ARTHRITIS & RHEUMATISM
Vol. 54, No. 11, November 2006, pp 3564–3572
Patients With Juvenile Psoriatic Arthritis Comprise
Two Distinct Populations
Matthew L. Stoll,1 David Zurakowski,1 Lise E. Nigrovic,1 David P. Nichols,2
Robert P. Sundel,1 and Peter A. Nigrovic3
Objective. Psoriatic arthritis (PsA) in children is
clinically heterogeneous. We examined a large popula-
tion of children with juvenile PsA for evidence of
phenotypic clustering that could suggest the presence of
distinct clinical entities.
Methods. We reviewed the medical records of 139
patients meeting the Vancouver criteria for juvenile
PsA. To identify segregation into phenotypic groups, we
compared younger patients with their older counter-
parts and subjected the whole population to 2-step
cluster analysis.
Results. Among patients with juvenile PsA, the
age at onset is biphasic, with peaks occurring at approx-
imately 2 years of age and again in late childhood.
Compared with children ages 5 years and older, younger
patients are more likely to be female, exhibit dactylitis
and small joint involvement, and express antinuclear
antibodies. Progression to polyarticular disease (>5
joints) is more common in younger children, although
joint involvement remains oligoarticular in the majority
of children. In contrast, older patents tend to manifest
enthesitis, axial joint disease, and persistent oligoar-
thritis. Uveitis is equally represented in both age
groups. Despite a higher utilization of methotrexate
therapy, younger patients required, on average, more
Supported in part by the Samara Jan Turkel Center for
Pediatric Autoimmune Disease. Dr. Lise E. Nigrovic’s work was
supported by a National Research Service Award grant (T32
HD40128).
1
Matthew L. Stoll, MD, PhD, David Zurakowski, PhD, Lise
E. Nigrovic, MD, MPH, Robert P. Sundel, MD: Children’s Hospital
Boston, Harvard Medical School, Boston, Massachusetts; 2David P.
Nichols, AM: University of Chicago and SPSS Inc., Chicago, Illinois;
3
Peter A. Nigrovic, MD: Children’s Hospital Boston, Harvard Medical
School, and Brigham and Women’s Hospital, Boston, Massachusetts.
Mr. Nichols owns stock and/or stock options in SPSS.
Address correspondence and reprint requests to Peter A.
Nigrovic, MD, Rheumatology, Children’s Hospital Boston, 300 Long-
wood Avenue, Fegan 6, Boston, MA 02115. E-mail: pnigrovic@
partners.org.
Submitted for publication March 13, 2006; accepted in revised
form July 24, 2006.
3564
DOI 10.1002/art.22173
© 2006, American College of Rheumatology
than twice as long to achieve clinical remission (23
months versus 9.2 months; P ⴝ 0.044). Cluster analysis
identified largely overlapping subgroups but suggested
that the presence of dactylitis, rather than age, has the
greatest capacity to predict essential features of the
clinical phenotype.
Conclusion. Juvenile PsA comprises 2 distinct
populations of patients. Although the pathophysiologic
correlate of this finding remains undefined, future
studies should avoid the assumption that PsA in child-
hood constitutes a single etiologic entity.
The classification of pediatric rheumatic disease
is hampered by a limited understanding of the patho-
genesis. Hence, patients have traditionally been grouped
according to clinical disease pattern; such grouping has
important implications for research and clinical care.
One such diagnostic grouping is juvenile psoriatic arthri-
tis (PsA). Juvenile PsA was initially described in children
with arthritis who at some point in their disease course
exhibited frank psoriasis (1–5); however, it is now well
accepted that juvenile PsA may be diagnosed in patients
without the classic skin rash but meeting other criteria,
including typical skin/nail changes and a positive family
history of psoriasis (6–9). Using this standard, juvenile
PsA is diagnosed in ⬃5% of children with arthritis seen
in pediatric rheumatology clinics, a prevalence slightly
higher than that of rheumatoid factor–positive juvenile
polyarticular arthritis (10).
