Sei sulla pagina 1di 12

ARTHRITIS & RHEUMATISM

Vol. 60, No. 11, November 2009, pp 34133424


DOI 10.1002/art.24876
2009, American College of Rheumatology
Classification, Presentation, and Initial Treatment of
Wegeners Granulomatosis in Childhood
David A. Cabral,
1
Ame rica G. Uribe,
1
Susanne Benseler,
2
Kathleen M. ONeil,
3
Philip J. Hashkes,
4
Gloria Higgins,
5
Andrew S. Zeft,
6
Daniel J. Lovell,
7
Daniel J. Kingsbury,
8
Anne Stevens,
9
Deborah McCurdy,
10
Peter Chira,
11
Leslie Abramson,
12
Thaschawee Arkachaisri,
13
Sarah Campillo,
14
Anne Eberhard,
15
Aimee O. Hersh,
16
Adam M. Huber,
17
Susan Kim,
18
Marisa Klein-Gitelman,
19
Deborah M. Levy,
20
Suzanne C. Li,
21
Thomas Mason,
22
Esi Morgan DeWitt,
23
Eyal Muscal,
24
Lorien Nassi,
25
Andreas Reiff,
26
Kenneth Schikler,
27
Nora G. Singer,
28
Dawn Wahezi,
29
and Amy Woodward,
30
for the ARChiVe (A Registry for Childhood Vasculitis: e-entry) Investigators Network
Objective. To compare the criteria for Wegeners
granulomatosis (WG) of the American College of Rheu-
matology (ACR) with those of the European League
Against Rheumatism/Pediatric Rheumatology Euro-
pean Society (EULAR/PRES) in a cohort of children
with WG and other antineutrophil cytoplasmic antibody
(ANCA)associated vasculitides (AAVs), and to de-
scribe the interval to diagnosis, presenting features, and
initial treatment for WG.
Methods. Eligible patients had been diagnosed by
site rheumatologists (termed the MD diagnosis) since
2004. This diagnosis was used as a reference standard
for sensitivity and specificity testing of the 2 WG
classification criteria. Descriptive analyses were con-
fined to ACR-classified WG patients.
Results. MD diagnoses of 117 patients (82 of
whom were female) were WG (n 76), microscopic
polyangiitis (n 17), ANCA-positive pauci-immune
glomerulonephritis (n 5), Churg-Strauss syndrome
(n 2), and unclassified vasculitis (n 17). The
sensitivities of the ACR and EULAR/PRES classifica-
tion criteria for WG among the spectrum of AAVs were
The initial feasibility study was supported by the Vasculitis
Foundation (formerly known as the Wegeners Granulomatosis Asso-
ciation), and early registry implementation was supported by a British
Columbia Childrens Hospital Foundation Telethon Grant.
1
David A. Cabral, MBBS, Ame rica G. Uribe, MD: British
Columbia Childrens Hospital, Vancouver, British Columbia, Canada;
2
Susanne Benseler, MD: Hospital for Sick Children, Toronto, Ontario,
Canada;
3
Kathleen M. ONeil, MD: University of Oklahoma Health
Sciences Center, Oklahoma City;
4
Philip J. Hashkes, MD, MSc:
Cleveland Clinic Foundation, Cleveland, Ohio;
5
Gloria Higgins, MD:
Nationwide Childrens Hospital, Columbus, Ohio;
6
Andrew S. Zeft,
MD: University of Utah Primary Childrens Medical Center, Salt Lake
City;
7
Daniel J. Lovell, MD, MPH: Cincinnati Childrens Hospital
Medical Center, Cincinnati, Ohio;
8
Daniel J. Kingsbury, MD: Legacy
Emanuel Childrens Hospital, Portland, Oregon;
9
Anne Stevens, MD:
Seattle Childrens Hospital, Seattle, Washington;
10
Deborah Mc-
Curdy, MD: University of California, Los Angeles;
11
Peter Chira, MD,
MS: Lucile Packard Childrens Hospital, Stanford University School of
Medicine, Stanford, California;
12
Leslie Abramson, MD: University of
Vermont, Burlington;
13
Thaschawee Arkachaisri, MD: Childrens
Hospital of Pittsburgh, Pittsburgh, Pennsylvania;
14
Sarah Campillo,
MD: The Montreal Childrens Hospital, McGill University Health
Centre, Montreal, Quebec, Canada;
15
Anne Eberhard, MD: Schneider
Childrens Hospital, New York, New York;
16
Aimee O. Hersh, MD:
University of California, San Francisco;
17
Adam M. Huber, MD, MSc:
IWK Health Centre, and Dalhousie University, Halifax, Nova Scotia,
Canada;
18
Susan Kim, MD: Childrens Hospital of Boston, Boston,
Massachusetts;
19
Marisa Klein-Gitelman, MD: Childrens Memorial
Hospital, Chicago, Illinois;
20
Deborah M. Levy, MD, MS: New York
Presbyterian Morgan Stanley Childrens Hospital, New York, New
York;
21
Suzanne C. Li, MD, PhD: Joseph M. Sanzari Childrens
Hospital, Hackensack University Medical Center, Hackensack, New
Jersey;
22
Thomas Mason, MD: Mayo Eugenio Litta Childrens Hospi-
tal, Mayo Clinic, Rochester, Minnesota;
23
Esi Morgan DeWitt, MD,
MSCE: Duke Childrens Hospital and Health Center, Duke University
Medical Center, Durham, North Carolina;
24
Eyal Muscal, MD: Texas
Childrens Hospital, Baylor College of Medicine, Houston;
25
Lorien
Nassi, MD: Texas Scottish Rite Hospital, University of Texas South-
western, Dallas;
26
Andreas Reiff, MD: Childrens Hospital Los Ange-
les, Los Angeles, California;
27
Kenneth Schikler, MD: University of
Louisville Health Sciences Center, Louisville, Kentucky;
28
Nora G.
Singer, MD: Case Medical Center, and Rainbow Babies and Childrens
Hospital University Hospitals, Cleveland, Ohio;
29
Dawn Wahezi, MD:
Childrens Hospital at Montefiore, Bronx, New York;
30
Amy Wood-
ward, MD, MPH: Riley Childrens Hospital, Indianapolis, Indiana.
Address correspondence and reprint requests to David A.
Cabral, MBBS, Division of Rheumatology, Room K4-121, British
Columbia Childrens Hospital, Vancouver, BC V6H 3V4, Canada.
E-mail: dcabral@cw.bc.ca.
Submitted for publication January 2, 2009; accepted in re-
vised form July 11, 2009.
3413
68.4% and 73.6%, respectively, and the specificities were
68.3% and 73.2%, respectively. Two more children were
identified as having WG by the EULAR/PRES criteria
than by the ACR criteria. For the 65 ACR-classified WG
patients, the median age at diagnosis was 14.2 years
(range 417 years), and the median interval from symp-
tom onset to diagnosis was 2.7 months (range 049
months). The most frequent presenting features by
organ system were constitutional (89.2%), pulmonary
(80.0%), ear, nose, and throat (80.0%), and renal
(75.4%). Fifty-four patients (83.1%) commenced treat-
ment with the combination of corticosteroids and cyclo-
phosphamide, with widely varying regimens; the re-
mainder received methotrexate alone (n 1),
corticosteroids alone (n 4), or a combination (n 6).
Conclusion. The EULAR/PRES criteria mini-
mally improved diagnostic sensitivity and specificity for
WG among a narrow spectrum of children with AAVs.
Diagnostic delays may result from poor characterization
of childhood WG. Initial therapy varied considerably
among participating centers.
Primary systemic vasculitis (PSV) of childhood
encompasses a group of rare conditions that have in
common primary vascular inflammation, often in critical
organs such as the heart, kidneys, lungs, and brain (1).
They are acutely and chronically life-threatening and
have high associated disease- and treatment-related
morbidity. Childhood PSV affects fewer than 25 per
100,000 children, with the acute subtypes including
Henoch-Schonlein purpura and Kawasaki disease ac-
counting for the majority of cases (2). The frequencies of
the distinct subtypes of chronic childhood PSV are
difficult to ascertain. Among the chronic childhood
primary systemic vasculitides, Wegeners granulomatosis
(WG) is one of the most common, with incidence rates
ranging between 0.03 and 3.2 per 100,000 children per
year (13). Chronic childhood PSV is the diagnosis
assigned to 3% of all patient referrals in some US
pediatric rheumatology clinics (4), and individual US/
Canadian pediatric rheumatologists will typically see 05
new patients per year (5). Consequently, most of our
knowledge about the presentation, course, outcome, and
optimal treatment of childhood PSV either comes from
a few small case series or has been adapted from studies
of adults, without validation of its true applicability to
children.
Between one-third and two-thirds of children
with chronic PSV are described as having unclassified
vasculitis (3,4), and one-third of children with WG
diagnosed by expert opinion (6) never fulfill the Amer-
ican College of Rheumatology (ACR) 1990 classification
criteria (7). It is not known whether these described
difficulties in assigning a specific classification are
related to the fact that the ACR 1990 criteria for the
classification of vasculitis (8) and the subsequent Chapel
Hill Consensus Conference (CHCC) disease definitions
(9) were based largely on adult data, or whether they
result from the fact that children with a developing
immune system have a modified disease expression. The
difficulties described for adult populations in distin-
guishing between the so-called antineutrophil cyto-
plasmic antibody (ANCA)associated vasculitides
(AAVs) (10), including WG, microscopic polyangiitis
(MPA), and Churg-Strauss syndrome (CSS), have not
been addressed in the limited pediatric reports of child-
hood PSV.
In 2005, under the auspices of the European
League Against Rheumatism (EULAR) and the Pediat-
ric Rheumatology European Society (PRES), existing
ACR criteria were modified with a view to improving
their applicability in children (11). The resulting pro-
posed system of classification and criteria (EULAR/
PRES criteria) have yet to be validated in a cohort of
children with vasculitis, and specifically, it is not known
whether the EULAR/PRES criteria for classifying WG
in children will capture additional children diagnosed
as having WG but not fulfilling ACR criteria, children
with other diagnostic subsets of AAV, or children with
previously unclassified chronic PSV.
In the context of establishing a network of pedi-
atric investigators interested in advancing our knowl-
edge about childhood PSV, we undertook a pilot, mul-
ticenter, contemporary inception cohort project called
ARChiVe (A Registry for Childhood Vasculitis:
e-entry) in collaboration with members of the Childhood
Arthritis and Rheumatology Research Alliance
(CARRA). This project initially focused on children
with WG together with other AAVs including MPA,
CSS, ANCA-positive pauci-immune glomerulonephritis
(GN), and unclassified vasculitis. A list of collaborating
centers and investigators in the ARChiVe network is
shown in Appendix A.
The specific aims of this pilot study were to
compare sensitivity and specificity of the adult-derived
ACR criteria for WG with those of the proposed
EULAR/PRES pediatric-specific criteria among a group
of children with chronic vasculitis whose diagnosis fell
within the spectrum of diseases related primarily by
ANCA association and small-to-medium vessel size and
whose clinical characteristics often overlapped. Addi-
