Autoimmunity Reviews 10 (2011) 444–454

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Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a u t r ev

Review

Recommendations for the management of mixed cryoglobulinemia syndrome in

hepatitis C virus-infected patients
Maurizio Pietrogrande a,1, Salvatore De Vita b,1, Anna Linda Zignego c,1, Pietro Pioltelli d,1,
Domenico Sansonno e,1, Salvatore Sollima f,1, Fabiola Atzeni g,1, Francesco Saccardo h,1, Luca Quartuccio b,1,
Savino Bruno i,1, Raffaele Bruno j,1, Mauro Campanini k,1, Marco Candela l,1, Laura Castelnovo h,1,
Armando Gabrielli m,1, Giovan Battista Gaeta n,1, Piero Marson o,1, Maria Teresa Mascia p,1, Cesare Mazzaro q,1,
Francesco Mazzotta r,1, Pierluigi Meroni s,1, Carlomaurizio Montecucco t,1, Elena Ossi u,1, Felice Piccinino v,1,
Daniele Prati w,1, Massimo Puoti x,1, Piersandro Riboldi y,1, Agostino Riva f,1, Dario Roccatello z,1,
Evangelista Sagnelli v,1, Patrizia Scaini aa,1, Salvatore Scarpato ab,1, Renato Sinico ac,1, Gloria Taliani ad,1,
Antonio Tavoni ae,1, Eleonora Bonacci a, Piero Renoldi ac,1, Davide Filippini af,1, Piercarlo Sarzi-Puttini g,1,
Clodoveo Ferri ag,1, Giuseppe Monti h,1, Massimo Galli f,⁎,1
a
Medicina Interna, Department of Medicine, Surgery and Dentistry, Policlinico San Marco of Zingonia, University of Milan, Italy
b
Rheumatology Clinic, DPMSC, University of Udine, Italy
c
Medicina Interna, University of Florence, Italy
d
Clinica Ematologica, AO San Gerardo, University of Milan — Bicocca, Italy
e
Medicina Interna, DIMO, University of Bari, Italy
f
Infectious Disease Unit, L. Sacco Department of Clinical Sciences, University of Milan, Italy
g
Rheumatology Unit, Ospedale L. Sacco, Milan, Italy
h
Medicina Interna, Ospedale di Saronno, AO Busto Arsizio, Italy
i
Dipartimento di Medicina Interna, AO Fatebenefratelli e Oftalmico, Milan, Italy
j
U.O. Malattie Infettive e Tropicali, Fondazione IRCCS Policlinico S Matteo, University of Pavia, Italy
k
Divisione di Medicina Generale, Ospedale Maggiore di Novara, AO Maggiore della Carità, Novara, Italy
l
ASUR Marche ZT6, Fabriano, Italy
m
Clinica Medica Generale, Ematologia ed Immunologia Clinica, University of Ancona, Italy
n
Unità di Epatologia, Seconda Università di Napoli, Naples, Italy
o
Unità Immunotrasfusionale, AO di Padova, Italy
p
Unità di Malattie dell'apparato locomotore a genesi immunologica — Policlinico, University of Modena, Italy
q
Medicina Generale, AO Santa Maria degli Angeli, Pordenone, Italy
r
Infectious Diseases Unit, Azienda Sanitaria Firenze, Florence, Italy
s
Clinica Reumatologica, University of Milan, Italy
t
Clinica Reumatologica, Fondazione IRCCS Policlinico S Matteo, University of Pavia, Italy
u
Clinica Medica 1, University of Padua, Italy
v
Dipartimento di Medicina Pubblica, Sezione Malattie Infettive, Seconda Università di Napoli, Naples, Italy
w
Department of Transfusion Medicine and Hematology, Ospedale Alessandro Manzoni, Lecco; and Laboratory of Experimental Hepatology, Centre of Transfusion Medicine,
Cellular Therapy and Cryobiology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
x
Department of Infectious Diseases, University of Brescia, Italy
y
Allergy, Clinical Immunology and Rheumatology Unit, Istituto Auxologico Italiano, Department. of Internal Medicine, University of Milan, Italy
z
Divisione di Nefrologia e Dialisi, Ospedale Giovanni Bosco, Turin, Italy
aa
UO Nefrologia, Spedali Civili, Brescia, Italy
ab
UO Reumatologia, Ospedale M. Scarlato, Scafati, Salerno, Italy
ac
UOS di Immunologia Clinica, Ospedale S. Carlo Borromeo, Milan, Italy
ad
Dipartimento di Malattie Infettive e Tropicali, Policlinico di Roma, La Sapienza University, Rome, Italy
ae
Dipartimento di Medicina Interna, Unità di Reumatologia, University of Pisa, Italy

⁎ Corresponding author at: Infectious Disease Unit, Università degli Studi di Milano, 20127 Milano, Italy.
E-mail address: massimo.galli@unimi.it (M. Galli).
1
For the GISC (Italian Group for the Study of Cryoglobulinemias).

1568-9972/$ – see front matter © 2011 Published by Elsevier B.V.

doi:10.1016/j.autrev.2011.01.008
 M. Pietrogrande et al. / Autoimmunity Reviews 10 (2011) 444–454 445

af
Unità di Reumatologia, Ospedale Niguarda Ca’ Granda, Milan, Italy
ag
Rheumatology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The objective of this review was to define a core set of recommendations for the treatment of HCV-
Received 12 January 2011 associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and
Accepted 28 January 2011 expert opinion.
Available online 15 February 2011 Methods: Expert physicians involved in studying and treating patients with MCS formulated statements after
discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently
Keywords:
supported by published data) were collected before the consensus conference by means of a questionnaire,
Cryoglobulinemia
Mixed cryoglobulinemia syndrome
and were considered when formulating the statements.
HCV Results: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the
Pegylated interferon first-line therapeutic option in patients with mild–moderate HCV-related MCS. Prolonged treatment (up to
Ribavirin 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory
Rituximab improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers,
Glucocorticoids peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in
Apheresis severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the
Cyclophosphamide
majority of conference participants discouraged the chronic use of low–medium GC doses. Apheresis remains
the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to
patients who do not respond to (or who are ineligible for) other treatments, and emergency situations.
Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are
scarce. Despite the limited available data, colchicine is used by many of the conference participants,
particularly in patients with mild–moderate MCS refractory to other therapies. Careful monitoring of the side
effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-
content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are
no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to
individual patients on the basis of the guidelines used in other vasculitides.
Conclusion: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of
its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional
guidelines for the management of MCS.
© 2011 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
3.1. Antiviral therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
3.2. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
3.3. Biological therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
3.4. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
3.5. Glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
3.6. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
3.7. Apheresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
3.8. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
3.9. Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
3.10. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
3.11. Colchicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
3.12. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
3.13. Low-antigen-content diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
3.14. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
3.15. Analgesic and non-steroidal anti-inflammatory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
3.16. Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

1. Introduction pathological significance but, in some cases, they may be responsible

Mixed cryoglobulins (MCs) are immune complexes that typically
consist of an IgM rheumatoid factor and immunoglobulins (most
frequently IgG) that can precipitate at temperatures below 37 °C [1].
Associated with acute and chronic infections, lymphoproliferative
disorders, and autoimmune diseases, they often have no real
for serious and debilitating vasculitis syndromes with organ damage
and a sometimes fatal outcome [2]. The mixed cryoglobulinemia
syndrome (MCS) or symptomatic mixed cryoglobulinemia is defined
by the Meltzer and Franklin triad of purpura, fatigue and arthralgia [3],
and can be classified as one of the immune complex-mediated
systemic vasculitides involving small-sized vessels. Since the
446 M. Pietrogrande et al. / Autoimmunity Reviews 10 (2011) 444–454
discovery of hepatitis C virus (HCV), it has been shown that the vast
majority of MCs previously defined as ‘essential’ or idiopathic can be
attributed to it [4–7]. Circulating cryoglobulins are frequently
detected in HCV-positive patients, but only a minority of patients
with chronic HCV infections (usually women aged more than
50 years) develop frank MCS [8]. However, although it is generally
considered to be rare, MCS is actually not uncommon, especially in
southern European countries where the prevalence of HCV infection is
high among the elderly.
Various attempts at defining a clinical classification have been
made since the 1990s and the GISC (Italian Group for the Study of
Cryoglobulinemia) has recently completed a large international
cooperative study aimed at establishing classification criteria on the
basis of standard methods [9].
Managing MCS means dealing with multiple and often very
different clinical patterns, activity and severity, and should have the
aim of preventing irreversible organ damage, reducing pain and
improving the patients' quality of life. However, the treatment is still
largely empirical. Any rational therapeutic approach should have
three main objectives [10]: to eradicate HCV; to limit or suppress B
lymphocyte proliferation; and to contain and symptomatically treat
the vasculitis and reduce the damage caused by circulating immune
complexes. Each of these therapeutic targets requires the use of
different classes of drugs or specific procedures, but there are still very
few data available from randomised controlled studies. Furthermore,
the involvement of different organs means that MCS may be
diagnosed by specialists in different fields, who tend to focus on the
therapeutic approaches that are more in line with their own
experience.
For this reason, the GISC promoted a consensus conference to
discuss currently used therapies and the published evidence
concerning their efficacy. The aim of this conference was to define a
core set of practical treatment recommendations by combining
clinical trial data and expert opinion.
2. Methods
For practical reasons, the GISC board organising the conference
focused on what is known about the drugs used to treat MCS. The
discussion was also strictly limited to the treatment of HCV-related MCS.
The Consensus Committee included physicians working in various
medical fields (internal medicine, rheumatology, haematology,
nephrology, hepatology, infectious diseases, and neurology) who
were involved in caring for patients with MCS.
The therapeutic schedules currently used by each GISC centre were
collected by means of a questionnaire and submitted for preliminary
evaluation by the GISC Scientific Board. The questionnaire asked which
of the following drugs or treatment procedures were used to treat MCS:
interferons ± ribavirin; pegylated interferons± ribavirin; anti-CD20;
glucocorticoids; immunosuppressors, including cyclophosphamide,
azatioprine, methotrexate, and cyclosporine; colchicine; NSAIDs and
other drugs used in pain control; apheretic procedures; and a low-
antigen-content diet. These were then divided into three groups to be
discussed at the conference: 1) antiviral (interferon-based) therapies;
2) biological (anti-CD20-based) therapies; and 3) other therapeutic
approaches.
A panel of four members (two senior clinicians plus two junior
clinicians as bibliographic reviewers) was formed for each group and,
after carefully reviewing the literature and questionnaires (see below),
each panel formulated preliminary statements to be discussed at the
consensus conference by the full Consensus Committee.
The literature review was carried out in phases based on the
Cochrane systematic review guidelines [11]. The results of the review
and the experts' discussions were then translated into epidemiological
terms using Sackett's patients, intervention, comparison and outcome
(PICO) methods [12]. Specific key words and MeSh terms were selected
in MEDLINE and variously combined to search for papers concerning the
treatment of patients aged more than 18 years with HCV-related MCS
available in MEDLINE, EMBASE and Cochrane Central. The search was
restricted to papers written in English, French and Italian.
The selected papers included randomised controlled trials (RCTs),
observational studies (prospective and retrospective cohort and case–
control studies), and case series of at least three patients. Given the
scarcity of data concerning some treatments, the Scientific Committee
also included single case reports that provided information about
otherwise neglected issues.
The publication details, patient characteristics, dosage, therapeutic
strategy and relevant outcomes were extracted from all of the included
articles using standard forms. Levels of evidence (Oxford, May 2001,
http://www.cebm.net) of each study were assessed and classified from
level 1a (a systematic review of RCTs) to level 4 (case series), with level
5 being used for expert opinions without any explicit critical appraisal.
The strength of the experts' recommendations was classified from A
(consistent level 1 studies) to D (inconsistent or inconclusive studies at
any level).
The statements formulated on these bases were then discussed by
the panel of experts together, and the recommendations were
reformulated by combining the best available evidence from the
literature with the experts' opinion. A second level of agreement was
provided for each recommendation by the committee members who
had acknowledged competence in the field of each recommendation.
