Stefania Viola

Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis

BACKGROUND Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials. METHODS In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis

OBJECTIVE To assess the clinical response to interleukin-1 (IL-1) blockade and in vitro IL-1beta and IL-18 secretion in patients with systemic-onset juvenile idiopathic arthritis (JIA). METHODS Twenty-two patients with systemic-onset JIA were treated with the IL-1 receptor antagonist (IL-1Ra) anakinra. Monocytes from 18 patients and 20 healthy donors were activated by different Toll-like receptor ligands. Intracellular and secreted IL-1beta and IL-18 were analyzed by Western blotting and enzyme-linked immunosorbent assay. RESULTS Ten patients with systemic-onset JIA exhibited a dramatic response to anakinra and were classified as complete responders. Eleven patients had an incomplete response or no response, and 1 patient could not be classified in terms of response. Compared with patients who had an incomplete response or no response, complete responders had a lower number of active joints (P = 0.02) and an increased absolute neutrophil count (P = 0.02). In vitro IL-1beta and IL-18 secretion in response to various stimuli was not increased and was independent of treatment efficacy. Likewise, secretion of IL-1Ra by monocytes from patients with systemic-onset JIA was not impaired. An overall low level of IL-1beta secretion upon exposure to exogenous ATP was observed, unrelated to treatment responsiveness or disease activity. CONCLUSION Two subsets of systemic-onset JIA can be identified according to patient response to IL-1 blockade. The 2 subsets appear to be characterized by some distinct clinical features. In vitro secretion of IL-1beta and IL-18 by monocytes from patients with systemic-onset JIA is not increased and is independent of both treatment outcome and disease activity.

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.

A New Approach to Clinical Care of Juvenile Idiopathic Arthritis: The Juvenile Arthritis Multidimensional Assessment Report

Objective. To develop and test a new multidimensional questionnaire for assessment of children with juvenile idiopathic arthritis (JIA) in standard clinical care. Methods. The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) includes 15 parent or patient-centered measures or items that assess well-being, pain, functional status, health-related quality of life, morning stiffness, disease activity, disease status and course, joint disease, extraarticular symptoms, side effects of medications, therapeutic compliance, and satisfaction with illness outcome. The JAMAR is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 7–18 years for use as a self-report. From March 2007 to September 2009, the questionnaire was completed by the parents of 618 children with JIA in 1814 visits and by 332 children in 749 visits. Results. The JAMAR was found to be feasible and to possess face and content validity. All parents and children reported that the questionnaire was simple and easy to understand. Completion and scoring appeared to be quick, requiring < 15 minutes. There were very few missing data. Parents’ proxy-reported and children’s self-reported data were remarkably concordant. The JAMAR provided thorough information for the study patients about recent medical history and current health status. It performed similarly across different children’s ages and characterized the level of disease activity and disability well. Conclusion. The development of the JAMAR introduces a new approach in pediatric rheumatology practice. This new questionnaire may help enhance the quality of care of children with JIA.

Safety and efficacy of infliximab and adalimumab for refractory uveitis in juvenile idiopathic arthritis: 1-year followup data from the Italian Registry.

Objective. To evaluate safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of juvenile idiopathic arthritis-related anterior uveitis (JIA-AU). Methods. Starting January 2007, patients with JIA-AU treated with IFX and ADA were managed by a standard protocol and data were entered into the National Italian Registry (NIR). At baseline, all patients were refractory to standard immunosuppressive treatment and/or were corticosteroid-dependent. Data recorded every 3 months included uveitis course, number/type of ocular complications, drug-related adverse events (AE), treatment change or withdrawal, and laboratory measures. Data of patients treated for at least 1 year were retrieved from the NIR and analyzed using descriptive statistics. Treatment efficacy was based on change in uveitis course and in number of ocular complications. Results. Up to December 2009, data for 108 patients with JIA-AU treated with anti-tumor necrosis factor-α agents were recorded in the NIR and data from 91, with at least 12 months’ followup, were included in the study. Forty-eight patients were treated with IFX, 43 with ADA. Forty-seven patients (55.3%) achieved remission of AU, 28 (32.9%) had recurrent AU, and 10 (11.8%) maintained a chronic course. A higher remission rate was observed with ADA (67.4% vs 42.8% with IFX; p = 0.025). Ocular complications decreased from 0.47 to 0.32 per subject. Five patients experienced resolution of structural complications. No patient reported serious AE; 8 (8.8%) experienced 11 minor AE (9 with IFX, 2 with ADA). Conclusion. IFX and ADA appear to be effective and safe for treatment of refractory JIA-related uveitis, with a better performance of ADA in the medium-term period.