tionally, we aimed to characterize the time from symp-
3414 CABRAL ET AL
tom onset to diagnosis, the presenting features, and the
initial treatment of the patients in the cohort with
ACR-defined WG.
PATIENTS AND METHODS
Since the launch of the ARChiVe registry in March
2007, pediatric rheumatologists at 30 CARRA-associated geo-
graphically diverse institutions in the US (n 26) and Canada
(n 4) have contributed patients. Eligible patients were all
children followed up at participating centers who were diag-
nosed after January 1, 2004 as having WG, MPA, CSS,
ANCA-positive pauci-immune GN, and unclassified vasculitis
and who were age 18 years at the time of diagnosis. The
diagnosis, established by the treating pediatric rheumatologist
at each of the ARChiVe network sites, was entered in the
database and considered to be the reference standard and
described in this article as the MD diagnosis. Using this
deliberately sensitive entry criterion, we anticipated that as
many as one-third of all patients might be entered as unclas-
sifiable (3,4), one-third of the patients diagnosed as having
WG might not be classifiable by ACR criteria (6,7), and some
patients with MPA might also fulfill criteria for WG (12).
Specific patient data items for categorical capture included all
criteria required for diagnosis using either the 1990 ACR (7)
or EULAR/PRES (11) classification systems (Table 1); pa-
tients in the cohort fulfilling criteria for diagnosis of WG
according to either of these criteria were identifiable by
computation of data.
For patients diagnosed between January 2004 and the
launch of ARChiVe in March 2007, data were collected by
review of available medical records. Data were collected
prospectively for patients who were diagnosed between March
2007 and November 2008. In both instances data collected
were for the period from clinical onset and presentation until
2 months after diagnosis. The ARChiVe uses a Web-based
interface for data entry of predominantly categorical variables,
which include the following: MD diagnosis; date of symptom
onset; demographic data; family and past medical history;
presenting/diagnostic features; physical examination findings
(including height, weight, blood pressure, and pubertal stag-
ing); results or reports of laboratory testing including ANCA
testing (cytoplasmic and/or perinuclear pattern of ANCA
[cANCA and/or pANCA, respectively]), histopathology, and
other procedures including diagnostic imaging, bronchoscopy,
and pulmonary function tests; and initial therapy detailing the
use of oral prednisone doses in mg/kg/day (low [0.5], medium
[0.51.5], high [1.5]) and intravenous (IV) corticosteroids,
oral or IV cyclophosphamide, other disease-modifying or
biologic therapies, and other concurrently used drugs (e.g.,
anticoagulants, antihypertensive medications).
Other data set items captured included all items de-
scribing disease activity that are used in the Birmingham
Vasculitis Activity Score (13,14) in addition to common pedi-
atric presenting features, unique diagnostic features for classi-
fication, or measurements of disease activity that were gener-
ated from a survey of CARRA members and incorporated into
a standardized data collection form by a subsequent vasculitis
consensus working group.
All data were reviewed at the main coordinating center
for completeness and quality. Data were reviewed to ensure
that there were no duplicate cases, since some of the institu-
tions in the ARChiVe network reported patients who were
either transferred from other medical institutions or referred
to them for a second opinion.
The study protocol was approved by the local research
ethics board at each participating center. Informed consent for
participation was obtained from parents, and informed consent
or assent was obtained from patients for both retrospective and
prospective recruitment as applicable.
Because the data were of a cross-sectional nature,
descriptive statistical analyses were performed. In order to
make our data comparable with those of previously reported
cohorts, we described presenting features and treatment of
patients who fulfilled 2 of the ACR classification criteria; this
does not mean to assume that the ACR criteria best define
childhood WG. Frequency and distribution of the sociodemo-
graphic, clinical, and treatment characteristics of pediatric WG
patients were provided using medians with ranges and percent-
ages where applicable.
To compare the ACR and EULAR/PRES classifica-
tion criteria for WG, all patients in the registry with any
physician-assigned diagnosis (WG, MPA, CSS, ANCA-positive
pauci-immune GN, or unclassified vasculitis) were analyzed.
To assess the degree of agreement between the MD, ACR, and
EULAR/PRES WG diagnoses, exploratory analyses to ascer-
tain convergent validity (chance-corrected agreement) were
performed using the kappa statistic (15). To determine dis-
criminant validity of criteria in the absence of a gold standard
is difficult; MD diagnosis of patients enrolled by 30 contrib-
uting physicians could not be considered a gold standard.
However, for these exploratory analyses we used the MD
Table 1. Comparison of the ACR and EULAR/PRES classification
criteria for WG*
1990 ACR criteria
A patient is said to have WG when 2 of the following 4 criteria
are present:
Nasal or oral inflammation
Abnormal chest radiograph
Abnormal urinary sediment (microhematuria [5 red blood
cells per high-power field] or red blood cell casts in
urine sediment)
Granulomatous inflammation on biopsy
EULAR/PRES criteria
A patient is said to have WG when 3 of the following 6 criteria
are present:
Nasal or sinus inflammation
Abnormal chest radiograph or chest CT scan
Abnormal urinalysis (hematuria and/or significant proteinuria)
Granulomatous inflammation on biopsy/necrotizing
pauci-immune GN
Subglottic, tracheal, or endobronchial stenosis
Anti-PR3 ANCA or cANCA staining
* Differences between American College of Rheumatology (ACR)
and European League Against Rheumatism/Pediatric Rheumatology
European Society (EULAR/PRES) classification systems and for
individual criteria are italicized. WG Wegeners granulomatosis;
CT computed tomography; GN glomerulonephritis; anti-PR3
antiproteinase 3; ANCA antineutrophil cytoplasmic antibody;
cANCA cytoplasmic ANCA.
WEGENERS GRANULOMATOSIS IN CHILDHOOD 3415
diagnosis, not as a gold standard, but as the reference standard
to calculate the ACR and EULAR/PRES classification criteria
sensitivity and specificity. All analyses were performed using
the Statistical package for the Social Sciences, version 16.0
(SPSS, Chicago, IL).
RESULTS
During the study period, 117 pediatric patients
(82 female [70.1%]) from 30 centers were recruited into
the ARChiVe cohort; 37 (31.6%) were collected pro-
spectively. The MD diagnoses of the patients in the
cohort were WG (n 76), MPA (n 17), ANCA-
positive pauci-immune GN (n 5), and CSS (n 2).
Seventeen patients were not considered classifiable un-
der any of these categories (unclassified vasculitis).
Evaluating classification, and comparing exist-
ing ACR and proposed EULAR/PRES criteria for WG.
Agreement was moderate between the MD diagnosis
and either the ACR criteria or the EULAR/PRES
criteria ( 0.346 and 0.476, respectively). How-
ever, there was substantial agreement between the ACR
criteria and the EULAR/PRES criteria ( 0.686). The
sensitivities of the ACR criteria and the EULAR/PRES
classification criteria for WG among the spectrum of
pediatric AAVs were 68.4% and 73.6%, respectively,
and the specificities were 68.3% and 73.2%, respectively
(Table 2).
Figure 1 is a Venn diagram showing the number
of patients in the cohort who were diagnosed as having
WG by MD diagnosis (n 76), by the ACR classifica-
tion criteria (n 65), or by the EULAR/PRES classifi-
cation criteria (n 67). Twenty-six patients were not
considered to have WG by MD diagnosis, ACR criteria,
or EULAR/PRES criteria.
Among the 65 patients with WG according to the
ACR criteria, the MD diagnosis differed in 13 (10 had
MPA and 3 had unclassified vasculitis). Among the 52
patients who did not meet the ACR criteria for WG, 17
had an MD diagnosis of WG, 2 were classified as having
WG by EULAR/PRES criteria, and 7 were classified as
having WG by both the MD diagnosis and the EULAR/
PRES criteria. The EULAR/PRES criteria that enabled
WG classification in these 9 patients were sinus involve-
ment and/or ANCA-positive serologic findings and/or
significant proteinuria, and, less frequently, subglottic/
tracheal/endobronchial stenosis and/or kidney biopsy
showing necrotizing pauci-immune GN (Table 3).
Among the 67 patients with WG according to the
EULAR/PRES criteria, the MD diagnosis differed in 11
(7 had MPA, 3 had unclassified vasculitis, and 1 had
ANCA-positive pauci-immune GN). Among the 50 pa-
tients who did not meet the EULAR/PRES criteria for
WG, 17 had an MD diagnosis of WG, 4 had WG by
ACR criteria, and 3 had WG by both MD diagnosis and
ACR criteria. The 7 patients who met ACR criteria
fulfilled only 2 of the 4 criteria that were also criteria of
the EULAR/PRES classification system (Table 3).
Figure 1. Venn diagram of assigned Wegeners granulomatosis (WG)
diagnosis among the 117 patients in the ARChiVe (A Registry for
Childhood Vasculitis: e-entry) cohort. The diagnosis of WG was
established by the treating pediatric rheumatologist at each of the
ARChiVe network sites (the MD diagnosis), by the American College
of Rheumatology (ACR) classification criteria, and by the European
League Against Rheumatism/Pediatric Rheumatology European So-
ciety (EULAR/PRES) classification criteria.
Table 2. Discriminant validity of the ACR and EULAR/PRES clas-
sification criteria for WG*
ACR
criteria
EULAR/PRESS
criteria
Sensitivity 68.4 73.6
Specificity 68.3 73.2
PPV 80.0 83.6
NPV 53.8 60.0
Overall accuracy 68.4 73.5
* Values are the percent. PPV positive predictive value; NPV
negative predictive value (see Table 1 for other definitions).
3416 CABRAL ET AL
T
a
b
l
e
3
.
D
a
t
a
o
n
t
h
e
1
6
p
a
t
i
e
n
t
s
f
r
o
m
t
h
e
A
R
C
h
i
V
e
s
t
u
d
y
c
o
h
o
r
t
w
h
o
c
o
u
l
d
f
u
l
f
i
l
l
a
s
u
f
f
i
c
i
e
n
t
n
u
m
b
e
r
o
f
e
i
t
h
e
r
E
U
L
A
R
/
P
R
E
S
c
l
a
s
s
i
f
i
c
a
t
i
o
n
c
r
i
t
e
r
i
a
o
r
A
C
R
c
l
a
s
s
i
f
i
c
a
t
i
o
n
c
r
i
t
e
r
i
a
(
b
u
t
n
o
t
b
o
t
h
)
f
o
r
d
i
a
g
n
o
s
i
s
o
f
W
G
*
N
a
s
a
l
i
n
f
l
a
m
m
a
t
i
o
n