Both the Vancouver criteria for juvenile PsA (6)
and the International League of Associations for Rheu-
matology (ILAR) nomenclature for juvenile idiopathic
arthritis (JIA) (8) consider PsA in children to represent
a single clinical entity. In several published series, how-
ever, clinical and genetic differences have been observed
between younger patients and older patients, although
small patient numbers have prohibited formal analysis
for subpopulations (6,9,11). Recognition of this hetero-
geneity resulted in a call for a more detailed clinical
TWO POPULATIONS OF PATIENTS WITH JUVENILE PsA
Table 1. Vancouver criteria for juvenile psoriatic arthritis*
Major criteria
Arthritis
Psoriasis
Minor criteria
Nail pitting
Dactylitis
Family history of psoriasis in a first- or second-degree relative
Psoriasis-like lesion
* Definite juvenile psoriatic arthritis (PsA) ⫽ 2 major criteria, or
arthritis plus 3–4 minor criteria; probable juvenile PsA ⫽ arthritis plus
2 minor criteria (for review, see ref. 6).
subgrouping within juvenile PsA, but more than a de-
cade later this has not been accomplished (11). The
identification of subgroups would be of considerable
interest, because it would enable more accurate pheno-
typic classification of patient groups for the purposes of
scientific investigation. Furthermore, distinct patient
groups might be expected to respond differentially to
treatment, potentially permitting more accurate thera-
peutic decision-making.
Accordingly, we studied our patients with juve-
nile PsA to determine whether they constitute a single
population or multiple populations. Here, we report that
juvenile PsA constitutes 2 distinct patient subgroups that
are distinguished by age at disease onset and the pres-
ence of dactylitis and are differentiated by sex ratio,
joints affected, laboratory values, and clinical course.
These findings suggest that current diagnostic criteria
capture 2 disease entities and indicate that PsA in
children is more complex than previously appreciated.
PATIENTS AND METHODS
Patients. We reviewed the charts of every patient seen
at the rheumatology clinic of Children’s Hospital Boston
between January 1997 and February 2005, for whom the
International Classification of Diseases, Ninth Revision codes
were 696.1 (psoriasis), 696.0 (PsA), or 756.11 (spondylar-
thritis).
Patients were included in the study if they fulfilled the
Vancouver criteria for probable or definite juvenile PsA (6)
(Table 1). These criteria were selected instead of the ILAR
criteria for psoriatic JIA (8), because many patients met
criteria on the basis of rashes that were judged as being
psoriasiform but were not formally diagnosed as psoriasis; such
a presentation is especially common in younger children (12).
We reviewed the medical records for pertinent historic
elements, physical examination findings, and laboratory values.
When available, studies obtained elsewhere that were con-
tained in the medical record were included in the review.
The following definitions were used to categorize
findings from chart review. A patient was considered to have
psoriasis if that diagnosis had been given definitively by a
3565
dermatologist or other physician; rashes noted by the examin-
ing rheumatologist and thought likely (but not definitively) to
represent psoriasis were considered psoriasis-like. Polyarticu-
lar arthritis was defined by the involvement of ⱖ5 joints
cumulatively at any point over the course of observation.
Oligoarticular arthritis was defined by involvement of ⬍5
joints. Small peripheral joints were considered to be the
metacarpophalangeal and interphalangeal joints of the hands
and the corresponding joints of the feet. Large peripheral
joints included the wrists, elbows, knees, and ankles. Axial
joints included the temporomandibular joints, shoulders, cer-
vical or lumbar spine, sacroiliac joints, and hips. Dactylitis was
defined as digital swelling extending beyond the margins of the
joint. All patients with dactylitis were considered also to have
small-joint arthritis in the corresponding digit(s), although
specific attribution to proximal interphalangeal or distal inter-
phalangeal joint involvement could not always be made. En-
thesitis was defined as any tenderness at tendinous, ligamen-
tous, capsular, or fascial insertions into bone, as determined by
the examining attending pediatric rheumatologist. Remission
was defined as the absence of clinically evident synovitis or
enthesitis, on or off medications; laboratory parameters were
not employed. Remission off medications was defined as
remission in any patient not actively receiving therapy, exclud-
ing nonsteroidal antiinflammatory drugs taken as needed but
less often than daily. Antinuclear antibody (ANA) values were
considered positive if they were above the upper limits of
normal for the laboratory in which the test was performed. A
Steinbrocker class was assigned by the rheumatologist review-
ing the chart, on the basis of functional restrictions reported at
the final visit (13). Institutional review board approval was
obtained for this study.
Statistical analysis. We compared categorical data and
proportions using the chi-square test or Fisher’s exact test, as
indicated. Means were compared with Student’s t-test, and
medians were compared with the Mann-Whitney U test.
Analysis of normality was performed with the Kolmogorov-
Smirnov test with Lilliefors correction, with a significant P
value indicating evidence of non-normality. Because this was
an exploratory study, we elected to display differences signifi-
cant at a 2-tailed P value of less than 0.05, uncorrected for
multiple comparisons (14,15). The more conservative Bonfer-
roni correction was also applied, and the resulting significance
thresholds are shown in the footnotes of the respective tables.
To analyze our data for clinical subsets, we applied
2-step cluster analysis using log-likelihood distance measures.
