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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To determine early outcomes and early improvements in a prospective inception cohort of children with juvenile idiopathic arthritis (JIA) treated with current standard therapies.

Methods

Patients selected were enrolled in an inception cohort of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study. The juvenile rheumatoid arthritis core criteria set measures were completed at enrollment and 6 months later. Frequencies of normal values for each of the core set measures and the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 (Pedi 70) criteria response rates achieved at 6 months after enrollment were calculated for each JIA-onset subtype group.

Results

Among 354 patients in the study, the median interval between diagnosis and enrollment was 0.7 months. At 6 months after enrollment, median values of active joint counts were highest in patients with rheumatoid factor (RF)–positive polyarthritis (4) and RF-negative polyarthritis (2), but were 0 or 1 for other subtypes. Fifty percent or more of patients with oligoarthritis, systemic arthritis, enthesitis-related arthritis, and undifferentiated arthritis had no active joints, and the ACR Pedi 70 criteria response rate was 48% or more in those with oligoarthritis, RF-negative polyarthritis, and systemic arthritis.

Conclusion

With current management strategies in clinical practice, improvement in disease activity was noted in considerable proportions of patients in all of the JIA subtype groups, but low levels of disease activity persisted in many. We expect that these early outcomes will prove to be significant predictors of long-term outcomes.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Numerous previous studies have examined the outcomes of chronic childhood arthritis, but their applicability and utility for patients seen currently is limited by several considerations (1–9). For example, the use of a variety of classification systems, including the American College of Rheumatology (ACR) and the European League Against Rheumatism criteria and different diagnostic criteria for psoriatic arthritis (PsA) or seronegative spondylarthritides in children, resulted in heterogeneous patient subgroups (10–15). In contrast, the International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis (JIA), now widely used, includes all forms of chronic arthritis of unknown etiology in children, with the exception of arthritis occurring as part of multisystem diseases (16). Changes in the treatment options available since the time of these previous studies also limit their present relevance. Moreover, the variety of outcome measures and definitions of remission used in past studies makes comparisons difficult, and the majority of studies have been retrospective with inherent disadvantages such as incomplete patient retrieval and data. Finally, most of the previous studies have assessed long-term outcomes, whereas a current concept in therapy is that early disease control and improvement lead to better ultimate disease outcome (17). However, our present knowledge is limited by the paucity of information about both disease control and improvement early in disease as well as long-term outcomes achieved with current treatment strategies.

Current therapies for JIA include nonsteroidal antiinflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), intraarticular steroids, and biologic agents, with increasingly earlier introduction of the last 3 types of treatment. We have recently described a 33% rate of inactive disease at 6 months after enrollment in an inception cohort of patients with JIA managed with current treatment approaches; however, the spectrum of improvement other than inactive disease status was not examined in that study (18). The ACR pediatric definitions of improvement, the ACR Pediatric 30 (Pedi 30), 50, and 70 criteria responses, based on the degree of improvement in a set of 6 core measures of disease activity, offer a uniform system of reporting improvement in disease, and have been used mainly in patients with juvenile rheumatoid arthritis (JRA) diagnosed by ACR (formerly the American Rheumatism Association) criteria or systemic, oligoarthritis, and polyarthritis subtypes of JIA diagnosed by ILAR criteria (10, 16, 17, 19–22). Although the core set measures and definitions of improvement are routinely used in clinical trials, they have not been applied to prospective cohort studies of patients treated in clinical practice. The aim of the present analyses was to determine the early outcomes in terms of each of the core criteria set measures and ACR pediatric criteria response rates achieved 6 months after enrollment in our prospective inception cohort of patients with JIA. The rationale for examining the early disease course in this cohort is that short-term outcomes may prove to be predictive of those in the long term.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) Study.