Subsequently published additional data were taken into account
when preparing the final report, which was resubmitted to the expert
panel for a final on-line discussion.
3. Results
3.1. Antiviral therapy
Since the discovery of the association between HCV and MCS,
many studies have assessed the efficacy of antiviral therapy [13].
Interestingly, because of its antiproliferative and immunomodulatory
effects, interferon-α (IFN) was successfully used to treat MC even
before the identification of HCV [14,15].
The antiviral treatment of MCS essentially followed the evolution of
chronic hepatitis C treatment, but the studies are difficult to compare
because of the heterogeneity of treatment regimens, patient selection,
response evaluations, and follow-up [16]. Furthermore, they all had poor
statistical power because of their small sample sizes. The first studies of
the effects of IFN monotherapy showed the remission of symptoms in
the majority of patients, but this benefit was often transient and relapses
were very frequent after treatment discontinuation [17–34]. However,
the presence of cryoglobulinemia did not affect the response to IFN in
patients with chronic HCV infection [34–36]. It is also worth noting that
the regression of peripheral blood and bone marrow monoclonal B
lymphocytes was observed in the MCS patients who cleared HCV as a
result of IFN therapy [37].
In comparison with IFN monotherapy, IFN plus ribavirin (RBV)
improved viral eradication and the cure of symptoms [38–44].
However, only the patients who cleared the virus achieved a complete
and sustained clinical response [38,39,41–43]. Once again, the
presence of cryoglobulins did not affect the response to antiviral
treatment [39] and it was confirmed that antiviral therapy can induce
the disappearance of circulating B cell clones bearing the t(14;18)
translocation [45–47].
Over the last ten years, the development of pegylated IFN (Peg-IFN)
α-2a and α-2b, which have prolonged bioavailability and greater
antiviral efficacy than standard IFN, has opened up new opportunities
for the treatment of HCV-related chronic hepatitis and MCS [48–50].
Peg-IFN combined with ribavirin is now the standard of care for HCV
treatment and leads to 41–54% sustained viral responses (SVRs) in the
case of genotype 1, and approximately 80% in the case of genotypes 2
 M. Pietrogrande et al. / Autoimmunity Reviews 10 (2011) 444–454
and 3. SVR is defined as undetectable HCV viremia six months after the
completion of antiviral therapy [51].
There are only two pilot studies of the treatment of MCS with Peg-
IFN + RBV [52,53], although additional data can be gathered from a few
other studies in which both standard IFN and Peg-IFN were used [54,55].
Mazzaro et al. [52] studied 18 consecutive MCS patients treated with
Peg-IFN α-2b (1 μg/kg/week) and RBV (1000 mg/day) for 48 weeks,
after which 15 patients (83%) had undetectable HCV RNA levels, and
most of the patients showed a clinical improvement. At the end of the 6-
month follow-up period, only eight patients (44%) were sustained
clinical and virological responders, and cryoglobulins had disappeared
in six cases (33%). One major weakness of this study was the use of a
Peg-IFN dose that was lower than that usually recommended in HCV
therapeutic guidelines.
Cacoub et al. [53] studied nine consecutive MCS patients (78% with
HCV genotype 1) who received Peg-IFN α-2b (1.5 μg/kg/week) and
RBV (800–1200 mg/day) for a mean of 13.5 months (range of 10–26).
After a mean follow-up of 18.6 months (range of 6–33) following the
discontinuation of antiviral therapy, seven patients (78%) showed a
SVR and were complete clinical responders, and one a partial
virological and a complete clinical response.
The treatment was found to be safe and well tolerated in both of
these studies, which demonstrated that in HCV-associated MCS
combined Peg-IFN + RBV therapy leads to a SVR rate similar to that
of HCV-infected patients without MCS, and strongly suggested this
combination as the first-line treatment for MCS patients.
However, few patients occasionally show the persistence of
cryoglobulins or symptoms even after the clearance of HCV RNA
[56,57]. Furthermore, antiviral treatment is sometimes associated with
major immune-mediated adverse events, such as peripheral sensory-
motor neuropathy, thyroiditis, rheumatoid-like polyarthritis, and other
vasculitic manifestations [8,17,58–63]. Because of its immunomodula-
tory properties, IFN may precipitate or exacerbate some pre-existing
and often subclinical disorders. Unfortunately, there are no parameters
for predicting these complications [8], and so antiviral therapy should be
very carefully administered to patients with mixed cryoglobulinemia-
related peripheral neuropathy or active skin ulcers. Moreover, some
patients may have major contraindications to IFN and/or RBV, such as
advanced age, uncompensated cirrhosis, major uncontrolled depressive
illness, significant coronary heart disease, untreated thyroid disease
[51], which makes antiviral treatment inadvisable.
Finally, the slow and uncertain response to antiviral therapy means
that particularly severe and rapidly progressive MCS complications
(including nephrotic or acute nephritic syndrome, extensive cutaneous
ulcers, widespread vasculitis, and hyperviscosity syndrome) require
prompter and more aggressive treatment; in such settings, antiviral
therapy may be used after or concomitantly with more rapid,
immunosuppressive regimens [8,16,64–66]. In clinical practise, the
treatment of MCS should therefore be tailored to the individual patient
on the basis of the progression and severity of its clinical manifestations
[8,64,65].
RCTs with adequately sized populations and an appropriate
follow-up are needed to clarify whether higher virological or clinical
response rates can be obtained using different antiviral schedules,
such as longer treatment duration in virological non-responders
showing a clinical and laboratory improvement (up to 48 weeks in the
case of HCV genotypes 2 or 3, and 72 weeks in the case of HCV
genotypes 1 or 4).
On the basis of their answers to the questionnaire, almost all of the
conference participants use Peg-IFN + RBV in HCV-related MCS,
although infectious disease specialists, gastroenterologists and
hepatologists are more likely to use antiviral therapy than rheuma-
tologists. Nevertheless, all of the experts agreed to extend the current
standard of care for chronic HCV infection to MCS.
Given the risks associated with progressive MCS, many of the
participants also believe that MCS patients older than age limits
447
established by the international guidelines can receive IFN-based
treatment in the absence of other major contraindications.