For this analysis, we selected the following 8 clinical and
laboratory variables: sex, presence of psoriasis, dactylitis, en-
thesitis, axial disease, oligoarticular onset, and ANA positivity
(all expressed as categorical variables), with age at onset as a
continuous variable. Only patients for whom complete infor-
mation was available were included. The goal was to identify
clusters that minimize differences within groups and maximize
differences between groups. The first step involved a preclus-
tering routine that arrayed patients into a cluster feature tree.
The initial patient defined a subcluster, and each additional
patient was added either to the existing subcluster or to a new
one, depending on the degree of similarity to patients in
existing subclusters. In the second step, subclusters within the
cluster feature tree were grouped using an agglomerative
hierarchical clustering algorithm designed to identify the opti-
mal number of clusters (from 1 to 15) based on functions of the
3566 STOLL ET AL

Table 2. Clinical characteristics of patients according to subclass of juvenile PsA*

Probable Definite
Total PsA PsA
Characteristic (n ⫽ 139) (n ⫽ 73) (n ⫽ 66) P
Female sex, % 59 49 70 0.015
Duration of followup, median (IQR) months 23 (8.5–49) 23 (9.1–42) 23 (6.2–55) NS
Psoriasis, % 25 0 53 ⬍0.001
Age, median (IQR) years 7.3 (2.5–11) 7.8 (2.6–10) 7.2 (2.3–12) NS
Joints affected, %
Any axial 20 25 15 NS
Temporomandibular 6.5 6.8 6.1 NS
Shoulder 2.9 5.5 0 NS
Spine 2.2 0 4.5 NS
Sacroiliac 0.7 0 1.5 NS
Hip 11 14 7.6 NS
Any peripheral large joint 80 77 83 NS
Elbow 13 14 12 NS
Wrist 25 27 23 NS
Knee 60 58 64 NS
Ankle 51 47 56 NS
Any peripheral small joint 57 56 58 NS
Metacarpophalangeal 18 15 21 NS
Proximal interphalangeal 24 25 24 NS
Distal interphalangeal 9.4 9.6 9.1 NS
Metatarsophalangeal 13 11 15 NS
Dactylitis, % 37 32 42 NS
Enthesitis, % 45 49 39 NS
ESR, mean ⫾ SD mm/hour 25 ⫾ 20 26 ⫾ 24 25 ⫾ 15 NS
C-reactive protein, mean ⫾ SD mg/dl 0.6 ⫾ 1 0.6 ⫾ 0.8 0.6 ⫾ 1 NS
Platelet count, ⫻1,000 cells/␮l, mean ⫾ SD 361 ⫾ 102 365 ⫾ 103 356 ⫾ 102 NS
White blood cell count, ⫻1,000 cells/␮l, mean ⫾ SD 8.7 ⫾ 3.7 8.8 ⫾ 4.1 8.5 ⫾ 3.3 NS
ANA status, no. positive/no. tested (%) 54/117 (46) 29/62 (47) 25/55 (45) NS
HLA–B27 status, no. positive/no. tested (%) 6/13 (46) 3/7 (43) 3/6 (50) NS
Treatment, %
Sulfasalazine 52 47 58 NS
Methotrexate 46 45 47 NS
Tumor necrosis factor inhibitors 12 8.2 17 NS
Any disease-modifying antirheumatic drug 74 68 80 NS
Disease course, %
Oligoarticular at first visit 89 92 86 NS
Oligoarticular at 6 months† 84 87 80 NS
Oligoarticular course† 77 82 71 NS
Uveitis ever, no. positive/no. tested (%) 6/76 (7.9) 3/46 (6.5) 3/30 (10) NS
Remission off therapy at last examination, %‡ 41 48 32 NS
Remission at last examination, %‡ 57 58 56 NS
Time to remission, median (IQR) months‡ 15 (4.1–42) 16 (5.3–36) 15 (3.0–48) NS
Steinbrocker class I at last visit, %‡ 81 79 84 NS

* Except where indicated otherwise, values are the mean ⫾ SD. Probable versus definite juvenile psoriatic arthritis (PsA)
was defined according to the Vancouver criteria (see Table 1). P values less than 0.05 were considered significant.
Bonferroni’s adjustment changed the significance threshold to P ⬍ 0.0013. IQR ⫽ interquartile range; NS ⫽ not
significant; ESR ⫽ erythrocyte sedimentation rate; ANA ⫽ antinuclear antibody.
† Among those with at least 6 months of followup (for probable PsA, n ⫽ 60; for definite PsA, n ⫽ 51).
‡ Reported for all patients with at least 2 visits (for probable PsA, n ⫽ 68; for definite PsA, n ⫽ 61).