ReACCh-Out is an ongoing multicenter prospective inception cohort study of JIA conducted at 16 pediatric rheumatology centers in Canada (14 academic and 2 community centers). The inclusion criterion is a diagnosis of JIA according to ILAR criteria made within 12 months before enrollment (16). Demographic data and rheumatologic, family, and medication histories were collected prospectively on standardized prepared forms at enrollment, and interim and medication histories were collected at subsequent study visits every 6 months for the first 2 years and then yearly. The 6-item JIA core criteria set, the Juvenile Arthritis Quality of Life Questionnaire, and the Quality of My Life Questionnaire were completed at each study visit (19, 23, 24). Where developmentally appropriate, children completed their own self-report questionnaires. Otherwise, they were completed by a parent. The study was performed in accordance with the Declaration of Helsinki. The study protocol was approved by research ethics boards at each participating center. Informed consent for participation was obtained from parents and informed consent or assent was obtained from patients as applicable.

Patients.

For the present report, a subset of patients from the ReACCh-Out Study was selected based on enrollment within 6 months after diagnosis, and completion of both enrollment and 6-month followup assessments between January 1, 2005 and December 31, 2007, as described previously (18). A maximum time interval of 6 months between diagnosis and enrollment was chosen in order to select patients close to diagnosis with limited exposure to medications at enrollment and yet obtain a reasonable sample size.

JIA subtype diagnoses.

ILAR JIA subtype diagnoses at enrollment were assigned as previously described (18). Briefly, JIA-onset subtype diagnoses provided by the site investigators were reviewed for compliance with the ILAR criteria. Rheumatoid factor (RF) was considered positive only if 2 tests done at least 3 months apart were positive, including tests performed at, before, or after enrollment. Diagnoses and supporting data available at enrollment were first reviewed by one author (KO) and then by computer software designed by 2 other investigators (DAC and VE). The software matches the subtype criteria to the submitted data, and has been tested in patients from 3 sites (Vancouver, St. John's, and Winnipeg). Where there were discrepancies between the subtype diagnoses assigned by the site investigator and these reviews, diagnoses were reassigned if the 2 reviews were in agreement or were referred to the site investigator if further information was required. As a result of this process, JIA subtypes were reassigned for 38 of 354 patients included in the study: 18 to undifferentiated JIA and 20 to other subtypes.

Assessment of outcomes.

The date of symptom onset was defined as the date of onset of the first symptoms of arthritis or, for systemic arthritis, the onset of fevers, approximated to the first day of the nearest month or to the middle month of a season.

The outcomes reported in this study are based on the core criteria set measures collected at the enrollment and 6-month study visits, including: active joint count (AJC); number of joints with limited range of motion; erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level; a 10-cm visual analog scale of physician global assessment of disease activity, in which higher scores indicate greater disease activity; a 10-cm visual analog scale of patient or parent global assessment of overall well-being, in which higher scores indicate worse well-being; and a measure of physical function, the Childhood Health Assessment Questionnaire (C-HAQ), in which 0 indicates the best function and 3 indicates the worst function (25).

The ACR Pedi 30, 50, and 70 criteria responses between enrollment and the 6-month followup were calculated (19, 20). In patients with a complete 6 core criteria set of measures at both time points, the ACR Pedi 30, 50, or 70 criteria responses corresponded to ≥30%, ≥50%, or ≥70% improvement, respectively, in 3 of 6 measures with ≤30% deterioration in no more than one measure, as originally defined (19, 20). In patients lacking one of the measures, most commonly ESR or CRP level, at one or both time points, the definition of response was modified and based on a ≥30%, ≥50%, or ≥70% improvement, respectively, in 3 of 5 measures with ≤30% deterioration in no more than one of the 5 remaining measures.

Statistical analysis.

Analyses were performed with SPSS, version 15.0 (SPSS, Chicago, IL). Differences among the groups were compared by the chi-square and Kruskal-Wallis tests. Data were reported as the median values with the interquartile range.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Enrollment demographics and clinical information.

