegia, diplopia
VII: facial [24, 25] Bells palsy
VIII: vestibulocochlear [18, 26, 27] Vertigo, hearing loss
IX: glossopharyngeal [22] Dysarthria, dysphagia
X: vagus [2830] Dysarthria, dysphagia, postural symptoms
XI: accessory [22] Sternocleidomastoid weakness, trapezius weakness
XII: hypoglossal [22] Dysarthria, dysphagia
#
: may be due to sarcoidosis of the nasal mucosa.

frequent neurological manifestation of sarcoidosis overall [2, 3, 9, 18, 22, 31]. Bilateral
dysfunction occurs, both simultaneously and sequentially.
The optic nerve is the second most commonly affected cranial nerve [31]. Although
sarcoid granulomas of the optic nerve are usually unilateral, they may involve both
nerves [32]. Sarcoidosis of the optic nerve may occur without systemic involvement [33].
When optic neuropathy occurs, especially in young patients, multiple sclerosis is
considered a likely cause. In these cases a chest radiograph with evidence of sarcoidosis
makes multiple sclerosis highly unlikely [34]. Optic nerve involvement due to sarcoidosis
can be divided into a chronic progressive type that responds poorly to corticosteroids [35]
and an acute type that responds to prednisone [2, 35, 36].
Other cranial nerves may also be affected. Cranial neuropathies may be single or
multiple [37, 38]. Heerfordts syndrome consists of cranial neuropathy (mostly the facial
nerve), uveitis, parotid gland enlargement and fever. This syndrome is highly suggestive
of sarcoidosis.
Finally, Horners syndrome due to disruption of the cervical sympathetic nerves [1], as
well as pupillary abnormalities, including internal ophthalmoplegia, Argyll Robertson
pupil and Adies pupil, have been described in sarcoidosis [18, 3942].

Papilloedema
The diagnosis of neurosarcoidosis should be entertained in young adults, particularly
females of childbearing age, with rapidly developing papilloedema, especially associated
with the seventh or other nerve palsies. In sarcoidosis patients, fundoscopy should always
be performed.

Aseptic meningitis
Meningeal symptoms may be acute or chronic. Symptoms and signs include fever,
headache, neck rigidity and sterile cerebrospinal fluid (CSF) with pleocytosis
(particularly lymphocytes) [43]. CSF glucose levels may be low in approximately one-
fifth of patients [44]. Sometimes mental status changes and polyradiculopathy are present
[45, 46]. The basal meninges may be affected, resulting in cranial neuropathy. Chronic
meningitis is often recurrent and requires long-term therapy, whereas acute meningitis
responds favourably to corticosteroids.

165
 E. HOITSMA, O.P. SHARMA

Hydrocephalus
Hydrocephalus is rare and may occur due to impaired absorption [12, 14, 47] or
obstruction [48, 49]. Besides causing headache and somnolence, hydrocephalus may
produce amnesia, dementia, urinary incontinence and gait disturbances [50, 51].

Cerebral sarcoid lesions

Granulomas may remain small or form large intracranial tumours and may be single
or multiple. They can occupy extradural, subdural and parenchymatous locations [52
55]. Occasionally, periventricular white matter lesions are observed (fig. 1a). The latter
may resemble multiple sclerosis or vascular changes. Asymptomatic periventricular white
matter lesions without meningeal enhancement in sarcoidosis patients aged w50 yrs are
most probably not due to sarcoidosis and can be regarded as age-related small vessel
disease.
The clinical features of mass lesions are similar to those of any space-occupying
intracranial mass. Granulomatous lesions are relatively frequently found in the
hypothalamus and/or pituitary gland [5660]. This may cause endocrine manifestations,
such as diabetes insipidus [61], adenopituitary failure [62, 63] and amenorrhoea
galactorrhoea syndrome [59], isolated or in various combinations. Infratentorial
granulomas are less common than supratentorial but cerebellar masses also occur
[22]. When no evidence of systemic sarcoidosis is found, differential diagnosis of pituitary
lesions consists of pituitary adenoma and lymphocytic adenohypophysitis [64].
Granulomatous cerebral angiitis also occurs in sarcoidosis [14, 65]. Ophthalmological
screening is helpful in uncovering angiitis. Diffuse cerebral vasculopathy may produce
psychosis, dementia and epileptic seizures [47, 6670]. Pseudotumour cerebri due to dural

a) b)

Fig. 1. Cerebral magnetic resonance imaging of case A: a) T1-weighted, revealing nonspecific white matter
lesions (arrows); and b) gadolinium-enhanced T2-weighted, revealing leptomeningeal-enhancing lesions (arrows).

166
 NEUROSARCOIDOSIS

sinus thrombosis as a presenting manifestation of neurosarcoidosis has also been

reported [71, 72].

Case A. A 55-yr-old female was seen for a second opinion. She had suffered from low
back pain, leg weakness and atypical position-independent dizziness and headache for
10 months. Physical examination revealed bilateral pyramidal syndrome with UK
Medical Research Council (MRC) grade 4/5 paraparesis of both iliopsoas, hamstring and
quadriceps muscles. She had extensor plantar responses and a pyramidal gait. Cerebral
magnetic resonance imaging (MRI) revealed nonspecific, nonenhancing white matter
lesions and leptomeningeal enhancing lesions (fig. 1). Spinal MRI showed a hyperintense
enhancing lesion at the 5th6th cervical spinal level. Lumbar puncture revealed a cell
density of 19 white blood cells?mm-3 (100% lymphocytes) without signs of malignancy and
increased protein and normal glucose and angiotensin-converting enzyme (ACE) levels.
Her history revealed pneumonia 4 months previously, just before the neurological
symptoms had started, and a tongue lesion for almost a year, which had been diagnosed as
a benign mycosis. On presentation, her tongue lesion was causing her more and more
trouble. Chest computed tomography (CT) revealed hilar adenopathy and pulmonary
infiltrates, and biopsy of the tongue lesion showed noncaseating granulomas, both
consistent with a diagnosis of sarcoidosis. She was treated with prednisone, after which
her symptoms improved. At present, she is still continuing her medication.

Seizures
Seizure may be the first manifestation of neurosarcoidosis; any type of seizure may
occur. The presence of seizures indicates chronicity and poor prognosis [73].

Case B. A 19-yr-old female presented in the emergency department with a first tonic-
clonic generalised seizure and postictal headache, confusion and dysphasia. Contrast-
enhanced CT and MRI revealed a left parieto-occipital enhancing lesion (fig. 2).
Differential diagnosis included malignancy, and lumbar puncture was performed, which
showed lymphocytosis without signs of malignancy. Laboratory investigation, including
calcium, ACE and lysozyme levels and erythrocyte sedimentation rate (ESR), revealed no
abnormalities. Chest radiography was performed in search of primary malignancy, which
showed hilar adenopathy and a pulmonary infiltrate. Mediastinal lymph node biopsy
showed noncaseating granulomas consistent with the diagnosis of sarcoidosis. She was
treated with prednisone and valproate and remained well for a period of 1 yr without
abnormalities on control CT. When prednisone was tapered down, she had two
recurrences, with cranial neuropathy and multiple cerebral enhancing lesions, and is
finally stable on 15 mg prednisone.

Psychiatric symptoms
Granulomatous infiltration of the central nervous system (CNS) may produce a wide
variety of mental symptoms. In a patient with multisystemic sarcoidosis and unexplained
mental deterioration, aggressive evaluation of the CNS is indicated. Symptoms may
respond to corticoid therapy [47, 69]. A subset of sarcoidosis patients present with mild
amnesic problems, without objective deterioration or neurological deficit. This might be
related to fatigue and concentration problems, or, in some cases, to postural tachycardia
syndrome (autonomic dysfunction; see case E) [74]. However, further study using
neuropsychological testing is required to explore this.

167
 E. HOITSMA, O.P. SHARMA

a) b)

Fig. 2. Post-contrast images showing a left parieto-occipital enhancing lesion in case B: a) computed
tomography; and b) T2-weighted magnetic resonance imaging.

Spinal sarcoidosis
Spinal sarcoidosis encompasses a spectrum of intraspinal diseases, including
arachnoiditis, extradural and intradural extramedullary lesions, and intramedullary
lesions [1, 75, 76]. Intramedullary spinal involvement is one of the rare manifestations of
the disease (fig. 3). Granulomas involving the spinal cord are often clinically and
radiologically indistinguishable from a malignant tumour [77, 78]. Patients may present
with transverse myelopathy with para- or tetraparesis [75, 7981], autonomic dysreflexia
[82] radicular syndrome [75] and cauda equina syndrome [8388].

Case C. A 33-yr-old Iranian male with paresis of the left leg who had had muscle cramps
for 2 months and urine retention for 2 weeks presented for a second opinion. His medical
history included histologically proven pulmonary sarcoidosis with spontaneous recovery
of pulmonary symptoms 6 months before presentation. Physical examination revealed
diffuse MRC grade 4/5 paresis of the left leg, clonus of the knee and ankle tendon reflex on
the left side and bilateral extensor plantar responses. There was decreased pain, vibration
and light touch sensation in both legs until the first thoracic spinal level. The results of
laboratory investigation, including ESR and levels of ACE and CSF ACE, protein,
glucose and white blood cells, were all within normal limits. Cerebral MRI revealed no
abnormalities, whereas spinal MRI showed a medullar lesion at the 2nd5th cervical level
(fig. 3). Subsequently, chest radiography was performed because of the patients medical
history, and, again, hilar adenopathy was found, compatible with a diagnosis of
sarcoidosis. Treatment with 80 mg prednisone q.d. was started, preceded by a q.d. dose of
1,000 mg methylprednisolone intravenously for 3 days. The neurological situation

168
 NEUROSARCOIDOSIS

Fig. 3. T2-weighted magnetic resonance imaging of the cervical spine in case C, showing hyperintense lesions
at the 2nd5th cervical spinal level (arrows)

stabilised. However, when prednisone was tapered after 10 weeks, symptoms increased.
Methotrexate was then started. At present, the patient is stable on 10 mg methotrexate
once a week along with 10 mg prednisone and 1 mg folic acid (q.d.).

Peripheral neuropathy
The clinical and pathological spectrum of sarcoid neuropathy is wide. Peripheral
neuropathy is considered to be rare in sarcoidosis [89, 90]. The pattern of large-fibre
neuropathy reported in sarcoidosis includes multiple mononeuropathies, polyradiculo-
pathy, Guillain-Barre syndrome and symmetric distal polyneuropathy, which may be
sensorimotor, mostly sensory or mostly motor [14, 90102]. Epineural and perineural
granulomas and granulomatous vasculitis can cause ischaemic axonal degeneration and
demyelination due to local pressure [89, 93, 94]. Nerve biopsy may be helpful in
diagnosing problems. In most patients, the clinical course of sarcoid neuropathy is
subacute [93], and many patients seem to respond to corticosteroid therapy [17].

Small fibre neuropathy

Recently small fibre neuropathy (SFN) was demonstrated in sarcoidosis [103105] and
appeared to be relatively frequent [104]. However, as standard nerve conduction tests
evaluate only large nerve fibre function and quantitative techniques for the assessment of
small nerve fibres are not routinely applied, the diagnosis of SFN can easily be missed.
SFN has only relatively recently been recognised as a distinct entity. If not recognised,
these symptoms may be an enigma to both patient and doctor. Recognition of SFN is
important as it may cause disabling symptoms. SFN may also involve autonomic nerve

169
 E. HOITSMA, O.P. SHARMA

fibres and, apparently, cardiac sympathetic denervation [106]. Whether life-threatening

symptoms, such as cardiac arrhythmias, occur in sarcoidosis when cardiac autonomic
denervation is involved requires further study. SFN may also cause restless leg syndrome
(RLS) [107]. RLS and periodic limb movement disorder (PLMD) are frequently
associated and related to sleep disturbances. PLMD and RLS have been found to be
present in sarcoidosis [108]. In table 2, symptoms suggestive of SFN are presented. The
pathophysiology and treatment of SFN in sarcoidosis are unknown and need further
study.

Case D. A 55-yr-old male with known pulmonary sarcoidosis for 2 yrs was referred to the
neurology department because of severe pain in his hands and lower legs and feet with
paraesthesiae. He could not tolerate bedclothes on his legs, and wore short trousers
without socks in winter because he could not tolerate clothes on his lower legs.
Furthermore, he was suffering from severe fatigue, profuse sweating, diarrhoea, bladder
emptying difficulties, sicca syndrome, paroxysmal palpitations with dizziness, after which
he once collapsed, and erectile dysfunction. Neurological examination revealed no
abnormalities except subjective dysaesthesia of the lower legs and feet. Differential
diagnosis included neuropathy with involvement of autonomic fibres. Electromyography
(EMG), nerve conduction studies and cardiovascular autonomic function test results were
normal. Thermal threshold testing (TTT) revealed abnormal temperature sensation
compatible with SFN. He was treated with prednisone without any success, and
subsequently put on methotrexate, again without any improvement. Neuropathic pain
treatment [109112] with gabapentin, amitriptyline, carbamazepine and local capsaicin
cream were all without benefit. Opioids gave some pain reduction and improved
diarrhoea. However, after a few weeks, he developed urine retention. At present, the
patient is severely disabled, mainly because of severe pain and fatigue, and has had to stop
working.

Case E. A 39-yr-old male with known pulmonary and neurological involvement

(hydrocephalus) of sarcoidosis since 2000 presented at the neurology department for a
second opinion in 2003 with symptoms of extreme fatigue, cognitive impairment, pain in
the palms and soles, weakness of the legs, and dizziness and blurred vision while standing.
He had been suffering from these symptoms for 2 yrs. Cerebral MRI revealed unchanged
hydrocephalus without any parenchymal lesions, and lumbar puncture showed normal
pressure and normal cell counts and protein and glucose levels. The posture-dependent
symptoms in combination with pain in the palms and soles were suggestive of SFN.
Table 2. Symptoms suggestive of small fibre neuropathy
Sensory symptoms
Pain
Paraesthesiae
Sheet intolerance
Restless leg syndrome
Symptoms of autonomic dysfunction
Hypo- or hyperhidrosis
Diarrhoea or constipation
Urinary incontinence or retention
Gastroparesis
Sicca syndrome
Blurry vision
Facial flushes
Orthostatic intolerance
Sexual dysfunction

170
 NEUROSARCOIDOSIS

Therefore, TTT was performed, revealing severely abnormal temperature sensation.

Cardiovascular autonomic function testing showed autonomic dysfunction. There was a
normal blood pressure response after changing position from the supine to standing
position, but an abnormal increase in cardiac frequency (to 63 beats?min-1; normally
v30 beats?min-1). Furthermore, blood pressure modulation frequency in the upright
position was too low (0.051 Hz). Both results, as well as the symptoms, are consistent with
the diagnosis of postural tachycardia syndrome [74]. He was treated with hydration,
increased salt intake and elastic support hose without much benefit. At present, he is on
50 mg fludrocortisone q.d., with some improvement in his symptoms.

Skeletal muscle involvement

Muscle involvement may be symptomatic or asymptomatic [113, 114]. Asymptomatic
granulomatous muscle involvement in sarcoidosis has been reported with a prevalence of
5080% [115], whereas symptomatic muscle involvement is much less common (range
1.42.3%) [116]. Patients usually present with pain, weakness and tenderness of the
involved muscles, muscle atrophy and sometimes even muscle cramps and contractures
[116]. Symptomatic involvement may be divided into the following types: 1) a palpable
nodular type, which is seen less frequently; 2) an acute myositis, which is rare and seen
more commonly in females; and 3) a chronic myopathic type, which is more common, is
slower in onset and occurs later in life [114, 116118]. As, in the majority, the
granulomatous infiltration is in connective tissue structures and necrosis of muscle fibres
is uncommon, EMG results may be quite normal [113]. However, EMG can reveal
myopathic changes. It may be difficult to distinguish myopathy due to sarcoidosis itself
from myopathy due to steroids, especially in chronic myopathy. In the first case, steroids
are indicated, whereas, in the second, steroids should be tapered. Steroid myopathy is
mostly seen with fluorinated corticosteroids (dexamethasone, triamcinolone and
betamethasone). A helpful distinction between the two is presented in table 3. Muscle
biopsy is most helpful here. Essentially, in sarcoid myopathy, lesions take the form of
granulomata in connective tissue, particularly in a perivascular distribution. The lesions
are quite focal and serial sections increase the chances of establishing a diagnosis [114]. In
steroid myopathy, type 2 fibre atrophy is typically found.

Diagnosis
Virtually every neurological problem could, indeed, be due to neurosarcoidosis, but
only few combinations of symptoms are clinically suggestive of neurosarcoidosis
(table 4). The diagnosis of neurosarcoidosis requires a compatible clinical or radiological

Table 3. Differences between myopathy due to sarcoidosis and due to steroids

Steroid-induced myopathy Sarcoid myopathy

Clinical features Myalgia; proximal weakness,
especially legs
Creatine kinase Mostly normal
Frequency Low: 221% in all patients
receiving steroids
Electromyography Low amplitude MUPs of short
duration
Biopsy Type-2 fibre atrophy
MUP: motor unit potential.
Myalgia; weakness: proximalwdistal; sometimes
palpable nodules, contractures or cramp
Sometimes elevated
50% of sarcoidosis patients have muscle
granulomas, often asymptomatic
Fibrillations and positive sharp waves; low
amplitude MUPs of short duration
Myositis; nodular myositis

171
 E. HOITSMA, O.P. SHARMA

Table 4. Neurosarcoidosis: differential diagnosis

Neurosarcoidosis Multiple sclerosis Behcets disease Infections

Age yrs 2040 2040 2040 Any
Sex Equal FwM MwF Equal
Chest radiograph Abnormal w90% Usually normal May be abnormal May be abnormal
Hypercalcaemia Present v15% Absent Absent May be present
Uveitis Present 25% Absent May be present May be present
Facial nerve involvement May occur May occur Absent Absent
Meningitis May occur May occur May occur May occur
CSF ACE Present Absent Absent Absent
CSF lysozyme Present Absent Absent Present
Oligoclonal IgG Present 30% Present 90% Absent May be present
Kveim test Positive Negative Negative Negative
CSF: cerebrospinal fluid; ACE: angiotensin-converting enzyme; Ig; Immunoglobulin; F: female; M: male.

picture of sarcoidosis and histological confirmation of noncaseating granulomas [119,

120]. Three clinical situations can be distinguished in patients with neurosarcoidosis: 1)
patients with neurological features and histologically confirmed active systemic
sarcoidosis; 2) patients with neurological features and a history of sarcoidosis without
any evidence of activity; and 3) patients with neurological features without a history of or
any evidence of systemic sarcoidosis.
In the first situation, neurological symptoms are most probably related to systemic
sarcoidosis and there is justification in starting therapy (fig. 4). However, when treatment
fails, the diagnosis should be reassessed and an attempt made to obtain biopsy specimens
in order to establish the correct diagnosis. In the second situation, in patients with a
history of sarcoidosis who present with neurological symptoms, neurosarcoidosis will be
considered early in the differential diagnosis. The need for biopsy is crucial in such a
situation. Conversely, in the third situation, neurosarcoidosis will rarely be considered at
an early stage. In these cases, neurosarcoidosis remains one of the more challenging
diagnostic problems [121, 122]. The present authors believe that the diagnostic approach
in the second and third situations should be the same (fig. 5). A prior history of

Start medication

Prednisone 1 mgkg-1day-1 orally 68 weeks; eventually

preceded by methylprednisolone 1,000 mgday-1 i.v. 3 days

Not effective Effective

Reassess diagnosis:
Nervous system biopsy
Exclude other causes

Diagnosis

Fig. 4. Diagnostic flow chart for patients with active systemic sarcoidosis and presentation with neurological
symptoms.

172
 NEUROSARCOIDOSIS

Establish activity/extent of sarcoidosis

Physical examination: Chest radiograph: Laboratory:

Lungs BAL Hb
Spleen ESR
Liver ACE
Lymph nodes Liver enzymes
Eyes Calcium
Skin sIL2R

Positive results Negative results

Choose biopsy site: Nervous system biopsy at

Lymph nodes site of symptoms
Liver
Lung
Skin

Diagnosis

Fig. 5. Diagnostic flow chart for patients not known to have sarcoidosis with neurological symptoms and for
patients with a history of sarcoidosis but without signs of active disease. BAL: bronchoalveolar lavage; Hb:
haemoglobin; ESR: erythrocyte sedimentation rate; ACE: angiotensin-converting enzyme; sIL-2R: soluble
interleukin-2 receptor.

sarcoidosis does not necessarily mean that any new problem of the patient is
automatically attributable to sarcoidosis. In the authors opinion, the approach in a
patient with a prior history of sarcoidosis without evidence of current active disease
should be the same as in a patient without a history of sarcoidosis.
In figures 4 and 5, the possible steps in establishing a diagnosis are presented [109,
120]. Whole-body gallium scanning [123, 124] or fluorodeoxyglucose positron emission
tomography (PET) [125] can be utilised in finding other suitable sites for biopsy.
Conjunctival biopsy, a technically simple, inexpensive and safe method, may also be used
for diagnosis. Given that as many as 54.1% of patients with sarcoidosis exhibit ocular
abnormality, it is worthwhile referring suspected cases for ophthalmological assessment
and considering conjunctival biopsy as a method of tissue diagnosis [126128].
While excluding other causes, the differential diagnosis of sarcoidosis should be
taken into account (table 5). Finally, if no evidence of systemic sarcoidosis is found
but a CNS biopsy reveals a sarcoid-like granulomatous reaction, there should be
awareness of the distinction between systemic neurosarcoidosis and a local (neurological)
sarcoid-like reaction, particularly related to an old scar [129] or a helminthic reaction
[16, 109, 130].

Neuroimaging
Neuroimaging studies, and especially MRI, are the most sensitive diagnostic tools in
detecting and localising neurological lesions. These tests, however, are not specific, since
radiological expressions are highly variable [131, 132].

173
 E. HOITSMA, O.P. SHARMA

Table 5. differential diagnosis of neurosarcoidosis

Infectious diseases
Leprosy
Tuberculosis
Whipples disease
Toxoplasmosis
Mycosis
Helminthic infections
Treponemal infections
Lyme disease
Granulomatous diseases
Wegeners granulomatosis
ChurgStrauss syndrome
Lymphomatoid granulomatosis
Tumours
Neurolymphomas
Gliomas
Meningiomas
(Leptomeningeal) metastases
Vasculopathies
Vasculitis
Behcets disease
Systemic diseases
Amyloidosis
Chronic subdural haematoma
Neurological diseases
Multiple sclerosis
Acute demyelinating encephalomyelitis

Cerebrospinal fluid
Routine CSF abnormalities are usually nonspecific and include mild pleocytosis,
increased protein content and sometimes mildly decreased glucose levels. Furthermore,
elevations of ACE [133139], immunoglobulin G index [140142], oligoclonal bands [9,
140, 141], CD4:CD8 lymphocyte ratios [143], and lysosyme and b2-microglobulin levels
[144] have been reported in CSF. Approximately one-third of patients with
neurosarcoidosis show normal CSF [11, 18, 119]. Moreover, in conditions such as
multiple sclerosis and systemic lupus erythematosus, similar CSF abnormalities may be
found.
CSF ACE levels appear to be elevated in more than half of patients with
neurosarcoidosis [134]. It should be emphasised, however, that high levels of
CSF ACE are not specific to neurosarcoidosis and have also been reported in
CNS infections and malignant tumours [134, 139]. Several studies found significantly
higher CSF ACE levels in active neurosarcoidosis compared to controls and compared
to sarcoidosis without nervous system involvement [133139]. Furthermore, in
serial measurements of CSF ACE, reflection of the clinical picture was found
[137, 138, 145]. No correlation was found between serum and CSF ACE levels in
patients with neurosarcoidosis, nor was there any correlation between serum ACE
levels and the clinical picture or CSF ACE and CSF total protein or CSF albumin
levels in such patients (an increase in CSF albumin level being an indicator of func-
tioning of the blood-brain barrier). Thus, CSF ACE is most probably synthesised
in the nervous system and released into the CSF by the CNS system sarcoid granulomas.
In conclusion, determination of CSF ACE level is not specific for neurosarcoidosis,
but seems to be particularly useful in monitoring disease activity and treatment
response.

174
 NEUROSARCOIDOSIS

Neurophysiological studies
Electroencephalography may reflect an early stage of acute encephalomeningitis and
epileptic discharges caused by the neurosarcoidosis. Visual evoked potentials, brainstem
evoked potentials and trigeminofacial reflexes can be useful in detecting cranial
neuropathy.
EMG and nerve conduction studies reveal large fibre neuropathy and myopathy,
whereas TTT and/or skin biopsy are needed to assess SFN. The latter techniques are not
yet routinely available. Assessment of autonomic dysfunction, present in SFN, requires
special equipment, such as quantitative sudomotor axon reflex testing. Cardiovascular
autonomic function testing using the so-called Ewing tests has a low sensitivity for
autonomic dysfunction in SFN [104, 146]. The widely available testing of sympathetic
skin response is neither specific nor sensitive [104, 147].
Polysomnography with EMG monitoring can be helpful in revealing PLMD and sleep
disturbances.

Clinical course and prognostic features

The long-term clinical outcome of neurosarcoidosis has not been thoroughly
evaluated. The low prevalence of the disease makes large long-term follow-up studies
difficult. Furthermore, the natural history of the disease remains unclear because of
therapeutic intervention [148].
The prognosis of patients with neurosarcoidosis varies. The disease may be
monophasic or self-limiting, it may come and go, or it may incessantly progress.
Apparently, more than two-thirds of patients with this disease respond to treatment and,
therefore, do well. In other cases, the progression may be slow and steady.
Neurosarcoidosis carries a mortality of 10%, more than twice that of all other
manifestations of the disease combined [149].
The course seems to depend on the type of nervous tissue involved: patients with dural
lesions, peripheral neuropathy, cranial nerve lesions and, to a lesser degree, non-
enhancing brain lesions seem to fare better than patients with leptomeningeal, brain
parenchymal and spinal lesions [1, 14, 150]. Patients with mass lesions or hydrocephalus
tend to show more relapses and are often resistant to therapy [151153]. Ferriby et al.
[154] found that sarcoidosis patients with CNS involvement during the course of the
disease had a higher Modified Oxford Handicap Scale score than those with peripheral
nervous system involvement (pv0.02). Thus, CNS involvement may be a predictive factor
for a less favourable disease course, and early and intensive treatment should be
particularly considered in such cases [154].
There have been no controlled studies and few prospective studies of therapy in
neurosarcoidosis. Evidence for improvement with treatment is anecdotally reported in
many cases, but progression of the disease may occur despite therapy [14, 155158]. Most
relapses occur while tapering prednisone to 10 mg [153]. Allen et al. [17] found, in
their prospective study of 32 patients with neurosarcoidosis, neurological improvement
in 16 out of 19 (84%) of their patients after therapy and five out of 13 (38%) of the
untreated patients. The most predictable response occurred in patients with peripheral
neuropathy: 12 out of 14 treated patients responded. Only one out of eight patients who
remained untreated improved spontaneously. Zajicek et al. [158] found progression of
disease in more than half of their 47 prospectively followed neurosarcoidosis patients,
despite corticosteroid and other immunosuppressive therapies.
In a retrospective study, Manz [4] compared five cases with incidental clinically

175
 E. HOITSMA, O.P. SHARMA

unapparent sarcoidosis, six with systemic sarcoidosis without CNS involvement and four
with a variety of neurological manifestations in addition to systemic sarcoidosis. They
died at a mean age of 55, 47 and 38 yrs, respectively. Thus it appears that sarcoidosis in
some patients may cause no or only trivial symptoms, whereas, in the other group of
younger patients, it may be severe and debilitating. If the CNS involvement occurs early
in the course, it pursues a rapidly progressive course with poor prognosis despite
appropriate management [4].

Therapy
Medication
Considering the morbidity and mortality of neurosarcoidosis, most authors
recommend early treatment. However, clear guidelines and indications, as well as
prospective controlled studies, are not available in neurosarcoidosis, and prospective
multicentric studies are warranted. As a result, recommendations about treatment are
based on experience rather than evidence.
The therapeutic medical options for neurosarcoidosis are similar to those in
sarcoidosis at other locations, and corticosteroids represent the drugs of first choice
[159]. Doses in neurosarcoidosis are higher than those advised for the treatment of other
localisations of sarcoidosis, including pulmonary. In general, the initial recommended
dose is 40 mg q.d., whereas, in neurosarcoidosis, an initial dose of 1 mg?kg body
weight-1?day-1 is usually recommended. In severe cases, high doses of intravenous
methylprednisolone may be used for a few days in order to obtain a high initial loading
dose. Some may use bolus pulsed methylprednisolone once a week, eventually along with
low daily doses of oral prednisone, or treatment on alternate days, to avoid the side-
effects associated with long-term high-dose oral treatment [158]. However, at present
there is not enough evidence to recommend this. Although corticosteroids suppress
inflammation in many patients, symptoms tend to recur in a subset of patients at doses of
prednisone of v1025 mg?day-1, or the equivalent in other corticoid types, making
cessation of corticoids difficult. Furthermore, the incidence of steroid-related side-effects
is extremely high with such prolonged treatment.
In patients in whom corticosteroids may be contraindicated, cytotoxic agents, such as
methotrexate, azathioprine, ciclosporin and cyclophosphamide, have been used [157,
158, 160162]. The choice of one or the other is more a matter of experience than of
double-blind studies. On the basis of safety and efficacy, methotrexate and azathioprine
may be preferred. Methotrexate has been the most widely reported drug for sarcoidosis,
and its utility in sarcoidosis has been reviewed [163]. It appears to be well tolerated and
associated with minimal toxic effects. The major problem is liver toxicity, for which
regular blood tests are needed. The response rate of methotrexate in neurosarcoidosis is
y60%, which is similar to that in chronic sarcoidosis [161]. Azathioprine has been
reported useful in chronic sarcoidosis, although others have been disappointed with its
ability in treating patients with refractory sarcoidosis [164]. Treatment with ciclosporin
has also resulted in variable outcomes [161]. It appears that y75% of neurosarcoidosis
patients respond to ciclosporin [157, 160]. The response rates for intravenously
administered cyclophosphamide seem to be y6080% in patients with corticosteroid-
resistant neurosarcoidosis [161, 162]. A short-course pulsed regimen appeared to
minimise cumulative toxicity [162]. The place of newer immunosuppressive agents, such
as mycophenolate mofetil, has yet to be determined.
Drugs that alter the immune system or block cytokine effect have also been used for

176
 NEUROSARCOIDOSIS

the treatment of patients with sarcoidosis. The antimalarial agents chloroquine and
hydroxychloroquine have been reported useful in the treatment of some patients with
neurological sarcoidosis [165]. Tumour necrosis factor (TNF) is released at higher levels
by alveolar macrophages from patients with active sarcoidosis, and the levels go down
with corticosteroid or methotrexate therapy [164]. These observations have led to studies
that suppress TNF release or block its effect on the cell. Immunomodulators known to
suppress TNF release are thalidomide and infliximab. Infliximab has been shown
effective in few cases with refractory sarcoidosis. In refractory neurosarcoidosis, it may
also be effective [166170]. The toxicity of treatment for up to 1 yr is low. However, the
effect of long-term treatment is still unclear [164]. An important complication associated
with infliximab has been the increased rate of tuberculosis [171].
Whether or not anti-TNF-a therapy is beneficial in SFN related to sarcoidosis is
unknown to date. However, the following case underlines this possibility. Theoretical
support for the effect of anti-TNF-a therapy on SFN may be found in the following. First,
it has been appreciated recently that pro-inflammatory cytokines, including TNF-a,
contribute to the development of inflammatory and neuropathic pain, as well as
hyperalgesia [172]. Secondly, TNF-a plays an important role in neuropathies such as
Guillain-Barre syndrome. In Guillain-Barre syndrome, small nerve fibres are also involved.
An elevated serum concentration of TNF-a shows a positive correlation with neuropathy
severity in patients with Guillain-Barre syndrome [173, 174]. Furthermore, the decrease in
serum TNF-a levels and increase in serum soluble TNF receptor levels show a positive
correlation with neuropathy recovery following treatment in these patients. Finally, the
presence of SFN in several immune-mediated diseases suggests a common final pathway in
the pathogenesis of the disorder that may be related to the ongoing inflammatory process.
This similarity might be related to cytokine release in immune-mediated diseases. Support
for the hypothesis that SFN in immune-mediated diseases is related to cytokine release is
found in pharmacological and physiological studies. These studies report that pro-
inflammatory cytokines, such as TNF-a, are strongly involved in the generation and
maintenance of neuropathic pain [172, 175178]. Therefore, it is tempting to speculate that
anti-TNF-a therapy might be beneficial in SFN.
Case F reveals two new and important issues. First, severe SFN appeared to be
reversible in this case. Secondly, TNF-a may be a crucial cytokine in the pathogenesis of
SFN related to sarcoidosis, and possibly in other immune-mediated inflammatory
diseases, as well as in diabetes. The successful reaction to anti-TNF-a therapy is very
promising, and this observation opens a window for new therapeutic and pathogenetic
SFN studies.
In figure 6, a therapeutic flow chart for neurosarcoidosis is presented. Side-effects, as
well as experience with certain drugs, may play a role in drug choice (table 6).

Case F. A 39-yr-old Caucasian man with known sarcoidosis for 2 yrs was diagnosed with
severe SFN with autonomic involvement. Owing to his clinical deterioration, he was
unable to work. Treatment with 40 mg prednisone q.d. was initiated, without benefit,
however, and tapered. Thereafter, methotrexate was added and increased up to 20 mg
weekly. Despite this, his symptoms deteriorated. Several neuropathic pain treatments
initiated achieved no improvement. He developed severe skin lesions on both hands. The
lesions were diagnosed as burns due to insensitivity to heat, attributable to the SFN.
Subsequently, infliximab was started at a dosage of 400 mg once every 4 weeks. This
was remarkably successful; all clinical features of sarcoidosis and SFN improved.
Control TTT and cardiovascular autonomic function testing both showed spectacular
improvement in his SFN features. Moreover, his quality of life improved substantially
and he even restarted working successfully.

177
 E. HOITSMA, O.P. SHARMA

Prednisone 1 mgkg-1day-1 orally, 68 weeks; eventually

preceded by methylprednisolone 1,000 mgday-1 i.v. 3 days

Effective Not effective

Continue 68 weeks Add MTX 1025 mg weekly

then try to wean + folic acid 1 mgday-1

No relapse Relapse Effective Not effective

Stop treatment Add MTX and/or other Try to wean Add other
immunosuppressant medication immunosuppressant,
to low dose corticoid after 36 months with or without
withdrawal of MTX

Effective Not effective Effective Not effective

Try to wean Consider Try to wean Consider

medication radiotherapy medication radiotherapy
after 36 months after 36 months

Fig. 6. Therapeutic flow chart for patients diagnosed with neurosarcoidosis. Recommendations are based on
experience rather than evidence. MTX: methotrexate.

Radiation
There are several reports on radiation therapy in refractory neurosarcoidosis [179
183]. Although evidence-based recommendations cannot be provided, radiation therapy
may be considered in patients who do not respond to medication.

Neurosurgical treatment
Neurosurgical resection of intracranial and spinal granulomas is only indicated in life-
threatening situations, or when insufficient effect is achieved with medical treatment.
However, extramedullary spinal lesions may be amenable to surgical resection with post-
operative steroid therapy [184]. Hydrocephalus usually requires ventriculoperitoneal
shunting [185, 186].

Conclusions
Neurosarcoidosis is a disease with many faces. Diagnosis is based on the combination
of clinical and radiological evidence and histological evidence of granuloma formation.
Judicious use of the recently developed CT, MRI and PET may obviate the need for

178
 Table 6. Medical treatment in neurosarcoidosis

Medication Starting dose Side-effects# Remarks

Corticosteroids
Prednisone 1 mg?kg-1?day-1 p.o. Osteoporosis, Cushings syndrome, hypertension,
diabetes mellitus, ulcus pepticum, pseudotumour
cerebri, glaucoma, cataract, euphoria, psychosis
Methylprednisolone 1000 mg?day-1 i.v. for 3 days Very rare within 3 days
Cytotoxic agents}
Methotrexate 1025 mg once weekly orally or s.c. Anaemia, neutropenia, hepatic dysfunction, pneumonitis Should be combined with folic acid
(1 mg?day-1 p.o.)
-1 -1
Ciclosporin 5 mg?kg ?day divided in 2 doses p.o. Renal insufficiency, hypertension Expensive
Azathioprine 50 mg t.i.d. orally Anaemia, neutropenia, hepatic dysfunction Cheap

179
Cyclophosphamide 50200 mg q.d., p.o. Cystitis, neutropenia Urinalysis monthly to monitor for
500 mg i.v. once every 23 weeks microscopic haematuria
Immunomodulators}
NEUROSARCOIDOSIS

Hydroxychloroquine 200 mg?day-1 p.o. Retinopathy, ototoxicity, myopathy, cardiomyopathy, Routine eye examinations every
neuropathy, neuropsychiatric 36 months
Infliximab 3 mg?kg-1 i.v. once in weeks 1, 3 and 5, Fever, headache, dizziness, flushes, nausea, abdominal Tuberculosis screening is indicated
then once every 6 weeks pain, dyspepsia, fatigue, myalgia, arthralgia, before treatment is started
polyneuropathy Contraindicated in patients with
heart failure
Should be combined with methotrexate
#
: all can cause infection due to immunosuppression; }: generally used as adjuncts to low-dose steroids, or as steroid-sparing agents when long-term treatment is
necessary; in refractory patients, they may be used in combination with high-dose steroids.
 E. HOITSMA, O.P. SHARMA

biopsy in selected cases. Once the diagnosis is established, treatment choices are limited,
and include corticosteroids, antimalarials and anticytotoxic agents.

Keynote messages
1) Neurosarcoidosis, like a chameleon, has many faces. It can involve any part of the
neurological apparatus. SFN is a recently recognised complication of sarcoidosis.
2) Histological evidence is needed to establish a firm diagnosis.
3) Corticosteroids are the drug of first choice in neurosarcoidosis. Several cytotoxic
agents, including methotrexate, cyclophosphamide and azathioprine, have been used.
Antimalarials have been found to be effective in selected cases. The value of new drugs
that block various cytokines needs to be established.

Summary
The nervous system is involved in 515% of patients with sarcoidosis. When present,
neurosarcoidosis can be serious and devastating. The disease presents in many
different ways and resembles many other neurological disorders. Thus, without biopsy
evidence, the diagnosis of nervous system sarcoidosis remains a troublesome clinical
dilemma. The firm diagnosis of neurosarcoidosis requires a biopsy specimen and
consistent neurological presentation in a patient with multisystemic sarcoidosis.
Corticosteroids represent the drug of first choice. In addition, several cytotoxic agents
and antimalarial agents are used to treat sarcoidosis. The future is pregnant with
expectations of new drugs that block inflammatory cytokines involved in the
pathogenesis of sarcoidosis.

Keywords: Neurosarcoidosis, small fibre neuropathy.

References
1. Stern BJ, Krumholz A, Johns C, Scott P, Nissim J. Sarcoidosis and its neurological manifestations.
Arch Neurol 1985; 42: 909917.
2. James DG, Sharma OP. Neurosarcoidosis. Proc R Soc Med 1967; 60: 11691170.
3. Sharma OP, Sharma AM. Sarcoidosis of the nervous system. A clinical approach. Arch Intern Med
1991; 151: 13171321.
4. Manz HJ. Pathobiology of neurosarcoidosis and clinicopathologic correlation. Can J Neurol Sci
1983; 10: 5055.
5. Iwai K, Tachibana T, Takemura T, Matsui Y, Kitaichi M, Kawabata Y. Pathological studies on
sarcoidosis autopsy. I. Epidemiological features of 320 cases in Japan. Acta Pathol Jpn 1993; 43:
372376.
6. Burns TM. Neurosarcoidosis. Arch Neurol 2003; 60: 11661168.
7. Minagar A, Hardjasudarma M, Kelley RE. Neurosarcoidosis. Neurology 2002; 59: 477.
8. Oksanen V. Neurosarcoidosis. Sarcoidosis 1994; 11: 7679.
9. Scott TF. Neurosarcoidosis: progress and clinical aspects. Neurology 1993; 43: 812.
10. Chan Seem CP, Spokes EG. Neurosarcoidosis. Lancet 1985; 2: 1363.
11. Sharma OP. Neurosarcoidosis. Chest 1991; 100: 301302.

180
 NEUROSARCOIDOSIS

12. Strefling AM, Summerville JW, Urich H. Involvement of choroid plexuses in neurosarcoidosis.
Acta Neuropathol (Berl) 1987; 74: 402404.
13. Kidd D, Beynon HL. The neurological complications of systemic sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2003; 20: 8594.
14. Oksanen V. Neurosarcoidosis: clinical presentations and course in 50 patients. Acta Neurol Scand
1986; 73: 283290.
15. Pentland B, Mitchell JD, Cull RE, Ford MJ. Central nervous system sarcoidosis. Q J Med 1985;
56: 457465.
16. Sharma OP, Lamb C. Cancer in interstitial pulmonary fibrosis and sarcoidosis. Curr Opin Pulm
Med 2003; 9: 398401.
17. Allen RK, Sellars RE, Sandstrom PA. A prospective study of 32 patients with neurosarcoidosis.
Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 118125.
18. Delaney P. Neurologic manifestations in sarcoidosis: review of the literature, with a report of 23
cases. Ann Intern Med 1977; 87: 336345.
19. Kieff DA, Boey H, Schaefer PW, Goodman M, Joseph MP. Isolated neurosarcoidosis presenting
as anosmia and visual changes. Otolaryngol Head Neck Surg 1997; 117: S183S186.
20. Jennings JW, Rojiani AM, Brem SS, Murtagh FR. Necrotizing neurosarcoidosis masquerading as
a left optic nerve meningioma: case report. AJNR Am J Neuroradiol 2002; 23: 660662.
21. Achiron L, Strominger M, Witkin N, Primo S. Sarcoid optic neuropathy: a case report. J Am
Optom Assoc 1995; 66: 646651.
22. Sharma OP. Cardiac and neurologic dysfunction in sarcoidosis. Sarcoidosis 1997; 18: 813825.
23. Arias M, Iglesias A, Vila O, Brasa J, Conde C. MR imaging findings of neurosarcoidosis of the
gasserian ganglion: an unusual presentation. Eur Radiol 2002; 12: 27232725.
24. Oki M, Takizawa S, Ohnuki Y, Shinohara Y. MRI findings of VIIth cranial nerve involvement in
sarcoidosis. Br J Radiol 1997; 70: 859861.
25. Sugita M, Sano M, Uchigata M, Aruga T, Matsuoka R. Facial nerve enhancement on gadolinium-
DTPA in a case with neurosarcoidosis. Intern Med 1997; 36: 825828.
26. von Brevern M, Lempert T, Bronstein AM, Kocen R. Selective vestibular damage in
neurosarcoidosis. Ann Neurol 1997; 42: 117120.
27. Sugaya F, Shijubo N, Takahashi H, Abe S. Sudden hearing loss as the initial manifestation of
neurosarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13: 5456.
28. Jardine DL, Melton IC, Bennett SI, Crozier IG, Donaldson IM, Ikram H. Baroreceptor
denervation presenting as part of a vagal mononeuropathy. Clin Auton Res 2000; 10: 6975.
29. Castroagudin JF, Gonzalez-Quintela A, Moldes J, Forteza J, Barrio E. Acute reversible dysphagia
and dysphonia as initial manifestations of sarcoidosis. Hepatogastroenterology 1999; 46: 2414
2418.
30. Jaffe R, Bogomolski-Yahalom V, Kramer MR. Vocal cord paralysis as the presenting symptom of
sarcoidosis. Respir Med 1994; 88: 633636.
31. Colover J. Sarcoidosis with involvement of the nervous system. Brain 1948; 71: 451475.
32. Blain JG, Riley W, Logothetis J. Optic nerve manifestations of sarcoidosis. Arch Neurol 1965; 13:
307309.
33. Wachtel AS, Saunders M. Optic nerve sarcoidosis. Mayo Clin Proc 1997; 72: 791.
34. Kumar N, Frohman EM. Spinal neurosarcoidosis mimicking an idiopathic inflammatory
demyelinating syndrome. Arch Neurol 2004; 61: 586589.
35. Graham EM, Ellis CJ, Sanders MD, McDonald WI. Optic neuropathy in sarcoidosis. J Neurol
Neurosurg Psychiatry 1986; 49: 756763.
36. Gelwan MJ, Kellen RI, Burde RM, Kupersmith MJ. Sarcoidosis of the anterior visual pathway:
successes and failures. J Neurol Neurosurg Psychiatry 1988; 51: 14731480.
37. Bandyopadhyay T, Das D, Das SK, Ghosh A. A case of neurosarcoidosis presenting with multiple
cranial nerve palsy. J Assoc Physicians India 2003; 51: 328329.
38. Palacios E, Rigby PL, Smith DL. Cranial neuropathy in neurosarcoidosis. Ear Nose Throat J 2003;
82: 251252.

181
 E. HOITSMA, O.P. SHARMA

39. De Broff B, Donahue S. Bilateral optic neuropathy as the initial manifestation of systemic
sarcoidosis. Am J Ophthalmol 1993; 116: 108111.
40. James DG, Zatouroff MA, Trowell J, Rose FC. Papilloedema in sarcoidosis. Br J Ophthalmol
1967; 51: 526529.
41. Karma A. Ocular sarcoidosis. Semin Respir Med 1992; 131: 425431.
42. Westlake J, Heath JD, Spalton DJ. Sarcoidosis involving the optic nerve and hypothalamus. Arch
Ophthalmol 1995; 113: 669670.
43. Plotkin GR, Patel BR. Neurosarcoidosis presenting as chronic lymphocytic meningitis. Pa Med
1986; 89: 3637.
44. Powers WJ, Miller FM. Sarcoidosis mimicking glioma: case report and review of intracranial
sarcoidosis like mass lesions. Neurology 1981; 31: 907910.
45. Mayer SA, Yim GK, Onesti ST, Lynch T, Faust PL, Marder K. Biopsy-proven isolated sarcoid
meningitis. Case report. J Neurosurg 1993; 78: 994996.
46. Jensen S, Jensen IW. Bilateral papilledema with normal CT-scan in neurosarcoidosis. Acta Med
Scand 1987; 222: 381383.
47. Willigers H, Koehler PJ. Amnesic syndrome caused by neurosarcoidosis. Clin Neurol Neurosurg
1993; 95: 131135.
48. Kumpe DA, Rao CV, Garcia JH, Heck AF. Intracranial neurosarcoidosis. J Comput Assist
Tomogr 1979; 3: 324330.
49. Cahill DW, Salcman M. Neurosarcoidosis: a review of the rarer manifestations. Surg Neurol 1981;
15: 204211.
50. Akhondi H, Barochia S, Holmstrom B, Williams MJ. Hydrocephalus as a presenting
manifestation of neurosarcoidosis. South Med J 2003; 96: 403406.
51. Maniker AH, Cho ES, Schulder M. Neurosarcoid infiltration of the ventricular catheter causing
shunt failure: a case report. Surg Neurol 1997; 48: 527529.
52. Veres L, Utz JP, Houser OW. Sarcoidosis presenting as a central nervous system mass lesion.
Chest 1997; 111: 518521.
53. Nowak DA, Widenka DC. Neurosarcoidosis: a review of its intracranial manifestation. J Neurol
2001; 248: 363372.
54. Stubgen JP. Neurosarcoidosis presenting as a retroclival mass. Surg Neurol 1995; 43: 8587;
discussion 8788.
55. Gizzi MS, Lidov M, Rosenbaum D. Neurosarcoidosis presenting as a tumour of the basal ganglia
and brainstem: sequential MRI. Neurol Res 1993; 15: 9396.
56. Randeva HS, Davison R, Chamoun V, Bouloux PM. Isolated neurosarcoidosis a diagnostic
enigma: case report and discussion. Endocrine 2002; 17: 241247.
57. Murialdo G, Tamagno G. Endocrine aspects of neurosarcoidosis. J Endocrinol Invest 2002; 25:
650662.
58. Gleckman AM, Patalas ED, Joseph JT. Sudden unexpected death resulting from hypothalamic
sarcoidosis. Am J Forensic Med Pathol 2002; 23: 4851.
59. Tamagno G, Murialdo G. Amenorrheagalactorrhea syndrome as an uncommon manifestation of
isolated neurosarcoidosis. Ann Ital Med Int 2001; 16: 260266.
60. Sato N, Sze G, Kim JH. Cystic pituitary mass in neurosarcoidosis. AJNR Am J Neuroradiol 1997;
18: 11821185.
61. Konrad D, Gartenmann M, Martin E, Schoenle EJ. Central diabetes insipidus as the first
manifestation of neurosarcoidosis in a 10-year-old girl. Horm Res 2000; 54: 98100.
62. Bullmann C, Faust M, Hoffmann A, et al. Five cases with central diabetes insipidus and
hypogonadism as first presentation of neurosarcoidosis. Eur J Endocrinol 2000; 142: 365
372.
63. Guoth MS, Kim J, de Lotbiniere AC, Brines ML. Neurosarcoidosis presenting as hypopituitarism
and a cystic pituitary mass. Am J Med Sci 1998; 315: 220224.
64. Ahmadi J, Meyers GS, Segall HD, Sharma OP, Hinton DR. Lymphocytic adenohypophysitis:
contrast-enhanced MR imaging in five cases. Radiology 1995; 195: 3034.

182
 NEUROSARCOIDOSIS

65. Urich H. Neurosarcoidosis or granulomatous angiitis: a problem of definition. Mt Sinai J Med

1977; 44: 718725.
66. Friedman SH, Gould DJ. Neurosarcoidosis presenting as psychosis and dementia: a case report.
Int J Psychiatry Med 2002; 32: 401403.
67. Popli AP. Risperidone for the treatment of psychosis associated with neurosarcoidosis. J Clin
Psychopharmacol 1997; 17: 132133.
68. Bona JR, Fackler SM, Fendley MJ, Nemeroff CB. Neurosarcoidosis as a cause of refractory
psychosis: a complicated case report. Am J Psychiatry 1998; 155: 11061108.
69. Sabaawi M, Gutierrez-Nunez J, Fragala MR. Neurosarcoidosis presenting as schizophreniform
disorder. Int J Psychiatry Med 1992; 22: 269274.
70. Caplan L, Corbett J, Goodwin J, Thomas C, Shenker D, Schatz N. Neuro-ophthalmologic signs in
the angiitic form of neurosarcoidosis. Neurology 1983; 33: 11301135.
71. Akova YA, Kansu T, Duman S. Pseudotumor cerebri secondary to dural sinus thrombosis in
neurosarcoidosis. J Clin Neuroophthalmol 1993; 13: 188189.
72. Redwood MD, Winer JB, Rossor M. Neurosarcoidosis presenting as benign intracranial
hypertension. Eur Neurol 1990; 30: 282283.
73. Krumholz A, Stern BJ, Stern EG. Clinical implications of seizures in neurosarcoidosis. Arch
Neurol 1991; 48: 842844.
74. Kanjwal Y, Kosinski D, Grubb BP. The postural orthostatic tachycardia syndrome: definitions,
diagnosis, and management. Pacing Clin Electrophysiol 2003; 26: 17471757.
75. Junger SS, Stern BJ, Levine SR, Sipos E, Marti-Masso JF. Intramedullary spinal sarcoidosis:
clinical and magnetic resonance imaging characteristics. Neurology 1993; 43: 333337.
76. Day AL, Sypert GW. Spinal cord sarcoidosis. Ann Neurol 1977; 1: 7985.
77. Vinas FC, Rengachary S, Kupsky WJ. Spinal cord sarcoidosis: a diagnostic dilemma. Neurol Res
2001; 23: 347352.
78. Rieger J, Hosten N. Spinal cord sarcoidosis. Neuroradiology 1994; 36: 627628.
79. Sauter MK, Panitch HS, Kristt DA. Myelopathic neurosarcoidosis: diagnostic value of enhanced
MRI. Neurology 1991; 41: 150151.
80. Castellano-Sanchez AA. Extensive leptomeningeal and intraparenchymatous spinal cord
neurosarcoidosis. South Med J 2000; 93: 815817.
81. Hayat GR, Walton TP, Smith KR Jr, Martin DS, Manepalli AN. Solitary intramedullary
neurosarcoidosis: role of MRI in early detection. J Neuroimaging 2001; 11: 6670.
82. Sakaibara R, Uchiyama T, Kuwabara S, et al. Autonomic dysreflexia due to neurogenic bladder
dysfunction; an unusual presentation of spinal cord sarcoidosis. J Neurol Neurosurg Psychiatry
2001; 71: 819820.
83. Prelog K, Blome S, Dennis C. Neurosarcoidosis of the conus medullaris and cauda equina.
Australas Radiol 2003; 47: 295297.
84. Shah JR, Lewis RA. Sarcoidosis of the cauda equina mimicking Guillain-Barre syndrome. J
Neurol Sci 2003; 208: 113117.
85. Abrey LE, Rosenblum MK, DeAngelis LM. Sarcoidosis of the cauda equina mimicking
leptomeningeal malignancy. J Neurooncol 1998; 39: 261265.
86. Ku A, Lachmann E, Tunkel R, Nagler W. Neurosarcoidosis of the conus medullaris and
cauda equina presenting as paraparesis: case report and literature review. Paraplegia 1996; 34: 116
120.
87. Verma KK, Forman AD, Fuller GN, Dimachkie MM, Vriesendorp FJ. Cauda equina syndrome
as the isolated presentation of sarcoidosis. J Neurology 2000; 247: 573574.
88. Fitzpatrick KJ, Chancellor MB, Rivas DA, Kumon H, Mandel S, Manon-Espaillat R. Urologic
manifestation of spinal cord sarcoidosis. J Spinal Cord Med 1996; 19: 201203.
89. Gainsborough N, Hall SM, Hughes RA, Leibowitz S. Sarcoid neuropathy. J Neurol 1991; 238:
177180.
90. Miller R, Sheron N, Semple S. Sarcoidosis presenting with an acute Guillain-Barre syndrome.
Postgrad Med J 1989; 65: 765767.

183
 E. HOITSMA, O.P. SHARMA

91. Strickland-Marmol LB, Fessler RG, Rojiani AM. Necrotizing sarcoid granulomatosis mimicking
an intracranial neoplasm: clinicopathologic features and review of the literature. Mod Pathol 2000;
13: 909913.
92. Oh SJ. Sarcoid polyneuropathy: a histologically proved case. Ann Neurol 1980; 7: 178181.
93. Said G, Lacroix C, Plante-Bordeneuve V, et al. Nerve granulomas and vasculitis in sarcoid
peripheral neuropathy: a clinicopathological study of 11 patients. Brain 2002; 125: 264275.
94. Nemni R, Galassi G, Cohen M, et al. Symmetric sarcoid polyneuropathy: analysis of a sural nerve
biopsy. Neurology 1981; 31: 12171223.
95. Vital C, Aubertin J, Ragnault JM, Amigues H, Mouton L, Bellance R. Sarcoidosis of the
peripheral nerve: a histological and ultrastructural study of two cases. Acta Neuropathol (Berl)
1982; 58: 111114.
96. Challenor YB, Felton CP, Brust JC. Peripheral nerve involvement in sarcoidosis: an
electrodiagnostic study. J Neurol Neurosurg Psychiatry 1984; 47: 12191222.
97. Galassi G, Gibertoni M, Mancini A, et al. Sarcoidosis of the peripheral nerve: clinical,
electrophysiological and histological study of two cases. Eur Neurol 1984; 23: 459465.
98. Elkin R, Willcox PA. Neurosarcoidosis. A report of 5 cases. S Afr Med J 1985; 67: 943946.
99. Baron B, Goldberg AL, Rothfus WE, Sherman RL. CT features of sarcoid infiltration of a
lumbosacral nerve root. J Comput Assist Tomogr 1989; 13: 364365.
100. Matthews WB. Sarcoid neuropathy. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds.
Peripheral Neuropathy. 2nd Edn. Philadelphia, PA, W.B. Saunders, 1984, pp. 20182026.
101. Scott TS, Brillman J, Gross JA. Sarcoidosis of the peripheral nervous system. Neurol Res 1993; 15:
389390.
102. Koffman B, Junck L, Elias SB, Feit HW, Levine SR. Polyradiculopathy in sarcoidosis. Muscle
Nerve 1999; 22: 608613.
103. Hoitsma E, Marziniak M, Faber CG, et al. Small fiber neuropathy in sarcoidosis. Lancet 2002;
359: 20852086.
104. Hoitsma E, Drent M, Verstraete E, et al. Abnormal warm and cold sensation thresholds suggestive
of small-fibre neuropathy in sarcoidosis. Clin Neurophysiol 2003; 114: 23262333.
105. Hoitsma E, Reulen JP, de Baets M, Drent M, Spaans F, Faber CG. Small fiber neuropathy: a
common and important clinical disorder. J Neurol Sci 2004; 227: 119130.
106. Hoitsma E, Faber CG, van Kroonenburgh MJPG, et al. Association of small fiber neuropathy
with cardiac sympathetic dysfunction in sarcoidosis. Sarcoidosis, Vasc Diffuse Lung Dis 2005;
22: 4350.
107. Polydefkis M, Allen RP, Hauer P, Earley CJ, Griffin JW, McArthur JC. Subclinical sensory
neuropathy in late-onset restless legs syndrome. Neurology 2000; 55: 11151121.
108. Verbraecken J, Hoitsma E, van der Grinten CP, Cobben NA, Wouters EF, Drent M. Sleep
disturbances associated with periodic leg movements in chronic sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2004; 21: 137146.
109. Hoitsma E, Faber CG, Drent M, Sharma OP. Neurosarcoidosis: a clinical dilemma. Lancet Neurol
2004; 3: 397407.
110. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management.
Lancet 1999; 353: 19591964.
111. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update
and effect related to mechanism of drug action. Pain 1999; 83: 389400.
112. Mendell JR, Sahenk Z. Clinical practice. Painful sensory neuropathy. N Engl J Med 2003; 348:
12431255.
113. Alpert JN, Groff AE, Bastion FO, Blum MA. Acute polymyositis caused by sarcoidosis, report of
a case and review of the literature. Mt Sinai J Med 1979; 46: 486488.
114. Stjernberg N, Cajander S, Truedsson H, Uddenfeldt P. Muscle involvement in sarcoidosis. Acta
Med Scand 1981; 209: 212216.
115. Silverstein A, Siltzbach LE. Muscle involvement in sarcoidosis. Asymptomatic, myositis, and
myopathy. Arch Neurol 1969; 21: 235241.

184
 NEUROSARCOIDOSIS

116. Jamal MM, Cilursu AM, Hoffman EL. Sarcoidosis presenting as acute myositis. Report and
review of the literature. J Rheumatol 1988; 15: 18681871.
117. Nidiry JJ, Mines S, Hackney R, Nabhani H. Sarcoidosis: a unique presentation of dysphagia,
myopathy, and photophobia. Am J Gastroenterol 1991; 86: 16791682.
118. Fonseca GA, Baca S, Altman RD. Acute myositis and dermatitis as the initial presentation of
sarcoidosis. Clin Exp Rheumatol 1993; 11: 553556.
119. Lynch JP 3rd. Neurosarcoidosis: how good are the diagnostic tests? J Neuroophthalmol 2003; 23:
187189.
120. Moore FG, Andermann F, Richardson J, Tampieri D, Giaccone R. The role of MRI and nerve
root biopsy in the diagnosis of neurosarcoidosis. Can J Neurol Sci 2001; 28: 349353.
121. Uchino M, Nagao T, Harada N, Shibata I, Hamatani S, Mutou H. Neurosarcoidosis without
systemic sarcoidosis case report. Neurol Med Chir (Tokyo) 2001; 41: 4851.
122. Cipri S, Gambardella G, Campolo C, Mannino R, Consoli D. Unusual clinical presentation of
cerebral-isolated sarcoidosis. Case report and review of the literature. J Neurosurg Sci 2000; 44:
140144.
123. Israel HL, Albertine KH, Park CH, Patrick H. Whole-body gallium 67 scans. Role in diagnosis of
sarcoidosis. Am Rev Respir Dis 1991; 144: 11821186.
124. Jarman PR, Whyte MK, Glass DM, Peters AM. Case report: imaging of central nervous system
sarcoidosis with gallium-67 single photon emission computed tomography. Br J Radiol 1996; 69:
192194.
125. Dubey N, Miletich RS, Wasay M, Mechtler LL, Bakshi R. Role of fluorodeoxyglucose positron
emission tomography in the diagnosis of neurosarcoidosis. J Neurol Sci 2002; 205: 7781.
126. Tuisku IS, Konttinen YT, Soinila S, Karma A, Tervo TM. Neurosarcoidosis mimicking Sjogrens
syndrome. Acta Ophthalmol Scand 2004; 82: 599602.
127. Liu DT, Lee VY, Tam PM, Chan WM. Ophthalmology for diagnosis of sarcoidosis. Lancet Neurol
2004; 3: 578.
128. Spaide RF, Ward DL. Conjunctival biopsy in the diagnosis of sarcoidosis. Br J Ophthalmol 1990;
74: 469471.
129. Williams JW. The identification of sarcoid granulomas in the nervous system. Proc Roy Soc Med
1967; 60: 3840.
130. Davis LE, Kornfeld M. Neurocysticercosis: neurologic, pathogenetic, diagnostic and therapeutic
aspects. Eur Neurol 1991; 31: 229240.
131. Pickuth D, Spielmann RP, Heywang-Kobrunner SH. Role of radiology in the diagnosis of
neurosarcoidosis. Eur Radiol 2000; 10: 941944.
132. Fels C, Riegel A, Javaheripour-Otto K, Obenauer S. Neurosarcoidosis: findings in MRI. Clin
Imaging 2004; 28: 166169.
133. Tahmoush AJ, Amir MS, Connor WW, et al. CSF-ACE activity in probable CNS
neurosarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 191197.
134. Oksanen V, Fyhrquist F, Somer H, Gronhagen-Riska C. Angiotensin converting enzyme in
cerebrospinal fluid: a new assay. Neurology 1985; 35: 12201223.
135. Jones DB, Mitchell D, Horn DB, Edwards CR. Cerebrospinal fluid angiotensin converting enzyme
levels in the diagnosis of neurosarcoidosis. Scott Med J 1991; 36: 144145.
136. Rubinstein I, Hoffstein V. Angiotensin-converting enzyme in neurosarcoidosis. Arch Neurol 1987;
44: 249250.
137. Oksanen V, Fyhrquist F, Gronhagen-Riska C, Somer H. CSF angiotensin-converting enzyme in
neurosarcoidosis. Lancet 1985; 1: 10501051.
138. Chan Seem CP, Norfolk G, Spokes EG. CSF angiotensin-converting enzyme in neurosarcoidosis.
Lancet 1985; 1: 456457.
139. Schweisfurth H, Schioberg-Schiegnitz S, Kuhn W, Parusel B. Angiotensin I converting enzyme in
cerebrospinal fluid of patients with neurological diseases. Klin Wochenschr 1987; 65: 955958.
140. Borucki SJ, Nguyen BV, Ladoulis CT, McKendall RR. Cerebrospinal fluid immunoglobulin
abnormalities in neurosarcoidosis. Arch Neurol 1989; 46: 270273.