S
i
n
u
s
i
n
f
l
a
m
m
a
t
i
o
n

A
b
n
o
r
m
a
l
c
h
e
s
t
r
a
d
i
o
g
r
a
p
h

A
b
n
o
r
m
a
l
c
h
e
s
t
C
T
s
c
a
n

A
b
n
o
r
m
a
l
u
r
i
n
a
l
y
s
i
s
(
h
e
m
a
t
u
r
i
a
)

A
b
n
o
r
m
a
l
u
r
i
n
a
l
y
s
i
s
(
s
i
g
n
i
f
i
c
a
n
t
p
r
o
t
e
i
n
u
r
i
a
)

G
r
a
n
u
l
o
m
a
t
o
u
s
i
n
f
l
a
m
m
a
t
i
o
n
o
n
b
i
o
p
s
y

N
e
c
r
o
t
i
z
i
n
g
p
a
u
c
i
-
i
m
m
u
n
e
G
N
o
n
b
i
o
p
s
y

S
u
b
g
l
o
t
t
i
c
,
t
r
a
c
h
e
a
l
,
o
r
e
n
d
o
b
r
o
n
c
h
i
a
l
s
t
e
n
o
s
i
s

A
n
t
i
-
P
R
3
A
N
C
A
o
r
c
A
N
C
A
s
t
a
i
n
i
n
g

P
a
t
i
e
n
t
s
f
u
l
f
i
l
l
i
n
g
3
o
f
6
E
U
L
A
R
/
P
R
E
S
c
r
i
t
e
r
i
a
f
o
r
W
G
,
b
y
a
g
e
i
n
y
e
a
r
s
(
n