Schwarz-Bayesian information criterion. Because the order of
patient entry into the cluster algorithm can affect the clusters
formed, we ran the analysis 100 times with randomly scrambled
patient order to assess the robustness of cluster findings (16).
Statistical analysis was performed using SPSS software (version
13.0; SPSS, Chicago, IL).
RESULTS
A total of 139 patients fulfilled the Vancouver
criteria for juvenile PsA (Table 2). The median age at
disease onset was 7.3 years, and 59% of the patients
were female. The duration of followup ranged from 1
visit to 8 years (median 23 months). Patients had be-
tween 1 and 33 visits (median 6).
Among the 139 patients, psoriasis was diagnosed
in 35 at some point over the course of observation.
Among the 104 children without psoriasis, 73 (53% of
the total group) met exactly 2 supplemental criteria, thus
fulfilling the diagnosis of probable PsA, while 31 chil-
TWO POPULATIONS OF PATIENTS WITH JUVENILE PsA
Figure 1. Age at onset of juvenile psoriatic arthritis. The data for age
at onset are inconsistent with a single normal distribution (P ⬍ 0.001
by Kolmogorov-Smirnov test with Lilliefors correction), conforming
best to 2 distributions (age at onset younger than age 5 years and 5
years of age and older [median ages 1.8 years and 10 years, respec-
tively]).
dren met 3 or more supplemental criteria. These 31
patients, plus the 35 patients with psoriasis, constituted
the group with definite juvenile PsA. As shown in Table
2, aside from the group of patients with definite juvenile
PsA having a higher percentage of psoriasis (53% versus
0% in the group with probable juvenile PsA; P ⬍ 0.001)
and females (70% versus 49% in the group with proba-
ble juvenile PsA; P ⫽ 0.015), there were no differences
in the demographic, clinical, or treatment parameters
between the group with definite juvenile PsA and the
group with probable juvenile PsA. Thus, the patients
were grouped for all subsequent data analysis.
The distribution of joint involvement is shown in
Table 2. In total, 28 children (20%) had some form of
axial disease. Of the larger joints, the knee was involved
most commonly, followed by the ankle, wrist, and elbow.
More than one-half of the patients exhibited synovitis of
the small joints of the hands or feet, including dactylitis
in more than one-third of patients. Enthesitis was diag-
nosed by the attending pediatric rheumatologist in 45%
of patients. Dactylitis was observed in 37% of patients
and, when present, was typically evident early in the
disease course: in 41 (80%) of 51 patients at the initial
evaluation and in 47 (92%) of 51 patients within the first
6 months of disease.
A histogram showing the age at onset of symp-
toms is provided in Figure 1. Two distributions are
apparent, with one peaking at approximately 2 years of
age and the other peaking in late childhood. Indeed, for
3567
the population as a whole the results of the Kolmogorov-
Smirnov test showed clear evidence of non-normality
(Lilliefors-corrected P ⬍ 0.001). Division into 2 sub-
groups according to age, optimally younger than age 5
years versus age 5 years and older, as determined by the
assessment of multiple potential cutoff values, resulted
in 2 populations, each deviating nonsignificantly from
normal by the Lilliefors-corrected Kolmogorov-Smirnov
test (P ⫽ 0.17 for children under age 5 years and P ⫽
0.20 for children 5 years of age and older).
Table 3 presents the clinical characteristics of
these 2 subpopulations. The younger patients (n ⫽ 49)
were significantly more likely to be female, to be ANA
positive, and to have polyarticular disease at the time of
presentation as well as at 6 months. Although the mean
erythrocyte sedimentation rates (ESRs) and levels of
C-reactive protein (CRP) were similar between sub-
groups, the mean platelet count was substantially ele-
vated in younger patients, consistent with ongoing sys-
temic inflammation. (The mean white blood cell count
was also higher among younger patients, but this differ-
ence was expected as a result of the different mean ages
of the subgroups; in contrast, the platelet count does not
vary with age [17]). Older children were more likely to
have axial disease and enthesitis. Uveitis occurred at a
similar frequency in both groups and in most cases was
asymptomatic and was discovered during routine oph-
thalmologic screening; one child in the older age group
reported associated photophobia.
Younger children were more likely to be treated
with methotrexate, while treatment with sulfasalazine
was far more common in the older children (Table 3).
Despite receiving care that was relatively more aggres-
sive, younger patients took substantially longer to enter
remission (defined as the absence of clinically detectable
synovitis or enthesitis, on or off medications) compared
with their older counterparts (23 months versus 9.2
months; P ⫽ 0.044). Overall, our patients had an excel-
lent functional outcome. At last evaluation, 81% of all
patients were in Steinbrocker class I, and the remainder
were in class II, with no differences between the age-
based subgroups (13). Both subgroups were equally
likely to be experiencing disease remission at the last
recorded visit (60% of patients with disease onset before
age 5 years versus 56% of those with disease onset at age
5 years or older [P ⫽ 0.66]; for remission off medica-
tions, 40% versus 41% [P ⫽ 0.92]).
