Effects of long‐term etanercept treatment on growth in children with selected categories of juvenile idiopathic arthritis

Objective

To evaluate the effects of long‐term etanercept treatment, with or without methotrexate, on growth in children with selected categories of juvenile idiopathic arthritis (JIA).

Methods

We conducted a 3‐year, open‐label, nonrandomized registry of 594 patients with polyarticular or systemic JIA treated with etanercept only, etanercept plus methotrexate, or methotrexate only. Height, weight, and body mass index (BMI) were assessed at baseline and at years 1, 2, and 3, using percentiles derived from US Centers for Disease Control and Prevention standardized growth charts.

Results

Statistically significant increases in the mean height percentiles from baseline were observed in etanercept‐treated patients at year 3 (4.8 percentile points) and in patients treated with etanercept plus methotrexate at years 1, 2, and 3 (2.4, 3.3, and 5.6 percentile points, respectively). Statistically significant increases from baseline in the mean weight percentiles were observed at years 1, 2, and 3 in both the etanercept group (7.4, 10.0, and 13.0 percentile points) and the etanercept‐plus‐methotrexate group (2.9, 6.9, and 8.4 percentile points, respectively). Statistically significant increases from baseline in the mean BMI percentiles were observed in both the etanercept group (range 9.6–13.8 percentile points) and the etanercept‐plus‐methotrexate group (range 2.1–5.2 percentile points). The mean height, weight, and BMI percentiles did not change significantly in patients in the methotrexate‐only group.

Conclusion

Etanercept treatment, with or without methotrexate, may contribute to the restoration of normal growth in children with JIA.

     

Long-term breastfeeding influences disease activity in a low-income juvenile idiopathic arthritis cohort

Clinical Rheumatology - To determine the influence of breastfeeding duration in the clinical activity of low-income juvenile idiopathic arthritis (JIA). Ninety-one JIA patients followed in...     

Development and validation of a clinical index for assessment of long‐term damage in juvenile idiopathic arthritis

Objective

To develop and validate a clinical measure of articular and extraarticular damage in patients with juvenile idiopathic arthritis (JIA).

Methods

The Juvenile Arthritis Damage Index (JADI), which is derived from physical examination and a brief review of the patient's clinical history, is composed of 2 parts: assessments of articular damage (JADI‐A) and extraarticular damage (JADI‐E). Instrument validation was accomplished by evaluating 158 JIA patients with disease duration of at least 5 years, seen consecutively over 21 months. The instrument's feasibility, face and content validity, construct and discriminative ability, internal consistency, and interrater reliability were examined.

Results

Among the 158 JIA patients, 47% and 37% had articular and extraarticular damage, respectively. The JADI was found to be feasible and to possess both face and content validity. The JADI‐A score correlated highly with the number of joints with limited range of motion (Spearman's r [r_S] = 0.72) and correlated moderately with the Childhood Health Assessment Questionnaire score (r_S = 0.41), Steinbrocker functional classification (r_S = 0.50), and Poznanski's score of radiographic damage (r_S = −0.54), thereby demonstrating good construct validity. Correlations with the JADI‐E score were lower, owing to the heterogeneity of its items. The JADI‐A discriminated well among different levels of disability. The internal consistency (Chronbach's alpha) of the JADI‐A and JADI‐E was 0.93 and 0.59, respectively. The intraclass correlation coefficients between pairs of independent observers ranged from 0.85 to 0.97.

Conclusion

The JADI exhibited good reliability, construct validity, and discriminative ability and is therefore a valid instrument for the assessment of long‐term damage in patients with JIA, in the context of both clinical management and research settings.

     

Long‐term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis

Objective

This study was undertaken to evaluate the long‐term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA).

Methods

Patients ages 2–18 years with rheumatoid factor (RF)–positive or RF‐negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (≥10 mg/m²/week [∼0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open‐label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment.

Results

A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure‐adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient‐years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient‐years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study.

Conclusion

These data confirm the findings of other long‐term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

     

Prevalence,risk factors,and outcome of uveitis in juvenile idiopathic arthritis: A long‐term followup study

Objective

To assess the prevalence, risk factors, and long‐term outcome of uveitis in patients with juvenile idiopathic arthritis (JIA).

Methods

An inception cohort of all 1,081 patients diagnosed as having JIA at a single tertiary care center was established. A questionnaire and followup telephone calls were used to confirm the diagnosis of uveitis. Ophthalmologists' records of patients with uveitis were collected. Kaplan‐Meier and Cox regression analyses were used to assess risk factors for developing uveitis and for complications of uveitis.

Results

After a mean followup time of 6.9 years, 142 of 1,081 patients (13.1%) had developed uveitis. Risk factors were young age at diagnosis, female sex, antinuclear antibody positivity, and the subtype of JIA. The relative contribution of these risk factors was different for the different subtypes of JIA. Until the end of the study, uveitis complications had developed in 53 of 142 patients with uveitis (37.3%; 4.9% of the total cohort). Only 16 of 175 involved eyes (9.1%) in 14 of 108 patients (13%; 1.3% of the total cohort) for whom ophthalmology reports were available had best corrected visual acuity less than 20/40 (mean followup time for uveitis of 6.3 years). Abnormal vision was associated with synechiae or cataract.