9
)
3
X
X
X
X
4
X
X
X
X
6
X
X
X
X
X
7
X
X
X
1
0
X
X
X
X
1
2
X
X
X
X
1
4
X
X
X
X
1
4
X
X
X
1
4
X
X
X
P
a
t
i
e
n
t
s
f
u
l
f
i
l
l
i
n
g
2
o
f
4
A
C
R
c
r
i
t
e
r
i
a
f
o
r
W
G
,
b
y
a
g
e
i
n
y
e
a
r
s
(
n

7
)
2
X
X
X
3
X
X
X
3
X
X
X
4
X
X
X
6
X
X
X
6
X
X
X
X
1
5
X
X
X
*
T
h
e
p
r
e
s
e
n
c
e
o
f
a
n
i
n
d
i
v
i
d
u
a
l
c
o
m
p
o
n
e
n
t
o
f
t
h
e
c
r
i
t
e
r
i
a
i
n
e
a
c
h
p
a
t
i
e
n
t
i
s
i
n
d
i
c
a
t
e
d
b
y
a
n
X
.
C
o
m
p
l
e
t
e
d
e
s
c
r
i
p
t
i
o
n
s
o
f
t
h
e
E
U
L
A
R
/
P
R
E
S
a
n
d
A
C
R
c
r
i
t
e
r
i
a
a
r
e
s
h
o
w
n
i
n
T
a
b
l
e
1
.
A
R
C
h
i
V
e

A
R
e
g
i
s
t
r
y
f
o
r
C
h
i
l
d
h
o
o
d
V
a
s
c
u
l
i
t
i
s
:
e
-
e
n
t
r
y
(
s
e
e
T
a
b
l
e
1
f
o
r
o
t
h
e
r
d
e
f
i
n
i
t
i
o
n
s
)
.

C
r
i
t
e
r
i
o
n
s
h
a
r
e
d
b
y
b
o
t
h
E
U
L
A
R
/
P
R
E
S
a
n
d
A
C
R
.