Of 882 consecutive eligible patients, 45 refused participation and 837 were enrolled in the ReACCh-Out Study between January 2005 and December 2007, of which 34 withdrew. Four hundred thirty-seven patients had completed both the enrollment and 6-month followup assessments by December 31, 2007. Of these, 354 were enrolled within 6 months after diagnosis and met the criteria for the present report, whereas 83 were excluded: 80 because they were enrolled after longer intervals and 3 because they lacked physician assessments at the 6-month followup visit. JIA subtype frequencies, sex distribution, and age at diagnosis and onset were similar in excluded patients compared with those included, but the interval from symptom onset to diagnosis was slightly shorter in the former (median 4.0 versus 4.5 months; P = 0.05).

Table 1 shows disease and demographic information at enrollment for the patients in the present study. At enrollment, there were 3 patients with extended oligoarthritis whose symptom onset was 6 months or more prior to enrollment. Their results are included with the rest of the oligoarthritis group. The median time from diagnosis to enrollment for each of the onset subtype groups was 1.2 months or less. The time to diagnosis was significantly different among the subtypes, with the RF-positive polyarthritis and enthesitis-related arthritis (ERA) subgroups having the longest interval from symptom onset to diagnosis. HLA–B27 was tested in 94% of the patients with ERA, but was positive in only 59%. Of 21 undifferentiated arthritis patients tested, 29% were HLA–B27 positive.

Table 1. Demographic and clinical data*
 OligoarthritisRF-negative polyarthritisRF-positive polyarthritisSystemic arthritisPsAERAUnd arthritisTotal
  • *

    Values are the median (interquartile range) unless otherwise indicated. RF = rheumatoid factor; PsA = psoriatic arthritis; ERA = enthesitis-related arthritis; Und = undifferentiated; ANA = antinuclear antibody.

  • P < 0.0001 for comparisons among subtypes made by Kruskal-Wallis or chi-square tests.

  • P = 0.001 for comparisons among subtypes made by Kruskal-Wallis or chi-square tests.

  • §

    P = 0.006 for comparisons among subtypes made by Kruskal-Wallis or chi-square tests.

No. (%)145 (41)71 (20)12 (3)26 (7)23 (7)36 (10)41 (12)354
Age at onset, years4.6 (2.2–9.7)8.2 (2.5–12.6)11.5 (8.9–14.6)5.9 (3.3–11.8)10.5 (5.4–12.3)11.6 (9.4–13.8)8.9 (3.5–12.8)7.9 (3.0–11.9)
Age at diagnosis, years5.7 (2.8–10.4)9.4 (3.1–12.9)12.3 (9.2–15.2)6.0 (3.4–12.2)11.3 (6.4–13.6)13.1 (11.0–14.5)10.1 (5.5–13.7)9.0 (3.5–13.0)
Disease duration to diagnosis, months4.3 (2.4–7.3)5.7 (3.0–10.4)6.8 (4.7–12.2)2.4 (1.6–3.9)4.7 (2.1–11.3)6.2 (3.0–14.2)4.4 (2.4–14.1)4.5 (2.5–8.8)
Disease duration to enrollment, months§5.4 (3.6–9.0)6.3 (4.3–11.3)6.8 (5.2–12.9)3.7 (2.8–5.7)6.5 (3.8–12.0)8.6 (4.1–16.3)7.1 (3.7–15.4)6 (3.7–10.4)
Time from diagnosis to enrollment, months0.7 (0–1.9)0.03 (0–1.4)0.9 (0–1.6)1.2 (0.5–2.8)1.0 (0–3.4)0 (0–3.3)0.8 (0–2.6)0.7 (0–1.9)
Female, %7580923557196366
ANA, no. tested (% positive)134 (62)68 (40)12 (42)23 (9)18 (56)29 (10)38 (34)322 (48)
RF, no. tested (% positive)124 (0)68 (0)12 (100)20 (0)19 (0)29 (0)34 (9)306 (5)
HLA–B27, no. tested (% positive)59 (12)26 (12)1 (0)3 (0)9 (11)34 (59)21 (29)153 (24)