Correlation between conventional disease activity measures in juvenile chronic arthritis

OBJECTIVE To estimate in a cross sectional analysis the degree of colinearity among the disease activity measures more commonly used in juvenile chronic arthritis (JCA). METHODS This study assessed in a single clinical evaluation three subjective variables, three measures of functional capacity, eight articular indices, and two laboratory indicators of systemic inflammation in 55 consecutive children with JCA. The relation between the clinical measures of JCA activity was determined by Pearson correlation coefficients. An r value of 0.7 or greater was considered evidence of colinearity. RESULTS Among the subjective variables, parent global assessment of overall well being and parent assessment of pain were correlated with each other; the physician assessment of disease activity did not show evidence of colinearity with any other variable. The functional status measures were correlated with each other, but not with the indices of articular inflammation. There was a high degree of colinearity among the articular variables, with the number of active joints and the overall severity score being correlated with each other as well as with all the single articular indices. The laboratory variables were correlated with each other, but not with any of the articular, functional or subjective variables. CONCLUSION Our results show a high degree of colinearity among the disease activity measures belonging to the same category, whereas this is uncommon for variables that investigate different domains of disease activity. These data underline the need to include the evaluation of each domain in the assessment of JCA activity.

The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis

OBJECTIVE To determine whether demographic, clinical, and laboratory variables measurable at baseline predict the clinical efficacy or major toxic effects of methotrexate (MTX) therapy in children with chronic arthritis. STUDY DESIGN Patient eligibility criteria: (1) monitored in our unit between 1986 and 1996 with a diagnosis of chronic arthritis and (2) treatment with MTX as the sole second-line agent and for at least 6 months. Outcomes investigated: (1) short-term (6-month) clinical response, (2) complete disease control, (3) disease relapse after MTX discontinuation after complete disease control, (4) aminotransferase elevation, (5) gastrointestinal toxicity. Independent variables that showed significant results with univariate tests or were clinically relevant for each outcome underwent multiple logistic or Poisson regression analyses. RESULTS Eighty patients were available for analysis. The disease onset subtype was systemic in 37 patients, polyarticular in 20 patients, and oligoarticular in 23 patients (all with polyarticular course: extended oligoarticular subtype). The extended oligoarticular subtype was the best predictor for both the short-term clinical response (odds ratio 6.80, P =.02) and, together with a better functional ability, the complete disease control (rate ratio 3.85, P =.03 and rate ratio 3.29, P =.006, respectively). Patients with this subtype of chronic arthritis tended to have earlier, and more frequently, a disease relapse after MTX discontinuation. Thrombocytosis was the only significant risk factor for liver biochemical abnormalities (rate ratio 2.94, P =.008), whereas no variable yielded significant results for gastrointestinal toxicity. CONCLUSION Patients with extended oligoarticular chronic arthritis were more likely to benefit from MTX therapy and to have a relapse after treatment discontinuation, suggesting that MTX is distinctly more effective in this subset of chronic arthritis.