185
 E. HOITSMA, O.P. SHARMA

141. McLean BN, Mitchell DN, Thompson EJ. Local synthesis of specific IgG in the cerebrospinal
fluid of patients with neurosarcoidosis detected by antigen immunoblotting using Kveim material.
J Neurol Sci 1990; 99: 165175.
142. Scott TF, Seay AR, Goust JM. Pattern and concentration of IgG in cerebrospinal fluid in
neurosarcoidosis. Neurology 1989; 39: 16371639.
143. Juozevicius JL, Rynes RI. Increased helper/suppressor T-lymphocyte ratio in the cerebrospinal
fluid of a patient with neurosarcoidosis. Ann Intern Med 1986; 104: 807808.
144. Oksanen V, Gronhagen-Riska C, Tikanoja S, Somer H, Fyhrquist F. Cerebrospinal fluid lysozyme
and b2-microglobulin in neurosarcoidosis. J Neurol Sci 1986; 73: 7987.
145. Oksanen V. New cerebrospinal fluid, neurophysiological and neuroradiological examinations in
the diagnosis and follow-up of neurosarcoidosis. Sarcoidosis 1987; 4: 105110.
146. Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests of sweating and
autonomic cardiovascular reflexes. Muscle Nerve 1992; 15: 661665.
147. Lacomis D. Small-fiber neuropathy. Muscle Nerve 2002; 26: 173188.
148. Wells CE. The natural history of neurosarcoidosis. Proc R Soc Med 1967; 60: 11721174.
149. James DG. Life-threatening situations in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1998; 15:
134139.
150. Christoforidis GA, Spickler EM, Recio MV, Mehta BM. MR of CNS sarcoidosis: correlation of
imaging features to clinical symptoms and response to treatment. Am J Neuroradiol 1999; 20: 655
669.
151. Walker A, Tyor W. Neurosarcoidosis. Curr Treat Options Neurol 2001; 3: 529535.
152. Schlitt M, Duvall ER, Bonnin J, Morawetz RB. Neurosarcoidosis causing ventricular loculation,
hydrocephalus, and death. Surg Neurol 1986; 26: 6771.
153. Luke RA, Stern BJ, Krumholz A, Johns CJ. Neurosarcoidosis: the long-term clinical course.
Neurology 1987; 37: 461463.
154. Ferriby D, de Seze J, Stojkovic T, et al. Long-term follow-up of neurosarcoidosis. Neurology 2001;
57: 927929.
155. Heck AW, Phillips LH 2nd. Sarcoidosis and the nervous system. Neurol Clin 1989; 7: 641
654.
156. Michotte A, Dequenne P, Jacobovitz D, Hildebrand J. Focal neurological deficit with sudden
onset as the first manifestation of sarcoidosis: a case report with MRI follow-up. Eur Neurol 1991;
31: 376379.
157. Agbogu BN, Stern BJ, Sewell C, Yang G. Therapeutic considerations in patients with refractory
neurosarcoidosis. Arch Neurol 1995; 52: 875879.
158. Zajicek JP, Scolding NJ, Foster O, et al. Central nervous system sarcoidosis diagnosis and
management. QJM 1999; 92: 103117.
159. Selroos O. Treatment of sarcoidosis. Sarcoidosis 1994; 11: 8083.
160. Stern BJ, Schonfeld SA, Sewell C, Krumholz A, Scott P, Belendiuk G. The treatment of
neurosarcoidosis with cyclosporine. Arch Neurol 1992; 49: 10651072.
161. Lower EE, Broderick JP, Brott TG, Baughman RP. Diagnosis and management of neurological
sarcoidosis. Arch Intern Med 1997; 157: 18641868.
162. Doty JD, Mazur JE, Judson MA. Treatment of corticosteroid-resistant neurosarcoidosis with a
short-course cyclophosphamide regimen. Chest 2003; 124: 20232026.
163. Baughman RP, Lower EE. A clinical approach to the use of methotrexate for sarcoidosis. Thorax
1999; 54: 742746.
164. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
165. Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients
with sarcoidosis with neurological involvement. Arch Neurol 1998; 55: 12481254.
166. Pettersen JA, Zochodne DW, Bell RB, Martin L, Hill MD. Refractory neurosarcoidosis
responding to infliximab. Neurology 2002; 59: 16601661.

186
 NEUROSARCOIDOSIS

167. Carter JD, Valeriano J, Vasey FB, Bognar B. Refractory neurosarcoidosis: a dramatic response to
infliximab. Am J Med 2004; 117: 277279.
168. Sollberger M, Fluri F, Baumann T, et al. Successful treatment of steroid-refractory
neurosarcoidosis with infliximab. J Neurol 2004; 251: 760761.
169. Katz JM, Bruno MK, Winterkorn JM, Nealon N. The pathogenesis and treatment of optic disc
swelling in neurosarcoidosis: a unique therapeutic response to infliximab. Arch Neurol 2003; 60:
426430.
170. Morcos Z. Refractory neurosarcoidosis responding to infliximab. Neurology 2003; 60: 12201221.
171. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis
factor a-neutralizing agent. N Engl J Med 2001; 345: 10981104.
172. Opree A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor-a, IL-1b,
and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin
gene-related peptide release from rat skin. J Neurosci 2000; 20: 62896293.
173. Radhakrishnan VV, Sumi MG, Reuben S, Mathai A, Nair MD. Serum tumour necrosis factor-a
and soluble tumour necrosis factor receptors levels in patients with Guillain-Barre syndrome. Acta
Neurol Scand 2004; 109: 7174.
174. Creange A, Belec L, Clair B, Raphael JC, Gherardi RK. Circulating tumor necrosis factor (TNF)-
a and soluble TNF-a receptors in patients with Guillain-Barre syndrome. J Neuroimmunol 1996;
68: 9599.
175. Sommer C, Marziniak M, Myers RR. The effect of thalidomide treatment on vascular pathology
and hyperalgesia caused by chronic constriction injury of rat nerve. Pain 1998; 74: 8391.
176. Schafers M, Geis C, Brors D, Yaksh TL, Sommer C. Anterograde transport of tumor necrosis
factor-a in the intact and injured rat sciatic nerve. J Neurosci 2002; 22: 536545.
177. Empl M, Renaud S, Erne B, et al. TNF-a expression in painful and nonpainful neuropathies.
Neurology 2001; 56: 13711377.
178. Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH. The pivotal role of tumour necrosis factor a in
the development of inflammatory hyperalgesia. Br J Pharmacol 1992; 107: 660664.
179. Menninger MD, Amdur RJ, Marcus RB Jr. Role of radiotherapy in the treatment of
neurosarcoidosis. Am J Clin Oncol 2003; 26: E115E118.
180. Kang S, Suh JH. Radiation therapy for neurosarcoidosis: report of three cases from a single
institution. Radiat Oncol Investig 1999; 7: 309312.
181. Rubinstein I, Gray TA, Moldofsky H, Hoffstein V. Neurosarcoidosis associated with
hypersomnolence treated with corticosteroids and brain irradiation. Chest 1988; 94: 205206.
182. Bejar JM, Kerby GR, Ziegler DK, Festoff BW. Treatment of central nervous system sarcoidosis
with radiotherapy. Ann Neurol 1985; 18: 258260.
183. Bruns F, Pruemer B, Haverkamp U, Fischedick AR. Neurosarcoidosis: an unusual indication for
radiotherapy. Br J Radiol 2004; 77: 777779.
184. Fried ED, Landau AJ, Sher JH, Rao C. Spinal cord sarcoidosis: a case report and review of the
literature. J Assoc Acad Minor Phys 1993; 4: 132137.
185. Hesselmann V, Wedekind C, Terstegge K, et al. An isolated fourth ventricle in neurosarcoidosis:
MRI findings. Eur Radiol 2002; 12: Suppl. 3, S1S3.
186. Foley KT, Howell JD, Junck L. Progression of hydrocephalus during corticosteroid therapy for
neurosarcoidosis. Postgrad Med J 1989; 65: 481484.

187
CHAPTER 12

Clinical aspects of ocular sarcoidosis

K. Ohara*, M.A. Judson#, R.P. Baughman}

*Kichijoji Minamicho Eye Clinic, Minamicho, Kichijoji, Musashino-Shi, Tokyo, Japan. #Division of
Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC, and
}
Division of Pulmonary and Critical Care Medicine, University of Cincinnati Medical Center, Cinicinnati,
OH, USA.

Correspondence: K. Ohara, Kichijoji Minamicho Eye Clinic, 1F, 2-4-12 Minamicho, Kichijoji, Musashino-
Shi, Tokyo 180-0003, Japan. Fax: 81 0422720504; E-mail: k-ohara@s3.dion.ne.jp

Sarcoidosis can involve any part of the eye and may be the major manifestation of the
disease, even leading to severe impairment. It can occur early or late in the disease course,
and may even "pre-date" the disease, since some patients initially diagnosed with
idiopathic uveitis will eventually develop systemic signs of sarcoidosis [1]. Therefore, it is
important that all sarcoidosis patients are evaluated for eye disease and that sarcoidosis
should be considered as the cause of abnormal eye findings.

Epidemiology, risk factors and genetics

The frequency of ocular involvement differs between various reports (table 1) [218].
American and European studies report eye disease in 1050% of sarcoidosis patients and

Table 1. Ocular involvement in sarcoidosis

First Author Year Ethnicity of Ocular involvement/ Percentage Comments

[ref.] majority of total cases
patients studied n
CRICK [4] 1961 English 93/185 50
JAMES [9] 1964 English 123/442 28
SILTZBACH [17] 1974 Worldwide 354/1609 22 Survey of centres around world
JAMES [8] 1976 Worldwide 539/3676 15 Survey of centres around world
OBENAUF [14] 1978 USA 202/532 38
JABS [7] 1986 USA 47/183 26
JAMES [10] 1986 Worldwide 572/5742 10 Survey of centres around world
JAMES [10] 1986 English 224/818 27
KARMA [11] 1988 Finland 79/281 28
ANGI [2] 1991 Italian 69/645 10
FITE [5] 1996 Catalonian 35/245 14
BAUGHMAN [3] 2001 USA, Caucasians 30/393 8 At initial presentation,
part of a larger study
BAUGHMAN [3] 2001 USA, African Americans 55/325 18 At initial presentation,
part of a larger study
PIETINALHO [16] 1996 Finnish 39/571 8 Part of two centre study
PIETINALHO [16] 1996 Japanese 344/686 50 Part of two centre study
IWATA [6] 1976 Japanese 55/70 78
UYAMA [18] 1976 Japanese 87/136 64
NAKAGAWA [13] 1978 Japanese 65/73 89
MIZUNO [12] 1986 Japanese 82/102 80
OHARA [15] 1992 Japanese 126/159 79

Eur Respir Mon, 2005, 32, 188209. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
188
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

include extraocular disorders, such as lacrimal gland enlargement or sicca syndrome.

Reports of Japanese sarcoidosis patients, that mention only eye involvement, found
ocular disease in 6489%. These studies were mostly reported by ophthalmologists. In a
study using standard criteria for diagnosis, ocular disease was ten times more frequent in
Japanese patients versus Finnish patients [16].
The low rate reported in some series may be due to the lack of thoroughness in
examining for ocular disease. Mass screening for sarcoidosis by physicians may result in
a low percentage of ocular involvement if an ophthalmological examination is not
routinely performed. However, there are probably true differences in the prevalence of
eye disease in different populations. To support this contention, Angi et al. [2] used a
diagnostic contact lens and performed a thorough eye examination and still found a low
prevalence of ocular sarcoidosis in an Italian population.
In America, ocular sarcoidosis is more prevalent in Blacks than Whites [3, 19]. In one
study, where a more detailed analysis of specific types of eye disease was performed,
additional racial disparities were identified; anterior uveitis was more common in Black
sarcoidosis patients, whereas posterior uveitis was more common in Whites. In addition,
chronic uveitis was more common in Whites, and was most commonly seen in White
female patients with late onset of systemic disease [19]. In another study examining the
phenotypic features of sarcoidosis at presentation in the USA, ocular disease was more
common in Blacks compared with Whites. It was more common in Black females when
the patient was diagnosed at an age v40 yrs, but more common in Black males if the
patient was aged w40 yrs at presentation [3]. Sarcoidosis eye disease is more common in
patients with the human leukocyte antigen polymorphism DRB1*0401 than in age-, race-
and sex-matched controls, which suggests that there is a genetic basis for this disease
phenotype [20].

Intraocular manifestations of ocular sarcoidosis

General comments
Primary and secondary intraocular manifestations are illustrated in figure 1 and 2.
Among various intraocular lesions, some lesions are selected as primary and significant

Mutton fat
Keratic precipitates
Busacca nodule
Koeppe nodule

Tent-like peripheral
Trabecular nodule anterior synechia

Snow ball or string of

pearls vitreous opacity

Choroidal nodule

Fig. 1. Schema of intraocular manifestation of sarcoidosis. Frontal and sagittal sections are illustrated.

189
 K. OHARA ET AL.

Vascular occlusion Neovascularisation of retina

Cystoid macular
oedema

Perivasculitis
Choroidal nodule

Retinal oedema Neovascularisation

of optic disc

Retinochoroidal exudate
Retinochoroidal atrophy (candle wax)

Fig. 2. Schema of intraocular manifestation of sarcoidosis. Fundus view is illustrated.

and are suggestive of sarcoidosis; their frequency in one series is shown in table 2 [15].
Lesions that are not solely seen in sarcoidosis, but are suggestive of sarcoidosis, include
granulomatous iritis or iridocyclitis, associated with "mutton-fat" keratic precipitates at
the posterior corneal surface (fig. 3), iris nodules at the pupillary margin (Koeppes
nodule; fig. 4) or iris surface (Busacca nodules). Trabecular nodules are also highly
suggestive of sarcoidosis (fig. 5) [6, 12]. Gray nodules are seen at the anterior chamber
angle. Nodules are situated on the trabecular meshwork, which serves as an outlet of the
aqueous humour to regulate intraocular pressure. Frequently, the nodules protrude to
the surface of the ciliary body or iris root. Tent-like peripheral anterior synechia (PAS)
has a conical shape and its conical top adheres to the trabecular meshwork (fig. 6). The
present authors assume that tent-like PAS is a scar and is formed when protruding
trabecular nodules retract the iris upward to the trabeculum. It is also probable that the
nodules in the iris root or ciliary body pull the iris toward the trabeculum [21].
"Snowball" or "string of pearls" type vitreous opacities are known as a sign of
sarcoidosis (fig. 7). The opacities are mostly situated in the inferior vitreous. Some
ophthalmologist feel snowballs form as an intermediate uveitis, a specific condition called
pars planitis [22]. Retinal perivasculitis is frequently found in sarcoidosis. In many cases,
perivasculitis is seen as segmental periphlebitis (fig. 8), and the vascular changes often are
located at the equatorial or peripheral retina (fig. 9). Normally, periphlebitis at the
central retina does not induce retinal exudation. When periphlebitis occludes the venous
circulation, the retinal haemorrhage appears, mimicking branch retinal vein occlusion
[23]. If the occlusion is extensive, neovascularisation, vitreous haemorrhage and

Table 2. Intraocular lesions found in ocular sarcoidosis

Lesions Percentage
Iritis 74
Mutton-fat precipitates# 51
Iris nodules# 30
Trabecular nodules 61
Tent-like peripheral anterior synechia 54
Snowball or string of pearls vitreous opacity 45
Retinal perivasculitis 67
Retinochoroidal patchy exudates 53
#
: Forms of iritis. Adapted from OHARA et al. [15].

190
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

Fig. 3. Slitlamp photograph showing mutton-fat keratic precipitates in granulomatous iritis.

Fig. 4. Slitlamp photograph showing Koeppes nodule in granulomatous iritis.

proliferative vitreoretinopathy follow. Relatively well-defined, discrete chorioretinal

exudates, seen as patchy exudates, are another sign suggestive of sarcoidosis. When
patchy exudates appear along the vein, and if periphlebitis is extensive, their appearance
resembles dripped candle wax (fig. 8). Histopathological studies disclosed intraocular
lesions which consisted of epithelioid cell granulomas [24, 25].

Ocular examination
The ocular examination should include intraocular pressure measurement, the use of a
slitlamp, gonioscopy (using a diagnostic contact lens to see the anterior chamber angle,
peripheral vitreous and retina; fig. 10), and indirect ophthalmoscopy. The slitlamp allows
the anterior inflammation to be seen. It provides binocular vision to perform gonioscopy
so that the anterior chamber angle may be viewed where the characteristic lesions, such
as trabecular nodules and tent-like PAS, are observed. The diagnostic contact lens, under

191
 K. OHARA ET AL.

Fig. 5. Gonioscopic photograph of anterior chamber angle showing trabecular nodules.

Fig. 6. Gonioscopic photograph of anterior chamber angle showing tent-like peripheral anterior synechia
(circled).

higher magnification, also allows the ocular fundus periphery to be examined where
retinal vascular and retinochoroidal exudation frequently occur, suggesting sarcoidosis.
Indirect ophthalmoscopy discloses the central and peripheral retina. Fluorescein fundus
angiography helps to detect subtle vascular leakage, and to see the presence of cystoid
macular oedema, which is a risk factor leading to decreased central vision (fig. 11).

Specific eye findings

Conjunctiva
Sarcoidosis involves the conjunctiva in 640% of cases [7, 14, 2629]. Three-quarters of
cases of conjunctival involvement are present at diagnosis [7]. Conjunctival involvement
is less commonly seen with chronic sarcoidosis [7]. Macroscopic lesions may appear as

192
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

Fig. 7. Snowball (arrow) and a string of pearls-like vitreous opacities (circled).

Fig. 8. Retinal periphlebitis with candle wax drippings (circled).

Fig. 9. Fluorescein angiography showing vascular leakage (circled) and patchy exudation (arrows).

193
 K. OHARA ET AL.

Fig. 10. Gonioscopy using a diagnostic contact lens and slitlamp.

Fig. 11. Typical cystoid macular oedema (circled) shown by fluorescein fundus angiography.

golden fleshy nodules located on the upper as well as lower and forniceal conjunctivae
[30]. These lesions may also be microscopic without evidence of visible lesions. The yield
of conjunctival biopsy (fig. 12) for the diagnosis of sarcoidosis is y33% in unselected
sarcoidosis patients [27, 29] and is unaffected by the presence or absence of uveitis [27].
The diagnostic yield of biopsy may be as high as 67% if conjunctival nodules are present
[29]. It is controversial whether or not blind biopsy of normal-appearing conjunctival
tissue is of value, with one study reporting a yield of 30% [29], while others have found
such biopsies to be fruitless [31, 32]. Recently, it has been suggested that in vivo confocal
microscopy may be useful in the diagnosis of conjunctival sarcoidosis based on a typical
appearance [33]. This technique may also be useful to determine when a conjunctival
biopsy will confirm the diagnosis of sarcoidosis [33].
Anterior uveitis
Anterior uveitis occurs in 2270% of patients [1, 7, 14, 28] and typically presents as an
iritis or iridocyclitis [34]. Symptoms include red eyes, pain, photophobia and blurred

194
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

Fig. 12. Nondirectional biopsy of the conjunctiva at lower conjunctival fornix.

vision. However, in up to 34% of cases, a patient may present without ocular symptoms
(a "quiet eye") [19]. It is for this reason that all patients with sarcoidosis, regardless of the
presence of ocular symptoms, undergo an eye evaluation that includes a slit lamp
examination. Large mutton-fat keratic precipitates, which are small aggregates of
inflammatory cells, are often seen with a gravitational distribution along the middle and
inferior region of the corneal endothelium (fig. 3) [34].
A distinction is usually made between acute and chronic anterior sarcoid uveitis. Some
series find acute anterior sarcoid uveitis more common [7], whereas others find the
opposite [14]. In general, patients with acute anterior sarcoid uveitis tend to be younger,
usually aged 2035 yrs, while those with chronic anterior sarcoid uveitis tend to be aged
3550 yrs [30]. Those with chronic disease tend to have milder eye symptoms. Anterior
chamber cell and flare and anterior vitreous cells can be seen in both acute and chronic
anterior sarcoid uveitis. Busacca nodules, almost exclusively seen with chronic anterior
sarcoid uveitis, are true granulomatous lesions found on the iris and are much less
common than keratic precipitates [30]. Another lesion of chronic anterior sarcoid uveitis
is the Koeppe nodule (fig. 4), which is a granulomatous lesion found only on the
papillary margin, and may become the nidus for the development of posterior synechiae
[30]. Occasionally, patients with chronic anterior sarcoid uveitis will demonstrate lesions
that are pathognomonic of granulomatous uveitis: pink, vascular and opaque iris
granulomas that are larger and much less common than either Busacca or Koeppe
nodules [30]. Chronic anterior sarcoid uveitis can lead to band keratopathy, glaucoma,
and cataract formation. Since corticosteroids (CS) may cause glaucoma and cataracts, it
is sometimes problematic to determine if these sequellae are from the disease or its
treatment.

Intermediate uveitis
Intermediate uveitis, a common manifestation of eye sarcoidosis, is defined as
inflammation of the vitreous, pars plana, and peripheral retina [1, 35]. The pars plana is a
narrow section of the ciliary body. Pars planitis, a subset of intermediate uveitis, results
in cellular accumulations in the vitreous known as "snowballs" (fig. 7). Some cases
demonstrate a unique opacified ridge in the peripheral retina along the pars plana,
especially inferiorly, known as a snowbank [1, 19, 35]. Patients with intermediate uveitis

195
 K. OHARA ET AL.

may be asymptomatic, or may have symptoms of floaters and blurred vision [1, 35].
Intermediate uveitis is not specific for sarcoidosis. It is most commonly idiopathic [19]
but may also be associated with multiple sclerosis and other inflammatory diseases [1,
35].

Posterior uveitis
Up to 28% of patients with eye sarcoidosis have posterior uveitis [14, 34].
Characteristic findings of posterior segment involvement include periphlebitis associated
with segmental cuffing, extensive sheathing and perivenous infiltrates referred to as
"candle wax drippings" or "taches de bouge" (fig. 8) [36]. These lesions may be subclinical
and only visible on fluorescein angiography (fig. 9) [36]. Candle wax drippings are seen
on funduscopic examination in up to 70% of patients with posterior sarcoid uveitis [37],
but they are not pathognomonic [30]. Capillary closure and ischaemia can result in
neovascularisation and vitreous haemorrhage [3740]. Choroidal granulomas are
observed in some cases as cream-colored lesions that may measure more than one
disc diameter [30, 34]. On resolution of the granuloma, an area of pigment epithelial
atrophy or scar may occur [30]. Cystoid macular oedema can result from chronic
inflammation associated with anterior, intermediate, or posterior uveitis [36, 41]. Rare
complications of posterior sarcoid uveitis include retinal detachment, optociliary shunts,
where dilated collateral veins on the optic head connect the central retinal vein to the
choroidal venous plexus, and arterial marcoaneurysms [36].
A major concern is that posterior sarcoid uveitis is associated with neurological
involvement in up to 27% of cases [36]. It is, therefore, imperative that a careful
funduscopic examination should be done on all patients with suspected posterior sarcoid
uveitis to differentiate it from optic nerve disease because of the therapeutic
consequences. In addition, the presence of uveitis and optic neuritis can be seen with
multiple sclerosis.

The differential diagnosis of uveitis

There are many infectious and noninfectious causes of uveitis (table 3). Sarcoidosis is
not a common cause of uveitis in unselected patients. In two separate series, sarcoidosis
was the cause of uveitis in only 2.5 and 12% of cases, respectively [42, 43]. In a third
study, where subjects all lived in south-eastern USA, the frequency of sarcoidosis as the
cause of uveitis was 11% [44]. Even when the Black subgroup in this study was examined,
sarcoidosis was the cause of uveitis in only 25% [44]. Therefore, uveitis of unknown cause
should not be assumed to be from sarcoidosis and appropriate diagnostic steps should be
undertaken to determine the cause.

Table 3. Differential diagnosis of uveitis

Noninfectious causes Infectious

Sarcoidosis Toxoplasmosis
Idiopathic panuveitis HIV/CMV
Spondyloarthropathy Lyme disease
Systemic lupus erythematosis Tuberculosis
Bechets disease Fungi
Wegeners granulomatosis Syphilis
Relapsing polychondritis Herpes simplex virus
CMV: cytomegalovirus.

196
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

Optic neuropathy
Although optic neuropathy from sarcoidosis is rare, it is a feared complication in that
in can rapidly cause permanent vision loss [1, 30]. Patients typically present with a rapid
decrease in vision in one eye [33]. Disturbances in colour perception and contrast
sensitivity may be detected [1]. Optic nerve involvement may be associated with papillitis,
papilloedema secondary to increased intracranial pressure, neovascularisation, and
granulomas of the optic head [30]. Optic atrophy may be the ultimate result of optic
nerve involvement [30]. Optic neuropathy requires systemic therapy. Patients often have
chronic disease and steroid sparing alternatives are commonly used for this condition.

Lacrimal gland
Sarcoidosis involvement of the lacrimal gland occurs in 1528% of patients with
sarcoid eye disease [7, 14]. The rates of asymptomatic lacrimal gland involvement with
sarcoidosis may be much higher, as one retrospective study found that 88% (101/114) of
sarcoidosis patients demonstrated gallium-67 (67Ga) uptake in the lacrimal glands [45].
Although lacrimal gland involvement usually causes no symptoms, some patients
develop keraotconjunctivitis sicca [46]. Enlargement of the lacrimal glands may be
palpable on physical examination and rarely enlargement is so massive that it may cause
proptosis [47]. The diagnosis of sarcoidosis can be made by biopsy of the lacrimal gland.
Biopsy is often considered when the gland is palpable or there is uptake of 67Ga scanning.

Extraocular muscles
Oculomotor nerve palsy can occur from sarcoid involvement of the 3rd, 4th, and 6th
cranial nerves. Although the facial nerve is the most common cranial nerve affected by
sarcoidosis, the 6th cranial nerve is the second most common cranial nerve affected [48
51]. Unilateral involvement is more common, but bilateral involvement can be seen [1].
Rarely, the extraocular muscles may be infiltrated with sarocid granulomas [1, 52]. These
patients usually present with diplopia and associated pain [52]. Magnetic resonance
imaging of the orbits is useful in the evaluation of sarcoidosis-associated ocular motility
abnormalities to distinguish extraocular muscle from cranial nerve involvement [1].

Miscellaneous eye conditions

Scleritis. Scleral involvement is rare in sarcoidosis. In two series of patients with

sarcoidosis eye disease, v3% had scleral involvement [7, 53]. Sarcoidosis scleral
involvement may manifest as diffuse inflammation, a plaque, or nodule (fig. 13) [54]. The
diagnosis may be made by biopsy of a scleral nodule [1].

Orbits. Diffuse orbital inflammation occasionally occurs in sarcoidosis [1]. Orbital

connective tissue involvement is usually unilateral and can result in ptosis, limitations in
extraocular muscle movement, and diplopia [1, 34].

Dacrocystitis. Dacrocystitis (inflammation of the tear duct system) can also occur in
sarcoidosis [1]. Granulomatous inflammation of the tear ducts may impair drainage and
cause painful swelling [1].

Cornea. Four patterns of corneal involvement with sarcoidosis have been noted:
1) inferior corneal thickening; 2) calcific band keratopathy; 3) stromal thinning; and 4)

197
 K. OHARA ET AL.

a)

b)

c)

Fig. 13. a) Scleral lesion due to sarcoidosis. Right eye of a sarcoidosis patient with macular oedema (arrow);
b) before treatment; and c) a year after treatment with infliximab (figs b and c courtesy of M. Drent).

198
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

interstitial keratitis [30]. Inferior corneal thickening is the most common of these
presentations [30]. Corneal band keratopathy, a white band on the cornea, usually causes
no symptoms. It is found in patients with chronic uveitis and is often associated with
hypercalcaemia [1].

Glaucoma. Open angle glaucoma may develop from sarcoidosis when granulomatous
inflammation forms in the trabecular area causing obstruction of the Schlemm canal [21,
43]. To complicate matters, glaucoma may also occur as a result of treatment of
sarcoidosis with CS.

Cataract. Cataracts have been reported in 817% of patients with ocular sarcoidosis [7,
14] and may be attributable to chronic granulomatous inflammation or from
corticosteroid treatment [14].

Common syndromes
Two classic presentations of sarcoidosis are associated with ocular involvement.
Lofgrens syndrome is the association of erythema nodosum and bilateral hilar lymph
adenopathy (BHL) due to sarcoidosis. Arthritis and iritis may be present in Lofgrens
syndrome [55]. Heerfordts syndrome may occur characterised by kerotconjunctivitis
sicca, parotid dysfunction with swelling, facial nerve paralysis and lacrimal gland
dysfunction [30, 56, 57].

Blaus syndrome
Blaus syndrome is an autosomal dominant condition with variable penetration that
consists of granulomatous arthritis, iritis and skin rash [58, 59]. The age of onset is
usually prior to 12 yrs of age [4, 58]. It is considered a separate entity from childhood
sarcoidosis on the basis of lack of visceral (including pulmonary) involvement, absence of
fever or vasculitis, and the mode of inheritance [58]. There appears to be a gene-
environmental interaction that results in the development of the syndrome [60]. The
genetic markers associated with Blaus syndrome were not found in sarcoidosis patients
[61].

The diagnosis of ocular sarcoidosis: general considerations

Sarcoidosis is a systemic granulomatous disease of unknown cause. The diagnosis of
sarcoidosis requires a compatible clinical picture, histological demonstration of
noncaseating granulomas, and exclusion of other diseases capable of producing a
similar histological or clinical picture [62]. Mycobacterial and fungal diseases must
always be considered as alternative diagnoses, regardless of the organ biopsied.
Therefore, stains and cultures for mycobacteria and fungi should be routinely performed
when sarcoidosis is a consideration. Since sarcoidosis is a diagnosis of exclusion, the
diagnosis can never be confirmed with 100% certainty.
The presence of noncaseating granulomas in a single organ does not establish the
diagnosis of sarcoidosis because, by definition, sarcoidosis is a systemic disease that
should involve multiple organs. There are idiopathic granulomatous diseases of
individual organs that are distinguished from sarcoidosis. For example, in the case of
eye disease, idiopathic panuveitis is defined as a granulomatous uveitis confined to the

199
 K. OHARA ET AL.

eye. It may be reclassified as a case of sarcoidosis if clinical features of extraocular disease

consistent with sarcoidosis develop [63].
The present authors define the intraocular lesions listed in table 2, though not
pathognomonic, as highly specific signs of sarcoidosis. Any two of these lesions make the
authors suspect sarcoidosis. Trabecular nodules, tent-like PAS or retinal perivasculitis
are assumed as highly characteristic, and the presence of any of these three makes the
current authors suspect sarcoidosis. The differential diagnosis of these lesions includes
other granulomatous and nongranulomatous diseases, and they must be excluded from
consideration before the diagnosis of sarcoidosis is secure. Behcets disease, although not
granulomatous, sometimes produces intraocular lesions mimicking perivasculitis and
snowball vitreous opacities of sarcoidosis. The recurring Vogt-Koyanagi-Harada
syndrome may show the granulomatous iridocyclitis.
The clinician may be faced with one of three diagnostic challenges concerning
confirming the diagnosis of ocular sarcoidosis: 1) diagnosis by ocular biopsy; 2) diagnosis
when the diagnosis of sarcoidosis has previously been confirmed in an extraocular organ;
and 3) diagnosis by an extraocular biopsy when sarcoidosis has not yet been diagnosed.
These situations will be discussed separately.

Making the diagnosis of ocular sarcoidosis by ocular biopsy

Biopsy of the eye is an invasive procedure. Therefore, it is rarely performed to make a
diagnosis of sarcoidosis. As previously discussed, conjunctival biopsy (fig. 12) has a
reasonable yield for the diagnosis of sarcoidosis if conjuctival nodules are observed [29].
Data is conflicting concerning the utility of a blind conjunctival biopsy for the diagnosis
of sarcoidosis when no macroscopic conjunctival lesion is seen [29, 31, 32]. Lacrimal
gland biopsies have a high yield when the lacrimal gland is palpable or there is uptake of
67
Ga on nuclear scanning. As lacrimal gland uptake on 67Ga scanning may occur in up to
88% of sarcoidosis patients [45], it is reasonable to perform this test when faced with a
patient who would otherwise require a more invasive biopsy for diagnosis.

Making the diagnosis of ocular sarcoidosis in an established

sarcoidosis patient
If the diagnosis of sarcoidosis has been established in an extraocular organ, the
diagnosis of ocular sarcoidosis may be made clinically without performing a biopsy.
Table 4 shows the relationship between finding ocular lesions in patients who present
with either eye or chest manifestations in a Japanese population [15]. Clinical criteria
have been established as part of the A Case Control Etiologic Study of Sarcoidosis
(ACCESS) [64]. Ocular findings consistent with sarcoidosis are listed in table 2. The
frequency of various ocular findings in sarcoidosis in one series is presented in table 2

Table 4. Initial clinical manifestations and intraocular lesions in sarcoidosis

Initial clinical manifestation Intraocular lesion present Intraocular lesion absent Total
Ocular 87 0 87
Chest# 39 33 72
Total 126 (79.2) 33 (20.8) 159 (100)
Data are presented as n or n (%). #: Chest manifestions include bilateral hilar adenopathy or respiratory
symptoms. Adapted from OHARA et al. [15].

200
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

[15]. It is essential to exclude alternative causes for the eye abnormalities before accepting
sarcoidosis as the cause.
The incidence of intraocular involvements was studied in 159 Japanese patients with
systemic sarcoidosis [15]. All patients were Japanese. BHL was found in 153 patients, and
histological diagnosis was made in 148 out of 159 patients (table 4). A total of 87 patients
(54.7%) who presented ocular lesions suggestive of sarcoidosis as an initial manifestation
were diagnosed after a systemic survey. Moreover, 72 patients (45.3%) had chest signs or
symptoms as initial manifestations and were referred to ophthalmic examination during
a diagnostic survey. Of 159 patients, 126 (79.2%) showed intraocular involvements at
diagnosis.
In patients with intraocular involvement, iritis including nongranulomatous iritis was
the most frequent lesion, being seen in 74.7% (table 2). Gonioscopic examinations using
a diagnostic contact lens revealed trabecular nodules and tent-like peripheral anterior
synechia in 61.2% and 54.5% of the patients, respectively. Snowball or string of pearls
vitreous opacities were seen in 45.5%. Retinal perivasculitis and spotty retinochoroidal
exudates were seen in 67.3% and 53.9% of the patients, respectively. High incidence of
anterior uveitis seen as iritis or trabecular lesions was compatible with the incidence
reported in previous studies [6, 12]. Posterior uveitis shown by vitreous opacities,
perivasculitis or retinochoroidal exudates were also frequent in the study.
Age distribution of the patients at diagnosis is shown in figure 14. This figure was
obtained from 169 diagnosed Japanese patients who showed intraocular involvement
[65]. The male/female ratio was 1/1.8. There was one peak at the third decade in male
patients, but there were two peaks in female patients at the third and sixth decades. The
second peak at sixth decade indicates a large number of female ophthalmic patients
showing uveitis as an initial manifestation of sarcoidosis. In a study in America, the
second peak of female patients was also noted. However, the American study
demonstrated a rise in the number of cases in males who were diagnosed with
sarcoidosis after the age of 40 yrs [3].
The data shown in table 2 indicates the presence of intraocular lesions in a significant
number of patients with sarcoidosis. Slight or mild iritis does not necessarily show
symptoms. Without slitlamp examination, iritis may be underdiagnosed. Trabecular
nodules and tent-like PAS cannot be detected without a slitlamp and diagnostic contact

16

12
Patients n

0
10 20 30 40 50 60 70 80
Age decade

Fig. 14. Age and sex distribution of Japanese patients with ocular sarcoidosis at the first visit. %: males; &:
females. Adapted from OHARA et al. [15].

201
 K. OHARA ET AL.

lens. Trabecular nodules are frequently seen in sarcoidosis but they are rarely found in
other uveitis. Trabecular nodules are often associated with a transient intraocular
pressure rise or glaucoma. It was postulated that trabecular nodules, called trabecular
sarcoidosis, and inflammatory lesions in the trabecular meshwork and Schlemms canal
block the aqueous outflow and increase the intraocular pressure [6, 21].

Making the diagnosis of ocular sarcoidosis in an extraocular

organ when the diagnosis of sarcoidosis is not established
Since ocular biopsy is an invasive procedure, it is usually preferable to make the
diagnosis of sarcoidosis in an extraocular organ. In addition, it may be important to
determine if extraocular disease is present, such as to separate idiopathic panuveitis from
sarcoid uveritis. Sarcoidosis should be considered as a potential diagnosis in all patients
with unexplained uveitis or another eye disease that may be a manifestation of
sarcoidosis. Such patents should undergo screening tests for sarcoidosis that should
include a chest radiograph. A complete medical history and physical examination should
be performed, and a further diagnostic work-up should be directed towards any
abnormalities that are detected. For example, if a skin lesion is found on physical
examination, it should be biopsied. Additional diagnostic tests to consider include serum
liver function tests and calcium. Positive results on these tests should prompt a further
diagnostic work-up. A serum angiotensin converting enzyme (ACE) may be obtained;
however, it is neither highly sensitive nor specific for the disease [44, 45]. However, an
elevated serum ACE should prompt a further work-up.
The evaluation is also affected by the underlying frequency of ocular sarcoidosis. For
example, ocular involvement is very common in Japanese sarcoidosis patients (table 1),
therefore, patients with unexplained uveitis are routinely evaluated for sarcoidosis. In
Japan, the diagnosis of ocular sarcoidosis is divided into histological and clinical. The
diagnostic criteria were established by the Research Committee for Diffuse Lung
Diseases (Ministry of Health, Labour and Welfare) in 1989 and were modified in 1997.
Briefly, histological diagnosis is made when clinical findings and/or diagnostic test data
suggestive of sarcoidosis are supported by histological specimen. Clinical diagnosis is
made if clinical findings are supported by the diagnostic test data. The diagnostic test
data require six examinations, including: 1) negative tuberculin skin test; 2) increased
serum c-globulin; 3) increased serum ACE; 4) increased serum lysozyme; 5) positive 67Ga
scan; and 6) positive bronchoalveolar lavage fluid (BAL). Clinical diagnosis is made only
if more than three of these six diagnostic test data are positive including either 1) or 3).
The most common scenario is that sarcoidosis eye disease will present in association
with an abnormal chest radiograph, as was reported in w92% (187/202) of ocular
sarcoidosis patients in one series [14]. The yield of bronchoscopy for the diagnosis of
sarcoidosis in patients with suspected eye involvement has been reported in several series.
Ohara et al. [65] has performed prospectively transbronchial lung biopsy (TBLB) in
60 patients of ocular sarcoidosis suspects who showed no BHL and sparse contributory
data. The patients had a combination of the six intraocular lesions shown in table 2. The
TBLB specimen showed noncaseating epithelioid granuloma in 37 patients (61.7%), and
the patients were diagnosed as having systemic sarcoidosis. There was no difference in
ocular manifestations between TBLB positive and negative patients. BAL data indicate
there were a significant number of patients with an increased percentage of lymphocytes
in TBLB-positive patients, but no difference was observed regarding the patients with an
increased ratio of CD4z/CD8z between TBLB-positive and negative patients. The data
support the present authors assumption that the six intraocular manifestations described

202
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

are highly characteristic to sarcoidosis. Increase in the percentage of lymphocytes and

CD4z/CD8z ratio in patients with negative TBLB indicates a subclinical alveolitis and
suggests these patients might have sarcoidosis at the cellular level, not forming
granuloma yet. Others have found BAL fluid lymphocytosis useful in supporting the
diagnosis [66]. However, an increase in BAL fluid lymphocytes and increased CD4z/
CD8z ratio has been found in idiopathic uveitis [67] with no cases demonstrating
systemic sarcoidosis during a prolonged follow-up period. However, these patients may
still have sarcoidosis.
In a separate group of 39 ophthalmic Japanese patients suggesting ocular sarcoidosis,
Takahashi et al. [68] performed high-resolution computed tomography (HRCT) of the
chest, BAL and TBLB to study the clinical relevance of lymphocytosis in BAL fluid for
the diagnosis of ocular sarcoidosis (table 5). HRCT was used to assess lung involvement,
and to compare the validity of lymphocytosis in BAL fluid and HRCT. There were 12
male and 27 female patients, and 21 of them were aged w40 yrs. All patients underwent
examination of serum ACE and serum lysozyme level, tuberculin skin test, chest
radiograph and 67Ga scintigram. The patients were divided into groups according to
HRCT findings: no involvement (HRCT-0; n=13), BHL without lung involvement
(HRCT-I; n=6), BHL and lung involvement (HRCT-II; n=20), and no BHL but lung
involvement (HRCT-III; n=0).
A total of 20 patients were histologically diagnosed as having sarcoidosis by TBLB,
and 19 patients remained undiagnosed. TBLB was positive in 19 out of 20 patients in the
HRCT-II group, but in one out of 19 patients in the HRCT-0 and HRCT-I group
(table 5; pv0.0001). Lymphocytosis (w15%) in BAL was identified in 16 out of 19
patients in the HRCT-0 and HRCT-I group and in all patients in the HRCT-II group.
Percentages of patients having increased CD4z/CD8zratios (w3.5) was not significantly
different among groups of HRCT-0, HRCT-I, and HRCT-II. Takahashi et al. [68]
concluded that HRCT yield was similar to TBLB regarding the degree of diagnostic
accuracy. BAL revealed significant lymphocytosis in patients with negative pulmonary
involvement in HRCT. TBLB-negative patients with an increased lymphocytosis might
suggest the presence of patients with sarcoidosis who manifest the disease clinically by
ocular involvements and subclinically by lymphocytosis of the lung. It may be possible
that the patients with negative TBLB and positive lymphocytosis in BAL are at the pre-
granulomatous stage, and they may disclose intrathoracic or other manifestations after
many years following the initial investigational study [63]. However, the lymphocytosis
may not be associated with sarcoidosis [67].
Analysis of the T-lymphocyte CD4z/CD8z ratio in cells recovered from induced
sputum has been examined in 17 patients with uveitis, 10 patients with sarcoidosis but
without uveitis, and five normal controls [69]. All subjects with a CD4z/CD8z ratio of
w2.5 and undiagnosed uveitis had sarcoidosis. The concentration of ACE in tears has
been found to be elevated in sarcoidosis patients [70]. However, the utility of this test for
the diagnosis of sarcoidosis is unknown.
Table 5. High-resolution computer tomography (HRCT) classification of the chest and results of
transbronchial Lung Biopsy (TBLB) and bronchoalveolar lavage (BAL) in ocular sarcoidosis patients

HRCT Patients TBLB positive BAL fluid BAL fluid lymphocyte

classification# n for granulomas lymphocytes w15% CD4z/CD8z ratio w3.5
0, I 19 1 16/19 11/16
II 20 19} 20/20 16/20
#
: HRCT classification: 0=no involvement, I=bilateral hilar adenopathy without lung involvement, II=bilateral hilar
involvement and lung involvement; }: differs significantly from classification 0, I (pv0.0001). Adapted from
TAKAHASHI et al. [68].

203
 K. OHARA ET AL.

Treatment
The primary lesions in table 2, if they are slight or mild, do not necessarily cause
deterioration of vision. Most visual deterioration is caused by secondary changes to
primary lesions, or when the inflammation is severe and extensive.
CS are the mainstay treatment of ocular sarcoidosis. Anterior uveitis (iritis) is treated
with eye drops. When iritis is severe and does not respond to eye drops, subconjunctival
injection of CS may suppress the inflammation. Mydriatics are always instilled to
suppress the inflammation and to avoid posterior synechia (adhesion of the iris to the
lens). Intraocular pressure should be monitored during the course of the disease, because
CS can induce intraocular pressure rise. Trabecular nodules, frequently seen without
signs of anterior segment inflammation, also induce pressure rise and glaucoma.
Systemic CS (prednisolone or prednisone at 40 mg?day-1 and tapered over 612
months) are indicated if anterior uveitis is severe and it does not respond to local CS.
Systemic CS are also given to simultaneous inflammation of anterior and posterior
segments of the eye (panuveitis), mild-to-severe vitreous opacity, extensive retinal
oedema, extensive perivasculitis with or without vascular occlusion, optic disc changes,
and cystoid macular oedema. Cystoid macular oedema (fig. 11) appears secondary to
intraocular inflammation, and is a principal cause of visual deterioration. Side-effects of
systemic CS are always monitored. Table 6 summarises the various areas of involvement
of 18 patients with chronic ocular sarcoidosis [41], demonstrating that chronic patients
often have multiple eye lesions.
Due to the toxicity of systemic CS, CS-sparing alternatives have been used in
sarcoidosis. Methotraxate is a steroid-sparing agent used for many chronic inflammatory
eye conditions. It has been reported as useful in chronic uveitis. In a series of 160 patients
with chronic uveitis due to various conditions, methotrexate was effective in 76% of the
cases [71]. In a study of 11 patients with sarcoidosis associated uveitis, Dev et al. [72]
found that the drug worked in 10 cases. In a retrospective analysis of 56 sarcoidosis
patients treated at one institutiton, two-thirds of the patients responded after i6 months
of methotrexate therapy (fig. 15). Of the 21 patients who did not respond to
methotrexate, only six responded to azathioprine as a single agent [73].
Leflunomide is a another cytotoxic agent which has a similar effect as methotrexate. It
has been reported that it was useful in treating 23 out of 28 (82%) chronic sarcoidosis-
associated eye conditions [74]. In rheumatoid arthritis, methotrexate plus leflunomide
has been shown to be superior to methotrexate alone [75]. In sarcoidosis-associated eye
diseases, 12 out of 15 cases responded to the combination therapy [74].
The new anti-tumour necrosis factor (TNF) agents have been studied in sarcoidosis.
Etanercept, a TNF receptor antagonist, was studied in a randomised, double-blind trial of
chronic ocular sarcoidosis. All patients had been treated with i6 months of methtotrexate

Table 6. Areas of eye involvement in patients with chronic ocular sarcoidosis

Manifestation Number
Total patients 18
Anterior uveitis 16
Posterior uveitis 5
Pars planitis 7
Vitreous 7
Retinal vasculitis 3
Cystoid macular oedema 2
Optic neuritis 2
Adapted from BAUGHMAN et al. [41].

204
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

Chronic ocular sarcoidosis

treated with methotrexate
n=56

Responded to methotrexate No response to methotrexate

n=35 (63%) n=21 (37%)

Azathioprine therapy
n=21

Responded to azathioprine No response to azathioprine

n=6 (29%) n=15 (71%)

Fig. 15. Clinical outcome of 56 patients with chronic ocular sarcoidosis treated with methotrexate. Of the
original group, 63% responded to methotrexate alone. All patients who did not respond to methotrexate were
then treated for i6 months with azathioprine. Only six out of the 21 patients responded to azathioprine as a
single agent [73].

but still had active disease. There was no difference in the response rate between the
etanercept and placebo groups [41]. In a study of chronic uveitis of all causes, Foster et al.
[76] placed patients on either etanercept or placebo and then withdrew the methotrexate.
The rate of relapse was the same in the etanercept and placebo group. Others have noted
that uveitis can occur while patients are receiving etanercept [77].
Infliximab is a monoclonal antibody directed against TNF. It has been reported as
useful in treating chronic uveitis in patients with Crohns disease, rheumatoid arthritis,
Behcets disease and idiopathic uveitis [7780]. In a study of seven cases of chronic ocular
sarcoidosis, all responded to infliximab [80]. This latter study included three patients
who had not responded to etanercept. Figure 13b and c are photographs from another
patient who received infliximab.
Figure 16 shows the visual outcome of 129 patients with intraocular involvements. The
outcome was generally favourable, but 7.3% of eyes resulted in visual deterioration with
visual acuity of v0.1 after 5 yrs [15]. In another study, 17 out of 106 eyes (16%) had a
visual acuity of v0.1 [81]. The major causes of visual deterioration were a history of

90
80
70
Number of eyes %

60
50
40
30
20
10
0
~0.1 ~0.5 ~0.8 ~2.0
Visual acuity
Fig. 16. Visual outcome of 129 sarcoidosis patients with intraocular involvements at various intervals. The
outcome was generally favourable but 7.3% of eyes resulted in visual acuity of v0.1 after 5 yrs. %: initial; &:
1 yr; &: v5 yrs; &: w5 yrs. Adapted from OHARA et al. [15].

205
 K. OHARA ET AL.

glaucoma, uncontrollable glaucoma during the course and treatment, cataract, vitreous
opacities, and macular degeneration due to cystoid macular oedema. Surgical treatment
can prevent blindness due to cataract. A preliminary report demonstrated that the
vitreous opacities and cystoid macular oedema were surgically treated successfully by
vitrectomy [82]. Vitrectomy is also used for proliferative vitreoretinopathy, and the
mechanisms and effectiveness of this surgical approach in long-lasting sarcoidosis may be
further elucidated.

Conclusion
Ocular disease is an important manifestation of sarcoidosis. While the incidence varies
among different sarcoidosis groups, all patients should have a specific ocular
examination [62]. Untreated ocular sarcoidosis can lead to cataracts, glaucoma, and
even blindness. Therapy is usually successful. The use of the cytotoxic and anti-cytokine
therapies is still under investigation. However, they hold great promise in reducing the
amount of CS used for chronic ocular sarcoidosis.

Summary
Ocular involvement is seen in a significant number of patients with sarcoidosis.
Involvement is more common in Japanese patients, where over half the sarcoidosis
patients have ocular disease. In Europe, up to one-third of patients may be affected.
Since eye disease may be silent, a detailed examination of the eye is strongly
recommended on all sarcoidosis patients. The most common ocular manifestation is
uveitis, but any portion of the eye may be affected.
In some cases, inflammation can be controlled by local therapy usually topical
steroids. When systemic therapy is needed, corticosteroids are usually effective.
However, the ocular toxicity of corticosteroids includes glaucoma and cataract
formation. For chronic ocular disease, there has been interest in use of methotrexate
and other cytotoxic agents.

Keywords: Corticosteroids, diagnosis, eye, lacrimal gland, ocular, sarcoidosis,

treatment, uveitis.

References
1. Bradley DA, Baughman RP, Raymond L, Kaufman AH. Ocular manifestations of sarcoidosis.
Sem Respir Crit Care Med 2002; 23: 543548.
2. Angi MR, De Caro G, Bergamo L, Scala P, Pucci V, Secchi AG. Low prevalence of uveitis in
Italian sarcoidosis patients. Sarcoidosis 1991; 8: 181182.
3. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control
study of sarcoidosis. Am J Respir Crit Care Med 2001; 164: 18851889.
4. Crick PP, Hoyle C, Smellie H. The eye in sarcoidosis. Br J Ophthalmol 1961; 45: 461481.
5. Fite E, Alsina JM, Mana J, Pujol R, Ruiz J, Morera J. Epidemiology of sarcoidosis in catalonia:
19791989. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13: 153158.
6. Iwata K, Nanba K, Sobue K, Abe H. Ocular sarcoidosis: Evaluation of intraocular findings. Ann
N Y Acad Sci 1976; 278: 445454.

206
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

7. Jabs DA, Johns CA. Ocular involvement in chronic sarcoidosis. Am J Opthalmol 1986; 102: 297
301.
8. James DG, Neville E, Siltzbach LE. A worldwide review of sarcoidosis. Ann N Y Acad Sci 1976;
278: 321334.
9. James DG, Anderson D, Langley D, Ainslie D. Ocular sarcoidosis. Br J Ophthalmol 1964; 48: 461
470.
10. James DG. Ocular sarcoidosis. Ann N Y Acad Sci 1986; 465: 551563.
11. Karma A, Huhti E, Poukkula A. Course and outcome of ocular sarcoidosis. Am J Ophthalmol
1988; 106: 467472.
12. Mizuno K, Takahashi J. Sarcoid cyclitis. Ophthalmology 1986; 93: 511517.
13. Nakagawa Y, Matsumoto K, Mimura Y, Yuasa T. Ophthalmological observation of sarcoidosis.
Nihon Ganpa Kiyo (Folia Ophthalmolgica Japonica) 1978; 29: 20092012.
14. Obenauf CD, Shaw HE, Sydnor CF, Klintworth GK. Sarcoidosis and its opthalmic
manifestations. Am J Opthalmol 1978; 86: 648655.
15. Ohara K, Okubo A, Sasaki H, Kamata K. Intraocular manifestations of systemic sarcoidosis. Jpn
J Ophthalmol 1992; 36: 452457.
16. Pietinalho A, Ohmichi M, Lofroos AB, Hiraga Y, Selroos O. The prognosis of sarcoidosis in
finland and hokkaido, Japan. A comparative five-year study of biopsy-proven cases. Sarcoidosis
Vasc Diffuse Lung Dis 2000; 17: 158166.
17. Siltzbach LE, James DG, Neville E, et al. Course and prognosis of sarcoidosis around the world.
Am J Med 1974; 57: 847852.
18. Uyama M, Ohkuma M, Asayama K, Hyashi M, Okinami S, Ueno S. Clinical pictures of sarcoid
uveitis. Nihon Ganpa Kiyo (Folia Ophthalmolgica Japonica) 1976; 27: 170177.
19. Rothova A, Alberts C, Glasius E, Kijlstra A, Buitenhuis HJ, Breebaart AC. Risk factors for ocular
sarcoidosis. Doc Ophthalmol 1989; 72: 287296.
20. Rossman MD, Thompson B, Frederick M, et al. HLA-DRB1*1101: a significant risk factor for
sarcoidosis in blacks and whites. Am J Hum Genet 2003; 73: 720735.
21. Hamanaka T, Takei A, Takemura T, Oritsu M. Pathological study of cases with secondary open-
angle glaucoma due to sarcoidosis. Am J Ophthalmol 2002; 134: 1726.
22. Kaufman AH, Foster CS. Cataract extraction in patients with pars planitis. Opthalmology 1993;
100: 12101217.
23. Ohara K, Okubo A, Sasaki H, Kamata K. Branch retinal vein occlusion in a child with ocular
sarcoidosis. Am J Ophthalmol 1995; 119: 806807.
24. Gass JD, Olson CL. Sarcoidosis with optic nerve and retinal involvement. Arch Ophthalmol 1976;
94: 945950.
25. Usui Y, Kaiser D, Kaiser E, See RF, Rao NA, Sharma OP. Update of ocular manifestations of
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 167175.
26. Karma A. Opthalmic changes in sarcoidosis. Acta Opthalmolagia 1979; 141: Suppl., 194.
27. Khan F, Wessley Z, Chazin SR, Seriff NS. Conjuctival biopsy in sarcoidosis. Annals of
Opthalmology 1977; 9: 671676.
28. Smith JA, Foster CS. Sarcoidosis and its ocular manifestations. Internat Ophthalmol Clin 1996;
36: 109125.
29. Spaide RF, Ward DL. Conjunctival biopsy in the diagnosis of sarcoidosis. Br J Ophthalmol 1990;
74: 469471.
30. Mayers M. Ocular sarcoidosis. Int Ophthalmol Clin 1990; 30: 257263.
31. James DG. Ocular sarcoidosis. Am J Med 1959; 26: 331339.
32. Crick R, Hoyle C, Mather G. Conjunctival biopsy in sarcoidosis. BMJ 1955; 4949: 11801181.
33. Wertheim MS, Mathers WD, Suhler EB, Wilson DJ, Rosenbaum JT. Histopathological features
of conjunctival sarcoid nodules using noninvasive in vivo confocal microscopy. Arch Ophthalmol
2005; 123: 274276.
34. Silver MR, Messner LV. Sarcoidosis and its ocular manifestations. J Am Optom Assoc 1994;
65: 321327.

207
 K. OHARA ET AL.

35. Boyd SR, Young S, Lightman S. Immunopathology of the noninfectious posterior and
intermediate uveitides. Surv Ophthalmol 2001; 46: 209233.
36. Rothova A. Ocular involvement in sarcoidosis. Br J Ophthalmol 2000; 84: 110116.
37. Spalton DJ. Fundus changes in sarcoidosis. Review of 33 patients with histological confirmation.
Trans Ophthalmol Soc UK 1979; 99: 167169.
38. Raymond LA, Spaulding AG, Vilter RW. Peripheral retinal neovascularization in sarcoidosis with
thalassemia. Ann Ophthalmol 1978; 10: 745748.
39. Steahly LP. Sarcoidosis and peripheral neovascularization. Ann Ophthalmol 1988; 20: 426427,
430.
40. Duker JS, Brown GC, McNamara JA. Proliferative sarcoid retinopathy. Ophthalmology 1988;
95: 16801686.
41. Baughman RP, Lower EE, Bradley DA, Raymond LA, Kaufman AH. Etanercept for refractory
sarcoidosis: results of a double blind randomized trial. Chest 2005; (In press).
42. Islam SM, Tabbara KF. Causes of uveitis at the eye center in saudi arabia: a retrospective review.
Ophthalmic Epidemiol 2002; 9: 239249.
43. Merayo-Lloves J, Power WJ, Rodriguez A, Pedroza-Seres M, Foster CS. Secondary glaucoma in
patients with uveitis. Ophthalmologica 1999; 213: 300304.
44. Merrill PT, Kim J, Cox TA, Betor CC, McCallum RM, Jaffe GJ. Uveitis in the Southeastern
United States. Curr Eye Res 1997; 16: 865874.
45. Sulavik SB, Palestro CJ, Spencer RP, Swyer AJ, Goldsmith SJ, Tierstein AS. Extrapulmonary sites
of radiogallium accumulation in sarcoidosis. Clin Nucl Med 1990; 15: 876878.
46. Rothova A. Posterior segment involvement in sarcoidosis. Ohno S, Aoki K, Usui M, Uchio E, eds.
Uveitis today. Amsterdam, Elsevier, 1998; pp. 207210.
47. Sacher M, Lanzieri CF, Sobel LI, Som PM. Computed tomography of bilateral lacrimal gland
sarcoidosis. J Comput Assist Tomogr 1984; 8: 213215.
48. Stern BJ, Krumholz A, Johns C, Scott P, Nissim J. Sarcoidosis and its neurological manifestations.
Arch Neurol 1985; 42: 909917.
49. Lower EE, Broderick JP, Brott TG, Baughman RP. Diagnosis and management of neurologic
sarcoidosis. Arch Intern Med 1997; 157: 18641868.
50. Zajicak JP, Scolding NJ, Foster O, et al. Central nervous system sarcoidosis - diagnosis and
management. Q J Med 1999; 92: 103117.
51. Oksanen V. Neurosarcoidosis: Clinical presentations and course in 50 patients. Acta Neurol Scand
1986; 73: 283290.
52. Constantino T, Digre K, Zimmerman P. Neuro-ophthalmic complications of sarcoidosis. Semin
Neurol 2000; 20: 123137.
53. Stavrou P, Foster CS. Diagnosis and treatment of uveitis. Foster CS, Vitale AT, eds. Diagnosis
and treatment of uveitis, 1st Edn. Philadelphia, WB Saunders, 2002; pp. 710725.
54. Qazi FA, Thorne JE, Jabs DA. Scleral nodule associated with sarcoidosis. Am J Ophthalmol 2003;
136: 752754.
55. Mana J, Gomez Vaquero C, Montero A, et al. Lofgrens syndrome revisited: a study of 186
patients. Am J Med 1999; 107: 240245.
56. Glocker FX, Seifert C, Lucking CH. Facial palsy in heerfordts syndrome: Electrophysiological
localization of the lesion. Muscle Nerve 1999; 22: 12791282.
57. James DG, Sharma OP. Parotid gland sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17: 27
32.
58. Manouvrier-Hanu S, Puech B, Piette F, et al. Blau syndrome of granulomatous arthritis, iritis, and
skin rash: a new family and review of the literature. Am J Med Genet 1998; 76: 217221.
59. Pastores GM, Michels VV, Stickler GB, Su WP, Nelson AM, Bovenmyer DA. Autosomal
dominant granulomatous arthritis, uveitis, skin rash, and synovial cysts. J Pediatr 1990; 117: 403
408.
60. Chamaillard M, Philpott D, Girardin SE, et al. Gene-environment interaction modulated by allelic
heterogeneity in inflammatory diseases. Proc Natl Acad Sci USA 100: 34553460.

208
 CLINICAL ASPECTS OF OCULAR SARCOIDOSIS

61. Rybicki BA, Maliarik MJ, Bock CH, et al. The blau syndrome gene is not a major risk factor for
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 203208.
62. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
sarcoidosis. SarcoidosisVasc Diffuse Lung Dis 1999; 16: 149173.
63. Foster CS. Ocular manifestations of sarcoidosis preceding systemic manifestations. Grassi C,
Rizzato G, Pozzi E, eds. Sarcoidosis and other granulomatous disorders. Amsterdam, Excerpta
Medica, 1988; pp. 177181.
64. Judson MA, Baughman RP, Teirstein AS, Terrin ML, Yeager H Jr, and the ACCESS Research
group. Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. Sarcoidosis
Vasc Diffuse Lung Dis 1999; 16: 7586.
65. Ohara K, Okubo A, Kamata K, Sasaki H, Kobayashi J, Kitamura S. Transbronchial lung biopsy
in the diagnosis of suspected ocular sarcoidosis. Arch Ophthalmol 1993; 111: 642644.
66. Bienfait MF, Hoogsteden HC, Baarsma GS, Adriaansen HJ, Verheijen-Breemhaar L. Diagnostic
value of bronchoalveolar lavage in ocular sarcoidosis. Acta Ophthalmol (Copenh) 1987; 65: 745
748.
67. Jouveshomme S, Fardeau C, Finet JF, et al. Alveolar lymphocytosis in patients with chronic
uveitis: Relationship to sarcoidosis. Lung 2001; 179: 305317.
68. Takahashi T, Azuma A, Abe S, Kawanami O, Ohara K, Kudoh S. Significance of lymphocytosis
in bronchoalveolar lavage in suspected ocular sarcoidosis. Eur Respir J 2001; 18: 515521.
69. Neudorfer M, Leibovitch I, Onn A, Loewenstein A, Fireman E. Induced sputum for identifying
sarcoidosis in patients with uveitis. Ophthalmology 2002; 109: 858861.
70. Immonen I, Friberg K, Sorsila R, Fyhrquist F. Concentration of angiotensin-converting enzyme
in tears of patients with sarcoidosis. Acta Ophthalmol (Copenh) 1987; 65: 2729.
71. Samson CM, Waheed N, Baltatzis S, Foster CS. Methotrexate therapy for chronic nonifectious
uveitis: Analysis of a case series of 160 patients. Ophthalmology 2001; 108: 11341139.
72. Dev S, McCallum RM, Jaffe GJ. Methotrexate for sarcoid-associated panuveitis. Ophthalmology
1999; 106: 111118.
73. Baughman RP, Lower EE, Bradley DA, Kaufman AH. Use of cytotoxic therapy for chronic
opthalmic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: Suppl., 17.
74. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
2004; 21: 4348.
75. Kremer JM, Caldwell JR, Cannon GW, et al. The combination of leflunomide and methotrexate in
patients with active rheumatoid arthritis who are failing on methotrexate treatment alone: a
double-blind placebo controlled study. Arthritis Rheum 2000; 43: S224.
76. Foster CS, Tufail F, Waheed NK, et al. Efficacy of etanercept in preventing relapse of uveitis
controlled by methotrexate. Arch Ophthalmol 2003; 121: 437440.
77. Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor
inhibition in the management of inflammatory eye disease and associated rheumatic disease.
Arthritis Rheum 2001; 45: 252257.
78. Joseph A, Raj D, Dua HS, Powell PT, Lanyon PC, Powell RJ. Infliximab in the treatment of
refractory posterior uveitis. Ophthalmology 2003; 110: 14491453.
79. Sfikakis PP, Theodossiadis PG, Katsiari CG, Kaklamanis P, Markomichelakis NN. Effect of
infliximab on sight-threatening panuveitis in behcets disease. Lancet 2001; 358: 295296.
80. Baughman RP, Bradley DA, Lower EE. Infliximab for chronic ocular inflammation. Int J Clin
Pharmacol Ther 2005; 43: 711.
81. Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS. Prognosticators for visual outcome in
sarcoid uveitis. Opthalmology 1996; 103: 18461853.
82. Kiryu J, Kita M, Tanabe T, Yamashiro K, Miyamoto N, Ieki Y. Pars plana vitrectomy for cystoid
macular edema secondary to sarcoid uveitis. Ophthalmology 2001; 108: 11401144.

209
CHAPTER 13

Sarcoidosis: joint, muscle and bone

involvement

T.L.Th.A. Jansen*, P.P.M.M. Geusens#

*Medical Centre Leeuwarden, Dept of Rheumatology, Leeuwarden, and #University Hospital Maastricht,
Dept of Rheumatology, Sarcoidosis Management Center, Maastricht, The Netherlands and Biomedical
Research Institute, University Hasselt, Belgium.

Correspondence: T.L.Th.A. Jansen, Medical Centre Leeuwarden, Dept of Rheumatology, POB 888, 8901
BR Leeuwarden, The Netherlands. E-mail: t.jansen@znb.nl

Sarcoidosis is a multisystem granulomotous disease in which multiple organs,

including the locomotor system, may be involved [15]. Osteoarticular manifestations of
sarcoidosis may be specific or nonspecific. They may be the presenting feature or may
occur late after onset, either isolated or combined with other clinical manifestations.
Clinical features of joint involvement are found in 14% of cases at presentation, and up to
38% during follow-up [5]. The frequency of clinical muscle and bone involvement at
presentation is low (v1%), and is found in 513% of patients during follow-up [5].
Locomotor involvement is often subclinical or not clinically recognised because of mild
or unspecific symptoms in spite of a high prevalence on biopsy, as shown for muscle
involvement [6]. Another systemic locomotor sequel is secondary osteoporosis, mostly
due to glucocorticoid therapy [1].

Sarcoid joint involvement

Joint manifestations, including arthritis and periarthritis, occur in 1438% of patients
[15]. Arthralgias are even more common (70%) [5]. Sarcoid rheumatic involvement is
generally divided into acute and chronic types [15]. There are so many differences
between acute and chronic arthritis that is has been questioned whether they represent
the same aspects of sarcoid joint disease [2].

