A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial)

Abstract

Objectives: To assess the efficacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA).

Methods: A multicentre, randomised, double-blind, placebo-controlled trial was conducted. The primary objective was to compare the efficacy of a 1-month treatment with anakinra (2 mg/kg subcutaneous daily, maximum 100 mg) with a placebo between two groups each with 12 patients with SJIA. Response was defined by a 30% improvement of the paediatric American College of Rheumatology criteria for JIA, resolution of systemic symptoms and a decrease of at least 50% of both C-reactive protein and erythrocyte sedimentation rate compared with baseline. After month 1 (M1), patients taking placebo were switched to anakinra. Secondary objectives included tolerance and efficacy assessment for 12 months, and analyses of treatment effect on blood gene expression profiling.

Results: At M1, 8/12 responders were receiving anakinra and 1 responder receiving placebo (p=0.003). Ten patients from the placebo group switched to anakinra; nine were responders at M2. Between M1 and M12, six patients stopped treatment owing to an adverse event (n=2), lack of efficacy (n=2) or a disease flare (n=2). Blood gene expression profiling at enrollment and at 6 months' follow-up showed one set of dysregulated genes that reverted to normal values in the clinical responders and a different set, including interferon (IFN)-inducible genes, that was induced by anakinra.

Conclusions: Anakinra treatment is effective in SJIA, at least in the short term. It is associated with normalisation of blood gene expression profiles in clinical responders and induces a de novo IFN signature.

Trial registration number: NCT00339157.

Figure 1

Study design. *Measurement of serum amyloid A and ferritin levels, assessment of the percentage of glycosylated ferritin, gene expression profiling analysis and cytokine measurements. †Measurement of the concentration of anakinra in plasma (pharmacokinetic analyses). ‡Measurement of serum anti-pneumococcal antibodies. D, day; M, month.

Figure 2

Patients' disposition. (A) Randomised placebo-controlled, double-blind trial (until M1). (B) Open-labelled phase (from M1 to M12). Arthritis activity leading to treatment withdrawal (= two patients withdrawn for a disease flare-up, at M2 and M3, respectively, and two patients withdrawn for a lack of response, at M4 and M5, respectively). *Two patients from the control group stopped treatment after 5 and 11 days, respectively, owing to pain from injections and were withdrawn from the trial after the M1 visit. †Cutaneous and digestive symptoms leading to the diagnosis of Crohn's disease shortly after M2. ‡Increase of serum transaminases over five times the upper limit of normal at M6. AE, adverse event; JIA, juvenile idiopathic arthritis; M, month; SAE, serious adverse event.

Figure 3

Modular analysis. (A) Annotated module map of patients with systemic-onset juvenile idiopathic arthritis (SJIA) at D1, M1 and M6. Expression levels in patients were compared with those of healthy controls. Spots indicate the proportion of genes that were significantly changed for each module (Mann–Whitney rank test, p<0.05). The black outline indicates the core signature common in the two groups of patients at D1. (B) Forty-nine representative genes from the module 3.1 were rearranged by hierarchical clustering in order to reveal differential expression. Expression values are normalised for each gene to the healthy group. Transformed expression levels are indicated by colour scale, with red representing relatively high expression and blue indicating relatively low expression. (C) Levels of inducible proteins IP10 and TRAIL were measured in the serum of patients with SJIA at D1 and M6. All results were analysed using a paired t-test. (D) SOCS3 expression was measured in whole blood of patients by microarray at D1 and M6. Results were analysed using a paired t-test. D, day; M, month.