3.2. Statements
• HCV RNA suppression is associated with an improvement or the
disappearance of the clinical and laboratory manifestations of HCV-
related mixed cryoglobulinemia syndrome (MCS). The achievement
of a sustained virological response (SVR) leads to a complete
recovery from all signs and symptoms of disease in the majority of
patients (3b C).
• In patients with HCV infection, the presence of MCS does not
substantially affect the rate of SVRs to combined pegylated
interferon and ribavirin therapy (4 C).
• An attempt at viral eradication should be considered a first-line
therapeutic option in patients with mild–moderate HCV-related
MCS in the absence of any major contraindication (4 C).
• The current guidelines for the treatment of chronic hepatitis C
should also be followed in the case of patients with HCV-related
MCS (1b A).
• An extended duration of treatment (up to 48 weeks for HCV
genotypes 2 or 3 and 72 weeks for HCV genotypes 1 or 4) may be
considered in the case of virological non-responders who show
clinical and laboratory improvements in MCS (5 D).
• The possible onset or worsening of some vasculitic manifestations
(e.g. peripheral neuropathy, skin ulcers, etc.) should be carefully
evaluated before starting treatment (5 D).
3.3. Biological therapy
Rituximab (RTX) and infliximab are the only two biological agents
that have been tested in MCS so far. RTX has led to encouraging results
in open studies and single case reports [67–93], whereas the initial
results obtained using infliximab were contrasting and did not
support its further use in MCS [94–96].
RTX is a monoclonal antibody against the CD20 antigen, which is
selectively expressed on B cells. CD20-positive cells are expanded and
activated in MCS, may harbour and present viral antigens, and play a
crucial pathogenetic role in cryoglobulin production. The rationale
underlying RTX treatment is to intervene downstream of the
triggering disease mechanism more selectively than when the
conventional immunosuppressive treatments are used [97].
It has been reported that RTX can improve or cure various clinical
manifestations of MCS, including fatigue, skin manifestations (purpura
and skin ulcers), arthralgias and arthritis, glomerulonephritis (GN) (in
about 90% of cases), peripheral neuropathy (in about 75% of cases) and
hyper-viscosity syndrome [67–93]. It has also been reported that it can
also be effective in some life-threatening cases of gastrointestinal
vasculitis [74,77]. GN responds to RTX within 1–6 months, more
frequently within the first three months. Skin ulcers usually improve
within three months, but complete healing requires a longer time
[67,68,70]. Both sensitive and motor neuropathy improve within 1–
5 months, with a stable or improved electromyography pic-
ture [67,68,70–72,89].
At the time of the final review of our statements (October 2010),
there were more than 150 published cases of MCS treated with RTX,
most of which came from uncontrolled studies or single case reports.
A recent multicentre RCT involving MCS patients who had failed or
were not eligible for antiviral therapy compared RTX monotherapy (at
the dose recommended in rheumatoid arthritis, i.e., 1 g every two weeks
for a total of two infusions, with or without low-dose steroids) with the
best conventional immunosuppressive treatment (corticosteroids,
cyclophosphamide, azathioprine or plasma exchange, as chosen by the
clinician) and the standard dose of RTX (375 mg/m2 in four weekly
infusions) used in most published MCS cases. The preliminary results of
the trial supported the superiority of RTX [98].
448 M. Pietrogrande et al. / Autoimmunity Reviews 10 (2011) 444–454
B cell depletion has occurred in the vast majority of MCS patients
receiving RTX. It has also been reported that RTX decreases serum
cryoglobulin and rheumatoid factor levels (although their disappearance
is less frequent), and increases C4 levels. The activity of RTX is also
supported by the restoration of some MCS-related immune abnormalities
[99], and the disappearance of bone marrow B cell clonal expansion
[100,101].
The duration of the response to RTX is difficult to define because
most of the studies lack long-term follow-up data. However, while
bearing in mind this limitation, it is worth noting that short-term
relapses (within 3–4 months of RTX discontinuation) have been
observed in a minority of patients, and long-term responses (more
than one year) have been the most frequent outcome. In some cases,
more intense induction regimens or maintenance regimens have been
attempted [69,71,73,74] Retreatment with RTX after a disease relapse
has proved to be effective in most cases [67,70,71,74,78,79].
Maintenance RTX therapy has rarely been described in patients with
MCS, but may be considered in those with severe nephritis or
abdominal vasculitis [71,73,74].
Interestingly, RTX has a steroid-sparing effect in patients with MCS
[67], some of whom (including cases with active nephritis) could be
treated without steroids ab initio or with only short glucocorticosteroids
courses [71,98].
Some authors suggest that naïve patients with serious clinical
manifestations may receive RTX before antiviral therapy, which can
be introduced later after the efficacy and safety of RTX have been
assessed [97]. This advice is based on the observation of continuing
MCS-related symptoms in patients with persistently negative serum
HCV RNA findings [57,102], which suggests that an autoimmune
process can become independent of viral triggering and play a
predominant role in the pathogenesis of the disease.
Short-term reactions to RTX infusions do not seem to be any more
frequent in MCS than in rheumatoid arthritis (RA), systemic lupus
erythematosus (SLE) or Sjogren's syndrome (SS). Serum sickness was
never observed in most studies and appeared to be rarely reported
(about 1% in pooling data), even with high RTX doses [80,98]. A French
Group, however, reported a higher incidence of serum sickness (about
10%), though stating that RTX is overall well tolerated in MCS [103].
Therefore, patients should be carefully monitored, in particular
when high cryocrit levels are present. Pre-medication with 100 mg of
methylprednisolone, anti-histamine drugs and paracetamol may
reduce the risk of such reactions [104]. In patients with a history of
heart failure or arrhythmia, consideration can be given to the
administration of half a dose per day on two consecutive days and/
or to prolonging the administration of each infusion.
RTX can increase HCV viral load, generally without significant liver
impairment or serum albumin decrease [67,68,70,75]. At the time of
submission of this paper, there were no data supporting a substantial
risk of liver toxicity directly caused by RTX or HCV reactivation,
although there is a lack of long-term follow-up data. Moreover, RTX
has been given to MCS patients with liver cirrhosis and led to an
improvement in MCS symptoms and liver function despite a transient
increase in serum HCV RNA [86,93].