Acute sarcoid arthritis

The most common form of joint involvement is an acute polyarthritis/periarthritis.
The arthritis may be migratory, intermittent or additive in time, and can precede other
manifestations of sarcoidosis by several months. These clinical presentations can,
therefore, resemble reactive arthritis [7], rheumatoid arthritis or even spondylarthro-
pathies [3]. More commonly, however, it is nonmigratory and accompanied by other
signs of sarcoidosis [5], known as the Lofgrens syndrome [79].
Classically, Lofgrens syndrome consists of a triad with bilateral hilar lymphadeno-
pathy, erythema nodosum and (peri)arthritis of large joints, particularly of the ankles
and knees, although other peripheral large and small joints can be involved [79]. This
presentation of acute sarcoidosis most frequently occurs in Caucasian females and is rare
in Afro-Americans [2]. Fever and other constitutional symptoms commonly accompany
Eur Respir Mon, 2005, 32, 210219. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
210
 RHEUMATIC PRESENTATIONS IN SARCOIDOSIS

acute sarcoid arthritis. Seasonal variation of acute sarcoid arthritis has been reported
with clustering in the spring [7, 9].
In a series of 186 Spanish patients with Lofgrens syndrome, 93% had erythema
nodosum and/or periarticular ankle inflammation at onset [9, 10]. At the time of
diagnosis 81% had no respiratory symptoms. In contrast, 81% had stage I abnormalities
on chest radiography, 16% stage II and 3% stage 0. Sonographic findings in 24
consecutive cases revealed joint effusion consistent with arthritis in 33%, periarthritis in
80% and a tenosynovitis in 33% patients [11].
Prognostically, Lofgrens syndrome is not recurrent in the majority of cases. In 17
cases followed prospectively over 2 yrs, the total duration of arthritis was 11 weeks
(range 2107 weeks) and erythema nodosum was mild and transient [7]. Of the 133
patients who were followed for a mean of almost 5 yrs, 8% continued to have active
disease and 6% had several recurrences between 18 months and 20 yrs after complete
resolution, although usually with mild organ dysfunction [9]. Thus, acute sarcoidosis
classified as Lofgrens syndrome has a favourable prognosis, except in Afro-Americans
and Asians [2]. Prolonged monitoring is necessary where prognosis is not so good.
Clinical features of acute or subacute monoarthritis, other than Lofgrens syndrome,
are only rarely reported [2]. Synovial fluid is inflammatory, with predominance of
lymphocytes [2]. Synovial or soft tissue biopsies can reveal granulomatous lesions [2].
There may be protracted courses and recurrences of arthritis [2].

Chronic sarcoid arthritis

Chronic sarcoid articular involvement is rare and appears to affect only 0.2% of
sarcoid patients [12, 13], usually together with other complications of sarcoidosis,
particularly chronic cutaneous sarcoidosis [3] and in Black patients [2, 3]. Medium-sized
and large joints are often affected symmetrically and a simulataneous tenosynovitis may
occur. Some cases have been described with severe destructive arthropathy requiring
total arthroplasty [14]. Synovial biopsy shows noncaseating granulomas. In some cases,
rheumatoid arthritis may be suspected, particularly when there is a coincident
rheumatoid factor, occurring in y30%. The course of chronic sarcoid arthritis is
characterised by periodic exacerbation and improvement with a good functional
outcome [2]. However, joint destruction or deformities may be seen, including Jaccouds
type arthropathy [2].
In children, a chronic juvenile arthritis may be mimicked by combination of
polyarthritis, uveitis and skin lesions [15]. A positive synovial biopsy may help establish
the diagnosis.

Sarcoid synovial and tendinous involvement

Periarticular manifestations appear much more commonly than previously thought, in
some reports in w60% of patients [2, 16, 17]. Tenosynovitis, articular cysts or infiltration
of subcutaneous tissue causing elephant foot-like thickening have been reported [17].
Tenosynovitis usually affects extensor tendons of the fingers more often than flexor
tendons, but carpal tunnel syndrome may also manifest itself [2]. Biopsy of synovium,
tendon sheaths or subcutaneous tissue may reveal noncaseating granulomas.
Some bone locations, such as dactylitis and sacroiliac location, are associated with
clinical and/or radiographic signs of joint involvement. These are further described in the
section on sarcoid bone involvement (see later).

211
 T.L.TH.A. JANSEN AND P.P.M.M. GEUSENS

Treatment of sarcoid joint involvement

In cases of acute sarcoid arthritis, most frequently it is sufficient to give cold packs
t.i.d. with a training programme combined with nonsteroidal anti-inflammatory drugs
(NSAIDs) (table 1) [2]. The outcome of articular involvement is generally favourable as
recovery is uneventful, generally within 16 months [2]. According to open label studies,
sarcoid arthritis has also been treated efficaciously by systemic glucocorticoids and
colchicine (oral or i.v.) [12]. Periarthritis is often responsive to rest, cold application and
NSAIDs, whereas glucocorticoids are generally not needed nor recommended.
A chronic destructive synovitis may need treatment with glucocorticoids intra-
articularly or systemically, and, in the latter case, is probably best combined with
methotrexate or azathioprine, though firm evidence from randomised controlled trials is
lacking [15]. Possibly, there is an indication for an anti-tumour necrosis factor (TNF)-a
strategy in selective cases with chronic destructive arthritis in the near future.
In children, a much more aggressive treatment is needed, often comprising of a
combination of glucocorticoids with immunosuppressants [15].

Sarcoid muscular involvement

There are several reasons why some patients with sarcoidosis develop muscle
problems, including involvement of the skeletal muscle by sarcoidosis, steroid-induced
myopathy, small fibre neuropathy and reduced physical activity.
Sarcoid muscle involvement is usually asymptomatic and resolves spontaneously,
although granulomas are commonly demonstrated by biopsy in 5080% of sarcoid cases
[6]. In a group of 29 sarcoid patients who spontaneously complained of fatigue, skeletal
muscle weakness was found that was associated with reduced health status and exercise
intolerance [18]. Gallium scintigraphy is considered the main method that can
demonstrate muscular involvement [19]. In some cases magnetic resonance imaging
(MRI) can be helpful for diagnosis, but small lesions can be overlooked [2].
Rarely, acute inflammatory myopathy resembling polymyositis, as well as palpable
myopathic nodules and a chronic progressive myopathy, have been described [6, 2023].
The latter myopathic type occurs predominantly in elderly females with a painful
bilateral involvement and often results in muscle weakness, atrophy and even muscle
contracture [23].
The rarest type is the acute sarcoid myositis, as is reported in 18 cases [20, 22]. This is
usually found in younger patients with proximal muscle weakness mimicking acute
polymyositis.
The diaphragm and intercostal muscles may also be impaired. It has been
demonstrated that patients with sarcoid granulomas infiltrating skeletal muscle had
Table 1. Treatment options in sarcoidosis with locomotor complaints

Analgesics Nonsteroidals Corticoid local Corticoid p.o.

Arthralgia zzz z - -
Myalgia zzz z - -
Arthritis z zzz zz z#
Enthesitis zzz zz z z/-
Myositis z zz - zzz#
Periostalgia zzz zzz - -
Osseous involvement zz zz - -#
zzz: highly indicated;zz: indicated;z: may be tried; -: not indicated. #: disease modifier should be considered.

212
 RHEUMATIC PRESENTATIONS IN SARCOIDOSIS

impaired respiratory muscle function [18, 24]. With a lack of a correlation between
subjective symptoms, i.e. exertional dyspnoea and/or fatigue, and chest radiograph
abnormalities, lung function may be explained by respiratory muscle impairment. The
relevance of inspiratory muscle impairment in sarcoid patients is underscored by
significant correlations found between dyspnoea scores and health status and quality of
life [2527]. In addition, it has been shown that small fibre neuropathy is a frequent
finding of sarcoid patients with fatigue [28].

Treatment of sarcoid muscle involvement

There are currently no studies available on the treatment of sarcoid muscle
involvement. In severe cases, glucocorticoids and immunosuppressive drugs are given
(table 1). For patients with muscle weakness, controlled physical training programmes
are advocated, as shown in other conditions [17, 29].

Sarcoid bone involvement

In 1928, Jungling described osteitis tuberculosa multiplex cystica with an estimated
incidence of 113%, the variation depending on radiological or clinical criteria [30]. Bone
involvement occurs between the ages of 3050 yrs and is more frequent in Blacks. It is
rarely a presenting feature (in v1% of patients) [5] and usually occurs in patients known
to have sarcoidosis with multisystemic involvement, in chronic pulmonary or
multivisceral sarcoidosis and in patients with chronic skin lesions, especially lupus
pernio [1]. Bone lesions are mainly seen in the bones of hands and feet, but other
locations, such as the skull, nasal bones and vertebrae, have been described. They are
usually asymptomatic, but may be painful, and, in case of severe lesions, adjacent joints
can be involved [3]. Radiological findings most frequently show cystic lesions, punched-
out lesions, osteolysis, reticularisation of cortical bone or cortical defects and, rarely,
sclerotic, periostitis or destructive lesions [4, 3133].
Biopsy reveals granulomas in the medullary cavity and destruction of the adjacent
bone tissue [3133]. Thereby confluent lacunae and cavities of varying sizes surrounded
by normal bone may occur. Margins may reveal subsequent sclerosis. Granulomatous
tissue may affect the periosteum and may invade neightbouring soft tissue.
Histomorphometry has shown increased bone resorption in the vicinity of intramedul-
lary sarcoid nodules, probably due to local mediators [4].
On technetium bone scanning an increased uptake is seen, suggesting, or sometimes
mimicking, neoplastic lesions [2]. To differentiate these from sarcoid lesions additional
imaging may be needed. Computed tomography (CT) scanning shows bone destruction
or sclerosis, particularly marginally, without extra-osseous mass or extension to soft
tissues. MRI scanning shows nonspecific lesions with a reduced signal on T1, and
increased signal on T2-weighted sequences, enhanced by Gadolinium. The combination
of these features does not preclude a neoplastic or infectious condition [2]. There is no
indication for routine radioisotope bone scanning in patients with sarcoidosis, and this
examination should be restricted to patients with clinical suspicion of osseous sarcoidosis
[34].

Dactylitis
Involvement of fingers, particularly 2nd and 3rd digits, and less frequently of toes, is
the most frequent bone manifestation [4]. Dactylitis may be asymptomatic but may also

213
 T.L.TH.A. JANSEN AND P.P.M.M. GEUSENS

cause moderate pain and stiffness. Distal phalangeal swellings are associated with purple-
violet, cyanotic discolouration, and splitting of nails or nail dystrophy. Acro-osteolysis
may give the appearance of pseudo-clubbing or sausage-like fingers [33].

Pelvic pathology
Involvement of the pelvis is featured by bony sclerosis, sometimes with lytic lesions
and surrounding condensation. In the majority of patients it is symptomatic, i.e. painful
[4]. A genuine sacroiliitis is rare, and in the literature this is reported only once [4].
Sacroiliac pathology is considered to be secondary to confluencing bone lesions of
sacrum and ilium. Such localisation cannot be established without a biopsy to rule out
tuberculosis or other infectious processes of that joint [4].

Skull
Lesions of the vault of the skull are rare. Less than 30 cases have been reported [35].
The incidence may be underestimated, as symptoms generally are absent or only minor,
such as headache or local swelling. Bony lacunae vary in size and localisation.
Radiographs show osteolysis of full thickness of the skull without peri-lesional
condensation. Cases of partial or complete regression, both spontaneous or with
treatment, have been described. Involvement of the base and of other cranial bones, i.e.
sinus, petrous bones, orbits, mandible, and nasal bone, seems to be found more
frequently with the widespread use of facial CT scans [4].

Vertebrae
Involvement of the spine is rare [4]. Complaints are manifested by a mechanical spinal
pain associated with stiffness, affecting the lumbar and lower dorsal spine in the majority
of patients. Neurological compression is rare, but may be the consequence of cervical
lesions. Radiographs generally reveal osteolytic features of vertebral body or pedicle but
occur with peripheral condensation, vertebral compression and lesions of the laminae
reminiscent of spondylodiscitis, particularly as there is sometimes a false paravertebral
spindle image associated with lesions of the ganglia [4]. Generally, there is no disc space
narrowing. Some cases of ivory or pseudo-pagetic vertebrae have been reported [4].

Treatment of sarcoid bone involvement

Sarcoid bone involvement responds poorly to glucocorticoids as well to other drugs
(table 1) [4]. Symptomatic relief may be obtained by NSAIDs, colchicine and
chloroquine [4].

Calcium metabolism and osteoporosis in sarcoidosis

Hypercalcaemia and hypercalciuria. Hypercalcaemia affects 10% of sarcoid patients.
Hypercalciuria is reported in 50% of cases and is associated with nefrolithiasis,
occurring in y1% of sarcoid cases. Hypercalcaemia is caused by increased extra-renal
production of 1,25 dihydroxyvitamin D3 by activated macrophages in the sarcoid
granulomas. Whether hypercalcaemia and hypercalciuria in sarcoidosis are risk factors
for osteoporosis is unknown. The aetiology, symptoms and treatment of hypercalcaemia
and hypercalciuria are described in Chapter 14.

214
 RHEUMATIC PRESENTATIONS IN SARCOIDOSIS

Osteoporosis
In addition to localised bone lesions due to sarcoid granulomas, generalised bone loss
has been described in sarcoid patients [3640]. The aetiology of osteoporosis is
multifactorial. In sarcoid patients, specific risk factors for osteoporosis include the
frequent use of glucocorticoids, hypercalcemia and hypercalciuria and their treatment
modalities (low calcium intake), and decreased physical activity. However, the relative
importance of these risk factors in relation to osteoporosis has not been evaluated
specifically in sarcoidosis. No data are available on fracture risk in sarcoidosis. However,
chronic use of glucocorticoids is associated with an increased fracture risk.
Only two studies reported bone mineral density (BMD) in untreated sarcoidosis [36,
37]. In 18 untreated pre-menopausal females, BMD was normal in the spine and in the
femoral neck, but in five post-menopausal females, BMD was lower in the spine and
marginally lower in the femoral neck [36]. In another study, 36 patients with untreated
sarcoidosis had a normal mean BMD, as measured by quantitative CT scanning (qCT),
and BMD was lowest in long-standing disease [37].
Many patients with sarcoidosis are treated with glucocorticoids. Long-term treatment
with glucocorticoids results in suppression of bone formation, accelerated bone loss and an
increased risk of fractures [38]. Studies specifically studying the effects of glucocorticoids in
sarcoidosis are also scarce. In a study of African-Americans with sarcoidosis, low BMD
was common, comparable to chronic obstructive pulmonary disease and was associated
with low body mass index (BMI) [39]. Using qCT, bone loss of 15% was found after 2 yrs,
and was even greater in post-menopausal females (-26% after 2 yrs) [40].

Prevention and treatment of glucocorticoid-induced osteoporosis in sarcoidosis

As always, the patients individual risk factors should be carefully reviewed when
initiating glucocorticoid therapy [41]. Factors that influence bone loss and fracture risk
include the dose of glucocorticoids, the underlying condition and the presence of other risk
factors, such as increasing age, sex, low BMI, previous personal and familial fracture, low
calcium intake, vitamin D deficiency (low sun exposition and/or low intake), low physical
activity, smoking, excessive alcohol consumption, menopausal status, hypogonadism in
males, decreased general health status and low BMD. These factors should be considered in
all patients that are anticipated to have treatment with glucocorticoids. An example of risk
calculation in glucocorticoid-treated patients is available and was based on age, sex, BMI,
dose of glucocorticoids, smoking, past fracture, past fall and underlying disease [42]. These
risk factors allowed calculation of the individual fracture risk. A female aged 65 yrs, with
low BMI, a previous history of fracture and falls, treated with 15 mg glucocorticoids q.d.
(total risk score 54) had a 5-yr fracture risk of 45%. A male with a similar history would
have a comparable fracture risk of 29% [42].
Many guidelines are available on the prevention and treatment of glucocorticoid
osteoporosis in patients that are expected to be, or already are, on long-term (w3 months)
glucocorticoid treatment [43]. As an example, an algorithm of the Dutch guidelines is
shown in figure 1 [44]. Bone measurement is not considered necessary in high-risk
patients (taking w15mg?day-1 of glucocoricoids, having a prevalent vertebral fracture,
taking intermediate doses of glucocorticoids (7.515 mg?day-1) together with having
other major risk factors (post-menopausal females, elderly males)). In such patients,
treatment with bisphosphonates is indicated, irrespective of BMD values. In other cases,
bone measurement in the hip and/or spine using dual X-ray absorptiometry is
recommended in all patients who are expected to take glucocorticoids forw3 months and
in patients who are on long-term glucocorticoid treatment. If BMD is then found to be

215
 T.L.TH.A. JANSEN AND P.P.M.M. GEUSENS

Start glucocorticoids

General advice
Cave: calcium and vitamin D

Dose and fracture history

High dose Low dose
(>15 mgday-1) Intermediate dose (<7.5 mgday-1)
or (7.515 mgday-1)
fracture Post-menopausal females Pre-menopausal females
males aged >70 yrs males aged <70 yrs
DXA
Radiograph
Start spine
High 13 yr
bisphosphonate risk Low risk

Fig. 1. Prevention of glucocorticoid osteoporosis in sarcoidsis. DXA: dual X-ray absorptiometry. Adapted
from [43].

low (e.g. a T-score of v-1.0), treatment with bisphosphonates should be considered. If

BMD is normal (T-scorew-1.0), measurements should be repeated after 612 months and
then at yearly intervals [44].
In addition, a radiograph of the spine is advocated when vertebral fractures are
suspected (in the presence of thoracic hyperkyphosis, height loss of w2 cm, an occiput-
wall distance of w0 cm or a rib-pelvis distance of v2 finger breadths) [45].
Proposed general measures in chronic glucocorticoid users include lifestyle changes,
such as good nutrition, cessation of smoking, moderate alcohol intake, appropriate
physical activity, exercise, maximal reduction of glucocorticoid dose, consideration of
alternative formulations or routes of administration, and prescription of alternative
immunosuppressive agents [41].
The use of calcium and vitamin D supplements, as advocated in all guidelines [43],
should in the case of sarcoidosis only be considered when calcium homeostasis is normal
(normal serum calcium and normal calciuria).
The use of long-term hormonal therapy in post-menopausal females is currently
controversial, since the results of the Womens Health Initiative Study indicated that the
advantages of hormonal therapy in post-menopausal females are less than the
disadvantages (risk for cardiovascular events and breast cancer) [46].
In sarcoid patients treated with glucocorticoids, salmon calcitonin (by nasal spray in
11 patients or intramuscular injection in 18 patients) over 2 yrs stabilised BMD in the
spine (measured by qCT) [47]. However, calcitonin is not recommended in most
guidelines or is only proposed as an alternative in case of contraindications or intolerance
for bisphosphonates [43].
Alendronate was studied over 1 yr in 15 sarcoid patients treated with glucocorticoids.
Alendronate stabilised BMD in the ultradistal radius (measured by dual photon
absorptiometry) [48]. Potent bisphosphonates (alendronate and risedronate) are
recommended for the prevention of glucocorticoid osteoporosis (fig. 1) [41, 44]. Fracture
reduction in glucocorticoid-induced osteoporosis (GIOP) has been shown (as a
secondary endpoint) in studies with alendronate and risedronate [49, 50]. It is advocated
that therapy with bisphosphonates to prevent or treat GIOP should last as long as
glucocorticoids are used [41, 44]. After stopping glucocorticoids, further treatment is
only indicated if the risk for osteoporotic fractures remains high, based on clinical risk
factors and BMD [43]. Many patients with sarcoidosis are of a young age. The use of

216
 RHEUMATIC PRESENTATIONS IN SARCOIDOSIS

bisphosphonates should be limited in pre-menopausal females of childbearing age, as

bisphosphonates have a long half-life and as the effects of bisphosphonates on foetal
bone growth are unknown.

Coexistent sarcoid involvement mimicking autoimmune disease

If salivary and/or lacrimal glands are affected by sarcoidosis, the clinical picture of
Sjogrens syndrome, an autoimmune disorder resulting in dryness of primarily the eyes
and mouth, is mimicked [51]. About a dozen of cases with sarcoidosis and Sjogrens
syndrome have been reported. In a series of 464 primary Sjogrens patients, only five met
criteria of coexistent sarcoidosis (1%). During long-term follow-up, five patients had
extra-glandular manifestations: four had a nonerosive polyarthritis and one a vasculitis
[51]. As the frequency of sarcoidosis in the population is in the range of 1080 per
100,000, the frequency of sarcoidosis in Sjogrens patients is y500-times higher than
in the normal population. In patients with sarcoid gland involvement, low-dose
corticosteroids induced regression of lymphadenopathy, but the sicca symptoms
remained together with anti-SSA and/or anti-SSB auto-antibodies [51].

Conclusions
Sarcoidosis is a multisystemic disease, with a wide spectrum of clinical presentation. It
can present with locomotor signs and symptoms, ranging from asymptomatic organ
involvement to overt clinical presentation in joints, muscles and bones, and from an acute
to a chronic condition. There are indications that symptomatic and immunosuppressive
therapies can be effective for some of the locomotor involvements, but clearly more data
are needed, especially with the availability of biologicals such as anti-TNF medications.
As many patients are treated with glucocorticoids, special attention is required for
prevention of glucocorticoid-induced osteoporosis, with general measures and potent
bisphosphonates necessary for patients at risk.

Summary
Sarcoidosis is a granulomatous systemic disease potentially involving the locomotor
system. The most common presentation is acute sarcoidosis in Lofgrens syndrome.
Alternative manifestations include chronic articular involvement, synovial and
tendinous involvement, muscular complications, and bone involvement, such as
dactylitis, pelvic pathology, skull abnormalities and spinal problems. Systemic
involvements may reflect coexistent autoimmune disease and disturbed calcium
metabolism resulting in osteopenia or osteoporosis.
Corticosteroids are commonly used to treat more serious cases, but may result in
additional risks of osteoporosis, which may currently be counteracted by bispho-
sphonates. Modern treatment options seem to be efficacious in chronic sarcoid
inflammation due to the ability to block tumour necrosis factor. However, further
studies are needed, specifically in the field of locomotor presentations of sarcoidosis.

Keywords: Arthritis, bone metabolism, dactylitis, glucocorticoids, myositis,

osteoporosis, sarcoidosis, tendonitis.

217
 T.L.TH.A. JANSEN AND P.P.M.M. GEUSENS

References
1. Barnard J, Newman LS. Sarcoidosis: immunology, rheumatic involvement, and therapeutics. Curr
Opin Rheumatol 2001: 8491.
2. Awada H, Abi-Karam G, Fayad F. Musculoskeletal and other extrapulmonary disorders in
sarcoidosis. Best Pract Res Clin Rheumatol 2003: 971987.
3. Pettersson T. Rheumatic features of sarcoidosis. Curr Opin Rheumatol 1998: 7378.
4. Wilcox A, Bharadwaj P, Sharma OP. Bone sarcoidosis. Curr Opin Rheumatol 2000: 321330.
5. West SG, Kotzin BL. Sarcoidosis. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME,
Weisman MH, eds. Rheumatology, 3rd Edn. Edinburgh, Mosby Elsevier, 2003; pp. 17351752.
6. Silverstein A, Siltzbach LE. Muscle involvement in sarcoidosis. Arch Neurol 1969; 21: 235241.
7. Glennas A, Kvien TK, Melby K, et al. Acute sarcoid arthritis: occurrence, seasonal onset, clinical
features and outcome. Br J Rheumatol 1995; 34: 4550.
8. Lofgren S, Lundback H. The bilateral hilar lymphoma syndrome. A study of the relation to age
and sex in 212 cases. Acta Med Scand 1952; 142: 259264.
9. Mana J, Gomez-Vaquero C, Montero A, et al. Lofgrens syndrome revisited: a study of 186
patients. Am J Med 1999: 107245.
10. Mana J, Gomez-Vaquero C, Salazar A, et al. Periarticular ankle sarcoidosis : a variant of Lofgren
syndrome. J Rheumatol 1996; 23: 874877.
11. Kellner H, Spathling S, Herzer P. Ultrasound findings in Lofgrens syndrome: is ankle swelling
caused by arthritis, tenosynovitis or periarthritis? J Rheumatol 1992; 19: 3841.
12. Torralba KD, Quismorio FP. Sarcoid arthritis: a review of clinical features, pathology and
therapy. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 95103.
13. James DG, Neville E, Carstairs LS. Bone and joint sarcoidosis. Semin Arthritis Rheum 1976; 6: 5381.
14. Sokoloff L, Bunim JJ. Clinical and pathological studies of joint involvement in sarcoidosis. N Engl
J Med 1959; 260: 841847.
15. Hafner R, Vogel P. Sarcoidosis of early onset. A challenge for the pediatric rheumatologist. Clin
Exp Rheumatol 1991; 11: 685691.
16. Lofgren S. Primary pulmonary sarcoidosis. I. Early signs and symptoms. Acta Med Scand 1953;
145: 424431.
17. James DG, Thompson AD, Wolcox A. Erythema nodosum as a manifestation of sarcoidosis.
Lancet 1956; 271: 218221.
18. Spruit MA, Thomeer MJ, Gosselink R, et al. Skeletal muscle weakness in patients with
sarcoidosis and its relationship with exercise intolerance and reduced health status. Thorax 2005;
60: 3238.
19. Otake S, Ishigaki T. Muscular sarcoidosis. Semin Musculoskelet Radiol 2001; 5: 167170.
20. Ost D, Yeldani A, Cugell D. Acute sarcoid myositis with respiratory muscle involvement. Chest
1995; 107: 879882.
21. Rizzato G, Montermurro L. The locomotor system. In: James DG, ed. Sarcoidosis and other
granulomatous disorders. New York, Marcel Dekker 1994; pp. 343373.
22. Jamal MM, Circursu AM, Hoffman EL. Sarcoidosis presenting as acute myositis. Report and
review of the literature. J Rheumatol 1988; 15: 18681871.
23. Kidd D, Beynon HLC. The neurological complications of systemic sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2003; 20: 8594.
24. Baydur A, Pandya K, Sharma OP, Kanel GC, Carlson M. Control of ventilation, respiratory
muscle strength, and granulomatous involvement of skeletal muscle in patients with sarcoidosis.
Chest 1993; 103: 396402.
25. Wirnsberger RM, Drent M, Hekelaar N, et al. Relationship between respiratory muscle function
and quality of life in sarcoidosis. Eur Respir J 1997; 10: 14501455.
26. Baydur A, Alsalek M, Louie SG, Sharma OP. Respiratory muscle strength, lung function and
dyspnea in patients with sarcoidosis. Chest 2001; 120: 102108.

218
 RHEUMATIC PRESENTATIONS IN SARCOIDOSIS

27. Brancaleone P, Perez T, Robin S, Neviere R, Wallaer B. Clinical impact of inspiratory muscle
impairment in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 219227.
28. Hoitsma E, Faber CG, Drent M, Sharma OP. Neurosarcoidosis: a clinical dilemma. Lancet Neurol
2004; 3: 397407.
29. Costabel U. Skeletal muscle weakness, fatigue and sarcoidosis. Thorax 2005; 60: 12.
30. Krause A, Goebel KM. Class II MHC antigen (HLA-DR3) predisposes to sarcoid arthritis. J Clin
Lab Immunol 1987; 24: 2527.
31. Sartoris DJ, Resnick D, Resnik C, Yaghmai I. Musculoskeletal manifestations of sarcoidosis.
Semin Roentgenol 1985; 20: 376386.
32. Perlman SG, Damergis J, Witorsch P, Cooney FD, Gunther SF, Barth WF. Vertebral sarcoidosis
with paravertebral ossification. Arthritis Rheum 1978; 21: 271276.
33. McBrine CS, Fisher MS. Acrosclerosis in Sarcoidosis. Radiology 1975; 115: 279281.
34. Milman N, Lund JO, Graudal N, Enevoldsen H, Evald T, Norgard P. Diagnostic value of routine
radioisotope bone scanning in a series of 63 patients with pulmonary sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2000; 17: 6770.
35. Horusitsky A, Dumont D, Valeyre D, et al. Osteoarticular manifestations of sarcoidosis.
Rheumatology in Europe 1998; 108111.
36. Sipahi S, Tuzun S, Ozaras R, et al. Bone mineral density in women with sarcoidosis. J Bone Miner
Metab 2004; 22: 4852.
37. Montemurro L, Fraioli P, Rizzato G. Bone loss in untreated longstanding sarcoidosis. Sarcoidosis
1991; 8: 2934.
38. Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci 2002; 966:
7381.
39. Adler RA, Funkhouser HL, Petkov VI, Berger MM. Glucocorticoid-induced osteoporosis in
patients with sarcoidosis. Am J Med Sci 2003; 325: 16.
40. Montemurro L, Fraioli P, Riboldi A, Delpiano S, Zanni D, Rizzato G. Bone loss in prednisone
treated sarcoidosis: a two-year follow-up. Ann Ital Med Int 1990; 5: Suppl. 3 Pt 1, 164168.
41. Sambrook PN. How to prevent steroid induced osteoporosis. Ann Rheum Dis 2005; 64: 176178.
42. van Staa TP, Geusens P, Pols HA, de Laet C, Leufkens HG, Cooper C. A simple score for estimat-
ing the long-term risk of fracture in patients using oral glucocorticoids. QJM 2005; 98: 191198.
43. Geusens PP. Review of the guidelines for osteoporosis. Current osteoporosis reports 2003; 5965.
44. Geusens PP, de Nijs RN, Lems WF, et al. Prevention of glucocorticoid osteoporosis: a consensus
document of the Dutch Society for Rheumatology. Ann Rheum Dis 2004; 63: 324325.
45. Green AD, Colon-Emeric CS, Bastian L, Drake MT, Lyles KW. Does this woman have
osteoporosis? JAMA 2004; 292: 28902900.
46. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in
healthy postmenopausal women: principal results From the Womens Health Initiative
randomized controlled trial. JAMA 2002; 288: 321333.
47. Montemurro L, Schiraldi G, Fraioli P, et al. Prevention of corticsteroid-induced osteoporosis with
salmon calcitonin in sarcoid patients. Calcif Tissue Int 1991; 49: 7176.
48. Gonnelli S, Rottoli P, Cepollaro C, et al. Prevention of corticosteroid-induced osteoporosis with
alendronate in sarcoid patients. Calcif Tissue Int 1997; 61: 382385.
49. Adachi JD, Saag KG, Delmas PD, et al. Two-year effects of alendronate on bone mineral density
and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-
controlled extension trial. Arthritis Rheum 2001; 44: 202211.
50. Wallach S, Cohen S, Reid DM, et al. Effects of risedronate treatment on bone density and
vertebral fracture in patients on corticosteroid therapy. Calcif Tissue Int 2000; 67: 277285.
51. Gal I, Kovacs J, Zeher M. Case series: coexistence of Sjogrens syndrome and sarcoidosis. J
Rheumatol 2000; 27: 25072510.

219
CHAPTER 14

Renal sarcoidosis and hypercalcaemia

O.P. Sharma

Correspondence: O.P. Sharma, Room 11-900, Los Angeles County-University of Southern California
Medical Center, 1200 North State Street, Los Angeles, CA 90033, USA. Fax: 1 3232262728; E-mail:
osharma@usc.edu

Although the kidneys are infrequently involved in sarcoidosis, physicians involved in

taking care of sarcoidosis patients need to be aware of this possibility in order to
diagnose and treat this dangerous disorder before it causes serious damage. Sarcoidosis
may either involve the kidneys directly or cause renal failure secondary to
hypercalcaemia, hypercalciuria and nephrocalcinosis.
Hypercalcaemia is an important complication of sarcoidosis. It is caused by
overproduction of 1,25-dihydroxyvitamin D3 (calcitriol or calcitriol) by activated
macrophages and the granulomatous tissue. Calcitriol, in turn, causes increased absorption
of calcium from the gut. Hypercalcaemia is not specific to sarcoidosis as it is found in other
granulomatous, as well as nongranulomatous, disorders, including tuberculosis,
coccidioidomycosis, histoplasmosis, leprosy and Wegeners granulomatosis.

Renal sarcoidosis
Incidence
Clinically manifest renal involvement is rare in sarcoidosis [13]. In A CaseControl
Etiologic Study of Sarcoidosis (ACCESS), clinical involvement of the kidneys was
observed in only 0.7% of patients (table 1) [4], although as many as 20% of patients with
sarcoidosis show granulomas in the kidneys [58]. Autopsy studies in Japanese patients
reveal an incidence of 26% [9]. Bergener et al. [10] diagnosed 46 patients with sarcoidosis
between 1995 and 2002. Fifteen (32%) of these patients exhibited renal abnormalities, of
whom 10 underwent kidney biopsy. Six patients exhibited nephrocalcinosis, of whom
two showed granulomatous interstitial nephritis, one interstitial nephritis without
granuloma and one immunoglobulin (Ig) A glomerulonephritis. In two patients, they
found a combination of granulomatous interstitial nephritis with either nephrocalcinosis
or IgA glomerulonephritis. Renal involvement was present only in patients with chronic
Table 1. Organ involvement in sarcoidosis

First author Scope Organ involvement %

[Ref.]
Lungs Skin EN LN/ Eye Liver NS Cardiac Spleen Ca2z Renal
(chronic) spleen metab
SILTZBACH [1] World 87 9 17 28 NA NA 4 NA NA 11 NA
JAMES [3] UK# 88 18 34 39 27 10 9 3 12 18 1
BAUGHMAN [4] ACCESS 95 15.9 8.3 11.8 11.5 8.3 4.6 2.3 4.6 3.7 0.7
EN: erythema nodosum; LN: lymph node; NS: nervous system; metab: metabolism; ACCESS: A CaseControl
Etiologic Study of Sarcoidosis; NA: not available. #: Royal Northern Hospital, London, UK (now closed).

Eur Respir Mon, 2005, 32, 220232. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
220
 RENAL SARCOIDOSIS AND HYPERCALCAEMIA

sarcoidosis, whereas patients with Lofgrens syndrome showed no renal involvement [10].
The renal involvement may be the initial manifestation of sarcoidosis, may appear during
the course of the illness or follow the onset of the disease after many years. Occasionally,
chronic hypercalcaemia or nephrolithiasis may be the only presenting feature of renal
sarcoidosis [11].

Diagnosis
The criteria for establishing the diagnosis of sarcoidosis are: 1) compatible clinical or
radiographic evidence of multisystemic involvement; 2) histological evidence of
noncaseating granuloma (fig. 1); and 3) negative results from special stains, cultures
and serological studies for other entities (e.g. absence of acid-fast bacilli or fungi in
sputum, body fluids or tissue biopsy specimens; negative complement fixation test results
for coccidioidomycosis, histoplasmosis and brucellosis; and negative PCR for Whipples
disease) [12]. A diagnosis based on only one of these features is misleading since clinical
or radiological manifestations present too wide a spectrum of differential diagnoses,
whereas noncaseating granulomas may be caused by bacteria, fungi, viruses and chemical
agents. Occasionally, lymphoma and malignancy can also generate a granulomatous
reaction [13].

Clinical features
Renal disease in sarcoidosis may be divided into the following clinical categories
(table 2).

Granulomatous interstitial nephritis. Although 20% of patients with sarcoidosis may

show granulomas in the kidneys, development of the clinical syndrome of granulomatous
interstitial nephritis is unusual. Utas et al. [14] described a patient who had developed
mild proteinuria. Creatinine clearance was 60 mL?min-1, renal biopsy showed typical
noncaseating granulomas with normal glomeruli, chest radiography and gallium scan
results were normal, and the patient exhibited uveitis. Thus, the patient most probably
had sarcoidosis. Nevertheless, in a review of 1,010 renal biopsy procedures, Schwarz

Fig. 1. Renal biopsy specimen showing noncaseating granulomas with many multinucleate giant cells
(haematoxylineosin stain).

221
 O.P. SHARMA

Table 2. Types of renal involvement in sarcoidosis

Granulomatous interstitial nephritis
Glomerulonephritis
IgA nephropathy (Bergers disease and glomerular disease)
Renal cell carcinoma
Granulomatous vasculitis or renal angiitis
Nephrocalcinosis and nephrolithiasis
Ig: immunoglobulin.

et al. [15] found only six instances of granulomatous interstitial nephritis, all of which were
caused by drugs; none were related to sarcoidosis. In another study of 76 cases of
granulomatous nephritis, drugs were the main causative agent [16].
Marie et al. [17] described a 60-yr-old male with diffuse joint pains, albuminuria and
haematuria. Serum angiotensin-converting enzyme (SACE) and autoantibody screening
results were normal. A renal biopsy specimen showed interstitial and granulomatous
nephritis; direct immunofluorescence and Ziehl-Nelson test results were negative.
Abdominal and thoracic computed tomography, echocardiography, and accessory
salivary gland and duodenum biopsy results were normal. Despite corticosteroid therapy,
the patients renal function and general condition deteriorated. Biopsy of the ileum
revealed the changes of Whipples disease, and PCR analysis of ribosomal RNA
demonstrated the presence of Tropheryma whipplei [17]. This patient not only showed no
clinical or radiological evidence of sarcoidosis but also failed to respond to corticosteroids.
This unusual presentation necessitated further evaluation, which confirmed the presence of
a rare illness. This case shows that, if all of the criteria recommended for diagnosing
sarcoidosis are not met, a diagnostic error is likely to appear.
Manes et al. [18] described a 59-yr-old male with acute renal failure, hypercalcaemia,
anaemia and unilateral facial nerve palsy. Renal biopsy revealed interstitial granulo-
matous nephritis. Corticosteroid therapy produced normalisation of calcium level,
recovery of renal failure and disappearance of 7th cranial nerve paralysis. In this patient,
renal failure appeared with the advent of other manifestations of sarcoidosis, and the
patient responded accordingly.

Glomerulonephritis. The histological changes of focal segmental sclerosis, membranous

glomerulonephritis, mesangioproliferative glomerulonephritis, IgA nephropathy and
crescentic glomerulonephritis have been described sporadically. Most such patients have
either proteinuria or clinical nephrotic syndrome. Hypertension occurs frequently but is
rarely a serious problem.
Membranous glomerulonephritis (nephropathy) associated with nephrotic syndrome
has been seen in sarcoidosis. Renal biopsy shows membranous nephropathy with or
without granulomas, and electron microscopy may reveal typical subepithelial deposits.
Corticosteriods are effective [1922]. Glomerular involvement is rare. The mechanism of
glomerular injury is not known, but IgG and complement deposits have been observed
[23]. In one patient with crescentic glomerulonephritis and granulomas, antineutrophilic
cytoplasmic antibodies were observed [24]. In another patient with granulomatous
glomerulonephritis, the diagnosis of Wegeners granulomatosis was entertained [25].
These patients do not satisfy the diagnostic criteria for sarcoidosis and most probably
represent cases of vasculitis.

Immunoglobulin A nephropathy (Bergers disease) and glomerular disease. Mem-

branous and proliferative glomerular abnormalities have both been described in
sarcoidosis. In 1968 in France, Berger and Hinglais [26] first described IgA
nephropathy. The histological picture is characterised by mesangial deposition of IgA,

222
 RENAL SARCOIDOSIS AND HYPERCALCAEMIA

variable amounts of complement component 3, IgM and IgG associated with mesangial
proliferative glomerulonephritis. Although the cause remains unknown, clinical
exacerbations usually follow a viral illness. Taylor and Ansell [27] reported a
sarcoidosis patient with IgA nephropathy and nephrotic syndrome. Nishiki et al. [28]
observed a similar patient who also had thyroiditis. Both of these patients responded to
corticosteroid therapy. Schmidt et al. [29] described the case of a 39-yr-old male who
developed end-stage renal failure due to IgA nephropathy and received a renal transplant.
After 17 months, the patient developed a massive pleural effusion and finger clubbing.
Lung and pleural biopsy revealed noncaseating granulomas. He responded to
corticosteroids [29]. Hamada et al. [30] reported one definite and two subclinical cases
of IgA nephropathy during the course of sarcoidosis. These anecdotal studies, however,
do not reveal the precise incidence of, or nature of, the relationship between sarcoidosis
and IgA nephropathy. It is not usual practice to obtain renal biopsy specimens from
patients with sarcoidosis unless renal function is severely impaired; hence, the incidence of
subclinical nephropathy remains unknown.

Renal carcinoma and sarcoidosis. It is well known that sarcoid granulomas may be
found in regional lymph nodes draining carcinomas or lymphomas. Granulomas have
also been found in cancerous or lymphomatous tissue. This local or limited
granulomatous response should not be confused with multisystemic sarcoidosis
(table 3). Occasionally, a neoplasm, particularly renal, testicular or breast, may
produce bilateral hilar adenopathy. Rarely, sarcoidosis and cancer may coexist in the
same patients. By applying strict diagnostic criteria, most reported cases can be separated
into a local granulomatous reaction and multisystemic sarcoidosis.
A 53-yr-old male was found to have microalbuminuria. His serum creatinine level was
1.4 mg?dL-1. Renal biopsy showed a perivascular granuloma and renal ultrasonography
suggested renal cell carcinoma. At operation, a papillary adenocarcinoma of the right
kidney was found. The rest of the kidney was normal, except for a small granulomatous
lesion, on histological examination. The chest radiograph and SACE and calcitriol levels
were normal. This represents a localised sarcoid reaction to renal cancer and not systemic
sarcoidosis [31]. Marinides et al. [32] described a patient with a renal papillary
adenocarcinoma and associated granulomatous reaction in the same kidney. Hyper-
nephroma has also been described as causing or coexisting with a granulomatous
response similar to sarcoidosis [3335].

Table 3. Differences between a nonspecific local sarcoid reaction due to a cancer and multisystemic
sarcoidosis

Local sarcoid reaction Multisystemic sarcoidosis

Organ involvement Usually one More than one
Age yrs Any 2050
Chest radiograph Usually normal or atypical with Abnormal in 90% and typical
unilateral involvement for sarcoidosis
HRCT May suggest cancer May suggest sarcoidosis
Elevated SACE % v5 w60
KveimSiltzbach test Negative Positive
BALF lymphocytes Absent Present
Slit-lamp examination Normal Positive in 1520%
Hypercalcaemia May be present in some cancers Present in 13%
Whole-body gallium scan Localised uptake Multisystemic uptake
HRCT: high-resolution computed tomography; SACE: serum angiotensin-converting enzyme; BALF: broncho-
alveolar lavage fluid.

223
 O.P. SHARMA

Granulomatous vasculitis. Although hyaline deposits in arterial walls occur frequently in

sarcoidosis, true obliterative granulomatous involvement of the renal arteries is
uncommon. When it occurs, it is usually associated with severe hypertension and
carries a poor prognosis.

Hypercalciuria/nephrocalcinosis. Persistent hypercalciuria may lead to

nephrocalcinosis, renal stones with obstruction of the collecting tubules and finally
renal failure. Renal stones were the presenting feature of sarcoidosis in 3.6% of 110
consecutive Italian patients with histologically proven sarcoidosis, followed by Rizzato
et al. [2] at a sarcoidosis clinic in Milan, Italy. Hamada et al. [30] found renal impairment
mostly in patients with hypercalcaemia, but nephrocalcinosis was not found in all cases.

Vitamin D and calcium metabolism

Vitamin D is both a hormone and a vitamin. The prohormone vitamin D3 is produced
in the skin through the effect of ultraviolet light (ultraviolet B) and transported to the
liver, where it is hydroxylated to 25-hydroxyvitamin D3, which, in turn, is hydroxylated
in the kidney to form the most active metabolite of vitamin D, calcitriol. Its production in
the kidney is closely regulated by parathyroid hormone and serum phosphate. Calcitriol
functions like a steroid hormone by binding to specific receptors and initiating the gene
transcription of various proteins. Its binding to specific receptors in the intestine and
generation of calcium-binding proteins increases calcium absorption. Calcitriol, by
binding to specific receptors in bone cells, stimulates osteoblasts to make osteocalcin, the
specific protein involved in bone mineralisation and differentiation of stem cells in the
bone marrow. It increases the formation of osteoclasts involved in bone resorption.
Calcitriol influences the differentiation of cells in the haematopoietic system, and T- and
B-lymphocyte function. It inhibits proliferation of cancer cells.

Synthesis and source of 1,25-dihydroxyvitamin D3

The most active metabolite of vitamin D, calcitriol, is produced in the kidney from 25-
hydroxycholecalciferol (25-(OH)D3), which is produced in the liver. Bell et al. [36] reported
that, in three sarcoidosis patients with hypercalcaemia, plasma levels of calcitriol were high
when calcium levels were raised and fell when calcium levels returned to normal either
spontaneously or after prednisone therapy. Further evidence that abnormally high levels of
calcitriol occur in hypercalcaemic sarcoidosis patients was provided by Mitchell et al. [37],
who reported a 28-yr-old female with hypoparathyroidism who had required vitamin D
therapy since the age of 19 yrs. She developed sarcoidosis and became hypercalcaemic. On
cessation of vitamin D therapy, her calcium levels returned to normal, but the
administration of hydrocortisone caused hypocalcaemia. Her plasma calcitriol level was
three times the highest level recorded in a patient with hypoparathyroidism undergoing
treatment with vitamin D [37]. Another patient studied by Zimmerman et al. [38] had
hypoparathyroidism but was able to discontinue vitamin D treatment with maintenance of
normal serum calcium levels when sarcoidosis developed. An elevated serum concentration
of calcitriol, a metabolite synthesised solely in normal nonpregnant human subjects,
occurred in a hypercalcaemic anephric male patient with sarcoidosis [39]. These
observations support the original contention of Henneman et al. [40] that the
hypercalcaemia of sarcoidosis is a form of vitamin D intoxication and also establish that
the hormone is produced at an extrarenal site. Adams et al. [41] showed that calcitriol causes
hypercalcaemia in sarcoidosis and that macrophages from patients with active disease are

224
 RENAL SARCOIDOSIS AND HYPERCALCAEMIA

the synthetic source of hormone. Mason et al. [42] identified a similar metabolite in
preparations of sarcoid granulomas incubated with calcitriol. The identity of the hormone
and its origin are now known, but the question remains as to why nature bothers to produce
this hormone. There has to be a reason. Albert Einstein wrote, in a letter to his friend Max
Born, "I cannot believe that God would choose to play dice with the world" [43]. Is the
production of calcitriol solely for the purpose of causing damage to tissue? Is it produced to
protect the body from an uncontrolled wild immunological response? Of course, there is the
third possibility that the hormone is a harmless by-product.

Role of 1,25-dihydroxyvitamin D3
The following lines of evidence support an immunoregulatory role for calcitriol: 1) the
presence of high-affinity intracellular receptors for calcitriol (vitamin D receptors (VDRs))
in lymphocytes, macrophages and dendritic cells [44, 45]; 2) the inhibition by calcitriol of
mitogen-induced lymphocyte proliferation and immunoglobulin production [46]; 3) the
reduction by calcitriol of interleukin (IL)-2 production by lymphocytes [47]; and 4) the
enhancement by calcitriol of the ability of macrophages to inhibit proliferation of
Mycobacterium tuberculosis in vitro [48, 49]. Thus, the hormonal form of vitamin D seems
to possess a role similar to that of cytokines. The precise lesion that controls the abnormal
regulation of calcitriol synthesis is obscure, but it may be due to a defective feedback
control of calcitriol production at the site of synthesis in macrophages or in target cells for
calcitriol, such as lymphocytes. Production of the hormone may, thus, be part of the
normal immune response in retaliation to antigenic stimulation, and may induce secretion
of other mediators. Calcitriol modulates the cytotoxic and antibody-producing functions
of lymphocytes. The action depends on the threshold of VDR expression, and is mediated
through inhibition of the T-cell cytokine IL-2. Calcitriol retards interferon gamma (IFN-c)
synthesis by T-cells, and this may act as part of the control of calcitriol synthesis by
macrophages that produce the hormone when stimulated by IFN-c. The inhibition of Ig
production is due to direct suppression of T-helper cells or macrophages [50]. The presence
of VDRs in T-cell-mediated natural killer cells indicates that calcitriol may modulate the
immune response to viral and neoplastic processes [51, 52].

Hypercalcaemia
Hypercalcaemia is one of the most common biochemical abnormalities found in
clinical practice. It may be discovered when serum calcium level is measured as a
screening test or as part of the evaluation for fatigue, unexplained weakness,
neuromuscular disability, renal stones or osteopenia. The three most common causes
of hypercalcaemia are primary hyperthyroidism, granulomatous disorders and
malignancy. Disturbance of vitamin D metabolism contributes to a state of disordered
calcium homeostasis in these disorders. In granulomatous disorders, including
sarcoidosis, Crohns disease, tuberculosis, leprosy and coccidioidomycosis, the
inappropriate endogenous overproduction of the metabolite calcitriol by activated
macrophages and granulomas is responsible for hypercalcaemia and hypercalciuria.
The reported incidence of hypercalcaemia in sarcoidosis ranges 263% [53]. The
frequency, with a few exceptions, tends to be higher in North American series; the
highest, 63%, was reported by McCort et al. [54]. Cummings [55] found calcium levels of
w11 mg?100 mL-1 in 35% of patients. Mayock et al. [56], in their review of 509 patients,
recorded a frequency of 17%. Only six of the 62 patients of Scadding [57] in London,
UK showed serum calcium levels of w11.0 mg?100 mL-1. Mather [58] reported a still
lower prevalence: only four of 86 untreated patients with sarcoidosis exhibited

225
 O.P. SHARMA

hypercalcaemia. In Finland, Putkonen et al. [59] could find only two patients with high
calcium levels in a series of 60. There is no conclusive evidence that race, age, sex,
occupation or geographical distribution influence the development of hypercalcaemia.
Although hypercalcaemia appears to be a consistent feature, the studies showing an
excessively high frequency of occurrence need to be revised. It is reasonable to accept the
incidence of 11% noted by James et al. [60] in their worldwide review of 3,676 patients
with sarcoidosis. Hypercalcaemia is usually transient in subacute sarcoidosis and
fluctuate and persistent in chronic sarcoidosis, depending on the activity of the disease.
Furthermore, hypercalcaemia may occur only at a certain phase during the long course
of chronic sarcoidosis. Consequently, to get a true picture of calcium abnormality, serum
calcium levels must be measured regularly and consistently over a long period of time. It
has been suggested that hypercalcaemia is more frequent during the summer months,
when exposure to the sun is at its peak [61, 62]. However, this is not the case.
Hypercalcaemia occurs frequently in sarcoidosis patients in London (UK), Reading
(UK), New York (NY, USA) and Lisbon (Portugal). Besides, Putkonen et al. [59] found
lower levels in summer months and slightly higher mean levels in late autumn.
Harrell and Fisher [63] were the first to recognise the relationship between vitamin D
and sarcoidosis. In 1939, they described the presence of hypercalcaemia in six of 11
patients with sarcoidosis. In one of their patients, serum calcium level rose from 9.6 to
14.2 mg?dL-1 after consumption of cod liver oil. These authors made three pertinent
clinical observations: 1) hypercalcaemia is a feature of sarcoidosis; 2) consuming a
vitamin-D-rich diet results in aggravation of hypercalcaemia; and 3) vitamin D might be
related to the calcium abnormality in sarcoidosis. Soon afterwards, Hemmeman et al. [40]
postulated that the disordered calcium homeostasis in sarcoidosis patients was strikingly
similar to that seen in patients with vitamin D intoxication. In 1963, Taylor et al. [64]
observed that, in 345 patients with sarcoidosis in North Carolina (USA), mean serum
calcium level in the winter months was 9.89 mg?dL-1, but rose to 10.26 mg?dL-1 in one of
the present authors patients who showed a response to corticosteroids, whereas,
amongst 12,027 controls, the levels during winter and summer months remained
unchanged. In the two hypercalcaemic patients of Dent [65] at University College
Hospital (London, UK), further rises in serum calcium level occurred after whole-body
ultraviolet light irradiation. Hendrix [66], conversely, gave two hypercalcaemic and
hypercalciuric patients with sarcoidosis a vitamin D-deficient diet and shielded them
from sunlight. In 8 weeks, serum calcium levels became normal, hypercalciuria subsided
and faecal excretion of calcium increased. These observations strengthened the belief that
the development of hypercalcaemia in sarcoidosis was due to enhanced target
responsiveness to vitamin D, increasing calcium absorption in the intestine, increasing
resorption in the bones and increasing excretion in the kidneys.

Clinical features
The symptoms and signs of hypercalcaemia include polyuria and polydipsia, renal
colic, lethargy, anorexia, dyspepsia and peptic ulceration, constipation, depression,
drowsiness and impaired cognition. Patients with malignancy and lymphomas may, in
addition, complain of weight loss.

Hypercalciuria, nephrocalcinosis and renal stones

Hypercalcaemia has long been recognised as a complication of sarcoidosis, but the
importance of hypercalciuria has been less thoroughly appreciated. Nevertheless,
hypercalciuria is three times more common than hypercalcaemia (table 4) [67].

226
 RENAL SARCOIDOSIS AND HYPERCALCAEMIA

Hypercalciuria has been reported to be more common in males than females, and, in
London (UK), in Caucasian than in West Indian patients. In patients with abnormal renal
function, hypercalciuria is always present when the patient has sarcoidosis-related
hypercalcaemia. The mechanism of hypercalciuria appears to be threefold: 1) absorptive,
associated with elevated calcitriol levels and abnormal urinary calcium:creatinine ratio; 2)
resorptive, associated with excessive dissemination of sarcoidosis, including in bones, and
high SACE (osteopenia may occur and hypercalciuria persist on a calcium-poor diet); and 3)
associated with osteoclast-activating factor, a bone-resorbing substance [68]. According to
Broulik et al. [69], the urinary excretion rate of calcium is based on the filtered load of
calcium when corrected for urinary calcium excretion; the tubular maximum resorptive rate
for calcium is not increased. These results suggest that calcitriol has no direct effect on renal
calcium handling, and hypercalciuria is due to the flow of calcium from the gut and bone.

Treatment
The magnitude and persistence of the hypercalcaemia are the key indications for
therapy. Severe hypercalcaemia, defined as a serum calcium concentration of
w14 mg?dL-1, is unusual in sarcoidosis. The goals of treatment include: 1) reduction
of oral and intravenous intake of calcium supplements, dietary calcium and vitamin D; 2)
maintenance of an expanded intravascular volume; 3) reduction of the inappropriate
production of calcitriol by sarcoid macrophages and granulomas; and 4) reduction of
calcitriol-induced intestinal calcium absorption and bone resorption.
Prednisone (2040 mg?day-1) is the drug of choice for reducing endogenous production
of calcitriol. Corticosteroids cause a swift decrease in circulating calcitriol and serum
calcium levels within 35 days. A decrease in urinary calcium excretion rate soon follows
within 710 days (fig. 2). Failure to normalise serum calcium levels after 2 weeks should
lead the clinician to exclude the possibility of a coexisting disorder, including
hyperparathyroidism, lymphoma, carcinoma and myeloma. Once the calcium abnormality
is brought under control, the prednisone dose can be reduced over a period of 46 weeks.
Serum calcium and urinary calcium excretion rate need to be monitored frequently. If the
patient develops unbearable corticosteroid side-effects or fails to respond, chloroquine or
hydroxychloroquine should be given. The latter two drugs are known to reduce serum
calcitriol production and serum calcium levels [7072]. The antifungal drug ketoconazole, a
known inhibitor of cytochrome P450 steroid oxidase, lowers circulating calcitriol and serum
calcium levels; however, the efficacy of these drugs is not widely known [73, 74]. The patient
should be instructed to avoid sunlight, curtail intake of major dietary sources of vitamin D
and calcium, and drink plenty of fluids. The major sources of vitamin D are fish (sardine,
salmon and cod), liver and egg yolk. In the USA and Scandinavia, dairy products are
supplemented with vitamin D, and each quart of milk is fortified with 400 IU of either
vitamin D2 or D3, but, in other countries, milk is usually not supplemented (1 quart
(UK)=1.14 L; 1 quart (US, liquid)=0.946 L). These precautions should be strictly adhered
to (table 5). Normocalcaemic patients with sarcoidosis may develop hypercalcaemia, renal

Table 4. Incidence of simultaneous serum-urine calcium elevation in 75

patients with sarcoidosis

Calcium elevation site Subjects n (%)

Serum or urine 37 (49)
Serum and urine 10 (13)
Urine alone 27 (36)
Serum alone 0 (0)
Modified from [67].

227
 O.P. SHARMA

a)
8000

WBCsmm-3
7000 l l
l
l l l
6000 l l
l
l l
l
l
l
5000
4000

b)
20
Eosinophils %

l
15 l l l l
l
10 l
l l l l l l
l

c) 15 l
l

14 l
Serum calcium
mg100 mL-1

13 l
l

12
11 l

10 l l
l l
l
40 30 20 10 l
9 X X X
l

May June July August

Month

Fig. 2. Response of hypercalcaemia to corticosteroid therapy: a) white blood cell (WBC) count, b) eosinophil
density, and c) serum calcium concentration. Double-headed arrows indicate prednisone dose (milligrams?day-1);
x-axis corresponds to middle of each month. Response is usually quick and occurs within 1 week

stones and renal failure. Urinary stones due to persistent hypercalciuria can be pulverised
by extracorporeal lithotripsy before resorting to surgery (fig. 3) [75].

Conclusion
The spectrum of sarcoidosis also encompasses renal sarcoidosis, a relatively uncommon
but difficult complication of the disease. Renal disease, if diagnosed early, can be subdued
with judicious use of corticosteroids, antimalarial drugs and immunosuppressive agents.
Renal sarcoidosis may be primary or associated with impaired calcium metabolism.
Although hypercalcaemia and hypercalciuria may both occur in sarcoidosis, the latter is
approximately three times more common than the former.

Table 5. Precautions for preventing nephrocalcinosis and stone formation in sarcoidosis

Diet
Fluid i34 L?24 h-1
Sodium Restrict intake
Protein Moderate
Calcium Avoid diets rich in vitamin D and calcium
Oxalate Avoid oxalate-rich foods, e.g. rhubarb
Drugs
Diuretics (thiazides) Reduce Ca2z excretion; helpful in patients with hypercalciuria
and recurrent stone formation
Allopurinol If serum urate and urate excretion high
Vitamin D supplements Avoid

228
 RENAL SARCOIDOSIS AND HYPERCALCAEMIA

a) b)

Fig. 3. Renal stones passed by the patient after successful extracorporeal lithotripsy: a) right kidney; and
b) left kidney. Scale bar=5 mm.

Summary
The classic renal lesion of sarcoidosis is an epithelioid cell granuloma. Distinction from
other diseases that may cause granulomas in the kidney, particularly renal neoplasm,
can be difficult. Sarcoidosis can directly involve various structures in the kidneys,
causing granulomatous nephritis, nongranulomatous nephritis and vasculitis. There-
fore, the firm and final diagnosis of renal sarcoidosis depends on tissue biopsy and a
clinical picture consistent with multisystemic sarcoidosis. Once the diagnosis is
established, therapy includes corticosteroids, antimalarial drugs and immuno-
suppressive agents. Hypercalcaemia rarely causes renal failure; hypercalciuria, however,
is associated with a high incidence of nephrocalcinosis. Hypercalciuria is more frequent
than hypercalcaemia and may be present without hypercalcaemia, but the reverse is not
true. Hypercalcaemia is always associated with hypercalciuria. Abnormalities of calcium
metabolism in sarcoidosis are due to increased production of 1,25-dihydroxyvitamin D3
(calcitriol) by sarcoid granulomas and activated macrophages.

Keywords: Angiotensin-converting enzyme, 1,25-dihydroxyvitamin D3, hypercalcaemia,

hypercalciuria, nephrocalcinosis, noncaseating granuloma.

References
1. Siltzbach L, James D, Neville E, et al. Course and prognosis of sarcoidosis around the world. Am J
Med 1974; 57: 847852.
2. Rizzato G, Palmieri G, Agrati A, et al. The organ-specific extrapulmonary presentation of
sarcoidosis: a frequent occurrence but a challenge to an early diagnosis. Sarcoidosis Vasc Diffuse
Lung Dis 2004; 21: 119126.

229
 O.P. SHARMA

3. Pathology. In: James D, Williams W. Sarcoidosis and other Granulomatous Disorders. Major
Problems in Internal Medicine. Vol. 24. New York, NY, W.B. Saunders Company 1985; pp. 3848.
4. Baughman R, Teirstein A, Judson M, et al. Clinical characteristics of patients in a case control
study of sarcoidosis. Am J Respir Crit Care Med 2001; 164: 18851889.
5. Longcope W, Freiman D. A study of sarcoidosis based on a combined investigation of 160 cases
including 30 autopsies from the John Hopkins Hospital and MGH. Medicine 1984; 31: 137.
6. Muther R, McCarron D, Bennett W. Renal manifestations of sarcoidosis. Arch Intern Med 1981;
141: 643646.
7. Hagege A, Baglin J, Prinseau J, et al. Sarcoidosis disclosed by renal insufficiency (3 cases). Sem
Hop 1983; 59: 28232826.
8. Guenel J, Chevet D. Interstitial nephritis in sarcoidosis. Presse Med 1990; 19: 12151217.
9. Tateno S, Kobayashi Y. Renal manifestations of sarcoidosis: a review. Nippon Rinsho 1994;
52: 16131618.
10. Bergener R, Hoffman M, Waldherr R, et al. Frequency of kidney disease in chronic sarcoidosis.
Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 118125.
11. Rizzato G, Colombo P. Nephrolithiasis as a presenting feature of chronic sarcoidosis: a
prospective study. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13: 167172.
12. Hunninghake G, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
13. Sharma O, Lamb C. Cancer in interstitial pulmonary fibrosis and sarcoidosis. Curr Opin Pulm
Med 2003; 9: 396401.
14. Utas C, Dogukan A, Patriroghu T, et al. Granulomatous interstitial nephritis in extrapulmonary
sarcoidosis. Clin Nephrol 1999; 51: 252254.
15. Schwarz A, Krause P, Kunzendorf V, et al. The outcome of interstitial nephritis: risk factors for
the transition from acute to chronic interstitial nephritis. Clin Nephrol 2000; 52: 179190.
16. Schwarz A, Krause P, Keller F, et al. Granulomatous interstitial nephritis after non-steroidal anti-
inflammatory drugs. Am J Nephrol ; 8: 410416.
17. Marie I, Lecomte F, Leveque H. Granulomatous nephritis as the first manifestation of Whipples
disease. Ann Intern Med 2000; 132: 9495.
18. Manes M, Molino A, Gaiter A, et al. Isolated renal failure secondary to sarcoidosis. Recenti Prog
Med 2000; 91: 441443.
19. Dimitriades C, Shetty AK, Vehaskari M, Craver RD, Gedalia A. Membranous nephropathy
associated with childhood sarcoidosis. Pediatr Nephrol 1999; 13: 444447.
20. Khan I, Simpson J, Catto G, et al. Membranous nephropathy and granulomatous interstitial
nephritis in sarcoidosis. Nephron 1994; 66: 459461.
21. Mundlein E, Green T, Ritz E. Graves disease and sarcoidosis in a patient with minimal
glomerulonephritis. Nephrol Dial Transplant 1996; 11: 860862.
22. Parry R, Falk C. Minimal change disease associated with sarcoidosis. Nephrol Dial Transplant
1997; 12: 21592160.
23. Quismorio F, Sharma O, Chandor S. Immunopathological studies on the cutaneous lesions in
sarcoidosis. Br J Dermatol 1977; 97: 635642.
24. Auinger M, Irsigler K, Breiteneder S, et al. Normocalcemic hepato-renal sarcoidosis with
crescentic glomerulonephritis. Nephrol Dial Transplant 1977; 12: 14741477.
25. Ahuja T, Mattana J, Valerraman E, et al. Wegeners granulomatosis followed by development of
sarcoidosis. Am J Kidney Dis 1996; 28: 893898.
26. Berger J, Hinglais N. Les depots intracapillaire dIgAIgG. [Intra-capillary deposits of IgA and
IgG]. J Urol Nephrol (Paris) 1968; 74: 694695.
27. Taylor J, Ansell I. Sarcoid sensitive nephritic syndrome and renal impairment in a patient with
sarcoidosis. Nephrol Dial Transplant 1996; 11: 355356.
28. Nishiki M, Murakama Y, Yamane Y, et al. Steroid sensitive nephritic syndrome, sarcoidosis and
thyroiditis. Nephrol Dial Transplant 1999; 14: 20082010.