E
U
L
A
R
/
P
R
E
S
c
r
i
t
e
r
i
o
n
t
h
a
t
i
s
e
i
t
h
e
r
a
m
o
d
i
f
i
c
a
t
i
o
n
o
f
a
n
A
C
R
c
r
i
t
e
r
i
o
n
o
r
a
n
e
w
c
r
i
t
e
r
i
o
n
.
WEGENERS GRANULOMATOSIS IN CHILDHOOD 3417
WG cohort. Sixty-five of the 117 patients met the
ACR criteria for WG; 63.1% of these patients were
female. The majority of patients were Caucasian
(69.2%), 4 were of mixed ethnicity, 3 were of East Indian
descent, 3 were African American, 2 were Hispanic, 1
was Asian, and 1 was of Middle Eastern origin; ethnicity
data were not available for 6 patients. The median age at
WG diagnosis was 14.2 years (range 417 years). The
median interval from symptom onset to diagnosis was
2.7 months (range 049 months). Eight of these 65 WG
Table 4. Frequency of presenting clinical features in pediatric patients with WG in 3 different single-center cohorts and in our multicenter
ARChiVe cohort*
Clinical feature
NIH
(n 23)
GOSH
(n 17)
HSC
(n 25)
ARChiVe
(n 65)
Constitutional/general NR NR 24 (96.0) 58 (89.2)
Malaise, fatigue NR NR NR 58 (89.2)
Fever 5 (22.0) NR 18 (72.0) 35 (53.8)
Weight loss 3 (13.0) 5 (29.0) 14 (56.0) 28 (43.1)
Pulmonary 5 (22.0) 14 (82.4) 20 (80.0) 52 (80.0)
Shortness of breath NR NR NR 38 (58.5)
Chronic cough NR 9 (53.0) NR 34 (52.3)
Hemoptysis/alveolar hemorrhage 2 (9.0) 3 (18.0) 11 (44.0) 29 (44.6)
Nodules 3 (13.0) 3 (17.6) 11 (44.0) 26 (41.9)#
Abnormal pulmonary function test results NR 3 (17.6) NR 27 (42.5)**
Fixed pulmonary infiltrates 2 (9.0) 1 (5.9) 4 (16.0) 14 (22.6)#
Oxygen dependency NR NR NR 12 (18.5)
Pleurisy 1 (4.0) NR 2 (8.0) 15 (23.1)
Renal NR 4 (23.5) 22 (88.0) 49 (75.4)
Abnormal urinalysis results NR 4 (23.5) 22 (88.0) 49 (75.4)
Biopsy-proven GN 2 (9.0) NR 16 (64.0) 34 (52.3)
Elevated serum creatinine NR NR 7 (28.0) 27 (41.5)
Ear, nose, and throat 20 (87.0) 17 (100.0) 21 (84.0) 52 (80.0)
Nasal involvement 11 (48.0) 7 (41.0) 10 (40.0) 42 (64.6)
Sinusitis 14 (61.0) 6 (35.0) 11 (44.0) 39 (60.0)
Otitis/mastoiditis 9 (39.0) NR 6 (24.0) 9 (13.8)
Subglottic involvement 1 (4.0) 7 (41.0) 1 (4.0) 9 (13.8)
Hearing loss 6 (26.0) NR 4 (16.0) 7 (10.8)
Oral ulcers 1 (4.0) 5 (29.0) 7 (28.0) 6 (9.2)
Eyes 3 (13.0) 9 (53.0) 13 (52.0) 24 (36.9)
Nonspecific red eye NR NR NR 10 (15.4)
Conjunctivitis 0 (0.0) 5 (29.0) 11 (44.0) 6 (9.2)
Scleritis 1 (4.0) 3 (18.0) 3 (12.0) 3 (4.6)
Cutaneous NR 9 (53.0) 8 (32.0) 23 (35.4)
Palpable purpura/petechiae NR NR 8 (32.0) 15 (23.1)
Gastrointestinal NR NR 3 (12.0) 27 (41.5)
Nonspecific abdominal pain NR 5 (29.0) NR 21 (32.3)
Chronic nausea NR NR NR 11 (16.9)
Musculoskeletal NR NR NR 37 (56.9)
Arthralgia/myalgia 7 (30.0) 9 (53.0) 16 (64.0) 35 (53.8)
Arthritis NR NR 8 (32.0) 13 (20.0)
Nervous system NR 2 (12.0) 2 (8.0) 16 (24.6)
Severe headache NR NR NR 9 (13.8)
Dizziness NR NR NR 8 (12.3)
Cardiovascular NR NR NR 0 (0.0)
Venous thrombosis NR NR 3 (12.0) 0 (0.0)
* Values are the number (%) of affected patients. NR frequency not reported (see Table 1 for other definitions).
National Institutes of Health (NIH) study, Bethesda, MD (Rottem et al, 1993 [16]). Absolute patient numbers were calculated from percentages
provided in the article.
Great Ormond Street Hospital (GOSH) for Children, London, UK (Belostotsky et al, 2002 [6]). Some clinical features in this cohort correspond
to the entire disease course since features at disease onset were not reported consistently.
Hospital for Sick Children (HSC), Toronto, Ontario, Canada (Akikusa et al, 2007 [17]).
A Registry for Childhood Vasculitis: e-entry (ARChiVe), 2008 (present study). Patients met 2 of the ACR classification criteria for WG.
# From 62 children who underwent chest imaging.
** From 35 children who had pulmonary function tests done.
Nasal involvement features were reported separately, with epistaxis occurring in 40% and nasal ulcers in 24% of children at disease onset.
Arthralgias and arthritis at disease onset were not reported separately.
3418 CABRAL ET AL
patients (12.3%) had a symptom onset to diagnosis
interval 12 months; patients with this longer interval to
diagnosis had a higher frequency of ear, nose, and throat
and cutaneous manifestations and less frequently had
renal features (data not shown).
Frequencies of presenting features by organ sys-
tem were as follows: constitutional/general (89.2%),
pulmonary (80.0%), ear, nose, and throat (80.0%), and
renal (75.4%). Additional categories and specific fea-
tures are listed in Table 4. Significant renal involvement
as manifested by serum creatinine elevated above the
95th percentile for age was found in 27 patients (41.5%);
dialysis was necessary in 7 patients (10.8%), and end-
stage renal disease was present in 1 patient. Of note,
among those patients with pulmonary disease, severe
involvement requiring continuous oxygen therapy or
mechanical ventilation occurred in 19% and 11%, re-
spectively. Of the 35 patients who had pulmonary func-
tion tests done, 27 had abnormal results; obstructive and
restrictive abnormalities were found to be equally rep-
resented.
The numbers and frequencies of patients pre-
senting with any of the criteria used in either the ACR or
the EULAR/PRES classification were as follows: nasal
bleed/ulcers/crusts, 64.6%; sinusitis, 60.0%; subglottic,
tracheal, or endobronchial stenosis, 16.9%; oral ulcers,
9.2%; abnormal findings on chest imaging (multiple
nodules, fixed infiltrates, and/or cavitation), 64.5% of 62
patients who underwent chest imaging; abnormal urin-
alysis results (5 red blood cells [RBCs] per high-power
field, RBC casts, or proteinuria), 70.8%; histologic evi-
dence of necrotizing pauci-immune GN, 12.3%; and
histologic evidence of granulomatous vasculitis at non-
renal sites, 24.6%. Serology tests for the presence of
Table 5. Autoantibody testing results among children with and those without WG according to the ACR
criteria*
Serologic test
With WG
(n 65)
Without WG
(n 52)
Immunofluorescence for cANCA, positive 43 (66.2) 12 (23.1)
Anti-PR3positive on ELISA 40 (93.0) 11 (91.7)
Anti-MPOpositive on ELISA 0 (0.0) 0 (0.0)
Negative on ELISA 2 (4.7) 1 (8.3)
ELISA not done 0 (0.0) 0 (0.0)
ELISA result not available 1 (2.3) 0 (0.0)
Immunofluorescence for pANCA, positive 14 (21.5) 20 (38.5)
Anti-PR3positive on ELISA 3 (21.4) 1 (5.0)
Anti-MPOpositive on ELISA 8 (57.1) 18 (90.0)
Negative on ELISA 2 (14.3) 0 (0.0)
ELISA not done 1 (7.1) 1 (5.0)
Immunofluorescence for pANCA and cANCA, positive 1 (1.5) 1 (2.0)
Anti-MPOpositive on ELISA 0 (0.0) 1 (100.0)
ELISA not done 1 (100.0) 0 (0.0)
Immunofluorescence not done 3 (4.6) 1 (2.0)
Anti-PR3 and anti-MPOpositive on ELISA 1 (33.3) 0 (0.0)
Anti-PR3positive on ELISA 1 (33.3) 0 (0.0)
ELISA not done 0 (0.0) 1 (100.0)
ELISA result not available 1 (33.3) 0 (0.0)
Negative for ANCA (cANCA and pANCA) 4 (6.2) 17 (32.7)
Anti-PR3positive on ELISA 0 (0.0) 3 (17.6)
Anti-MPOpositive on ELISA 0 (0.0) 1 (5.9)
Negative on ELISA 4 (100.0) 12 (70.6)
ELISA not done 0 (0.0) 1 (5.9)
Antinuclear antibodies, tested 50 (76.9) 44 (84.6)
Positive 17 (34.0) 16 (36.4)
Negative 33 (66.0) 28 (63.6)
Anticardiolipin antibodies and/or lupus anticoagulant, tested 34 (52.3) 19 (36.5)
Positive 6 (17.6) 5 (26.3)
Negative 28 (82.4) 14 (73.7)
Antiglomerular basement membrane antibodies, tested 9 (13.8) 3 (5.8)
Positive 2 (22.2) 0 (0.0)
Negative 7 (77.8) 3 (100.0)
* Values are the number (%) of patients. ELISA enzyme-linked immunosorbent assay; anti-MPO
antimyeloperoxidase; pANCA perinuclear ANCA (see Table 1 for other definitions).
Transiently positive for both patients.
WEGENERS GRANULOMATOSIS IN CHILDHOOD 3419
ANCAs by immunofluorescence yielded positive results
in 58 children with WG (89.2%) (43 with cANCA
[66.2%], 14 with pANCA [21.5%], and 1 with both
cANCA and pANCA [1.5%]); 4 patients were negative
for both cANCA and pANCA, and serology tests were
not performed for 3 patients. Using enzyme-linked
immunosorbent assay, antiproteinase 3 (anti-PR3) pos-
itivity was reported in 44 patients (67.7%), antimy-
eloperoxidase (anti-MPO) positivity was reported in 8
patients (12.3%), and 1 patient was found to be both
anti-PR3 and anti-MPO positive. Results of ANCA
testing and other autoantibody tests are summarized in
Table 5.
Histopathology. Fifty-four patients had 1 bi-
opsy performed (36 renal biopsies and 38 nonrenal
biopsies). Nonrenal histopathology showing granuloma-
tous vasculitis included the following: lower airways/
lungs (6 of 13 biopsy samples), paranasal sinuses (4 of 8
biopsy samples), upper airways (3 of 6 biopsy samples),
skin (2 of 6 biopsy samples), and nasal septum (1 of 3
