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)

Pierre Quartier, Florence Allantaz, Rolando Cimaz, Pascal Pillet, Claude Messiaen, Christophe Bardin, Xavier Bossuyt, Anne Boutten, Jacques Bienvenu, Agnes Duquesne, Olivier Richer, Damien Chaussabel, Agnes Mogenet, Jacques Banchereau, Jean-Marc Treluyer, Paul Landais, Virginia Pascual, Pierre Quartier, Florence Allantaz, Rolando Cimaz, Pascal Pillet, Claude Messiaen, Christophe Bardin, Xavier Bossuyt, Anne Boutten, Jacques Bienvenu, Agnes Duquesne, Olivier Richer, Damien Chaussabel, Agnes Mogenet, Jacques Banchereau, Jean-Marc Treluyer, Paul Landais, Virginia Pascual

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.

Conflict of interest statement

Competing interests None.

Figures

Figure 1
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
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
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

References

    1. Petty RE, Southwood TR, Manners P, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390–2
    1. Woo P, Southwood TR, Prieur AM, et al. Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis Rheum 2000;43:1849–57
    1. Quartier P, Taupin P, Bourdeaut F, et al. Efficacy of etanercept for the treatment of juvenile idiopathic arthritis according to the onset type. Arthritis Rheum 2003;48:1093–101
    1. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008;371:998–1006
    1. Spiegel LR, Schneider R, Lang BA, et al. Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study. Arthritis Rheum 2000;43:2402–9
    1. Pascual V, Allantaz F, Arce E, et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005;201:1479–86
    1. Allantaz F, Chaussabel D, Stichweh D, et al. Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade. J Exp Med 2007;204:2131–44
    1. Lequerré T, Quartier P, Rosellini D, et al. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008;67:302–8
    1. Gattorno M, Piccini A, Lasigliè D, et al. The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2008;58:1505–15
    1. Zeft A, Hollister R, LaFleur B, et al. Anakinra for systemic juvenile arthritis: the Rocky Mountain experience. J Clin Rheumatol 2009;15:161–4
    1. Worwood M, Cragg SJ, Wagstaff M, et al. Binding of human serum ferritin to concanavalin A. Clin Sci 1979;56:83–7
    1. Vignes S, Le Moël G, Fautrel B, et al. Percentage of glycosylated serum ferritin remains low throughout the course of adult onset Still's disease. Ann Rheum Dis 2000;59:347–50
    1. Jeurissen A, Moens L, Raes M, et al. Laboratory diagnosis of specific antibody deficiency to pneumococcal capsular polysaccharide antigens. Clin Chem 2007;53:505–10
    1. Chaussabel D, Quinn C, Shen J, et al. A modular analysis framework for blood genomics studies: application to systemic lupus erythematosus. Immunity 2008;29:150–64
    1. Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202–9
    1. Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31:2290–4
    1. Solle M, Labasi J, Perregaux DG, et al. Altered cytokine production in mice lacking P2X(7) receptors. J Biol Chem 2001;276:125–32
    1. Ilowite N, Porras O, Reiff A, et al. Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study. Clin Rheumatol 2009;28:129–37
    1. Salliot C, Dougados M, Gossec L. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 2009;68:25–32
    1. Ruemmele FM, Prieur AM, Talbotec C, et al. Development of Crohn disease during anti-TNF-alpha therapy in a child with juvenile idiopathic arthritis. J Pediatr Gastroenterol Nutr 2004;39:203–6
    1. Dallocchio A, Canioni D, Ruemmele F, et al. Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etanercept: a French retrospective study. Rheumatology (Oxford) 2010;49:1694–8
    1. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009;27:229–65
    1. Fall N, Barnes M, Thornton S, et al. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheum 2007;56:3793–804
    1. Palucka AK, Blanck JP, Bennett L, et al. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA 2005;102:3372–7
    1. Ogilvie EM, Khan A, Hubank M, et al. Specific gene expression profiles in systemic juvenile idiopathic arthritis. Arthritis Rheum 2007;56:1954–65
    1. Wong PK, Egan PJ, Croker BA, et al. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest 2006;116:1571–81
    1. Pauli EK, Schmolke M, Wolff T, et al. Influenza A virus inhibits type I IFN signaling via NF-kappaB-dependent induction of SOCS-3 expression. PLoS Pathog 2008;4:e1000196.
    1. Martinelli S, Urosevic M, Daryadel A, et al. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J Biol Chem 2004;279:44123–32
    1. Pascual V, Farkas L, Banchereau J. Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol 2006;18:676–82
    1. Dinarello CA. Interleukin-1beta and the autoinflammatory diseases. N Engl J Med 2009;360:2467–70

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