230
 RENAL SARCOIDOSIS AND HYPERCALCAEMIA

29. Schmidt R, Bender F, Change W, et al. Sarcoidosis after renal transplant. Transplantation 1999;
68: 14201423.
30. Hamada H, Nagai S, Ono T, et al. Sarcoidosis complicated with IgA nephropathy. Sarcoidosis
Vasc Diffuse Lung Dis 2003; 20: 6973.
31. Gobel V, Kettritz R, Schneider W, et al. The protean face of renal sarcoidosis. J Am Soc Nephrol
2001; 12: 616623.
32. Marinides G, Hajdu I, Grans R. Unique association of renal carcinoma and sarcoid reaction in the
kidney. Nephron 1994; 67: 477480.
33. Moder K, Litin S, Gaffey T. Renal cell carcinoma associated with sarcoid-like tissue reaction.
Mayo Clin Proc 1990; 65: 14981501.
34. Campbell F, Douglas-Jones A. Sarcoid-like granulomas in primary renal-cell carcinoma.
Sarcoidosis 1993; 10: 128131.
35. Hoffbrand B. The kidney in sarcoidosis. In: James DG, ed. Sarcoidosis and other Granulomatous
Disorders. New York, NY, Marcel Dekker, 1994; pp. 335343.
36. Bell N, Stern P, Pantzer E, et al. Evidence that increased circulating 1 alpha, 25-dihydroxy
vitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest
1979; 64: 218225.
37. Mitchell T, Stamp T, Jenkins J. Hypercalcemic sarcoidosis in hypoparathyroidism. BMJ 1983;
1: 764765.
38. Zimmerman J, Holick M, Silver J. Normocalcemia in hypothyroid patient with sarcoidosis:
evidence for parathyroid hormone independent synthesis of 1,25-dihydroxy vitamin-D. Ann Intern
Med 1983; 98: 338340.
39. Barbour G, Coburn J, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric
patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J
Med 1981; 305: 440443.
40. Henneman P, Dempsey E, Carol E, et al. The causes of hypercalcemia in sarcoidosis and its
treatment with cortisone and sodium phytate. J Clin Invest 1956; 35: 12291242.
41. Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25-hydroxyvitamin D3 by cultured
pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983; 72: 18561860.
42. Mason R, Frankel T, Chan Y, et al. Vitamin D conversion by sarcoid lymph node homogenate.
Ann Intern Med 1984; 100: 5961.
43. Seldes G. The Great Quotations. Secaucus, NJ, Castle Books, 1960; p. 226.
44. Cadranel J. Vitamin D, endocrine and paracrine mediators in cases of pulmonary granulomatosis.
Rev Mal Respir 1995; 12: 119120.
45. Bhalla A, Amento E, Clemens T, et al. Specific high-affinity receptors for 1,25-dihydroxy vitamin
D3 in human peripheral blood mononuclear cells, presence in monocytes and induction in T
lymphocytes following activation. J Clin Endocrinol Metab 1983; 57: 13081310.
46. Rigby W, Noelle R, Krause K, et al. The effect of 1, 25-dihydroxy vitamin D on human T lymphocyte
activation and proliferation: a cell cycle analysis. J Immunol 1985; 135: 22792286.
47. Haq A. 1-25-Dihydroxy vitamin D (calcitriol) suppresses IL-2 murine thymocyte proliferation.
Thymus 1986; 8: 295306.
48. Adams J, Modlin R, Diz MM, Barnes PF. Potentiation of the macrophage 25-hydroxyvitamin D-
1-hydroxylation reaction by human tuberculous pleural effusion fluid. J Clin Endocrinol Metab
1989; 69: 457460.
49. Barnes P, Modlin R, Bikle D, et al. Transpleural gradient of 1,25-dihydroxy vitamin D in
tuberculous pleutitis. J Clin Invest 1989; 83: 15271532.
50. Provvedini D, Tsoukas C, Deftos L, et al. 1a,25-Dihydroxyvitamin D-binding macromolecules in
human B-lymphocytes: effects on immunoglobulin production. J Immunol 1986; 136: 27342740.
51. McFadden R, Vickers K, Fraher L. Lymphocyte chemokinetic factors derived from human tonsils:
modulation by 1,25-dihydroxy vitamin D (calcitriol). Am J Respir Cell Mol Biol 1991; 4: 4249.
52. Rigby W, Denome S, Fanger M. Regulation of lymphokine production and human T lymphocyte
activation by 1,25-dihydroxy vitamin D3. J Clin Invest 1987; 79: 16591664.

231
 O.P. SHARMA

53. Sharma O. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med
2000; 6: 442447.
54. McCort J, Wood R, Hamilton J, et al. Sarcoidosis: a clinical and roentgenographic study of 28
proven cases. Arch Intern Med 1947; 80: 293321.
55. Cummings M. Epidemiologic and clinical observations in sarcoidosis. Ann Intern Med 1959;
50: 879890.
56. Mayock R, Bertrand P, Morrison C, et al. Manifestations of sarcoidosis: an analysis of 145
patients with a review of nine series from the literature. Am J Med 1963; 35: 6789.
57. Scadding J. The kidney and calcium metabolism in sarcoidosis. In: Scadding JG, Mitchell DN, eds.
Sarcoidosis. London, Chapman and Hall Medical, 1985: pp. 390413.
58. Mather G. Calcium metabolism and bone changes in sarcoidosis. BMJ 1957; 1: 248253.
59. Putkonen T, Hannuksela N, Hahme H. Calcium and phosphorus metabolism in sarcoidosis. Acta
Med Scand 1965; 177: 327335.
60. James D, Neville E, Siltzbach L. A worldwide review of sarcoidosis. Ann N Y Acad Sci 1976;
278: 321334.
61. Cronin C, Dimnear S, OMahony D, et al. Precipitation of hypercalcemia in sarcoidosis by foreign
sun holidays: report of four cases. Postgrad Med J 1990: 307309.
62. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of
vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3
synthesis in human skin. J Clin Endocrinol Metab 1988; 67: 373378.
63. Harrell G, Fisher S. Blood chemical changes in Boecks sarcoid with particular reference to
protein, calcium and phosphorus values. J Clin Invest 1939; 18: 687693.
64. Taylor R, Lynch H, Winsor W. Seasonal influence of sunlight on the hypercalcemia of sarcoidosis.
Am J Med 1963; 35: 6769.
65. Dent C. Calcium metabolism in sarcoidosis. Postgrad Med J 1970; 46: 471473.
66. Hendrix J. The remission of hypercalcemia and hypercalciuria in systemic sarcoidosis by vitamin
D depletion. Clin Res 1963; 11: 220225.
67. Sharma O, Trowell J, Cohen N, et al. Abnormal calcium metabolism in sarcoidosis. In: Turiaf J,
Chabot J, eds. La Sarcoidose: Rapports de la IV Conference Internationale. [Proceedings of the IV
International Conference on Sarcoidosis]. Paris, Masson & Cie, 1967; pp. 627631.
68. Mundy G, Raisz L, Cooper R, et al. Evidence for the secretion of an osteoclast stimulating factor
in myeloma. N Engl J Med 1974; 291: 10411046.
69. Broulik P, Votava V, Pacovsky V. The tubular maximum for calcium reabsorption in patients with
chronic active sarcoidosis. Eur Respir J 1990; 3: 447449.
70. Adams J, Diz M, Sharma O. Effective reduction in the serum 1,25-dihydroxy vitamin D and
calcium concentration in sarcoidosis associated hypercalcemia with short course of chloroquine
therapy. Ann Intern Med 1989; 111: 437438.
71. Barre P, Gascon-Barre M, Meakins J, et al. Hydroxychloroquine treatment of hypercalcemia in a
patients with sarcoidosis undergoing hemodialysis. Am J Med 1987; 82: 12591262.
72. OLeary T, Jones G, Yip A, et al. The effects of chloroquine on serum 1,25-dihydroxy vitamin D
and calcium metabolism in sarcoidosis. N Engl J Med 1986; 315: 727730.
73. Adams JS, Sharma OP, Diz MM, Endres DB. Ketoconazole decreases the serum 1,25-dihydroxy
vitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol
Metab 1990; 70: 10901095.
74. Ejaz AA, Zabaneh RI, Tiwari P, Nawab ZM, Leehey DJ, Ing TS. Ketoconazole in the treatment of
recurrent nephrolithiasis associated with sarcoidosis. Nephrol Dial Transplant 1994; 9: 14921494.
75. Sharma OP, Alfaro C. Hypercalciuria and renal stones in a sarcoidosis patient treated by
extracorporeal shockwave lithotripsy. Sarcoidosis 1986; 3: 79.

232
CHAPTER 15

Rare manifestations of sarcoidosis

D.R. Moller

Correspondence: D.R. Moller, Division of Pulmonary and Critical Care Medicine, Dept of Medicine, The
Johns Hopkins University, 5501 Hopkins Bayview Circle, Rm. 4B63, Baltimore, MD 21224, USA. E-mail:
dmoller@jhmi.edu

Sarcoidosis may be associated with granulomatous inflammation in any part of the

body, usually in more than one area [1]. Rare manifestations of sarcoidosis include unusual
patterns of organ involvement, or are the result of granulomatous inflammation
developing in unusual locations for sarcoidosis. In other rare cases, sarcoidosis is
associated with a second disorder. Although the frequency of individual rare
manifestations is by definition low, together they represent a major cause of morbidity
and mortality related to sarcoidosis [1, 2]. Given the protean manifestations of sarcoidosis
and potential involvement of any tissue, a comprehensive compilation of all reported rare
manifestations of sarcoidosis is not possible in this monograph. Nonetheless, an approach
to patients who may have rare manifestation of sarcoidosis can be constructed. These rare
manifestations reflect the known pathophysiology and clinical behaviour of more common
and easily recognisable systemic sarcoidosis. Alternative diagnoses must be excluded,
particularly when there are deviations from well-established manifestations or an expected
clinical course for sarcoidosis. Given their rarity, none of the clinical approaches or
treatment recommendations for the conditions discussed below have been subjected to
clinical trials, rigorous or otherwise. The author has seen patients with the conditions listed
below, and offers an approach based on this experience and selected published literature.
Emphasis will be placed on a systematic approach to these rare manifestations, focusing on
organ systems that are not covered by other sections of this Monograph.

General considerations
An initial framework for approaching the challenge of diagnosing and treating rare
manifestations of sarcoidosis can be formulated based on current knowledge of the
disease and the expected clinical behaviour of sarcoidosis. In all cases, granulomatous
inflammation from sarcoidosis interferes with local tissue homeostasis and function;
thus, organ impairment is dependent on its location. When the clinician is confronted
with identifying whether a rare manifestation of sarcoidosis is present in a patient with
known sarcoidosis, an internet search of the medical literature is part of a recommended
initial approach to establish a possible association. Invariably, the clinician must be
prepared to consider competing diagnoses, particularly when a diagnosis of sarcoidosis
has not been established. To confirm an association with sarcoidosis or an alternative
diagnosis, directed diagnostic evaluations including biopsy, may be needed. In other
situations, a trial of corticosteroid (CS) therapy may be indicated to assess whether there
is a clinical response consistent with sarcoidosis.
With rare manifestations of sarcoidosis, a leading concern is whether the specific
clinical problem is the result of an alternative, nonsarcoidosis pathological process. The
following generalisations on the clinical behaviour of sarcoidosis provide a useful
Eur Respir Mon, 2005, 32, 233250. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
233
 D.R. MOLLER

starting point to assess a priori the likelihood of whether a clinical manifestation may be a
result of sarcoidosis or due to an alternative process. First, organ involvement usually
defines itself early in the disease regardless of whether the organs involved are commonly
or rarely found to be involved in sarcoidosis. For example, only 23% of patients in the A
Case Control Etiologic Study of Sarcoidosis (ACCESS) study were found to have one or
more new organ systems involved with sarcoidosis during a 2-yr follow-up evaluation;
the presence of extrapulmonary involvement at presentation was a risk factor for new
organ development [3]. Clinical experience suggests new organ involvement is even rarer
after w2 yrs of defined disease. The implication of this clinical observation is that new
onset organ involvement that develops years after an initial diagnosis of sarcoidosis must
be suspected as having an alternative explanation.
Secondly,w90% of patients with sarcoidosis follow one of two mutually exclusive courses,
either remission, generally within the first 23 yrs, or a chronic progressive course with
progressive organ impairment [1]. Remissions, once they occur, rarely recur (exceptions
discussed below). Distinct presentations of sarcoidosis are associated with a different
likelihood of these two outcomes. For example, Lofgrens syndrome has a remission rate of
7080%, whereas patients with lupus pernio or fibrocystic pulmonary sarcoidosis rarely
undergo remission [1]. For patients with chronic sarcoidosis, the rate of progression varies
from individual to individual, as does their response to treatment. Suppression of
inflammation by CS therapy or other anti-inflammatory therapies should not be considered
remission, but temporary suppression of the inflammation. If the underlying sarcoidosis
inflammation has not undergone remission, the inflammation will return upon tapering or
discontinuing therapy, with a variable period of temporary quiescence as the inflammation
develops to a critical point where organ function is significantly impaired. Rarely,
sarcoidosis follows a remitting-relapsing course usually involving the neurological or ocular
systems. The implication of these observations is that new onset symptoms that develop
after a period of remission, particularly a prolonged one, should not be attributed to
sarcoidosis until alternative explanations are reasonably excluded.
Thirdly, CS therapy is almost always successful in suppressing the inflammation in
sarcoidosis, at least over the short term. For visceral sarcoidosis (pulmonary, cardiac,
hepatosplenic), there is usually a precisely defined threshold dose of CS therapy that is
effective, and this threshold dose rarely changes even after decades of chronic disease.
Neurological and ocular sarcoidosis may be exceptions to this generalisation, sometimes
with lower CS requirements later in the disease. The implication of these clinical
observations is that new symptoms that arise in the context of a patient on a previously
effective treatment regimen (assuming compliance is not an issue) must be carefully
evaluated for alternative explanations rather than attributed to the emergence of a rare
manifestation of sarcoidosis. For example, new pulmonary infiltrates in stable, treated
sarcoidosis are more likely to have an alternative explanation, such as infection or
pulmonary oedema, than acting as a "flare" of pulmonary sarcoidosis. Clinical
manifestations that do not respond to typical CS dosing must also be reconsidered
for alternative explanations rather than attributed to a rare manifestation of sarcoidosis.
Although exceptions to the generalisations above occur, these guidelines may help the
clinician decide how vigorously to pursue alternative explanations for clinical
manifestations that are rarely part of the spectrum of sarcoidosis.

Clinical manifestations
Rare manifestations by organ system
Selected rare clinical manifestations are presented below and summarised in table 1.

234
 RARE MANIFESTATIONS

Pulmonary sarcoidosis. Findings of pulmonary hypertension or cor pulmonale are seen

in 14% of patients, usually from severe fibrocystic lung disease. Rarely, a granulomatous
pulmonary vasculitis is seen that is not explained by the degree of interstitial disease
reflected by chest imaging and severely reduced pulmonary function. Dyspnoea out of
proportion to the degree of interstitial pulmonary disease should lead to an evaluation for
pulmonary hypertension. Limited experience suggests these patients may benefit from
drug therapies used for primary pulmonary hypertension [4]. Cardiac sarcoidosis should
also be considered as an explanation for unexplained dyspnoea in sarcoidosis [5].
Unusual patterns of pulmonary involvement include the presence of mycetomas,
dominant mass-like nodular sarcoidosis or isolated nodules that raise concern of possible
malignancy or infection. Lobar atelectasis is very uncommon in sarcoidosis but may be
caused by endobronchial nodules or enlarged adjacent lymph nodes. Superior vena cavae
syndrome has rarely been documented to be caused by sarcoidosis [6]. Pleural effusions
from direct granulomatous involvement of the pleural surface is rare in sarcoidosis and
should prompt evaluation to exclude alternative causes, such as infection, malignancy,
pulmonary embolism, or causes of transudative effusions [2].

Necrotising sarcoid granulomatosis. Often considered a variant of sarcoidosis, this rare

disease is characterised by large, confluent, noncaseating granulomata involving both
pulmonary arteries and veins [7]. Systemic vasculitis is not present. Patients may be
asymptomatic or have cough, dyspnoea, fever, chest pain, or constitutional symptoms.
Chest radiographs typically demonstrate multiple, usually noncavitating, nodules. Pleural
disease with pleurisy or pleural effusions occurs in the majority of patients and may be a
clue to the diagnosis. Surprisingly, the prognosis is good with spontaneous remission or a
rapid response to CS therapy in many patients.

Sarcoidosis of the upper respiratory tract. Sarcoidosis of the upper respiratory tract
(SURT) occurs in 510% of patients, usually in those with longstanding disease. Severe
nasal congestion and chronic sinusitis are typically unresponsive to decongestants and
nasal steroids. Rarely, chronic sinusitis or surgical intervention may result in destruction
of the nasal septum and a "saddle nose" deformity. Laryngeal sarcoidosis may manifest
with hoarseness, stridor and, rarely, as acute respiratory failure secondary to upper
airway obstruction. Sleep apnoea has also rarely been directly attributed to SURT rather
than a more common association with weight gain from CS therapy [8]. Often SURT is
associated with chronic skin lesions, particularly lupus pernio, and joint involvement,
which should prompt careful screening for manifestations of SURT [9].

Oropharyngeal manifestations. Although rare, the oral cavity may be involved in

sarcoidosis with severe consequences. Tonsillar or pharyngeal involvement (with mass or
cartilaginous destruction) often raises a concern of malignancy. Tongue involvement with
mass or macroglossia also raises the possibility of malignancy or amyloidosis unless
sarcoidosis is apparent elsewhere. Herefordt syndrome, or "uveoparotid fever", is a well
known, but uncommon manifestation of acute sarcoidosis characterised by a pattern of
fever, parotid and lacrimal gland enlargement, bilateral hilar adenopathy and, often,
uveitis and cranial neuropathies.
The Melkersson-Rosenthal syndrome is a rare entity that causes recurrent or
progressive orofacial swelling with lip and plicated tongue enlargement; there is frequent
salivary gland involvement and cranial neuropathies, particularly VII nerve palsies [10,
11]. Histopathological findings usually reveal sarcoid-like noncaseating epithelioid
granulomas. The cause of this orofacial granulomatosis is unknown but conceivably is a
variant of Crohns disease or sarcoidosis. Case reports suggest intralesional or systemic

235
 D.R. MOLLER

Table 1. Rare manifestations of sarcoidosis based on organ systems

Organ system Rare clinical features (selected)

Pulmonary Pulmonary vasculitis
Mycetomas
Cavitating nodules
Lobar atelectasis
Tracheal, bronchial stenosis
Superior vena cavae syndrome
Pleural disease
Pneumothorax
Upper airway Saddle nose deformity
Respiratory failure from upper airway obstruction
Sleep apnoea
Oropharynx Tonsillar sarcoidosis
Pharyngeal sarcoidosis
Periodontal disease
Tongue mass
Skin Subcutaneous sarcoidosis
Ichthyosis
Alopecia
Scar granulomas
Ocular Optic neuritis
Retinal vasculitis
Granulomatous orbital inflammation
Hepatic Massive hepatomegaly
Jaundice with pruritis
Cirrhosis with portal hypertension
Massive splenomegaly
Gastrointestinal Pancreatic mass
Gastric involvement
Small or large intestine involvement
Appendicitis
Nervous system Optic chiasma involvement
Aseptic meningitis
Cerebritis (white matter involvement)
Cerebral vascular occlusion
Encephalitis
Hypothalamic/pituitary involvement
Corpus callosum involvement
Hydrocephalus
Horners syndrome, Argyll Robertson or Adies pupil
Cerebellar involvement
Pseudotumour cerebrei
Brain stem involvement
Transverse myelitis, intraspinal mass
Cauda equina or spinal root involvement
Mononeuritis multiplex
Peripheral neuropathies
Small fibre neuropathy (common?)
Cardiac/vascular Valvular disease
Pericardial disease
Ventricular or atrial mass
Sudden death (not rare?)
Joints/musculoskeletal Polymyositis
Bone cysts: long bones, skull, vertebrae
Haematological Hypogammaglobulinaemia
Lymphoedema
Idiopathic thrombocytopenia purpora
Endocrine/exocrine gland Heerfordts syndrome
Hypopituitarism, diabetes insipidus
Thyroid mass, thyroiditis

236
 RARE MANIFESTATIONS

Table 1. Continued

Organ system Rare clinical features (selected)

Parotid mass
Lacrimal gland, dacryoadenitis
Sicca syndrome
Renal/genitourinary Renal failure
Uterine mass
Ovarian involvement
Menometrorrhagia
Testicular mass
Epididymitis
Intermittent azoospermia

steroids may be helpful in the initial stages. There are scattered reports of other drugs
that are occasionally effective, but the disorder is often resistant to medical therapy;
surgical cheiloplasty may be attempted to ameliorate disfigurement.

Chronic cutaneous sarcoidosis. With plaques and subcutaneous nodules affecting the
face, particularly around the nose, cheeks and eyes, is termed lupus pernio. Lupus pernio
is more common in patients of African descent; it is rare in Caucasians [1]. Less
commonly, sarcoidosis may manifest with extensive, deep subcutaneous nodules with
oedema, particularly of the lower extremities; the term Darier-Roussy sarcoidosis was
earlier used to describe this problem [12]. This sarcoidosis manifestation is often poorly
responsive to treatment, though antimalarial drugs, moderate doses of CS, methotrexate
or thalidomide may be partially effective.
Granulomatous nodules often develop at sites of previous scars. Rarely, nodules in the
skin may develop at sites of tattoos, body piercings or previously punctured sites of the
skin or oral mucosa [13]. Other reports document granulomas at sites of silica injections,
although the nodules were probably due to sarcoid-like foreign body reaction [14]. More
troublesome are reports of sarcoidosis developing in individuals with silicone prostheses
[15]. A causal association remains speculative and not supported by larger
epidemiological studies, although one report has documented that removal of prostheses
was followed by remission of sarcoidosis [16].

Ocular manifestations. Anterior uveitis is the most common eye lesion in sarcoidosis and
frequently is the initial presenting manifestation. Rarer ocular manifestations include
optic neuritis or retinitis, either of which may present dramatically with blindness (see
Chapter 12 of this monograph).

Abdominal manifestations. Hepatic involvement is documented iny1020% sarcoidosis

patients; rarely granulomatous hepatitis is the sole manifestation of the disease [1, 2]. Active
hepatic inflammation may be associated with fever, tender hepatomegaly and pruritus.
Granulomatous hepatitis with markedly elevated serum liver function tests e.g.w35 times
normal, usually with an obstructive pattern, may portend a poor prognosis with progressive
cirrhosis and portal hypertension if untreated. CS or immunosuppressive therapies are
usually effective in preventing progressive hepatic insufficiency in these cases. Methotrexate
is usually avoided because of its potential to cause liver toxicity. In rare cases, sarcoidosis
may be associated with primary sclerosing cholangitis or primary biliary cirrhosis,
diagnosed by the presence of higher titres of specific antimicrosomal or antimitochondrial
antibodies. In these instances, the liver disease does not respond to CS therapy.

Abdominal "triad" sarcoidosis. A variant of sarcoidosis, often called abdominal

sarcoidosis, manifests with a "triad" of liver, spleen and bone marrow involvement, often

237
 D.R. MOLLER

with hypercalcaemia. Although this pattern of involvement may be seen in a patient with
multisystem sarcoidosis that includes pulmonary involvement, the greater challenge is for
the clinician to recognise this triad syndrome when it is seen without other common
manifestations of systemic sarcoidosis. Hepatomegaly, splenomegaly with a moth-eaten
radiographic appearance, liver function abnormalities, hypersplenism, abdominal
lymphadenopathy, hypercalcaemia and prominent constitutional symptoms are often
present. If a diagnosis of systemic sarcoidosis has not been established, usually an intra-
abdominal biopsy is needed to exclude malignancy. Granulomas in the liver or bone
marrow are nonspecific and should be used to confirm a diagnosis of sarcoidosis only
when malignancy or infection are reasonably excluded. If there is associated pulmonary
disease or peripheral lymphadenopathy, an intrathoracic or lymph-node biopsy may help
confirm a diagnosis of sarcoidosis. Noncaseating granulomas, from a bronchoscopic
biopsy, provide confidence in a sarcoidosis diagnosis only when there are no atypical
features that favour rigorously excluding malignancy. Abdominal sarcoidosis usually
responds to low-to-moderate doses of CS (e.g. prednisone 1020 mg?day-1), although
side-effects are common and steroid sparing alternatives are often tried.
Symptomatic gastrointestinal involvement in sarcoidosis is unusual. Rarely, direct
oesophageal involvement from sarcoidosis may cause dysphagia, but more commonly
this symptom is caused by extensive mediastinal lymphadenopathy that impinges on the
oesophagus. Gastric sarcoidosis may manifest as dyspepsia or abdominal pain;
endoscopic biopsy demonstrates noncaseating granulomas typical of sarcoidosis. The
condition usually responds to CS therapy. Alhough autopsy studies show scattered
granulomas are often present in the gut in sarcoidosis, clinically symptomatic intestinal
sarcoidosis is rare. The presence of a second disorder, such as Crohns disease, ulcerative
colitis or coeliac disease, must be considered in these instances (see later).

Neurosarcoidosis. Neurosarcoidosis can involve any part of the central or peripheral

nervous system, together manifesting iny510% of patients with sarcoidosis. Many of its
myriad manifestations are rare (discussed in Chapter 11 of this Monograph; table 1).

Cardiac sarcoidosis. Although certain manifestations of cardiac sarcoidosis are rare, the
effects may be devastating and should remain high in the differential of patients with a
known diagnosis of sarcoidosis (discussed in Chapter 9 of this Monograph; table 1).

Haematological sarcoidosis. Persistent, bulky lymphadenopathy occursv10% of the time

[1, 2]. Splenomegaly, occasionally massive, occurs inv5% of cases and is often associated
with hepatomegaly and, occasionally, hypercalcaemia. Nonclonal hypergammaglobulin-
aemia is present in i4050% of patients. A decrease in the gamma globulin fraction should
lead to an evaluation for common variable immunodeficiency (CVID). Pancytopenia may
be caused by hypersplenism, or bone marrow infiltration with granulomas. Although
peripheral lymphopenia is common, rarely, a profound lymphopenia raises concern of HIV
disease. Sarcoidosis is associated with idiopathic thrombocytopenic purpura (ITP) or
autoimmune haemolytic anaemia, although this is rare [17]. One report documented the
utility of high dose steroids to treat ITP associated with sarcoidosis [18].
Chronic lymphoedema is a rare manifestation of sarcoidosis, usually due to scarring of
intra-abdominal or regional lymphatics of the lower extremities from chronic
inflammation. This condition is often associated with considerable morbidity and a
generally poor response to medical or surgical intervention; early treatment with effective
doses of CS or other anti-inflammatory agents is an unproven, but recommended
approach to these patients.

238
 RARE MANIFESTATIONS

Endocrine/exocrine gland. Hypothalamic/pituitary insufficiency is not an uncommon

manifestation of neurosarcoidosis. Pituitary apoplexy or diabetes insipidus are rare,
potentially life-threatening manifestations of neurosarcoidosis. Rarely, sarcoidosis can
involve the thyroid gland, presenting as a nodule, mass or thyroiditis [19, 20]. Sicca
symptoms are not uncommon, caused by inflammation of the salivary and parotid glands.
Steuer et al. [21] reported a case of sarcoidosis presenting after resection of an
adrenocortical adenoma. They speculate that the activity of sarcoidosis was suppressed
before surgery by the high circulating cortisol concentrations, and was subsequently
unmasked by the adrenalectomy. Steuer et al. [21] emphasise that this case illustrates the
suppressive rather than curative effects of steroids on sarcoidosis.

Renal disease. Renal insufficiency in sarcoidosis is usually caused by nephrocalcinosis or

obstructive uropathy from kidney stones. Rarely, direct granulomatous involvement of the
kidneys occurs and is a cause of renal failure. Membranous glomerulonephritis has rarely
been associated with sarcoidosis, and tends to be steroid responsive. AA amyloidosis has
also been reported in association with sarcoidosis with associated proteinuria [22].

Genitourinary involvement. Sarcoidosis involving the genitourinary tract is rare [1]. In

males, sarcoidosis of the reproductive system has been estimated to occur in v0.2% of
clinically diagnosed cases and 5% in autopsy studies [23]. Genitourinary manifestations of
sarcoidosis include testicular masses and acute epididymo-orchitis with testicular swelling.
Biopsy is usually indicated to exclude malignancy in patients with testicular mass regardless
of a prior diagnosis of sarcoidosis. Occasionally, impotentia has been reported, possibly
related to sarcoidosis of the central nervous system or small fibre neuropathy [24, 25].
The effects of genitourinary sarcoidosis on fertility and gonadal function have not
been examined in detail. Rees et al. [26] reported a case of bilateral testicular sarcoidosis
with azoospermia and hypogonadism in whom high-dose CS therapy resulted in partial
recovery of spermatogenesis and gonadal function. Svetec et al. [27] reported a similar
case with epididymal sarcoidosis resulting in secondary infertility. Since sarcoidosis may
adversely affect fertility without obvious symptoms, these investigators suggest that
patients interested in paternity consider a semen analysis at the time of disease diagnosis.
Sarcoidosis of the genitourinary system is also considered to be rare in females;
however, the prevalence of sarcoidosis of the uterus or ovary is unknown since
involvement of these organs may be nonsymptomatic and a diagnosis is based on
histological examination of removed organs. Uterine or ovarian involvement may cause
dysmenorrhoea or manifest as a mass that raises concern for tumours; the latter
manifestation mandates a biopsy to exclude primary or metastatic tumours [28].
Involvement of the endometrium is rare and can be found in elderly females with post-
menopausal metrorrhagia as a focal disease without any other organs effected [29].
Sarcoidosis involving the vagina or vulva has also been reported [30].
In both males and females, documented bladder involvement is rare [31]; more
common is the association of localised or systemic granulomas in association with
primary genitourinary malignancies.

Pregnancy and sarcoidosis. Clinical experience suggests pregnancy has little effect on the
long-term course of sarcoidosis [1, 32, 33]. Spontaneous improvement in chronic
sarcoidosis has been found in some patients during pregnancy and a reduction in CS
dosing may be possible during this time. However, in these patients, an exacerbation often
follows several months following delivery, consistent with a progression of disease
activity, and requires a return to a prior maintenance CS dose. Other than CS, there are no

239
 D.R. MOLLER

therapies that are considered safe to use during pregnancy because of the potential for
foetal toxicity or teratogenicity.
The reasons for clinical improvement in some patients with sarcoidosis who become
pregnant are not known. Conceptually, the improvement during pregnancy is consistent
with the known shift in balance of cytokine profiles away from T-helper cell (Th) type 1
reactivity to Th2-type reactivity during normal pregnancy [34]. This premise does not
only explain why sarcoidosis patients may improve during pregnancy and worsen after
delivery, but also provides an explanation for why patients with asthma, a Th2 dominant
disorder, are likely to worsen during pregnancy.

Rare associations with enhanced Th1 immunity

There are several clinically disparate situations associated with enhancement of Th1
immunity that are associated with development or recrudescence of sarcoidosis (table 2).
These associations provide additional support to the consensus concept that the
pathogenesis of sarcoidosis involves highly polarised Th1 immune responses, presumably
to unknown tissue antigens [35]. These dominant Th1 responses are characterised by
increased production of interferon (IFN)-c, interleukin (IL)-12, IL-18, and tumour
necrosis factor-a at sites of granulomatous inflammation [36].

T-helper cell type 1 promoting agents. The most clear-cut example of this association is
the development of sarcoidosis following the use of therapeutics that are known to
enhance Th1 immune responses. For example, administration of IFN-a, IFN-c and IL-2
biological agents have been associated with onset of new or recrudescent sarcoidosis [37].
IFN-b has also been associated with sarcoidosis when used in multiple sclerosis; for this
biological agent, both Th1 and Th2 promoting effects of this drug have been described.
Since it is likely that other therapeutics with Th1 promoting effects will be employed in the
future, physicians should remain suspicious for sarcoidosis developing in patients being
treated with new agents with immunomodulatory effects. Although of unproven benefit,
discontinuing the specific therapy should be considered, if possible. If there is a compelling
reason for continuing the therapy, the sarcoidosis inflammation generally responds to low
dose CS therapy or hydroxychloroquine.

Common variable immunodeficiency. There is a well-established association of

sarcoidosis with CVID [38, 39]. Although fundamentally a disorder of antibody (B-cell)
production, CVID is heterogeneous in its pathogenesis with associated T-cell defects in
y50% of patients [39]. Due to cross-regulation of Th1 and Th2 responses, it is likely that a
subset of patients with CVID are characterised by deficient Th2 (antibody-promoting)
responses that results in dysregulated, enhanced Th1 immune responses, perhaps a
necessary prelude to the development of sarcoidosis in these patients. Poorly formed
granulomas in response to infections occur in CVID, particularly the lung, and must be
distinguished from the development of systemic sarcoidosis. Systemic sarcoidosis may
develop in y10% of patients with known CVID [38] or, rarely, CVID may be discovered
following a diagnosis of sarcoidosis. In children, a diagnosis of CVID usually precedes
Table 2. T-helper cell type 1 promoting conditions associated with sarcoidosis
Therapy with IFN-a, IL-2, IFN-c, IFN-b
Common variable immunodeficiency
Immune reconstitution in HIV patients undergoing HAART therapy
Various collagen vascular disorders
IFN: interferon; IL: interleukin; HAART: highly active antiretroviral therapy.

240
 RARE MANIFESTATIONS

development of sarcoidosis. Sarcoidosis in these children frequently manifests with

abdominal involvement with hepatosplenic enlargement or progressive pulmonary
infiltrates; the latter require exclusion of infection before a sarcoidosis diagnosis is
made. Since sarcoidosis in children is rare, a diagnosis of sarcoidosis in this age group
mandates an evaluation to exclude CVID. Since CVID occurs at any age, a high index of
suspicion must be maintained for possible CVID in adults with sarcoidosis. Recurrent
sinopulmonary infections or a decreased gamma globulin fraction in patients with
sarcoidosis may be clues to the diagnosis. Recently, Bates et al. [40] described a subset of
patients with CVID and granulomatous-lymphocytic interstitial lung disease with
histological changes of lymphocytic interstitial pneumonia (LIP), lymphoid hyper-
plasia or follicular bronchiolitis in association with granulomatous inflammation. This
subgroup of patients had a significantly worse prognosis, with a poor response to CS therapy
and evolution to lymphoproliferative disease in 31% of patients. This author speculates that
this cohort is a distinct subgroup of CVID patients separate from those CVID patients with
systemic noncaseating granulomas typical of sarcoidosis and without dominant features of
LIP, follicular bronchiolitis or nonspecific interstitial pneumonia.
In all cases, gamma globulin replacement is indicated to reduce the risk of infections
and prevent its consequences, such as bronchiectasis and pulmonary fibrosis. In the
present authors experience, low-dose CS therapy (prednisone 10 mg?day-1 or
equivalent alternate day therapy) or occasionally, hydroxychloroquine alone, is sufficient
to treat those patients with CVID and typical sarcoidosis-type systemic inflammation.
The treatment of the subset of CVID patients with granulomatous-lymphocytic lung
disease is not clear given their poor response to CS and the need to try to avoid
immunosuppressive agents because of the underlying immunodeficiency.

Immune reconstitution in HIV patients. A third clinical situation in which sarcoidosis

develops in the context of imbalanced immunity involves HIV patients with immune
reconstitution following highly active antiretroviral therapy (HAART) [41]. Although it is
often difficult to be confident that granulomatous inflammation in the lungs of HIV
individuals is not infectious in nature, sarcoidosis associated with HAART has been
associated with skin and pulmonary involvement typical for sarcoidosis. CS have been
reported to be beneficial in treating sarcoidosis in this clinical situation. In the present
authors experience, the combination of hydroxychloroquine plus inhaled steroids for
pulmonary involvement has been effective in preventing progressive pulmonary function
impairment or skin disease and avoiding the necessity of oral CS therapy in some of these
patients. Perhaps success of this minimal treatment regimen is a reflection of the tenuous
nature of the enhanced Th1 immune reconstitution found in these individuals.

Rare associations with autoimmune and other chronic inflammatory diseases

Sarcoidosis is rarely associated with a second, distinct autoimmune disease (table 3).
The frequency of an individual developing both sarcoidosis and a second autoimmune
disorder appears to be higher than by chance alone, supporting a causal association [1,
42]. Conceptually, many of these autoimmune diseases are associated with dysregulated
Th1 immunity that would explain at least one common pathogenetic pathway shared
between them. Given the considerable overlap in the systemic manifestations of
sarcoidosis and many autoimmune disorders, the second disorder may be difficult to
diagnose. In general, clues to the presence of an associated autoimmune disease are
found by either clinical manifestations that are outside the spectrum of known
sarcoidosis, or an unexpected clinical course or response to therapy (from either a
sarcoidosis or autoimmune perspective). An example of the former situation is the

241
 D.R. MOLLER

Table 3. Rare associations of sarcoidosis with other systemic and organ-specific diseases

Organ system Clinical disorder

Pulmonary Scleroderma
Oropharyngeal Melkersson-Rosenthal syndrome
Skin Pyoderma gangrenosum
Scleroderma
Porphyria cutanea tarda
Vitiligo
Ocular Idiopathic granulomatous orbital inflammation?
Abdominal Primary sclerosing cholangitis
Primary biliary cirrhosis
Coeliac disease
Crohns disease
Ulcerative colitis
Neurological Progressive multifocal leukoencephalopathy
Joint/musculoskeletal Rheumatoid arthritis
Lupus erythematosis
Scleroderma
Mixed connective tissue disease and overlap syndromes
Marfan
Haematological Common variable immunodeficiency
HIV with immune reconstitution
Autoimmune haemolytic anaemia
Thrombocytopenia
Exocrine gland Sjogrens syndrome
Hashimoto thyroiditis
Renal Membranoproliferative glomerulitis
Amyloidosis
Systemic diseases Autoimmune diseases
Vasculitis
Granulomatous vasculitis overlap with sarcoidosis
Malignancy Lymphoma
GU cancers: renal, testicular, bladder, ovarian, prostate
Myeloproliferative disorders
Thyroid cancer
GU: genitourinary.

presence of sclerodactyly or sclerodermatous skin changes indicating scleroderma in a

patient with sarcoidosis or, conversely, the presence of intrathoracic lymphadenopathy
and widespread noncaseating granulomas in the lungs without an infectious aetiology in
a patient with known scleroderma. An example of the latter situation is a sarcoidosis
patient with a steroid-unresponsive progression of cholestatic jaundice; the presence of
antimitochondrial or antimicrosomal antibodies may point to an association with
primary biliary cirrhosis or sclerosing cholangitis. Rheumatoid arthritis or lupus
erythematosis may be seen with sarcoidosis but require typical clinical manifestations
and high titre rheumatoid factor or antinuclear antibody (ANA)s since low titres of
rheumatoid factor or ANA are commonly seen in sarcoidosis without clinical features of
these autoimmune disorders. One study has found evidence for endocrine autoimmunity
in 19% of patients with sarcoidosis [43].
One rare disease association to note is that of sarcoidosis and Crohns disease or
ulcerative colitis [44, 45]. The presence of typical endoscopic findings for these latter
disorders usually allows an unequivocal diagnosis in the presence of systemic sarcoidosis.
Conversely, although Crohns disease can be associated with modestly enlarged peripheral
or intrathoracic lymphadenopathy and a lymphocytic alveolitis, the presence of extensive
pulmonary infiltrates and intrathoracic lymphadenopathy with typical epithelioid
granulomas on biopsy provides evidence for systemic sarcoidosis. In the present authors

242
 RARE MANIFESTATIONS

experience, when sarcoidosis is seen together with Crohns disease or ulcerative colitis, the
two diseases tend to follow independent courses and response to therapy is characteristic
for each disorder. The same is also true for autoimmune diseases, such as scleroderma.
Coeliac disease may also be associated with sarcoidosis. Irish investigators found a
higher prevalence of coeliac disease in their patients with sarcoidosis, leading them to
recommend screening their sarcoidosis population for this disorder [46]. In Sweden,
Papadopoulos et al. [47] demonstrated gastric autoimmunity and gluten-associated
immune reactivity in almost 40% of patients with sarcoidosis with the former being the
most frequent gastrointestinal immune manifestation [47]. However, despite this high
frequency of humoral autoimmunity, the frequencies of clinical pernicious anaemia or
coeliac disease were not increased compared with a control population.

Rare associations with cancer

Noncaseating granulomas may be seen in or nearby tumours and, less frequently, in
regional draining lymph nodes. These local sarcoid reactions have been most commonly
reported in lymphomas, breast cancer, primary lung cancer, renal cell, ovarian and
stomach cancers. Fungal or mycobacterial infection, foreign body or other causes of local
granulomas must be excluded. Local sarcoidosis reactions are defined by their limited
distribution. Much less commonly, multiorgan granulomas consistent with systemic
sarcoidosis develop simultaneously or shortly following the development of cancer or
following chemotherapy [48, 49]. The most well-established associations are with
lymphoma or testicular cancer. Less commonly, primary lung cancer, uterine, ovarian,
breast or liver cancer or myelogenous leukemia is seen with sarcoidosis, though the
coexistence of these disorders could be due to chance occurrences. In the situations above,
sarcoidosis usually presents with mediastinal or hilar lymphadenopathy or occasionally
with pulmonary interstitial nodules or infiltrates. Both the primary malignancy
and associated granulomatous nodules from sarcoidosis may demonstrate 18F-
fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scanning
(fig. 1). In these instances, a diagnosis of sarcoidosis is usually established by mediastinal
lymph node or open lung biopsy because of the concern of recurrent malignancy (or
associated granulomatous infections). In the current authors experience, there is usually
little functional lung impairment from pulmonary sarcoidosis in these instances, and
treatment is often unnecessary with eventual remission. Although the link between certain
cancers, cancer chemotherapy and sarcoidosis remain controversial, it is plausible that the
basis for these associations is due to dysregulated Th1/Th2 immunity in these situations.
Consistent with this premise, several cases of sarcoidosis and 5q-myelodysplasia have been
reported; this chromosomal abnormality results in deletion of several Th2 genes (IL-4, IL-
13, CSF2) that probably profoundly affect Th1/Th2 regulation [50].

Rare manifestations from late recurrence of sarcoidosis

A widely held view is that once sarcoidosis undergoes remission, the disease rarely
recurs. The exceptions to this "rule" often involve ocular or neurological sarcoidosis,
which uncommonly follows a remittingrelapsing course. The present author has seen
several cases of late onset neurological involvement, particularly cranial neuropathies
that develop suddenly, many years, even decades, following disease remission. Eighth
nerve involvement with hearing loss, tinnitus or balance problems may be most common,
but other cranial nerves also may be affected. Direct confirmation that the underlying
cause is due to sarcoidosis is often lacking because of possible alternatives, such as
diabetes or cerebral vascular disease. Nonetheless, some patients respond to CS therapy

243
 D.R. MOLLER

a)

b)

Fig. 1. a) A three-dimensional reconstruction of a corrected positron emission tomography scan from a patient
with a pathologically proven primary lung cancer in the right lower lobe (arrow) and multiple lesions with
increased uptake of 18F-2-fluoro-2-deoxglucose from granulomatous lesions consistent with sarcoidosis. b) A
high-resolution computed tomography scan of the same patient. This 52-yr-old female was suffering from
sarcoidosis-related complaints with fever, weight loss, arthralgias and fatigue for 2 months. The patient had a
successful lobectomy; the sarcoidosis was monitored without treatment. Scans appear courtesy of M. Drent
(Sarcoidosis Management Centre, University Hospital Maastricht, The Netherlands) and M.J.P.G. van
Kroonenburgh (Dept of Nuclear Medicine, University Hospital Maastricht, The Netherlands).

if begun soon after symptom onset, consistent with recurrent sarcoidosis. Recurrent
erythema nodosum as part of recurrent Lofgrens syndrome has also been described [51].
Late recrudescence of pulmonary or other visceral involvement from sarcoidosis remain
rare and are the topic of few medical reports except when associated with special
circumstances, such as following chemotherapy for cancer or the use of Th1 promoting
agents. Given the rarity of recurrent sarcoidosis, alternative processes must always be
considered before attributing the cause to sarcoidosis.

244
 RARE MANIFESTATIONS

Approach to diagnosis of rare manifestations

The approach to rare manifestations of sarcoidosis differs depending on whether a
diagnosis of systemic sarcoidosis has been established or not. There is no pathognomonic
histopathology for sarcoidosis; a diagnosis is based on a compatible clinical picture,
histological evidence of noncaseating granulomas and the absence of other known causes
of this pathological response [1]. When a clinical manifestation that is rarely associated
with sarcoidosis is encountered, patients with a confident diagnosis of systemic
sarcoidosis (confirmed by biopsy) may be approached by the following strategy. 1)
Evaluate the likelihood that the rare manifestation is a result of sarcoidosis. In this case,
a search of the medical literature is often helpful to substantiate a previously documented
rare association with sarcoidosis [52]. 2) Assess the risk of waiting for a response to
treatment that is indicated based on either systemic sarcoidosis or the specific rare
manifestation. If the rare manifestation is known to occur in sarcoidosis, and the risk of
missing an alternative diagnosis, such as malignancy or superimposed infection is low, a
treatment trial is usually indicated. For example, scattered periventricular enhancing
brain lesions on magnetic resonance imaging (MRI) in a patient with a recent diagnosis
of systemic sarcoidosis might be treated empirically if cerebral spinal fluid examination
reveals no evidence for malignancy or infection. Clinicians must always be willing to re-
evaluate for alternative explanations if there is not a prompt response to therapy
expected for sarcoidosis. Physicians must maintain a high index of suspicion for
nonsarcoidosis diagnoses particularly when new manifestations develop after years of
disease, after clinical remission, or in the context of stable treated sarcoidosis.
If a clinical manifestation deviates from that seen in sarcoidosis, or defining an
alternative diagnosis cannot be delayed, a more definitive diagnostic approach is
indicated. In this situation, directed biopsy of the involved tissue should be considered,
even when there is documentation of a prior biopsy that confirmed an original diagnosis
of sarcoidosis. For example, the development of an isolated nodular infiltrate or mass in
a prior smoker with a history of pulmonary sarcoidosis and a stage I chest radiograph
should prompt a recommendation to biopsy to exclude primary lung cancer.
In clinical circumstances in which a diagnosis of systemic sarcoidosis has not been
established, a direct diagnostic approach to the rare manifestation must usually be
undertaken to exclude competing causes. This situation frequently occurs when evidence
for multiorgan involvement is lacking. For example, a meningeal tumour, intraspinal mass,
large or asymmetric intrathoracic or abdominal lymphadenopathy warrants direct surgical
biopsy to exclude malignancy though sarcoidosis may be in the differential diagnosis.
Patients with sarcoidosis in the differential diagnosis should also undergo evaluation for
systemic sarcoidosis that may provide a safer biopsy approach, if confirmation of a
sarcoidosis diagnosis will obviate the need for a more difficult biopsy procedure. Imaging
techniques, such as gallium scan or more recently, FDG-PET scanning, may be helpful in
these instances to help define sites of clinically occult inflammation that might provide an
alternative diagnostic approach. Laboratory tests are not helpful in confirming a rare
manifestation of sarcoidosis but may assist in establishing an alternative diagnosis.

Therapeutic trial
A biopsy to confirm a rare association with sarcoidosis may not be attempted for several
reasons: 1) inaccessibility of an involved site; 2) undue morbidity that might be associated
with a directed biopsy procedure; or 3) patient refusal. In these situations, a trial of CS
should be considered. A treatment trial to assist in the determination of whether a clinical
problem is a manifestation of sarcoidosis should use CS as the most reliably effective drug

245
 D.R. MOLLER

and the only therapy known to rapidly suppress the granulomatous inflammation.
Possibly, infliximab also may affect a rapid response, but experience to date is limited.
The keys to an effective therapeutic trial are the following: determine objective measures
by which response will be measured; use an effective dose for the organ/tissue involved; and
use an adequate length of time. High doses of corticosteroids may acutely reduce oedema,
but the underlying granulomatous inflammation typically takes weeks, even months, for
maximal suppression. Thus, a trial of CS should generally continue for i23 months
before concluding whether the manifestation is treatment responsive. Depending on the
organ/system involved, there is often a minimally effective dose that is required for
suppression of the granulomatous inflammation. For example, to assess reversibility in
possible cardiac sarcoidosis or pulmonary hypertension from granulomatous pulmonary
vascular disease, prednisone 2030 mg?day-1 is usually sufficient for a therapeutic trial
dose. Intractable cardiac arrhythmias usually warrant a higher CS dose. Abdominal
sarcoidosis typically responds to prednisone 1520 mg?day-1. Higher doses may provide
additional confidence in assessing potential responsiveness, but may not be necessary, as
long as the length of the trial is adequate. None of these anecdotal observations has been
substantiated by clinical trials. Functional response to adequate CS therapy usually
undergoes a logarithmic improvement that plateaus in weeks to months, but the final level
of improvement will be dependent on the amount of fibrosis or irreversible tissue damage
that is present before the trial is started. In patients with extensive fibrosis there may be little
functional improvement; response to treatment in these instances may be assessed by
stability of disease in patients who previously had documented progressive decline in organ
function, e.g. as in pulmonary, cardiac or hepatic sarcoidosis.

Treatment
CS are the cornerstone of therapy for rare manifestations of sarcoidosis given their
overall reliability in acutely providing symptomatic relief and reversing organ
dysfunction in almost all patients with active inflammation. Guidelines for the use
and dosing of CS have been largely based on clinical experience with few well-controlled
clinical trials, and controversy exists regarding their overall effectiveness in altering the
long-term course of the disease. Nonetheless, a consensus view is that these drugs should
be used for the initial treatment of serious, organ-threatening or life-threatening
manifestations of sarcoidosis, whether the manifestations are rare or common [1]. The
antimalarial drugs, hydroxychloroquine and chloroquine, may be useful as first-line
drugs for dominant skin, nasal mucosal and sinus sarcoidosis, but have not been
consistently effective for pulmonary or systemic disease. Hypercalcaemia, laryngeal,
bone and joint involvement have been reported to respond to either hydroxychloroquine
or chloroquine. Given the overall safety of these drugs and their lack of
immunosuppression, these drugs are frequently tried as steroid-sparing or replacing
drugs for nonlife-threatening sarcoidosis. The indications for the use of immunosup-
pressive therapies and other CS-sparing drugs for more serious manifestations in those
with chronic sarcoidosis are discussed elsewhere in this Monograph.

Conclusions
Rare manifestations of sarcoidosis involve unusual patterns of multi-organ
involvement or specific organs uncommonly affected in sarcoidosis. These rare

246
 RARE MANIFESTATIONS

manifestations reflect a pathophysiology and behaviour similar to commonly recognised

clinical manifestations of sarcoidosis.
Rare cases of sarcoidosis are associated with Th1 promoting biological agents,
common variable immunodeficiency or HIV patients with immune reconstitution,
situations that may reflect dysregulated Th1 immunity in sarcoidosis. Sarcoidosis may
rarely be associated with a second disorder, such as autoimmune disease or cancer.
A literature search by internet search engines should be utilised to determine whether
unexpected manifestations have been previously reported for sarcoidosis. In patients with a
confirmed diagnosis of sarcoidosis, a treatment trial for rare manifestations is often
justified if the risk of missing an alternative diagnosis is low. If a diagnosis of systemic
sarcoidosis has not been established, a directed biopsy approach to the rare manifestation is
usually needed to exclude competing causes. Imaging techniques, such as gallium or PET
scanning or MRI, may provide evidence for a pathological process but are nonspecific.
A CS trial to treat or confirm a link to sarcoidosis requires an adequate dose and
duration to assess responsiveness; re-evaluation for alternative explanations is indicated
if there is not a prompt response to therapy expected for sarcoidosis.

Summary
Although most sarcoidosis patients develop manifestations within a clinical frame-
work typical for sarcoidosis, a small number of patients develop unusual
manifestations that challenge clinicians to diagnose and establish treatment for
these problems. These rare manifestations are usually the result of either an
uncommon pattern of systemic involvement or granulomatous inflammation
developing in an unusual location for sarcoidosis. Despite being rarely seen, these
clinical manifestations reflect the same underlying pathophysiological mechanisms
and clinical behaviour common to more easily recognisable systemic sarcoidosis.
Similarly, the known T-helper cell type 1 (Th1) polarisation in sarcoidosis provides the
clinician with a reminder that Th1-promoting therapeutics, such as interferon-a,
common variable immunodeficiency or immune reconstitution in HIV patients, are
associated with development of sarcoidosis. Sarcoidosis may also be associated with
autoimmune disease or cancer, although this is rare.
An approach to sarcoidosis patients with possible rare manifestations must be
individualised according to whether a diagnosis of sarcoidosis has already been
established or not. As an initial step, an internet search may substantiate previous
experience with similar manifestations. The clinician will often need to: 1) recommend
additional diagnostic testing or biopsy, unless there is already biopsy-proven systemic
sarcoidosis; and 2) check the rare manifestation is consistent with sarcoidosis and that
the chance of an alternative diagnosis is low. In this latter situation, the clinician may
recommend a trial of corticosteroid treatment to support an association with
sarcoidosis. In patients without a confirmed diagnosis of sarcoidosis, a directed
evaluation with biopsy is usually indicated.
In all situations, the clinician must remain vigilant that unusual manifestations of
sarcoidosis may, in fact, represent an alternative condition. Although the diagnostic
approach to rare manifestations must be individualised, the patient and clinician are
usually rewarded by establishing a link to sarcoidosis so that treatment specific to
sarcoidosis can be tailored for maximal benefit.

Keywords: Autoimmunity, sarcoidosis, T-helper cell type 1 immunity.

247
 D.R. MOLLER

Acknowledgements. This work was supported in part by the Life and Breath Foundation
and the Hospital for the Consumptives of Maryland (Eudowood). The author has no
conflicting financial interests.

References
1. Statement on Sarcoidosis. Joint statement of the American Thoracic Society (ATS), European
Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous
Diseases (WASOG) adopted by the ATS Board of Directors and by the ERS Executive
Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736755.
2. Baughman RP, Tierstein AS, Judson MA, et al. Clinical characteristics of patients in a case control
study of sarcoidosis. Am J Resp Crit Care Med. 2001; 164: 18851889.
3. Judson MA, Baughman RP, Thompson BW, et al. ACCESS research group two year prognosis of
sarcoidosis: the ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 204211.
4. Preston IR, Klinger JR, Landzberg MJ, Houtchens J, Nelson D, Hill NS. Vasoresponsiveness of
sarcoidosis-associated pulmonary hypertension. Chest 2001; 120: 866872.
5. Sharma OP. Diagnosis of cardiac sarcoidosis: an imperfect science, a hesitant art. Chest 2003;
123: 1819.
6. Narayan D, Brown L, Thayer JO. Surgical management of superior vena caval syndrome in
sarcoidosis. Ann Thorac Surg. 1998; 66: 946948.
7. Popper HH, Klemen H, Colby TV, Churg A. Necrotising sarcoid granulomatosis-is it different
from nodular sarcoidosis? Pneumologie 2003; 57: 268271.
8. Shah RN, Mills PR, George PJ, Wedzicha JA. Upper airways sarcoidosis presenting as obstructive
sleep apnoea. Thorax 1998; 53: 232233.
9. James DG, Barter S, Jash D, MacKinnon DM, Carstairs LS. Sarcoidosis of the upper respiratory
tract (SURT). J Laryngol Otol 1982; 96: 711718.
10. Rogers RS 3rd. Melkersson-Rosenthal syndrome and orofacial granulomatosis. Dermatol Clin
1996; 14: 371379.
11. Mignogna MD, Fedele S, Lo Russo L, Lo Muzio L. The multiform and variable patterns of onset
of orofacial granulomatosis. J Oral Pathol Med 2003; 32: 200205.
12. Vainsencher D, Winkelmann RK. Subcutaneous sarcoidosis. Arch Dermatol 1984; 120: 10281031.
13. Papageorgiou PP, Hongcharu W, Chu AC. Systemic sarcoidosis presenting with multiple tattoo
granulomas and an extra-tattoo cutaneous granuloma. J Eur Acad Dermatol Venereol 1999;
12: 5153.
14. Lombardi T, Kuffer R, Dubrez B. Polishing-paste-induced silica granuloma of the gingiva.
Dermatology 2001; 203: 177179.
15. Chang KC, Chan KT, Chong LY, Lau KS, Tam CM, Lam CW. Cutaneous and pulmonary
sarcoidosis in a Hong Kong Chinese woman with silicone breast prostheses. Respirology 2003;
8: 379382.
16. Teuber SS, Howell LP, Yoshida SH, Gershwin ME. Remission of sarcoidosis following removal of
silicone gel breast implants. Int Arch Allergy Immunol. 1994; 105: 404407.
17. Kondo H, Sakai S, Sakai Y. Autoimmune haemolytic anaemia, Sjogrens syndrome and
idiopathic thrombocytopenic purpura in a patient with sarcoidosis. Acta Haematol 1993; 89: 209
212.
18. Chakrabarti S, Behera D, Varma S, Bambery P. High-dose methyl prednisolone for autoimmune
thrombocytopenia in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: 188.
19. Lemerre D, Caron F, Delval O, et al. Thyroid manifestations of sarcoidosis: a case report. Rev
Pneumol Clin 1999; 55: 393396.
20. Nakamura H, Genma R, Mikami T, et al. High incidence of positive autoantibodies against

248
 RARE MANIFESTATIONS

thyroid peroxidase and thyroglobulin in patients with sarcoidosis. Clin Endocrinol (Oxf) 1997;
46: 467472.
21. Steuer A, Cavan DA, Lowy C. Sarcoidosis presenting after resection of an adrenocortical
adenoma. BMJ 1995; 310: 567568.
22. Rainfray M, Meyrier A, Valeyre D, Tazi A, Battesti JP. Renal amyloidosis complicating
sarcoidosis. Thorax 1988; 43: 422423.
23. Porter N, Beynon HL, Randeva HS. Endocrine and reproductive manifestations of sarcoidosis.
QJM 2003; 96: 553561.
24. Niedner R, Wokalek H. Disorders of potency caused by sarcoidosis. Hautarzt 1985; 36: 563
565.
25. Hoitsma E, Reulen JP, de Baets M, Drent M, Spaans F, Faber CG. Small fiber neuropathy: a
common and important clinical disorder. J Neurol Sci 2004; 227: 119130.
26. Rees DA, Dodds AL, Rathbone N, Davies JS, Scanlon MF. Azoospermia in testicular sarcoidosis
is an indication for corticosteroid therapy. Fertil Steril 2004; 82: 16721674.
27. Svetec DA, Waguespack RL, Sabanegh ES Jr. Intermittent azoospermia associated with
epididymal sarcoidosis. Fertil Steril 1998; 70: 777779.
28. Parveen AS, Elliott H, Howells R. Sarcoidosis of the ovary. J Obstet Gynaecol 2004; 24: 465.
29. DiCarlo FJ Jr, DiCarlo JP, Robboy SJ, Lyons MM. Sarcoidosis of the uterus. Arch Pathol Lab
Med 1989; 113: 941943.
30. Klein PA, Appel J, Callen JP. Sarcoidosis of the vulva: a rare cutaneous manifestation. J Am Acad
Dermatol 1998; 39: 281283.
31. Tammela T, Kallioinen M, Kontturi M, Hellstrom P. Sarcoidosis of the bladder: a case report and
literature review. J Urol 1989; 141: 608609.
32. Selroos O. Sarcoidosis and pregnancy: a review with results of a retrospective survey. J Intern Med
1990; 227: 221224.
33. Chapelon Abric C, Ginsburg C, Biousse V, et al. Sarcoidosis and pregnancy. A retrospective study
of 11 cases. Rev Med Interne 1998; 19: 305312.
34. Raghupathy R. TH1-type immunity is incompatible with successful pregnancy. Immunology
Today 1997; 18: 478482.
35. Muller-Quernheim J. Sarcoidosis: immunopathogenetic concepts and their clinical application.
Eur Respir J 1998; 12: 716738.
36. Moller DR, Forman JD, Liu MC, et al. Enhanced expression of IL-12 associated with Th1
cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996; 156: 49524960.
37. Marzouk K, Saleh S, Kannass M, Sharma OP. Interferon-induced granulomatous lung disease.
Curr Opin Pulm Med 2004; 10: 435440.
38. Fasano MB, Sullivan KE, Sarpong SB, et al. Sarcoidosis and common variable immunodeficiency.
Report of 8 cases and review of the literature. Medicine (Baltimore) 1996; 75: 251261.
39. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable
immunodeficiency. Ann Intern Med 1997; 127: 613617.
40. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-
lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin
Immunol 2004; 114: 415421.
41. Lenner R, Bregman Z, Teirstein AS, DePalo L. Recurrent pulmonary sarcoidosis in HIV-infected
patients receiving highly active antiretroviral therapy. Chest 2001; 119: 978981.
42. Sharma OP. Sarcoidosis and other autoimmune disorders. Curr Opin Pulm Med 2002; 8: 452456.
43. Papadopoulos KI, Hornblad Y, Liljebladh H, Hallengren B. High frequency of endocrine
autoimmunity in patients with sarcoidosis. Eur J Endocrinol 1996; 134: 331336.
44. Johard U, Berlin M, Eklund A. Sarcoidosis and regional enteritis in two patients. Sarcoidosis Vasc
Diffuse Lung Dis 1996; 13: 5053.
45. Fries W, Grassi SA, Leone L, et al. Association between inflammatory bowel disease and
sarcoidosis. Report of two cases and review of the literature. Scand J Gastroenterol 1995; 30: 1221
1223.

249
 D.R. MOLLER

46. Rutherford RM, Brutsche MH, Kearns M, Bourke M, Stevens F, Gilmartin JJ. Prevalence of
coeliac disease in patients with sarcoidosis. Eur J Gastroenterol Hepatol 2004; 16: 911915.
47. Papadopoulos KI, Sjoberg K, Lindgren S, Hallengren B. Evidence of gastrointestinal immune
reactivity in patients with sarcoidosis. J Intern Med 1999; 245: 525531.
48. Brincker H. Coexistence of sarcoidosis and malignant disease: causality or coincidence?
Sarcoidosis 1989; 6: 3143.
49. Romer FK, Hommelgaard P, Schou G. Sarcoidosis and cancer revisited: a long-term follow-up
study of 555 Danish sarcoidosis patients. Eur Respir J 1999; 14: 482483.
50. Airaghi L, Montori D, Zorzi F, Miadonna A, Tedeschi A. Sarcoidosis in a patient with 5q-
myelodysplasia. A possible pathogenetic link between the two diseases. Monaldi Arch Chest Dis
2000; 55: 378380.
51. Mana J, Montero A, Vidal M, Marcoval J, Pujol R. Recurrent sarcoidosis: a study of 17 patients
with 24 episodes of recurrence. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 212221.
52. National Library of Medicine. PubMed. www.ncbi.nlm.nih.gov/entrez/query.fcgi. Date last
accessed: May 19 2005.

250
CHAPTER 16

Sarcoidosis in children

A. Clement, R. Epaud, B. Fauroux

Paediatric Pulmonology Dept and Research Unit, Institut National de la Sante et de la Recherche
Medicale (INSERM) U719, Hopital dEnfants Armand Trousseau, Paris, France.

Correspondence: A. Clement, Paediatric Pulmonology Dept and Research Unit, INSERM U719, Hopital
dEnfants Armand Trousseau, 26 Avenue du Dr Arnold Netter, 75571 Paris Cedex 12, France. Fax: 33
144736718; E-mail: annick.clement@trs.aphp.fr

Sarcoidosis is relatively uncommon among children. Its diagnosis is based on a

combination of suggestive clinical features, with histologically documented noncaseating
granuloma, in the absence of other known causes of granuloma formation.

Epidemiology
The incidence and prevalence of sarcoidosis are reported to be influenced by age, race
and geographical localisation. The disease shows a peak between the ages of 2040 yrs.
Although the youngest reported patients were infants aged 2 and 3 months, most of the
cases reported in children have occurred in pre-adolescents and adolescents [1, 2]. From
the national patient registry of patients with sarcoidosis in Denmark during the period
19791994, 48 patients with a confirmed diagnosis were aged 15 yrs [3]. The calculated
incidence was 0.29 cases per 100,000 person-yrs in those aged 15 yrs. In children aged
4 yrs, the incidence was 0.06 cases per 100,000 person-yrs, increasing gradually to 1.02
cases per 100,000 person-yrs in children aged 1415 yrs. It is important to point out that
the age-specific incidence and prevalence of paediatric sarcoidosis remain uncertain since
it is, without doubt, an underdiagnosed condition. Indeed, the disease can be
asymptomatic, particularly in its earliest stages, and, in most countries, children do
not undergo routine chest radiography.
Marked racial differences in the incidence and prevalence of sarcoidosis have been
reported by many authors. For example, in the USA, the prevalence of adult sarcoidosis
is approximately three times higher in Blacks than in Caucasians [4]. Various reports in
the literature also indicate that race and ethnicity affect both the pattern of organ
involvement and disease severity. In a follow-up study conducted in 21 children with
pulmonary sarcoidosis, 12 were Black [5]. In addition, the number of organs involved
was greater in the Black than in the Caucasian children.
From all of the reports in various populations of adult patients with sarcoidosis, the
wide variations in incidence and prevalence suggest the influence of genetic factors on
disease susceptibility. A genetic influence is further supported by familial cases of sarcoi-
dosis [6, 7]. To date, linkage studies in familial sarcoidosis have shown that some areas of
the genome are linked to sarcoidosis, with the strongest linkage reported for the major
histocompatibility complex genes [8]. Currently, no data are available on familial cases of
sarcoidosis involving paediatric patients. As for adults, gene polymorphisms of
inflammatory mediators may be associated with expression of the disease in children.
The pro-inflammatory genes of interest most probably include the tumour necrosis
Eur Respir Mon, 2005, 32, 251258. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
251
 A. CLEMENT ET AL.

factor-a gene [9]. Other polymorphisms of potential relevance are polymorphisms of

angiotensin-converting enzyme (ACE), with reported associations of genotypes
influencing serum ACE levels and specific manifestations of the disease in adult patients
[10].