The treatments used are shown in Table 2. Only 49 patients (14%) were receiving no treatment at the time of enrollment. The majority of patients had received NSAIDs prior to enrollment. Prednisone was most often used in patients with RF-positive polyarthritis and systemic arthritis. The majority of patients with RF-negative or RF-positive polyarthritis and 31–36% of patients with systemic arthritis, PsA, or undifferentiated arthritis were started on DMARDs prior to or at enrollment (Table 2). Among all of the patients started on DMARDs before or at enrollment, the median interval from diagnosis to starting DMARDs was 0 months (interquartile range 0–0.4 months). By the 6-month followup assessment, 41% of the patients (n = 145) were receiving DMARDs. Methotrexate was the most common DMARD used (92.4%), followed by sulfasalazine (12.4%), hydroxychloroquine (4.1%), and cyclosporine (1.4%). Thirteen patients were receiving 2 DMARDs and 1 patient was receiving 3 DMARDs concurrently.

Table 2. Medications*
 Oligoarthritis (n = 145)RF-negative polyarthritis (n = 71)RF-positive polyarthritis (n = 12)Systemic arthritis (n = 26)PsA (n = 23)ERA (n = 36)Und arthritis (n = 41)Total (n = 354)
  • *

    Values are the number (percentage) unless otherwise indicated. No patients were receiving biologic agents prior to or at enrollment or at the 6-month visit. RF = rheumatoid factor; PsA = psoriatic arthritis; ERA = enthesitis-related arthritis; Und = undifferentiated; NSAIDs = nonsteroidal antiinflammatory drugs; IQR = interquartile range; DMARDs = disease-modifying antirheumatic drugs.

  • N = 280 total patients.

  • N = 37 total patients.

  • §

    N = 41 total patients.

  • N = 55 total patients.

  • #

    Administered between enrollment and the 6-month assessment.

Medications started prior to or at enrollment        
No treatment prior to enrollment21 (15)11 (16)1 (8)3 (12)4 (17)5 (14)4 (10)49 (14)
NSAIDs        
Started prior to enrollment122 (84)59 (83)11 (92)22 (85)19 (83)29 (81)35 (85)297 (84)
Time from start to enrollment, median (IQR) months2.3 (1.3–4.2)2.4 (1.3–3.6)2.7 (1.7–6.1)2.6 (1.4–3.5)3.0 (2.1–4.0)2.5 (1.6–4.7)3.1 (1.4–5.2)2.5 (1.5–4.0)
Started at enrollment15 (10)10 (14)1 (8)03 (13)5 (14)3 (7)37 (11)
Prednisone        
Started prior to enrollment1 (1)6 (9)5 (42)14 (54)3 (13)3 (8)8 (20)40 (11)
Time from start to enrollment, median (IQR) months1.1 (0.9–1.2)1.3 (1.0–2.4)1.5 (1.3–3.0)1.5 (0.7–2.9)0.4 (0.3–0.5)5.4 (2.6–6.7)1.6 (0.7–4.7)1.5 (0.9–3.6)
Started at enrollment1 (1)7 (10)2 (17)3 (12)02 (6)2 (5)17 (5)
Intraarticular injections        
Started prior to enrollment18 (12)3 (4)001 (4)3 (8)2 (5)27 (8)
Time from start to enrollment, median (IQR) months§0.9 (0.3–2.3)1.1 (1.0–1.7)  1.8 (0.8–4.4)3.0 (0.9–5.1)0.5 (0.6–2.3)0.9 (0.5–2.3)
Started at enrollment8 (6)00001 (3)09 (3)
DMARDs        
Started prior to enrollment3 (2)22 (31)8 (67)7 (27)5 (22)6 (17)8 (20)59 (17)
Time from start to enrollment, median (IQR) months1.2 (1.1–1.5)1.5 (1.1–2.4)1.4 (0.8–2.5)2.1 (1.1–3.6)1.3 (0.4–2.5)3.2 (1–5.3)3.1 (1.3–4.2)1.5 (1.1–3.2)
Started at enrollment3 (2)16 (23)3 (25)1 (4)1 (4)7 (19)5 (12)36 (10)
Medications current at 6 months after enrollment        
No treatment31 (21)4 (6)003 (13)2 (6)6 (15)46 (13)
NSAIDs104 (72)59 (83)12 (100)22 (85)19 (83)29 (81)25 (61)270 (76)
Prednisone3 (2)8 (11)6 (50)18 (69)2 (9)3 (8)7 (17)47 (13)
Intraarticular injections#36 (25)15 (21)2 (17)1 (4)6 (26)1 (3)10 (24)71 (20)
DMARDs19 (13)55 (78)12 (100)14 (54)10 (44)17 (47)18 (44)145 (41)

