ARTHRITIS & RHEUMATISM

Vol. 63, No. 9, September 2011, pp 2809–2818

DOI 10.1002/art.30426
© 2011, American College of Rheumatology

Ongoing Disease Activity and Changing Categories in

a Long-Term Nordic Cohort Study of
Juvenile Idiopathic Arthritis

Ellen Nordal,1 Marek Zak,2 Kristiina Aalto,3 Lillemor Berntson,4 Anders Fasth,5
Troels Herlin,6 Pekka Lahdenne,3 Susan Nielsen,2 Bjørn Straume,7 and Marite Rygg,8
for the Nordic Study Group of Pediatric Rheumatology

Objective. To describe the disease characteristics, children. At the last followup visit, remission off medi-
long-term course, and outcome of patients with juvenile cation was observed in 42.4% of the children, 8.9% were
idiopathic arthritis (JIA) in a population-based setting. in remission on medication, and 48.7% were not in
Methods. Consecutive cases of JIA from defined remission. The highest rates of remission were observed
geographic areas of Denmark, Finland, Sweden, and in patients with persistent oligoarticular JIA and in
Norway in whom disease onset occurred in 1997–2000 those with systemic JIA.
were included in a prospective, multicenter cohort Conclusion. In this long-term prospective study of
study. The study was designed to be as close to a JIA in a population-based Nordic setting, ongoing dis-
population-based study as possible, with centers partic- ease was evident in a majority of the children. The
ipating only if they were able to include in their catch- present results underline the need to identify early
ment area all children in whom JIA was diagnosed. predictors of outcome, to further improve therapy, and
Results. Of 500 children included, 440 (88.0%) to continue long-term followup of patients with JIA.
had repeated visits, with the last visit occurring at least
7 years after disease onset (median 98 months, range Juvenile idiopathic arthritis (JIA) is a diverse
84–147 months). Changes in the International League entity of chronic childhood arthritis. The disease spec-
of Associations for Rheumatology category were ob- trum spans from time-limited monarthritis to ongoing
served in 10.8% of the children, and, in addition, destructive polyarticular disease and may include severe
extended oligoarthritis developed in 34.7% of the group systemic features or sight-threatening uveitis. In an era
with oligoarticular JIA. During the observation period, of modern medical treatment, updated knowledge on
58.0% of the children were treated with disease-
the clinical course and outcome of JIA is essential. Such
modifying antirheumatic drugs, including biologic med-
knowledge provides a fundamental basis for making
ications. Ongoing disease activity was mostly mild, but
clinical decisions regarding treatment and followup, for
some JIA-related damage developed in 22.9% of the
presenting evidence-based information on prognosis to
Supported by grants from the Helse Nord Research Program. affected children and their parents, and for health
1
Ellen Nordal, MD: University Hospital of North Norway and planning for chronic childhood diseases on a societal
University of Tromsø, Tromsø, Norway; 2Marek Zak, MD, Susan level.
Nielsen, MD: Rigshospitalet, Copenhagen, Denmark; 3Kristiina Aalto,
MD, PhD, Pekka Lahdenne, MD, PhD: Hospital for Children and When studying the long-term outcome of JIA,
Adolescents and University of Helsinki, Helsinki, Finland; 4Lillemor one should be aware of 2 common pitfalls (1). First, the
Berntson, MD, PhD: Uppsala University, Uppsala, Sweden; 5Anders
Fasth, MD, PhD: University of Gothenburg, Gothenburg, Sweden;
duration and chronicity of the disease may be underes-
6
Troels Herlin, MD, PhD: Århus University Hospital, Skejby, Den- timated, because studies of cross-sectional design will
mark; 7Bjørn Straume, MD: University of Tromsø, Norway; 8Marite miss fluctuations of disease activity over time (1–3).
Rygg, MD, PhD: Norwegian University of Science and Technology
and St. Olavs Hospital, Trondheim, Norway. Second, selection bias in studies from tertiary centers
Address correspondence to Ellen Nordal, MD, Department may overestimate the prevalence of the more severe
of Pediatrics, University Hospital of North Norway, N-9038 Tromsø, cases and categories of JIA. Hospital-based cohorts and
Norway. E-mail: ellen.nordal@unn.no.
Submitted for publication November 26, 2010; accepted in register studies have limitations in terms of validity and
revised form April 21, 2011. reliability, emphasizing the need for long-term followup
2809
2810 NORDAL ET AL