Conclusion

Risk factors for developing uveitis were different among subtypes of JIA. The long‐term outcome of JIA‐associated uveitis in our cohort was excellent despite the high rate of complications.

     

Long‐term outcome in patients with juvenile idiopathic arthritis

Objective

To describe the long‐term outcome of juvenile idiopathic arthritis (JIA).

Methods

All patients with JIA referred to a pediatric rheumatology center between 1978 and 1988 were identified and invited to undergo an assessment. Patients with JIA from a population‐based cohort from East Berlin were included. The outcome assessment considered changes in body function and structure (e.g., mortality, joint abnormalities, disease activity), activities at the individual level (Health Assessment Questionnaire), and participation in society (e.g., mobility, educational and vocational background).

Results

Of 260 eligible patients, 215 (83%) were evaluated. Subtypes of JIA at disease onset included oligoarthritis (40%), polyarthritis (14%), systemic arthritis (14%), psoriatic arthritis (1%), enthesitis‐related arthritis (15%), and other arthritis (16%). Followup was conducted after a median of 16.5 years. No deaths occurred in this cohort. At followup, approximately half of the patients had active disease and/or changes in body structures to a variable extent. Approximately one‐third of patients rated themselves as being functionally limited. Patients demonstrated good social integration: few mobility problems were reported, and the educational achievements of patients were higher and their rate of unemployment was lower compared with the age‐matched population. No significant differences in outcome were found between the population‐based and the referral‐based cohorts.

Conclusion

Even though approximately half of the JIA patients had more or less distinctive changes in body function and/or structure after a disease duration of >15 years, fewer than 10% were severely disabled or handicapped. Because JIA often persists into adulthood, long‐term followup and care are necessary.

     

Frequency of osteopenia in adolescents with early‐onset juvenile idiopathic arthritis: A long‐term outcome study of one hundred five patients

Objective

To determine the frequency of low bone mineral content (BMC) and low bone mineral density (BMD) as long‐term complications in adolescents with early‐onset juvenile idiopathic arthritis (JIA), and to identify disease variables, patient characteristics, and biochemical bone markers related to low bone mass.

Methods

One hundred five (87%) of 121 adolescent patients with early‐onset JIA (ages 13–19 years, 80 girls and 25 boys, mean age at onset of JIA 2.8 years), from a cohort first admitted to the hospital between 1980 and 1985, were assessed after a mean disease duration of 14.2 years. BMC and BMD of the total body, the lumbar spine at L2–L4, and the femoral neck were measured by dual‐energy x‐ray absorptiometry. Age‐ and sex‐specific reference values from a pooled, healthy reference population were used to calculate Z scores. Low bone mass was defined as a Z score less than −1 SD.

Results

Among the 103 adolescent JIA patients who underwent total‐body imaging, 41% had low total‐body BMC and 34% had low total‐body BMD. Compared with adolescent JIA patients who had normal total‐body BMC, those with low BMC had lower mean weight (P < 0.001), height (P < 0.001), lean mass (P < 0.001), and remission rates (P = 0.016), had longer duration of active disease (P = 0.013), had higher numbers of active and mobility‐restricted joints (P < 0.001 and P = 0.001, respectively), had more disability (P = 0.011), had higher frequencies of joint erosions (P < 0.001), and had higher erythrocyte sedimentation rates (P = 0.033). In multiple linear regression analyses of total‐body BMC, 88% of the variance was explained by the duration of active disease, the number of joints with restricted mobility, the bone area, urinary deoxypyridinoline values, age, weight, and height.

Conclusion

Forty‐one percent of the adolescents with early‐onset JIA had low bone mass >11 years after disease onset. The development of low total‐body BMC was related to the duration of active disease, disease severity, measures of bone resorption, weight, and height.

     

Minimal disease activity,remission, and the long‐term outcomes of rheumatoid arthritis

Objective

To determine the prevalence of minimal disease activity (MDA) and remission in patients with rheumatoid arthritis (RA), to assess the effect of anti–tumor necrosis factor (anti‐TNF) therapy on MDA, and to determine the extent to which MDA status improves long‐term outcomes.

Methods

Using the Patient Activity Scale (PAS) as a surrogate, we assessed the prevalence of MDA and remission in 18,062 patients with RA using the newly developed Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria for MDA.

Results

MDA was noted in 20.2% of 18,062 patients and persistent MDA, operationally defined as having MDA during ≥2 consecutive 6‐month observation periods, occurred in 13.5% of 7,433 patients followed longitudinally. Disease activity at remission levels was noted in 7%. Among patients with MDA, 82% received disease‐modifying antirheumatic drugs or biologic agents. Following anti‐TNF initiation, the cumulative probability of achieving MDA at 2 and 6 years was 4.1% and 7.6%, respectively, and persistent MDA probabilities were 2.7% and 4.5%, respectively. Regardless of RA duration, patients with MDA had substantially better outcomes, including a 10‐fold reduction in work disability and an approximately 2‐fold reduction in total joint replacement and mortality.

