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Patients with juvenile psoriatic arthritis comprise two distinct populations.

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ARTHRITIS & RHEUMATISM
Vol. 54, No. 11, November 2006, pp 3564–3572
DOI 10.1002/art.22173
© 2006, American College of Rheumatology
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
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 childhood constitutes a single etiologic entity.
Objective. Psoriatic arthritis (PsA) in children is
clinically heterogeneous. We examined a large population 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 counterparts 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 approximately 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 oligoarthritis. Uveitis is equally represented in both age
groups. Despite a higher utilization of methotrexate
therapy, younger patients required, on average, more
The classification of pediatric rheumatic disease
is hampered by a limited understanding of the pathogenesis. 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 arthritis (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 Rheumatology (ILAR) nomenclature for juvenile idiopathic
arthritis (JIA) (8) consider PsA in children to represent
a single clinical entity. In several published series, however, 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 heterogeneity resulted in a call for a more detailed clinical
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 Longwood Avenue, Fegan 6, Boston, MA 02115. E-mail: [email protected]
partners.org.
Submitted for publication March 13, 2006; accepted in revised
form July 24, 2006.
3564
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 decade later this has not been accomplished (11). The
identification of subgroups would be of considerable
interest, because it would enable more accurate phenotypic 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 therapeutic decision-making.
Accordingly, we studied our patients with juvenile 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 presence 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 (spondylarthritis).
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 contained 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 examining rheumatologist and thought likely (but not definitively) to
represent psoriasis were considered psoriasis-like. Polyarticular 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, cervical 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 interphalangeal joint involvement could not always be made. Enthesitis was defined as any tenderness at tendinous, ligamentous, 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, excluding 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 reviewing 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 KolmogorovSmirnov 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 significant at a 2-tailed P value of less than 0.05, uncorrected for
multiple comparisons (14,15). The more conservative Bonferroni 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, enthesitis, 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 information 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 preclustering 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 optimal 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*
Characteristic
Female sex, %
Duration of followup, median (IQR) months
Psoriasis, %
Age, median (IQR) years
Joints affected, %
Any axial
Temporomandibular
Shoulder
Spine
Sacroiliac
Hip
Any peripheral large joint
Elbow
Wrist
Knee
Ankle
Any peripheral small joint
Metacarpophalangeal
Proximal interphalangeal
Distal interphalangeal
Metatarsophalangeal
Dactylitis, %
Enthesitis, %
ESR, mean ⫾ SD mm/hour
C-reactive protein, mean ⫾ SD mg/dl
Platelet count, ⫻1,000 cells/␮l, mean ⫾ SD
White blood cell count, ⫻1,000 cells/␮l, mean ⫾ SD
ANA status, no. positive/no. tested (%)
HLA–B27 status, no. positive/no. tested (%)
Treatment, %
Sulfasalazine
Methotrexate
Tumor necrosis factor inhibitors
Any disease-modifying antirheumatic drug
Disease course, %
Oligoarticular at first visit
Oligoarticular at 6 months†
Oligoarticular course†
Uveitis ever, no. positive/no. tested (%)
Remission off therapy at last examination, %‡
Remission at last examination, %‡
Time to remission, median (IQR) months‡
Steinbrocker class I at last visit, %‡
Total
(n ⫽ 139)
Probable
PsA
(n ⫽ 73)
Definite
PsA
(n ⫽ 66)
59
23 (8.5–49)
25
7.3 (2.5–11)
49
23 (9.1–42)
0
7.8 (2.6–10)
70
23 (6.2–55)
53
7.2 (2.3–12)
20
6.5
2.9
2.2
0.7
11
80
13
25
60
51
57
18
24
9.4
13
37
45
25 ⫾ 20
0.6 ⫾ 1
361 ⫾ 102
8.7 ⫾ 3.7
54/117 (46)
6/13 (46)
25
6.8
5.5
0
0
14
77
14
27
58
47
56
15
25
9.6
11
32
49
26 ⫾ 24
0.6 ⫾ 0.8
365 ⫾ 103
8.8 ⫾ 4.1
29/62 (47)
3/7 (43)
15
6.1
0
4.5
1.5
7.6
83
12
23
64
56
58
21
24
9.1
15
42
39
25 ⫾ 15
0.6 ⫾ 1
356 ⫾ 102
8.5 ⫾ 3.3
25/55 (45)
3/6 (50)
52
46
12
74
89
84
77
6/76 (7.9)
41
57
15 (4.1–42)
81
47
45
8.2
68
92
87
82
3/46 (6.5)
48
58
16 (5.3–36)
79
58
47
17
80
86
80
71
3/30 (10)
32
56
15 (3.0–48)
84
P
0.015
NS
⬍0.001
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
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 between 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, respectively]).