Among the patients with systemic arthritis, 2 had received intravenous methylprednisolone, each at 1.5 months prior to enrollment, and 3 had received intravenous immunoglobulin at 1.1, 1.7, and 3.8 months prior to enrollment. A considerable proportion (69%) of patients with systemic arthritis remained on corticosteroids at the 6-month assessment. Among patients with oligoarthritis, 21% were receiving no treatment by the 6-month assessment, and altogether, 43% had received intraarticular injections since diagnosis. Intraarticular injections were also used frequently in patients with RF-negative polyarthritis and PsA. Triamcinolone hexacetonide was used almost exclusively for the injections. Two patients, 1 with RF-positive polyarthritis and 1 with systemic arthritis, were started on anti–tumor necrosis factor treatment at the 6-month study visit, but no patient received biologic therapy prior to that time.

Enrollment and 6-month followup core criteria set measures.

The results of the core criteria set measures at enrollment and 6 months later are shown in Table 3. At enrollment, AJCs and C-HAQ scores were highest in patients with RF-positive and RF-negative polyarthritis. At 6 months, median AJCs were low in all of the subtypes, reaching 0 for patients with oligoarthritis and undifferentiated arthritis. The highest median values were 2 and 4 for patients with RF-negative and RF-positive polyarthritis, respectively. Except for the RF-positive polyarthritis group, median C-HAQ values corresponded to no (C-HAQ score 0) or mild disability (C-HAQ score <0.5).

Table 3. Core set measures at enrollment and at 6 months*
 OligoarthritisRF-negative polyarthritisRF-positive polyarthritisSystemic arthritisPsAERAUnd arthritis
0 months6 months0 months6 months0 months6 months0 months6 months0 months6 months0 months6 months0 months6 months
  • *

    RF = rheumatoid factor; PsA = psoriatic arthritis; ERA = enthesitis-related arthritis; Und = undifferentiated; AJC = active joint count; N = number of patients assessed; IQR = interquartile range; ROM = range of motion; MD global = physician global assessment of disease activity; P global = patient or parent global assessment of overall well-being; C-HAQ = Childhood Health Assessment Questionnaire; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein.

AJC              
 N145144717112122626232336364141
 Median109216421413120
 IQR1–20–15–180–59–301–91–50–21–100–21–70–20–60–2
Limited ROM              
 N145143717112122626232336354141
 Median10405100111010
 IQR0–20–10–80–33–110–40–20–20–50–20–20–20–30–2
MD global              
 N143143717111122626232336354141
 Median2.10.14.61.25.31.52.80.62.30.44.60.92.40.5
 IQR0.9–3.80–0.93–70.1–2.82.5–7.10.4–3.20.9–5.50–2.01.2–5.10–2.21.9–6.50.1–2.90.7–70–2.5
P global              
 N132125676110102425182133303637
 Median10.22.00.64.52.61.00.21.80.22.81.220.7
 IQR0.1–3.70–1.21.0–4.60–2.91–80.4–8.20–40–1.50.4–5.30–1.22.0–5.80–4.10.2–3.90–2.5
C-HAQ              
 N132125676110102425182133303637
 Median0.300.50.31.00.90.400.200.50.20.50.1
 IQR0–0.60–0.30.1–1.10–0.60.8–1.40.1–1.90–1.10–0.40.1–0.80–0.20.1–1.20–0.70.1–0.80–0.7
ESR, mm/ hour              
 N1265867521192524191435203818
 Median211120105227451140101614168
 IQR10–386–197–446–1830–813–3919–865–3512–565–205–306–209–602–15
CRP level,  mg/liter              
 N1035358351082522171331143115
 Median3462253333535552
 IQR0–70–61–141–63–331–115–620–390–360–61–161–80–181–4