Disease expression
Clinical manifestations in sarcoidosis are the consequences of local tissue infiltration
with sarcoid granulomas. Therefore, disease expression depends on the organ or system
involved, and a variety of symptoms and physical findings can be observed. As indicated
above, sarcoidosis in children is not detected by abnormal routine chest radiographs, and
children are not found to be asymptomatic at the time of diagnosis. The modes of
presentation include nonspecific constitutional symptoms, alone or associated with
symptoms related to specific organ involvement [1114]. In the recent report of 48
children with sarcoidosis in Denmark [3], the most common nonspecific symptoms were
fatigue, weight loss and fever. Clinical findings mainly include respiratory manifesta-
tions, lymphadenopathy, skin lesions, and ocular and central nervous system
abnormalities. Disease expression seems to be influenced by age, with skin, eye and
joint manifestations being more frequently observed on initial presentation in younger
children.

Lung involvement
The respiratory symptoms most commonly observed include cough and dyspnoea.
Physical examination results can be normal, or may document the presence of crackles
and rhonchi. As for adults, chest radiographic descriptions range stages 0IV. The most
common radiographic findings in children are hilar lymph node enlargement, with or
without lung changes. In the recent Danish report, chest imaging results were normal in
10% of cases (stage 0); 71% of the patients exhibited hilar lymphadenopathy (stage I),
8.3% parenchymal involvement (stage II), and only one parenchymal involvement alone
(stage III). None of the 48 children showed evidence of irreversible pulmonary fibrosis
[3].
The lung function abnormalities observed in children are mainly characterised by
reductions in vital capacity (VC) and functional residual capacity [5]. Decreases in
dynamic lung compliance and the transfer factor of the lung for carbon monoxide
(TL,CO) are also reported. Abnormalities in arterial blood gas levels are not frequently
observed [15].

Extrathoracic involvement
Peripheral lymphadenopathy is one of the most common physical findings in children
with sarcoidosis. Nineteen (40%) of the 48 paediatric patients in the Danish study
exhibited peripheral lymphadenopathy, and this localisation contributed to the diagnosis
in 15 patients by showing the typical epithelioid cell granulomas without necrosis [3]. The
spleen can also be involved, frequently with splenomegaly.
Ocular symptoms are common, and may be the initial manifestation of the disease [14,
16, 17]. In the report of 21 children with sarcoidosis, uveitis was the presenting symptom
in nine cases [5]. In the Danish report, 29% of the patients showed eye involvement.
Anterior segment diseases are the most frequent, with chronic granulomatous uveitis,

252
 SARCOIDOSIS IN CHILDREN

acute iritis and conjunctival granulomas. Posterior segment diseases are less common
(periphlebitis and chorioretinal granuloma).
Skin lesions are observed in approximately a quarter of patients [18, 19]. Many types of
lesion are found, including purplish papules, plaques, subcutaneous nodules and
hypopigmented lesions. Lupus pernio and erythema nodosum are not frequently
observed in children.
Liver involvement is usually mild, with mainly an asymptomatic increase in hepatic
enzyme levels. In rare cases, hepatomegaly can be documented. In children, needle biopsy
of the liver can be proposed for disease diagnosis, even without any signs of liver
involvement [5].
Neurosarcoidosis is seldom recognised in children. Baumann and Robertson [20]
recently reported 29 cases, in patients aged between 3 months and 18 yrs, with 48% aged
v13 yrs. Seizures were the most common symptom. A total of 21% showed
hypothalamic dysfunction. Five children presented with headache, four with motor
signs and three with papilloedema. Twenty-four per cent showed mass lesions on
imaging. This study tends to indicate that neurosarcoidosis shows different character-
istics in children compared with adults. The authors concluded that children are more
likely to have seizures, probably because of space-occupying lesions, and less likely to
show cranial nerve palsies.
Cystic bone lesions are rare in children and often associated with skin lesions. Joint
pains are reported in y20% of patients, with acute polyarthritis or chronic arthropathy
observed in y510%. Granulomas are rarely found in joint tissue in the case of transient
arthralgia [19].
Cardiac involvement is uncommon in children. It is mainly recognised by use of a
conventional electrocardiogram. Information on heart disease in the paediatric group is
very limited, and cardiac investigations should be performed in all children with
sarcoidosis. In young adults, the main manifestations are arrhythmia, conduction
abnormalities and congestive heart failure [21].
Other organ involvement reported in children includes the kidney, which may result in
nephrocalcinosis and renal failure, the parotid gland with uveoparotid fever, the tonsils,
and the pituitary gland with diabetes insipidus [11, 12].

Diagnostic approach
The diagnosis of sarcoidosis is currently based on a combination of suggestive clinical
features, with histologically documented noncaseating granuloma, in the absence of
other known causes of granuloma formation. Several laboratory investigations, such as
bronchoalveolar lavage (BAL), blood tests (ACE) and gallium scanning, can provide
additional evidence of sarcoidosis, but tissue biopsy is required for diagnosis.

Biopsy
The site for biopsy is dependent on the manifestations of the disease. In adult patients,
transbronchial lung biopsy is the recommended procedure in most cases. However, this
procedure can only be proposed in older children in specialised centres. In other
situations, possible sites of biopsy mainly include visible skin lesions, superficial lymph
nodes, minor salivary glands and the liver. Needle aspiration of the liver represents an
interesting option in children in whom no other sites can be proposed [5]. In very extreme
situations, surgical lung biopsy may be indicated.
The basic histopathological lesion is the noncaseating epithelioid cell granuloma. The

253
 A. CLEMENT ET AL.

granuloma consists of highly differentiated mononuclear phagocytes (epithelioid cells

and giant cells) and lymphocytes. The central portion of the granuloma consists of
predominantly CD4z lymphocytes, whereas CD8z lymphocytes are present in the
peripheral zone. The sarcoid granuloma may develop fibrotic changes that usually begin
at the periphery and travel centrally. Granulomas may occasionally exhibit focal
coagulative necrosis. Sarcoid granulomas are of a similar nature in any organ.

Other investigations
It is important to perform BAL in all children suspected of having sarcoidosis. Lung
involvement is characterised by a predominant increase in the absolute and relative
numbers of lymphocytes [4]. However, other lung disease may demonstrate lymphocytic
alveolitis similar to that in sarcoidosis. The CD4:CD8 ratio has been reported by several
groups to be increased in sarcoidosis [22, 23]. However, neither the number of
lymphocytes nor the CD4:CD8 ratio in BAL fluid is a specific feature of any pulmonary
disorder. A combination of results, an elevated total cell count, predominantly
lymphocytes, together with a nearly normal percentage of eosinophils and polymorpho-
nuclear neutrophils, and the lack of plasma cells, may help in distinguishing sarcoidosis
from extrinsic allergic alveolitis, pulmonary fibrosis and bacterial infection.
Among the biological markers commonly measured are ACE and lysozyme levels,
calcium metabolism parameters and biochemical liver function [24, 25]. Serum ACE
levels are elevated in 4090% of patients. The sources of this circulating enzyme most
probably include the epithelioid cells and macrophages at the site of inflammation, and
may reflect the total body granuloma burden. The levels of ACE at diagnosis have no
prognostic significance, and are not different between patients who deteriorate and those
who improve. Calcium metabolism can be deregulated in patients with sarcoidosis. This
is mainly explained by granuloma production of the active form of vitamin D.
Consequently, hypercalcaemia and hypercalcinuria can be observed, and, in some
situations, may impair renal function. In the Danish study, hypercalcaemia was observed
in almost 30% of the children.
Among other investigations, gallium scanning has been used in several paediatric
groups. However, as for adult patients, it is of limited clinical utility in children with
sarcoidosis [4]. Anergy to tuberculin is classic in sarcoidosis, and may provide
additional support for the diagnosis. In adults, a growing number of biochemical
parameters in serum and BAL fluid are currently being proposed for the management of
patients, such as levels of soluble interleukin-2 receptor, which seems to be a better
predictor of pulmonary severity than ACE level. These parameters need to be studied in
children.

Patient management and prognosis

Once the diagnosis is confirmed, the type and number of organs involved need to be
assessed, together with the severity of the different lesions [26, 27]. This is critical for
therapeutic discussions [2830]. As for adult patients, the clinical findings that require
corticosteroid therapy remain controversial. In children with mild disease, such as
anterior uveitis or skin lesions, topical steroid may be all that is necessary. In children
with more severe forms of the disease, oral and/or systemic forms of steroids are
employed. Systemic therapy is clearly indicated for eye disease not responding to topical
therapy, cardiac disease, neurological disease and hypercalcaemia. For lung sarcoidosis,

254
 SARCOIDOSIS IN CHILDREN

most paediatric physicians feel that progressive symptomatic disease with altered
pulmonary function should be treated.
Depending on disease severity, the steroid treatment is oral steroid either alone or in
combination with intravenous pulse methylprednisolone therapy. Oral prednisone is
generally started at a dose of 2 mg?kg body weight-1?day-1, and slowly tapered over 2
3 months to the lowest dose. The gradual tapering is guided by disease status. In severe
situations, steroid pulses are started using 300 mg?m-2 methylprednisolone daily for
3 days, repeated once every 46 weeks [31]. The duration of steroid treatment in children
with sarcoidosis has not been established, and it is most unlikely that there will a
consensus in the near future as randomised prospective trials cannot be performed in the
paediatric population. From several reports in the literature, 18 months may be
reasonable treatment duration. In any case, patients need to be monitored for relapse
after reduction or discontinuation of therapy. Alternative drugs alone or in association
with steroids can be proposed in children, based on reports on management of adult
sarcoidosis. These include mainly cytotoxic agents and the antimalarial drugs
chloroquine and hydroxychloroquine. To date, reports in children with these
medications are very limited [3234].
At present, the management of sarcoidosis remains empirical. This is because the
course of the disease is difficult to predict in an individual patient. In addition, there is
ample evidence that many adults experience spontaneous remission within 6 months
after diagnosis. The degree of uncertainty surrounding the treatment of sarcoidosis is
even greater in children than in adults since few paediatric studies have been published
and long-term data from adults may not be relevant to children. For pulmonary disease,
events related to lung growth may influence the course of sarcoidosis. Marcille et al.
[35] analysed data from 19 patients diagnosed with sarcoidosis in childhood and followed
for a mean of 21 yrs. Pulmonary function test results remained abnormal in 68% of the
patients. Although the adults included in this study may not be representative of the
population of patients with a diagnosis of sarcoidosis during childhood, the findings
suggest that the long-term outcome of sarcoidosis may be different in children and
adults.
In the study of 21 children with pulmonary sarcoidosis, four were initially managed
without specific medication [5]. All four exhibited mild symptoms and normal pulmonary
function test results. During follow-up, repeated pulmonary function testing results
remained normal. The initial BAL fluid contained an increased population of
lymphocytes, and, 12 yrs after the diagnosis, BAL fluid analysis showed persistently
high percentages of lymphocytes, with an increased CD4z:CD8z ratio. In 17 children,
glucocorticoid treatment was initiated based on clinical presentation and symptoms, sites
and types of extrapulmonary disease, and results of pulmonary function tests. On initial
evaluation, all 17 children had alterations in VC, dynamic lung compliance and/or TL,CO,
and 11 showed chest radiographic abnormalities. All children underwent repeated
physical evaluations, during which the presence, nature and severity of symptoms were
noted. After 6 months, chest radiography results had returned to normal in 10 of the 11
children with initial abnormalities. Improvements were seen in VC and TL,CO. By
contrast, no significant modifications in BAL fluid results were recorded. After 12 and
18 months, pulmonary function test results were unchanged compared to the 6-month
evaluation, and all 17 children yielded normal chest radiographs. No further significant
improvements were seen in pulmonary function test results during the 34 yrs of follow-
up. Interestingly, BAL studies showed a persistent increase in the proportion of
lymphocytes throughout follow-up.
Based on these results, the following management of children with pulmonary
sarcoidosis can be proposed. BAL should be performed at the initial evaluation to
document alveolitis; however, nothing seems to be gained from repeating this

255
 A. CLEMENT ET AL.

investigation during follow-up in the absence of specific indications. Once the decision to
initiate glucocorticoid therapy is made, treatment efficacy should be evaluated based on
clinical manifestations, chest radiographs and pulmonary function test results. The
treatment can be stopped even if the pulmonary function test results remain abnormal,
but the child should then be carefully monitored for relapse.
Based on the small number of reports on sarcoidosis in children, it is not easy to give
valuable information on prognosis. It is felt from the experience of paediatric physicians
that the overall prognosis is generally good, with rapid improvement upon corticosteroid
treatment. Very young children seem to experience more severe forms of the disease. In
adults, it has been recently suggested that the number of polymorphonuclear neutrophils
in BAL fluid may be useful in distinguishing patients with a more favourable outcome
from those showing a more severe course. There are currently no data available in
children to support this hypothesis.

Conclusion
Sarcoidosis is an example of a difficult diagnosis in children, as it is based on a
combination of suggestive clinical features in the absence of other known causes of
granuloma formation. Appropriate anti-inflammatory treatment has not been well
defined in terms of molecules, doses and durations, especially in children. In addition,
valuable markers of disease activity and severity are still lacking. Although sarcoidosis is
thought to have a good prognosis in children, much of the current understanding and
management is based on empirical information and data drawn from adult patient
reports. This implies that prospective studies are urgently needed in the paediatric
population. Also, a genetic predisposition is strongly suggested, with recent associations
reported with the major histocompatibility complex genes in adult patients in
sarcoidosis. Search for genetic influences should be developed in children.

Summary
Sarcoidosis is a chronic inflammatory disease in which granulomatous lesions can
develop in many organs. It is a rare disease in children, affecting mainly adolescents.
Its diagnosis is based on a combination of suggestive clinical features, with
histologically documented noncaseating granuloma, in the absence of other known
causes of granuloma formation. Information on genetic predisposition are lacking in
children. The clinical expression of the disease is dominated by the involvement of the
lung, eyes, skin, lymph nodes and liver. Management of paediatric patients remains
empirical, due to the absence of validated criteria of disease activity and severity. Most
children with sarcoidosis receive corticosteroids, a reasonable treatment duration
being 18 months. The prognosis is clinically good, but long-term persistence of lung
function abnormalities and alveolitis on bronchoalveolar lavage is frequently
observed.

Keywords: Children, granulomatous disorder, lung, sarcoidosis.

256
 SARCOIDOSIS IN CHILDREN

References
1. Byg KE, Milman N, Hansen S. Sarcoidosis in Denmark 19801994. A registry-based incidence
study comprising 5536 patients. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 4652.
2. Roy M, Sharma OP, Chan K. Sarcoidosis presenting in infancy: a rare occurrence. Sarcoidosis
Vasc Diffuse Lung Dis 1999; 16: 224227.
3. Hoffmann AL, Milman N, Byg KE. Childhood sarcoidosis in Denmark 19791994: incidence,
clinical features and laboratory results at presentation in 48 children. Acta Paediatr 2004; 93: 30
36.
4. Costabel U. Sarcoidosis: clinical update. Eur Respir J 2001; 18: Suppl. 32, 56s68s.
5. Baculard A, Blanc N, Boule M, et al. Pulmonary sarcoidosis in children: a follow-up study. Eur
Respir J 2001; 17: 628635.
6. Luisetti M, Beretta A, Casali L. Genetic aspects in sarcoidosis. Eur Respir J 2000; 16: 768780.
7. McGrath DS, Daniil Z, Foley P, et al. Epidemiology of familial sarcoidosis in the UK. Thorax
2000; 55: 751754.
8. Rybicki BA, Iannuzzi MC, Frederik MM, et al. Familial aggregation of sarcoidosis. A case-
control etiological study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001; 164: 2085
2091.
9. Schurmann M, Reichel P, Muller-Myhsok B, Schlaak M, Muller-Quernheim J, Schwinger E.
Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care
Med 2001; 164: 840846.
10. McGrath DS, Foley PJ, Petrek M, et al. ACE gene I/D polymorphism and sarcoidosis pulmonary
disease severity. Am J Respir Crit Care Med 2001; 164: 197201.
11. James D. Sarcoidosis and Other Granulomatous Disorders. New York, Marcel Dekker, 1994.
12. James D, Kendig E. Childhood sarcoidosis. Sarcoidosis 1988; 5: 5759.
13. Kendig E. The clinical picture of sarcoidosis in children. Pediatrics 1974; 54: 289292.
14. Milman N, Hoffmann A, Byg K. Sarcoidosis in children. Epidemiology in Danes, clinical features,
diagnosis, treatment and prognosis. Acta Paediatr 1998; 87: 871878.
15. Lamberto C, Nunes H, Le Toumelin P, Duperron F, Valeyre D, Clerici C. Membrane and
capillary blood components of diffusion capacity of the lung for carbon monoxide in pulmonary
sarcoidosis: relation to exercise gas exchange. Chest 2004; 125: 20612068.
16. Lindsley CB, Petty RE. Overview and report on international registry of sarcoid arthritis in
childhood. Curr Rheumatol Rep 2000; 2: 343348.
17. Stoffel PB, Sauvain MJ, von Vigier RO, Beretta-Piccoli BC, Ramelli GP, Bianchetti MG. Non-
infectious causes of uveitis in 70 Swiss children. Acta Paediatr 2000; 89: 955958.
18. Yanardag H, Pamuk ON, Karayel T. Cutaneous involvement in sarcoidosis: analysis of the
features in 170 patients. Respir Med 2003; 97: 978982.
19. Fetil E, Ozhkan S, Ilknur T, Kavukcu S, Kusku E, Lebe B. Sarcoidosis in a preschooler with only
skin and joint involvement. Pediatr Dermatol 2003; 20: 416418.
20. Baumann RJ, Robertson WC. Neurosarcoid presents differently in children than in adults.
Pediatrics 2003; 112: Suppl. 6 Pt 1, e480e486.
21. Syed J, Myers R. Sarcoid heart disease. Can J Cardiol 2004; 20: 8993.
22. Tessier V, Chadelat K, Baculard A, Housset B, Clement A. BAL in children. A controlled study of
differential cytology and cytokine expression profiles by alveolar cells in pediatric sarcoidosis.
Chest 1996; 109: 14301438.
23. Chadelat K, Baculard A, Grimfeld A, et al. Pulmonary sarcoidosis in children : serial evaluation of
bronchoalveolar lavage cells during corticosteroid treatment. Pediatr Pulmonol 1993; 16: 4147.
24. Hunninghake GW, Costabel U, Masayuki A, et al. ATS/ERS/WASOG statement on sarcoidosis.
American Thoracic Society, European Respiratory Journal, World Association of Sarcoidosis and
other granulomatous disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
25. Hunninghake G, Costabel U, Ando M, et al. Statement on sarcoidosis. Joint Statement of the

257
 A. CLEMENT ET AL.

American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World
Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS
Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care
Med 1999; 160: 736755.
26. Pattishall E, Kendig E. Sarcoidosis in children. Pediatric Pulmonol 1996; 22: 195203.
27. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet 2003; 361: 11111118.
28. Rothkrantz-Kos S, van Dieijen-Visser MP, Mulder PG, Drent M. Potential usefulness of
inflammatory markers to monitor respiratory functional impairment in sarcoidosis. Clin Chem
2003; 49: 15101517.
29. Judson M. An approach to the treatment of pulmonary sarcoidosis with corticosteroids. The six
phases of treatment. Chest 1999; 115: 11581165.
30. Judson MA, Baughman RP, Thompson BW, et al. Two year prognosis of sarcoidosis: the
ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 204211.
31. Desmarquest P, Tamalet A, Fauroux B, et al. Chronic intestitial lung disease in children: response
to high-dose intravanous methylprednisolone pulses. Pediatr Pulmonol 1998; 26: 332338.
32. Gedalia A, Molina JF, Ellis GSJ, Galen W, Moore C, Espinoza LR. Low-dose methotrexate
therapy for childhood sarcoidosis. J Pediatr 1997; 130: 2529.
33. Hilton JM, Cooper DM, Henry RL. Hydroxychloroquine therapy of diffuse pulmonary
sarcoidosis in two Australian male children. Respirology 1997; 2: 7174.
34. Paramothayan S, Lasserson T, Walters EH. Immunosuppressive and cytotoxic therapy for
pulmonary sarcoidosis. Cochrane Database Syst Rev 2003; 3: CD003536.
35. Marcille R, McCarthy M, Barton J, Merten D, Spock A. Long-term outcome of pediatric
sarcoidosis with emphasis on pulmonary status. Chest 1992; 102: 14441449.

258
CHAPTER 17

Diagnostic approach to sarcoidosis

U. Costabel*, J. Guzman#, M. Drent}

*Dept of Pneumology/Allergy, Ruhrlandklinik, Essen, and #General and Experimental Pathology, Ruhr
University, Bochum, Germany. }Sarcoidosis Management Centre, Dept of Respiratory Medicine,
University Hospital Maastricht, Maastricht, The Netherlands.

Correspondence: U. Costabel, Dept of Pneumology/Allergy, Tuschener Weg 40, Ruhrlandklinik, D-45239

Essen, Germany. Fax: 49 2014334029; E-mail: erj.costabel@t-online.de

There is no single diagnostic test for sarcoidosis. The presence of noncaseating

granulomas in a single organ, such as skin, does not establish a diagnosis of sarcoidosis.
The finding of a granuloma is not specific for this disease, since many other conditions
can cause granulomas.
The diagnosis of sarcoidosis is based on the following criteria: 1) a compatible clinical
and/or radiological picture; 2) histological evidence of noncaseating granulomas; and 3)
exclusion of other diseases capable of producing a similar histological or clinical picture.
In suspected sarcoidosis, the diagnostic procedures aim to accomplish the following
goals [1]: 1) provide histological confirmation of the disease; 2) evaluate the extent and
severity of organ involvement; 3) assess whether the disease is stable or likely to progress;
and 4) determine if the patient will benefit from treatment.

Initial presentation
As sarcoidosis is a multi-organ disorder, patients may present initially to various
organ specialists, depending on the symptoms. They may be seen by an ophthalmologist,
a dermatologist, a rheumatologist, or any other specialist who will then perform the
appropriate organ-specific examinations. If sarcoidosis is suspected or confirmed, the
patient should be referred to a pulmonary specialist who would then take over the
management of the patient, since the intrathoracic manifestations are the most frequent,
and the pulmonary specialist usually sees most of the patients. If there is a need for
consultation of another organ specialist during the follow-up, the pulmonary physician
will transfer the patient, but should keep the general management of the patient during
the course of his disease. In this regard, the management of patients with sarcoidosis
requires a multidisciplinary approach.

Compatible clinical picture

Nonspecific constitutional symptoms, including fever (generally low-grade, but up to
40uC has been observed), weight loss (usually limited to 26 kg during the 1012 weeks
prior to presentation), and malaise are present in about one-third of patients, whereas
fatigue and weakness can be seen in up to 70% of patients [2]. Sarcoidosis should always
be included in the differential diagnosis of fever of unknown origin.
The clinical findings related to the involvement of specific organs vary in frequency.
Eur Respir Mon, 2005, 32, 259264. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
259
 U. COSTABEL ET AL.

Dyspnoea and cough are often reported, since pulmonary involvement is the most
frequent.
There are two different types of onset in sarcoidosis patients. Acute sarcoidosis has an
abrupt onset and may present as Lofgrens syndrome, which is characterised by bilateral
hilar adenopathy, ankle arthritis, erythema nodosum and frequently constitutional
symptoms. Generally, chronic sarcoidosis has an insidious onset, and organ-related
symptoms are often related to the pulmonary infiltration. Constitutional symptoms are
less common than in the acute form.

Compatible radiographic picture

The chest radiographic findings vary to a great extent and they are discussed in detail in
chapters 8 and 18 of this Monograph. Clinical and radiological findings alone are highly
reliable in patients with stage I disease (accuracy 98%); the diagnostic reliability in stage II
disease is also good (89%), but it is less for stage III (52%) or stage 0 (23%) disease [3, 4]. In a
classical study of 100 consecutive patients with bilateral hilar adenopathy (BHL), over 95%
of asymptomatic individuals with BHL and normal physical examination had sarcoidosis
[5]. Malignancies were the cause of BHL in 11 out of 100 patients, and all were
symptomatic. Therefore, histological confirmation may not be needed in asymptomatic
patients who have symmetrical BHL. However, when the hilar lymph adenopathy is
asymmetrical, massive or associated with large paratracheal enlargement, biopsy
confirmation is strongly advised. In patients with a classical Lofgrens syndrome, biopsies
are usually not necessary. Biopsy of erythema nodosum should be avoided, since
histopathology shows no granuloma but nonspecific inflammation and vasculitis.
It is important to ask for previous chest radiographs. If they can be provided and show
minor BHL, which may have been overlooked, and later show the development to stage
II disease, such characteristic changes during the course may be sufficient to allow a
diagnosis of sarcoidosis without biopsy confirmation.

Biopsy procedures and BAL

Biopsies can be obtained from easily accessable organs, such as peripheral lymph
nodes, the skin, or the nasal mucosa. Historically, biopsies of scalene lymph nodes or
mediastinoscopy were often performed. Nowadays, fiberoptic bronchoscopy with
mucosal biopsy, transbronchial lung biopsy, transbronchial needle aspiration, and
bronchoalveolar lavage (BAL) is the recommended procedure of choice [1]. The risks of
the procedures are very low in experienced hands. The diagnostic yield of transbronchial
lung biopsy is high, reaching up to 80%, if four to five adequate samples are obtained [6].
Bronchial mucosal biopsies should also be taken since the histological demonstration of
granuloma is possible in 4060%, even when the bronchial mucosa is grossly normal.
When gross endoscopic findings, such as mucosal nodularity, oedema or hypervascu-
larity are present, the yield may reach 90% [7].
The BAL fluid shows an increase in lymphocytes in 90% of sarcoidosis patients at the
time of diagnosis. Such a BAL lymphocytosis is nonspecific and seen in many other
disorders. When interpreting the cell differentials in regard to the differentiation of
sarcoidosis versus other disorders, not a single parameter is important, but a combination
of several features including: a normal or only mildly elevated total cell count with a
predominance of lymphocytes, usually a normal percentage of eosinophils and
neutrophils, and a lack of plasma cells and foamy alveolar macrophages is characteristic

260
 DIAGNOSTIC APPROACH TO SARCOIDOSIS

for sarcoidosis. Recently, Drent et al. [8] were able to differentiate between major
interstitial lung disorders with a computer program for BAL data, using a discriminate
analysis of logistic regression, with excellent accuracy [8]. A BAL CD4z/CD8z ratio of
w3.5 is very specific for sarcoidosis. Three independent groups have shown very similar
values for the sensitivity and specificity of BAL CD4z/CD8z ratios [911]. A ratio of
w3.5 has a sensitivity of 5259% and a specificity of 9496%. The three studies reached
similar conclusions; in patients with a clinical/radiological picture typical of sarcoidosis,
an elevated CD4z/CD8z ratio in BAL may confirm the diagnosis and obviate the need
for confirmation by additional biopsy. In the study of Winterbauer et al. [10],
transbronchial lung biopsy had a specificity of 89% for the distinction between
sarcoidosis and other forms of diffuse lung disease, and was, therefore, no better than the
CD4z/CD8z ratio for this distinction. A recent study aimed to quantify how the
likelihood for a given diagnosis changes with the knowledge of BAL cell differentials and
the CD4z/CD8zratio. Welker et al. [12] found that, when lymphocytes were combined
with the CD4z/CD8z ratio, the probability of sarcoidosis was doubled if the CD4z/
CD8z ratio was high. They were able to demonstrate an added informative value of the
CD4z/CD8z ratio, especially in sarcoidosis and extrinsic allergic alveolitis [12].
If bronchoscopic biopsies or BAL failed and no other easily accessible sites are
identified, mediastinoscopy or surgical lung biopsy (usually by VATS) may be indicated.
Biopsy of the liver is not specific and not recommended as a routine procedure. A
detailed comparison of the biopsy procedures and the histopathological changes is
provided in chapter 6 of this Monograph.

Additional investigations
Several tests are recommended in the initial evaluation of sarcoidosis as routine
procedure for all patients (table 1). Pulmonary function tests have only a modest
correlation with the chest radiograph. They provide a baseline for detection of
improvement or deterioration during the further course of the disease, and should be
done at the time of diagnosis even in patients without pulmonary signs and symptoms.
Only 20% of patients with stage I disease show abnormalities in pulmonary function
tests, compared with 4070% in the other radiographic stages [13]. The most sensitive
tests are the carbon monoxide diffusion capacity of the lung and the vital capacity. The
typical finding is a restrictive pattern, whereas an obstructive pattern is seen in up to 30%
of patients, and bronchial hyperreactivity is present in 25%. Changes in gas exchange
with exercise are even more sensitive than lung function tests at rest [14]. Blood testing is
performed to exclude hypercalcaemia and significant hepatic, renal or haematological
Table 1. Recommended tests for initial evaluation of sarcoidosis

Type of evaluation
History (occupational and environmental exposure, symptoms)
Physical examination
Posteroanterior chest radiography
Pulmonary function tests: spirometry and carbon monoxide diffusion capacity
Peripheral blood counts: white blood cells, red blood cells, platelets
Serum chemistries: calcium, liver enzymes, creatinine, blood urea nitrogen
Urine analysis
Electrocardiography
Routine ophthalmologic examination
Tuberculin skin test
Adapted from [1].

261
 U. COSTABEL ET AL.

involvement. Routine ophthalmological investigation, including an initial slit lamp

examination, is obligatory in all patients in order to exclude a clinically silent uveitis.
Chest computed tomography (CT) scans are not routinely needed. In some patients
(y30% of patients, according to the experience of the present authors) high-resolution
CT (HRCT) is indicated for the following reasons. 1) Atypical clinical and/or chest
radiographic findings; 2) a normal chest radiograph but a clinical suspicion of the
disease; 3) suspected complications of lung disease, such as bronchiectasis, aspergilloma,
and traction emphysema; or 4) superimposed infection or malignancy. The characteristic
findings of HRCT are described in detail in chapter 18. Briefly, apart from hilar and
mediastinal adenopathy, the characteristic findings are nodular infiltrates with
bronchovascular and subpleural distribution, thickened interlobular septa, architectural
distortion, and conglomerate masses originating from coalescence of nodules in the
perihilar, peribronchovascular, or subpleural regions [15]. In contrast to the conventional
chest radiographic findings, the appearance and the extent of disease on HRCT, such as
thickening or irregularity of the bronchovascular bundle, intraparenchymal nodules,
septal and nonseptal lines and focal pleural thickening, correlate with parameters of
respiratory functional impairment, both at rest and at maximal exercise [16].
Further investigations are needed if extrapulmonary sarcoidosis is suspected. These
investigations are discussed in detail in the organ manifestation chapters of this
monograph. It is important to recognise extrathoracic involvement early, since the
prognosis is dictated not only by the radiographic stages, but also by certain organ
manifestations, many of those having an adverse impact on prognosis (table 2) [17].

Assessment of activity
The term "activity" is frequently used in sarcoidosis, but often misinterpreted. Activity
should not be mixed up with the extent or severity of the disease (i.e. the number of
involved organs, or the density of granulomas within an involved organ), should also not
be associated with unfavourable prognosis (e.g. the highly active acute disease,
manifesting as Lofgrens syndrome, has the best prognosis), and also not be
misinterpreted with the necessity of initiating corticosteroid therapy [18]. Active disease
means that the disease has not yet come to a rest, that there is still ongoing T-cell and
macrophage inflammation and granuloma formation (reflected by increased soluble
interleukin (IL)-2 receptor levels or angiotensin-converting enzyme (ACE) levels) with
the potential that the disease may progress, whereas inactive disease means that the
disease has come to a rest and will probably not progress any further.
A long list of laboratory and cell biological markers has been discussed as potential
indices of active disease, either in serum or in BAL fluid [1719]. However, none of them
Table 2. Adverse prognostic factors in sarcoidosis

Type of factor
Lupus pernio
Chronic uveitis
Age of onset w40 yrs
Chronic hypercalcaemia
Nephrocalcinosis
Black race
Progressive pulmonary sarcoidosis
Nasal mucosal involvement
Cystic bone lesions
Neurosarcoidosis
Myocardial involvement

262
 DIAGNOSTIC APPROACH TO SARCOIDOSIS

can be recommended for routine assessment, perhaps with the exception of serum ACE,
reflecting the granuloma burden, and the soluble IL-2 receptor, reflecting the activity of the
T-cell component [2022]. Serum ACE may be useful in monitoring the course of disease.
Increased ACE activity will usually be reduced within a few weeks of the start of
corticosteroid treatment. In the future, revised normal ranges, corrected for the ACE
genotype, might improve the clinical significance of this marker [23]. The quantification
and subtyping of lymphocytes in BAL fluid have not fulfilled the early promise of being
useful markers of disease activity. The prognostic value of increased neutrophils seems to
be more promising. Two independent studies found a higher number of neutrophils in BAL
fluid in a group of patients who deteriorated in the follow-up, but further experience and
prospective studies are necessary to confirm this for the individual patient [20, 24].
At present, the best way to assess the activity of sarcoidosis is still through traditional
clinical investigations. The clinical activity is assessed on the basis of onset, worsening
or persistence of symptoms, or signs directly related to sarcoidosis. These may be
constitutional symptoms, or the new development or changes of skin lesions, in
combination with changes in chest radiography and lung function tests. However, it is
of more clinical relevance to depict disease extent and severity than the activity of
sarcoidosis in an individual patient.

Summary
The diagnostic approach to sarcoidosis is a complex procedure. There is no single
diagnostic test for this disease. The diagnosis is based on three criteria: a compatible
clinical and/or radiological picture, histological evidence of noncaseating granulomas,
and exclusion of other diseases that may produce a similar histological or clinical
picture. The diagnostic procedures should accomplish the following goals: 1) provide
histological confirmation of the disease; 2) evaluate the extent and severity of organ
involvement; 3) assess whether the disease is stable or likely to progress; and 4)
determine if the patient will benefit from treatment.
The clinical picture depends on the type of onset. Acute sarcoidosis has an abrupt
onset and may present as Lofgrens syndrome. Chronic sarcoidosis has an insidious
onset, and organ-related symptoms are often caused by the pulmonary infiltration. It
is important to know that nonspecific constitutional symptoms, including fever,
weightloss, and fatigue, may occur in a high proportion of patients.
The chest radiographic findings have various diagnostic reliability: stage I disease has an
accuracy of 98% and, thus, a high diagnostic reliability, stage II is still good (89%), but
the diagnostic reliability is low in the other stages. Biopsies can be obtained from easily
accessable organs, such as peripheral lymph nodes, or the skin. In most cases, fibreoptic
bronchoscopy with various biopsy techniques is the recommended procedure of choice.
In the bronchoalveolar lavage fluid, a lymphocytosis is quite sensitive, but less specific,
whereas an increased CD4z/CD8zratio increase is less sensitive, but highly specific for
sarcoidosis. Additional tests include pulmonary function testing, laboratory tests and
screening for important extrathoracic organ involvement.
The best way to assess the activity remains through traditional clinical investigations, on
the basis of onset, worsening or persistance of symptoms or signs directly related to
sarcoidosis. No single biochemical or cell biological marker has a better predictive value
for prognosis or disease state than the classic chest radiographic staging system.

Keywords: Activity, diagnostic approach, sarcoidosis, severity.

263
 U. COSTABEL ET AL.

References
1. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
2. Drent M, Wirnsberger RM, De Vries J. Association of fatigue with an acute phase response in
sarcoidosis. Eur Respir J 1999; 13: 718722.
3. Hiraga Y, Hosoda Y. Acceptability of epidemiological diagnostic criteria for sarcoidosis without
histological confirmation. In: Mikami R, Hosoda Y, eds. Sarcoidosis. Tokyo, University of Tokyo
Press, 1981; pp. 373377.
4. Reich JM, Bouns MC, OConnor EA, Edwards MJ. Mediastinoscopy in patients with presumptive
stage I sarcoidosis. Chest 1998; 113: 147153.
5. Winterbauer RH, Belic N, Moores KD. A clinical interpretation of bilateral hilar addenopathy.
Ann Intern Med 1973; 79: 6571.
6. Gilman MJ, Wang KP. Transbronchial lung biopsy in sarcoidosis: an approach to determine the
optimal number of biopsies. Am Rev Respir Dis 1980; 122: 721724.
7. Armstrong JR, Radke JR, Kvale PA, et al. Endoscopic findings in sarcoidosis. Ann Otol 1981;
90: 339434.
8. Drent M, Jacobs JA, Cobben NA, et al. Computer program supporting the diagnostic accuracy of
cellular BALF analysis: a new release. Respir Med 2001; 95: 781786.
9. Costabel U, Zaiss AW, Guzman J. Sensitivity and specifity of BAL findings in sarcoidosis.
Sarcoidosis 1992; 9: Suppl. 1, 211214.
10. Winterbauer RH, Lammert J, Selland M, et al. Bronchoalveolar lavage cell populations in the
diagnosis of sarcoidosis. Chest 1993; 104: 352361.
11. Thomeer M, Demedts M. Predicitive value of CD4/CD8 ratio in bronchoalveolar lavage in the
diagnosis of sarcoidosis (abstract). Sarcoidosis Vasc Diffuse Lung Dis 1997; 14: Suppl. 1, 36.
12. Welker L, Jorres RA, Costabel U, Magnussen H. Predictive value of BAL cell differentials in the
diagnosis of interstitial lung diseases. Eur Respir J 2004; 24: 10001006.
13. Lynch JP 3rd, Kazerooni EA, Gay SE. Pulmonary sarcoidosis. Clin Chest Med 1997; 18: 755785.
14. Delobbe A, Perrault H, Maitre J, Robin S, et al. Impaired exercise response in sarcoid patients
with normal pulmonary function. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 148153.
15. Wells A. High resolution computed tomography in sarcoidosis: a clinical perspective. Sarcoidosis
Vasc Diffuse Lung Dis 1998; 15: 140146.
16. Drent M, De Vries J, Lenters M, et al. Sarcoidosis: assessment of disease severity using HRCT.
Eur Radiol 2003; 13: 24622471.
17. Costabel U. Sarcoidosis: clinical update. Eur Respir J 2001; 18: Suppl. 32, 56s68s.
18. Costabel U, du Bois RD, Eklund A. Consensus conference: activity of sarcoidosis. Sarcoidosis
1994; 11: 2733.
19. Costabel U, Teschler H. Biochemical changes in sarcoidosis. Clin Chest Med 1997; 18: 827842.
20. Ziegenhagen MW, Rothe ME, Schlaak M, Muller-Quernheim J. Bronchoalveolar and serological
parameters reflecting the severity of sarcoidosis. Eur Respir J 2003; 21: 407413.
21. Grutters JC, Fellrath JM, Mulder L, et al. Serum soluble interleukin-2 receptor measurement in
patient with saroidosis: a clinical evaluation. Chest 2003; 124: 186195.
22. Rothkrantz-Kos S, van Dieijen-Visser MP, Mulder PGH, Drent M. Potential usefulness of
inflammatory markers to monitor respiratory functional impairment in sarcoidosis. Clin Chem
2003; 49: 15101517.
23. Sharma P, Smith I, Maguire G, et al. Clinical value of ACE genotyping in diagnosis of sarcoidosis.
Lancet 1997; 349: 16021603.
24. Drent M, Jacobs JA, De Vries J, et al. Does the cellular bronchoalveolar lavage fluid profile reflect
the severity of sarcoidosis? Eur Respir J 1999; 13: 13381344.

264
CHAPTER 18

Sarcoidosis: imaging features

J.A. Verschakelen

Dept of Radiology, University Hospitals, Leuven, Belgium.

Correspondence: J. Verschakelen, Dept of Radiology, University Hospitals, Herestraat 49, B-3000

Leuven, Belgium. Fax: 32 16343765; E-mail: johny.verschakelen@uz.kuleuven.ac.be

Sarcoidosis is a granulomatous disease of unknown aetiology that shows multi-

systemic involvement and that is predominantly seen in young and middle-aged patients,
with a slightly higher prevalence in females [1]. The histological hallmark of sarcoidosis is
noncaseating granulomas with proliferation of epitheloid cells [2]. Although the disorder
is multisystemic, pulmonary manifestations typically dominate. Chest radiographs are
abnormal in 9095% of patients with bilateral hilar adenopathy as the most common
radiological finding [1, 3]. Although cough and dyspnoea may be present in patients
with thoracic involvement, 3060% of the patients are asymptomatic making the find-
ings on the chest radiograph incidental. The initial manifestation of the disease can also
be related to the involvement of structures outside the chest [1, 3, 4]. Although skin and
ocular lesions are most common, the liver, spleen, parotid glands, central nervous system
(CNS), genitourinary system, and the bones and muscles may also be involved.
The diagnosis of sarcoidosis is commonly established on the basis of clinical and
radiological findings supported by histological findings. Thoracic involvement is often
easily recognised on a chest radiograph when hilar adenopathy is present (fig. 1).
However, although probably not necessary in every patient, computed tomography (CT)
and High-resolution CT (HRCT) can play an important role in the diagnosis and staging

a) b)

Fig. 1. a) Posteroanterior and b) lateral chest radiograph show broadening of the paratracheal mediastinum,
nodular opacities in both hila (white arrows) and a convex border of the aortic pulmonary window caused by
enlarged lymph nodes. Notice also some reticular involvement of the lung parenchyma.

Eur Respir Mon, 2005, 32, 265283. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
265
 J.A. VERSCHAKELEN

of thoracic sarcoidosis (fig. 2) [5]. CT cannot only demonstrate subtle mediastinal

adenopathy, which is hardly or not visible on a chest radiograph, but can also better
show lung parenchymal involvement. Moreover, some (HR)CT features are moderately
characteristic for the disease. Although magnetic resonance imaging (MRI) may be
useful in the evaluation of mediastinal and pulmonary involvement, the main develop-
ment of this technique has taken place in the evaluation of neurosarcoidosis, and to a
lesser degree in bone, muscle and cardiac sarcoidosis [6].
In this review the radiological presentation of sarcoidosis will be discussed and
illustrated. The review will start with a description of the radiograph and CT features
of mediastinal and pulmonary involvement of sarcoidosis and the correlation of these
features with disease activity and pulmonary function. Also, a paragraph on cardiac
involvement is included. In the second part the imaging characteristics of selected
extrathoracic manifestations of sarcoidosis will be discussed briefly.

Intrathoracic manifestations of sarcoidosis

Common features

Lymphadenopathy. More than 80% of the patients with sarcoidosis have intrathoracic
adenopathy at the time of the presentation [79]. These enlarged lymph nodes are
classically located in both hila, in the pre- and right paratracheal mediastinum, in the
aortopulmonary window, in the subcarinal area and, less frequently, in the anterior and
posterior mediastinum. However, only the right paratracheal and hilar lymph nodes
and those located in the aortic pulmonary window can easily identified on a poster-
oanterior and lateral chest radiograph (fig. 1) [1012]. A CT examination is usually
necessary to show the involvement of the other node groups (fig. 2) [12]. Although
contrast-enhanced (CE) CT will better differentiate between enlarged lymph nodes and
the vascular structures in the mediastinum, and especially in the hila, injection of con-
trast is not always necessary to make the diagnosis. Mediastinal adenopathy without
hilar involvement or with unilateral hilar involvement is rare but can be seen especially
in older patients [13]. Hamper et al. [14] found unilateral hilar adenopathy in six out of
29 patients who were aged w50 yrs when the initial diagnosis of sarcoidosis was made.
In this study, two patients had isolated mediastinal lymph node enlargement. Calcifica-
tion can occur in affected nodes, especially in patients with longstanding sarcoidosis, and

a) b)

Fig. 2. a) Axial and b) coronal computed tomography images in a patient with sarcoidosis. Enlarged lymph
nodes can be seen in the mediastinum and in both hila.

266
 IMAGING FEATURES

can be amorphous, punctuate, or eggshell (fig. 3) [7, 13]. One study, examining nodes with
CT in 49 patients with biopsy-proven sarcoidosis, showed nodal calcification in 53%
of patients [15]. Hilar adenopathy was often bilateral, while the eggshell pattern was seen
in 42% of patients with nodal calcification [16, 17].

Pulmonary parenchymal disease. Lung involvement in sarcoidosis is present in 2550%

of patients and has a strong predilection for the upper lung [3, 4]. In addition, although
both diffuse and peripheral patterns are seen, the abnormalities are often centrally
distributed [18].

Chest radiograph. Reticular, reticulonodular or focal alveolar opacities are the most
characteristic features on a chest radiograph (fig. 4ac) [14, 19]. Confluent areas of lung
consolidation and multiple well-circumscribed pulmonary nodules are less commonly
seen [14, 2023]. A ground-glass pattern is only very rarely present [24]. End-stage disease
may manifest as conglomerated masses, and broad and coarse septal bands with archi-
tectural distortion, hilar retraction, upper lobe volume loss and, finally, honeycomb
change and large bullae (fig. 4d). Extensive calcification may be encountered within
fibrotic granulomas [13]. These processes are usually seen predominantly in the central
and upper lung; a distribution that is typical for sarcoidosis, but can also be seen in
tuberculosis and silicosis. In advanced fibrosis, enlarged pulmonary arteries indicating
pulmonary arterial hypertension and bronchiectasis may be observed.

Computed tomography. Pulmonary infiltrates and their distribution pattern are usually
better appreciated on a CT examination. The cross-sectional format of CT allows a better

Fig. 3. Lateral chest radiograph (detail) showing multiple calcified lymph nodes in the hilum and in the
mediastinum (arrows). Most calcifications show an eggshell pattern (arrows).

267
 J.A. VERSCHAKELEN

a) b)

c) d)

Fig. 4. a) Reticular, b) reticulonodular and c) focal alveolar opacities are the most characteristic features on a
chest radiograph. d) End-stage disease characterised by the presence of conglomerated masses and coarse septal
bands with architectural distortion, hilar retraction and upper lobe volume loss. Notice also the pulmonary
calcifications (arrows).

recognition of the axial distribution of the disease, whilst coronal reformations generated
from spiral CT can more accurately show the craniocaudal distribution [25, 26]. Due
to their higher density, resolution CT scans may detect parenchymal changes that
are below the resolution of conventional chest radiographs. Moreover, with CT and,
especially with HRCT, a detailed analysis of the lung parenchymal changes becomes
possible and this technique can often depict whether a disease shows a predominant
vascular, airway or lymphatic distribution or whether the disease is predominantly
located in the interstitial tissue. This is particularly helpful in the diagnosis of sarcoid-
osis. Indeed, sarcoid granulomas are typically distributed along the lymphatic vessels,
which run within the interstitial tissues of the bronchovascular bundles down to the
terminal bronchioles, in the interlobular septa and subpleural [27].
The (HR)CT features of lung parenchymal involvement in sarcoidosis depend upon
the stage and chronicity of the disease. Nodules which vary in size from 2 mm to 1 cm are
the most commonly seen pulmonary parenchymal abnormality (fig. 5) [2832]. These
nodules represent aggregates of granulomas, with or without peribronchiolar fibrosis

268
 IMAGING FEATURES

a)

b)

c)

Fig. 5. Nodules representing aggregates of granulomas are the most commonly seen pulmonary parenchymal
abnormality on computed tomography (CT) (ac). They are typically located in the lymphatics along the large
and small bronchovascular bundles (causing thickened bronchovascular bundles; black arrow), and, to a lesser
extent, in the subpleural lymphatics (causing nodular delineation of the pleura and of the fissure; black
arrowheads), in the interlobular septal (giving rise to a beaded appearance of these septa; white arrows) and
centrilobular lymphatics (giving rise to peripheral centrilobular nodules; white arrowheads) (a and b). Confluent
nodular opacities can present on CT as areas of lung consolidation, possibly with an air bronchogram (c).

269
 J.A. VERSCHAKELEN

[33]. On (HR)CT these nodules usually are sharply defined, have irregular margins [34]
and are typically located in the lymphatics along the large and small broncho-
vascular bundles (causing thickened bronchovascular bundles), and to a lesser extent in
the subpleural lymphatics (causing nodular delineation of the pleura and of the fissure),
in the interlobular septal (giving rise to a beaded appearance of these septa) and
centrilobular lymphatics (giving rise to peripheral centrilobular nodules) (fig. 5a, b) [32,
34, 35].
The thickening of the bronchovascular bundles and beaded appearance of the
interlobular septa and fissures may mimic lymphangitic carcinomatosis, especially
when this thickening is more uniform and less nodular. Differential diagnosis between
the two entities is usually possible by the upper lobe preponderance in sarcoidosis,
and the more extensive and linear thickening of the interlobular septa in lymphangitic
carcinomatosis [36]. In addition, lymphangitic carcinomatosis is frequently unilateral,
whereas sarcoidosis is typically bilateral in nature. The differential diagnosis with other
nodular diseases is based on the study of the distribution pattern and the delineation of
the nodules [37, 38]. Although sharply defined, haematogeneous metastases usually show
a random distribution. Also, miliary infection (tuberculosis, fungus) shows a random
distribution and can be well- or ill-defined. Hypersensitivity pneumonitis, bronchiolitis
and haemorrhage can also have a nodular appearance but these nodules are usually
ill-defined and located in the centre part of the secondary pulmonary lobule. Nodules
seen in organising pneumonia and Langerhans cell histiocytosis are usually well-defined
and also show a centrilobular distribution.
Confluent nodular opacities can present on CT as areas of lung consolidation with air
bronchograms (fig. 5c). This parenchymal consolidation is usually bilateral and symme-
trical and shows an upper and midlung distribution. Also, areas of ground-glass opacity
may be seen. When ground-glass opacity is seen on thick-slice CT scans, small nodules
may be identified on thinner slices [39]. The cause of ground-glass attenuation on HRCT
is uncertain. It has been suggested that this feature corresponds to active alveolitis and
reversible disease (fig. 6a) [40]. However, ground-glass opacity with a coarse texture and
with traction bronchiectasis may reflect irreversible fibrotic changes (fig. 6b). It should be
emphasised, however, that these areas of ground-glass opacity can be caused by increased
perfusion secondary to vascular redistribution. This vascular redistribution is secondary
to the decreased perfusion in the surrounding areas which results from hypoventilation
caused by bronchiolar narrowing (mosaic pattern) (fig. 6c and d). Sometimes a "crazy
paving" pattern can be observed. This pattern consists of ground-glass attenuation with
superimposed interlobular septal thickening [41].
Although lung nodules and consolidation, when evaluated over time, often disappear
or decrease in number and extent, fibrosis may develop in advanced disease and signs
that reflect irreversible disease can then be observed [4244]. These signs include fibrous
bands, and architectural distortion of the fissures, (thickened) interlobular septa, bronchi
and blood vessels (fig. 7a). Also, retraction of the hila, bronchiectasis and cystic radio-
lucencies including cysts, bullae and paracicatricial emphysema, are seen (fig. 7b) [29, 31,
32]. These fibrotic and cystic changes are typically worse in the upper lobes and follow
large airways in a perihilar distribution (fig. 7) [30, 34, 45, 46]. This upper lobe and
perihilar distribution is usually specific enough to suggest the diagnosis of sarcoidosis,
although in a very small percentage of patients sarcoidosis may produce HRCT signs
almost identical to idiopathic pulmonary fibrosis, i.e. signs of fibrosis in a peripheral,
subpleural and lower lobe distribution [47]. Mycetomas may complicate upper lobe
bullae [34]. In some patients, dense mass-like lesions with air bronchograms may be
observed [31, 33, 42, 44]. These correspond to bronchial and bronchiolar dilatation with
surrounding fibrosis.
Air-trapping is another very common CT feature in patients with sarcoidosis and

270
 IMAGING FEATURES

a) b)

c) d)

Fig. 6. Ground-glass opacity on thin-slice computed tomography can indicate active a) alveolitis, but it can
also be caused by b) irreversible fibrosis and by c) increased perfusion secondary to vascular redistribution
(mosaic pattern). This mosaic pattern is accentuated on expiratory scans (d).

is seen in all stages of the disease [29, 4850]. This sign can only be appreciated on
expiratory CT scans and is characterised by the presence of multiple patchy areas of
decreased attenuation, i.e. areas that do not increase in density and decrease in size on the
expiratory scans (fig. 8). Often the lung attenuation is normal on inspiratory scans,
although, as mentioned earlier, in some patients a mosaic pattern is already seen on the
inspiratory scans (fig. 6c and d). Air-trapping is very common and was noted in 89% of
patients in one study and in 95% of patients in another study [29, 49]. It may involve any

a) b)

Fig. 7. Advanced disease with lung fibrosis characterised by the presence of fibrous bands, architectural
distortion of the fissures, septa, bronchi and blood vessels (a and b). Also retraction of the hila, bronchiectasis
and cystic radiolucencies can be seen (b).

271
 J.A. VERSCHAKELEN

a)

b)

c)

AW

Fig. 8. High-resolution computed tomography (HRCT) at a) end-inspiration and b) at end-expiration. c) Air-

trapping is very common, may involve any lung zone and reflects small airway narrowing caused by granulomas
(arrows) adjacent to the small airways (AW). Scale bar=1,000 mm. Figure 8c appears courtesy of B. Vrugt (Dept
of Pathology, Martini Hospital, Groningen, The Netherlands).

272
 IMAGING FEATURES

lung zone and may be the only CT feature of pulmonary sarcoidosis [51]. It reflects small
airway narrowing, which is very probably caused by granulomas adjacent to the small
airways (fig. 8c) [52].
It should be emphasised that multiples of these CT patterns may co-exist in individual
patients (the combination of central homogeneous areas of lung consolidation and
surrounding small nodules is very suggestive for sarcoidosis) and may evolve over time,
and that signs of potentially reversible disease can be seen in combination with findings
that reflect irreversible fibrosis [53]. Table 1 shows the most frequent CT features of
sarcoidosis.

Uncommon features
Although more frequently seen on a CT scan than on a chest radiograph, primary
cavitation as a result of central necrosis due to confluent granulomas is rare. It was
evident in v1% of patients on a chest radiograph in one study and in 2% of patients on
CT in another study [54, 55]. If cavitation occurs, superimposed infection should be
considered.
Pleural effusion is seen in only 14% of patients with sarcoidosis on a chest radiograph
and a little more frequently on CT scans [21, 44, 56, 57]. Pleural thickening is often seen
and is usually not caused by pleural involvement with sarcoidosis, but is the result of
fibrotic retraction of extrathoracic soft tissue and fat.
As mentioned earlier fibrotic changes are often responsible for the development of small
bullous changes (fig. 7b). More rarely, large bullae develop [58]. The cause of these
lesions is unknown. Possible causes include air-trapping and alveolar distension due to
bronchiolar narrowing, destruction of lung tissue by active alveolitis and retraction and
collapse of the surrounding lung with air-filling of more compliant airspaces [59].
Rarely sarcoidosis presents as a solitary pulmonary nodule (fig. 9) [22, 60, 61].
Mycetomas may develop in any of the above mentioned cystic spaces and are seen in
about 13% of patients [62, 63]. Typically they develop in the upper lobes [62, 64]. The
observer should be alerted when new pleural thickening adjacent to a known cystic
space develops because this can be the first sign of a developing mycetoma.
Pneumothorax is another rare manifestation of sarcoidosis which usually occurs late
in the course of the disease [65].

Disease activity and correlation with pulmonary function

Although its value is relatively limited, the chest radiograph is still widely used to
predict the severity of pulmonary involvement and to have an idea about the prognosis of

Table 1. CT features of sarcoidosis

Sharply defined nodular opacities located in the central lung and upper lobes in:
The peribronchovascular interstitium
Relation to the centrilobular structures
The interlobular septa
The pleural surfaces
Large nodules, lung consolidation and conglomerate masses
Ground-glass opacity
Mosaic attenuation and air-trapping
Findings of fibrosis:
Septal thickening
Traction bronchiectasis
Honeycombing
Mediastinal and hilar lymph node enlargement, usually symmetrical

273
 J.A. VERSCHAKELEN

Fig. 9. Sarcoidosis presenting as a solitary pulmonary nodule (arrow).

disease (table 2) [66, 67]. A score based on chest radiograph findings is used and defines
five radiographic stages of intrathoracic changes, including: stage 0: normal chest
radiograph; stage 1: lymphadenopathy only; stage 2: lymphadenopathy with paren-
chymal infiltration; stage 3: parenchymal disease only; stage 4: pulmonary fibrosis [1].
The limited value of this score is related to the complexity of the lung involvement with
both airway and interstitial changes often not visible on a conventional chest radiograph
and resulting in complex lung function abnormalities [68].
Given the better image quality and the higher density resolution of CT and HRCT,
allowing an earlier detection of disease and a better study of its extent, it can be expected
that this technique is more valuable in evaluating parameters of disease activity and
functional impairment. Several investigators have indeed evaluated the type and extent
of disease on CT and their correlations with pulmonary function. Various attempts
were also made to score sarcoidosis with HRCT based on different criteria [28, 6972].
MUller et al. [30] compared findings of sarcoidosis on thick-slice CT scans (10 mm)
and chest radiographs with dyspnoea scores and pulmonary function tests (PFTs) and
found significant correlations. The extent of disease on CT correlated slightly better with
the carbon monoxide diffusing capacity of the lung (DL,CO) than did the profusion of
opacities on chest radiographs, but correlations of CT with other PFT parameters, such
as vital capacity (VC) and total lung capacity (TLC) were similar to chest radiographs;
these authors suggested that neither CT nor the chest radiograph can be considered
a good predictor of functional impairment in any individual patient with sarcoidosis.
Similar observations were made by others [31, 71]. In contrast, Brauner et al. [31] found
weak correlations between CT scores of sarcoidosis and different functional para-
meters, such as TLC, VC, forced expiratory volume in one second and DL,CO but these
correlations were no better than conventional chest radiographs. Also Remy-Jardin et al.
[71] found a significant but weak correlation between the extent of abnormalities on CT
and impairment of lung function. However, these lung changes did not reflect disease

Table 2. Chest radiograph scoring of sarcoidosis#

Stage 0: 515
Stage 1: 4565
Stage 2: 3040
Stage 3: 1015
Stage 4: 5
#
: Table shows the percentages of patients in each stage at the time of presentation.

274
 IMAGING FEATURES

activity. Other studies looked at the patterns of CT abnormality and found that the
pattern of CT abnormality influenced PFT results [29, 45, 69]. In one study, bronchial
distortion was associated with lower expiratory flow rates, while the honeycomb pattern
was more associated with restriction and reduced DL,CO, TLC and forced vital capacity
(FVC) [69]. Davies et al. [49] found that the extent of air-trapping correlated with
percentage of predicted (% pred) residual volume/TLC and % pred maximal mid-
expiratory flow rate between 2575% of the VC. Magkanas et al. [51] found a significant
correlation between the extent of air-trapping and the residual volume and the residual
volume-total lung capacity ratio. Although these studies showed, among selected patient
groups, modest to good correlations between some radiographic and CT features and
some PFT parameters, the practical value of these associations in the individual patient
is limited and it is doubtful whether it gives any benefit in the management of this patient
[73].
Also the attempts to produce CT scoring systems for sarcoidosis were not always
successful [28, 6972]. Oberstein et al. [74] described a HRCT scoring system which
registers quality and quantity of lung parenchyma affected, pleural thickening and
enlargement of lymph nodes; they found a good correlation between their scoring system
and the number of polymorphous clear neutrophils in BAL fluid which was found to be
related to disease severity [7476]. Drent et al. [68] used a HRCT scoring system adapted
from Oberstein et al. [74] containing six HRCT patterns: 1) thickening or irregularity
of the bronchovascular bundle; 2) parenchymal consolidation, including ground-glass
opacifications; 3) intraparenchymal nodules; 4) septal and nonseptal lines; 5) focal
pleural thickening; and 6) enlargement of the lymph nodes. They found that the scores
of thickening or irregularity of the bronchovascular bundle, intrapulmonary nodules,
septal and nonseptal lines, and focal pleural thickening were significantly correlated
with several pulmonary function parameters both at rest and at maximal exercise.
Parenchymal consolidations, including ground-glass opacifications, and enlargement
of lymph nodes turned out to be of minor importance.
Some CT features have prognostic significance, but because of the important
variability between patients it is doubtful whether CT can predict disease outcome or
response to therapy. Certain CT features, such as distortion, cysts, traction bron-
chiectasis and bronchiolectasis reflect fibrosis and indicate poor responsiveness to
therapy [4245, 71, 77]. In contrast, nodular opacities, lung consolidation, ground-
glass opacity, and septal and nonseptal lines may represent either granulomatous
inflammation or fibrosis or a combination of both changes and are potentially rever-
sible with appropriate therapy [28, 4143, 45, 71, 77]. Ground-glass opacity showed the
same characteristics as in other diffuse lung diseases [78]; it may be a sign of acute
inflammation and reversible disease but with a coarse texture and with traction
bronchiectasis or bronchiolectasis it more likely reflects irreversible fibrotic changes.
One study also showed that air-trapping was in part reversible under steroid treat-
ment [79], confirming the observation that airway obstruction, as measured with PFTs,
can be reversed by treatment [80].

Cardiac involvement
Although cardiac involvement is often present (it was observed in 25% of patients in
an autopsy series [81]), it is only depicted in y5% of patients [82]. Patients are very
often asymptomatic, but when the conduction pathway is involved symptoms, such as
ventricular arrhythmia and heart blockage, which may result in sudden cardiac arrest,
can occur [83]. In fact, cardiac sarcoidosis is responsible for 50% of deaths [83, 84]. Also,
congestive heart failure is sometimes seen.

275
 J.A. VERSCHAKELEN

CT is of little value in the diagnosis of cardiac sarcoidosis. Some myocardial thinn-

ing at the site of involvement is occasionally seen. MRI is a better technique and can be
used for early detection of disease. The sites of involvement manifest as areas of increased
signal intensity on T2-weighted images or as areas of enhancement on T1-weighted
images (fig. 10) [85].

Extrathoracic involvement (selected sites)

Central nervous system involvement
Up to 25% of patients with sarcoidosis have asymptomatic involvement of the CNS at
autopsy [8688]. However, clinically recognisable disease is seen inv10% of patients [86,
87]. Neurosarcoidosis has a predilection for the base of the brain and can cause cranial
nerve palsy as one of the first symptoms [89]. The optic nerve and chiasm are also
frequently involved [90, 91]. Gadolinium-enhanced MRI is the imaging modality of
choice because it is more sensitive than CT and can depict a wide spectrum of abnor-
malities (fig. 11) [92]. The lesions can be solitary or multiple and typically present as
hyperintense masses on T2-weighted images [93]. After administration of contrast these
lesions typically enhance when biologically active. Signal intensity decreases in response
to therapy (fig. 11b). Unfortunately, MRI may be normal in much localised disease while
infections, some malignancies, vasculitis and multiple sclerosis can produce MRI features
similar to those seen in sarcoidosis [94]. Sarcoidosis can also cause aseptic meningitis.
The meningeal lesions are usually not seen on unenhanced MRI but often show diffuse
enhancement on contrast-enhanced (CE) T1-weighted imaging. Also, the spinal cord can
be involved. On T2-weighted MRI, an intramedullary lesion with decreased signal
intensity can be observed. These lesions show enhancement on contrast-enhanced T1-
weighted images [93, 95].
Ocular involvement is seen in up to 80% of patients and typically presents as a bilateral
uveitis [1]. Involvement of the lacrimal glands can also occur and is commonly bilateral.
CE CT or MRI typically shows enlarged, enhancing lacrimal glands.

a) b) c)

Fig. 10. Cardiac sarcoidosis in a female aged 41 yrs presenting with asymptomatic atrioventricular block. a) T1-
weighted fast spino-echo (SE) magnetic resonance imaging (MRI). b) Contrast-enhanced inversion recovery (CE-
IR) MRI with late imaging in the cardiac short-axis (same level as a), and c) horizontal long-axis. Moderate
thickening of the inferolateral LV wall is visible on SE-MRI (a; arrow). In this area, a focal strong enhancement
is found with a thin nonenhancing subendocardial and subepicardial rim (b; arrow). On the horizontal long-axis
view, several areas of strong enhancement are found throughout the LV wall, probably representing several
noncaseating granulomas (c; arrows). Scans appear courtesy of J. Bogaert (Dept of Radiology, University
Hospitals, Leuven, Belgium).

276
 IMAGING FEATURES

a) b)

Fig. 11. Neurosarcoidosis a) before and b) after treatment. Sagittal gadolinium-enhanced T1-weighted spin-
echo image showing an infundibular mass in the pituitary stalk (a). After treatment (b), no residual mass is
seen. Scans appear courtesy of P. Demaerel (Dept of Radiology, University Hospitals, Leuven, Belgium).