in nonselected and well-defined study populations (4). VAS (0 ⫽ no activity and 10 ⫽ maximum activity). HLA–B27
The last revision of the International League of Associ- antigens were analyzed at the time of disease onset, and
analyses of ANAs and rheumatoid factor (RF) were per-
ations for Rheumatology (ILAR) classification of JIA is
formed twice, at least 3 months apart. Each physician inter-
stated to represent a work in progress more than a static preted the results of the ANA and RF analyses as positive or
framework (5). The presence of antinuclear antibodies negative according to the reference values used by the local
(ANAs) and early-onset disease have recently been laboratory. In Sweden, Denmark, Finland, and Trondheim,
suggested as potential new category determinants in the Norway, ANAs were measured using immunofluorescence on
HEp-2 cells. In Tromsø, Norway, an ANA enzyme-linked
less well-defined JIA categories, in order to make cate-
immunosorbent assay (ELISA) was used; these results were
gories in the ILAR classification more homogeneous later excluded from the analyses, due to the limited clinical
(5–10). value in JIA (21). RF status was determined by ELISA
The uniform health system of the Nordic coun- (Denmark), nephelometry (Norway and Sweden), latex ag-
tries facilitates population-based studies and long-term glutination testing (Sweden), and immunoturbidimetric test-
ing (Finland). C-reactive protein was measured with im-
followup (11–15). The main objective of this Nordic munoassays, with upper normal values ranging from ⬍3 to
study was to describe the clinical manifestations, course, ⬍10 mg/liter; in the study protocol, the cut-off value for the
and outcome of JIA, according to the ILAR classifica- whole population was set to ⬍10 mg/liter.
tion, in a multicenter cohort during the first decade after At the final study visit, ⬃8 years after disease onset,
disease onset. extended information was collected, including an update on
family history. The Juvenile Arthritis Damage Index (JADI)
(22) was scored by the pediatric rheumatologist; articular
PATIENTS AND METHODS damage was scored on a scale in which 0 ⫽ no damage and
72 ⫽ maximum damage, extraarticular damage was scored on
Patients. In this prospective, multicenter cohort study, a scale in which 0 ⫽ no damage and 17 ⫽ maximum damage,
consecutive incident cases of newly diagnosed JIA from de- and global articular and extraarticular damage were scored on
fined geographic areas of Denmark, Finland, Norway, and a 10-cm VAS in which 0 ⫽ no damage and 10 ⫽ maximum
Sweden were included. The inclusion period was from January damage. Questionnaires on self-reported health-related qual-
1, 1997 to June 30, 2000 (for 3.5 years in Norway, 3.0 years in ity of life were registered; the Child Health Questionnaire
Sweden, Finland, and Copenhagen, Denmark, and for 1.5 (CHQ) was used for patients younger than age 18 years
years in Århus, Denmark). The incidence of JIA in the study (16–20), and the HAQ (23) (0 ⫽ best and 3 ⫽ worst) and Short
area in 1997–1998 was 15 per 100,000 children/year, as previ- Form 36 health survey (SF-36) (24) were used for patients
ously reported (11). older than age 18 years. The CHQ and the SF-36 are generic
During the study period, pediatric rheumatologists instruments comprising subscales on aspects of physical, emo-
from 12 participating centers registered all children with tional, and social health, yielding a physical score and a
JIA diagnosed according to the ILAR criteria. In the Nordic psychosocial summary score, with higher scores indicating
countries, all visits to primary care physicians and public better health (range 0–100, mean ⫾ SD 50 ⫾ 10) (25). For the
hospitals are mostly free of charge for children under 16 years final visit, participating patients received a letter of invitation
of age, and the healthcare systems include regular visits at a followed by a reminding letter; patients who did not respond
child health center for preschool children. With the aim of were contacted by telephone and asked to participate in a visit.
making the study as close to population-based as possible, In the minority of cases in which a final study visit was not
letters were repeatedly sent to the primary health care and all possible, the patients were asked to participate in a telephone
orthopedic, pediatric, and rheumatology specialists in the interview. The standardized telephone interview contained all
catchment areas during the inclusion period, requesting refer- information that otherwise, per protocol, was collected during
ral of potentially eligible patients. Family histories, extensive visits, and these patients were asked to fill in and return
clinical data including complete joint counts, medications used, relevant questionnaires.
patient/parent-completed health assessment measures, and JIA categories were determined according to the
results of blood tests were registered per protocol in a database ILAR criteria (5), based on all available information that was
at all study visits. A study visit was planned every 6 months registered at each visit during the study period, and for the
during the first year after disease onset and then every 1–2 majority of patients were determined separately by 2 of the
years during the observation period; in some centers, however, authors (LB and EN). A few discrepancies were settled by joint
fewer visits were registered. The minimum requirement for evaluation. In case of missing or conflicting information, each
continued inclusion in the followup study group was 2 regis- center was asked for clarifications repeatedly during the study.
tered visits, including the baseline visit and a followup visit Protocol details and definitions were clarified in the Nordic
more than 7 years after disease onset. JIA cohort study steering-group meeting twice yearly during
Scores for the Childhood Health Assessment Ques- the study period. Disease onset was defined as the date when
tionnaire (C-HAQ; 0 ⫽ best and 3 ⫽ worst) (16–20) and scores the child, according to anamnestic information, fulfilled the
on a 10-cm visual analog scale (VAS) for pain (0 ⫽ no pain and criteria for active arthritis or experienced the onset of systemic
10 ⫽ worst pain) and overall well-being (global health; 0 ⫽ features, not necessarily confirmed by a physician. Uveitis was
best and 10 ⫽ poorest) were provided by children who were registered as present and active when an ophthalmologist
older than age 9 years and by the parents of younger children. prescribed treatment for inflammation of the uvea. Remission
Global disease activity was assessed by the physicians, using a status was determined by the participating physicians accord-
Table 1. Clinical characteristics of patients in the Nordic JIA cohort at the first study visit, according to JIA categories*
JIA category