Although age is a very important guide for clini-
cians who are structuring a differential diagnosis, it has
limited appeal as the defining characteristic of a complex
clinical subgroup. To investigate whether age at symp-
tom onset might serve as a marker of other clinical and
3568 STOLL ET AL

Table 3. Clinical characteristics of patients according to age*

⬍5 years ⱖ5 years
Characteristic (n ⫽ 49) (n ⫽ 90) P
Female sex, % 76 50 0.003
Duration of followup, median (IQR) months 23 (9.2–46) 22 (7.5–52) NS
Psoriasis, % 14 31 0.029
Age, median (IQR) years 1.8 (1.4–2.5) 10 (7.7–12) ⬍0.001
Joints affected, %
Any axial 10 26 0.031
Temporomandibular 4.1 7.8 NS
Shoulder 4.1 2.2 NS
Spine 0 3.3 NS
Sacroiliac 0 1.1 NS
Hip 4.1 14 NS
Any peripheral large joint 82 79 NS
Elbow 14 12 NS
Wrist 24 26 NS
Knee 61 60 NS
Ankle 59 47 NS
Any peripheral small joint 76 47 0.001
Metacarpophalangeal 18 18 NS
Proximal interphalangeal 26 23 NS
Distal interphalangeal 14 6.7 NS
Metatarsophalangeal 16 11 NS
Dactylitis, % 63 22 ⬍0.001
Enthesitis, % 22 57 ⬍0.001
ESR, mean ⫾ SD mm/hour 27 ⫾ 17 25 ⫾ 21 NS
C-reactive protein, mean ⫾ SD mg/dl 0.8 ⫾ 1 0.5 ⫾ 0.8 NS
Platelet count, ⫻1,000 cells/␮l, mean ⫾ SD 408 ⫾ 98 337 ⫾ 96 0.001
White blood cell count, ⫻1,000 cells/␮l, mean ⫾ SD 10.5 ⫾ 4.8 7.8 ⫾ 2.6 0.002
ANA status, no. tested/no. positive (%) 25/39 (64) 29/78 (37) 0.006
HLA–B27 status, no. tested/no. positive (%) 1/3 (33.3) 5/10 (50) NS
Treatment, %
Sulfasalazine 39 59 0.023
Methotrexate 59 39 0.022
Tumor necrosis factor inhibitors 10 13 NS
Any disease-modifying antirheumatic drug 74 74 NS
Course, %
Oligoarticular at first visit 80 94 0.007
Oligoarticular at 6 months† 69 92 0.002
Oligoarticular course† 67 82 NS
Uveitis ever, no. positive/no. tested (%) 3/38 (7.9) 3/38 (7.9) NS
Remission off therapy at last examination, %‡ 40 41 NS
Remission at last examination, %‡ 60 56 NS
Time to remission, median (IQR) months‡ 23 (11–49) 9.2 (3.4–37) 0.044
Steinbrocker class I at last visit, %‡ 82 81 NS

* P values less than 0.05 were considered significant. Bonferroni’s adjustment changed the significance threshold to P ⬍
0.0013. See Table 1 for definitions.
† Among those with at least 6 months of followup (for age younger than 5 years, n ⫽ 39; for age 5 years or older, n ⫽
72).
‡ Reported for all patients with at least 2 visits (for age younger than 5 years, n ⫽ 45; for age 5 years or older, n ⫽ 84).

laboratory features, we applied cluster analysis, using
age at onset as a continuous variable and sex, ANA
status, psoriasis, dactylitis, axial arthritis, enthesitis, and
oligoarticular onset as categorical variables. The selec-
tion of these variables was informed by our earlier
exploration of the age-based subgroups but was driven
also by our assessment that they represent, to a substan-
tial degree, the clinical heterogeneity observed in prac-
tice. Variables were chosen prior to the application of
the cluster algorithm and were not further amended in
the course of data analysis. For the purpose of cluster
analysis, we included only patients for whom complete
information was available. In practice, this led to the
exclusion of 22 patients whose ANA status was not
contained in the hospital medical record.
Consistent with our earlier findings, cluster ana-
lysis detected 2 distinct populations within the data set.