Figure 1 shows the frequencies of normal values for the 6 core criteria set of measures at the 6-month followup. The frequencies of scores of 0 for the AJC and physician global assessment of disease activity and normalization of the CRP level differed among the subtypes (P < 0.0001 for AJC and physician global assessment of disease activity and P = 0.048 for CRP level). Fifty percent or more of patients with oligoarthritis, systemic arthritis, ERA, and undifferentiated arthritis had scores of 0 for AJC at 6 months, whereas patients with RF-negative or RF-positive polyarthritis had far lower frequencies (31% and 8%, respectively). Among the JIA subtypes, no differences were found in the proportions of patients achieving a parent or patient global assessment of overall well-being of 0 (P = 0.052), a C-HAQ score of 0 (P = 0.088), the number of joints with limited range of motion of 0 (P = 0.22), or normalization of the ESR (P = 0.48), but the small number of patients in some groups precludes conclusions, especially in regard to the first two of these measures. Among the patients with ERA, low frequencies of scores of 0 for global assessments (18% for physician global assessment of disease activity and 30% for patient or parent global assessment of overall well-being) were found despite 50% having an AJC of 0; however, the frequency of enthesitis was 46% of 35 patients at enrollment and remained considerable, at 31% of 36 patients at 6 months.

thumbnail image

Figure 1. Frequencies of normal values for the 6 core criteria set of measures at 6 months after enrollment. A, Oligoarthritis: n = 144, rheumatoid factor (RF)–negative polyarthritis: n = 71, RF-positive polyarthritis: n = 12, systemic arthritis: n = 26, psoriatic arthritis (PsA): n = 23, enthesitis-related arthritis (ERA): n = 36, and undifferentiated (UND) arthritis: n = 41. Differences among the subtypes were significant for an active joint count (AJC) of 0 (P < 0.0001) and a physician global assessment of disease activity (MD Global) of 0 (P < 0.0001), but not for the number of joints with a limited range of motion (LROM; P = 0.22). B, Oligoarthritis: n = 125, RF-negative polyarthritis: n = 61, RF-positive polyarthritis: n = 10, systemic arthritis: n = 25, PsA: n = 21, ERA: n = 30, and UND arthritis: n = 37. Differences among the subtypes were significant for normal C-reactive protein (CRP) level (P = 0.048), but not for patient or parent global assessment of overall well-being (P Global) of 0 (P = 0.052) or Childhood Health Assessment Questionnaire (CHAQ) score of 0 (P = 0.088). ESR = erythrocyte sedimentation rate.

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ACR Pedi 30, 50, and 70 criteria responses at 6 months after enrollment

Figure 2 shows the ACR Pedi 30, 50, and 70 criteria response rates for patients with 5 or 6 pairs of core criteria set measures performed at both enrollment and 6 months. ACR Pedi 70 criteria response rates were highest in patients with systemic JIA, oligoarthritis, and RF-negative polyarthritis (48–55%); intermediate in patients with RF-positive polyarthritis, undifferentiated arthritis, and ERA (44–46%); and lowest in patients with PsA (35%). There were no differences in the ACR pediatric criteria response rates among the subtypes (Figure 2). However, small group sizes preclude conclusions. A total of 159 patients had complete pairs of 6 core criteria measures and 128 patients had pairs of 5 core criteria set measures. In each group of patients, those with 6 and those with 5 core criteria sets, ACR Pedi 30, 50, and 70 criteria response rates were also similar among the JIA subtypes (data not shown).