Polyarticular
No. of
patients Total cohort Systemic Oligoarticular RF negative RF positive Psoriatic Enthesitis-related Undifferentiated
Characteristic assessed (n ⫽ 440) (n ⫽ 17) (n ⫽ 225)† (n ⫽ 94) (n ⫽ 4) (n ⫽ 6) (n ⫽ 34) (n ⫽ 60)
Female sex, no. (%) 440 291 (66.1) 11 (64.7) 156 (69.3) 70 (74.5) 3 (75.0) 0 (0.0) 6 (17.6) 45 (75.0)
ANA positive, no. (%)‡ 391 107 (27.4) 0 (0) 66 (32.4) 29 (34.1) 1 (33.3) 0 (0) 2 (7.1) 9 (17.6)
HLA–B27 positive, no. (%) 385 83 (21.6) 0 (0) 30 (15.6) 16 (18.6) 0 (0) 0 (0) 25 (78.1) 12 (26.1)
Age at disease onset, years 440 5.5 (2.5–9.7) 4.7 (2.2–6.4) 4.9 (2.2–8.5) 4.8 (2.3–8.5) 11.7 (9.5–13.2) 5.9 (3.2–7.2) 10.5 (8.6–12.3) 8.1 (3.5–11.9)
ONGOING DISEASE ACTIVITY IN PATIENTS WITH JIA

Active joint count 399 3 (1–6) 3 (2–6) 2 (1–3) 7 (6–14) 11 (8–21) 1 (1–2) 2 (1–5) 4 (1–7)
CRP, mg/liter 332 14 (0–35) 146 (83–184) 11 (0–24) 24 (0–47) 27 (10–44) 12 (0–32) 23 (10–53) 0 (0–28)
ESR, mm/hour 333 35 (16–56) 101 (84–110) 30 (15–50) 42 (20–60) 28 (8–47) 16 (14–58) 41 (12–70) 24 (14–28)
Parent/patient’s global 271 1.0 (0.2–3.0) 1.6 (0.5–2.0) 2.2 (0.7–2.2) 2.0 (0.8–4.0) 1.5 (0.8–3.3) 1.4 (0.8–2.5) 2.4 (0.4–4.3) 1.1 (0.5–3.5)
assessment of well-being
score (0–10-point VAS)§
Physician’s global assessment of 248 1.0 (0.5–3.0) 1.0 (1.0–4.5) 1.0 (0–2.0) 2.0 (1.0–5.0) 1.7 (0.5–2.4) 1.6 (0.8–2.3) 3.0 (2.0–5.0) 1.2 (0.6–3.0)
overall disease activity score
(0–10-point VAS)
C-HAQ score (scale 0–3) 278 0.3 (0.0–1.0) 0 (0–0.1) 0.1 (0–0.8) 0.9 (0.3–1.4) 1.0 (0–1.3) 0.9 (0.4–1.9) 0.5 (0–1.1) 0.3 (0–0.6)
JADAS27 (scale 0–57) 197 5.0 (2.0–10.5) 3.0 (1.9–16.1) 3.0 (1.0–6.2) 10.3 (5.3–17.3) 5.2 (1.3–14.7) 5.5 (4.2–6.8) 9.3 (4.5–14.2) 6.9 (3.5–9.8)

* Except where indicated otherwise, values are the median (interquartile range). The first study visit occurred a median of 7 months after disease onset. Values for the active joint
count are the cumulative numbers of joints with active arthritis during the first 6 months after disease onset. Values for the C-reactive protein (CRP) level and the erythrocyte
sedimentation rate (ESR) are the maximum values reported during the first 6 months after disease onset. JIA ⫽ juvenile idiopathic arthritis; RF ⫽ rheumatoid factor; VAS ⫽ visual
analog scale; C-HAQ ⫽ Childhood Health Assessment Questionnaire; JADAS27 ⫽ Juvenile Arthritis Disease Activity Score in 27 joints.
† Assessed 6 months after disease onset, according to the International League of Associations for Rheumatology classification criteria.
‡ Antinuclear antibody (ANA) positivity was defined as positive results of 2 tests performed ⬎3 months apart.
§ Scores were provided by patients who were older than age 9 years and by the parents of younger patients.
2811
2812 NORDAL ET AL