RTX may induce the severe reactivation of hepatitis B virus (HBV)
infection and so, regardless of the presence of HBV DNA, should only
be used in HBsAg-positive patients when strictly needed, and in
combination with antiviral therapy. The same policy should be
adopted in the case of potential occult HBV carriers (HBsAg-
negative/anti-HBc-positive patients) [105].
Severe infections (lethal disseminated cryptococcosis and severe
bacterial pneumonia) have been reported after RTX administration in
two severely immunocompromised renal transplant recipients with
type III cyoglobulin-related graft dysfunction [73,106]. On the contrary,
no life-threatening infections have been reported in patients with
typical HCV-related MCS. Progressive multifocal leukoencefalopathy has
been never reported in MCS after rituximab therapy. However, it must
be remembered that the published reports have rarely provided long-
term follow-up data.
The conference participants concluded that special care should
be given to the prevention and management of infections, par-
ticularly in patients previously treated with immunosuppressants
or steroids, or those with low serum immunoglobulin levels. De
novo hypo-gammaglobulinemia [76], panniculitis [67], neutropenia
[67,71,75,101] and retinal vascular occlusion [67,68] have been
rarely reported as side effects of RTX treatment for MCS. The
administration of aspirin has been proposed in the case of patients
at cardiovascular risk [67] or with GN [69].
Direct experience of the use of RTX for patients with MCS was
reported by about 70% of the conference participants.
It has been hypothesised that the combination of antiviral and RTX
therapy has a synergistic effect. Retrospective data and case reports
have been published by French and Italian Authors [65,66,75,97].
Two very recent studies have compared combined therapy with
antiviral treatment alone. A prospective, non-randomised cohort
study of 93 patients found that combined therapy reduced the time
to clinical remission (5.4 ± 4 versus 8.4 ± 4.7 months; P = 0.004),
improved renal response rates (but not those of other organic
manifestations), and led to higher rates of cryoglobulin clearance
and clonal VH1-69+ B cell suppression than Peg-IFN + RBV alone
[107]. The authors concluded that the combined therapy is well
tolerated and more effective than antiviral therapy alone. Similar
results were achieved by the second study, which involved 37 patients
[108].
However, none of these studies was designed to define the best
first-line treatment in MCS and the advantages of combined therapy
versus RTX monotherapy have never been investigated up to now in
randomised trials. Some of the experts participating in the conference
prefer the sequential treatment option (starting with RTX or antiviral
therapy depending on the condition of the patient), and others
favoured combination therapy ab initio. Nevertheless, all agreed that
further investigations are required.
3.4. Statements
• Rituximab (RTX) is the only biological therapy that has proved to be
beneficial in MCS, and should be considered when treating patients
with severe clinical manifestations such as glomerulonephritis, skin
ulcers or peripheral neuropathy (3 C).
• In the same clinical situations, RTX should be preferred over other more
conventional treatments such as glucocorticoids, immunosuppressants
or apheresis (3 C).
• In the same clinical situations, RTX may significantly reduce
glucocorticoids administration (3 C).
• The monitoring of RTX infusion reactions should follow the
guidelines used in the other clinical situations in which the drug
is used (5 C).
• Patients receiving RTX should be carefully monitored for infectious
complications, especially those with severe immunodepression (5 C).
• HCV viral load and liver function should be carefully monitored in
patients receiving RTX, and antiviral prophylaxis should be given to
HBV carriers (5 C) statements.
• Rituximab may be used in combination with antivirals in some cases
of MCS (4 B).
3.5. Glucocorticoids
Glucocorticoids (GCs) are widely used to treat systemic vasculitis
and, in the critical manifestation of MCS, have been prescribed at high
doses (1–10 mg/kg) or as pulse therapy. Data from small case series
support the effectiveness of high-dose pulse therapy in controlling
disease flares [109–112]. The answers to our questionnaire indicated
that high-dose pulse therapy is used by 94.7% of GISC centres, in the
 M. Pietrogrande et al. / Autoimmunity Reviews 10 (2011) 444–454
majority of cases for one single cycle and to treat a critical condition
(renal, neurological or hyperviscosity syndromes).
The long-term administration of low–medium GC doses (0.1–
0.5 mg/kg/day) is widely used in clinical practise, but the results of
small controlled studies are conflicting [111–114]. Moreover, no studies
have evaluated the effectiveness of long-term GC administration,
although it is well known that the side effects of long-lasting steroid
therapy can be very serious and irreversible. All of the GISC centres
reported the use of low (0.1–0.5 mg/kg/day) or intermediate GC doses
(0.5–2 mg/kg/day) to control vasculitis symptoms or pain in MCS
patients: only occasionally and for short courses in 32%, and with
treatment limited to a few weeks in a further 18%, but 36% have
prescribed chronic treatments for more than one year.
GCs are frequently used in combination with other drugs [109–
116], and a RCT comparing INF with combined IFN and steroid
treatment found that the combination led to better results [111].
The consensus panel concluded that high-dose GC pulse therapy is
useful during MCS flares but, although there is considerable clinical
experience of the use of low steroid doses, there are few data from
controlled studies and therapeutic efficacy is controversial. Moreover,
the side effects of long-lasting steroid therapy can be serious and
irreversible, and careful patient monitoring is recommended to
prevent them.
3.6. Statements
• High-dose or pulsed glucocorticoid (GC) therapy plays a substantial
role in the management of critical patients with renal or neurological
complications or serious vasculitic manifestations (4 C).
• The use of low–intermediate GC doses (0.1–0.5 mg/kg/day) has
proved ineffective (1b A), but it has been reported that they
improve the results of IFN therapy (1b A).
• In the opinion of some experts, short courses (weeks) of low–
intermediate GC doses might be considered to control vasculitic
flares in patients who do not respond or who are refractory to other
treatments (5 D).
• Chronic treatment with low GC doses should be avoided whenever
possible and in any case carefully monitored. Alternative therapies
(colchicine, a low-antigen-content diet) should be considered for
the maintenance treatment of MCS (5 D).