thumbnail image

Figure 2. American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), 50, and 70 criteria response rates between enrollment and 6 months. One hundred fifty-nine patients completed 6 core criteria set measures and 128 completed 5 core criteria set measures both at enrollment and at 6 months. ACR pediatric criteria response rates for all of these patients have been combined. Comparisons among the subtypes yielded no significant differences (P = 0.61, 0.75, and 0.83 for comparisons of ACR Pedi 30, 50, and 70 criteria, respectively, among the subtypes). RF = rheumatoid factor; PSA = psoriatic arthritis; ERA = enthesitis-related arthritis; UND = undifferentiated.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The ReACCh-Out Study provides a unique opportunity to prospectively examine the outcomes of a large inception multicenter cohort of children with JIA. In the present report, we analyzed the short-term outcomes and the ACR pediatric criteria response rates documented during the first 6 months after enrollment in 354 patients. A significant proportion of patients with JIA other than those with oligoarticular onset started DMARDs prior to or at enrollment and within 1 month or less of diagnosis. However, biologic therapies were not used within the first 6 months after study enrollment or 7 months after diagnosis. Although nearly half (43%) of the patients with oligoarthritis received intraarticular injections between diagnosis and the 6-month followup assessment, 13% received DMARDs.

In regard to outcomes, median values for all of the 6 core criteria set of measures at the 6-month followup were low, and significant proportions of the patients achieved the ACR Pedi 70 criteria response within the time limits of the study. Nevertheless, despite the measured improvements, 50% or more of the patients in each subtype with the exception of patients with oligoarthritis and those in the undifferentiated arthritis group continued to have active arthritis. We recently reported that 33% of the patients in our JIA cohort achieved clinically inactive disease 6 months after enrollment (46% of patients with oligoarticular onset, 19% with RF-negative polyarthritis, 8% with RF-positive polyarthritis, 27% with systemic arthritis, 35% with PsA, 19% with ERA, and 32% with undifferentiated arthritis) (18), using a definition based on that of Wallace et al (26). Altogether, our findings suggest significant improvement but persistent low-grade activity in the short term for many newly diagnosed patients with JIA who are managed with current treatment strategies.

Although the patients selected for this report were enrolled within 6 months after diagnosis, it is notable that the disease duration from symptom onset was considerably longer, with median intervals as long as 9 months. However, with the exception of patients with RF-positive and RF-negative polyarthritis, disease severity at enrollment appeared to be relatively mild, with low median values of the core criteria set measures. This may be due in part to prior treatments, as it should be noted that more than half of the patients in this study had commenced treatments prior to enrollment. The lack of study assessments at the time of treatment initiations is relevant to the calculation of changes in measures between the 2 study points, but not to the reported absolute outcomes achieved early in the disease. It may be argued that the reported response rates underestimate improvement since we could not include that which occurred before enrollment.

Improvement early in the disease course has also been reported in other recent studies. Selvaag et al reported improvement from enrollment to 3 years in most disease measures, and Bowyer et al found that 20–50% of patients were off of medications at 1 year after diagnosis (7, 27). Both of these studies included patients diagnosed in the early or mid-1990s. High proportions were treated with DMARDs, 60% in the study by Selvaag et al and at least 55–62% with systemic or polyarticular JRA (diagnosed by ACR [formerly the American Rheumatism Association] criteria [10]) in the study by Bowyer et al. In the study by Bowyer et al, intraarticular corticosteroids were also used frequently during the first year of treatment. In our cohort, the types of treatments used were similar except for a higher proportion of patients with polyarthritis receiving DMARDs.

To our knowledge, there are no publications that have assessed the ACR pediatric criteria response rates in an inception cohort, and therefore no direct comparisons can be made. However, to put our results in perspective, in 2 recent clinical trials, 44% and 33% of patients with a severe polyarticular disease course who had failed treatment with methotrexate achieved an ACR Pedi 70 criteria response after 7 and 12 months, respectively, with etanercept, and in another trial, 52% reached this response after 1 year of infliximab treatment (21, 22, 28). The ACR Pedi 70 criteria response rate 6 months after starting methotrexate was 26% in a study of patients with polyarthritis, systemic arthritis, and extended oligoarthritis (17). In our study, 55% of patients with RF-negative polyarthritis achieved an ACR Pedi 70 criteria response, suggesting a good short-term outcome.