ing to the preliminary criteria described by Wallace et al (26). at least 7 years after the onset of disease (median 98
Remission status was corrected by one of the authors (EN) if months, range 84–147 months). Of these final registra-
it was inconsistent with any of the recorded disease activity
variables. The occurrence of periods with inactive disease and tions, 376 (85.5%) were clinic visits, and 64 were tele-
remission and the Juvenile Arthritis Disease Activity Score phone interviews. Telephone interviews were mainly
based on 27 joints (JADAS27; 0 ⫽ no disease activity and 57 ⫽ performed when clinical followup had been transferred
maximum disease activity) were assessed by one of the authors from the pediatric rheumatologist either to adult care
(EN), using all available registrations (27).
Approval from medical ethics committees was granted because of age or to primary health care due to remis-
according to the regulations of each participating country. sion. During the disease course, patients had a median
Written informed consent was obtained from the parents of of 5 clinic visits with full data registration (range 2–10).
children younger than age 16 years and from the children who To our knowledge, only 3 of all eligible patients with JIA
were age 16 years or older.
Statistical analysis. Statistical analyses were per- did not agree to take part in the study. A comparison of
formed using Stata version 11 software. Descriptive statistics the followup group and the 12.0% of children lost to
were used to summarize the clinical characteristics of the followup revealed no significant differences in baseline
population and measures of disease activity. Chi-square and characteristics with respect to the number of active joints
Fisher’s exact tests were used as appropriate for comparison of
dichotomous variables, and the Mantel-Haentzel method was during the first 6 months after disease onset, the C-HAQ
used for stratified analyses to control for confounding. The and JADAS27 scores, or the proportion with oligoar-
Mann-Whitney U test was used for comparing medians for ticular arthritis.
skewed data. Student’s t-test was used to compare means for Characteristics of the patients at the first study
continuous outcome variables between groups. P values less
than 0.05 were considered significant. visit. The median time interval between disease onset
and the diagnosis of arthritis by a physician was 47 days
(interquartile range [IQR]) 14–98 days) (data not
RESULTS
shown). The first registration was performed a median
Study group. Of 500 included children with JIA, of 7 months (IQR 6–8 months) after disease onset. The
440 (88.0%) had a followup visit or telephone interview age of the children at the time of disease onset ranged

Figure 1. Distribution of International League of Associations for Rheumatology classification criteria categories in the Nordic juvenile idiopathic
arthritis cohort, 6 months after disease onset and at the final study visit (median 98 months after disease onset). RF ⫽ rheumatoid factor.
ONGOING DISEASE ACTIVITY IN PATIENTS WITH JIA 2813