3.7. Apheresis
Many different apheretic procedures have been used to treat
various clinical situations associated with MCS but, in the absence of
controlled trials and large cohort studies, the available data comes only
from case reports [109,117–132]. Most of these date back to before the
association of HCV and MCS was recognised, and apheretic methods
used were significantly different. A number of observations support
the role of apheresis in improving acute renal disease [118–120] and in
treating neuritis [115,118] and ulcers [109,132]. Furthermore, it
remains the first-choice treatment for cryoglobulinemic hyper-
viscosity syndrome despite the lack of RCT data, which are obviously
difficult to obtain in this rare and dramatic condition. The use of
combined apheresis and immunosuppressants is supported by some
clinical reports [124–129], but the majority of conference participants
suggested great caution in using these drugs, which should be avoided
in the case of HBV-infected patients.
There is some evidence that apheresis synchronised with the
intravenous administration of high-dose immunoglobulins can be
used to treat ulcers and MC-related peripheral neuropathy, but this
may also have a considerable immunosuppressive effect [132].
Apheresis is used in 84% of GISC centres, the majority of them
(87%) using it in combination with cytotoxic drugs; 53% of the centres
accept treatments lasting for more than three months. Almost all of
449
the centres reserve its use to the treatment of critical complications
(renal or neurological impairment, or hyper-viscosity syndrome).
Plasma exchange and double filtration are considered the best
apheretic approaches [119,132], with many experts preferring plasma
exchange in the case of life-threatening complications. There was no
agreement among the experts concerning treatment intensity,
duration or frequency.
3.8. Statements
• Apheresis (usually combined with other treatments) can be used in
the case of severe, life-threatening cryoglobulinemic manifestations (4
C), and is the treatment of choice for hyper-viscosity syndrome (5 B).
• Apheresis can be used to treat severe cryoglobulinemic manifestations
when other therapies have failed or cannot be used (4 C).
• Apheresis should be used very cautiously in patients with severe
HCV liver disease (5 D), and the evolution of HCV or HBV infection
should be carefully monitored after apheresis, particular when it has
been combined with immunosuppressants (5 D).
3.9. Cyclophosphamide
Cyclophosphamide (CTX) is the cytotoxic drug that is most
frequently used in MCS patients [121–129] but, as it is usually used
in combination with apheresis or other drugs, it is often impossible to
distinguish its specific effects. Moreover, most of the available data
was collected before it was discovered that HCV is a major determinant
of MCS and the risk of using CTX in HCV-infected patients is poorly
defined. The rationale underlying the use of CTX to treat MCS seems to
be that of obtaining temporary immunosuppression after acute
apheretic treatment, but there are no data from large cohort studies
or RCTs to support this. Our systematic search of the literature revealed
only small case series [121–129] in which CTX has been mainly
considered in the case of membrano-proliferative GN or severe
polyneuropathy. The use of an intravenous CTX bolus is believed to
be safer than oral administration as it reduces the cumulative dose
[133].
Almost all of the GISC centres use CTX in combination with
apheresis. HCV infection and liver function should be carefully
monitored after the administration of CTX.
The use of other immunosuppressants such as cyclosporine,
azathioprine, and methotrexate to treat MCS was only anecdotal
and could not be evaluated because of the lack of data.
3.10. Statements
• Despite some observations of improvements in renal function and
purpura after cyclophosphamide (CTX) treatment, the use of CTX
alone to treat MCS is not recommended. However, its combined use
with apheresis can be considered in the case of serious MCS-related
conditions, when other therapeutic approaches fail or are contra-
indicated (4 C).
• CTX increases plasma HCV RNA levels (4 C) and the effects of CTX on
liver function should be strictly monitored.
3.11. Colchicine
The rationale underlying the use of colchicine to treat MCS is based
on the drug's activity in reducing Ig secretion [134,135]. A controlled,
retrospective study of 17 patients treated with colchicine 1 mg/day for
6–48 months showed that it had favourable effects on purpura,
weakness, leg ulcers and MCS-related laboratory abnormalities. Mild
to substantial gastrointestinal side effects may occur during the first
days/weeks of therapy, and prolonged treatment can cause haemato-
logical abnormalities [134].
450 M. Pietrogrande et al. / Autoimmunity Reviews 10 (2011) 444–454
Colchicine is prescribed for symptomatic patients in 56% of GISC
centres, 44% of which currently prescribe treatments lasting 2–3 years,
stopping only when side effects appear or the patients enter stable
remission. In the experts' opinion, colchicine seems to be safe and
effective in controlling the symptoms of patients with mild MCS and, in
such cases, can also be considered as a means of sparing steroid
therapy when other treatments can not be administered.
3.12. Statements
• Purpura and pain can be improved by administering colchicine
1 mg/day for at least six months (4 C).
• Long-term treatment may maintain the effect and reduce glucocorticoid
consumption (3b B).
3.13. Low-antigen-content diet
A low-antigen-content (LAC) diet can improve phagocyte activity
and modify the composition of immune complexes. MCS patients who
strictly follow such a diet experience a significant reduction in
symptoms within 4–8 weeks [136,137]. A chronic LAC diet has a
steroid sparing effect, reduces purpura and pain, is not expensive, and
does not cause adverse effects; [138] however, some patients are not
completely compliant or are unable to change their eating habits [116].
A LAC diet is currently used in 74% of GISC centres, 57% of which
limit its use to symptomatic patients, 78% prescribe it for as long as
possible (without any pre-defined limit), and 43% continue its
prescription during MCS flares.
3.14. Statements
• A low-antigen-content (LAC) diet improves MCS symptoms and
laboratory abnormalities when strictly followed for 4–8 weeks (1b A).
• A LAC diet can be considered as supportive treatment in all
symptomatic MC patients (3b B).
3.15. Analgesic and non-steroidal anti-inflammatory drugs
Pain is one of the major symptoms of MCS, and often severely
limits the patients' quality of life. Interventions aimed at controlling
pain are frequently necessary, even when patients are undergoing a
LAC diet or receiving antiviral therapy or colchicine. No published data
are available concerning the use of analgesics or non-steroidal anti-
inflammatory drugs (NSAIDs) in patients with MCS.