Conclusion

Remission remains uncommon in RA, and the prevalence of new remission in community practice is substantially lower than noted in published trials of biologic therapy. On average, persons with MDA appear to have persistently mild RA. This might be the effect of milder RA and/or more effective treatment in early RA. The PAS had satisfactory levels of agreement with the full MDA criteria and appears suitable for use in clinical and epidemiologic research.     

Long‐term safety and efficacy of abatacept in children with juvenile idiopathic arthritis

Objective

We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease‐modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long‐term extension (LTE) phase of that study.

Methods

This report describes the long‐term, open‐label extension phase of a double‐blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6–17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open‐label LTE phase and reflect ≥21 months (589 days) of treatment. Safety results include all available open‐label data as of May 7, 2008.

Results

Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double‐blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open‐label lead‐in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient.

Conclusion

Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4‐month open‐label lead‐in phase.

     

Predictors of early inactive disease in a juvenile idiopathic arthritis cohort: Results of a Canadian multicenter,prospective inception cohort study

Objective

To determine early predictors of 6‐month outcomes in a prospective cohort of patients with juvenile idiopathic arthritis (JIA).

Methods

Patients selected were those enrolled in an inception cohort study of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study, within 6 months after diagnosis. The juvenile rheumatoid arthritis core criteria set and quality of life measures were collected at enrollment and 6 months later. Outcomes evaluated included inactive disease, Juvenile Arthritis Quality of Life Questionnaire (JAQQ) scores, and Childhood Health Assessment Questionnaire (C‐HAQ) scores at 6 months.

Results

Thirty‐three percent of patients had inactive disease at 6 months. Onset subtype and most baseline core criteria set measures correlated with all 3 outcomes. Relative to oligoarticular JIA, the risks of inactive disease were lower for enthesitis‐related arthritis, polyarthritis rheumatoid factor (RF)–negative JIA, and polyarthritis RF‐positive JIA, and were similar for psoriatic arthritis. In multiple regression analyses, the baseline JAQQ score was an independent predictor of all 3 outcomes. Other independent baseline predictors included polyarthritis RF‐negative and systemic JIA for inactive disease; C‐HAQ score and polyarthritis RF‐positive JIA for the 6‐month C‐HAQ score; and active joint count, pain, and time to diagnosis for the 6‐month JAQQ score.

Conclusion

Clinical measures soon after diagnosis predict short‐term outcomes for patients with JIA. The JAQQ is a predictor of multiple outcomes. Time to diagnosis affects quality of life in the short term.     

Chitotriosidase activity in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is an inflammatory joint disease of unknown etiology. The pathogenesis is driven by T and B cells. The role of macrophages remains unclear. Chitotriosidase belongs to the chitinase protein family and is secreted by activated macrophages. The chitinases are able to catalyze the hydrolysis of chitin or chitin-like substrates such as 4-methylumbelliferyl chitotrioside. Chitotriosidase activity was determined using the substrate 4-methylumbelliferyl beta-DNN'N'-triacetylchitotrioside (4-MU-TCT, SIGMA Chemical Co.). The substrate and serum were incubated with the serum in a citrate/phosphate buffer. The reaction was stopped by adding a buffer (Na(2)CO(3)). The fluorescence of 4-methylumbelliferone was evaluated by fluorimeter at excitation 360 nm and emission 450 nm. We report about chitotriosidase measurements in patients with JIA. The chitotriosidase level in synovial fluid was up to approximately 1,000 nmol/(h ml) at disease onset before therapy. The level in the sera was below 600 nmol/(h ml). Serum chitotriosidase levels could represent the activity of macrophages in the synovial fluid in JIA.     

Development and validation of a composite disease activity score for juvenile idiopathic arthritis

Objective

To develop and validate a composite disease activity score for juvenile idiopathic arthritis (JIA), the Juvenile Arthritis Disease Activity Score (JADAS).

Methods

The JADAS includes 4 measures: physician global assessment of disease activity, parent/patient global assessment of well‐being, active joint count, and erythrocyte sedimentation rate. These variables are part of the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, and Pedi 70 criteria for improvement. Validation analyses were conducted on >4,500 patients and included assessment of construct validity, discriminant validity, and responsiveness to change. Three versions of the JADAS were tested based on 71‐joint (range 0–101), 27‐joint (range 0–57), or 10‐joint (range 0–40) counts. Statistical performances of the JADAS were compared with those of 2 rheumatoid arthritis composite scores, the Disease Activity Score in 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI).

Results

The JADAS demonstrated good construct validity, yielding strong correlations with JIA activity measures not included in the score and moderate correlations with the Childhood Health Assessment Questionnaire. Correlations obtained for the 3 JADAS versions were comparable, but superior to those yielded by the DAS28 and CDAI. The area under the curve of the JADAS predicted long‐term disease outcome, measured as radiographic progression over 3 years. In 2 clinical trials, the JADAS discriminated well between ACR Pedi 30, Pedi 50, and Pedi 70 response and revealed strong responsiveness to clinical change.

Conclusion

The JADAS was found to be a valid instrument for assessment of disease activity in JIA and is potentially applicable in standard clinical care, observational studies, and clinical trials.