from 0.1 to 15.9 years (median 5.5 years) (Table 1). The Table 2. Drug treatment received by patients in the Nordic juvenile
cumulative number of active joints during the first 6 idiopathic arthritis cohort*
months after disease onset ranged from 1 to 40 (median During the study At the final study
3). The prevalence of oligoarticular category was 51.1%. Treatment period (n ⫽ 440) visit (n ⫽ 440)
Disease course and outcome. ILAR categories. NSAIDs† 426 (96.8) 53 (12.0)
The distribution of ILAR categories continued to Corticosteroids
Intraarticular 326 (74.1) –
change from the time of the first evaluation 6 months Systemic 142 (32.3) 5 (1.1)
after disease onset and throughout the observation Methotrexate, total 213 (48.4) 99 (22.5)
period (Figure 1). Of the 225 children with oligoarticular Methotrexate, oral 211 (48.0) 78 (17.7)
Methotrexate, parenteral 66 (15.0) 21 (4.8)
disease at baseline, 78 (34.7%) had an extended course Biologic agents‡ 77 (17.5) 55 (12.5)
involving more than 4 joints. An additional 10.8% of the Etanercept 54 (12.3) 27 (6.1)
children changed the ILAR-defined JIA category during Infliximab 31 (7.0) 20 (4.5)
Adalimumab 9 (2.0) 8 (1.8)
the disease course. There was a marked increase in the Other medications§ 150 (34.1) 30 (6.8)
proportion of patients with enthesitis-related arthritis DMARDs¶ 255 (58.0) 134 (30.5)
(7.7% at baseline versus 11.1% at the last followup) or No medications 11 (2.5) 284 (64.5)
psoriatic arthritis (1.4% versus 3.2%), and the number of * Values are the number (%) of patients.
patients with undifferentiated arthritis also increased. † Nonsteroidal antiinflammatory drugs (NSAIDs) administered peri-
The reasons why a patient was moved from one ILAR odically on demand were not included.
‡ One patient received anakinra, rituximab, and later adalimumab.
category to another during followup were mainly either § Hydroxychloroquine (80 during the study period and 13 at the
onset of enthesitis, sacroileitis, acute uveitis, or psoriasis, final visit), sulfasalazine (63 during the study period and 10 at the final
or new information on the onset of any of these condi- visit), cyclosporine (20 during the study period and 3 at the final visit),
leflunomide (8 during the study period and 5 at the final visit), in-
tions in a first-degree relative of the patient. Among the travenous immunoglobulin (6 during the study period and 0 at the final
66 children with undifferentiated arthritis at the final visit), azathioprine (5 during the study period and 1 at the final visit),
followup visit, 42 were excluded from other categories gold (2 during the study period and 0 at the final visit), and mycophe-
nolate mofetil (2 during the study period and 2 at the final visit).
due to heredity, and 14 fulfilled criteria for ⬎1 category. Patients may have received more than 1 of these medications.
Ten patients did not fulfill the criteria for any category, ¶ Disease-modifying antirheumatic drugs (DMARDs) included metho-
including 6 patients with a polyarticular course who had trexate, biologic agents, or other medications.
no registered result for RF status and 1 patient with only
1 RF-positive test result.
Medication. During the study period, 74.1% of the group with persistent oligoarticular disease, 9.8%
the patients received intraarticular corticosteroid injec- were receiving DMARDs, and in both the group with
tions (median 3, range 0–70) (Table 2). The proportion extended oligoarticular disease and the group with RF-
of children who received intraarticular corticosteroid negative polyarticular disease, 46% were receiving
injections was the same in the group with polyarticular DMARDs (Table 3). One patient with systemic JIA
disease and the group with oligoarticular disease, and underwent autologous bone marrow transplantation and
56.2% of the children received intraarticular cortico- experienced a partial response. At the end of the study,
steroid injections within a median of the first 7 months. 84.9% of the patients in the group with persistent
Disease-modifying antirheumatic drugs (DMARDs) oligoarticular disease and 64.5% of the total cohort were
were started within 7 months after disease onset in 9.3% not receiving medications on a regular basis.
of the group with oligoarticular disease, 47.6% of the Uveitis. Uveitis developed in 89 (20.2%) of the
group with polyarticular disease, and 24.8% of the patients with JIA; in 83% of these patients, uveitis was
registered cohort. During the disease course, 25.0% of diagnosed within the first 4 years after the onset of
the group with persistent oligoarticular disease, 76.9% disease (data not shown).
of the group with extended oligoarticular disease, 83.7% Disease activity and damage at the last followup
of the group with polyarticular RF-negative disease, and visit. The median cumulative number of active joints
58.0% of the total cohort were treated with DMARDs during the disease course was 6 (range 1–61). At the last
(including biologic medications). Of the 185 children visit, however, the median active joint count was 0
who were never treated with DMARDs, 59.4% received (range 0–42) (Table 3); the median number of joints
1 or more intraarticular corticosteroid injections, and with restricted movement was also 0 (range 0–21). The
93.5% received nonsteroidal antiinflammatory drugs. levels of inflammation markers and the median self-
At the final visit, 30.5% of patients were receiving reported health assessment scores were within normal
DMARDs, including 22.5% who were receiving metho- limits, and the median JADAS27 score was 0.9. The
trexate and 12.5% who were receiving biologic agents. In median VAS pain score was 0 (IQR 0–1.4), but one-
 2814

Table 3. Characteristics of patients in the Nordic JIA cohort at the final study visit, according to JIA categories*
JIA category

Oligoarticular Polyarticular
No. of
patients Total cohort Systemic Persistent Extended RF negative RF positive Psoriatic Enthesis-related Undifferentiated
Characteristic assessed (n ⫽ 440) (n ⫽ 18) (n ⫽ 132) (n ⫽ 78) (n ⫽ 80) (n ⫽ 3) (n ⫽ 14) (n ⫽ 49) (n ⫽ 66)