Among the potentially useful drugs controlling pain, the participating
centres currently use gabapentin or pregabalin (87% of cases),
acetaminophen (62%), opioids (31%), NSAIDs (31%), amitriptyline
(25%), and benzodiazepines (12%), with the treatment for each patient
being tailored on the basis of the physician's approach. The experts
participating in the conference agreed to suggest acetaminophen as the
first-choice analgesic. Combined analgesic treatments seem to be
necessary in patients with severe pain associated with peripheral
neuropathy.
3.16. Statements
• Interventions aimed at controlling any pain in MCS patients should
be attempted even during the administration of ‘etiological’
treatments (5 C).
• In the absence of controlled studies, the management of pain in MCS
patients should be individually tailored and based on the drugs that
have proved to be effective in controlling pain due to other
vasculitides and neuropathies (5 C.)
The consensus recommendations are summarised in Table 1.
4. Discussion
The complexity of the etiopathogenesis of MCS and its polymorphic
clinical manifestations make its treatment particularly challenging. Our
Consensus Conference specifically focused on current strategies for
treating MSC ‘as a whole’, leaving discussion of the management of its
particular manifestations, such as skin ulcers, peripheral neuropathy,
and GN to future projects. The relatively rare HCV-negative MCS and the
monoclonal cryoglobulinemias (type I cryoglobulinemias in the
immunochemical classification of Brouet et al.) [139] were also
excluded as they presumably have a different pathogenesis from that
of HCV-related MCS.
The main limitation of the conference (but also the most important
reason for holding it) was the scarcity of data from controlled trials of
MCS treatment. However, the available data concerning the patho-
genesis of the syndrome could be used as a reference to make some
treatment suggestions when there were few or no clinical data.
It was widely agreed that, regardless of the severity of MCS, an
attempt to eradicate HCV should be made whenever possible because
suppressing viral replication may limit or (in the most favourable
cases) arrest the immunopathogenic process triggered by HCV
[37,45–47,52–54]. Although the current guidelines for the treatment
of chronic hepatitis C do not contraindicate antiviral treatment in
patients with normal ALT and/or serum cryoglobulin levels, the
percentage of MCS patients receiving antiviral treatment remains
relatively low, regardless of the virus genotype, and depending on the
specialisation of the caring centre. The lack of studies assessing the
long-term results and side effects of antiviral treatment for MSC, or
the best therapeutic schedule, may reduce the chances of its use,
particularly in patients with mild–moderate liver disease.
In clinical practise, the treatment of HCV-related MCS should be
tailored to each individual patient on the basis of the progression and
severity of the clinical manifestations. RCTs with an adequate
statistical power and appropriate follow-up are required to clarify
whether better response rates can be obtained by extending treatment
duration in virological non-responders who show clinical and
laboratory improvements after a standard course of Peg-IFN + RBV.
Given the complete absence of data concerning the use of HCV
polymerase or protease inhibitors in patients with MCS, no recommen-
dations could be included in this paper. It is conceivable that trials of
these drugs in MCS patients will be proposed in the near future.
RTX treatment is proposed for patients with severe MCS, i.e. with
active GN, skin ulcers, or worsening/refractory peripheral neuropathy
[67–93]. A number of important papers on the use of this drug have been
very recently published [66,88–93,108], but the clinical criteria for its use
in MCS patients, as well as its optimal positioning in relation to antiviral
therapy, need to be better defined. Preliminary data from the first long-
term, multicentre, RCT comparing RTX monotherapy with conventional
immunosuppressive treatment encouraged the use of RTX in patients
not responding to or ineligible for antiviral therapy [98]. In our experts'
opinion, high-dose glucocorticoid therapy can be administered together
with RTX, but should be tapered and discontinued as soon as possible.
The steroid-sparing effect of RTX has been highlighted [98] and is a very
important question that deserves further investigation.
There is a rationale for combining RTX and antiviral therapy, but the
advantages must be thoroughly investigated. Many other questions
concerning the use of RTX in MCS patients remain open, including its
long-term effects on liver function and immune response, response
duration, re-treatment, and possible maintenance strategies, particu-
larly in the case of severe, life-threatening manifestations.
There was general agreement concerning the use of high-dose and
pulsed GC therapy during MCS flares, when the severity of the clinical
picture requires emergency intervention. On the contrary, the benefit of
the chronic administration of low–medium doses was one of the most
debated issues: the effectiveness of this treatment is questioned, and there
is some evidence from controlled studies against its use. Moreover, the age
 M. Pietrogrande et al. / Autoimmunity Reviews 10 (2011) 444–454
Table 1
Consensus recommendations for the treatment of HCV-related MCS.
Disease stage Treatment
All patients Peg-IFN + RBV; consider LAC diet
Patients with serious complications RTX; consider the association of high-dose or
(i.e. GN, neuropathy, skin ulcers) pulsed GC therapy
Apheresis
High-dose GC
CTX
Patients with life-threatening conditions Apheresis
High-dose GC
CXT
Patients with mild–moderate symptoms, Consider colchicine
non-responders, or those with contraindications Consider RTX in rapidly deteriorating situations
to antiviral treatment
Chronic pain Consider gabapentin or pregabalin,
acetaminophen, NSAIDs, amitriptyline, opioids
Peg-IFN: pegylated interferon; RBV: ribavirin; RTX: rituximab; GC: glucocorticoids; CTX: cyclophosphamide; NSAIDs: non-steroidal anti-inflammatory drugs. See text for dosages
and treatment duration.
of many patients, the frequent presence of co-morbidities, concomitant
chronic HCV infection, and the risk of other infections are all significant
caveats. However, as shown by the responses to the questionnaire, this
therapeutic approach has been and is still widely used in GISC centres,
particularly in the case of patients with mild–moderate MCS, and when
IFN or RTX therapy are considered too hazardous. Nevertheless, the
majority of the participating experts thought that the long-term
administration of low–medium GC doses should be discouraged for its
side effects.
Colchicine may be an alternative for patients who have failed on, or
could not be treated with antivirals or RTX. However, although it is
quite widely use in GISC centres, most of the available data are
anecdotal and little is known about the long-term side effects.