Abdominal involvement
As in the CNS, many patients with sarcoidosis show liver and spleen involvement at
autopsy, but only few develop dysfunction of these organs [96]. Usually some enlarge-
ment of liver and spleen is seen and can be depicted with CT and MRI. Only 1015% of
patients show hypointense and hypoattenuating liver and/or spleen nodules ranging in
size from 520 mm that correspond with coalescing granulomas [96101]. Differential
diagnosis with more common diseases, such as metastases and lymphoma can be diffi-
cult. In lymphoma, however, lymph node enlargement is more pronounced and the
retrocrural lymph nodes are more frequently involved [96, 99]. Simultaneous involve-
ment of liver and spleen makes metastatic disease less likely and favours the diagnosis of
sarcoidosis and lymphoma.
Involvement of the gastrointestinal tract is rare and when present it is usually
associated with pulmonary disease [102]. The stomach is the most common site of
involvement and the radiological signs of the disease are very aspecific ranging from
mucosal thickening, mimicking Menetrier disease, to lesions, mimicking gastric ulcers
or linitis plastica.
Involvement of the genitourinary tract is seen in v5% of patients. Sarcoidosis most
frequently affects the kidneys, but in male patients the epididimys and the testis can also
be involved [103]. CE CT scan may show signs of interstitial nephritis or less frequently
multiple low-attenuation nodules that resemble lymphoma or metastases [104, 105].
When the epididimys is involved, MRI can show heterogeneous and nodular enlarge-
ment with a slight increase in signal intensity on the T2-weighted image [103].

Other sites of involvement

Extrathoracic lymphadenopathy can be seen in sarcoidosis patients. Indeed, about
one-third of patients indeed have enlarged cervical lymph nodes and their recogni-
tion is important in case a biopsy is considered. Massive abdominal lymphadeno-
pathy, especially in the paraaortic region does also occur but is relatively rare. Imaging

277
 J.A. VERSCHAKELEN

a) b)

Fig. 12. Sarcoidosis of the epiglottis. Axial contrast-enhanced computed tomography images. a) Thickening
and superficial enhancement of the free edge of the epiglottis (arrow), with marked infiltration of the pre-
epiglottic fat (arrowhead). b) Slightly thickened infrahyoid epiglottis (arrowhead); the aryepiglottic folds (arrows)
also appear thickened and show superficial enhancement. Scans appear courtesy of R. Hermans (Dept of
Radiology, University Hospitals, Leuven, Belgium).

appearances of these nodes are, however, aspecific and differentiation from metastatic
disease or malignant lymphoma may be difficult.
Involvement of the parotic glands is seen in y6% of patients with sarcoidosis and is
commonly bilateral and associated with widespread disease in other organs [1, 106]. MRI
shows enlarged parotid glands, demonstrating increased signal intensity on T2-weighted
images and enhancement after administration of contrast. Also, involvement of the
epiglottis is possible (fig. 12).
The musculoskeletal system can also be involved, but usually this only occurs when
the disease is generalised. Inflammatory changes in the joints are usually not iden-
tified radiologically but can be identified with MRI. When the muscles in particular are
involved, characteristic nodules may appear [107]. These nodules typically show low
signal intensity in the central part, which is related to the fibrotic changes while, because
of the presence of granulomas, the periphery of the nodules exhibits bright signal
intensity on T2-weighted images and enhancement after administration of contrast [108].
Skeletal involvement is seen in y510% of patients with sarcoidosis and the disease
most frequently affects the phalanges of the hands and feet, although involvement of
the vertebral bodies can occur [109, 110]. Radiographic signs include intact articular
spaces, bone erosion, which can be extensive and result in pathological fractures, and
multiple cyst-like radiolucent areas. Often a subcutaneous soft tissue mass is also present
[111]. Long bone and axial skeletal involvement may, however, be occult at conven-
tional radiography, but depicted at MRI, with an appearance that resembles that of
osseous metastases [112].

278
 IMAGING FEATURES

Summary
The diagnosis of sarcoidosis is usually established on the basis of clinical and
radiological findings supported by histological findings. More than 80% of patients
with sarcoidosis have intrathoracic adenopathy at the time of presentation. When hilar
adenopathy is present, this intrathoracic adenopathy is often easily recognised on a
chest radiograph. Computed tomography (CT) can depict additional mediastinal
lymph nodes that are hardly or not visible on a chest radiograph. However, CT, and
especially high-resolution CT, is especially helpful when pulmonary parenchymal
disease is present. While some CT signs are moderately characteristic for the disease,
CT can also play a role in the study of disease extent and can, to a certain degree,
predict the reversibility of lung changes. Although magnetic resonance imaging may
be useful in the evaluation of mediastinal and pulmonary involvement, the main
development of this technique has taken place in the evaluation of neurosarcoidosis,
and to a lesser degree in bone, muscle and cardiac sarcoidosis.

Keywords: Computed tomography, imaging, interstitial lung disease, sarcoidosis.

References
1. Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European
Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous
Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive
Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736755.
2. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336: 12241234.
3. Lynch J, Kazerooni E, Gay S. Pulmonary sarcoidosis. Clin Chest Med 1997; 18: 755785.
4. Johns CJ, Michele TM. The clinical management of sarcoidosis: a 50-year experience at the Johns
Hopkins Hospital. Medicine (Baltimore) 1999; 78: 65111.
5. Mana J, Teirstein AS, Mendelson DS, Padilla ML, DePalo LR. Excessive thoracic computed
tomographic scanning in sarcoidosis. Thorax 1995; 50: 12641266.
6. Mana J. Magnetic resonance imaging and nuclear imaging in sarcoidosis. Curr Opin Pulm Med
2002; 8: 457463.
7. Miller BH, Rosado-de-Christenson ML, McAdams HP, Fishback NF. Thoracic sarcoidosis:
radiologic-pathologic correlation. Radiographics 1995; 15: 421437.
8. James DG, Neville E, Siltzbach LE, et al. A worldwide review of sarcoidosis. Ann NY Acad Sci
1976; 278: 321334.
9. Koyama T, Ueda H, Togashi K, Umeoka S, Kataoka M, Nagai S. Radiologic manifestations of
sarcoidosis in various organs. Radiographics 2004; 24: 87104.
10. Theros EG. RPC of the month from the AFIP. Radiology 1969; 92: 15571561.
11. Bein ME, Putman CE, McLoud TC, et al. A reevaluation of intrathoracic lymphadenopathy in
sarcoidosis. AJR Am J Roentgenol 1978; 131: 409415.
12. Sider L, Horton ES Jr. Hilar and mediastinal adenopathy in sarcoidosis as detected by computed
tomography. J Thorac Imaging 1990; 5: 7780.
13. Rockoff SD, Rohatgi PK. Unusual manifestations of thoracic sarcoidosis. AJR Am J Roentgenol
1985; 144: 513528.
14. Hamper UM, Fishman EK, Khouri NF, et al. Typical and atypical CT manifestations of
pulmonary sarcoidosis. J Comput Assist Tomogr 1986; 10: 928936.

279
 J.A. VERSCHAKELEN

15. Gawne-Cain ML, Hansell DM. The pattern and distribution of calcified mediastinal lymph nodes
in sarcoidosis and tuberculosis: a CT study. Clin Radiol 1996; 51: 263267.
16. McLoud TC, Putman CE, Pascual R. Eggshell calcification with systemic sarcoidosis. Chest 1974;
66: 515517.
17. Niimi H, Kang EY, Kwong JS, Carignan S, Muller NL. CT of chronic infiltrative lung disease:
prevalence of mediastinal lymphadenopathy. J Comput Assist Tomogr 1996; 20: 305308.
18. Bergin CJ, Coblentz CL, Chiles C, et al. Chronic lung diseases: specific diagnosis by using CT. AJR
Am J Roentgenol 1989; 152: 11831188.
19. Wells A. Clinical usefulness of high resolution computed tomography in cryptogenic fibrosing
alveolitis. Thorax 1998; 53: 10801087.
20. Battesti JP, Saumon G, Valeyre D, et al. Pulmonary sarcoidosis with an alveolar radiographic
pattern. Thorax 1982; 37: 448452.
21. Littner MR, Schachter EN, Putman CE, et al. The clinical assessment of roentgenographically
atypical pulmonary sarcoidosis. Am J Med 1977; 62: 361368.
22. Rose RM, Lee RG, Costello P. Solitary nodular sarcoidosis. Clin Radiol 1985; 36: 589595.
23. Sharma OP, Hewlett R, Gordonson J. Nodular sarcoidosis: an unusual radiographic appearance.
Chest 1973; 64: 189192.
24. Tazi A, Desfemmes-Baleyte T, Soler P, et al. Pulmonary sarcoidosis with a diffuse ground-glass
pattern on the chest radiograph. Thorax 1994; 49: 793797.
25. Johkoh T, Muller NL, Nakamura H. Multidetector spiral high-resolution computed tomography
of the lungs: distribution of findings on coronal image reconstructions. J Thorac Imaging 2002;
17: 291305.
26. Eibel R, Turk T, Kulinna C, Schopf UJ, Bruning R, Reiser MF. Value of multiplanar
reformations (MPR) in multi-slice spiral CT of the lung. Rofo 2001; 173: 5764.
27. Kitaichi M. Pathology of pulmonary sarcoidosis. Clin Dermatol 1986; 4: 108115.
28. Leung AN, Brauner MW, Caillat-Vigneron N, et al. Sarcoidosis activity: correlation of HRCT
findings with those of 67Ga scanning, bronchoalveolar lavage, and serum angiotensin-converting
enzyme assay. J Comput Assist Tomogr 1998; 22: 229234.
29. Hansell DM, Milne DG, Wilsher ML, et al. Pulmonary sarcoidosis: morphologic associations of
airflow obstruction at thin-section CT. Radiology 1998; 209: 697704.
30. Muller NL, Mawson JB, Mathieson JR, et al. Sarcoidosis: correlation of extent of disease at CT
with clinical, functional, and radiographic findings. Radiology 1989; 171: 613618.
31. Brauner MW, Grenier P, Mompoint D, Lenoir S, deCremoux H. Pulmonary sarcoidosis:
evaluation with high-resolution CT. Radiology 1989; 172: 467471.
32. Muller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of 25
patients. AJR Am J Roentgenol 1989; 152: 11791182.
33. Nishimura K, Itoh H, Kitaichi M, et al. Pulmonary sarcoidosis: correlation of CT and
histopathologic findings. Radiology 1993; 189: 105109.
34. Traill ZC, Maskell GF, Gleeson FV. High-resolution CT findings of pulmonary sarcoidosis. AJR
Am J Roentgenol 1997; 168: 15571560.
35. Hwang JH, Kim TS, Lee KS, et al. Bronchiolitis in adults: pathology and imaging. J Comput Assist
Tomogr 1997; 21: 913919.
36. Honda O, Johkoh T, Ichikado K, et al. Comparison of high resolution CT findings of sarcoidosis,
lymphoma, and lymphangitic carcinoma: is there any difference of involved interstitium? J Comput
Assist Tomogr 1999; 23: 374379.
37. Voloudaki AE, Tritou IN, Magkanas EG, Chalkiadakis GE, Siafakas NM, Gourtsoyiannis NC.
HRCT in military lung disease. Acta Radiol 1999; 40: 451456.
38. Gruden JF, Webb WR, Naidich DP, McGuinness G. Multinodular disease: anatomic localiza-
tion at thin-section CT multireader evaluation of a simple algorithm. Radiology 1999; 210: 711
720.
39. Muller NL, Miller RR. Ground-glass attenuation, nodules, alveolitis, and sarcoid granulomas.
Radiology 1993; 189: 3132.

280
 IMAGING FEATURES

40. Chiles C. Imaging features of thoracic sarcoidosis. Semin Roentgenol 2002; 37: 8293.
41. Rossi SE, Erasmus JJ, Volpacchio M, Franquet T, Castiglioni T, McAdams HP. "Crazy-paving"
pattern at thin-section CT of the lungs: radiologic-pathologic overview. Radiographics 2003;
23: 15091519.
42. Brauner MW, Lenoir S, Grenier P, et al. Pulmonary sarcoidosis: CT assessment of lesion
reversibility. Radiology 1992; 182: 349354.
43. Murdoch J, Muller NL. Pulmonary sarcoidosis: changes on follow-up CT examination. AJR Am J
Roentgenol 1992; 159: 473477.
44. Wells A. High resolution computed tomography in sarcoidosis: a clinical perspective. Sarcoidosis
Vasc Diffuse Lung Dis 1998; 15: 140146.
45. Abehsera M, Valeyre D, Grenier P, et al. Sarcoidosis with pulmonary fibrosis: CT patterns and
correlation with pulmonary function. AJR Am J Roentgenol 2000; 174: 17511757.
46. Lynch J, Kazerooni E. Sarcoidosis. In: Sperber M, ed. Radiological Diagnosis of Chest Disease,
2nd Edn. London, Springer-Verlag, 2001; pp. 193220.
47. Padley SP, Padhani AR, Nicholson A, Hansell DM. Pulmonary sarcoidosis mimicking
cryptogenic fibrosing alveolitis on CT. Clin Radiol 1996; 51: 807810.
48. Gleeson FV, Traill ZC, Hansell DM. Evidence of expiratory CT scans of small-airway obstruction
in sarcoidosis. AJR Am J Roentgenol 1996; 166: 10521054.
49. Davies CW, Tasker AD, Padley SP, et al. Air trapping in sarcoidosis on computed tomography:
correlation with lung function. Clin Radiol 2000; 55: 217221.
50. Bartz RR, Stern EJ. Airways obstruction in patients with sarcoidosis: expiratory CT scan findings.
J Thorac Imaging 2000; 15: 285289.
51. Magkanas E, Voloudaki A, Bouros D, et al. Pulmonary sarcoidosis. Correlation of expiratory
high-resolution CT findings with inspiratory patterns and pulmonary function tests. Acta Radiol
2001; 42: 494501.
52. Shaw RJ, Djukanovic R, Tashkin DP, Millar AB, duBois RM, Orr PA. The role of small airways
in lung disease. Respir Med 2002; 96: 6780.
53. Johkoh T, Ikezoe J, Kohno N, et al. Usefulness of high-resolution CT for differential diagnosis of
multi-focal pulmonary consolidation. Radiat Med 1996; 14: 139146.
54. Mayock R, Bertrand P, Morrison C, et al. Manifestations of sarcoidosis: analysis of 145 patients,
with a review of nine series selected from the literature. Am J Med 1963; 36: 6789.
55. Grenier P, Brauner M, Valeyre D. Computed tomography in the assessment of diffuse lung
disease. Sarcoidosis Vasc Difffuse Lung Dis 1999; 16: 4756.
56. Soskel N, Sharma OP. Pleural involvement in sarcoidosis: case presentation and detailed review of
the literature. Semin Respir Med 1992; 13: 492514.
57. Sharma OP, Gordonson J. Pleural effusion in sarcoidosis: a report of six cases. Thorax 1975;
30: 95101.
58. Packe GE, Ayres JG, Citron KM, et al. Large lung bullae in sarcoidosis. Thorax 1986; 41: 792797.
59. Judson MA, Strange C. Bullous sarcoidosis: a report of three cases. Chest 1998; 114: 14741478.
60. Chrisholm JC, Lang GR. Solitary circumscribed pulmonary nodule: an unusual manifestation of
sarcoidosis. Arch Intern Med 1966; 118: 376378.
61. Pinsker KL. Solitary pulmonary nodule in sarcoidosis. JAMA 1978; 240: 13791380.
62. Tomlinson JR, Sahn SA. Aspergilloma in sarcoid and tuberculosis. Chest 1987; 92: 505508.
63. Kaplan J, Johns CJ. Mycetomas in pulmonary sarcoidosis: nonsurgical management. Johns
Hopkins Med J 1979; 145: 157161.
64. Israel HL, Lenchner GS, Atkinson GW. Sarcoidosis and aspergilloma: the role of surgery. Chest
1982; 82: 430432.
65. Froudarakis ME, Bouros D, Voloudaki A, et al. Pneumothorax as a first manifestation of
sarcoidosis. Chest 1997; 112: 278280.
66. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and other Granulomatous Disorders: statement on
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.

281
 J.A. VERSCHAKELEN

67. DeRemee RA. The roentgenographic staging of sarcoidosis: historic and contemporary
perspectives. Chest 1983; 83: 128133.
68. Drent M, DeVries J, Lenters M, et al. Sarcoidosis: assessment of disease severity using HRCT. Eur
Radiol 2003; 13: 24622471.
69. Bergin CJ, Bell DY, Coblentz CL, et al. Sarcoidosis: correlation of pulmonary parenchymal
pattern at CT with results of pulmonary function tests. Radiology 1989; 171: 619624.
70. Mimori Y. Sarcoidosis: correlation of HRCT findings with results of pulmonary function tests and
serum angiotensin-converting enzyme assay. Kurume Med J 1998; 45: 247256.
71. Remy-Jardin M, Giraud F, Remy J, Wattinne L, Wallaert B, Duhamel A. Pulmonary sarcoidosis:
role of CT in the evaluation of disease activity and functional impairment and in prognosis
assessment. Radiology 1994; 191: 675680.
72. Lynch DA, Webb WR, Gamsu G, Stulbarg M, Golden J. Computed tomography in pulmonary
sarcoidosis. J Comput Assist Tomogr 1989; 13: 405410.
73. Lynch JP 3rd. Computed tomographic scanning in sarcoidosis. Semin Respir Crit Care Med 2003;
24: 393418.
74. Oberstein A, vonZitzewitz H, Schweden F, Muller-Quernheim J. Non-invasive evaluation of the
inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc
Diffuse Lung Dis 1997; 14: 6572.
75. Drent M, Jacobs JA, DeVries J, Lamers RJS, Liem IH, Wouters EFM. Does the cellular
bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis?Eur Respir J 1999; 13: 13381344.
76. Ziegenhagen MW, Rothe ME, Schlaak M, Muller-Quernheim J. Bronchoalveolar and serological
parameters reflecting the severity of sarcoidosis. Eur Respir J 2003; 21: 407413.
77. Nishimura K, Itoh H, Kitaichi M, et al. CT and pathological correlation of pulmonary
sarcoidosis. Semin Ultrasound CT MR 1995; 16: 361370.
78. Remy-Jardin M, Giraud F, Remy J, et al. Importance of ground-glass attenuation in chronic
diffuse infiltrative lung disease: pathologic-CT correlation. Radiology 1993; 189: 693698.
79. Fazzi P, Sbragia P, Solfanelli S, Troilo S, Giuntini C. Functional significance of the decreased
attenuation sign on expiratory CT in pulmonary sarcoidosis: report of four cases. Chest 2001;
119: 12701274.
80. Lavergne F, Clerici C, Sadoun D, Brauner M, Battesti JP, Valeyre D. Airway obstruction in
bronchial sarcoidosis: outcome with treatment. Chest 1999; 116: 11941999.
81. Ratner SJ, Fenoglio JJ Jr, Ursell PC. Utility of endomyocardial biopsy in the diagnosis of cardiac
sarcoidosis. Chest 1986; 90: 528533.
82. Iwai K, Sekiguti M, Hosoda Y, et al. Racial difference in cardiac sarcoidosis incidence observed at
autopsy. Sarcoidosis 1994; 11: 2631.
83. Syed J, Myers R. Sarcoid heart disease. Can J Cardiol 2004; 20: 8993.
84. Paule P, Braem L, Heno P, et al. Diagnosis of cardiac sarcoidosis and follow-up of 24 consecutive
patients. Rev Med Interne 2004; 25: 357362.
85. Vignaux O, Dhote R, Duboc D, et al. Clinical significance of myocardial magnetic reson-
ance abnormalities in patients with sarcoidosis: a 1-year follow-up study. Chest 2002; 122: 1895
1901.
86. Manz HJ. Pathobiology of neurosarcoidosis and clinicopathologic correlation. Can J Neurol Sci
1983; 10: 5055.
87. Chapelon C, Ziza JM, Piette JC, et al. Neurosarcoidosis: signs, course and treatment in 35
confirmed cases. Medicine (Baltimore) 1990; 69: 261276.
88. Lury KM, Smith JK, Matheus MG, Castillo M. Neurosarcoidosis review of imaging findings.
Semin Roentgenol 2004; 39: 495504.
89. Sharma OP. Neurosarcoidosis: a personal perspective based on the study of 37 patients. Chest
1997; 112: 220228.
90. Zajicek JP, Scolding NJ, Foster O, et al. Central nervous system sarcoidosis: diagnosis and
management. Q J Med 1999; 92: 103117.

282
 IMAGING FEATURES

91. Smith JK, Matheus MG, Castillo M. Imaging manifestations of neurosarcoidosis. Am J

Roentgenol 2004; 182: 289295.
92. Sherman JL, Stern BJ. Sarcoidosis of the CNS: comparison of unenhanced and enhanced MR
images. AJNR Am J Neuroradiol 1990; 11: 915923.
93. Lexa FJ, Grossman RI. MR of sarcoidosis in the head and spine: spectrum of manifestations and
radiographic response to steroid therapy. Am J Neuroradiol 1994; 15: 973982.
94. Williams DW 3rd, Elster AD, Kramer SI. Neurosarcoidosis: gadolinium-enhanced MR imaging.
J Comput Assist Tomogr 1990; 14: 704707.
95. Fels C, Riegel A, Javaheripour-Otto K, Obenauer S. Neurosarcoidosis: findings in MRI. Clin
Imaging 2004; 28: 166169.
96. Warshauer DM, Molina PL, Hamman SM, et al. Nodular sarcoidosis of the liver and spleen:
analysis of 32 cases. Radiology 1995; 195: 757762.
97. Warshauer DM, Semelka RC, Ascher SM. Nodular sarcoidosis of the liver and spleen: appearance
on MR images. J Magn Reson Imaging 1994; 4: 553557.
98. Kessler A, Mitchell DG, Israel HL, et al. Hepatic and splenic sarcoidosis: ultrasound and MR
imaging. Abdom Imaging 1993; 18: 159163.
99. Britt AR, Francis IR, Glazer GM, et al. Sarcoidosis: abdominal manifestations at CT. Radiology
1991; 178: 9194.
100. Warshauer DM, Dumbleton SA, Molina PL, et al. Abdominal CT findings in sarcoidosis:
radiologic and clinical correlation. Radiology 1994; 192: 9398.
101. Thanos L, Zormpala A, Brountzos E, Nikita A, Kelekis D. Nodular hepatic and splenic
sarcoidosis in a patient with normal chest radiograph. Eur J Radiol 2002; 41: 1011.
102. Farman J, Ramirez G, Rybak B, Lebwohl O, Semrad C, Rotterdam H. Gastric sarcoidosis. Abdom
Imaging 1997; 22: 248252.
103. Kodama K, Hasegawa T, Egawa M, Tomosugi N, Mukai A, Namiki M. Bilateral epididymal
sarcoidosis presenting without radiographic evidence of intrathoracic lesion: review of sarcoidosis
involving the male reproductive tract. Int J Urol 2004; 11: 345348.
104. Sato A. Renal dysfunction in patients with sarcoidosis. Intern Med 1996; 35: 523524.
105. Hughes JJ, Wilder WM. Computed tomography of renal sarcoidosis. J Comput Assist Tomogr
1988; 12: 10571058.
106. James DG, Sharma OP. Parotid gland sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2000;
17: 2732.
107. Abril A, Cohen MD. Rheumatologic manifestations of sarcoidosis. Curr Opin Rheumatol 2004;
16: 5155.
108. Otake S, Ishigaki T. Muscular sarcoidosis. Semin Musculoskelet Radiol 2001; 5: 167170.
109. Mangino D, Stover DE. Sarcoidosis presenting as metastatic bony disease. A case report and
review of the literature on vertebral body sarcoidosis. Respiration 2004; 71: 292294.
110. Lisle D, Mitchell K, Crouch M, Windsor M. Sarcoidosis of the thoracic and lumbar spine: imaging
findings with an emphasis on magnetic resonance imaging. Australas Radiol 2004; 48: 404407.
111. Neville E, Carstairs LS, James DG. Sarcoidosis of bone. Q J Med 1977; 46: 215227.
112. Moore SL, Teirstein AE. Musculoskeletal sarcoidosis: spectrum of appearances at MR imaging.
Radiographics 2003; 23: 13891399.

283
 CHAPTER 19

Clinical usefulness of nuclear imaging

techniques in sarcoidosis

J. Mana*, M. van Kroonenburgh#

*Dept of Internal Medicine, Bellvitge Institute of Medical Research, Bellvitge Hospital, University of
Barcelona, Barcelona, Spain, and #Dept of Nuclear Medicine/Sarcoidosis Management Centre, University
Hospital Maastricht, Maastricht, The Netherlands.

Correspondence: J. Mana, Servicio de Medicina Interna, Hospital Universitario de Bellvitge, Feixa Llarga
s/n, LHospitalet de Llobregat, 08907 Barcelona, Spain. Fax: 34 932607967; E-mail: jmana@csub.scs.es

Nuclear imaging techniques play a role in the assessment and management of patients
with sarcoidosis. A variety of radiopharmaceuticals have been introduced for this
purpose since the late 1970s. The present chapter focuses on these radiopharmaceuticals,
scintigraphic imaging techniques, and their role and clinical value in sarcoidosis.
Correlation with other imaging modalities, biochemical parameters and pulmonary
function tests are discussed. Integration of the currently available data and the present
authors own experience have permitted the development of an algorithm, in which the
current authors suggest a clinical guideline focused on optimal use of nuclear imaging
techniques in the initial study of patients with sarcoidosis.

Gallium-67 scintigraphy
Gallium-67 is a radioisotope that accumulates in malignant tumours, including
lymphomas, and inflammatory processes [1]. 67Ga is taken up in granulomatous tissue,
probably by activated macrophages. Although 67Ga uptake is usually suppressed by the
administration of corticosteroids, uptake persistence in patients with active sarcoidosis
undergoing treatment has been reported [2].
The reported sensitivity of 67Ga scanning in detecting pulmonary sarcoidosis ranges
6090%. In addition, its specificity is relatively poor because most interstitial lung
disorders show positive 67Ga scan results [1]. The most common 67Ga uptake in
sarcoidosis is intrathoracic, which typically shows bilateral hilar and right paratracheal
lymphadenopathy and/or lung parenchyma uptake. Whole-body 67Ga scanning is useful
for studying the extent and distribution of the disease, in that it detects the presence of
inflammatory activity in clinically silent but involved organs and provides extrathoracic
sites for biopsy [3, 4]. Extrapulmonary accumulation of 67Ga has been reported in many
organs (fig. 1), indicating the systemic character of the disease [1, 46].
Interestingly, Sulavik et al. [7] reported some combinations of different patterns of
67
Ga distribution as characteristic of sarcoidosis. The image produced by the 67Ga
uptake of the right paratracheal and bilateral hilar lymph nodes, resembling the Greek
letter lambda, was classified as the lambda pattern. The image produced by the 67Ga
uptake of the lacrimal and parotid glands, resembling the face of a panda, was classified
as the panda pattern. The lambda pattern was seen in 72% of patients with sarcoidosis,
the panda pattern in 79%, and both patterns simultaneously in 62%. However, a panda
pattern of itself is not specific to sarcoidosis, since it has also been observed in human
Eur Respir Mon, 2005, 32, 284300. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
284

Monograph (ERM59136.3d) 12/8/05 11:15:27 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

a) b)

Fig. 1. Gallium-67 scan showing multiple uptake in the skull, right mandibular bone, both parotid glands, and
cervical and supraclavicular lymph nodes in a patient with positive skull and cervical lymph node biopsy results:
a) front view, and b) lateral view. Images reproduced from [5] with permission.

HIV-positive patients, Sjogrens syndrome, following irradiation of the head or neck,

particularly as lymphoma treatment, graft-versus-host disease, rheumatoid arthritis and
systemic lupus erythematosus [7, 8]. Israel et al. [3] found a lower sensitivity of the
lambda pattern (29%) and panda pattern (13%) in sarcoidosis patients. Figure 2 shows
the lambda and panda patterns in a patient with Lofgrens syndrome [9].
Several studies have focused on the role of the 67Ga scan in the prognosis of
sarcoidosis. Niden et al. [10] reported that the lesser the degree of pulmonary 67Ga
uptake the better the prognosis of the patient. Likewise, restoration and maintenance of
normal 67Ga scan results during therapy was a good prognostic sign, since such patients
did not show loss of pulmonary function. Baughman et al. [11] reported that 68% of
patients with positive lung 67Ga scan results exhibited worsening of the disease at 2 yrs,
whereas, negative scan results suggested a small likelihood of disease activity at 2 yrs.
Other studies could not confirm these findings [12, 13].
In a European multicentric study [14] that included 632 patients, there was no strict
correlation between 67Ga uptake and the presence of abnormalities on chest radiography
(CXR) (table 1). According to these results, 67Ga scintigraphy was more accurate in
detecting the presence of intrathoracic involvement in a significant number of cases with
normal CXR results. However, 23% of cases with evidence of intrathoracic involvement
on CXR failed to show 67Ga uptake. In addition, the 67Ga scan was more sensitive than
CXR in detecting changes, either improvement or prediction of relapses, in the follow-up
of untreated patients.
Some studies have compared thoracic high-resolution computed tomography (HRCT)
with pulmonary 67Ga scan results, and have shown only limited correlation between the
two techniques. Lynch et al. [15] found that five patients with positive 67Ga scan results
showed some degree of pulmonary involvement on HRCT, but two out of five patients
with normal 67Ga scan results also showed parenchymal lung disease on HRCT. In
addition, the extent of nodularity seen on HRCT did not correlate with activity on the
67
Ga scan. Bergin et al. [16] also reported a lack of correlation between the two
techniques, although patches of parenchymal involvement on computed tomography
(CT) corresponded in location to focal areas of 67Ga uptake. Leung et al. [17], however,

285

Monograph (ERM59136.3d) 12/8/05 11:15:27 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

Fig. 2. Gallium-67 scan showing bilateral hilar and right paratracheal lymphadenopathy uptake (lambda
pattern) and lacrimal and parotid gland uptake (panda pattern) in a patient with Lofgrens syndrome. Image
reproduced from [9] with permission.

studied a series of 29 patients with pulmonary sarcoidosis and reported good correlation
between findings on HRCT and indices of disease activity measured by 67Ga scan.
Nevertheless, more recent studies have shown that HRCT appears to be a more
appropriate tool for assessing the pathological changes and functional impairment
associated with the inflammatory activity of sarcoidosis [1820]. Drent et al. [21]

286

Monograph (ERM59136.3d) 12/8/05 11:15:29 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

Table 1. Gallium-67 (67Ga) uptake in untreated patients at different chest radiographic (CXR) stages of
sarcoidosis

CXR stage Patients n Elevated 67Ga uptake n (%) Non-elevated 67Ga

uptake n (%)
Mediastinal and/ Pulmonary
or pulmonary
0 82 36 (43.9) 10 (12.2) 46 (56.1)
I 190 164 (86.3) 40 (21.1 26 (13.7)
II 248 213 (85.9) 160 (64.5) 35 (14.1)
III 112 71 (63.4) 65 (58.0) 41 (36.6)
All 632 484 (76.6) 265 (41.9)# 148 (23.4)
#
: the number of patients with elevated pulmonary uptake expressed as a percentage of those with elevated
mediastinal and/or pulmonary uptake is 54.8%. Image reproduced from [14] with permission.

reported good correlation between pulmonary abnormalities on HRCT, but not CXR,
with respiratory functional impairment, particularly abnormal gas exchange. In
consequence, HRCT is considered superior to 67Ga scan for assessing the inflammatory
activity and severity of intrathoracic involvement in sarcoidosis.
In the aforementioned European study [14], serum angiotensin-converting enzyme
(SACE) level was increased in 29% of patients with negative scans results; this measure
was more sensitive than the 67Ga lung scan in only 7% of all untreated patients.
Conversely, 67Ga scan results were positive in 58% of patients with normal SACE level,
and more sensitive than SACE level in 30% of untreated patients. Consequently, the 67Ga
scan was more sensitive than SACE level in detecting active sarcoidosis, although SACE
was a superior indicator in a small number of cases. Other authors have also confirmed
the higher sensitivity of the 67Ga scan result over SACE level as an indicator of disease
activity [2, 2224], although some have suggested that SACE level is more specific [23]. In
contrast, other studies found a strong correlation between both techniques [25, 26]. These
different results could be explained by the fact that the two techniques, SACE level and
67
Ga scan, represent different aspects of granuloma formation, and the presence of an
ACE inhibitor in the serum of 30% of patients with sarcoidosis, which would explain the
normal SACE level in some cases with active sarcoidosis [26].
In the European study [14], SACE level and 67Ga uptake during corticosteroid therapy
for active pulmonary sarcoidosis were increased in 17 and 38% of patients, respectively.
One month after stopping therapy, the percentages rose to 70 and 59%, which suggests
that SACE level detects relapses sooner than the 67Ga scan does. Another study found
the 67Ga scan to be more sensitive than bronchoalveolar lavage (BAL) in detecting
changes during corticosteroid therapy [27]. Close correlation between the degree of 67Ga
uptake and the increase in vital capacity after treatment has been described [28].
However, 67Ga uptake was not of value in predicting treatment response [12].
Turner-Warwick et al. [29] reported that serial 67Ga scans, lavage lymphocyte
counts and SACE level measurements were no more sensitive than serial CXR and
pulmonary function tests in monitoring patients during therapy. An abnormal 67Ga scan,
of itself, is not an indication for therapy. Similarly, the presence of new 67Ga uptake
during or after discontinuation of corticosteroid therapy may be useful in confirming a
relapse in doubtful cases, but is not an indication of the need to reintroduce
corticosteroids. Nevertheless, Nosal et al. [22] reported that the combination of
SACE level and 67Ga scan result had a diagnostic specificity of 99%, and suggested that,
if the results of both examinations were negative, the diagnosis of sarcoidosis was highly
improbable.
Some authors have reported a strong correlation between lung parenchymal 67Ga
uptake and the intensity of alveolitis defined by the number of T-lymphocytes in BAL

287

Monograph (ERM59136.3d) 12/8/05 11:15:31 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

fluid [3032], although others found no such correlation [2]. One reason for this lack of
correlation is that BAL fluid reflects the intensity of the T-lymphocytic alveolitis, which
may predominate in the early phases of the disease, whereas 67Ga lung scan results reflect
the presence of activated macrophages and granulomas, which usually prevail in later
phases.
In pulmonary sarcoidosis, pulmonary function test results can be normal in the
presence of alveolitis. Line et al. [31] found little correlation between the degree of
alveolitis measured by BAL or 67Ga scan and the extent of lung function impairment. In
contrast, some studies found that even low-grade 67Ga uptake by the pulmonary
parenchyma was associated with some degree of lung restriction, whereas others showed
close correlation between the degree of 67Ga uptake and the increase in vital capacity
after corticosteroid therapy [28].
Owing to reduced sensitivity and specificity, the 67Ga scan is of limited value in the
assessment of activity, diagnosis and management of sarcoidosis. In consequence, its
routine use is not currently recommended in the initial evaluation of sarcoidosis except in
certain select clinical settings. The most appropriate use of the 67Ga scan in sarcoidosis is
assisting in the diagnosis and determination of the extent and distribution of the disease
in cases with diagnostic difficulties. Patients with normal CXR results and a clinical
picture suggestive of isolated extrathoracic sarcoidosis, such as uveitis, inflammatory
central nervous system disease or monovisceral granulomatosis of unknown origin,
particularly liver and lymph node granulomatosis, may benefit from the 67Ga scan. The
finding of the typical lambda and/or panda patterns supports the diagnosis and
reinforces the indication of histological confirmation [8]. Whole-body scanning may also
detect other clinically silent extrathoracic uptake of 67Ga, providing sites for biopsy [3, 4].
Likewise, in the cases of Lofgrens syndrome and asymptomatic stage I with doubtful
hilar lymphadenopathy on CXR, without histological confirmation, the finding of a
lambda pattern on 67Ga scan may contribute to more confidence in the diagnosis [33].
However, normal 67Ga scan results do not preclude the presence of granulomas in any
organ. The 67Ga scan has not been proved useful in predicting prognosis and should not
be used as an indicator of therapy [12, 13]. Nevertheless, it may be useful in
distinguishing fibrotic from active lung disease, contributing to the decision as to whether
to suppress or continue corticosteroid therapy, confirming a relapse after discontinuation
of therapy in doubtful cases and assessing activity before lung transplantation [1].

Thallium-201 scintigraphy
The radioisotope thallium-201 accumulates in normal myocardial cells. The 201Tl scan
permits noninvasive estimation of the regional distribution of myocardial blood
perfusion. In cardiac sarcoidosis, 201Tl scintigraphy performed under resting conditions
typically shows segmental areas of decreased perfusion in the ventricular myocardium
that correspond to areas of fibrogranulomatous replacement [34, 35]. In the absence of
coronary artery disease, these defects suggest cardiac involvement by sarcoidosis,
particularly if they disappear or decrease in size during 201Tl stress imaging [34, 3638].
This phenomenon, called reverse distribution, suggests the presence of granulomas in the
myocardium and is useful in differentiating cardiac sarcoidosis from myocardial
ischaemia [35, 36]. However, this finding is not always present and is not specific to
cardiac sarcoidosis since it may also occur in other cardiomyopathies [35]. Tellier et al.
[39] reported that perfusion defects were also partially or totally reversible after the
intravenous administration of dipyridamole, a potent vasodilator of the coronary
microcirculation, and suggested that the mechanism for the perfusion defects could be

288

Monograph (ERM59136.3d) 12/8/05 11:15:31 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

the presence of reversible disorders at the coronary microvascular level rather than
myocardial granulomas or fibrosis. However, because of the possibility of small focal
lesions, normal 201Tl scan results do not exclude the presence of cardiac sarcoidosis [34].
Kinney et al. [40] noted the presence of abnormalities on 201Tl scan in w30% of
patients with sarcoidosis without clinically suspected cardiac involvement. Sharma et al.
[35] found positive resting 201Tl scan results in 34% of patients with systemic sarcoidosis
and observed that all left ventricular defects decreased in size on stress imaging.
Haywood et al. [36] detected either left or right ventricular defects in 37% of patients in
whom two-dimensional echocardiography had failed to show segmental ventricular
contraction abnormalities. In another study, performed on 41 patients with sarcoidosis,
myocardial 201Tl single-photon emission computed tomography (SPECT) was performed
and mean washout ratios measured. Abnormal findings, including all types of
abnormality, were found in 26 patients [38].
The combined use of 201Tl and 67Ga imaging of the heart, particularly with SPECT,
may increase recognition of cardiac sarcoidosis [41, 42]. However, Okayama et al. [43]
reported that, when 201Tl revealed myocardial defects, cardiac 67Ga uptake did not add
more diagnostic information; it was, however, predictive of the efficacy of corticosteroid
treatment. Kinney and Caldwell [44] found that positive 201Tl scan results had no
prognostic significance, although the periodic evaluation of perfusion defects was useful
in monitoring the progress of myocardial sarcoidosis and its response to therapy [36, 37].
In consequence, the 201Tl scan should not be used indiscriminately in screening for the
presence of cardiac involvement in sarcoid patients without cardiac symptoms [1, 9]. In
addition to cardiac sarcoidosis, marked uptake of 201Tl has also been reported in bone
lesions resulting from sarcoidosis [45]. Other heart perfusion imaging agents, such as
technetium-99m-sestamibi (99mTc) [46, 47], or metabolic imaging using iodine-123-
labelled free fatty acid scintigraphy [48] have also been reported to be useful in the
assessment of myocardial sarcoidosis.

Technetium-99m bone scintigraphy

Bone scintigraphy shows high sensitivity and somewhat lower specificity in assessing
bone processes. Localised increased uptake can be seen in a variety of processes, such as
bone metastasis, traumatisms, infections and inflammatory lesions, including sarcoidosis
and degenerative lesions [49]. The frequency of bone involvement in sarcoidosis ranges 3
13%, although, as bone involvement is often asymptomatic, the true prevalence is not
known. The small bones of the hands and feet are more commonly involved, but any
bone can be affected (fig. 3). The most frequent means of detecting bone sarcoidosis is
looking for the presence of a bone radiological abnormality in a patient with known
sarcoidosis. However, the differential diagnosis of these types of bones lesion is often
broad [50]. Bone scintigraphy is more sensitive than either radiography or 67Ga
scintigraphy in the detection of skeletal bone lesions caused by sarcoidosis [51]. Yaghmai
[52], in a series of 136 cases of sarcoidosis involving bone, demonstrated that the bone
scan depicted 30% more lesions than plain radiography. For this reason, the true
frequency of bone involvement by sarcoidosis is probably underestimated due to the
asymptomatic nature of most of these lesions and the absence of justification for bone
scanning in all patients with sarcoidosis. A bone scan, unlike the 67Ga scan, is not able to
detect intrathoracic and other extrathoracic sites of involvement by sarcoidosis [10, 53].
Recently, Milman et al. [49] assessed the value of routine bone scintigraphy in the
detection of osseous and joint lesions in a series of 63 Caucasian patients with pulmonary
sarcoidosis, none of whom exhibited symptoms suggesting bone involvement. Minor

289

Monograph (ERM59136.3d) 12/8/05 11:15:31 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

a) b)

Fig. 3. Radionuclide bone scan revealing hot spots in the skull, right mandibular bone and right clavicle in the
same patient as shown in figure 1: a) front view, and b) lateral view. Images reproduced from [5] with
permission.

scan abnormalities were present in 24 (38%) patients, in bones, joints or both.

Radiographically, only one of these patients showed a typical bone lesion of sarcoidosis.
As the diagnostic yield of bone scanning in sarcoidosis appears to be very small, it should
be reserved for cases with symptomatic osseous involvement and patients with abnormal
radiography results suggesting bone or joint involvement.

111
Indium-octreotide scintigraphy
Scintigraphy using indium-111-diethylenetriamine penta-acetic acid-d-Phe1-octreotide
(octreotide) is useful in the assessment and management of neuroendocrine and other
malignant tumours [54]. It has been reported that normal and activated lymphocytes and
macrophages express somatostatin receptors [55, 56]. As a consequence, several reports
have focused on the usefulness of this radiolabelled somatostatin analogue in detecting
somatostatin receptors expressed on cells in granulomatous diseases, including sarcoidosis.
zturk et al. [57] communicated two cases of sarcoidosis that showed increased uptake
O
of 111In-octreotide. Vanhagen et al. [55] investigated the usefulness of whole-body
somatostatin receptor scintigraphy (SRS) in 13 patients with sarcoidosis. Granuloma
localisations were visualised in all patients, and additional sites were found in 69%. In
addition, scintigraphy results became negative in two patients successfully treated with
corticosteroids, whereas, in three patients in whom corticosteroids were unsuccessful,
scintigraphy results remained positive. Eklund et al. [58] evaluated the usefulness of this
technique in detecting extrathoracic manifestations of sarcoidosis. They found that four
out of five patients with sarcoidosis displayed extrathoracic findings. Kwekkeboom et al.
[59] analysed the value of SRS in the assessment of disease activity, prediction of prognosis
and correlation with clinical course in 46 patients with sarcoidosis. Previously known
mediastinal, hilar and interstitial involvement was recognised in 36 out of 37 patients. In
addition, these findings were also made in a further seven patients with normal CXR

290

Monograph (ERM59136.3d) 12/8/05 11:15:31 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

results, and, in five of these, it pointed to interstitial disease. In 13 patients, SRS revealed
previously undetected extrathoracic uptake, particularly in parotid glands, supraclavicular
lymph nodes, nose, eyes and granulomatous skin lesions. No uptake of radioactivity was
seen in three patients at the site of skin eruption caused by erythema nodosum. In the whole
series, SRS detected new granuloma sites in 23 out of 46 (50%) patients, but missed known
granuloma sites, including cutaneous, ocular, liver and brain sites, in 28% of patients.
Significant relationships were not found between SRS results and the need for
corticosteroid treatment. Neither the degree of radioactive accumulation nor any specific
pattern of pathological uptake was predictive of disease prognosis. SRS results usually
correlated with the progression of the disease. In five out of six patients who showed CXR
improvement under corticosteroid therapy, a decrease in pathological uptake was also
demonstrated on the scintigram. Lebtahi et al. [60] compared SRS with 67Ga scan results in
the evaluation of pulmonary and extrapulmonary involvement in 18 patients with
sarcoidosis. The 67Ga scan revealed abnormalities in 16 out of 18 (89%) patients, and
detected 64 out of 99 (65%) clinically involved sites. SRS found abnormalities in 18 out of
18 (100%) patients, and detected 82 out of 99 (83%) clinically involved sites. Of the nine
treated patients, the 67Ga scan showed abnormalities in seven (78%), detecting 23 out of 39
(59%) clinically involved sites, whereas SRS found abnormalities in nine (100%), detecting
32 out of 39 (82%) clinically involved sites. However, 40% of extrathoracic sites were missed
by SRS. Recently, Shorr et al. [61] studied 22 subjects with sarcoidosis, predominantly
with intrathoracic involvement, and reported a strong correlation between positive scan
results and sarcoidosis activity, particularly with CXR stage and pulmonary function. SRS
revealed intense uptake in two cases of cardiac involvement and also in one case of
neurosarcoidosis. Apart from one patient with cutaneous involvement, the remaining
subjects did not show clinical evidence of extrathoracic sarcoidosis. They emphasised,
however, that SRS does not preclude the need for biopsy to confirm the diagnosis of
sarcoidosis or to exclude malignancy. The possible usefulness of 111In-octreotide in the
study of cardiac sarcoidosis is currently undergoing evaluation [62].

Iodine-123-meta-iodobenzylguanidine scintigraphy
123
Iodine-meta-iodobenzylguanidine (MIBG), an analogue of noradrenaline, is a
tracer for the functioning of sympathetic neurons. Cardiac sympathetic nerves take up
123
I-MIBG. This permits visualisation of the presynaptic sympathetic innervation of the
heart. Defects on MIBG scans in sarcoidosis have been reported [6365], but, to date, the
underlying mechanism has remained unclear. One possible explanation postulated is that
local ischaemia or myocardial inflammation may play an important role. Recently, it was
found that small fibre neuropathy (SFN) occurs frequently in sarcoidosis [66].
Moreover, an imbalance of sympathetic tone is considered to increase the propensity
for developing ventricular arrhythmias in various cardiac diseases and conditions [67].
Autonomic dysregulation might contribute to fatal arrhythmias and unexplained sudden
death in sarcoidosis. It is known from patients with neuropathy that the involvement of
small autonomic nerve fibres is a predictor of cardiovascular mortality [68, 69]. Sudden
death is a rare but dramatic complication [70]. In the case of sarcoidosis, it is thought to
be due mainly to cardiac involvement. Active granulomatous infiltration and resulting
myocardial fibrosis are considered to be the substrate.
Cardiac sympathetic dysfunction, assessed by use of myocardial 123I-MIBG scanning,
appears to be heterogeneous in sarcoidosis patients and dependent on the presence or
absence of SFN [71]. In 18 out of 47 (38%) of these cases, mild-to-moderate heterogeneity
of 123I-MIBG uptake in the myocardium was demonstrated.

291

Monograph (ERM59136.3d) 12/8/05 11:15:32 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

Positron emission tomography

The role of whole-body positron emission tomography (PET) using fluorine-18-
fluorodeoxyglucose (FDG) is well established in the management of patients with cancer.
In recent years, 18F-FDG-PET imaging has also been proposed to have a role in the
diagnosis and management of patients with several types of infection, inflammatory
processes and a variety of benign thoracic disorders [72, 73]. The technique is based on
the demonstration, in experimental studies, of increased glucose metabolism in tumours
and inflamed tissues [74]. Lewis and Salama [75] first described 18F-FDG uptake by
intrathoracic and extrathoracic sarcoid lymph nodes, as well as by lesions of erythema
nodosum. The uptake disappeared after corticosteroid treatment. Brudin et al. [76]
reported an increase in pulmonary 18F-FDG uptake in patients with active sarcoidosis,
reflecting inflammatory activity that was confirmed by lung biopsy. Sazon et al. [77]
demonstrated a strong correlation between the presence of 18F-FDG uptake and the
presence of sarcoidosis activity measured by conventional procedures. 18F-FDG-PET
also detected recurrence of sarcoidosis in transplanted lung, confirmed by transbronchial
biopsy [78].
Yamada et al. [79] described how both 18F-FDG and carbon-11-labelled methionine
uptake on PET were useful for imaging patients with sarcoidosis. In addition, they
reported that the 18F-FDG/11C-methionine uptake ratio was of prognostic value and
useful in pre-treatment evaluation. Increased 18F-FDG accumulation in sarcoidosis was
subsequently reported by other groups [72, 73]. However, one of the main limitations of
18
F-FDG-PET uptake is in differentiating benign lesions, particularly sarcoidosis, from
malignant ones. Pitman et al. [80] suggested that all masses or nodules with increased
18
F-FDG uptake should be considered malignant once sarcoidosis and tuberculosis have
been excluded. Alavi et al. [73] retrospectively compared 18F-FDG-PET images with
thoracic CT results and described several patterns of 18F-FDG uptake in sarcoidosis,
suggesting that their recognition could be helpful in differentiation from malignancy. The
most common pattern, present in 71% of cases, was the so-called typical pattern, in which
PET images consisted of bilateral hilar, mediastinal and pulmonary uptake, similar to
those seen on 67Ga scan. These lesions correlated with thoracic CT results, and most
patients had had their diagnosis of sarcoidosis confirmed prior to PET imaging.
Therefore, the new diagnostic value provided by PET was minimal. The second pattern
was seen in 19% of cases and was called discrepant because PET showed multiple foci of
intense uptake, both intrathoracic and extrathoracic, and particularly splenic, whereas
CT showed only a solitary nodule. This pattern was indistinguishable from those of
malignant processes such as lymphoma. In the presence of this 18F-FDG-PET pattern,
findings on CT may help to define the nature of the lesions. Malignant lesions usually
grow slowly and are often only visible initially on PET and not on CT. In contrast,
inflammatory lesions are metabolically more active, and they can change quickly, grow in
a short interval of time and cause discrepancies, such as the presence of a single or a few
lesions on CT and numerous lesions on 18F-FDG-PET. In consequence, a significant
discrepancy between 18F-FDG-PET and CT results is more suggestive of sarcoidosis.
The third pattern of 18F-FDG uptake in sarcoidosis, seen in 10% of cases, was called the
"tumour of unknown primary". In this pattern, both CT and 18F-FDG-PET revealed
multiple small pulmonary lesions, suggestive of metastases from an unknown primary
tumour. Owing to the high sensitivity of 18F-FDG-PET in detecting malignancy, the
detection of multiple metastases without detecting a primary tumour would support the
diagnosis of sarcoidosis rather than malignancy.
Oriuchi et al. [81] compared the use of another PET tracer, 18F-fluoro-a-
methyltyrosine (FMT), with that of 18F-FDG and showed that, although both sarcoid

292

Monograph (ERM59136.3d) 12/8/05 11:15:32 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

and malignant lesions contained increased 18F-FDG, only malignant lesions showed
increased 18F-FMT accumulation. Consequently, 18F-FMT seems to be a useful PET
tracer when sarcoid lesions need to be differentiated from lung cancer. 18F-FDG-PET
uptake has also been reported to occur at extrathoracic sites of sarcoidosis involvement,
such as skeletal sarcoidosis [8284], cardiac sarcoidosis [85] and neurosarcoidosis [86].
The extent of involvement and quantification of sarcoidosis activity are probably more
accurately assessed by 18F-FDG-PET than by 67Ga scan and other imaging studies. In
addition, hybrid 18F-FDG-PET and CT study, with high-resolution images, may help to
better differentiate active from fibrotic residual lesions. Therefore, it may be useful in the
follow-up of selected patients with sarcoidosis. Figure 4 shows a hybrid 18F-FDG-PET
and CT study in a patient with sarcoidosis.
The dual-isotope technique of nitrogen-13-ammonia/18F-FDG-PET could also
identify cardiac involvement in patients with sarcoidosis [87]. Seventeen patients with
cardiac sarcoidosis underwent cardiac 13N-NH3/18F-FDG PET. Systemic sarcoidosis
was diagnosed by histologically proven noncaseating epithelioid granuloma. Only six
patients showed myocardial 201Tl defects and only three exhibited abnormal 67Ga
accumulation in the heart. Thirteen patients showed 13N-NH3 defects and 14 increased
18
F-FDG uptake in the heart; 12 patients exhibited both 13N-NH3 defects and increased
18
F-FDG uptake, two increased 18F-FDG uptake but no 13N-NH3 defect, and one 13N-
NH3 defects but no increased 18F-FDG uptake. 13N-NH3 defects were observed
frequently in the basal anteroseptal wall of the left ventricle, and increased 18F-FDG
uptake was observed frequently in the basal and mid-anteroseptal lateral wall of the left
ventricle. Involvement of the apex was rare. Seven patients were treated with steroid
hormone and underwent follow-up cardiac PET 1 month after steroid therapy. 13N-NH3
defects exhibited no significant change after steroid therapy, whereas increased 18F-FDG
uptake was markedly diminished in magnitude and intensity in five patients and
disappeared completely in two.
Okumura et al. [88] compared 18F-FDG PET images with scintigraphic findings using
99m
Tc-methoxyisobutylisonitrile (MIBI) and 67Ga. Ten out of 16 patients were
considered to exhibit cardiac complications on clinical grounds with tissue confirmation,

a) b)

Fig. 4. a) Hybrid computed tomography and b) 18F-fluorodeoxyglucose positron emission tomography (PET)
study showing multiple pulmonary lesions with a high glucose metabolism rate in a 63-yr-old male diagnosed as
having pulmonary sarcoidosis 30 yrs earlier, with apparent remission. One year previously he had been
diagnosed as having rectal cancer and was treated with surgery and radiotherapy. Biopsy of pulmonary lesions
showed noncaseating granulomas. Images obtained from C. Gamez and A. Fernadez, PET Unit, Imaging
Diagnosis Institute, Bellvitge University Hospital, Barcelona, Spain.

293

Monograph (ERM59136.3d) 12/8/05 11:15:32 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

such as positive endomyocardial biopsy, severe ventricular arrhythmia, greater than

second degree atrioventricular block and echocardiographically proven ventricular
dysfunction. Among these patients with cardiac complications, abnormal myocardial
uptake of 18F-FDG was observed in all (100%), which confirms the significantly higher
frequency compared to 99mTc-MIBI-SPECT (80%) and 67Ga scintigraphy (50%).
Although abnormal 18F-FDG accumulation was observed in regions with decreased
uptake of 99mTc-MIBI in many cases, localisation of regional abnormality of each tracer
was frequently independent. This discrepancy may reflect the inflammatory and
degenerative process of the myocardium in cardiac sarcoidosis. Recently, Okumura
et al. [89] also demonstrated that 18F-FDG PET was more sensitive than either 99mTc-
MIBI-SPECT and 67Ga scintigraphy in detecting the early stage of cardiac sarcoidosis
that is associated with fewer perfusion defects and greater inflammatory activity, before
advanced myocardial impairment.
PET may have great potential in the diagnosis and management of cardiac sarcoidosis,
particularly for patients with an implanted pacemaker or cardiovertor. However, larger
prospective studies using cardiac magnetic resonance imaging (MRI), PET and 111In-
octreotide are needed to better evaluate its role in the assessment of cardiac sarcoidosis
[90].
Of great promise in the future could be the use of the positron emitter 68Ga (instead of
67
Ga), either as radioisotope or labelled with the somastatin receptor ligand 1,4,7,10-
tetraazacylcododecane-N,N9,N99,N999-tetraacetic acid-d-Phe1-Tyr3-octreotide (DOTA-
TOC) [91]. Since 68Ga can be obtained from a generator system, it could be easily
implemented in clinical practice.

Clinical approach and flow chart

The best means of assessment of pulmonary sarcoidosis is good quality CXR and
pulmonary function test results (fig. 5). When CXR results are doubtful or atypical for
sarcoidosis, HRCT is better than 67Ga scan for studying the mediastinum and
pulmonary parenchyma. Bronchoscopy with BAL and transbronchial biopsy completes
the study of pulmonary sarcoidosis. In this context, neither 67Ga nor other nuclear
imaging techniques provides more significant information. Nevertheless, in the cases of
Lofgrens syndrome and asymptomatic stage I with doubtful hilar lymphadenopathy on
CXR, without histological confirmation, the finding of a lambda pattern on 67Ga scan
may contribute to more confidence in the diagnosis. In the follow-up of patients with
pulmonary sarcoidosis, 67Ga scan may be useful in distinguishing fibrosis from active
inflammation, confirming relapses after suppression of treatment and assessing activity
before lung transplantation. A hybrid 18F-FDG-PET and CT study may be very useful in
better differentiating active from fibrotic residual lesions in the lung.
Whole-body 67Ga scan is also very useful in cases which present with normal CXR
results and a clinical picture suggestive of isolated extrathoracic sarcoidosis, such as
uveitis, inflammatory central nervous system disease or monovisceral granulomatosis,
particularly liver and lymph node granulomatosis, of unknown origin. The finding of a
lambda and/or panda pattern supports the diagnosis of sarcoidosis. Whole-body 67Ga
scan is also useful in assessing the extent of the disease and may provide sites for biopsy.
18
F-FDG-PET and SRS are not specific for the diagnosis of sarcoidosis. However,
they probably better assess the extent of involvement and quantification of sarcoidosis
activity than do the 67Ga scan and other radionuclide imaging examinations, and may be
of value in subgroups of patients in whom there are diagnostic difficulties.
In the case of suspicion of cardiac sarcoidosis, 201Tl scintigraphy is a complementary

294

Monograph (ERM59136.3d) 12/8/05 11:15:33 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

Suspicion of sarcoidosis

Intrathoracic Extrathoracic

Lung, Mediastinum Heart Bone Soft tissue

ECG, Holter MRI, Bone scintigraphy Abdominal CT, Whole-body 67Ga,

CXR typical CXR normal, 123I-MIBG-PET or PET-CT, SRS or
doubtful or atypical SRS Biopsy 68Ga-DOTATOC?

Negative Negative Brain MRI

HRCT BAL or Stop Stop
(neurosarcoidosis)

PFT BAL TBB

Fig. 5. Flow chart suggesting which tests are best to use in the assessment of sarcoidosis. CXR: chest
radiography; MRI: magnetic resonance imaging; MIBG: meta-iodobenzylguanidine; PET: positron emission
tomography; SRS: somatostatin receptor scintigraphy; CT: computed tomography; DOTATOC: 1,4,7,10-
tetraazacylcododecane-N,N9,N99,N999-tetraacetic acid-D-Phe1-Tyr3-octreotide; HRCT: high-resolution CT; BAL:
bronchoalveolar lavage; PFT: pulmonary function test; TBB: transbronchial biopsy.

tool to two-dimensional echocardiography, 24-h monitoring and cardiac catheterisation

with endomyocardial biopsy. A normal 201Tl scan, however, does not rule out the
presence of cardiac involvement. 99mTc-sestamibi is currently replacing 201Tl in some
centres. 18F-FDG-PET has been reported to be better than 201Tl scan for studying
cardiac sarcoidosis, and the value of SRS is currently under evaluation. 123I-MIBG
scintigraphy can be useful in assessing cardiac autonomic dysfunction, which is often
associated with the presence of SFN. Cardiac MRI has recently been introduced as a very
accurate tool in the diagnosis and management of cardiac sarcoidosis.
Brain involvement of sarcoidosis is better assessed by MRI, although nuclear imaging
techniques have been reported as capable of detecting the presence of neurological
involvement. Bone scintigraphy is very sensitive for detecting the presence of sarcoid
bone lesions.

Conclusions
Nuclear imaging in sarcoidosis is a rapidly changing field, with new possibilities
appearing on the horizon as others are discontinued. At present, the role of scintigraphy
in confirming diagnosis and guiding therapy in sarcoidosis is limited. The most
appropriate use of 67Ga scintigraphy in sarcoidosis is assisting in the determination of the
extent and distribution of the disease in cases in whom there are diagnostic difficulties,
particularly in those with isolated extrathoracic sarcoidosis. It is conceivable that the
extent of involvement and quantification of sarcoidosis activity can be more accurately
assessed in the future by 18F-FDG-PET, particularly when combined with CT or in
combination with new tracers such as 68Ga DOTATOC or 68Ga alone. Nuclear imaging
techniques are particularly helpful in the follow-up of patients for differentiating active
inflammation from fibrosis.

295

Monograph (ERM59136.3d) 12/8/05 11:15:33 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

Summary
Nuclear imaging techniques play a role in the assessment of sarcoidosis. Several
possibilities are available, and promising new techniques are in development.
Scintigraphic techniques are useful in distinguishing fibrotic from active lung disease,
confirming relapse in doubtful cases, assessing activity before lung transplantation and
the detection of cardiac involvement and extrathoracic localisation.
The improvement in image resolution in modern postitron emission tomography and
single-photon emission computed tomography scanners, with or without computed
tomography, allows more accurate imaging and quantification, whereas the use of new
radiopharmaceuticals could provide more insight into the physiology and extent of the
disease. In this chapter, a flow chart has been created in order to facilitate clinicians
decisions about which tests are best to use in the assessment of sarcoidosis.

Keywords: Gallium-67 scintigraphy, indium-111-octreotide scintigraphy, iodine-123-

meta-iodobenzylguanidine scintigraphy, positron emission tomography, technetium-
99m bone scintigraphy, thallium-201 scintigraphy.

References
1. Mana J. Nuclear imaging: 67gallium, 201thallium, 18F-labeled fluoro-2-deoxy-d-glucose positron
emission tomography. Clin Chest Med 1997; 18: 799811.
2. Beaumont D, Herry JY, Sapene M, Bourget P, Larzul JJ, de Labarthe B. Gallium-67 in the
evaluation of sarcoidosis: correlations with serum angiotensin-converting enzyme and
bronchoalveolar lavage. Thorax 1982; 37: 1118.
3. Israel HL, Albertine KH, Park CH, Patrick H. Whole-body gallium 67 scans. Role in diagnosis of
sarcoidosis. Am Rev Respir Dis 1991; 144: 11821186.
4. Sulavik SB, Palestro CJ, Spencer RP, Swyer AJ, Goldsmith SJ, Teirstein AS. Extrapulmonary sites
of radiogallium accumulation in sarcoidosis. Clin Nucl Med 1990; 15: 876878.
5. Mana J, Segarra MI, Casas R, Mairal L, Fernandez-Nogues F. Multiple atypical bone
involvement in sarcoidosis. J Rheumatol 1993; 20: 394396.
6. Liem IH, Drent M, Antevska E, Lamers RJS, Heidendal GAK. Intensive muscle uptake of
gallium-67 in a patient with sarcoidosis. J Nucl Med 1998; 39: 16051607.
7. Sulavik SB, Spencer RP, Palestro CJ, Swyer AJ, Teirstein AS, Goldsmith SJ. Specificity and
sensitivity of distinctive chest radiographic and/or 67Ga images in the noninvasive diagnosis of
sarcoidosis. Chest 1993; 103: 403409.
8. Sulavik SB, Spencer RP, Weed DA, Shapiro HR, Shiue ST, Castriotta RJ. Recognition of
distinctive patterns of gallium-67 distribution in sarcoidosis. J Nucl Med 1990; 31: 19091914.
9. Mana J. MRI and nuclear imaging in sarcoidosis. Curr Opin Pulm Med 2002; 8: 457463.
10. Niden AH, Mishkin FS, Salem F, Thomas AV, Kamdar V. Prognostic significance of gallium lung
scans in sarcoidosis. Ann N Y Acad Sci 1986; 465: 435443.
11. Baughman RP, Shipley R, Eisentrout CE. Predictive value of gallium scan, angiotensin-converting
enzyme level, and bronchoalveolar lavage in two-year follow-up of pulmonary sarcoidosis. Lung
1987; 165: 371377.
12. Hollinger WM, Staton GW, Fajman WA, Gilman MJ, Pine JR, Check IJ. Prediction of
therapeutic response in steroid-treated pulmonary sarcoidosis. Evaluation of clinical parameters,
bronchoalveolar lavage, gallium-67 lung scanning, and serum angiotensin-converting enzyme
levels. Am Rev Respir Dis 1985; 132: 6569.

