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

ObjectivesTo assess the efficacy of the interleukin 1 receptor antagonist anakinra in systemic-onset juvenile idiopathic arthritis (SJIA).MethodsA 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.ResultsAt 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 enrolment 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.ConclusionsAnakinra 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.

Comparison of biomarkers for systemic juvenile idiopathic arthritis

“…Expression array data overlapped with previous studies: 41 (including IL1B, NFATC3, STAT4 and other genes associated with the innate immune response), 2 (ATP2B1 and RNF14) and 64 genes were also identified by Ling et al, Allantaz et al, and the ANAJIS trial, respectively (8,29,30). Of the nine genes Articles in our group that met the more stringent false discovery rate, interestingly ZC3H12B encodes a protein with a role in proinflammatory actions of macrophages (31).…”

Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis

“…After 1 mo, there was a significant difference in response rates, with 67% (8/12) of anakinratreated subjects achieving the primary end point compared with 8% (1/12) in the placebo group. Gene expression profiling demonstrated normalization of previously dysregulated genes and upregulation of interferon (IFN)-inducible genes among the anakinra-treated subjects (54). The second study was a multicenter international observational trial analyzing 46 s-JIA patients treated with anakinra.…”

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

“…With the development of next generation sequencing and transcriptomics, it is likely that the role of NLRC4 in other inflammatory diseases will be identified. Elevated levels of NLRC4 transcripts were observed in patients with active systemic-onset juvenile idiopathic arthritis [75].…”