Age at last visit, 440 14.2 (10.8–18.0) 14.2 (11.1–15.1) 13.6 (10.8–16.9) 12.3 (10.1–16.4) 13.2 (10.7–17.4) 21.4 (19.1–21.5) 14.1 (13.2–15.1) 18.4 (15.0–20.7) 15.8 (11.2–19.9)
median (IQR) years
Active joint count, 438 0 (0–0) 0 (0–0) 0 (0–0) 0 (0–1) 0 (0–1) 0 (0–1) 0 (0–0) 0 (0–0) 0 (0–0)
median (IQR)
Cumulative no. of 438 6 (2–12) 6 (3–12) 2 (1–3) 9 (6–12) 13 (8–23) 13 (13–31) 7 (3–9) 5 (3–13) 10 (4–16)
active joints, median
(IQR)
ESR, median (IQR) 272 8 (4–12) 5 (2–11) 7 (4–11) 9 (5–14) 8 (4–11) 4 (2–15) 7 (5.5–11) 8 (4–12) 9 (3–13)
mm/hour
JADAS27, median 230 0.9 (0–3.5) 0 (0–3.2) 0 (0–1.6) 1.6 (0.3–4.4) 1.1 (0–3.5) 3.0 (0–8.7) 0 (0–3.0) 0.9 (0–3.0) 1.5 (0.1–5.3)
(IQR)
C-HAQ/HAQ score 352 113 (32.1) 3 (23.1) 13 (13.3) 29 (46.0) 28 (38.9) 2 (66.7) 4 (30.8) 13 (35.1) 21 (39.6)
⬎0
VAS pain score ⬎0 345 172 (49.9) 4 (30.8) 26 (27.1) 43 (70.5) 39 (54.9) 2 (66.7) 4 (30.8) 22 (61.1) 32 (61.5)
Parent/patient’s global 342 172 (50.3) 3 (23.1) 25 (26.0) 39 (67.2) 43 (60.6) 2 (66.7) 5 (38.5) 22 (61.1) 33 (63.5)
assessment of well-
being score ⬎0†
Physician’s global 312 145 (46.5) 3 (25.0) 21 (26.9) 34 (58.6) 37 (53.6) 2 (66.7) 5 (41.7) 19 (57.6) 24 (51.1)
assessment of
overall disease
activity score ⬎0
CHQ physical 207 40 (19.3) 1 (11.1) 4 (7.0) 10 (23.3) 8 (18.2) – 1 (12.5) 7 (38.9) 9 (32.1)
summary score ⬍40
CHQ psychosocial 207 18 (8.7) – 2 (3.5) 6 (14.0) 5 (11.4) – 1 (12.5) – 4 (14.3)
summary score ⬍40
JADI global 227 52 (22.9) 3 (25.0) 9 (15.8) 14 (34.2) 13 (30.2) 1 (100) 3 (50.0) 5 (16.7) 4 (10.8)
assessment of
articular and
extraarticular
damage score ⬎0
JADI articular score 227 30 (13.2) 2 (16.7) 3 (5.2) 7 (17.5) 9 (20.9) 1 (100) 2 (33.3) 4 (13.3) 2 (5.4)
⬎0
JADI extraarticular 227 27 (11.9) 3 (25.0) 7 (12.3) 8 (19.5) 3 (7.0) – 1 (16.7) 2 (6.7) 3 (8.1)
score ⬎0
DMARDs present‡ 440 134 (30.5) 3 (16.7) 13 (9.8) 36 (46.2) 37 (46.3) 1 (33.3) 5 (35.7) 15 (30.6) 24 (36.4)
Continuously active 390 116 (29.7) 3 (18.8) 13 (11.6) 28 (39.4) 28 (42.4) 1 (33.3) 3 (27.3) 15 (31.3) 25 (40.3)
disease§

* Except where indicated otherwise, values are the number (%) of patients. The last study visit occurred a median of 98 months after disease onset. Scores for parent/patient’s global
assessment of well-being, physician’s global assessment of overall disease activity, and the Juvenile Arthritis Damage Index (JADI) were based on a 0–10-point visual analog scale
(VAS). JIA ⫽ juvenile idiopathic arthritis; RF ⫽ rheumatoid factor; IQR ⫽ interquartile range; ESR ⫽ erythrocyte sedimentation rate; JADAS27 ⫽ Juvenile Arthritis Disease
Activity Score based on 27 joints (range 0–57); C-HAQ ⫽ Childhood Health Assessment Questionnaire (scale 0–3); CHQ ⫽ Child Health Questionnaire (range 0–100).
† Scores were provided by patients who were older than age 9 years and by the parents of younger patients.
‡ Current treatment with disease-modifying antirheumatic drugs (DMARDs), including biologic agents.
§ No periods of disease remission off medication (inactive disease off medication ⬎12 months) for a median of 98 months (range 84–147 months) after disease onset.
NORDAL ET AL
ONGOING DISEASE ACTIVITY IN PATIENTS WITH JIA 2815