Dynamic contrast-enhanced magnetic resonance imaging in the assessment of disease activity in patients with juvenile idiopathic arthritis

OBJECTIVE To determine the capability and reliability of dynamic contrast-enhanced MRI (DCE-MRI) in the assessment of disease activity in juvenile idiopathic arthritis (JIA). METHODS DCE-MRI of the clinically more affected wrist or hip joints was undertaken in 21 patients, coupled with standard clinical assessment and biochemical analysis. Synovial inflammation was assessed by computing the maximum level of synovial enhancement (ME), the maximum rate of enhancement (MV) and the rate of early enhancement (REE) from the enhancement curves generated from region of interest independently delineated by two readers in the area of the ME. Correlations between dynamic parameters and clinical measures of disease activity, and static MRI synovitis score were investigated. RESULTS In patients with wrist arthritis, REE correlated with the wrist swelling score (r(s) = 0.72), ESR (r(s) = 0.69), pain assessment scale (r(s) = 0.63) and childhood HAQ (r(s) = 0.60). In patients with hip arthritis, ME correlated with the hip limitation of motion (r(s) = 0.69). Static MRI synovitis score based on post-gadolinium enhancement correlated with MV (r(s) = 0.63) in patients with wrist arthritis and with ME (r = 0.68) in those with hip arthritis. The inter-reader agreement assessed by intra-class correlation coefficient (ICC) for ME, MV and REE (ICC = 0.98, 0.97 and 0.84, respectively) was excellent. CONCLUSIONS DCE-MRI represents a promising method for the assessment of disease activity in JIA, especially in patients with wrist arthritis. As far as we know, this study is the first to demonstrate the feasibility, reliability and construct validity of DCE-MRI in JIA. These results should be confirmed in large-scale longitudinal studies in view of its further application in therapeutic decision making and in clinical trials.

The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis

Objective: To investigate the relationship between the magnitude of clinical response in the first 6 months of methotrexate (MTX) therapy and long-term outcome in children with juvenile idiopathic arthritis (JIA). Methods: The clinical charts of 125 JIA patients who were started with MTX and then followed for at least 5 years were reviewed. Based on the level of American College of Rheumatology (ACR) Pediatric response at 6 months, patients were divided in four mutually exclusive groups: (1) non-responders, (2) responders at 30%, (3) responders at 50%, and (4) responders at 70%. The long-term outcome in each response group was evaluated by calculating the percentage change in active and restricted joint counts from baseline to 1, 2 and 5 years and the frequency of inactive disease at 5 years. Results: At 6 months, 42 patients were classified as non-responders, 24 as 30% responders, 26 as 50% responders, and 33 as 70% responders. Patients who had achieved a 70% response showed a significantly greater percentage improvement in active joint count between baseline to 5 years compared with non-responders and 30% responders, and a significantly greater percentage improvement in restricted joint count between baseline to 5 years compared with 30% responders. The 70% responders also had a greater frequency of inactive disease at 5 years compared with 30% responders, Conclusions: Our results show that the achievement of an ACR Pediatric 70 response at 6 months after start of MTX therapy predicts a more favorable long-term outcome of patients with JIA.

Assessing current outcomes of juvenile idiopathic arthritis: A cross-sectional study in a tertiary center sample

OBJECTIVE To investigate the disease outcomes of a cross-sectional sample of children with longstanding juvenile idiopathic arthritis (JIA) seen between September 2002 and December 2006, and to provide a benchmarking of outcomes obtained with current treatment. METHODS All consecutive patients were included if they met the following criteria: diagnosis of JIA, disease duration > or = 5 years, and informed consent. Outcome assessments included disease activity, inactive disease, minimal disease activity, pain, physical function, health-related quality of life (HRQOL), auxometric measurements, and articular and extraarticular damage. RESULTS A total of 310 patients were included. At study visit, patients had on average a low level of disease activity. However, only 21.8% met the criteria for inactive disease, and less than 50% met the definition of minimal disease activity. Additionally, 19.2% had moderate to severe Childhood Health Assessment Questionnaire disability and 3.6% were in Steinbrocker class III-IV. Approximately 10% had major impairment in HRQOL. A total of 34.2% had damage in > or = 1 joint or joint group and 26.1% showed extraarticular damage. Of the 125 patients who underwent a wrist radiograph, 35.2% had significant structural damage and 8.7% had growth retardation. CONCLUSION Our patients had on average a low level of disease activity, little or no physical disability, and a satisfactory HRQOL. However, a sizable proportion of patients had persistently active disease, impaired function, and damage. These findings underscore the critical need for treatments and treatment strategies that have the ability to better control disease activity and to reduce the development of disease-related morbidities.