296

Monograph (ERM59136.3d) 12/8/05 11:15:33 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

13. Mana J, Salazar A, Pujol R, Manresa F. Are the pulmonary function tests and the markers of
activity helpful to establish the prognosis of sarcoidosis? Respiration 1986; 63: 298303.
14. Rizzato G, Blasi A. A European survey on the usefulness of 67Ga lung scans in assessing
sarcoidosis. Experience in 14 research centers in seven different countries. Ann N Y Acad Sci 1986;
465: 463478.
15. Lynch DA, Webb WR, Gamsu G, Stulbarg M, Golden J. Computed tomography in pulmonary
sarcoidosis. J Comput Assist Tomogr 1989; 13: 405410.
16. Bergin CJ, Bell DY, Coblentz CL, et al. Sarcoidosis: correlation of pulmonary parenchymal
pattern at CT with results of pulmonary function tests. Radiology 1989; 171: 619624.
17. Leung AN, Brauner MW, Caillat-Vigneron N, Valeyre D, Grenier P. Sarcoidosis activity:
correlation of HRCT findings with those of 67Ga scanning, bronchoalveolar lavage, and serum
angiotensin-converting enzyme assay. J Comput Assist Tomogr 1998; 22: 229234.
18. Remy-Jardin M, Giraud F, Remy J, Wattinne L, Wallaert B, Duhamel A. Pulmonary sarcoidosis:
role of CT in the evaluation of disease activity and functional impairment and in prognosis
assessment. Radiology 1994; 191: 675680.
19. Oberstein A, von Zitzewitz H, Schweden F, Muller-Quernheim J. Non invasive evaluation of the
inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc
Diffuse Lung Dis 1997; 14: 6572.
20. Mimori Y. Sarcoidosis: correlation of HRCT findings with results of pulmonary function tests and
serum angiotensin-converting enzyme assay. Kurume Med J 1998; 45: 247256.
21. Drent M, De Vries J, Lenters M, et al. Sarcoidosis: assessment of disease severity using HRCT.
Eur Radiol 2003; 13: 24622471.
22. Nosal A, Schleissner LA, Mishkin FS, Lieberman J. Angiotensin-I-converting enzyme and gallium
scan in noninvasive evaluation of sarcoidosis. Ann Intern Med 1979; 90: 328331.
23. Klech H, Kohn H, Kummer F, Mostbeck A. Assessment of activity in sarcoidosis. Sensitivity and
specificity of 67gallium scintigraphy, serum ACE levels, chest roentgenography, and blood
lymphocyte subpopulations. Chest 1982; 82: 732738.
24. Schoenberger CI, Line BR, Keogh BA, Hunninghake GW, Crystal RG. Lung inflammation in
sarcoidosis: comparison of serum angiotensin-converting enzyme levels with bronchoalveolar
lavage and gallium-67 scanning assessment of the lymphocyte alveolitis. Thorax 1982; 37: 1925.
25. Kohn H, Klech H, Mostbeck A, Kummer F. 67Gallium scanning for assessment of disease activity
and therapy decisions in pulmonary sarcoidosis in comparison to chest radiography, serum ACE
and blood T-lymphocytes. Eur J Nucl Med 1982; 7: 413416.
26. Lieberman J, Schleissner LA, Nosal A, Sastre A, Mishkin FS. Clinical correlations of serum
angiotensin-converting enzyme (ACE) in sarcoidosis. A longitudinal study of serum ACE,
67
gallium scans, chest roentgenograms, and pulmonary function. Chest 1983; 84: 522528.
27. Lawrence EC, Teague RB, Gottlieb MS, Jhingran SG, Lieberman J. Serial changes in markers of
disease activity with corticosteroid treatment in sarcoidosis. Am J Med 1983; 74: 747756.
28. Baughman RP, Fernandez M, Bosken CH, Mantil J, Hurtubise P. Comparison of gallium-67
scanning, bronchoalveolar lavage, and serum angiotensin-converting enzyme levels in pulmonary
sarcoidosis. Predicting response to therapy. Am Rev Respir Dis 1984; 129: 676681.
29. Turner-Warwick M, McAllister W, Lawrence R, Britten A, Haslam PL. Corticosteroid treatment
in pulmonary sarcoidosis: do serial lavage lymphocyte counts, serum angiotensin converting
enzyme measurements, and gallium-67 scans help management? Thorax 1987; 41: 903913.
30. Crystal RG, Roberts WC, Hunninghake GW, Gadek JE, Fulmer JD, Line BR. Pulmonary
sarcoidosis: a disease characterized and perpetuated by activated lung T-lymphocytes. Ann Intern
Med 1981; 94: 7394.
31. Line BR, Hunninghake GW, Keogh BA, Jones AE, Johnston GS, Crystal RG. Gallium-67
scanning to stage the alveolitis of sarcoidosis: correlation with clinical studies, pulmonary function
studies, and bronchoalveolar lavage. Am Rev Respir Dis 1981; 123: 440446.
32. Keogh BA, Hunninghake GW, Line BR, Crystal RG. The alveolitis of pulmonary sarcoidosis.

297

Monograph (ERM59136.3d) 12/8/05 11:15:34 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

Evaluation of natural history and alveolitis-dependant changes in lung function. Am Rev Respir
Dis 1983; 128: 256265.
33. Mana J, Gomez-Vaquero C, Montero A, et al. Lofgrens syndrome revisited: a study of 186
patients. Am J Med 1999; 107: 240245.
34. Bulkley BH, Rouleau JR, Whitaker JQ, Strauss HW, Pitt B. The use of 201thallium for myocardial
perfusion imaging in sarcoid heart disease. Chest 1977; 72: 2732.
35. Sharma OP, Maheshwari A, Thaker K. Myocardial sarcoidosis. Chest 1993; 103: 253258.
36. Haywood LJ, Sharma OP, Siegel ME. Detection of myocardial sarcoidosis by thallium-201
imaging. J Natl Med Assoc 1982; 74: 959964.
37. Fields CL, Ossorio MA, Roy TM, Denny DM, Varga DW. Thallium-201 scintigraphy in the
diagnosis and management of myocardial sarcoidosis. South Med J 1990; 83: 339342.
38. Yamamoto N, Gotoh K, Yagi Y, et al. Thallium-201 myocardial SPECT findings at rest in
sarcoidosis. Ann Nucl Med 1993; 7: 97103.
39. Tellier P, Paycha F, Antony I, et al. Reversibility by dipyridamole of thallium-201 myocardial scan
defects in patients with sarcoidosis. Am J Med 1988; 85: 189193.
40. Kinney EL, Jackson GL, Reeves WC, Zelis R, Beers E. Thallium-scan myocardial defects and
echocardiographic abnormalities in patients with sarcoidosis without clinical cardiac dysfunction.
An analysis of 44 patients. Am J Med 1980; 68: 497503.
41. Hirose Y, Ishida Y, Hayashida K, et al. Myocardial involvement in patients with sarcoidosis. An
analysis of 75 patients. Clin Nucl Med 1994; 19: 522526.
42. Kurata C, Sakata K, Taguchi T, et al. SPECT imaging with Tl-201 and Ga-67 in myocardial
sarcoidosis. Clin Nucl Med 1990; 15: 408411.
43. Okayama K, Kurata C, Tawarahara K, Wakabayashi Y, Chida K, Sato A. Diagnostic and
prognostic value of myocardial scintigraphy with thallium-201 and gallium-67 in cardiac
sarcoidosis. Chest 1995; 107: 330334.
44. Kinney EL, Caldwell JW. Do thallium myocardial perfusion scan abnormalities predict survival in
sarcoid patients without cardiac symptoms? Angiology 1990; 41: 573576.
45. Degirmenci B, Mavi A, O zkal S, et al. Tl-201 uptake in bone and soft tissue involvement of
sarcoidosis. Clin Nucl Med 2001; 26: 499501.
46. Le Gudulec D, Menad F, Faraggi M, Weinmann P, Battesti JP, Valeyre D. Myocardial
sarcoidosis. Clinical value of technetium-99m sestamibi tomoscintigraphy. Chest 1994; 106: 1675
1682.
47. Eguchi M, Tsuchihashi K, Hotta D, et al. Technetium-99m sestamibi/tetrofosmin myocardial
perfusion scanning in cardiac and noncardiac sarcoidosis. Cardiology 2000; 94: 193199.
48. Kaminaga T, Takeshita T, Yamauchi T, Kawamura H, Yasuda M. The role of Iodine-123-labeled
15-(p-iodophenyl)-3R,S-methylpentadecanoic acid scintigraphy in the detection of local
myocardial involvement of sarcoidosis. Int J Cardiol 2004; 94: 99103.
49. Milman N, Lund JO, Graudal N, Enevoldsen H, Evald T, Norgard P. Diagnostic value of routine
radioisotope bone scanning in a series of 63 patients with pulmonary sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2000; 17: 6770.
50. Wilcox A, Bharadwaj P, Sharma OP. Bone sarcoidosis. Curr Opin Rheumatol 2000; 12: 321
330.
51. Shorr AF, Murphy FT, Gilliland WR, Hnatiuk OW. Osseous disease in patients with pulmonary
sarcoidosis and musculoskeletal symptoms. Respir Med 2000; 94: 228232.
52. Yaghmai I. Radiographic, angiographic and radionuclide manifestations of osseous sarcoidosis.
Radiographics 1983; 3: 375396.
53. Sun SS, Tsai SC, Hung CJ, et al. Tc-99m MDP and Ga-67 citrate scintigraphic findings in
sarcoidosis with osseous involvement. Clin Nucl Med 2001; 26: 472473.
54. Dalm VA, Van Hagen PM, Krenning EP. The role of octreotide scintigraphy in rheumatoid
arthritis and sarcoidosis. Q J Nucl Med 2003; 47: 270278.
55. Vanhagen PM, Krenning EP, Reubi JC, et al. Somatostatin analogue scintigraphy in
granulomatous diseases. Eur J Nucl Med 1994; 21: 497502.

298

Monograph (ERM59136.3d) 12/8/05 11:15:34 Rev 7.51n/W (Jan 20 2003) (gamma)

 NUCLEAR IMAGING TECHNIQUES IN SARCOIDOSIS

56. ten Bokum AMC, Hofland LJ, de Jong G, et al. Immunohistochemical localization of
somatostatin receptor sst2A in sarcoid granulomas. Eur J Clin Invest 1999; 29: 630636.
57. O zturk E, Gunalp B, O zguven M, et al. The visualization of granulomatous disease with
somatostatin receptor scintigraphy. Clin Nucl Med 1994; 19: 129132.
58. Eklund A, Jacobsson H, Larsson SA, Skold CM. Detection of extrathoracic manifestations in
sarcoidosis with somatostatin analogue scintigraphy. Sarcoidosis Vasc Diffuse Lung Dis 1997; 14:
146151.
59. Kwekkeboom DJ, Krenning EP, Kho GS, Breeman WA, Van Hagen PM. Somatostatin receptor
imaging in patients with sarcoidosis. Eur J Nucl Med 1998; 25: 12841292.
60. Lebtahi R, Crestani B, Belmatoug N, et al. Somatostatin receptor scintigraphy and gallium
scintigraphy in patients with sarcoidosis. J Nucl Med 2001; 42: 2126.
61. Shorr AF, Helman DL, Lettieri CJ, Montilla JL, Bridwell RS. Depreotide scanning in sarcoidosis:
a pilot study. Chest 2004; 126: 13371343.
62. Smedema JP, van Kroonenburgh M, Snoep R, Backes W, Gorgels AP. Images in cardiovascular
medicine. Cardiac sarcoidosis in a patient with hypertrophic cardiomyopathy demonstrated by
magnetic resonance imaging and single photon emission computed tomography dual-isotope
scintigraphy. Circulation 2004; 110: e529e531.
63. Misumi I, Kimura Y, Hokamura Y, et al. Scintigraphic detection of regional disruption of the
adrenergic nervous system in sarcoid heart disease. Jpn Circ J 1996; 60: 774778.
64. Matsuo S, Nakamura Y, Matsui T, Matsumoto T, Kinoshita M. Detection of denervated but
viable myocardium in cardiac sarcoidosis with I-123 MIBG and Tl-201 SPECT imaging. Ann Nucl
Med 2001; 15: 373375.
65. Imai E, Kaminaga T, Takada K, Kutomi K, Furui S. Radioactive defect on I-123 MIBG
myocardial SPECT imaging in a patient with cardiac sarcoidosis. Clin Nucl Med 2002; 27: 729
730.
66. Hoitsma E, Marziniak M, Faber CG, et al. Small fibre neuropathy in sarcoidosis. Lancet 2002;
359: 20852086.
67. Wichter T, Matheja P, Eckardt L, et al. Myocardial iodine-123- metaiodobenzylguanidine(123I-
MIBG) imaging in Brugada syndrome. Circulation 2002; 106: 5960.
68. Tuck RR, McLeod JG. Autonomic dysfunction in Guillain-Barre syndrome. J Neurol Neurosurg
Psychiatry 1981; 44: 983990.
69. Ewing DJ, Campbell IW, Clarke BF. Assessment of cardiovascular effects in diabetic autonomic
neuropathy and prognostic implications. Ann Intern Med 1980; 92: 308311.
70. Ewing DJ, Boland O, Neilson JM, Cho CG, Clarke BF. Autonomic neuropathy, QT interval
lengthening, and unexpected deaths in male diabetic patients. Diabetologia 1991; 34: 182
185.
71. Hoitsma E, Faber CG, van Kroonenburgh MJPG, et al. Cardiac sympathetic dysfunction and
small fiber neuropathy: a common problem in sarcoidosis? Sarcoidosis Vasc Diffuse Lung Dis 2005;
22: 4350.
72. Zhuang H, Alavi A. 18-Fluorodeoxyglucose positron emission tomographic imaging in the
detection and monitoring of infection and inflammation. Semin Nucl Med 2002; 32: 4759.
73. Alavi A, Gupta N, Alberini JL, et al. Positron emission tomography imaging in nonmalignant
thoracic disorders. Semin Nucl Med 2002; 32: 293321.
74. Jones HA, Clark RJ, Rhodes CG, Schofield JB, Krausz T, Haslett C. In vivo measurement
of neutrophil activity in experimental lung inflammation. Am J Respir Crit Care Med 1994;
149: 16351639.
75. Lewis PJ, Salama A. Uptake of fluorine-18-fluorodeoxyglucose in sarcoidosis. J Nucl Med 1994;
35: 16471649.
76. Brudin LH, Valind S, Rhodes CG, et al. Fluorine-18 deoxyglucose uptake in sarcoidosis measured
with positron emission tomography. Eur J Nucl Med 1994; 21: 297305.
77. Sazon DA, Sharma OP, Santiago S, Williams AJ. Fluorodeoxyglucose positron emission
tomography in pulmonary sarcoidosis. Sarcoidosis 1994; 11: Suppl. 1, 363367.

299

Monograph (ERM59136.3d) 12/8/05 11:15:34 Rev 7.51n/W (Jan 20 2003) (gamma)

 A
J. MAN , M. VAN KROONENBURGH

78. Kiatboonsri C, Resnick S, Chan KM, et al. The detection of recurrent sarcoidosis by FDG-PET in
a lung transplant recipient. West J Med 1998; 168: 130132.
79. Yamada Y, Uchida Y, Tatsumi K, et al. Fluorine-18-fluorodeoxyglucose and carbon-11-
methionine evaluation of lymphadenopathy in sarcoidosis. J Nucl Med 1998; 39: 11601166.
80. Pitman AG, Hicks RJ, Binns DS, et al. Performance of sodium iodide based 18F-
fluorodeoxyglucose positron emission tomography in the characterization of indeterminate
pulmonary nodules or masses. Br J Radiol 2002; 75: 114121.
81. Oriuchi N, Inoue T, Tomiyoshi K, et al. F-18-fluoro-a-methyltyrosine (FMT) and F-18-
fluorodeoxyglucose (FDG) PET in patients with sarcoidosis. J Nucl Med 1999; 40: 878.
82. Kobayashi A, Shinozaki T, Shinjyo Y, et al. FDG PET in the clinical evaluation of sarcoidosis
with bone lesions. Ann Nucl Med 2000; 14: 311313.
83. Ludwig V, Fordice S, Lamar R, Martin WH, Delbeke D. Unsuspected skeletal sarcoidosis
mimicking metastatic disease on FDG positron emission tomography and bone scintigraphy. Clin
Nucl Med 2003; 28: 176179.
84. Aberg C, Ponzo F, Raphael B, Amorosi E, Moran V, Kramer E. FDG positron emission
tomography of bone involvement in sarcoidosis. AJR Am J Roentgenol 2004; 182: 975977.
85. Takeda N, Yokoyama I, Hiroi Y, et al. Positron emission tomography predicted recovery of
complete A-V nodal dysfunction in a patient with cardiac sarcoidosis. Circulation 2002; 105: 1144
1145.
86. Dubey N, Miletich RS, Wasay M, Mechtler LL, Bakshi R. Role of fluorodeoxyglucose positron
emission tomography in the diagnosis of neurosarcoidosis. J Neurol Sci 2002; 205: 7781.
87. Yamagishi H, Shirai N, Takagi M, et al. Identification of cardiac sarcoidosis with 13N-NH3/18F-
FDG PET. J Nucl Med 2003; 44: 10301036.
88. Okumura W, Iwasaki T, Ueda T, et al. Usefulness of 18F-FDG PET for diagnosis of cardiac
sarcoidosis. Kaku Igaku 1999; 36: 341348.
89. Okumura W, Iwasaki T, Toyama T, et al. Usefulness of fasting 18F-FDG PET in identification of
cardiac sarcoidosis. J Nucl Med 2004; 45: 19891998.
90. Smedema JP, van Kroonenburgh MJ, Snoep G, Bekkers SC, Gorgels AP. Diagnostic value of PET
in cardiac sarcoidosis. J Nucl Med 2004; 45: 1975.
91. Hofmann M, Maecke H, Borner R, et al. Biokinetics and imaging with the somatostatin receptor
PET radioligand 68Ga-DOTATOC: preliminary data. Eur J Nucl Med 2001; 28: 17511757.

300

Monograph (ERM59136.3d) 12/8/05 11:15:34 Rev 7.51n/W (Jan 20 2003) (gamma)

CHAPTER 20

Therapy for sarcoidosis

R.P. Baughman, E.E. Lower

University of Cincinnati Medical Center, Cincinnati, OH, USA.

Correspondence: R.P. Baughman, 1001 Holmes Eden Ave, Cincinnati, OH 45267-0565, USA. Fax: 1
5135585110; E-mail: bob.baughman@uc.edu

The recommended treatments for sarcoidosis differ from none to a combination of

cytotoxic agents [1]. A major reason for this wide spectrum of treatment relates to the
variation in disease outcome. Moreover, treatment options vary because no treatment
cures the disease, but is rather a means of controlling symptoms. Finally, there is the
preference of the patient and treating physician. All of these reasons impact on the
decision regarding drug usage and duration of therapy.
The approach to therapy in sarcoidosis revolves around several important issues.
These are summarised in table 1.
One issue concerns the symptoms a patient is suffering from. In most series, at least a
third of sarcoidosis patients are asymptomatic and, therefore, never require treatment for
symptoms [24]. In one study, a third of patients with parenchymal involvement on chest
radiography experienced chest radiographic improvement over a 6-month observation
period [5]. This group had benign disease, with only 20% of the patients considered sick
enough to require systemic therapy on presentation. The highest recorded proportion of
patients requiring systemic therapy on presentation is 67%. This was from a clinic of
mostly African-American patients [6].
For the asymptomatic patient with persistent parenchymal infiltrates, two studies have
suggested that therapy changes the natural history of the disease. In one study, patients were
treated with 18 months of continuous systemic therapy versus systemic therapy only if
needed. In the latter group, six out of 31 (19%) received corticosteroid therapy. Despite the
fact that not all patients in the control group received no therapy, the control patients
overall exhibited a persistently lower Vital Capacity (VC) and higher level of dyspnoea 5 yrs
after the discontinuation of any therapy [5]. In a study comparing a regimen of 3 months of
systemic corticosteroids followed by 15 months of inhaled steroids (budesonide) versus
placebo, Pietinalho et al. [7] reported that corticosteroid treatment was associated with a
significantly higher carbon monoxide diffusing capacity of the lung and better chest
radiographic pattern than in placebo patients at the end of treatment. An additional analysis
5 yrs after completion of therapy found persistent benefit of corticosteroid therapy for
18 months in patients with parenchymal infiltrates at the time of treatment [8]. Interestingly,
the authors also reported that patients treated with placebo experience a higher rate of
deterioration requiring systemic therapy during the 5-yr observation period.

Table 1. Questions to be answered in deciding on therapy for sarcoidosis

Is the patient symptomatic?
Can the symptoms be controlled with topical therapy?
Does the patient exhibit life- or organ-threatening disease?
Is the patient experiencing, or is likely to experience, chronic disease?
Does the patient have a relative or absolute contraindication to any specific therapy?

Eur Respir Mon, 2005, 32, 301315. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
301
 R.P. BAUGHMAN, E.E. LOWER

The success of budesonide in the study of Pietinalho et al. [8] raises the question as to
whether sarcoidosis patients can be controlled using inhaled therapy alone. Although the
use of inhaled budesonide was more efficacious than placebo in some studies [9, 10],
others have not found budesonide useful in controlling pulmonary disease [11].
Fluticasone has not been found useful in treating either acute or chronic symptomatic
disease [12, 13]. However, these drugs may still be useful in controlling cough, if that is
the major problem [12].
Topical therapy appears more successful for controlling skin lesions and anterior
uveitis. Corticosteroids, in various preparations, have been used since the mid-1990s [14].
Tacrolimus has recently been reported as a beneficial topical therapy for refractory
cutaneous disease [15]. Ocular disease has been treated with topical drops and periocular
injections of corticosteroids [16]. However, local therapy can lead to complications, such
as glaucoma and cataract formation [17]. There is also a report that topical ocular corti-
costeroid therapy delays the resolution of pulmonary sarcoidosis [18].
The use of systemic therapy for sarcoidosis is usually driven by symptoms. An absolute
requirement for systemic therapy includes manifestations which are life- or organ-
threatening. In long-term studies analysing mortality due to sarcoidosis, the most
common causes of death are pulmonary, cardiac, neurological and hepatic [1921].
Table 2 lists the mortality reported in a cohort of patients followed at a specialised clinic,
and focuses on the relative frequency of death caused by pulmonary, neurological and
cardiac disease [19]. For pulmonary disease, a low VC is a relative indicator of increased
mortality. The treatment of respiratory disease may improve survival. For example, three
out of nine patients showing a lowest VC of v1 L died due to respiratory failure. Only
one out of six patients whose VC increased with therapy tow1 L died; however, two out
of four patients without improvement in their VC died during the 7-yr observation period
[19]. Subsequent studies performed on patients with respiratory failure awaiting lung
transplantation suggest that the presence of pulmonary hypertension is associated with
increased mortality. An elevated right atrial pressure was associated with the worst
prognosis [2224].
In an attempt to identify prognostic markers of chronic disease, several studies have
noted certain markers that are associated with resolution of disease, and others that are
associated with a prolonged disease state. The landmark study of Neville et al. [25] of
818 patients is summarised in figure 1. In addition, renal calculi are another marker of
chronic disease [26].
One biological marker of chronic disease has been increased neutrophil and eosinophil
numbers in bronchoalveolar lavage (BAL) fluid [27]. The increased neutrophil numbers
are associated with increased interleukin-8 levels in the BAL fluid [28]. Recent studies
have confirmed the importance of this finding [29, 30].
Regardless of presentation, the clinical outcome of the patient is best determined with
time. Although figure 1 illustrates that patients with erythema nodosum and stage 1 chest
radiographs usually experience disease resolution within 2 yrs, a subgroup of patients
Table 2. Mortality in a cohort of patients with sarcoidosis followed for 7 yrs

Organ involvement Cases n Deaths n (%)

Any 479 22 (4.6)
Lung
Vital capacity w1.5 L 438 3 (0.68)
Vital capacity v1.5 L 41 10 (24)
Cardiac 20 3 (15)
Neurological 54 4 (7.4)
Data taken from [19].

302
 THERAPY FOR SARCOIDOSIS

90
80
70
60
Resolution %

50
40
30
20
10
0
EN Stage I Ocular Cardiac CNS Lupus
CXR pernio
Clinical feature
Fig. 1. Frequency of resolution of chest radiograph (CXR) after 2 yrs in sarcoidosis patients presenting with
various clinical features. EN: erythema nodosum; CNS: central nervous system. Adapted from [25].

exists with even this benign presentation who require long-term therapy [31]. In a recent
worldwide survey of sarcoidosis clinics, w50% of patients followed for w5 yrs after
diagnosis still required therapy. This includes 10% of patients experiencing disease
relapse requiring increased systemic therapy in the previous year. Figure 2 indicates that
there was no major geographical difference in the incidence of chronic disease between
the five centres [31].
Relative and absolute contraindications exist for all drug therapies. In sarcoidosis,

60

50

40
Patients %

30

20

10

0
Worse Not worse NST >1 yr NST NST >1 yr NST NST >1 yr NST
before 1 yr before 1 yr
Persistant disease Minimal disease Resolution
Fig. 2. Percentage of patients (n=50) from each multinational site (&: Kyoto, Japan; &: Milan, Italy; p:
Maastricht, The Netherlands; &: Charleston, NC, USA; %: Cincinnati, OH, USA) in each general category
i5 yrs after diagnosis. Patients could show resolution (no evidence of disease) or minimal (v10% of maximal
disease) or persistent (w10% of maximal disease) disease, and could have never been given systemic therapy
(NST), none in the previous year (NST w1 yr) or received therapy in the past year. Patients with persistent
disease may also have worsened in the past year. Data taken from [32].

303
 R.P. BAUGHMAN, E.E. LOWER

patients who have received corticosteroids are often anxious to find alternatives. As more
treatment options become available for sarcoidosis, the clinician can avoid toxicity.
However, the perfect drug for sarcoidosis is yet to be found.
In an era of rising health costs, clinicians need to consider the potential cost of various
agents. Corticosteroids are very inexpensive, whereas some of the newer agents, such as
infliximab, are relatively expensive.

Individual agents
Corticosteroids
Corticosteroids remain the standard agent to which all other drugs are compared
(table 3). Introduced in the 1950s for sarcoidosis [33], these drugs were quickly shown to
be effective in treating the disease [34]. The early reports of the success of corticosteroids
in treating sarcoidosis were followed by a series of negative studies when the drug was
compared to placebo in randomised trials [35, 36]. Other groups found the drug quite
useful in the management of chronic pulmonary disease [37, 38].
A meta-analysis of corticosteroid therapy for sarcoidosis confirmed the value of this
treatment [39]. However, this meta-analysis also highlights some of the problems of prior
clinical trials, including the exclusion of symptomatic patients (who were all treated) and
the relatively short follow-up. When corticosteroids were administered for w6 months,
drug therapy was significantly better than placebo [40].
The most controversial area of corticosteroid therapy is the asymptomatic individual
with persistent infiltrates. As noted above, there are two trials demonstrating benefit for
patients with persistent infiltrates even if they show no symptoms. Two regimens have
been studied: systemic corticosteroids for 18 months [5], and 3 months of systemic
corticosteroids followed by 15 months of high-dose inhaled budesonide [8]. However, the

Table 3. Drug therapy for sarcoidosis

Class Drug Dose Comments

Corticosteroids Prednisone 540 mg Initial dose higher; reduce to minimal,
tolerable and effective dose
Prednisolone 540 mg
Budesonide 8001600 mg Inhaled therapy
Triamcinolone Used in topical therapy for skin
Cytotoxic Methotrexate 515 mg weekly Takes up to 6 months to be effective
Azathioprine 50250 mg daily More leukopenic than methotrexate
Chlorambucil 212 mg daily Higher rate of malignancy than other
agents
Leflunomide 1020 mg daily Similar to methotrexate, but less nausea
Cyclophosphamide 50150 mg orally daily Higher rate of side-effects, but associated
or 5002000 mg with higher response rate than other
i.v. every 2 weeks cytotoxic agents
Antimicrobial agents Chloroquine
Hydroxychloroquine 200400 mg daily Less ocular toxicity than chloroquine
Minocycline 100200 mg daily Rarely associated with immune toxicity
Cytokine modulation Pentoxifylline 200400 mg up to High doses may be needed to block TNF
3 times?day-1
Thalidomide 50200 mg daily Teratogenic, a potential major concern
Infliximab 5 mg?kg-1 i.v. every Increased rate of infection and allergic
48 weeks after reaction
loading doses
TNF: tumour necrosis factor.

304
 THERAPY FOR SARCOIDOSIS

amount of improvement demonstrated at the end of treatment and 5 yrs later does not
appear to be clinically significant. In addition, there is concern that the institution of
corticosteroid therapy may increase the likelihood of development of chronic disease [6],
although this was not seen in the two controlled trials [5, 8]. Following these studies, one
recommendation is that asymptomatic patients with persistent disease should not be
treated with corticosteroids [1].
The initial and maintenance dose of corticosteroids varies from centre to centre. It
appears that the dose used to place a patient in remission is higher than that needed to
maintain the remission. As summarised in figure 3, Judson [41] described the six phases
of corticosteroid therapy for sarcoidosis. The duration of therapy in each stage varies
between patients and treating physicians. Overall, patients usually receive i1 yr of
therapy.
For pulmonary disease, the recommended initial dose of prednisone (or prednisolone)
is 2040 mg?day-1 [1]. The dose is tapered over the next 6 months to v20 mg. Some
clinicians prefer to use an alternate-day regimen. A higher initial dose is often used for
cardiac or neurological disease.
Corticosteroid therapy is not without toxicity. H. Cushing first described hypercorti-
solism as a clinical entity. Pharmacological doses of glucocorticoids can lead to
hyperglycaemia, hypertension, weight gain, osteoporosis, acne, glaucoma and cataracts.
Figure 4 summarises the most common daily toxicities reported by patients treated for
pulmonary sarcoidosis for 1 yr. Those receiving prednisone at a dose of w10 mg?day-1
reported a significantly higher rate of each complaint [12].

Methotrexate
The antimetabolite methotrexate has become one of the standard agents used for
sarcoidosis [1, 42, 43]. Widespread use has developed because of its efficacy against
various disease manifestations, including cutaneous lesions [44, 45], pulmonary disease
[42, 44], arthritic manifestations [46], ocular disease [16, 46, 47] and neurological disease

High
Corticosteroid dose

Low
Initial Taper to Maintenance Taper Obser- Relapse
dose maintenance dose off vation
Phase

Fig. 3. The six phases of corticosteroid therapy for patients with sarcoidosis. Although not all patients relapse,
with relapse, the dose of treatment required is often as high as that needed to induce the initial remission [41].

305
 R.P. BAUGHMAN, E.E. LOWER

35

30

25
Complication rate %
20

15

10

0
GORD Easy Insomnia Depr Mood weight Inc.
bruising gain appetite
Complication

Fig. 4. Self-reported rate of individual complications (%: always; &: most of the time) due to systemic
corticosteroids during a 1-yr study [12]. GORD: gastro-oesophageal reflux disease; Depr: depression; Mood:
moodiness; Inc.: increased.

[48]. In all of these manifestations, methotrexate has been reported as effective in at least
two-thirds of patients treated.
The original description of methotrexate usage for sarcoidosis was in 1968 [49]. Owing
to concerns regarding hepatotoxicity, the drug was initially used for only brief periods,
oftenv6 months. In a series of patients with refractory disease treated with methotrexate
for prolonged periods, it was demonstrated that methotrexate could take up to 6 months
to show objective evidence of effectiveness [50]. This delay in effect of methotrexate is
also seen with other cytotoxic drugs. With the introduction of the methotrexate protocol
using drug for i6 months before evaluating effectiveness, methotrexate has been widely
used for sarcoidosis.
The major toxicities of methotrexate can be divided into acute and chronic. Acute
problems include leukopenia, gastrointestinal symptoms and mucosal ulcers. These side-
effects are dose-related and can often be minimised by the use of folic acid. For the
symptomatic patient or patient receiving w10 mg methotrexate per week, the authors
usually prescribe 1 mg folic acid daily [51]. Leucovorin can decrease the side-effects
appreciated with high-dose methotrexate. However, this is more expensive and usually
not needed at the low doses prescribed for sarcoidosis. Since methotrexate is excreted by
the kidneys, patients with significant renal impairment should not receive the drug.
Chronic use of methotrexate can be associated with potential pulmonary toxicity and
hepatotoxicity. Although methotrexate pulmonary toxicity seems to be associated with
the cumulative dose, it can be seen at any time during therapy [52, 53]. On treating 209
sarcoidosis patients with methotrexate, six were reported to have developed cough that
resolved with discontinuation of the drug [54]. Interestingly, patients with methotrexate-
associated cough did not experience cough when treated with leflunomide [55].
Hepatotoxicity has long been described with methotrexate. Although official guidelines
have been established for performing liver biopsy procedures in rheumatoid arthritis
patients undergoing long-term methotrexate therapy [56], no such guidelines have been
developed for sarcoidosis patients. One group usually performs liver biopsy procedures
after every 1 g cumulative dose of methotrexate. To date, methotrexate-associated toxicity
has been seen in liver biopsy specimens, but no clinically significant liver damage has

306
 THERAPY FOR SARCOIDOSIS

been identified [57]. Other groups have monitored patients using serum liver function
tests only [42].

Azathioprine
This cytotoxic drug has been widely used for other interstitial lung diseases, including
pulmonary fibrosis [58]. Azathioprine has been reported useful in pulmonary sarcoidosis
[5961], however not all authors have reported efficacy in treating chronic pulmonary
disease [62]. The major limitation of current reports regarding azathioprine is the small
number of patients studied. Most series include v15 patients, with the exception of one
[54], which reported that 19 out of 35 sarcoidosis patients were either stable or in
remission with azathioprine therapy. In addition to pulmonary disease, it has been
reported as useful in treating neurological [63] and hepatic disease. Since it has less liver
toxicity than methotrexate, it may be a safer drug to use in hepatic impairment. However,
severe hepatotoxicity has been reported with azathioprine [64].
The usual oral dose of azathioprine is 23 mg?kg-1. The major toxicities are leukopenia
and gastrointestinal toxicity. In some series, these side-effects have led to discontinuation
of the drug in w20% of patients [65]. Polymorphisms of the thiopurine S-
methyltransferase can predict the pancytopenia from azathioprine, but are not predictive
of gastrointestinal toxicity [66].

Other cytotoxic drugs

Other cytotoxic drugs have also been reported as beneficial in sarcoidosis. However,
experience with these drugs has been more limited. In some cases, these drugs may have a
specific ideal niche.
Leflunomide was developed as an analogue of methotrexate with significantly less
toxicity [67, 68]. Pulmonary toxicity is a rare but serious problem with methotrexate. It
does not appear to be a problem with leflunomide [55, 68]. Since leflunomide shows less
toxicity than methotrexate, it has been used in combination with methotrexate to treat
inflammation [69]. A randomised trial showed that these agents were synergistic in the
treatment of rheumatoid arthritis [70].
For sarcoidosis patients, leflunomide was reported as effective in 25 out of 32 (78%)
patients treated [55]. This included 12 out of 15 (80%) treated with both methotrexate
and leflunomide. The drug was well tolerated, with only three (9%) patients discontinuing
the drug because of toxicity. All three discontinued the drug because of gastrointestinal
toxicity.
Chlorambucil has also been reported as efficacious in eight out of 10 chronic
sarcoidosis patients [71]. However, there does not seem to be an additional benefit of
chlorambucil over methotrexate or azathioprine. Since chlorambucil is associated with
an increased risk of myeloproliferative malignancies, the drug has been used sparingly in
sarcoidosis.
Cyclophosphamide has also been used for refractory sarcoidosis, especially
neurological disease [48, 72, 73]. It has been reported as successful in patients who
have failed other therapies [48, 74]. Cyclophosphamide is a cytotoxic agent clearly
associated with increased risk of malignancy. This is especially the case when the drug is
given orally as a daily agent. In patients treated for w1 yr on a daily basis, the risk of
bladder cancer increases [75]. This risk of cancer appears to be less when the drug is given
using an intermittent i.v. regimen. Therefore, the recommended regimen for treating
neurosarcoidosis is an intermittent i.v. regimen [48, 72].

307
 R.P. BAUGHMAN, E.E. LOWER

Antimicrobial agents
Since the early 1960s, antimalarial agents have been used to treat sarcoidosis [76, 77].
Since these agents work as anti-inflammatory drugs, they have been used for various
rheumatological conditions, such as rheumatoid arthritis and lupus erythematosus.
Benefits of both hydroxychloroquine and chloroquine have been reported in the
treatment of cutaneous sarcoidosis [7678]. This efficacy is, in part, related to the
concentration of these drugs in the integument. In addition, these agents are effective in
the treatment of hypercalcaemia due to sarcoidosis [79]. The agents also seem effective in
selected cases of neurosarcoidosis [80]. The overall effectiveness of antimalarial drugs for
sarcoidosis appears to be v50% [54].
Ocular toxicity is a major concern with the use of chloroquine, but appears to be much
less frequent with the use of hydroxychloroquine [81]. Gastrointestinal intolerance is
dose-limiting in some patients.
Minocycline and doxycycline have also been reported beneficial in treating cutaneous
sarcoidosis [82]. In one series of chronic cases, eight out of 12 patients experienced a
complete response of their skin lesions. The mechanism of action of these drugs remains
unclear. As tetracyclines are bactericidal for Propionibacterium acnes, these drugs may
work by killing the putative agent of sarcoidosis, P. acnes [83]. However, other
antibiotics, such as clindamycin, which readily kill P. acnes, show no apparent benefit in
sarcoidosis. Perhaps minocycline and doxycycline act as anti-inflammatory agents [84,
85], since these drugs have been reported useful in other chronic inflammatory
conditions, such as scleroderma [86] and rheumatoid arthritis [87].

Immune modulators
There are several other efficacious agents for the treatment of sarcoidosis. The
common mechanism of action of these drugs is their effect on the immune response,
especially the suppression of tumour necrosis factor (TNF), a key cytokine in chronic
sarcoidosis. Several groups have shown that alveolar macrophages from patients with
active sarcoidosis release increased levels of TNF [8890]. Recent studies have
demonstrated that patients with active disease, despite corticosteroid therapy, may
still release excessive amounts of TNF [91]. This has led to the introduction of agents
with anti-TNF activity [92].
Pentoxifylline suppresses cytokine release by alveolar macrophages [93]. This
suppression of release by alveolar macrophages seems to be more effective against
TNF than against other cytokines in active sarcoidosis [94]. This drug has been reported
as successful in treating acute sarcoidosis [95].
Thalidomide is another agent known to suppress TNF release by alveolar
macrophages [96]. This drug has been reported useful in treating cutaneous sarcoidosis
[9799]. However, at the doses useful for treating cutaneous lesions, TNF activity was
not suppressed in the cutaneous lesions of sarcoidosis [100]. Since thalidomide has other
anti-inflammatory and anti-angiogenic properties [101], its mechanism of action in
sarcoidosis remains unclear [100].
Since thalidomide is a teratogenic drug, patients treated with this drug in the USA
must participate in a closely supervised drug administration programme. The other
toxicities of thalidomide are usually dose-related and include somnolence, constipation,
peripheral neuropathy and rash. In a dose escalation study of cutaneous sarcoidosis, 12
out of 14 patients responded to 100 mg thalidomide, whereas all responded to 200 mg
[97]. Since patients tolerated the 100 mg dose well, this has become the authors
recommended initial dose of the drug.

308
 THERAPY FOR SARCOIDOSIS

With the use of molecular biology, biological agents which block TNF have been
developed. These include the TNF receptor antagonist etanercept and the chimeric
monoclonal antibody infliximab. These agents are both effective for rheumatoid arthritis
[102, 103]. However, infliximab [104], but not etanercept [105], has been found effective in
treating Crohns disease.
Infliximab has been reported beneficial for the treatment of refractory sarcoidosis
[106109]. Various disease manifestations, including cutaneous lesions [106, 108],
pulmonary disease [106], ocular disease [108, 110, 111] and neurological disease [107],
respond to therapy. A multicentric multinational placebo-controlled trial examining the
effectiveness of infliximab for pulmonary sarcoidosis is underway.
Not all TNF blockers are beneficial. Etanercept, a TNF receptor antagonist, has not
been found to be effective for most cases of pulmonary sarcoidosis in an open-label
clinical trial [112]. In a randomised double-blind trial, etanercept was no more effective
than placebo in controlling chronic ocular sarcoidosis [113].
The reason for the apparent differences in response rate between etanercept and
infliximab is not entirely clear. One possible explanation is the difference in mechanism of
action (a receptor antagonist versus an antibody). Another possibility is that infliximab
can lead to antibody binding on the surface of cells, releasing TNF. In turn, this can lead
to apoptosis induced by infliximab, but not etanercept [114].
Several major toxicities are encountered with the anti-TNF therapies. One of the more
serious concerns is the increased risk of tuberculosis and similar infections [115]. The risk
seems to be higher for infliximab than for etanercept. In addition, both drugs can lead to
allergic reactions. With etanercept, the reaction is usually confined to the subcutaneous
injection site. Infliximab, which is delivered i.v., can cause systemic reactions, including
anaphylaxis. When both drugs were studied as possible treatment for patients with
advanced heart failure, there was a possible increase in mortality for those receiving
either anti-TNF therapy [116, 117]. Since follow-up is short, the long-term risk with these
drugs remains unclear. An association with non-Hodgkins lymphoma has been
suggested for both etanercept and infliximab [118], but the overall risk still seems to be
low and may be related to the underlying disease [119].

Conclusion
Therapy for sarcoidosis has become a matter of choosing the best agent for each
patient. Therapeutic protocols are increasingly composed of multiple agents, rather than
relying on a single drug [120]. The clinician now has multiple agents for treating the
patient.

309
 R.P. BAUGHMAN, E.E. LOWER

Summary
The decision to treat a patient is dependent on many factors, the most important being
whether or not the patient is symptomatic. Initial systemic therapy for symptomatic
sarcoidosis usually includes corticosteroids. However, most symptomatic patients
require months to years of therapy. Therefore, alternatives to corticosteroids have
been studied. These include methotrexate and azathioprine. Of these two cytotoxic
drugs, methotrexate has been the more extensively investigated. Both drugs work in
the majority of, but not all, patients.
Refractory sarcoidosis patients exist, who show persistent disease despite high doses of
corticosteroids. Agents that block tumour necrosis factor (TNF) have been shown to
be of benefit in some of these refractory cases. Thalidomide has been useful in
refractory skin lesions. Infliximab, a monoclonal antibody directed against TNF has
been shown to be helpful in some cases of severe refractory disease. With this array of
available agents, the clinician can choose to use either single agents or combinations of
agents for treating the individual sarcoidosis patient. The goal of therapy is to
minimise symptoms with the lowest risk to the patient.

Keywords: Azathioprine, hydroxychloroquine, infliximab, methotrexate, prednisone.

References
1. Hunninghake GW, Costabel U, Ando M, et al. American Thoracic Society/European Respiratory
Society/World Association of Sarcoidosis and Other Granulomatous Disorders: statement on
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149173.
2. Hunninghake GW, Gilbert S, Pueringer R, et al. Outcome of the treatment for sarcoidosis. Am J
Respir Crit Care Med 1994; 149: 893898.
3. Rizzato G, Montemurro L, Colombo P. The late follow-up of chronic sarcoid patients previously
treated with corticosteroids. Sarcoidosis 1998; 15: 5258.
4. Nagai S, Shigematsu M, Hamada K, et al. Clinical courses and prognoses of pulmonary
sarcoidosis. Curr Opin Pulm Med 1999; 5: 293298.
5. Gibson GJ, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of
long term corticosteroid treatment. Thorax 1996; 51: 238247.
6. Gottlieb JE, Israel HL, Steiner RM, et al. Outcome in sarcoidosis. The relationship of relapse to
corticosteroid therapy. Chest 1997; 111: 623631.
7. Pietinalho A, Tukiainen P, Haahtela T, et al. Oral prednisolone followed by inhaled budesonide in
newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled, multicenter study.
Chest 1999; 116: 424431.
8. Pietinalho A, Tukiainen P, Haahtela T, et al. Early treatment of stage II sarcoidosis improves 5-
year pulmonary function. Chest 2002; 121: 2431.
9. Selroos O, Lofroos AB, Pietinalho A, et al. Inhaled budesonide for maintenance treatment of
pulmonary sarcoidosis. Sarcoidosis 1994; 11: 126131.
10. Zych D, Pawlicka L, Zielinski J. Inhaled budesonide vs prednisone in the maintenance treatment
of pulmonary sarcoidosis. Sarcoidosis 1993; 10: 5661.
11. Milman N, Graudal N, Grode G, et al. No effect of high-dose inhaled steroids in pulmonary
sarcoidosis: a double-blind, placebo-controlled study. J Intern Med 1994; 236: 285290.
12. Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 198204.

310
 THERAPY FOR SARCOIDOSIS

13. du Bois RM, Greenhalgh PM, Southcott AM, et al. Randomized trial of inhaled fluticasone
propionate in chronic stable pulmonary sarcoidosis: a pilot study. Eur Respir J 1999; 13: 1345
1350.
14. Khatri KA, Chotzen VA, Burrall BA. Lupus pernio: successful treatment with a potent topical
corticosteroid. Arch Dermatol 1995; 131: 617618.
15. Katoh N, Mihara H, Yasuno H. Cutaneous sarcoidosis successfully treated with topical
tacrolimus. Br J Dermatol 2002; 147: 154156.
16. Bradley DA, Baughman RP, Raymond L, et al. Ocular manifestations of sarcoidosis. Semin Respir
Crit Care Med 2002; 23: 543548.
17. Carnahan MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic
corticosteroids. Curr Opin Ophthalmol 2000; 11: 478483.
18. Nara M, Sasamori K, Shimura S, et al. Long-term use of corticosteroid eye drops delays the
spontaneous remission of pulmonary sarcoidosis. Tohoku J Exp Med 2004; 202: 275282.
19. Baughman RP, Winget DB, Bowen EH, et al. Predicting respiratory failure in sarcoidosis patients.
Sarcoidosis 1997; 14: 154158.
20. Ferriby D, de Seze J, Stojkovic T, et al. Long-term follow-up of neurosarcoidosis. Neurology 2001;
57: 927929.
21. Reich JM. Mortality of intrathoracic sarcoidosis in referral vs population-based settings: influence
of stage, ethnicity, and corticosteroid therapy. Chest 2002; 121: 3239.
22. Arcasoy SM, Christie JD, Pochettino A, et al. Characteristics and outcomes of patients with
sarcoidosis listed for lung transplantation. Chest 2001; 120: 873880.
23. Judson MA. Lung transplantation for pulmonary sarcoidosis. Eur Respir J 1998; 11: 738744.
24. Shorr AF, Davies DB, Nathan SD. Predicting mortality in patients with sarcoidosis awaiting lung
transplantation. Chest 2003; 124: 922928.
25. Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an
analysis of 818 patients. Q J Med 1983; 208: 525533.
26. Rizzato G, Colombo P. Nephrolithiasis as a presenting feature of chronic sarcoidosis: a
prospective study. Sarcoidosis 1996; 13: 167172.
27. Lin YH, Haslam PL, Turner-Warwick M. Chronic pulmonary sarcoidosis: relationship between
lung lavage cell counts, chest radiograph, and results of standard lung function tests. Thorax 1985;
40: 501507.
28. Baughman RP, Keeton D, Lower EE. Relationship between interleukin-8 and neutrophils in the
BAL fluid of sarcoidosis. Sarcoidosis 1994; 11: S217S220.
29. Drent M, Jacobs JA, de Vries J, et al. Does the cellular bronchoalveolar lavage fluid profile reflect
the severity of sarcoidosis?. Eur Respir J 1999; 13: 13381344.
30. Ziegenhagen MW, Rothe ME, Schlaak M, et al. Bronchoalveolar and serological parameters
reflecting the severity of sarcoidosis. Eur Respir J 2003; 21: 407413.
31. Mana J, Gomez VC, Montero A, et al. Lofgrens syndrome revisited: a study of 186 patients. Am J
Med 1999; 107: 240245.
32. Baughman RP, Drent M, Rizzato G, et al. Proposed clinical phenotype of sarcoidosis. Am J Respir
Crit Care Med 2003; 167: A170.
33. Siltzbach LE. Effects of cortisone in sarcoidosis: a study of thirteen patients. Am J Med 1952;
12: 139160.
34. James DG, Carstairs LS, Trowell J, et al. Treatment of sarcoidosis: report of a controlled
therapeutic trial. Lancet 1967; 2: 526528.
35. Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am
Rev Respir Dis 1973; 107: 609614.
36. Young RL, Harkelroad LE, Lorden RE, et al. Pulmonary sarcoidosis: a prospective evaluation of
glucocorticoid therapy. Ann Intern Med 1970; 73: 207212.
37. Johns CJ, Zachary JB, Ball WC. A ten year study of corticosteroid treatment of pulmonary
sarcoidosis. Johns Hopkins Med J 1974; 134: 271283.

311
 R.P. BAUGHMAN, E.E. LOWER

38. Zaki MH, Lyons HA, Leilop L, et al. Corticosteroid therapy in sarcoidosis: a five year controlled
follow-up. N Y State Med J 1987; 87: 496499.
39. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review.
JAMA 2002; 287: 13011307.
40. Selroos O, Sellergren TL. Corticosteroid therapy of pulmonary sarcoidosis. Scand J Respir Dis
1979; 60: 215212.
41. Judson MA. An approach to the treatment of pulmonary sarcoidosis with corticosteroids: the six
phases of treatment. Chest 1999; 115: 11581165.
42. Vucinic VM. What is the future of methotrexate in sarcoidosis? A study and review. Curr Opin
Pulm Med 2002; 8: 470476.
43. Baughman RP, Lower EE. A clinical approach to the use of methotrexate for sarcoidosis. Thorax
1999; 54: 742746.
44. Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;
155: 846851.
45. Webster GF, Razsi LK, Sanchez M, et al. Weekly low-dose methotrexate therapy for cutaneous
sarcoidosis. J Am Acad Dermatol 1991; 24: 451454.
46. Gedalia A, Molina JF, Ellis GS, et al. Low-dose methotrexate therapy for childhood sarcoidosis.
J Pediatr 1997; 130: 2529.
47. Dev S, McCallum RM, Jaffe GJ. Methotrexate for sarcoid-associated panuveitis. Ophthalmology
1999; 106: 111118.
48. Lower EE, Broderick JP, Brott TG, et al. Diagnosis and management of neurologic sarcoidosis.
Arch Intern Med 1997; 157: 18641868.
49. Lacher MJ. Spontaneous remission response to methotrexate in sarcoidosis. Ann Intern Med 1968;
69: 12471248.
50. Lower EE, Baughman RP. The use of low dose methotrexate in refractory sarcoidosis. Am J Med
Sci 1990; 299: 153157.
51. Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate
therapy for rheumatoid arthritis. Ann Intern Med 1994; 121: 833841.
52. Zisman DA, McCune WJ, Tino G, et al. Drug-induced pneumonitis: the role of methotrexate.
Sarcoidosis Vasc Diffuse Lung Dis 2001; 18: 243252.
53. White DA, Rankin JA, Stover DE, et al. Methotrexate pneumonitis: bronchoalveolar lavage
findings suggest an immunologic disorder. Am Rev Respir Dis 1989; 139: 1821.
54. Baughman RP, Lower EE. Alternatives to corticosteroids in the treatment of sarcoidosis.
Sarcoidosis 1997; 14: 121130.
55. Baughman RP, Lower EE. Leflunomide for chronic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
2004; 21: 4348.
56. Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis.
Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis
Rheum 1994; 37: 316328.
57. Baughman RP, Koehler A, Bejarano PA, et al. Role of liver function tests in detecting
methotrexate-induced liver damage in sarcoidosis. Arch Intern Med 2003; 163: 615620.
58. Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of
idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical
trial. Am Rev Respir Dis 1991; 144: 291296.
59. Pacheo Y, Marechal C, Marechal F, et al. Azathioprine treatment of chronic pulmonary
sarcoidosis. Sarcoidosis 1985; 2: 107113.
60. Sharma OP, Hughes DTD, James DG, et al. Immunosuppressive therapy with azathioprine in
sarcoidosis. In: Levinsky L, Macholoa F, eds. Fifth International Conference on Sarcoidosis and
other Granulomatous Disorders. Prague, Charles University, 1971; pp. 635637.
61. Muller-Quernheim J, Kienast K, Held M, et al. Treatment of chronic sarcoidosis with an
azathioprine/prednisolone regimen. Eur Respir J 1999; 14: 11171122.

312
 THERAPY FOR SARCOIDOSIS

62. Lewis SJ, Ainslie GM, Bateman ED. Efficacy of azathioprine as second-line treatment in
pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 8792.
63. Agbogu BN, Stern BJ, Sewell C, et al. Therapeutic considerations in patients with refractory
neurosarcoidosis. Arch Neurol 1995; 52: 875879.
64. Romagnuolo J, Sadowski DC, Lalor E, et al. Cholestatic hepatocellular injury with azathioprine: a
case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol 1998; 12: 479
483.
65. de Jong DJ, Goullet M, Naber TH. Side effects of azathioprine in patients with Crohns disease.
Eur J Gastroenterol Hepatol 2004; 16: 207212.
66. Schwab M, Schaffeler E, Marx C, et al. Azathioprine therapy and adverse drug reactions in
patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase
polymorphism. Pharmacogenetics 2002; 12: 429436.
67. Cohen S, Cannon GW, Schiff M, et al. Two-year, blinded, randomized, controlled trial of
treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization
of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis
Rheum 2001; 44: 19841992.
68. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of lefluno-
mide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000;
39: 655665.
69. Kremer JM. Methotrexate and leflunomide: biochemical basis for combination therapy in the
treatment of rheumatoid arthritis. Semin Arthritis Rheum 1999; 29: 1426.
70. Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in patients with
active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind,
placebo-controlled trial. Ann Intern Med 2002; 137: 726733.
71. Kataria YP. Chlorambucil in sarcoidosis. Chest 1980; 78: 3642.
72. Doty JD, Mazur JE, Judson MA. Treatment of corticosteroid-resistant neurosarcoidosis with a
short-course cyclophosphamide regimen. Chest 2003; 124: 20232026.
73. Hoitsma E, Faber CG, Drent M, Sharma OP. Neurosarcoidosis: a clinical dilemma. Lancet Neurol
2004; 3: 397407.
74. Demeter SL. Myocardial sarcoidosis unresponsive to steroids. Treatment with cyclophosphamide.
Chest 1988; 94: 202203.
75. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and
bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996; 124: 477484.
76. British Tuberculosis Association. Chloroquine in the treatment of sarcoidosis. Tubercle 1967; 48:
257272.
77. Siltzbach LE, Teirstein AS. Chloroquine therapy in 43 patients with intrathoracic and cutaneous
sarcoidosis. Acta Med Scand 1964; 425: 302S308S.
78. Jones E, Callen JP. Hydroxychloroquine is effective therapy for control of cutaneous sarcoidal
granulomas. J Am Acad Dermatol 1990; 23: 487489.
79. Adams JS, Diz MM, Sharma OP. Effective reduction in the serum 1,25-dihydroxyvitamin D and
calcium concentration in sarcoidosis-associated hypercalcemia with short-course chloroquine
therapy. Ann Intern Med 1989; 111: 437438.
80. Sharma OP. Effectiveness of chloroquine and hydroxychloroquine in treating selected patients
with sarcoidosis with neurologic involvement. Arch Neurol 1998; 55: 12481254.
81. Jones SK. Ocular toxicity and hydroxychloroquine: guidelines for screening. Br J Dermatol 1999;
140: 37.
82. Bachelez H, Senet P, Cadranel J, et al. The use of tetracyclines for the treatment of sarcoidosis.
Arch Dermatol 2001; 137: 6973.
83. Eishi Y, Suga M, Ishige I, et al. Quantitative analysis of mycobacterial and propionibacterial
DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 2002;
40: 198204.

313
 R.P. BAUGHMAN, E.E. LOWER

84. Kloppenburg M, Verweij CL, Miltenburg AM, et al. The influence of tetracyclines on T cell
activation. Clin Exp Immunol 1995; 102: 635641.
85. Kalish RS, Koujak S. Minocycline inhibits antigen processing for presentation to human T cells:
additive inhibition with chloroquine at therapeutic concentrations. Clin Immunol 2004; 113: 270
277.
86. Le CH, Morales A, Trentham DE. Minocycline in early diffuse scleroderma. Lancet 1998;
352: 17551756.
87. Stone M, Fortin PR, Pacheco-Tena C, et al. Should tetracycline treatment be used more
extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in
disease activity. J Rheumatol 2003; 30: 21122122.
88. Baughman RP, Strohofer SA, Buchsbaum J, et al. Release of tumor necrosis factor by alveolar
macrophages of patients with sarcoidosis. J Lab Clin Med 1990; 115: 3642.
89. Pueringer RJ, Schwartz DA, Dayton CS, et al. The relationship between alveolar macrophage TNF,
IL-1, and PGE2 release, alveolitis, and disease severity in sarcoidosis. Chest 1993; 103: 832838.
90. Ziegenhagen MW, Benner UK, Zissel G, et al. Sarcoidosis: TNF-a release from alveolar
macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med 1997;
156: 15861592.
91. Ziegenhagen MW, Rothe E, Zissel G, Muller-Quernheim J. Exaggerated TNFa release of
alveolar macrophages in corticosteroid resistant sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
2002; 19: 185190.
92. Baughman RP, Iannuzzi M. Tumour necrosis factor in sarcoidosis and its potential for targeted
therapy. BioDrugs 2003; 17: 425431.
93. Marques LJ, Zheng L, Poulakis N, et al. Pentoxifylline inhibits TNF-a production from human
alveolar macrophages. Am J Respir Crit Care Med 1999; 159: 508511.
94. Tong Z, Dai H, Chen B, et al. Inhibition of cytokine release from alveolar macrophages in
pulmonary sarcoidosis by pentoxifylline: comparison with dexamethasone. Chest 2003; 124: 1526
1532.
95. Zabel P, Entzian P, Dalhoff K, et al. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit
Care Med 1997; 155: 16651669.
96. Tavares JL, Wangoo A, Dilworth P, et al. Thalidomide reduces tumour necrosis factor-a
production by human alveolar macrophages. Respir Med 1997; 91: 3139.
97. Baughman RP, Judson MA, Teirstein AS, et al. Thalidomide for chronic sarcoidosis. Chest 2002;
122: 227232.
98. Carlesimo M, Giustini S, Rossi A, et al. Treatment of cutaneous and pulmonary sarcoidosis with
thalidomide. J Am Acad Dermatol 1995; 32: 866869.
99. Baughman RP, Lower EE. Newer therapies for cutaneous sarcoidosis: the role of thalidomide and
other agents. Am J Clin Dermatol 2004; 5: 385394.
100. Oliver SJ, Kikuchi T, Krueger JG, et al. Thalidomide induces granuloma differentiation in sarcoid
skin lesions associated with disease improvement. Clin Immunol 2002; 102: 225236.
101. Moller DR, Wysocka M, Greenlee BM, et al. Inhibition of IL-12 production by thalidomide.
J Immunol 1997; 159: 51575161.
102. Kavanaugh A, Clair EW, McCune WJ, et al. Chimeric anti-tumor necrosis factor-a monoclonal
antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy.
J Rheumatol 2000; 27: 841850.
103. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile
rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000;
342: 763769.
104. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing
Crohns disease. N Engl J Med 2004; 350: 876885.
105. Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohns disease: a randomized,
double-blind, placebo-controlled trial. Gastroenterology 2001; 12: 10881094.

314
 THERAPY FOR SARCOIDOSIS

106. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
2001; 18: 7074.
107. Pettersen JA, Zochodne DW, Bell RB, et al. Refractory neurosarcoidosis responding to infliximab.
Neurology 2002; 59: 16601661.
108. Roberts SD, Wilkes DS, Burgett RA, et al. Refractory sarcoidosis responding to infliximab. Chest
2003; 124: 20282031.
109. Yee AMF, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor
necrosis-a therapy. Ann Intern Med 2001; 135: 2731.
110. Joseph A, Raj D, Dua HS, et al. Infliximab in the treatment of refractory posterior uveitis.
Ophthalmology 2003; 110: 14491453.
111. Baughman RP, Bradley DA, Lower EE. Infliximab for chronic ocular inflammation. Int J Clin
Pharmacol Ther 2005; 43: 711.
112. Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive
pulmonary sarcoidosis. Chest 2003; 124: 177185.
113. Baughman RP, Bradley DA, Raymond LA, et al. Double blind randomized trial of a tumor
necrosis factor receptor antagonist (etanercept) for treatment of chronic ocular sarcoidosis. Am J
Respir Crit Care Med 2002; 165: A495.
114. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces
apoptosis in lamina propria T-lymphocytes from patients with Crohns disease. Gastroenterology
2003; 124: 17741785.
115. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis
factor-a neutralizing agent. N Engl J Med 2001; 345: 10981104.
116. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of
infliximab, a chimeric monoclonal antibody to tumor necrosis factor-a, in patients with moderate-
to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure
(ATTACH) trial. Circulation 2003; 107: 31333140.
117. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic
heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL).
Circulation 2004; 109: 15941602.
118. Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and
lymphoma development: twenty-six cases reported to the Food and Drug Administration.
Arthritis Rheum 2002; 46: 31513158.
119. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-
tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004; 50: 17401751.
120. Baughman RP, Ohmichi M, Lower EE. Combination therapy for sarcoidosis. Sarcoidosis Vasc
Diffuse Lung Dis 2001; 18: 133137.

315
CHAPTER 21

Rehabilitation programmes in sarcoidosis: a

multidisciplinary approach

M.A. Spruit*, E.F.M. Wouters#, R. Gosselink*

*Dept of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences, Katholieke

Universiteit Leuven and Respiratory Rehabilitation, University Hospital Gasthuisberg, Leuven, Belgium.
#
Dept of Respiratory Medicine, University Hospital Maastricht, Maastricht, The Netherlands.

Correspondence: R. Gosselink, Universitair Ziekenhuis Gasthuisberg, Herestraat 49, 3000 Leuven,

Belgium. Fax: 32 16347126; E-mail: Rik.Gosselink@uz.kuleuven.ac.be

Patients with sarcoidosis suffer from a broad range of persistent symptoms, such as
fatigue, dyspnoea and general weakness [1]. To date, specific nonpharmacological
treatments to reduce the aforementioned symptoms are mostly lacking in the
management of patients with sarcoidosis. Nevertheless, exercise training has shown to
improve health status, exercise capacity, skeletal muscle function and complaints of
fatigue and dyspnoea in patients with chronic pulmonary or cardiac diseases [2, 3]. The
present chapter will provide a rationale for nonpharmacological treatments in patients
with sarcoidosis with persistent clinical symptoms.

Sarcoidosis-related symptoms
Fatigue
Although fatigue is clinically difficult to quantify, qualify, and to treat, it has been
widely accepted as a highly prevalent and disabling clinical feature in patients with
sarcoidosis [46]. Recently, 73% of the outpatients with sarcoidosis had a score of w22
points on the Fatigue Assessment Scale (FAS) [4], indicating that a majority of the
patients had self-reported complaints of fatigue. Although the determination of the cut-
off score is questionable (e.g. the cut-off score was set at percentile 80 of the scores
obtained in two samples of healthy controls), the cross-sectional study of De Vries et al.
[4] showed that a score of w22 points on the FAS was independent of an impaired
pulmonary function, the treatment of prednisone, and of the circulating levels of soluble
interleukin 2 receptor and amyloid A. Other possible underlying causes may, therefore,
be responsible for this observed high prevalence of fatigue. In fact, fatigue has been
related to muscle dysfunction. Respiratory muscle weakness, as well as skeletal muscle
weakness, was positively related to complaints of fatigue [6, 7]. It will, however, be
difficult to ascertain which is the chicken and which is the egg in this situation. In
addition, the possible role of endocrinological disturbances in the development and/or
maintenance of complaints of fatigue have never been studied in patients with
sarcoidosis. Nevertheless, male patients with sarcoidosis appear to have reduced
circulating levels of testosterone [8], which has been known to be related to complaints of
fatigue in other chronic diseases [9, 10].
Eur Respir Mon, 2005, 32, 316326. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
316
 REHABILITATION IN SARCOIDOSIS

Dyspnoea
A majority of outpatients with sarcoidosis experience dyspnoea during activities of
daily living. In a cross-sectional study, 39% of the patients experienced dyspnoea while
walking at a rapid pace on level ground, 19% while walking at their own pace on level
ground and 14% at rest [11]. Although forced vital capacity and transfer factor of the
lung for carbon monoxide were significantly lower than those of healthy control subjects,
they did not correlate with the severity of perceived dyspnoea [11]. Low respiratory
muscle strength, however, was related to worse scores for dyspnoea on the modified
British Medical Research Council scale [11]. Unfortunately, the relationship between
skeletal muscle dysfunction and the degree of dyspnoea experienced during day-to-day
activities has never been studied in patients with sarcoidosis. Nonetheless, reduction in
the strength of the inspiratory muscles [6, 7, 11] may contribute substantially to the
intensity of dyspnoea during day-to-day activities. Moreover, physical deconditioning
[7], inefficient ventilation and a reduced arterial oxygen tension [1214] may also
contribute to an increased sense of dyspnoea in rest and during exercise.

Pain
Less is known about the prevalence of pain in patients with sarcoidosis. Recently,
however, the presence of pain has been evaluated in a cohort of 821 Dutch patients with
sarcoidosis. Pain was reported in 72% of the patients, and could be divided in arthralgia
(54%), muscle pain (40%), headache (28%) and chest pain (27%) [15]. The data were not
compared with a healthy population, so the real prevalence of pain in sarcoidosis
currently remains unknown. Nevertheless, pain appeared to be a substantial problem in
sarcoidosis and the number of types of pain a patient with sarcoidosis was suffering from
(ranging 05) was found to be related to a lower quality of life [15]. In addition, lower
(worse) scores on the Medical Short Form-36 section "pain" have been related positively
to quadriceps muscle weakness in patients with sarcoidosis who spontaneously
complained of fatigue at the outpatient consultation [7]. This is in line with the fact
that the variation in the number of types of pain could partially be explained by less
energy and by the presence of feeling tired [15]. Therefore, in developing the most
appropriate therapeutic approach, including rehabilitation programmes, the possible
impact of pain, pain behaviour and coping strategies should be well thought-out beside
all other relevant aspects of the disease.