fourth of the children reported pain scores ⬎1.4, and the Table 4. Remission status of patients in the Nordic JIA cohort at the
maximum score was 8.5. Although the mean CHQ final study visit*
physical and psychosocial scores were within normal Remission Remission
limits, 19.3% of the total group and 38.9% of the group off on Not in
JIA category medication† medication‡ remission§
with enthesitis-related arthritis had a CHQ physical
score of ⬍40. Damage was reported in 52 children Systemic (n ⫽ 18) 15 (83.3) 0 (0) 3 (16.7)
(22.9%), and 19.2% of these had not received DMARDs Oligoarticular
Persistent (n ⫽ 126) 83 (65.9) 4 (3.2) 39 (31.0)
or biologic agents. The highest JADI scores for articular Extended (n ⫽ 75) 16 (21.3) 12 (16.0) 47 (62.7)
and global damage were observed in children in the Polyarticular
group with systemic disease and the group with poly- RF negative (n ⫽ 79) 22 (27.9) 11 (13.9) 46 (58.2)
RF positive (n ⫽ 3) 1 (33.3) 0 (0) 2 (66.7)
articular RF-negative disease. Psoriatic (n ⫽ 13) 3 (23.1) 3 (23.1) 7 (53.9)
Absence from school and physical education. At Enthesitis-related (n ⫽ 49) 15 (30.6) 4 (8.2) 30 (61.2)
the last followup visit, 83.2% of the children reported no Undifferentiated (n ⫽ 64) 26 (40.6) 4 (6.3) 34 (53.1)
Total (n ⫽ 427) 181 (42.4) 38 (8.9) 208 (48.7)
absence from school or work due to JIA during the
previous 2 months, while 4.8% were absent from school * Values are the number (%) of patients. The final study visit occurred
a median of 98 months after disease onset. Inactive disease is defined
or work for more than 5 days in the same period. At the as no joints with active arthritis, no fever, rash, serositis, splenomegaly,
last followup, 76.7% of the school-age children partici- or generalized lymphadenopathy attributable to juvenile idiopathic
pated fully in physical education, while 17.2% partici- arthritis (JIA), no active uveitis, a normal erythrocyte sedimentation
rate or C-reactive protein level, if tested, and a physician’s global
pated partly, and 6.0% did not participate (data not assessment of disease activity indicating no disease activity. RF ⫽
shown). rheumatoid factor.
Remission status. During the observation period, † Inactive disease for ⬎12 months while the patient was not receiving
medication.
a continuously active disease course (with no remission ‡ Inactive disease for ⬎6 months while the patient was receiving
off medication) was observed in 29.7% of the 390 medication.
patients with data sufficient for evaluation (Table 3). § No disease remission either on or off medication, as defined above.
Approximately half of these children (48.7%) experi-
enced a relapsing disease course, with periods of remis-
sion off medication lasting for ⱖ1 year, followed by new with patients in the rest of the cohort (P ⬍ 0.0001). The
periods of disease activity. This relapsing disease course lowest rate of remission off medication was observed in
was observed in 45.1% of the group with persistent the group with extended oligoarticular JIA.
oligoarticular disease, 56.3% of the group with extended The presence of ANAs was not associated with
oligoarticular disease, and 51.5% of the group with any particular outcome pattern with regard to disease
polyarticular RF-negative disease. remission in either the total JIA cohort or in select
At the last visit, 42.4% of the patients were in categories of JIA, excluding the systemic, polyarticular
remission off medication, with inactive disease for the RF-positive, and enthesitis-related categories. However,
last 12 months; 8.9% had remission on medication, and remission off medication was achieved less frequently
48.7% were not in remission (Table 4). Among the and remission on medication was achieved more fre-
patients with disease in remission, 29.3% had used quently in children who were younger than age 5 years at
DMARDs including biologic agents (ranging from the time of disease onset. The difference between age
13.3% in the group with persistent oligoarticular disease groups regarding remission rates was significant in select
to 63.6% in the group with polyarticular RF-negative categories (P ⫽ 0.035) (in the total cohort P ⫽ 0.05),
JIA). Four (2.2%) of the patients whose disease was in also when controlling for confounding by stratification
remission off medication had been treated with biologic for the different JIA categories (data not shown).
agents; 3 of these 4 patients had systemic JIA. Among
patients whose disease was not in remission, 77.9% had
DISCUSSION
been treated with DMARDs, including 51.3% of those
with persistent oligoarticular disease and 89.1% of those The results of this longitudinal study support the
with RF-negative polyarticular disease. Among patients concept of JIA as a chronic disease (15,28,29) by show-
whose disease was in remission on medication, 94.7% ing that a majority of patients experienced continuously
had received DMARDs, including biologic agents. A ongoing disease activity or a relapsing course during the
significantly higher rate of disease remission off medi- first decade of JIA. Similar results for select categories
cation was observed among patients with persistent of JIA were observed by Wallace et al (1), using the
oligoarticular JIA and those with systemic JIA compared newly developed remission criteria in retrospective stud-
2816 NORDAL ET AL