Allocation of patients to these clusters was highly robust,
remaining stable to random scrambling of patient order
in each of 100 iterations. The clinical characteristics of
TWO POPULATIONS OF PATIENTS WITH JUVENILE PsA 3569

Table 4. Clinical characteristics of patients according to cluster assignment*

Cluster 1 Cluster 2
Characteristic (n ⫽ 40) (n ⫽ 77) P
Female sex, % 75 52 0.016
Duration of followup, median (IQR) months 27 (10–49) 24 (8.8–55) NS
Psoriasis, % 10 29 0.022
Age under 5 years, % 60 20 ⬍0.001
Age, median (IQR) years 2.7 (1.4–8.5) 9.5 (6.2–11) ⬍0.001
Joints affected, %
Any axial 12 25 NS
Temporomandibular 5 7.8 NS
Shoulder 2.5 3.9 NS
Spine 0 3.9 NS
Sacroiliac 0 1.3 NS
Hip 5 13 NS
Any peripheral large joint 75 84 NS
Elbow 22 9.1 0.045
Wrist 30 27 NS
Knee 55 64 NS
Ankle 58 48 NS
Any peripheral small joint 100 32 ⬍0.001
Metacarpophalangeal 38 12 0.001
Proximal interphalangeal 42 18 0.005
Distal interphalangeal 12 7.8 NS
Metatarsophalangeal 20 7.8 NS
Dactylitis, % 100 1.3 ⬍0.001
Enthesitis, % 35 52 NS
ESR, mean ⫾ SD mm/hour 26 ⫾ 16 24 ⫾ 22 NS
C-reactive protein, mean ⫾ SD mg/dl 0.7 ⫾ 1 0.5 ⫾ 1 NS
Platelet count, ⫻1,000 cells/␮l, mean ⫾ SD 394 ⫾ 106 340 ⫾ 92 0.017
White blood cell count, ⫻1,000 cells/␮l, mean ⫾ SD 9.6 ⫾ 3.5 8.1 ⫾ 3.8 NS
ANA status, no. tested/no. positive (%) 28/47 (60) 26/77 (34) ⬍0.001
HLA–B27 status, no. tested/no. positive (%) 0/2 (0) 5/9 (56) NS
Treatment, %
Sulfasalazine 52 56 NS
Methotrexate 62 43 0.044
Tumor necrosis factor inhibitors 18 12 NS
Any disease-modifying antirheumatic drug 82 75 NS
Course, %
Oligoarticular at first visit 75 97 ⬍0.001
Oligoarticular at 6 months† 67 95 ⬍0.001
Oligoarticular† 58 89 ⬍0.001
Uveitis ever, no. tested/no. positive (%) 2/31 (6.5) 3/37 (8.1) NS
Remission off therapy at last examination, %‡ 26 47 0.026
Remission at last examination, %‡ 54 59 NS
Duration to remission, median (IQR) months‡ 25 (8.6–52) 15 (4.4–41) NS
Steinbrocker class I at last visit, %‡ 82 82 NS

* Variables used in cluster assignments are shown in boldface. P values less than 0.05 were considered significant.
Bonferroni’s adjustment changed the significance threshold to P ⬍ 0.0013. See Table 1 for definitions.
† Among those with at least 6 months of followup (for cluster 1, n ⫽ 35; for cluster 2, n ⫽ 62).
‡ Reported for all patients with at least 2 visits (for cluster 1, n ⫽ 41; for cluster 2, n ⫽ 71).

the 2 clusters corresponded well with the features of our
2 groups defined by age alone (Table 4 and Figure 2).
The median ages of children in the 2 clusters were 2.7
years (cluster 1) and 9.5 years (cluster 2), compared with
1.8 years and 10 years for the age-based grouping. Again,
patients in the cluster of younger children were more
likely to be female and to have small joint involvement,
polyarticular disease, and ANA positivity, while patients
in the older cluster were again equally divided among
the sexes and were more likely to have oligoarticular
disease.
Using cluster analysis, differences in both axial
joint involvement and enthesitis became nonsignificant,
while the percentage of patients achieving remission off
medications was significantly lower in the younger-age
cluster. Most strikingly, the key defining feature of
cluster assignment became the presence of dactylitis:
100% of patients in the younger-age cluster (cluster 1)
3570
Figure 2. Comparison of subpopulations of patients with juvenile psoriatic arthritis as defined by age at symptom onset (left) and cluster analysis
(right). Antinuclear antibody (ANA) positivity is expressed as the percentage of patients for whom ANA data were available.
had dactylitis, compared with only 1.3% of patients in
the older-age cluster (cluster 2). Age at onset, although
critical to formation of the clusters as determined by
repetition of the analysis without this variable, was less
clearly segregated: only 60% of patients within the
dactylitis cluster had disease onset at an age younger
than 5 years, while 20% of patients in the nondactylitis
cluster also had disease onset at this age range.