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 probable 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 diagnosed 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 symptoms 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 KolmogorovSmirnov test showed clear evidence of non-normality
(Lilliefors-corrected P ⬍ 0.001). Division into 2 subgroups 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 subgroups, the mean platelet count was substantially elevated in younger patients, consistent with ongoing systemic inflammation. (The mean white blood cell count
was also higher among younger patients, but this difference 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 ophthalmologic 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 aggressive, 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 excellent 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 agebased 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 medications, 40% versus 41% [P ⫽ 0.92]).
Although age is a very important guide for clinicians who are structuring a differential diagnosis, it has
limited appeal as the defining characteristic of a complex
clinical subgroup. To investigate whether age at symptom onset might serve as a marker of other clinical and
3568
STOLL ET AL
Table 3. Clinical characteristics of patients according to age*
Characteristic
Female sex, %
Duration of followup, median (IQR) months
Psoriasis, %
Age, median (IQR) years
Joints affected, %
Any axial
Temporomandibular
Shoulder
Spine
Sacroiliac
Hip
Any peripheral large joint
Elbow
Wrist
Knee
Ankle
Any peripheral small joint
Metacarpophalangeal
Proximal interphalangeal
Distal interphalangeal
Metatarsophalangeal
Dactylitis, %
Enthesitis, %
ESR, mean ⫾ SD mm/hour
C-reactive protein, mean ⫾ SD mg/dl
Platelet count, ⫻1,000 cells/␮l, mean ⫾ SD
White blood cell count, ⫻1,000 cells/␮l, mean ⫾ SD
ANA status, no. tested/no. positive (%)
HLA–B27 status, no. tested/no. positive (%)
Treatment, %
Sulfasalazine
Methotrexate
Tumor necrosis factor inhibitors
Any disease-modifying antirheumatic drug
Course, %
Oligoarticular at first visit
Oligoarticular at 6 months†
Oligoarticular course†
Uveitis ever, no. positive/no. tested (%)
Remission off therapy at last examination, %‡
Remission at last examination, %‡
Time to remission, median (IQR) months‡
Steinbrocker class I at last visit, %‡
⬍5 years
(n ⫽ 49)
ⱖ5 years
(n ⫽ 90)
P
76
23 (9.2–46)
14
1.8 (1.4–2.5)
50
22 (7.5–52)
31
10 (7.7–12)
0.003
NS
0.029
⬍0.001
10
4.1
4.1
0
0
4.1
82
14
24
61
59
76
18
26
14
16
63
22
27 ⫾ 17
0.8 ⫾ 1
408 ⫾ 98
10.5 ⫾ 4.8
25/39 (64)
1/3 (33.3)
26
7.8
2.2
3.3
1.1
14
79
12
26
60
47
47
18
23
6.7
11
22
57
25 ⫾ 21
0.5 ⫾ 0.8
337 ⫾ 96
7.8 ⫾ 2.6
29/78 (37)
5/10 (50)
0.031
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.001
NS
NS
NS
NS
⬍0.001
⬍0.001
NS
NS
0.001
0.002
0.006
NS
39
59
10
74
80
69
67
3/38 (7.9)
40
60
23 (11–49)
82
59
39
13
74
94
92
82
3/38 (7.9)
41
56
9.2 (3.4–37)
81
0.023
0.022
NS
NS
0.007
0.002
NS
NS
NS
NS
0.044
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 selection 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 substantial degree, the clinical heterogeneity observed in practice. 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 analysis 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*
Characteristic
Female sex, %
Duration of followup, median (IQR) months
Psoriasis, %
Age under 5 years, %
Age, median (IQR) years
Joints affected, %
Any axial
Temporomandibular
Shoulder
Spine
Sacroiliac
Hip
Any peripheral large joint
Elbow
Wrist
Knee
Ankle
Any peripheral small joint
Metacarpophalangeal
Proximal interphalangeal
Distal interphalangeal
Metatarsophalangeal
Dactylitis, %
Enthesitis, %
ESR, mean ⫾ SD mm/hour
C-reactive protein, mean ⫾ SD mg/dl
Platelet count, ⫻1,000 cells/␮l, mean ⫾ SD
White blood cell count, ⫻1,000 cells/␮l, mean ⫾ SD
ANA status, no. tested/no. positive (%)
HLA–B27 status, no. tested/no. positive (%)
Treatment, %
Sulfasalazine
Methotrexate
Tumor necrosis factor inhibitors
Any disease-modifying antirheumatic drug
Course, %
Oligoarticular at first visit
Oligoarticular at 6 months†
Oligoarticular†
Uveitis ever, no. tested/no. positive (%)
Remission off therapy at last examination, %‡