ies. Prospective longitudinal data have been sought to category, which otherwise is known for having the most
confirm these results, and the ongoing nature of the severe disease course (28). The high rate of remission
disease was demonstrated in this cohort study (1,3). observed in the group with persistent oligoarticular
The paramount goal of current treatment in JIA disease is consistent with that in previous studies (28,29).
is to achieve inactive disease and remission with or Prognostication based on ILAR categories at the time of
without medication (7,30,31). The use of biologic agents disease onset is difficult, because one-third of children in
in pediatric patients represents the beginning of a new the group with initial oligoarticular arthritis later expe-
era in the medical treatment of JIA, and treatment with rienced the development of extended disease, with out-
etanercept was first described at the same time as the comes and remission data similar to or even worse than
start of our study (32). Indications and approvals have those of children in the polyarticular, psoriatic, and
increased as efficacy and safety data on biologic agents enthesitis-related categories. These results underline the
in children have emerged (33–35). In our study, the use need to identify early predictors or biologic determi-
of biologic medications during the disease course in nants of persistent oligoarticular disease (40,41).
17.5% of patients reflects the steadily increasing use of Early-onset disease and the presence of ANAs
these agents during the last decade, and the percentage are suggested as important descriptors to be incorpo-
of treated patients might have been higher based on rated in a revised ILAR classification system (7–10).
current recommendations. Martini et al and Ravelli et al discussed the presence of
In addition to the biologic agents, medical treat- ANAs as an important descriptor in select categories
ment was dominated by intraarticular corticosteroid of JIA, such as oligoarticular JIA, polyarticular RF-
injections and methotrexate, often in combination. Con- negative JIA, and psoriatic JIA (7,10). Therefore, we
sistent with current treatment recommendations, intra- chose to study the influence of ANA status and young
articular corticosteroid injections were commonly re- age at disease onset on disease remission in our data
ceived, and very few patients were receiving systemic both for the whole cohort and for select categories,
corticosteroids at the last study visit (36,37). The early excluding the systemic, polyarticular RF-positive, and
timing and high number of intraarticular corticosteroid enthesitis-related arthritis categories. We observed that
injections, together with the high number of patients remission status was not influenced by ANA status.
receiving systemic treatment, may partly explain the However, fewer children with a young age at disease
favorable outcome with low disease activity and minimal onset achieved disease remission off medication com-
damage in most patients. Similar results were observed pared with children with late-onset disease, independent
in a recent study by Solari et al (38). However, in 2 of ILAR categories. Recently, indications of biologic
Canadian JIA cohort studies, fewer patients were differences in JIA subgroups according to age at disease
treated with intraarticular corticosteroid injections and onset have emerged, showing that the B cell gene
DMARDs (28,39). The first Canadian study is older, and expression signature can distinguish between early-onset
the followup time in the more recent study was short. and late-onset JIA regardless of the number of affected
Achieving inactive disease and remission may imply joints (9). Recently, Hollenbach et al (42) reported that
accepting the use of potent drugs with potentially serious HLA class II associations with JIA were significantly
long-term side effects. different in patients with early-onset disease and those
A considerable and continuous change in JIA with late-onset disease.
categories during the disease course was observed in this The preliminary criteria for clinical remission
study. We observed that the onset of psoriasis or fea- described by Wallace et al (26) has certain limitations in
tures of enthesitis-related arthritis in the child or a longitudinal studies. Using these criteria, the remission
first-degree relative may occur at any age, and there is status of an individual patient whose disease has been
reason to believe that further changes will occur over inactive for at least 6 months while he or she was
time. receiving medication would change from remission on
At the end of the study, the disease remission medication to inactive disease off medication. However,
status of patients in the groups with persistent oligoar- even if disease remains inactive, there is by definition no
ticular disease and systemic disease markedly differed remission during the first 12 months after medication
from the status of patients in all of the other categories. was stopped. Remission off medication is finally
Even though the number of patients in the group with achieved when inactive disease off antirheumatic medi-
systemic disease was small, the results indicate that in a cation persists for more than 12 months (26). An addi-
population-based setting, the prognosis is also favorable tional definition of remission in a patient with persistent
for a considerable proportion of patients in this JIA inactive disease that occurs during the first 12 months
ONGOING DISEASE ACTIVITY IN PATIENTS WITH JIA 2817

after medication is stopped would make sense and be (Borås), Johan Robinsson (Trollhättan), and Anna-Lena
useful. The results of our study support the notion that Nilsson (Östersund).
remission is not a “steady state,” which is consistent with
recent findings by Knowlton et al showing that the gene AUTHOR CONTRIBUTIONS
expression profiles of patients with JIA in remission are All authors were involved in drafting the article or revising
not comparable with those of healthy individuals but are it critically for important intellectual content, and all authors ap-
closer to those of patients with active JIA (43,44). proved the final version to be published. Dr. Nordal, Dr. Straume, and
Dr. Rygg had full access to all of the data in the study and takes
The prospective, longitudinal design and responsibility for the integrity of the data and the accuracy of the data
population-based context of this multicenter study are analysis.
its strengths. The proportion of children lost to followup Study conception and design. Nordal, Zak, Aalto, Berntson, Fasth,
Herlin, Lahdenne, Nielsen, Rygg.
is small compared with the number of patients lost to Acquisition of data. Nordal, Zak, Aalto, Berntson, Fasth, Herlin,
followup in other longitudinal studies (15,28,29). The Lahdenne, Nielsen, Rygg.
first registered visit took place at a time as close as Analysis and interpretation of data. Nordal, Zak, Aalto, Berntson,
possible to 6 months after the onset of disease; this Fasth, Straume, Rygg.
implies that initial disease activity peaks are not neces-
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