DISCUSSION
In the absence of a biologic gold standard, the
classification of rheumatologic diseases is obligatorily
based on clinical, laboratory, and occasionally genetic
data. For this purpose, close phenotyping is essential to
ensure that subsequent research is not hampered by the
conflation of distinct disorders. However, the relevant
variables for such classification are not trivially ascer-
tained. This is evident in the uncertainty surrounding the
classification of adult PsA. Moll and Wright (18) cate-
gorized patients into 5 clinical subcategories based on
patterns of joint involvement, yet these subcategories
have had limited utility in clinical practice and in re-
search, in part because joint involvement may evolve
over time (19).
This problem is compounded in pediatric rheu-
matology by the observation that children commonly
present with arthritis years before the development of
skin involvement (2,5,6,9,20). To the extent that such
patients can be identified, for example via the Vancou-
ver and ILAR criteria, observers have considered the
possibility that important clinical subgroups of juvenile
PsA may exist (11,21). Southwood et al (6) and Truck-
enbrodt and Hafner (5) observed a biphasic age-at-onset
curve, while Shore and Ansell (2) and Roberton et al (9)
noted that younger patients were more likely to be
female. However, none of these series had the statistical
power to discriminate clinical subpopulations.
STOLL ET AL
Using the Vancouver criteria, we assembled a
series of patients with juvenile PsA; in our study, the
number of patients was approximately twice the number
of patients in each of the largest prior cohorts (2,9,11).
Analysis of this data set provides the first statistical
evidence that children with juvenile PsA fall into 2
distinct phenotypic subgroups. We observed that pa-
tients younger than age 5 years are more likely to be
female and ANA positive and to have dactylitis; they are
also more likely to experience polyarticular onset. Al-
though the ESRs and the CRP levels at presentation
were equivalent between subgroups, an elevated platelet
count suggested more systemic inflammation in the
younger children. In contrast, children older than age 5
years were evenly split between males and females and
were more likely to be ANA negative, to exhibit enthesi-
tis and axial joint involvement, and to present with and
continue to have oligoarticular involvement. Perhaps sur-
prisingly, uveitis was equally prevalent in both groups.
In addition to these clinical differences, younger
and older patients appeared to exhibit divergent re-
sponses to therapy. Sulfasalazine is rarely prescribed for
children younger than age 2 years due to a paucity of
safety data in this age group (22); therefore, it was not
unexpected to observe that younger patients were
treated less often with sulfasalazine and more often with
methotrexate. Despite therapy with what is generally
considered a more potent agent (23), disease in younger
patients took almost twice as long to enter remission
compared with disease in older children, although nearly
60% of children in both groups ultimately achieved
disease control during the study period.
These observations complement previous studies
of HLA associations in juvenile PsA. Ansell and col-
leagues performed HLA typing on 70 children meeting
the Vancouver criteria for juvenile PsA (11). Compari-
sons within the group suggested interesting HLA differ-
TWO POPULATIONS OF PATIENTS WITH JUVENILE PsA
ences between patients with onset before versus after 6
years of age. Indeed, it was recently proposed that age at
onset may be quite important in the identification of
etiologically homogeneous subtypes of juvenile arthritis
(24). Early onset may reflect an aberrant response to an
endemic infectious pathogen encountered within the
first few years of life, while later onset could represent a
response to accumulated injury or to an environmental
trigger encountered more rarely or at a later phase in
life. Indeed, age dependence is evident in both psoriasis
and PsA in adults, with patients with disease onset at an
age younger than 40 years exhibiting stronger HLA
linkage and a higher genetic risk of relatives being
similarly afflicted (25).
Although analysis by age at onset confirmed
indications from prior literature, we wished to refine our
analysis to explore further the clinical and laboratory
features that optimally identify subpopulations of pa-
tients with juvenile PsA. Cluster analysis is a statistical
technique that can detect latent relationships within a
complex data set between individuals with multiple
distinct characteristics, in this case age at onset, sex,
ANA status, oligoarticular involvement, dactylitis, en-
thesitis, axial disease, and psoriasis (16). Individuals are
grouped together in clusters in an attempt to minimize
differences between cluster members while maximizing
differences between individuals in different clusters.
Discretion in the choice of input variables and in the
assumptions used to calculate similarity renders cluster
analysis, as used here, an essentially exploratory statis-
tical technique. Furthermore, the cluster analysis algo-
rithms we used gave equal weights to differences in the
various categorical variables, potentially distorting bio-
logic relevance. For example, it may not be the case that
2 individuals who are ANA positive are “just as similar”
as are 2 individuals of the same sex or 2 individuals who
share the presence of dactylitis. With these caveats,
cluster analysis provides an objective method to deter-
mine whether a heterogeneous group contains distinct
subsets without assuming the primacy of any 1 variable
(e.g., age at onset).