Remission at last examination, %‡
Duration to remission, median (IQR) months‡
Steinbrocker class I at last visit, %‡
Cluster 1
(n ⫽ 40)
Cluster 2
(n ⫽ 77)
P
75
27 (10–49)
10
60
2.7 (1.4–8.5)
52
24 (8.8–55)
29
20
9.5 (6.2–11)
0.016
NS
0.022
⬍0.001
⬍0.001
12
5
2.5
0
0
5
75
22
30
55
58
100
38
42
12
20
100
35
26 ⫾ 16
0.7 ⫾ 1
394 ⫾ 106
9.6 ⫾ 3.5
28/47 (60)
0/2 (0)
25
7.8
3.9
3.9
1.3
13
84
9.1
27
64
48
32
12
18
7.8
7.8
1.3
52
24 ⫾ 22
0.5 ⫾ 1
340 ⫾ 92
8.1 ⫾ 3.8
26/77 (34)
5/9 (56)
NS
NS
NS
NS
NS
NS
NS
0.045
NS
NS
NS
⬍0.001
0.001
0.005
NS
NS
⬍0.001
NS
NS
NS
0.017
NS
⬍0.001
NS
52
62
18
82
75
67
58
2/31 (6.5)
26
54
25 (8.6–52)
82
56
43
12
75
97
95
89
3/37 (8.1)
47
59
15 (4.4–41)
82
NS
0.044
NS
NS
⬍0.001
⬍0.001
⬍0.001
NS
0.026
NS
NS
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
STOLL ET AL
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 ascertained. This is evident in the uncertainty surrounding the
classification of adult PsA. Moll and Wright (18) categorized patients into 5 clinical subcategories based on
patterns of joint involvement, yet these subcategories
have had limited utility in clinical practice and in research, in part because joint involvement may evolve
over time (19).
This problem is compounded in pediatric rheumatology 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 Vancouver and ILAR criteria, observers have considered the
possibility that important clinical subgroups of juvenile
PsA may exist (11,21). Southwood et al (6) and Truckenbrodt 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.
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 patients 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. Although 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 enthesitis and axial joint involvement, and to present with and
continue to have oligoarticular involvement. Perhaps surprisingly, uveitis was equally prevalent in both groups.
In addition to these clinical differences, younger
and older patients appeared to exhibit divergent responses 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 colleagues performed HLA typing on 70 children meeting
the Vancouver criteria for juvenile PsA (11). Comparisons 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 patients 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, enthesitis, 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 statistical technique. Furthermore, the cluster analysis algorithms we used gave equal weights to differences in the
various categorical variables, potentially distorting biologic 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 determine 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 generated the provocative alternative hypothesis that differences observed across the age spectrum result from the
nonuniform age distribution of a subform of arthritis
featuring dactylitis. This hypothesis would also be consistent 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 pathophysiology of dactylitis (tenosynovitis, small joint arthritis, periostitis, enthesitis) might reflect a distinct pathogenesis 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 consistent 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 clinicians in our center that such testing rarely impacts on
diagnostic or therapeutic decisions (29). Because previous 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 common 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 compared 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 differences between subgroups reflect the presence or absence 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 polyarticular 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
STOLL ET AL
exposures for which age is a marker, such as infections,
vaccinations, and environmental toxins. The second interpretation 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 involvement 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 subgroups 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.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
ACKNOWLEDGMENT
We thank Dr. Bryce A. Binstadt for graphics expertise
and for thoughtful review of the manuscript.
23.
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