biopsy samples). No granulomatous vasculitis was found
in 2 reported biopsy samples of the gastrointestinal tract.
In all but 2 kidney biopsy samples, the histopathology
showed GN, with 22.2% being described as necrotizing
pauci-immune GN.
Treatment. Fifty-four patients (83.1%) were
treated with a combination of corticosteroids and cyclo-
phosphamide; 27 of these received oral cyclo-
phosphamide, 21 received IV cyclophosphamide, and 6
initially received IV cyclophosphamide and were
switched to oral cyclophosphamide early in the disease
course. Forty-five patients (69.2%) received high-dose
IV pulse corticosteroids. Among 60 patients (92.3%)
receiving oral corticosteroids, 2 were receiving a low-
dose regimen, 31 were receiving a medium dose, and 27
were receiving a high dose. Four children were treated
with corticosteroids only (2 received medium-dose cor-
ticosteroids and 2 received high-dose corticosteroids).
Six patients (9.2%) received a combination of cortico-
steroids and methotrexate, and 1 patient (1.5%) was
treated with methotrexate only. Thirty-four patients
(52.3%) were started on trimethoprim/sulfamethoxazole
(TMP/SMX), generally as Pneumocystis jiroveci pneumo-
nia prophylaxis. Other therapeutic modalities used in-
cluded plasmapheresis (9 patients), extracorporeal
membrane oxygenation (2 patients), IV immunoglobulin
(IVIG) (2 patients), and rituximab (1 patient).
DISCUSSION
This report of 65 patients with pediatric-onset
WG (ACR defined) from 30 US and Canadian centers
describes the largest cohort of such children to date. The
3 largest series previously reported from the US (n 23)
(16), the UK (n 17) (6), and Canada (n 25) (17)
were single-center series that collected patients over 24,
17, and 21 years, respectively. Unlike the others, this
current report does not describe any followup data.
However, through the concurrent establishment of a
network of interested investigators supported by a Web-
based data entry interface system (ARChiVe), we have
identified a relatively contemporary cohort of patients
(diagnosed since 2004) for future prospective study.
Because of the rarity of WG in children, it is not feasible
for any single center to establish a similarly sized cohort
(5). Furthermore, the nature of this multicenter network
reduces the likelihood that patients are selected for
greater disease severity, a potential bias that might be
attributed to cohorts from single large referral centers.
In classifying WG, the limited convergence of
MD diagnosis with either ACR criteria or EULAR/
PRES criteria is not surprising, since the premise for
diagnosis of patients as having any disease differs from
that for classification. Because the EULAR/PRES crite-
ria were built upon the existing ACR criteria, there was
a reasonable convergence between them, and as such,
the sensitivity and specificity were likely to be similar.
Among the 76 patients referred to ARChiVe with the
physician diagnosis of WG, 52 could be classified as
having WG according to ACR criteria; in an additional
13 children with ACR-defined WG, the MD diagnosis
differed. Use of the proposed pediatric EULAR/PRES
criteria minimally improved diagnostic sensitivity and
specificity over those of the ACR criteria; although the
EULAR/PRES classification scheme identified 9 pa-
tients with WG in addition to those identified by the
ACR criteria, 7 of the patients identified as having WG
according to the ACR criteria could not meet 2 criteria
required for EULAR/PRES classification (Table 3).
Interestingly, by applying the modification proposed by
the WG etanercept trial investigators (18) of adding a
positive enzyme immunoassay finding for anti-PR3 as a
fifth criterion, sensitivity of the ACR criteria increased
substantially (to 86.8%) without a significant change in
specificity.
The low sensitivity and specificity of both sets of
criteria likely reflect the denominator. In our analyses,
sensitivity and specificity for classification of WG were
tested among a group of patients with vasculitides
related by size of the vessel predominantly involved
(small to medium) and the association with ANCAs.
Patients in any diagnostic subset of AAV in this cohort
were more likely to have WG than a vasculitis diagnosis
3420 CABRAL ET AL
other than AAV. Thus, we would anticipate that the
sensitivity and specificity would improve significantly if
the criteria were tested among a population of pediatric
patients that included the wider spectrum of vasculitides
of differing predominant vessel sizes, from Henoch-
Schonlein purpura (small vessel) through polyarteritis
nodosa (PAN) (medium vessel) to Takayasu arteritis
(large vessel).
Among the patient population that we studied,
the most difficult differential diagnosis was the distin-
guishing of WG from MPA. Neither the ACR nor the
EULAR/PRES have defined categorical classification
criteria for MPA. Using the CHCC characterization of
MPA (9), 36 of 117 patients in our cohort could be
defined as having MPA, and among these patients, 24
could concurrently be diagnosed as having WG accord-
ing to ACR criteria. Since WG and MPA share many
features, there are clearly difficulties in defining mutu-
ally exclusive classification criteria for these 2 disorders.
Some authorities believe that these 2 entities should be
considered together under the rubric of AAV (10). The
algorithm by Watts et al (12) was developed to catego-
rize adult patients among those with AAV or PAN into
a single nonoverlapping classification; those investiga-
tors criticize the poor individual performance of ACR
criteria, CHCC definitions, and Lanham criteria (19)
with respect to defining mutually exclusive classification
categories. This algorithm applies the different criteria
in a stepwise approach, first defining WG patients where
criteria are most specific, and subsequently and sequen-
tially applying elements of different criteria to the
remaining patients to classify each into a single category.
The EULAR/PRES criteria, a pediatric modification
of the ACR criteria, did not address this criticism.
Basic demographics, clinical features, and treat-
ment modalities for ACR-defined WG patients in the
ARChiVe cohort were comparable with those reported
elsewhere in that the patients were predominantly fe-
male and Caucasian and the age at onset was mostly in
the adolescent years. Our patients median interval from
symptom onset to diagnosis (2.7 months) was similar to
those reported by Akikusa et al and Rottem et al (2
months and 8 months, respectively) (16,17) in spite of
the great diversity of geographic and economic back-
grounds of our population and differences in health care
policy between Canada and the US. The upper end of
the range (49 months) remains disconcerting; the 8
ARChiVe patients (12.3%) with an interval to diagnosis
of 12 months presented predominantly with ear, nose,
and throat and cutaneous features and had fewer renal
manifestations than those patients who were diagnosed
within 12 months of symptom onset. The implication of
this disparity is that diagnosis is delayed in the absence
of initial critical organ involvement.
The frequencies of specific presenting clinical
features of our cohort and those of the 3 previous largest
cohorts are compared in Table 4. We corroborated the
high incidence of renal involvement at disease onset
described by Akikusa et al and by investigators in some
smaller series (17,20,21) relative to the adult experience
(22,23), whereas there was a somewhat lower incidence
in the other 2 large series. Pulmonary involvement was
as common as renal disease among ARChiVe patients,
with severe pulmonary involvement (oxygen dependency
and/or requirement for mechanical ventilation) occur-
ring in 15 patients (23.1%). Findings on imaging studies
(pulmonary nodules and infiltrates) in our population
were comparable with those reported in other pediatric
WG series, with a lower proportion of abnormal imaging
findings in patients without pulmonary symptoms in our
cohort (data not shown) compared with that reported by
Rottem et al (17% versus 41%) (16).
The frequency of ear, nose, and throat features
among ARChiVe patients was similar to that reported in
other pediatric WG series. Subglottic stenosis is noted in
some reports to occur frequently in pediatric-onset WG
compared with WG in adults, such that this feature was
included in the EULAR/PRES criteria (derived by
expert consensus) for classifying WG (11). In our cohort,
after nasal and sinus involvement, subglottic stenosis was