JIA subtype differences were most notable when normalization of each of the 6 core criteria set measures was considered. Consistent with other studies, children with RF-positive polyarthritis fared the worst. There are less data available in the literature for outcomes of ERA patients, making the descriptions in this study unique. Although half of the patients with ERA had no active joints at 6 months, a minority had normal physician global assessment of disease activity or patient or parent global assessment of overall well-being. This discrepancy may be due to other disease manifestations and symptoms such as enthesitis, which was persistent in many patients. Since the core criteria set of measures was based on patients with JRA classified by ACR (formerly the American Rheumatism Association) criteria (10, 19), they do not include a measure for enthesitis, and this may be a disadvantage when assessing outcomes for patients with ERA.

The low frequency of HLA–B27 in our ERA group was unexpected. Three recent studies using the ILAR criteria report a variable frequency of HLA–B27 in patients with ERA ranging from 53% to 91% (29–31). These reports originated in different countries, but the duration of followup was prolonged in all 3 studies. The prevalence of HLA–B27 in patients with ERA may depend on ethnic background, but also on disease duration, since the patients may be reassigned to other JIA categories or diagnoses as their disease evolves. Further followup of our cohort may clarify the association of HLA–B27 with ERA.

Published analyses suggest that disease activity within the first 6 months after onset may be predictive of longer-term outcomes such as remission, functional outcome, and joint damage in patients with JIA (32, 33). A recent study also demonstrated that an ACR Pedi 70 criteria response to methotrexate after 6 months of therapy was associated with improved outcomes, including lower AJC and inactive disease after 5 years, compared with those with lower responses or nonresponders (17). The authors concluded that the early disease course and response to treatment may be stronger predictors of long-term outcome than disease characteristics at onset (17). In patients with systemic JIA, the need for corticosteroids at 6 months after diagnosis is also a predictor of poor functional outcome (33). Altogether, these studies support the importance of documenting short-term outcomes, and support the premise that the results found in our study are likely to be of predictive value in the long term.

Advantages of the present study include the prospective study design and nationwide enrollment that would avoid bias toward severe disease, the application of a standardized set of disease measures that will facilitate comparisons among studies, and the inclusion of all JIA subsets that will provide critical information of the less well-studied subtypes. As discussed above, a limitation of the study was the enrollment of many of the participants after treatment initiation. In addition, many patients did not have complete 6 core criteria data sets, with ESR and CRP level measures missing most commonly. These limitations reflect the fact that the ReACCh-Out Study was designed to accommodate clinical settings.

In summary, we have reported the short-term outcomes in terms of the 6 core criteria set measures and ACR pediatric criteria response rates over the first 6 months after enrollment in a prospective cohort of patients with JIA treated with therapies currently used in clinical practice. Early outcomes were encouraging, with low median values of core set measures in all subtypes and relatively high rates of ACR Pedi 70 criteria responses seen even within the more severe JIA subtypes; however, the majority of patients still had active disease and many patients with systemic JIA still required corticosteroids at 6 months after enrollment or a median of 7 months after diagnosis. We believe that our findings will have predictive value for long-term outcomes.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Oen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Oen, Ciarán M. Duffy, Tse, Ellsworth, Johnson, Miettunen, Feldman, Yeung, Tucker.

Acquisition of data. Oen, Ciarán M. Duffy, Tse, Ramsey, Ellsworth, Chédeville, Chetaille, Saint-Cyr, Cabral, Spiegel, Schneider, Lang, Huber, Dancey, Rosenberg, Cameron, Johnson, Dorval, Scuccimarri, Campillo, Petty, Karen N. Watanabe Duffy, Boire, Haddad, Houghton, Laxer, Turvey, Miettunen, Gross, Guzman, Benseler, Espinosa, Yeung, Tucker.

Analysis and interpretation of data. Oen, Tse, Ramsey, Ellsworth, Chédeville, Cabral, Silverman, Miettunen, Guzman, Benseler, Yeung, Tucker.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The authors thank the patients in the REACCh-Out Study for their generous participation and the research assistants at each center. The authors also thank Michele Gibbon, BA, Garbis Meshefedjian, PhD, Mary Cheang, and Peter N. Malleson for their substantial contributions to data acquisition, data analysis, and/or project coordination.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
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