Respiratory muscle weakness

Respiratory muscle weakness has been found in patients with sarcoidosis as compared
with age-matched healthy controls (fig. 1) [6, 7, 11, 16]. Reduced inspiratory mouth
pressure may be due to granulomatous involvement of the main inspiratory muscle (e.g.
the diaphragm) [17, 18]. Moreover, the pharmacological treatment with oral
corticosteroids may affect respiratory muscle function in patients with sarcoidosis, as
seen previously in patients with chronic obstructive pulmonary disease [19]. Nevertheless,
no significant differences were found in maximal inspiratory mouth pressure between
patients who received oral corticosteroids in the 6-month period preceding the tests
(7621% predicted) and those who did not (8221% predicted, p=0.52) [7]. Wirnsberger
et al. [6] reported similar data. In addition, patients who had used corticosteroids
previously, and at the time of assessment, had significantly better maximal inspiratory
mouth pressure than those patients who did not (p=0.027) [20]. To date, no biopsies have
been taken from the respiratory muscles of patients with sarcoidosis to elucidate the

317
 M.A. SPRUIT ET AL.

150

125

% predicted 100

75

50

25

0
PI,max QPT 6MWD VO2

Fig. 1. Peak inspiratory mouth pressure (PI,max), isometric quadriceps femoral muscle peak torque (QPT), the
distance walked in 6 minutes (6MWD) and peak oxygen uptake (V9O2) in the patients with sarcoidosis (&) and
the healthy control subjects (&). Data obtained from [7].

possible underlying mechanisms of respiratory muscle weakness. Moreover, respiratory

muscle function has never been assessed by using magnetic stimulation of the phrenic
nerve [21]. Therefore, the possible contamination of the results of the respiratory muscle
force test by motivation of patients with sarcoidosis cannot be excluded.
Respiratory muscle endurance has also been shown to be reduced in patients with
sarcoidosis as compared with healthy control subjects and to be related to the categories
"mobility", "body care" and "movement" of the Sickness Impact Profile (SIP)
questionnaire [6]. These SIP categories, however, did not differ between patients with
sarcoidosis and the healthy control subjects. Therefore, the clinical relevance of the
aforementioned significant relationships needs to be determined.

Skeletal muscle weakness

Skeletal muscle weakness is assumed to be present in patients with sarcoidosis [22].
However, to date only two cross-sectional trials have investigated the presence of skeletal
muscle weakness (i.e. isometric quadriceps peak torque and isometric handgrip force).
Wirnsberger et al. [6] were the first to study skeletal muscle force in outpatients with
sarcoidosis. They did not find significant differences in skeletal muscle force between
patients with sarcoidosis and healthy control subjects. In contrast, Spruit et al. [7] did
find a significant difference in quadriceps peak torque and handgrip force between
outpatients with sarcoidosis and healthy control subjects (fig. 1) [7]. Although a type II
error cannot be excluded in the former study [6], the different results between the two
studies are probably due to the fact that only about 35% of the patients studied by
Wirnsberger et al. [6] had self-reported complaints of fatigue, while all patients in the
study by Spruit et al. [7] reported complaints of fatigue. In fact, sarcoidosis patients with
self-reported complaints of fatigue had more pronounced respiratory muscle weakness
[6], a lower fat-free mass over body weight ratio, and reported more frequently exercise
intolerance and muscle pain compared with sarcoidosis patients without fatigue [5].
Fatigue may, therefore, be interrelated with indices of physical deconditioning. If this
opens avenues for new therapeutic options, it seems, at least in part, to be dependent on
the possible underlying causes of skeletal muscle weakness.

318
 REHABILITATION IN SARCOIDOSIS

Physical deconditioning. To date, skeletal muscle fibre type distribution and size have
never been studied in a group of consecutive patients with sarcoidosis. Moreover, the mid
thigh cross-sectional area, assessed using computed tomography, and its relationship with
skeletal muscle strength have never been studied. Nevertheless, physical deconditioning
may be one of the underlying causes of skeletal muscle weakness in patients with
sarcoidosis. For example, fatigue most probably can reduce patients day-to-day physical
activities [7]. Consequently, reduced physical activities can induce general deconditioning,
which, in turn, contributes to increased perceived fatigue and more physical inactivity.
Thus, patients may end up in a negative vicious circle of deconditioning. Recently,
complaints of fatigue were related to skeletal muscle weakness [7] and to a lower fat-free
mass over body weight ratio in patients with sarcoidosis [5]. This may all be suggestive for
a role of physical deconditioning in the development and/or maintenance of skeletal
muscle weakness in patients with sarcoidosis. Moreover, significant improvements in
skeletal muscle force following an exercise training programme may also be indicative for
the involvement of physical deconditioning in skeletal muscle weakness in patients with
sarcoidosis.

Oral corticosteroids. Oral corticosteroids have shown to improve radiological

abnormalities following 624 months of treatment and produce a small improvement
in vital capacity and diffusing capacity in patients with pulmonary sarcoidosis [23]. The
effects of oral corticosteroids on skeletal muscle function have not explicitly been studied
in patients with sarcoidosis. Nevertheless, oral corticosteroids may have a detrimental
effect on skeletal muscle force, as seen previously in elderly subjects with chronic
obstructive pulmonary disease and in adults with cystic fibrosis [19, 24].
A significant inverse relationship has been found between the mean daily dose of oral
steroids and quadriceps peak torque in the patients who received oral steroids in the
6-month period preceding the tests [7]. However, skeletal muscle force did not differ
between patients with or without a history of oral corticosteroid treatment [6, 7].
Moreover, normal or improved skeletal muscle function has been reported after
treatment with high doses of oral corticosteroids in patients with sarcoidosis [2527].
Therefore, the effects of oral corticosteroid treatment on skeletal muscle function in
patients with sarcoidosis remain unclear. Probably, these effects may be determined by
the presence or absence of sarcoidosis in skeletal muscle tissue.

Sarcoidosis in skeletal muscles. The incidence and prevalence of sarcoidosis skeletal

muscle involvement have never been studied in large observational studies in patients with
sarcoidosis. Nonetheless, muscle involvement seems to be widely accepted [22]. This is
most probably based on several studies that were undertaken y50 yrs ago to study the
possible clinical usefulness of random biopsies of the gastrocnemius muscle as a
diagnostic aid in patients that were suspected of sarcoidosis. For example, Myers et al.
[28] described four patients with migratory polyarthritis resembling rheumatic fever or
rheumatoid arthritis and with histological evidence compatible with sarcoidosis who did
not have clinical manifestations referable to skeletal muscle involvement. Noncaseating
epitheloid granulomas were demonstrated by lymph node biopsy in one case and by
striated muscle biopsy in the remaining three cases [28]. In addition, Phillips and Phillips
[29] reported four out of five positive muscle biopsies taken from the gastrocnemius
muscle in patients that were also suspected of having sarcoidosis. Although it is
noteworthy that the granulomas were found in routine muscle biopsies that were taken at
random from the gastrocnemius muscle, it is be questionable whether the sarcoid-like
lesions were a manifestation of rheumatoid arthritis. However, this does not appear to be
likely. In fact, progressive skeletal muscle atrophy with the simultaneous presence of

319
 M.A. SPRUIT ET AL.

discrete muscular alterations (i.e. wider separation of myofibrils, dilated sarcotubular

system, pleomorphic mitochondria, myofibril flaking, and lipofuscin deposition in the
subsarcolemmal region) are suggestive of rheumatoid myositis associated with
rheumatoid arthritis [30]. It may, therefore, be reasonable that Myers et al. [28]
presented three patients with sarcoidosis who were likely to have muscle involvement.
More recently, open biopsies were taken from the quadriceps femoris muscle in nine
nonsmoking outpatients with sarcoidosis to study the presence of noncaseating
granulomas. Haematoxylin-eosin staining proved the presence of noncaseating
granulomas in skeletal muscle tissue and in the endomysium in only three patients,
without signs of myopathy, atrophy or peripheral neuropathy [16]. These findings are
somewhat in contrast with the results of a retrospective study by Prayson [31], who did
find electromyographic evidence for sensorimotor polyneuropathy and/or (generalised or
necrotising) myopathy in six patients with sarcoidosis with clinical symptoms of muscle
weakness involving the extremities, muscle pain, weight loss and paresthesias.
To date, only a few studies have used invasive techniques to study the presence of
sarcoidosis in skeletal muscles in relatively small samples. The results show discrepancies,
which may be in line with the heterogeneous presentation of sarcoidosis. If skeletal
muscle involvement is present, a destruction of the muscle fibres previously occupying the
position of the granulomas can be expected, together with early degenerative changes
with loss of striation and displacement by the enlarging granulomas [28]. Skeletal muscle
weakness seems to be of multiple origin in patients with sarcoidosis. Additional studies,
including muscle biopsies, are necessary to unravel the underlying mechanisms of skeletal
muscle weakness and dysfunction in patients with sarcoidosis.

Involuntarily weight loss

An increased inflammatory status has shown be related to involuntarily weight loss in
patients with various chronic diseases [3235]. Increased airway and systemic
inflammation has also been reported in patients with sarcoidosis [7, 36, 37]. Its
relationship with involuntarily weight loss has never been studied in patients with
sarcoidosis. Nevertheless, some cases with severe weight loss in a short period have been
reported. For example, a 26-yr-old African-American female patient with migratory
polyarthritis reported a weight loss of 9.07 kg (20 lb) in 2 months, together with
increasing weakness, feverishness, sweats and glands that became larger and more widely
distributed [28]. Moreover, a 28-yr-old Caucasian male was readmitted to the hospital
with anorexia and a weight loss of 7.26 kg (16 lb) [29]. Although nutritional support may
only be beneficial for sarcoidosis patients with low body mass index (y25% of elderly
patients with sarcoidosis [38]), it may be considered to be added to a multidisciplinary
rehabilitation programme.

Exercise intolerance
Reduced exercise intolerance has been reported in patients with sarcoidosis. Indeed,
low oxygen uptake and low external load have been found at the end of symptom-limited
peak cycle ergometry tests in patients with sarcoidosis compared with healthy control
subjects [7, 1214, 39, 40]. Moreover, 6 min walk distance (6MWD) in patients with
sarcoidosis differed y200 m with the mean walking distance of healthy control subjects
[7]. Exercise intolerance has been related to the excessive and inefficient ventilation and
oxygen diffusing impairment [12, 14]. Moreover, skeletal muscle dysfunction has been
related to exercise intolerance. Quadriceps muscle weakness was inversely related to
reduced achieved peak external work load and to 6MWD in sarcoidosis patients who

320
 REHABILITATION IN SARCOIDOSIS

complained of fatigue at the outpatient clinic, irrespective of age, sex, height and/or body
weight [7]. In fact, 67% of the patients with sarcoidosis stopped the symptom-limited
peak cycling exercise test due to leg complaints [13], which is most probably due to
skeletal muscle weakness [41]. Unfortunately, skeletal muscle endurance has never been
studied in patients with sarcoidosis, but may also be an underlying cause of reduced
exercise capacity [42].

Reduced health status and quality of life

Reduced (disease specific) health status and reduced quality of life have been reported
in patients with sarcoidosis and have been related to various clinical outcomes [6, 4346].
For example, quadriceps muscle weakness was significantly related to six of the eight
multiple item scales of the Medical Short Form-36 questionnaire (Spearman correlations
coefficients -0.44 -0.70) [7]. In contrast, forced expiratory volume in one second and
forced vital capacity were not related to the reductions in health status and sarcoidosis-
related symptoms [47]. Therefore, it may be reasoned that improved muscle function can
result in an improved health status in patients with sarcoidosis. In addition, the presence
of symptoms of anxiety and depression have been related to a higher degree of
interference of reduced physical health and increased emotional problems with normal
social activities in patients with sarcoidosis [7]. Therefore, psychosocial counselling may
also improve patients health status.

Rehabilitation
Outpatient exercise training
The effects of exercise training in patients with chronic obstructive pulmonary disease
have been studied extensively and have resulted in beneficial effects, such as clinically
relevant improvements in perceived dyspnoea, perceived fatigue, exercise capacity and
health status [48]. Moreover, exercise training as part of a multidisciplinary rehabilitation
programme has shown to be of clinical benefit in patients with fibromyalgia [49] or
chronic fatigue syndrome [50].
The effects of exercise training in patients with restrictive pulmonary disease have only
been scantly studied. Recently, patients with post-tuberculosis lung disorder with a
restrictive pulmonary function showed significant improvements in the 6MWD and on
the Transition Dyspnoea Index score following 9-week outpatient exercise training
programme [51]. These improvements were similar to those observed in patients with
moderate-to-severe chronic obstructive pulmonary disease (COPD) and lasted up to 6
months after the termination of the exercise training programme [51]. The latter study
corroborated former findings of Foster and Thomas [52], who were the first to compare
the effects of a 4-week exercise training programme on 6MWD between patients with
COPD and those with a diagnosis other than COPD (including pulmonary fibrosis,
bronchiectasis, fibrothorax, scoliosis, lung resection and thoracoplasty). No peer-
reviewed manuscripts have been published concerning the effects of exercise training in
patients with sarcoidosis. Currently, the effects of a 12-week exercise training programme
on disease-related quality of life and exercise capacity are studied in a prospective
randomised controlled cross-over trial in the University Hospital Gasthuisberg, Leuven,
Belgium. The exercise training programme consists of local dynamic resistance exercises
for muscle groups of the upper and lower extremity and whole-body endurance type of
exercises performed on a treadmill, cycle ergometer, arm ergometer and a step up, as

321
 M.A. SPRUIT ET AL.

described previously [53]. Preliminary analyses showed significant median improvements

in the total score on the Sarcoidosis Health Questionnaire (0.58 points), peak cycling
load (17% of the predicted value, fig. 2) and cycling endurance time at 70% of the initial
peak cycling load (1,319 s), while the control group remained stable [54]. Therefore,
exercise training may have a positive effect on health status and exercise capacity in
patients with clinically stable sarcoidosis. Exercise training may even be of greater value
for those who are listed for lung transplantation. Indeed, patients with advanced
sarcoidosis had a very low exercise tolerance (mean 6MWD y310 m) [39]. This may
result in a post-transplantation course with fewer complications and faster ambulation of
the patients. Moreover, rehabilitation programmes are still indicated following lung
transplantation. Indeed, normal daily activities did not affect exercise performance in
lung transplant recipients w6 months after lung transplantation in patients with various
disease [55]. Nonetheless, an aerobic exercise training programme improved submaximal
and peak exercise performance significantly [55]. This is most probably due to the
presence of exercise intolerance due to skeletal muscle dysfunction following lung
transplantation [56].

Multidisciplinary rehabilitation
Exercise training will most probably be the cornerstone of a multidisciplinary
rehabilitation programme. Additional nonpharmacological treatments, such as nutri-
tional supplements, respiratory muscle training, and psychosocial counselling, will
depend on the functional status of the patient at baseline screening. Nevertheless,
nutritional supplements implemented in an 8-week rehabilitation programme resulted in
significant increases in body weight and fat-free mass in depleted patients with COPD
[57]. Unfortunately, oral corticosteroid treatment significantly impaired the response to
nutritional supplementation therapy [57], and may, therefore, also be less effective in
patients with sarcoidosis who receive oral corticosteroids. Inspiratory muscle weakness
has shown to be partially reversible in patients with COPD [58]. Moreover, functional
exercise capacity improved significantly in patients with a peak inspiratory mouth
pressure of v60% of predicted values [58]. Finally, psychological counselling has shown
to be beneficial to improve the physical activity level in patients diagnosed with chronic
fatigue syndrome [59].

125
l

l
Peak load % predicted

l l
100
l l l l
l
l l
l l l l
l
75 l l
l
l l
l
l l l

l l l

50 l

Pre 12 week Pre 12 week

Fig. 2. The changes over time in peak cycling load following a 12-week exercise training programme () or
after a control period (- - -) in outpatients with sarcoidosis. Data obtained from [54].

322
 REHABILITATION IN SARCOIDOSIS

Oxygen therapy
To date, a positive effect of home oxygen therapy on survival has not been demonstrated in
patients with interstitial lung disease [60]. Nevertheless, inhaling humidified oxygen (60%)
10 min before the start of and during a constant work rate cycling endurance test at 80% of
the peak load resulted in a significant increase in exercise time as compared to breathing
humidified room air in 16 patients with interstitial lung disease (one patient with sarcoidosis)
with a moderately severe impaired pulmonary function at rest [61]. In fact, the change in
endurance time due to supplemental oxygen was inversely related to the severity of restric-
tive lung disease and positively to the magnitude of oxyhaemoglobin desaturation during the
cycling endurance exercise in humidified room air [61]. In addition, supplemental oxygen
(60%) resulted in an significant increase in peak exercise capacity in seven patients with
interstitial lung disease (one patient with sarcoidosis) who all had significant arterial oxygen
desaturation during an incremental cycling exercise test while breathing room air (516%)
[62]. Supplemental oxygen during physical exercises may, therefore, be beneficial for the
patients with the most manifest decrease in oxygen saturation during endurance exercises
and the most striking pulmonary restriction. This topic merits further investigation.

Conclusions
Sarcoidosis is a chronic disease with many uncertainties about its pathogenesis, course,
and management [63]. Exercise intolerance and reduced health status appear to be
common findings in patients with sarcoidosis. However, these clinical features are not
simple consequences of the changes in pulmonary function. In fact, skeletal muscle
weakness and physical deconditioning have been shown to be important contributors to
exercise intolerance and reduced health status in patients with sarcoidosis [6, 7].
Although the aforementioned disease-related clinical complaints have frequently been
reported in patients with sarcoidosis, the effects of exercise training have not been studied
in this population. Nonetheless, a clear rationale is present to study the effects of exercise
training in patients with sarcoidosis. Moreover, some patients with sarcoidosis may
benefit from additional therapeutic options, such as psychosocial counselling, dietary
interventions and supplemental oxygen.

Summary
Daily complaints of dyspnoea and fatigue, respiratory and skeletal muscle weakness,
exercise intolerance, and reduced health status and quality of life have been reported in
patients with sarcoidosis, irrespective of the impaired pulmonary function. Physical
inactivity may be one of the underlying causes.
Patients with sarcoidosis may benefit from an intensive exercise training programme,
which has shown to improve health status, exercise capacity, skeletal muscle function and
complaints of fatigue and dyspnoea in patients with other chronic diseases. Moreover,
some patients with sarcoidosis may also benefit from additional therapeutic options, such
as psychosocial counselling, dietary interventions and supplemental oxygen.
Preliminary results of a randomised controlled trial studying the effects of exercise
training on exercise capacity and disease-specific quality of life in patients with
sarcoidosis are promising. Nonetheless, this topic merits further investigations.

Keywords: Exercise capacity, exercise training, quality of life, rehabilitation, sarcoidosis,

skeletal muscle.

323
 M.A. SPRUIT ET AL.

References
1. Wirnsberger RM, de Vries J, Wouters EF, Drent M. Clinical presentation of sarcoidosis in The
Netherlands an epidemiological study. Neth J Med 1998; 53: 5360.
2. Lacasse Y, Brosseau L, Milne S, et al. Pulmonary rehabilitation for chronic obstructive pulmonary
disease. Cochrane Database Syst Rev 2002; 3: CD003793.
3. Rees K, Taylor RS, Singh S, Coats AJ, Ebrahim S. Exercise based rehabilitation for heart failure.
Cochrane Database Syst Rev 2004; 3: CD003331.
4. de Vries J, Michielsen HJ, Van Heck GL, Drent M. Measuring fatigue in sarcoidosis: the Fatigue
Assessment Scale (FAS). Br J Health Psychol 2004; 9: 279291.
5. Drent M, Wirnsberger RM, de Vries J, Dieijen-Visser MP, Wouters EF, Schols AM. Association
of fatigue with an acute phase response in sarcoidosis. Eur Respir J 1999; 13: 718722.
6. Wirnsberger RM, Drent M, Hekelaar N, et al. Relationship between respiratory muscle function
and quality of life in sarcoidosis. Eur Respir J 1997; 10: 14501455.
7. Spruit MA, Thomeer MJ, Gosselink R, et al. Skeletal muscle weakness in patients with sarcoidosis
and its relationship with exercise intolerance and reduced health status. Thorax 2005; 60: 3238.
8. Adler RA, Funkhouser HL, Petkov VI, Berger MM. Glucocorticoid-induced osteoporosis in
patients with sarcoidosis. Am J Med Sci 2003; 325: 16.
9. Casaburi R, Bhasin S, Cosentino L, et al. Effects of testosterone and resistance training in men
with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170: 870878.
10. Wagner GJ, Rabkin JG, Rabkin R. Testosterone as a treatment for fatigue in HIVz men. Gen
Hosp Psychiatry 1998; 20: 209213.
11. Baydur A, Alsalek M, Louie SG, Sharma OP. Respiratory muscle strength, lung function, and
dyspnea in patients with sarcoidosis. Chest 2001; 120: 102108.
12. Medinger AE, Khouri S, Rohatgi PK. Sarcoidosis: the value of exercise testing. Chest 2001;
120: 93101.
13. Miller A, Brown LK, Sloane MF, Bhuptani A, Teirstein AS. Cardiorespiratory responses to
incremental exercise in sarcoidosis patients with normal spirometry. Chest 1995; 107: 323329.
14. Sietsema KE, Kraft M, Ginzton L, Sharma OP. Abnormal oxygen uptake responses to exercise in
patients with mild pulmonary sarcoidosis. Chest 1992; 102: 838845.
15. Hoitsma E, de Vries J, Santen-Hoeufft M, Faber CG, Drent M. Impact of pain in a Dutch
sarcoidosis patient population. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 3339.
16. Baydur A, Pandya K, Sharma OP, Kanel GC, Carlson M. Control of ventilation, respiratory
muscle strength, and granulomatous involvement of skeletal muscle in patients with sarcoidosis.
Chest 1993; 103: 396402.
17. Dewberry RG, Schneider BF, Cale WF, Phillips LH. Sarcoid myopathy presenting with
diaphragm weakness. Muscle Nerve 1993; 16: 832835.
18. Pringle CE, Dewar CL. Respiratory muscle involvement in severe sarcoid myositis. Muscle Nerve
1997; 20: 379381.
19. Decramer M, Lacquet LM, Fagard R, Rogiers P. Corticosteroids contribute to muscle weakness in
chronic airflow obstruction. Am J Respir Crit Care Med 1994; 150: 1116.
20. Brancaleone P, Perez T, Robin S, Neviere R, Wallaert B. Clinical impact of inspiratory muscle
impairment in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004; 21: 219227.
21. Man WD, Moxham J, Polkey MI. Magnetic stimulation for the measurement of respiratory and
skeletal muscle function. Eur Respir J 2004; 24: 846860.
22. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European
Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous
Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive
Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736755.
23. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review.
JAMA 2002; 287: 13011307.

324
 REHABILITATION IN SARCOIDOSIS

24. Barry SC, Gallagher CG. Corticosteroids and skeletal muscle function in cystic fibrosis. J Appl
Physiol 2003; 95: 13791384.
25. Hearth-Holmes M, Campbell GD Jr. Muscle weakness, fatigue, and joint pain in a 52-year-old
woman. Chest 1995; 108: 563564.
26. Jamal MM, Cilursu AM, Hoffman EL. Sarcoidosis presenting as acute myositis. Report and
review of the literature. J Rheumatol 1988; 15: 18681871.
27. Mozaffar T, Lopate G, Pestronk A. Clinical correlates of granulomas in muscle. J Neurol 1998;
245: 519524.
28. Myers GB, Gottlieb AM, Mattman PE, Eckley GM, Chason JL. Joint and skeletal muscle
manifestation in sarcoidosis. Am J Med 1952; 12: 161169.
29. Phillips RW, Phillips AM. The diagnosis of Boecks sarcoid by skeletal muscle biopsy. Arch Intern
Med 1956; 98: 732736.
30. de Palma L, Chillemi C, Albanelli S, Rapali S, Bertoni-Freddari C. Muscle involvement in
rheumatoid arthritis: an ultrastructural study. Ultrastruct Pathol 2000; 24: 151156.
31. Prayson RA. Granulomatous myositis. Clinicopathologic study of 12 cases. Am J Clin Pathol
1999; 112: 6368.
32. Di Francia M, Barbier D, Mege JL, Orehek J. Tumor necrosis factor-alpha levels and weight loss
in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994; 150: 14531455.
33. Libera LD, Vescovo G. Muscle wastage in chronic heart failure, between apoptosis, catabolism
and altered anabolism: a chimaeric view of inflammation? Curr Opin Clin Nutr Metab Care 2004;
7: 435441.
34. Nelson KA, Walsh D. The cancer anorexia-cachexia syndrome: a survey of the Prognostic
Inflammatory and Nutritional Index (PINI) in advanced disease. J Pain Symptom Manage 2002;
24: 424428.
35. Wang AY, Sea MM, Tang N, et al. Resting energy expenditure and subsequent mortality risk in
peritoneal dialysis patients. J Am Soc Nephrol 2004; 15: 31343143.
36. Ziegenhagen MW, Schrum S, Zissel G, Zipfel PF, Schlaak M, Muller-Quernheim J. Increased
expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with
progressing idiopathic pulmonary fibrosis and sarcoidosis. J Investig Med 1998; 46: 223231.
37. Ziegenhagen MW, Muller-Quernheim J. The cytokine network in sarcoidosis and its clinical
relevance. J Intern Med 2003; 253: 1830.
38. Chevalet P, Clement R, Rodat O, Moreau A, Brisseau JM, Clarke JP. Sarcoidosis diagnosed in
elderly subjects: retrospective study of 30 cases. Chest 2004; 126: 14231430.
39. Arcasoy SM, Christie JD, Pochettino A, et al. Characteristics and outcomes of patients with
sarcoidosis listed for lung transplantation. Chest 2001; 120: 873880.
40. Delobbe A, Perrault H, Maitre J, Robin S, et al. Impaired exercise response in sarcoid patients
with normal pulmonary function. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 148153.
41. Jones NL, Killian KJ. Exercise limitation in health and disease. N Engl J Med 2000; 343: 632
641.
42. Vant Hul A, Harlaar J, Gosselink R, Hollander P, Postmus P, Kwakkel G. Quadriceps muscle
endurance in patients with chronic obstructive pulmonary disease. Muscle Nerve 2004; 29: 267
274.
43. Chang B, Steimel J, Moller DR, et al. Depression in sarcoidosis. Am J Respir Crit Care Med 2001;
163: 329334.
44. Chang JA, Curtis JR, Patrick DL, Raghu G. Assessment of health-related quality of life in patients
with interstitial lung disease. Chest 1999; 116: 11751182.
45. Drent M, Wirnsberger RM, Breteler MH, Kock LM, de Vries J, Wouters EF. Quality of life and
depressive symptoms in patients suffering from sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis
1998; 15: 5966.
46. Wirnsberger RM, de Vries J, Breteler MH, Van Heck GL, Wouters EF, Drent M. Evaluation of
quality of life in sarcoidosis patients. Respir Med 1998; 92: 750756.

325
 M.A. SPRUIT ET AL.

47. Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. Health-related quality of life of
persons with sarcoidosis. Chest 2004; 125: 9971004.
48. Spruit MA, Troosters T, Trappenburg JC, Decramer M, Gosselink R. Exercise training during
rehabilitation of patients with COPD: a current perspective. Patient Educ Couns 2004; 52: 243248.
49. Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;
292: 23882395.
50. Viner R, Gregorowski A, Wine C, et al. Outpatient rehabilitative treatment of chronic fatigue
syndrome (CFS/ME). Arch Dis Child 2004; 89: 615619.
51. Ando M, Mori A, Esaki H, et al. The effect of pulmonary rehabilitation in patients with post-
tuberculosis lung disorder. Chest 2003; 123: 19881995.
52. Foster S, Thomas HM III. Pulmonary rehabilitation in lung disease other than chronic obstructive
pulmonary disease. Am Rev Respir Dis 1990; 141: 601604.
53. Spruit MA, Gosselink R, Troosters T, De Paepe K, Decramer M. Resistance versus endurance
training in patients with COPD and peripheral muscle weakness. Eur Respir J 2002; 19: 10721078.
54. Spruit MA, Thomeer MJ, Gosselink R, Derom E, Demedts MG, Decramer M. EXercise
TRAining in Sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005; (Abstract In press).
55. Stiebellehner L, Quittan M, End A, et al. Aerobic endurance training program improves exercise
performance in lung transplant recipients. Chest 1998; 113: 906912.
56. Evans AB, Al Himyary AJ, Hrovat MI, et al. Abnormal skeletal muscle oxidative capacity after
lung transplantation by 31P-MRS. Am J Respir Crit Care Med 1997; 155: 615621.
57. Creutzberg EC, Wouters EF, Mostert R, Weling-Scheepers CA, Schols AM. Efficacy of
nutritional aupplementation therapy in depleted patients with chronic obstructive pulmonary
disease. Nutrition 2003; 19: 120127.
58. Lotters F, van Tol B, Kwakkel G, Gosselink R. Effects of controlled inspiratory muscle training in
patients with COPD: a meta-analysis. Eur Respir J 2002; 20: 570576.
59. Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised controlled trial of patient education to
encourage graded exercise in chronic fatigue syndrome. BMJ 2001; 322: 387390.
60. Crockett AJ, Cranston JM, Antic N. Domiciliary oxygen for interstitial lung disease. Cochrane
Database Syst Rev 2001; 3: CD002883.
61. Bye PT, Anderson SD, Woolcock AJ, Young IH, Alison JA. Bicycle endurance performance of
patients with interstitial lung disease breathing air and oxygen. Am Rev Respir Dis 1982; 126: 1005
1012.
62. Harris-Eze AO, Sridhar G, Clemens RE, Gallagher CG, Marciniuk DD. Oxygen improves
maximal exercise performance in interstitial lung disease. Am J Respir Crit Care Med 1994;
150: 16161622.
63. Martin WJ 2nd, Iannuzzi MC, Gail DB, Peavy HH. Future directions in sarcoidosis research.
Summary of an NHLBI Working Group. Am J Respir Crit Care Med 2004; 170: 567571.

326
CHAPTER 22

Transplantation for sarcoidosis

I. Saleem*, S.O. Beirne}, J.J. Egan*,#

*Advanced Lung Disease and Irish National Lung Transplant Program, The Mater Misericordiae Hospital,
#
Saint Vincents University Hospital and Our Lady Hospital for Sick Children, and }The Conway Institute,
Dublin Molecular Medicine Centre. University College Dublin, Dublin, Ireland.

Correspondence: J.J. Egan, The Mater Misericordiae Hospital, University College Dublin, Eccles Street,
Dublin 7, Ireland. Fax: 35 316605451; E-mail: jegan@mater.ie

The course and prognosis of sarcoidosis varies greatly. A characteristic feature is the
high rate of spontaneous remission, however, chronic disease may occur in 1030% of
patients. Chronic sarcoidosis is defined as disease which persists for w2 yrs. Mortality
from sarcoidosis is only 15%, but 75% of all deaths are due to advanced pulmonary
sarcoidosis. To date, it remains difficult to predict which patients may develop chronic
progressive severe disease.
Regrettably, the treatment options for chronic stage IV sarcoidosis are limited.
Generally, lung transplant is reserved for those who have failed to respond to maximal
medical therapy. Due to the variability of the clinical course of sarcoidosis, timing of
transplant can be difficult. Accurate, disease-specific predictors of mortality in
sarcoidosis patients with chronic pulmonary disease have not been well defined.
Furthermore, the relative rarity of end-stage sarcoidosis makes the creation of mortality
prediction models difficult. This chapter will review both the current understanding of
the optimal criteria applied for estimating the need for transplantation and the outcome
of sarcoidosis patients who undergo transplantation.

Pulmonary function testing

The most common pulmonary function abnormalities seen in sarcoidosis are a
reduction in the carbon monoxide diffusing capacity of the lung (DL,CO) and a reduction
in lung volumes and vital capacity (VC). Obstructive defects may occur (y30% of cases)
and are generally unresponsive to bronchodilator therapy. Most sarcoidosis patients
considered for lung transplantation have a severe restrictive ventilatory defect. Patients
with a forced vital capacity (FVC) ofv1.5 L are at the greatest risk of mortality [1]. Often
the transfer factor is discordantly low compared with the VC. However, a lack of
consistency in the ability of lung function testing to reliably predict mortality may reflect
the heterogeneous patterns of disease which occur in stage IV disease.

Radiological evaluation
High-resolution computed tomography (HRCT) patterns and their relationship to
pulmonary function testing may clarify why lung function tests may be of limited value in
predicting disease severity. In a study of 80 patients, sarcoidosis-related fibrosis was
divided into three categories based on the dominant HRCT findings [2]. These patterns
Eur Respir Mon, 2005, 32, 327334. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
327
 I. SALEEM ET AL.

included central bronchial distortion, honeycomb pattern and a linear pattern, which
occurred in 47%, 29% and 24% of patients, respectively. The fibrotic changes,
particularly bronchial distortion and honeycombing, are predominantly in the upper
and/or middle lobes in most patients, whereas linear opacities are often diffuse.
These radiological patterns are associated with different clinical and lung function
characteristics. The mean duration of disease was longest in patients with bronchial
distortion, a mean of 13 yrs, compared with 9.6 yrs in patients with honeycombing and
8.7 yrs in patients with linear opacities. The patients who demonstrated honeycombing
had a greater degree of lung function impairment compared with those with linear and
bronchial changes. Patients with HRCT honeycombing had a mean total lung capacity
of 62% of predicted (% pred), the FVC was 58 % pred and DL,CO was 44 % pred (fig. 1)
Patients with dominant bronchial distortion had a FVC of 93 % pred, a forced expiratory
volume in one second (FEV1) of 64 % pred and a DL,CO of 58 % pred. Linear opacities on
HRCT were generally found to cause less functional impairment, the FVC was 84 %
pred, FEV1 77 % pred and DL,CO was 65 % pred. A minority of patients with linear
opacities had a pattern of diffuse septal reticulation which was associated with
pulmonary hypertension. This subgroup had severe functional impairment. Nodularity,
suggestive of reversible disease, occurred most commonly in association with linear
opacities and only rarely with honeycombing.

Criteria for referral for transplant

In order to define clinical parameters which may illustrate factors determining
survival, a single centre retrospective analysis has characterised sarcoidosis patients who
were referred and underwent lung transplantation [3]. Between 1991 and 2000, 56
patients were evaluated for lung transplantation, and 43 out of this group were listed.
The mean age of patients was 45 yrs and the diagnosis was made 13 yrs prior to listing. A

Fig. 1. A 62-yr-old male with Sarcoidosis. High-resolution computed tomography scan showing upper lobe
end-stage fibrosis with honey combing and traction bronchiectasis. The patients pulmonary artery is dilated
consistent with pulmonary hypertension.

328
 TRANSPLANTATION FOR SARCOIDOSIS

total of 23 (55% of patients) died awaiting transplantation. The mean pulmonary artery
pressure (Ppa) and right atrial pressure (RAP) were significantly higher in the group of
patients who died. Of the patients who died, 80% had a mean Ppa of 35 mmHg compared
with 40% of living patients (unadjusted relative risk (RR) of mortality=3.2; p=0.02).
Significant elevation of RAP (i.e., i15 mmHg) was present in 45% of deceased patients
(unadjusted RR of mortality=7.6; pv0.0001). When these were adjusted for confounding
variables, a RAP w15 mmHg was the only variable independently associated with death
on the waiting list.
In an effort to further characterise the features of sarcoidosis patients requiring lung
transplantation, Shorr et al. [4] retrospectively examined the outcome of sarcoidosis
patients (n=427) listed for lung transplantation in the USA and compared them with the
2,115 idiopathic pulmonary fibrosis (IPF) patients [4]. Sarcoidosis patients made up only
3.5% of the total number registered for transplantation, whilst 17.3% had IPF.
Compared with IPF patients (mean age=51.4 yrs), sarcoidosis patients were significantly
younger (mean age=45.4 yrs; pv0.0001). Sarcoidosis patients were also predominantly
female (66%) and African American (70%), while IPF patients were predominantly
White (79.5%) and male (60.7%). Lung function was lower in sarcoidosis patients, with a
FVC of 42.6 % pred and an FEV1 of 36 % pred, compared with IPF patients whose FVC
was 45 % pred and FEV1 was 46 % pred. Notably, sarcoidosis patients were more likely
to have pulmonary hypertension, mean Ppa of 34.4 mmHg compared with 25.6 mmHg in
IPF patients. Mortality after listing was high in both groups; 28% of sarcoidosis patients
and 31% of IPF died on the waiting list.
Consequently the United Network of Organ Sharing (UNOS) registry was reviewed
and data pertaining to sarcoidosis patients was collected in an effort to derive a model of
variables capable of providing an ability to predict survival [5]. A total of 405 patients
were identified of whom 27% died on the waiting list. Lung function studies did not
discriminate between those who died and those who continued to survive. African
Americans had significantly greater risk of dying with an odds ratio of 2.5. Elevated Ppa
was again observed as being associated with limited survival. Survivors had a mean Ppa
of 31 mmHg compared with 41 mmHg in nonsurvivors. The use of supplemental oxygen
was greater in the nonsurvivors (mean=2.9 L?min-1) compared with survivors
(mean=2.1 L?min-1). Combining these three variables allowed a predictive mathematical
model of moderate ability to be derived discriminating between survivors and
nonsurvivors in 65% of cases. Therefore, patients, especially African Americans,
requiring oxygen with elevated Ppa are at greatest risk of death. Generally, a greater
understanding and knowledge of the clinical variables influencing survival is required.

Outcome following lung transplantation

Limited data exists on the outcomes of sarcoidosis patients undergoing lung
transplantation. A single centre study has described the outcome of sarcoidosis patients
who have undergone lung transplantation [3]. A total of 12 patients underwent lung
transplantation, four single lung and eight double sequential lung transplants. This
occurred, on average, 494 days following listing for transplantation. Of the 12 patients,
five died following transplantation. Aspergillus infection was the cause of death in three
of the patients, one death due to intraoperative haemorrhage and one due to aspiration
pneumonia and haemolytic uraemic syndrome. Two of the 12 lung transplant recipients
developed evidence of recurrent sarcoidosis on biopsy, but this was considered to be of
little clinical significance.
A larger study was performed by Shorr et al. [6], evaluating the short-term outcome of

329
 I. SALEEM ET AL.

UNOS-registered sarcoidosis patients who underwent lung transplantation between 1995

and 2000. In total, 4,721 lung transplants were carried out, of which 133 (2.8%) were for
sarcoidosis. Unadjusted 30-day survival for sarcoidosis was 83% compared with 91% for
other diagnoses. This indicated a near double unadjusted risk of mortality for the
sarcoidosis cohort compared with others. Sarcoidosis patients were more likely to be
African American and female. Medicaid (USA) was the most frequent insurer in
sarcoidosis patients (13.5% versus 7.5%). Sarcoidosis patients were also younger than
patients undergoing lung transplantation for other indications. There was a trend
towards sarcoidosis patients being more likely to require mechanical ventilation (4.5%) at
the time of transplantation than other groups (2.2%). Furthermore, sarcoidosis patients
were more likely to undergo heart-lung transplant and double lung transplantation.
The strongest predictor of short-term mortality was heart-lung transplantation. Being
present in the intensive care unit at the time of transplantation also increased the risk of
mortality. Graft failure was the most common cause of death at 30 days, accounting for
two of every five deaths. It was 2.7 times more likely to be the cause of death in
sarcoidosis patients. Infection was the cause of death in only 8.7% of sarcoidosis patients
compared with 22.1% in other groups of patients.
Overall, sarcoidosis confers an increased risk of mortality at 30 days compared with
transplantation for other conditions, but this increased risk can be explained by factors
other than the underlying diagnosis. Sarcoidosis patients are more likely to require heart-
lung transplantation and to be female and African American. Race influenced mortality,
with African-American recipients and those receiving organs from African American
donors being 50% more likely to die at 30 days. This impact was independent of
insurance status.
The distribution of donor races was similar for all diagnosis. Thus, as most Sarcoidosis
patients in the USA were African American, they were more likely to have donor-
recipient racial mismatching. This racial mismatching may be a factor in predisposing
patients to subclinical rejection. Immunosuppressive therapies to date have been studied
predominantly in White populations and their pharmacokinetics and pharmaco-
dynamics may not be the same in the predominantly African-American population
undergoing lung transplantation for sarcoidosis.

Disease recurrence
A retrospective analysis of 1,394 lung transplant recipients has been undertaken in an
effort to define the impact and characteristics of recurring primary pulmonary diseases,
including sarcoidosis [7]. Computed tomography (CT) scans and pathologic specimens of
patients were reviewed. Of 26 patients who underwent transplantation for sarcoidosis
(three single, five double and one heart-lung), sarcoidosis recurred in nine cases (35%)
and, overall, was the commonest disease to recur. The CT findings of sarcoidosis disease
recurrence following lung transplantation were variable. Radiological manifestations
included either a solitary pulmonary nodule or numerous miliary nodules.
In another study, the natural history of sarcoidosis following lung transplantation has
been reported in nine single lung transplant recipients [8]. In this study, two
contemporaneous recipients receiving transplants for chronic obstructive pulmonary
disease (n=30) and inflammatory lung disease (n=13) served as control groups. All
recipients survived beyond 30 days and 1-yr survival was 67%. Sequential lung biopsies
were performed in eight of the nine sarcoidosis recipients. Recurrence of granulomas was
identified in five of these eight recipients (62.5%). The mean time to diagnosis of recurrent

330
 TRANSPLANTATION FOR SARCOIDOSIS

sarcoidosis was 224 days. There was no radiological evidence or symptoms relating to
disease recurrence in any of these five patients.
All recipients showed significant improvement in FVC from 1.54 L to 2.55 L.
Sarcoidosis patients with recurrent disease also showed improvement in VC from 1.53 L
to 2.71 L. There was no difference in the prevalence of acute cellular rejection between
the groups. Chronic rejection (obliterative bronchiolitis) occurred in 50% the sarcoidosis
recipients.
In another series, lung transplantation was performed on 12 sarcoidosis patients [9].
Ten underwent single lung transplantation and two underwent double lung transplanta-
tion. Survival was 70% at 3 yrs and 56% at 5 yrs. Three patients developed obliterative
bronchiolitis at 6, 18, and 45 months. Three patients had histological evidence of
sarcoidosis recurrence. The transbronchial biopsies had been undertaken for other
reasons and incidentally identified noncaseating granulomas. A diagnosis of recurrent
sarcoidosis was made after exclusion of mycobacteria, fungi, and Pneumocystis carinii
infection. The granulomas were identified at 5, 6, and 56 months after transplantation. In
one patient, the appearance of granulomas was associated with an irreversible decline in
lung function despite aggressive medical therapy, including increasing immunosuppres-
sion. This deterioration necessitated re-transplantation. In the other two patients the
appearance of granulomas was transitory and without any serious clinical problems.
Whilst histological recurrence is common after lung transplantation for sarcoidosis, this
is usually not of clinical significance.

Disease-specific characteristics and lung transplantation

There are several unique, disease-specific characteristics which need to be considered in
sarcoidosis patients in the context of selection for transplantation and post-operative
management. These include the presence of mycetomas, pulmonary hypertension and
bronchiectasis.

Mycetoma
A particular complication of stage IV sarcoidosis in patients with fibrocystic disease is
the development of mycetomas. These are saprophytic fungal infections usually caused
by members of the Aspergillus family developing within cavities in the lungs of patients
with advanced sarcoidosis. They may give rise to life-threatening haemoptysis. Surgical
resection is often difficult and carries significant mortality and morbidity rates.
Embolisation of bronchial arteries has been utilised to treat this problem. Generally, a
mycetoma is considered to be a relative contraindication to lung transplantation.
The presence of mycetomas in the lungs of patients undergoing lung transplantation is
predictive of poor post-transplant outcome. Careful screening for mycetoma by chest
radiograph and computed tomography (CT) is essential prior to transplant to identify
these patients at higher risk. Antifungal therapy prior to transplant will not usually
eradicate the mycetoma and, generally, patients are often to unwell to undergo resection.
The removal of diseased lung during the transplant removes most of the fungal
organisms, but enough may remain in the trachea and proximal bronchi potentially
resulting in post-transplant fungal infection.

Pulmonary hypertension
The presence of pulmonary hypertension in sarcoidosis patients is a consistent feature
of patients with limited survival (fig. 2). Some studies report an incidence of 50% in

331
 I. SALEEM ET AL.

Fig. 2. A 60-yr-old man with sarcoidosis. High-resolution computed tomography scan showing extensive
confluent areas of linear fibrosis and dilated pulmonary arteries consistent with pulmonary hypertension.

patients with stage III disease. The mechanism(s) of pulmonary hypertension in

sarcoidosis has not been defined with great clarity. It may be due to fibrosis of the lung
parenchyma and destruction of pulmonary vessels resulting in an obliterated pulmonary
vascular bed. Extrinsic compression of pulmonary vessels by sarcoidosis lymphadeno-
pathy may also contribute. An open study of 14 patients receiving vasodilator therapy
suggests that vasoconstrictive mediators may also play a role in sarcoidosis-associated
pulmonary hypertension [10]. In this study, eight patients received an acute challenge
with inhaled nitric oxide (iNO), six patients received i.v. epoprostenol and five patients
received calcium channel blockers. A favourable short-term response was defined as a
w20% decrease in pulmonary vascular resistance (PVR). This was observed in seven out
of the eight in response to the iNO, four of the six who received i.v. epoprostenol and two
out of five in response to oral calcium channel blockers. Both iNO and epoprosentol
significantly reduced the PVR and increased cardiac output, but iNO was the only
vasodilator to significantly reduce the Ppa. The only significant response to calcium
channel blockers was to reduce systemic vascular resistance.
Long-term vasodilator therapy was then commenced in the patients who had a
response to the vasodilator challenge. Five patients received long-term iNO and one
received i.v. epoprostenol. Follow-up 6-minute walk test improved in all five of the
patients on long-term iNO. Follow-up haemodynamic data collected in three patients
showed a sustained effect. These three patients subsequently died (although only one had
progressive right heart failure). The two remaining patients continued on iNO. These
data suggest that patients with sarcoidosis-related pulmonary hypertension often have
clinically relevant pulmonary vascular reversibility, despite severe parenchymal lung
disease.

Bronchiectasis and type of transplant

The transplant procedure of choice for sarcoidosis has not been specified. Generally,
the decision is made on an individual patient basis. Patients with fibrocystic pulmonary
disease have a high incidence of bronchiectasis. Recurrent infections are common in this

332
 TRANSPLANTATION FOR SARCOIDOSIS

group of patients; therefore, double sequential lung transplant is indicated. Double lung
transplant recipients have superior pulmonary function compared with single lung
recipients, but exercise tolerance in both groups is similar. Therefore, because of the great
shortage of organs, single lung transplant is an acceptable alternative for patients with
honeycomb-pattern fibrosis. Heart-lung transplantation may be offered to patients with
associated pulmonary hypertension. However, the presence of associated pleural disease
in some sarcoidosis patients may result in significant problems following heart-lung
transplantation, as the need for bypass may augment bleeding from the pleural surfaces.

Cardiac, renal and liver transplantation for sarcoidosis

Rarely, patients may be considered for solid organ transplantation for sarcoidosis-
related heart, liver or kidney disease. Generally, if required, isolated heart or liver or
kidney transplantation is appropriate in patients with end-stage extrapulmonary disease.
The limited data available indicates that outcome following transplantation is acceptable
in these other forms of organ transplantation. However, such patients remain at risk of
disease recurrence as is observed following lung transplantation. A key consideration in
such patients is that the advanced disease is isolated to one organ.
Up to 16 heart transplant recipients with a diagnosis of sarcoidosis have been
described in the literature [11, 12]. A total of 15 liver and 51 kidney transplants have also
been identified. Isolated cases of histological disease recurrence have been described
following heart, liver and kidney transplantation, but the clinical course of these cases
have been favourable.

Summary
Organ transplantation is an accepted method of treatment for sarcoidosis patients
with advanced organ failure, including lung, liver or heart disease. Transplantation
can be performed successfully in sarcoidosis patients. However, predicting the precise
time for referral can be difficult and, therefore, early referral is advised. The
management of sarcoidosis-associated pulmonary hypertension is important in this
circumstance.
Survival statistics vary but a primary diagnosis of sarcoidosis, carries an increased risk
of mortality following transplantation. Recurrence is frequent (estimated to be y50%
following lung transplantation), but is most often asymptomatic, and tends not to
compromise graft function or patient survival. Regrettably, transplantation is limited
by the availability of donated organs.

Keywords: End-stage, recurrence, sarcoidosis, transplantation.

333
 I. SALEEM ET AL.

References
1. Baughman RP, Winget DB, Bowen EH, et al. Predicting respiratory failure in sarcoidosis patients.
Sarcoid Vasc Diffuse Dis 1997; 14: 15458.
2. Abehsera M, Valeyre D, Grenier P, Jaillet H, Battesti JP, Brauner MW. Sarcoidosis with
pulmonary fibrosis CT patterns and correlation with pulmonary function. Am J Roentgenol 2000;
174: 17511757.
3. Arcasoy SM, Christie JD, Pochettino A, et al. Characteristics and outcomes of patients with
sarcoidosis listed for lung transplantation. Chest 2001; 120: 873880.
4. Shorr AF, Davies DB, Nathan SD. Outcomes for patients with sarcoidosis awaiting lung
transplantation. Chest 2002; 122: 233238.
5. Shorr AF, Davies DB, Nathan SD. Predicting mortality in patients with sarcoidosis awaiting lung
transplantation. Chest 2003; 124: 922928.
6. Shorr AF, Helman DL, Davies DB, Nathan SD. Sarcoidosis, race, and short-term outcomes
following lung transplantation. Chest 2004; 125: 990996.
7. Collins J, Hartman MJ, Warne TF, et al. Frequency and CT findings of recurrent disease after lung
transplantation. Radiology 2001; 219: 503509.
8. Nunley DR, Hattler B, Keenan RJ, et al. Lung transplantation for end-stage pulmonary
sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 93100.
9. Walker S, Mikhail G, Banner N, et al. Medium term results of lung transplantation for end stage
pulmonary sarcoidosis. Thorax 1998; 53: 281284.
10. Preston IR, Klinger JR, Landzberg MJ, Houtchens J, Nelson D, Hill NS. Vasoresponsiveness of
sarcoidosis-associated pulmonary hypertension. Chest 2001; 120: 866872.
11. Barbers RG. Role of transplantation (lung, liver, and heart) in sarcoidosis. Clin Chest Med 1997;
18: 865874.
12. Padilla ML, Schilero GJ, Teirstein AS. Sarcoidosis and transplantation. Sarcoidosis Vasc Diffuse
Lung Dis 1997; 14: 1622.

334
CHAPTER 23

History of the WASOG and current activities

G. Rizzato

Niguarda Hospital, Milan, Italy.

Correspondence: G. Rizzato, Juvara 9, 20129 Milan, Italy. Fax: 39 022666906; E-mail: rizzatog@tin.it

The World Association for Sarcoidosis and Other Granulo-

matous Disorders (WASOG) was founded on the September 7,
1987 in Milan, Italy, during the World Congress for Sarcoidosis
(held in Milan), with a Deed of Constitution by Public Notary P.
Guzzetti (Notarial File 8048, Serial 616). The Founder Members
were G. James (President), G. Rizzato (General Secretary and
Treasurer), A. Blasi, J. Chretien, Y. Hosoda, T. Izumi, W. Jones
Williams, G. Semenzato, O.P. Sharma and A. Teirstein. The deed
of constitution and original statutes have been previously
published [1]. The Statutes were changed at the time of the Kumamoto World Congress
(in Japan) and the current By-Laws are also published (Public Notary L. Guarnieri,
Milan, Italy) [2].
At the time of the Milan Congress, the Journal Sarcoidosis (two issues per year)
became the official voice of the WASOG. Over the years, its scientific level has improved.
As a result, in November 1993 it was included in Current Contents/Clinical Medicine, and
in October 1994 the Journal received coverage in Index Medicus/Medline. Its inclusion in
these major databases induced many authors to submit articles on various subjects and it
soon became clear that the title of the Journal was no longer appropriate for its content
as many articles were concerning interstitial lung diseases other than sarcoidosis.
Consequently in 1996, after a resolution taken at the time of the London World Congress
(UK, 1995), its name was changed to Sarcoidosis, Vasculitis and Diffuse Lung Diseases.
The flourishing of this Journal during the last few years, thanks to the hard work of the
current Editor in Chief G. Semenzato and the current Associate Editor C. Agostini, is
demonstrated by the growth of the impact factor. Since the start of 2000, the periodicity
has passed from two to three issues per year. The Journal is currently (April 2005) ranked
eighth in the specialist list of respiratory journals, given by the Institute of Scientific
Information (Stamford, CT, USA). However, if four Journals of basic research,
molecular biology, physiology and thoracic surgery are not considered, the Journal is
ranked fourth, just a notch below Chest.
What is the interest of the WASOG members? Internal Medicine has given birth to a
number of sons and daughters (cardiology, gastroenterology, etc., and among them
pneumology), and now their sons and daughters are giving birth to independent
grandsons and grand-daughters; cardiology has delivered electrophysiology and others;
gastroenterology has delivered hepatology and others, each one with their own experts,
journals and congresses. Pneumology is delivering physiopathology, bronchology,
thoracic oncology, etc. What is our position? Many interstitial lung diseases (e.g.
rheumatoid arthritis) are part of a larger systemic problem, where the lung may be a
minor target; others (e.g. idiopathic pulmonary fibrosis) are nearly exclusively a lung
problem from the beginning. Thus, the future lies as a branch midway between
Eur Respir Mon, 2005, 32, 335336. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
335
 G. RIZZATO

pneumology and internal medicine, but it is clear that currently the WASOG has its own
experts, Journal, society and patients.
What about the activities of the society? When G. James organised the first congress of
the sarcoidosis movement in London, UK (1958), there were 22 participants from eight
countries. In a few years, the delegates of the congresses had reached 400. The WASOG
members are now y300 from 30 different countries. The WASOG World Congress is
held every 3 yrs; the next will be in Denver, CO, USA, in June 2005 (organisers: L.
Newman and R. Baughman), and in Athens, Greece, June 2008 (endorsed by the
Hellenic Lung Society; organiser: S. Constantopoulos). The topics of the Congresses
reflect the interest of the WASOG members to extend the scientific programme to all the
interstitial lung diseases, but the final programme is still in the hands of the organiser. A
look to the Denver programme shows that the major topic will be sarcoidosis. However,
this will probably not be the case for the Athens Congress. In addition, the WASOG has
started a series of international congresses on diffuse lung diseases; the first congress was
held in Venice, Italy (organiser: M.G. Boccieri) in June 2001, the second was held in
Siena (organiser: P. Rottoli), Italy, November 2003, and the third will be held in Catania,
Italy, June 2006 (organiser: N. Crimi).
The activities of the WASOG are directed by an Executive Committee of 16 Members.
Current Officers are O.P. Sharma (President), B. Baughman (vice-president for the
USA), U. Costabel (vice-president for Europe), S. Nagai (vice-president for Asia/Pacific),
G. Rizzato (General Secretary) and G. Semenzato (Treasurer). For those interested in
more information on the WASOG, the website (in the hands of C. Agostini) is available
[3]. According to new bylaws, the association has its registered office at the address of the
Treasurer. Thus, the current official address is that of G. Semenzato, Universita` degli
Studi di Padova, Via Giustiniani 2, 35128 Padova, Italy (g.semenzato@unipd.it).

References
1. Guzzetti P. Deed of constitution and statutes of WASOG. Sarcoidosis 1988; 5: 8385.
2. Guarnieri L. WASOG bye-laws. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18: 203204.
3. Agostini C. WASOG website. http://www.pinali.unipd.it/sarcoid. Date last updated: May 2005;
Date last accessed: 12 July 2005.

336
CHAPTER 24

Sarcoidosis patient groups

P.Y. Polite

Correspondence: P.Y. Polite, Sarcoidosis Research Institute, 3475 Central Avenue, Memphis, TN 38111,
USA. E-mail: paulapolite@bellsouth.net

Challenges faced by sarcoidosis patients

Sarcoidosis patients face many complex challenges. A high percentage of patients
experience a difficult diagnosis or a misdiagnosis. There have even been reports of a
patient who presented symptoms at the age of 12 yrs, but did not receive a proper
diagnosis of sarcoidosis until the age of 40 yrs. Other patients have received a
misdiagnosis of cancer or have been accused of imagining their symptoms and referred to
psychiatrists.
In the treatment of their disease, many patients are prescribed prednisone. Prednisone
has many adverse side-effects, including weight gain, diabetes, high blood pressure,
mood swings, depression, difficulty sleeping at night, heartburn, acne, thinning of the
skin and bones, cataracts, glaucoma and adrenal gland insufficiency. Patients struggle
with the side-effects of weight gain, mood swings and depression as these symptoms
adversely affect their quality of life (QoL). Many patients are faced with the difficult
decision of whether to endure the side-effects of the medication or the symptoms of the
disease.
Fatigue is a huge QoL issue. A major percentage of sarcoidosis patients experience
severe fatigue which impairs their ability to function at their normal level. Another QoL
issue that patients experience is that they look completely healthy. Many times when
patients complain of their symptoms to family, friends and colleagues they are not taken
seriously or are accused of making up their symptoms. Also, others do not understand
why patients are not able to perform work or participate in social activities as they
previously did prior to their illness as they "look fine".

Patient groups and their importance

Sarcoidosis patients should have a central place in the related medical care. To
improve this care, patient societies were started. In Europe, the first patient society was
founded in The Netherlands in 1978. Thereafter, many other countries followed this
initiative (see Appendix). In the USA, sarcoidosis patient groups were first formed in
1991. Additionally, in 2001, a European (and later a Mondial) society, the European
Association of Patients Organisations of Sarcoidosis and other Granulomatous
Disorders (EPOS), was founded by the Deutsche Sarkoidose-Vereinigung (Germany),
the Sarcoidose Belangenvereniging Nederland (The Netherlands), the Sarcoidosis and
Interstitial Lung Association (UK), and the Schweizerische Sarkoidose-Vereinigung
(Switzerland). EPOS was founded as the international umbrella under which all national
patients organisations will be represented. EPOS has clearly marked targets and ideals.
These include active participation in the foundation of (new) national organisations and
Eur Respir Mon, 2005, 32, 337339. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448X. ISBN 1-904097-22-7.
337
 P.Y. POLITE

also to stimulate international research and provide a forum for the exchange of ideas,
experiences and expertise. The priority remains the provision of adequate information
for patients and all others involved, in the broadest sense. The suffering of the long-term
sarcoidosis patient must be recognised as unsatisfactory. Not only is the cause unknown
but a medical cure remains undiscovered. In order to help these patients and those who
aim to help them, EPOS was brought into being.
All societies have members suffering from sarcoidosis, as well as active supporters. The
aims of all these societies are to provide a forum and a network for those having similar
experiences and their partners, to provide appropriate and up-to-date information and
organise regional, national and international meetings for patients and physicians. It is of
benefit to patients to communicate with others who have the same symptoms as it
confirms that those symptoms are real and not just in their minds. Talking to other
patients lends credibility to patients and their families that others are experiencing the
same frustrations. Patients are also provided with the opportunity to discuss their
diagnosis and treatment plans that have been effective for them.

Programmes and services offered by patient groups

Many patient groups host educational conferences, provide videos, newsletters,
websites and literature that provide invaluable information to enable patients to
understand and manage their disease.
Patient organisations have also developed and implemented programmes to promote
the publics awareness about sarcoidosis. Increased awareness also increases the
probability of better diagnosis by a physician.
Some sarcoidosis groups engage in research initiatives to identify the cause and cure
for the disease, and to improve diagnosis, prevention and treatment. Patient websites and
hotlines are available to help patients locate physicians knowledgeable of the disease. The
organisations have their own advice boards with various members, including
psychologists, lawyers, insurance physicians, and physiotherapists, to ensure that the
information provided is as broad as possible. Many groups are involved in advocacy
efforts to foster support for sarcoidosis initiatives from the local, state and federal
entities.
Another important task of the societies is to promote research related to sarcoidosis.

National and international collaborative efforts

For several years there has been cooperation between the sarcoidosis patient societies
within Europe, as well as between Europe, the USA and Japan. These cooperations will
be explored in the near future. To promote the interest of sarcoidosis patients in the best
way possible, delegates of various patient societies became a member of the World
Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) and
participated in the international congresses. Some of the sarcoidosis groups have
collaborated to host an educational patient conference in conjunction with the WASOG
in Denver, USA (June 12, 2005).
Sarcoidosis patient groups have successfully joined forces to collaborate on projects
that have proven beneficial to patients. As a result of these efforts in the USA, the
National Institutes of Health has formed a Trans-Institute Working Group to develop a
comprehensive research agenda for sarcoidosis. This is a phenomenal step as sarcoidosis
affects so many different organs and systems within the body. Furthermore, sarcoidosis

338
 SARCOIDOSIS PATIENT GROUPS

patient societies try to stimulate the interest of researchers to design studies related to this
disease. For example, an award is given to a young researcher every year by the Dutch
Sarcoidosis Society to a promising research project in The Netherlands dedicated to
sarcoidosis.
In the USA, the Foundation for Sarcoidosis Research (FSR) is a nonprofit
organisation dedicated to improving care for sarcoidosis patients and finding a cure
for this disease. Since its establishment in 2000, the FSR has worked diligently to provide
resources to thousands of patients, their families and their physicians, and has funded
several domestic and international research efforts. FSR has a long history of educating
consumers and their healthcare professionals, as well as providing direct support to
critically needed research. FSRs annual awareness campaign the "Kick In to Stop
Sarcoidosis" (KISSTM) reaches hundreds of thousands of people with a combination of
education events, printed articles, televised health reports and public service announce-
ments. The FSR board of directors feels strongly that the causes of this disease, and
ultimately a cure, will be uncovered through rigorous and extensive scientific research.
The FSRs Research Grants Program is the nations first privately funded programme for
sarcoidosis research. They support young researchers by providing young investigators
awards for excellence in sarcoidosis research at the latest American Thoracic Society and
WASOG meetings. Furthermore, they stimulate research by offering partnership grants
for sarcoidosis research. It is vital that the FSR maintain a high level of support for
sarcoidosis patients and expand the type and availability of provided services. In the
coming months, this would include plans for new patient and professional education
initiatives; moreover, the FSR intends to continue its efforts to fund research to find
better treatments and hopefully, someday, a cure for this devastating disease.
In summary, sarcoidosis patient groups play an integral role in patient care and are a
driving force in the quality of the science and research that will ultimately identify the
cause and find a cure for this complex and debilitating disease.

339
APPENDIX

Websites of national and international

sarcoidosis patient societies

Austria
sterreichischer Sarkoidose Vereinigung (OSV)
O
E-mail address: sarkoidose@gmx.at
No website available yet.
Belgium
Vereniging Voor Sarcodosepatienten (BVS)
E-mail address: hilde.santermans@uz.kuleuven.ac.be
Website: http://www.sarcoidose.be
EPOS
European Association of Patients Organizations of Sarcoidosis and other
Granulomatous Disorders
E-mail: info@sarcoidosis-epos.com
Website: http://www.sarcoidosis-epos.com
France
Reseau International de Soutien des Malades de la Sarcodose Reseau (RISMS)
E-mail address: risms@wanadoo.fr
Website: http://www.sarcoidose-infos.com/index.html
Germany
Deutsche Sarkoidose-Vereinigung (DSV)
The DSV is an association of patients and their relatives. It was founded in 1987 and
currently has y3,400 members.
E-mail address: sarkoidose@aol.com
Website: http://www.sarkoidose.de
Japan
Japanese Patient Association
E-mail address: info@kyo-sar.com
Website: http://www.kyo-sar.com
The Netherlands
Sarcodose Belangenvereniging Nederland (SBN)
This association was founded in 1978 and has currently y2,300 members and w100
supporters.
E-mail address: info@sarcoidose.nl
Website: http://www.sarcoidose.nl
Switzerland
Schweizerische Sarkoidose-Vereinigung (SSARV)
E-mail address: info@sarkoidose.ch
Website: http://www.sarkoidose.ch

Eur Respir Mon, 2005, 32, 340341. Printed in UK - all rights reserved. Copyright ERS Journals Ltd 2005; European Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7.
340
UK
Sarcoidosis and Interstitial Lung Association
E-mail address: info@sarcoidosis.org.uk
Website: http://www.sarcoidosis.org.uk

USA
Sarcoid Networking Association
E-mail address: webmaster@sarcoidosisnetwork.org
Website: http://www.sarcoidosisnetwork.org
Foundation for Sarcoidosis Research (FSR)
E-mail address: info@stopsarcoidosis.org
Website: http://www.stopsarcoidosis.org

WASOG
World Association of Sarcoidosis and Other Granulomatours Disorders
E-mail address: g.semenzato@unipd.it
Website: http://www.pinali.unipd.it/sarcoid

341