only slightly more frequent than otitis/mastoiditis or
hearing loss. Nonetheless, it still may be valuable as a
criterion because it may be more specific for WG, having
a narrower differential diagnosis than other upper respi-
ratory symptoms. Inclusion of subglottic stenosis as a
criterion may enable classification of patients through
EULAR/PRES who would not otherwise be described
as having WG; one such patient was diagnosed in this
cohort.
We found a lower frequency of ocular manifes-
tations (conjunctivitis and scleritis in particular) than
previously reported. In contrast, the frequency of gas-
trointestinal and neurologic symptoms was greater in
our patients compared with their frequency in reported
series.
The high frequency of thrombotic events de-
scribed in 2 previous reports (17,24) was not found in
our series. Additionally, half of our patients were tested
for antiphospholipid antibodies and lupus anticoagulant,
with only 18% of those tested having a positive result at
the time of diagnosis (the reasons for antibody testing
were not documented in the registry). This proportion is
WEGENERS GRANULOMATOSIS IN CHILDHOOD 3421
similar to that reported in adult patients (25). Throm-
botic events may potentially occur in our patient cohort
later in the disease course, although in the existing
reports, thrombotic events occurred within a few weeks
of diagnosis, and such patients in our cohort would
arguably have been identified within our data capture
time frame.
In treating pediatric WG, the standard practice of
initial treatment for 83% of ARChiVe patients was
cyclophosphamide and corticosteroids, although there
was diversity and several permutations of regimens and
routes of administration. Early use of cyclophosphamide
was similar to that reported by Rottem et al and
Belostotsky et al (82.6% and 94%, respectively) (6,16).
Methotrexate was not frequently used in the early 1980s;
however, in the ARChiVe cohort it was used in 10.7% of
patients, a rate similar to that described in the Toronto
cohort. Use of TMP/SMX in ARChiVe patients was
higher than that reported by Belostotsky et al (6) (51%
versus 29%); however, except for 1 patient, it was
prescribed as P jiroveci pneumonia prophylaxis. Other
therapies such as plasmapheresis, extracorporeal mem-
brane oxygenation, IVIG, and rituximab were rarely
used. No patients began therapy using azathioprine,
mycophenolate mofetil, or biologic medications other
than rituximab at the time of diagnosis. We recognize
that there are recent reports of rituximab use as initial
therapy in newly diagnosed adult and pediatric WG
patients (26,27), but at the time of this report those
pediatric patients had not been entered into the registry.
Some considerations must be applied to the
interpretation of our findings, particularly with respect
to previous WG series. First, our data were collected
cross-sectionally and predominantly in a retrospective
way. However, data collection was done using a stan-
dardized Web-based data entry system that was regu-
larly reviewed centrally for data consistency and quality
to minimize incomplete information. Furthermore, the
retrospective time frame was the shortest (5 years) and
most contemporary. Patient recruitment to the ongoing
ARChiVe registry cohort will be predominantly pro-
spective, thereby improving the quality and complete-
ness of data capture. Also, having data collected in many
institutions will provide us with a broader overview of
the different clinical approaches to pediatric vasculitis in
practice across the US and Canada. Second, because
ARChiVe data collection currently consists of a one-
time data entry point at the time of diagnosis, we are not
able to provide information on patient outcomes. Future
longitudinal data collection from this patient cohort is
planned.
In this cohort, the largest collection of pediatric
patients with WG to date, some patients were found to
have a considerable delay from symptom onset to time
of diagnosis, particularly when there was initially non-
critical organ disease. Lack of appreciation of the female
preponderance in childhood disease and differences in
presentation from adult patients may contribute to the
diagnostic delay. The diversity of initial treatments used
for patients in this cohort suggests that there may be no
standard approach to therapy. This difference may pre-
dominate among patients with noncritical organ disease.
Further analysis of treatment regimen stratified by dis-
ease severity at onset and subsequent outcome will be
necessary to determine optimal outcomes while mini-
mizing treatment toxicities. Estimations of disease sever-
ity by adapting severity classification systems used in
adults will be integrated into future outcome studies of
this cohort. We did not find that the newly proposed
pediatric EULAR/PRES vasculitis classification criteria
presented significant improvement over the ACR crite-
ria for classifying WG; however, a second iteration of the
criteria is being refined and will be testable in our
growing cohort.
ACKNOWLEDGMENTS
We are indebted to all participating patients and their
families, without whom this study would not be possible. The
origins of this project were in the CARRA; although the
ARChiVe network now extends beyond this, we gratefully
acknowledge that it would not be sustainable without the
endorsement and ongoing support of the CARRA and its
membership.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Cabral had full access to all of the
data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study conception and design. Cabral, Uribe, Benseler, ONeil, Hash-
kes, Zeft, Lovell, Kingsbury, Stevens, Chira, Abramson, Arkachaisri,
Eberhard, Hersh, Levy, Li, Morgan DeWitt, Reiff, Schikler, Singer.
Acquisition of data. Cabral, Uribe, Benseler, ONeil, Hashkes, Hig-
gins, Lovell, Kingsbury, Stevens, McCurdy, Chira, Abramson,
Arkachaisri, Campillo, Eberhard, Hersh, Huber, Kim, Klein-Gitelman,
Li, Mason, Morgan DeWitt, Muscal, Nassi, Schikler, Singer, Wahezi,
Woodward.
Analysis and interpretation of data. Cabral, Uribe, Huber, Muscal,
Schikler.
Study administration and coordination. Cabral.
REFERENCES
1. Lindsley CB, Laxer RM. Granulomatous vasculitis, giant cell
arteritis and sarcoidosis. In: Cassidy JT, Petty RE, Laxer RM,
3422 CABRAL ET AL
Lindsley CB, editors. Textbook of pediatric rheumatology. Phila-
delphia: Elsevier Saunders; 2005. p. 53960.
2. Gardner-Medwin JM, Dolezalova P, Cummins C, Southwood TR.
Incidence of Henoch-Schonlein purpura, Kawasaki disease, and
rare vasculitides in children of different ethnic origins. Lancet
2002;360:1197202.
3. Malleson PN, Fung MY, Rosenberg AM. The incidence of pedi-
atric rheumatic diseases: results from the Canadian Pediatric
Rheumatology Association Disease Registry. J Rheumatol 1996;
23:19817.
4. Bowyer S, Roettcher P, the Pediatric Rheumatology Database
Research Group. Pediatric rheumatology clinic populations in the
United States: results of a 3 year survey. J Rheumatol 1996;23:
196874.
5. Wilkinson NM, Page J, Uribe AG, Espinosa V, Cabral DA.
Establishment of a pilot pediatric registry for chronic vasculitis is
both essential and feasible: a Childhood Arthritis and Rheuma-
tology Alliance (CARRA) survey. J Rheumatol 2007;34:2246.
6. Belostotsky VM, Shah V, Dillon MJ. Clinical features in 17
paediatric patients with Wegener granulomatosis. Pediatr Nephrol
2002;17:75461.
7. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend
WP, et al. The American College of Rheumatology 1990 criteria
for the classification of Wegeners granulomatosis. Arthritis
Rheum 1990;33:11017.
8. Fries JF, Hunder GG, Bloch DA, Michel BA, Arend WP, Cala-
brese LH, et al. The American College of Rheumatology 1990
criteria for the classification of vasculitis: summary. Arthritis
Rheum 1990;33:11356.
9. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL,
et al. Nomenclature of systemic vasculitides: proposal of an
international consensus conference. Arthritis Rheum 1994;37:
18792.
10. Hellmich B, Flossmann O, Gross WL, Bacon P, Cohen-Tervaert
JW, Guillevin L, et al. EULAR recommendations for conducting
clinical studies and/or clinical trials in systemic vasculitis: focus on
anti-neutrophil cytoplasm antibody-associated vasculitis. Ann
Rheum Dis 2007;66:60517.
11. Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, et
al. EULAR/PReS endorsed consensus criteria for the classifica-
tion of childhood vasculitides. Ann Rheum Dis 2006;65:93641.
12. Watts R, Lane S, Hanslik T, Hauser T, Hellmich B, Koldingsnes