Using cluster analysis, the optimum number of
subpopulations in our cohort was found to be 2, with
clinical and laboratory characteristics that corresponded
well but not perfectly to those of the subgroups defined
by age at onset alone (Table 4 and Figure 2). However,
cluster analysis using the specified input variables gen-
erated the provocative alternative hypothesis that differ-
ences observed across the age spectrum result from the
nonuniform age distribution of a subform of arthritis
featuring dactylitis. This hypothesis would also be con-
sistent with the age-dependent distribution of HLA
3571
subtypes observed by Ansell and colleagues (11) and
invites speculation as to the manner in which the patho-
physiology of dactylitis (tenosynovitis, small joint arthri-
tis, periostitis, enthesitis) might reflect a distinct patho-
genesis for this subform of disease (26,27). Our data are
unable to adjudicate between the age-based subgroups
and the dactylitis-based clusters, because both are con-
sistent with all available information.
Another alternate explanation for heterogeneity
would be unmeasured factors, including perhaps most
prominently the presence of HLA–B27 as a known risk
factor for axial disease in adult PsA (28). In this series,
the number of patients tested for the HLA–B27 antigen
was low, likely reflecting the prevailing opinion of clini-
cians in our center that such testing rarely impacts on
diagnostic or therapeutic decisions (29). Because previ-
ous studies have documented that the prevalence of
HLA–B27 among patients with a diagnosis of juvenile
PsA according to the Vancouver criteria is ⬍20%, it is
clear that this factor could not, by itself, define either of
the subgroups we identified (11,30). Published data for
children meeting the Vancouver criteria for juvenile PsA
suggest that HLA–B27 could be somewhat more com-
mon in children with an age at onset of ⬎6 years (3
[11.5%] of 26 versus 11 [25%] of 44; P ⫽ 0.17 [analyzed
from raw data provided in ref. 11]). Correspondingly, of
the 6 patients in our cohort who were positive for
HLA–B27, 5 had disease onset at age 5 years or older; 3
of 6 HLA–B27–positive patients had axial disease com-
pared with none of 7 patients who were negative for the
antigen (P ⫽ 0.07, by Fisher’s exact test).
To address the concern that the observed differ-
ences between subgroups reflect the presence or ab-
sence of HLA–B27, we repeated our analysis excluding
every child with axial disease, thus maximally depleting
HLA–B27–positive patients from the cohort. Despite
excluding these 28 children, we still observed that
younger children were more likely to be female, to
demonstrate small joint involvement, to have a polyar-
ticular course, and to have elevated platelet counts and
ANA positivity, and were less likely to have enthesitis
(all P ⬍ 0.05; data not shown). This analysis suggests
that, even in the absence of axial disease and HLA–B27,
older children have different epidemiologic and clinical
features compared with their younger counterparts.
Along with other findings in this essentially exploratory
study, the role of HLA–B27 in juvenile PsA will require
investigation and validation in other cohorts.
The finding that children with PsA fall into 2
phenotypic groups is open to at least 2 interpretations. The
first is that the arthritic manifestations of psoriasis change
with the age of the patient at disease onset or with
3572
exposures for which age is a marker, such as infections,
vaccinations, and environmental toxins. The second inter-
pretation is that there are, in fact, 2 broad types of PsA in
children, arising through the activity of distinct genetic and
environmental factors. Based on the data presented here,
we are unable to decide between these 2 possibilities.
However, differences in sex ratios, ANA status, and HLA
types (11) between the 2 phenotypic populations suggest
that divergent pathophysiologic processes may be involved,
thus favoring the second hypothesis.
In summary, we identified 139 children who
fulfilled the Vancouver criteria for juvenile PsA. Our
data confirm the existence of 2 distinct subpopulations
within this cohort: a group of younger children, most of
whom are female, experience more small joint involve-
ment and dactylitis and require longer to achieve disease
remission, and an older group split evenly between boys
and girls and with an increased incidence of axial disease
and enthesitis. Alternately, roughly similar groups can
be identified by the presence of dactylitis, a strong
correlate of young age. Although both of these sub-
groups may still properly be considered to have arthritic
manifestations of the psoriatic diathesis, they should no
longer be assumed to be a homogeneous population for
the purpose of etiologic and therapeutic studies.
ACKNOWLEDGMENT
We thank Dr. Bryce A. Binstadt for graphics expertise
and for thoughtful review of the manuscript.
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