Apheresis (with or without CTX) should be restricted to life-
threatening situations in which the other therapeutic approaches
have failed or could not be used.
A LAC diet is safe and inexpensive, and can be considered in all
cases of MCS. Its only limitation is patient compliance, which may be
insufficient.
Finally, the conference strongly recommended the need to manage
pain, which often greatly affects the quality of life of MCS patients.
Unfortunately, this aspect has not yet been considered in any
controlled trial.
In conclusion, recent findings concerning the pathogenesis of MCS
and the current availability of new drugs have significantly increased
the possibility of treating MCS, and there is a possibility that other
new drugs might improve treatment further in the near future.
However, there is still a lack of RCT, and so physicians must still tailor
individual treatments and make choices that are not always based on
solid data. In the meantime, we hope that the recommendations made
in this paper will help to support medical decision making.
Take-home messages
• Mixed cryoglobulins (MCs) are immune complexes that can precip-
itate at temperatures below 37 °C associated with acute and chronic
infections, lymphoproliferative disorders, and autoimmune diseases.
• The treatment is still largely empirical, but the rational therapeutic
approach should have three main objectives — to eradicate HCV; to
limit or suppress B lymphocyte proliferation; and to contain and
symptomatically treat the vasculitis and reduce the damage caused
by circulating immune complexes.
451
Notes
Antiviral therapy according to guidelines for HCV infections;
consider prolonged treatments (up to 18 months).
New MCS-related symptoms and IFN/RBV side effects should
be carefully monitored.
RTX can precede antiviral therapy in cases with serious
complication and is more effective than conventional
immunosuppressive treatments.
Careful monitoring of RTX side effects and liver function is mandatory.
Consider in non-responders to RTX. Apheresis is the elective treatment
for hyper-viscosity syndrome.
Consider RTX
Long-term use of low–medium dose of GC is discouraged.
A new treatment with Peg-IFN + RBV could be considered in
relapsed patients.
No data from controlled trials.
Treatment should be tailored to the individual patient.
• The GISC board organised the conference that is focused on what is
known about the drugs used to treat MCS, and formulated the
statements and the recommendations by combining the best
available evidence from the literature with the experts' opinion.
• In clinical practise, the treatment of HCV-related MCS should be
tailored to each individual patient on the basis of the progression
and severity of the clinical manifestations.
• All of the conference participants use pegylated interferon +
ribavirin in HCV-related MCS, although infectious disease specia-
lists, gastroenterologists and hepatologists are more likely to use
antiviral therapy than rheumatologists. Nevertheless, all of the
experts agreed to extend the current standard of care for chronic
HCV infection to MCS.
• Rituximab treatment is proposed for patients with severe MCS,
i.e. with active glomerulonephritis, skin ulcers, or worsening/
refractory peripheral neuropathy.
• There is a rationale for combining rituximab and antiviral therapy,
but the advantages must be thoroughly investigated.
• Long-term administration of low–medium corticosteroid doses
should be discouraged for its side effects.
• Colchicine may be an alternative for patients who have failed on, or
could not be treated with antivirals or rituximab.
• Apheresis (with or without cyclophosphamide) should be restricted
to life-threatening situations in which the other therapeutic
approaches have failed or could not be used.
• A low-antigen-content diet is safe and inexpensive, and can be
considered in all cases of MCS.
• To manage pain, which often greatly affects the quality of life of MCS
patients, is strongly recommended.
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Targeting the complement system: still a pathway to walk in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by a frequent neuropsychiatric involvement, occurring in 14-
75% of patients, the so-called neuropsychiatric (NP) SLE.
Several pathogenic mechanisms have been called in the condition, including those involving matrix-metalloproteinase 9, pro-inflammatory
cytokines, vascular abnormalities, neuropeptides, medications, and primary neurologic and psychiatric disorders.
The condition is associated with increased mortality and elucidating the exact underlying mechanism causing the CNS pathology may bring
to great improvement in the prognosis of SLE patients.
The complement system is an essential component of innate immunity but also plays an important role in modulating adaptive immunity. Its
activation contributes to the pathogenesis of several autoimmune and inflammatory conditions, as well as it seems to contribute to increased
or sustained inflammation and damage in SLE.
The activation of the complement system brings to the generation of the anaphylatoxins C3a and C5a, which levels seem to correlate with
CNS disease in SLE patients. The binding of these molecules to their receptors, C3aR and C5aR respectively, exacerbates inflammation and
apoptosis, key events in experimental lupus brain.
Apoptosis observed in MRL/lpr mice can be regulated through different pathways, such as the PI3K/Akt pathway and its negative modulator,
phosphatase and tensin homolog deleted on chromosome ten (PTEN). This event leads to the formation of potentially pathogenic molecules
such as IL-1β, RANTES, MCP-1 and MIP-2 that can mediate CNS functioning and play a role in NPSLE.
It was showed in experimental mice models, the MRL/lpr mice, that complement inhibition by the upstream complement regulator, Crry, an
inhibitor of the convertases, or by the absence of factor B, a ‘key’ protein of the alternative pathway, significantly alleviates CNS disease.
Recently, Jacob and colleagues (Lupus. 2010;19:73–82) explored the role of C3a/C3aR signaling on these variables. To determine the role of
C3aR in CNS lupus, the authors treated thirteen MRL/lpr mice with the selective non-peptide antagonist of C3aR, C3aRa from the time of
clinical onset of disease at 13 weeks of age to the time of LD50 at 19 weeks. They found that C3aR mRNA and protein expression results up
regulated in brains of MRL/lpr mice. DNA laddering showed a reduction of apoptosis after treatment, with reduced activity of TUNEL staining
and caspase3. The mRNA expression of other proinflammatory molecules that cause apoptosis, such as TNFα, MIP2, and INFγ resulted
reduced as well. The phosphorylation of the survival molecules Akt and Erk was increased with decrease in PTEN and reduced iNOS
expression. Thus, complement demonstrated its potential in in causing neurodegeneration in SLE, especially through the C3a/C3aR signaling
pathway. The prevention of the generation of anaphylatoxins and other downstream products could represent a valid therapeutic alternative
in the treatment of human NPSLE. Further studies are warranted in the field.
Carlo Perricone, M.D.