W, et al. Development and validation of a consensus methodology
for the classification of the ANCA-associated vasculitides and
polyarteritis nodosa for epidemiological studies. Ann Rheum Dis
2007;66:2227.
13. Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P,
et al. Birmingham Vasculitis Activity Score (BVAS) in systemic
necrotizing vasculitis. QJM 1994;87:6718.
14. Flossmann O, Bacon P, de Groot K, Jayne D, Rasmussen N, Seo
P, et al. Development of comprehensive disease assessment in
systemic vasculitis. Ann Rheum Dis 2007;66:28392.
15. Kramer MS, Feinstein AR. Clinical biostatistics. LIV. The biosta-
tistics of concordance. Clin Pharmacol Ther 1981;29:11123.
16. Rottem M, Fauci AS, Hallahan CW, Kerr GS, Lebovics R, Leavitt
RY, et al. Wegener granulomatosis in children and adolescents:
clinical presentation and outcome. J Pediatr 1993;122:2631.
17. Akikusa JD, Schneider R, Harvey EA, Hebert D, Thorner PS,
Laxer RM, et al. Clinical features and outcome of pediatric
Wegeners granulomatosis. Arthritis Rheum 2007;57:83744.
18. Haas JP, Metzler M, Ruder H, Waldherr R, Boswald M, Ruppre-
cht T. An unusual manifestation of Wegeners granulomatosis in a
4-year-old girl. Pediatr Neurol 2002;27:714.
19. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis
with asthma and eosinophilia: a clinical approach to the Churg-
Strauss syndrome. Medicine (Baltimore) 1984;63:6581.
20. Stegmayr BG, Gothefors L, Malmer B, Muller Wiefel DE, Nilsson
K, Sundelin B. Wegener granulomatosis in children and young
adults: a case study of ten patients. Pediatr Nephrol 2000;14:
20813.
21. Hall SL, Miller LC, Duggan E, Mauer SM, Beatty EC, Hellerstein
S. Wegener granulomatosis in pediatric patients. J Pediatr 1985;
106:73944.
22. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS,
Travis WD, et al. Wegener granulomatosis: an analysis of 158
patients. Ann Intern Med 1992;116:48898.
23. Wegeners Granulomatosis Etanercept Trial Research Group.
Limited versus severe Wegeners granulomatosis: baseline data on
patients in the Wegeners granulomatosis etanercept trial. Arthri-
tis Rheum 2003;48:2299309.
24. Von Scheven E, Lu TT, Emery HM, Elder ME, Wara DW.
Thrombosis and pediatric Wegeners granulomatosis: acquired
and genetic risk factors for hypercoagulability. Arthritis Rheum
2003;49:8625.
25. Sebastian JK, Voetsch B, Stone JH, Romay-Penabad Z, Lo GH,
Allen NB, et al. The frequency of anticardiolipin antibodies and
genetic mutations associated with hypercoagulability among pa-
tients with Wegeners granulomatosis with and without history of
a thrombotic event. J Rheumatol 2007;34:244650.
26. Lee RW, DCruz DP. Novel therapies for anti-neutrophil cyto-
plasmic antibody-associated vasculitis. Drugs 2008;68:74770.
27. Hollister JR, Soep JB, Dragone L. Rituximab treatment for severe
Wegeners granulomatosis: a cyclophosphamide-is sparing strategy
[unpublished abstract]. ACR Keystone Pediatric Rheumatology
symposium, March 2008, Keystone, CO.
APPENDIX A: COLLABORATORS IN THE ARChiVe
NETWORK
Coordinating center. British Columbia Childrens Hospital,
Vancouver, British Columbia, Canada: David A. Cabral (Study Prin-
cipal Investigator), Ame rica G. Uribe (Study Coordinator), Victor
Espinosa (Information Technology Manager, Statistician), Jaime Guz-
man, Kristin Houghton, Peter Malleson, Kimberly Morishita, Ross
Petty, Lori Tucker, Stuart Turvey (Site Investigators). Participating
centers. Case Medical Center, and Rainbow Babies and Childrens
Hospital University Hospitals, Cleveland, OH: Nora G. Singer (Site
Principal Investigator), Elizabeth B. Brooks (Site Investigator), Mary
Lesko (Site Coordinator). Childrens Hospital of Boston, Boston, MA:
Susan Kim (Site Principal Investigator), Fatma Dedeoglu, Robert
Fuhlbrigge, Melissa Hazen, Mary Beth Son, Robert Sundel (Site
Investigators). Childrens Hospital Los Angeles, Los Angeles, CA:
Andreas Reiff (Site Principal Investigator), Diane Brown, Bracha
Shaham (Site Investigators), Ana Cabrera (Site Coordinator). Chil-
drens Hospital at Montefiore, Bronx, NY: Norman T. Ilowite (Site
Principal Investigator), Dawn Wahezi (Site Investigator). Childrens
Hospital of Pittsburgh, Pittsburgh, PA: Thaschawee Arkachaisri (Site
Principal Investigator), Raphael Hirsh, Daniel Kietz, Paul Rosen,
Margalit Rosenkrank, Kathryn Torok (Site Investigators). Childrens
Memorial Hospital, Chicago, IL: Marisa Klein-Gitelman (Site Princi-
pal Investigator), Lauren Pachman (Site Investigator), Aisha Ali (Site
Coordinator). Cincinnati Childrens Hospital Medical Center, Cincin-
nati, OH: Daniel J. Lovell (Site Principal Investigator), Hermine
Brunner, Thomas Griffin, Alexi Grom (Site Investigators), Anne
Johnson (Site Coordinator). Cleveland Clinic Foundation, Cleveland,
OH: Philip J. Hashkes (Site Principal Investigator), Steven Spalding
(Site Investigator), Deborah Bork (Site Coordinator). Duke Childrens
Hospital and Health Center, Duke University Medical Center,
Durham, NC: Esi Morgan DeWitt (Site Principal Investigator), Stacy
Ardoin, Egla Rabinovich, Laura Schanberg (Site Investigators),
Rhonda Wilder (Site Coordinator). Hospital for Sick Children, To-
ronto, Ontario, Canada: Susanne Benseler (Site Principal Investiga-
tor). IWK Health Centre, and Dalhousie University, Halifax, Nova
WEGENERS GRANULOMATOSIS IN CHILDHOOD 3423
Scotia, Canada: Adam M. Huber (Site Principal Investigator), Bianca
A. Lang, Suzanne Ramsey, Elizabeth Stringer (Site Investigators),
Aleasha Warner (Site Coordinator). Joseph M. Sanzari Childrens
Hospital, Hackensack University Medical Center, Hackensack, NJ:
Suzanne C. Li (Site Principal Investigator), Kathleen Haines, Yukiko
Kimura, Jennifer Weiss (Site Investigators). Legacy Emanuel Chil-
drens Hospital, Portland, OR: Daniel J. Kingsbury (Site Principal
Investigator). Lucile Packard Childrens Hospital, Stanford University
School of Medicine, Stanford, CA: Peter Chira (Site Principal Inves-
tigator), Imelda Balboni, Reuven Bromberg, Michal Cidon, Jennifer
Frankovich, Dana Gerstbacher, Joyce J. Hsu, Tzielan Lee, Jane L.
Park, Christy Sandborg, Steven Song (Site Investigators). Mayo Euge-
nio Litta Childrens Hospital, Mayo Clinic, Rochester, MN: Thomas
Mason (Site Principal Investigator), Ann Reed (Site Investigator). The
Montreal Childrens Hospital, McGill University Health Centre, Mon-
treal, Quebec, Canada: Sarah Campillo (Site Principal Investigator),
Gae lle Che deville, Ciara n Duffy, Karen Duffy, Rosie Scuccimarri (Site
Investigators), Michele Gibbon (Site Coordinator). Nationwide Chil-
drens Hospital, Columbus, OH: Gloria Higgins (Site Principal Inves-
tigator). New YorkPresbyterian Morgan Stanley Childrens Hospital,
New York, NY: Deborah M. Levy (Site Principal Investigator),
Andrew Eichenfield, Lisa Imundo (Site Investigators), Candido Batres
(Site Coordinator). Riley Childrens Hospital, Indianapolis, IN: Su-
zanne Bowyer (Site Principal Investigator), Susan Ballinger, Thomas
Klausmeier, Amy Woodward (Site Investigators), Andrea Hudgins
(Site Coordinator). Schneider Childrens Hospital, New York, NY:
Anne Eberhard (Site Principal Investigator). Seattle Childrens Hos-
pital, Seattle, WA: Anne Stevens (Site Principal Investigator), Helen
Emery, Kristin Hayward, Christi Inman, Sarah Ringold, Elizabeth
Shaw, Troy Torgerson, Jennifer Turner, Carol Wallace, Jennifer
Wargula (Site Investigators), Sarah Halford (Site Coordinator). Texas
Childrens Hospital, Baylor College of Medicine, Houston, TX: Eyal
Muscal (Site Principal Investigator), Barry L. Myones (Site Investiga-
tor). Texas Scottish Rite Hospital, University of Texas Southwestern,
Dallas: Marilynn Punaro (Site Principal Investigator), Lorien Nassi,
Virginia Pascual (Site Investigators). University of California, Los
Angeles: Deborah McCurdy (Site Principal Investigator). University of
California, San Francisco: Aimee O. Hersh (Site Principal Investiga-
tor), Emily von Scheven (Site Investigator). University of Louisville
Health Sciences Center, Louisville, KY: Kenneth Schikler (Site Prin-
cipal Investigator), Adrienne Michels (Site Coordinator). University of
Oklahoma Health Sciences Center, Oklahoma City: Kathleen M.
ONeil (Site Principal Investigator), Michael Henrickson, James Jarvis
(Site Investigators). University of Utah Primary Childrens Medical
Center, Salt Lake City: Andrew S. Zeft (Site Principal Investigator),
John Bonsack, Sampath Prahalad (Site Investigators). University of
Vermont, Burlington: Leslie Abramson (Site Principal Investigator).
3424 CABRAL ET AL

Potrebbero piacerti anche