Quartier P, Allantaz F, Cimaz R, et al. 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)

Université Paris-Descartes and Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.
Annals of the rheumatic diseases (Impact Factor: 10.38). 12/2010; 70(5):747-54. DOI: 10.1136/ard.2010.134254
Source: PubMed


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

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    • "Human recombinant IL-1 receptor antagonist (IL-1ra) can block the IL-1 mediated effects, and restore the balance of Th17/Treg cells. Even though the exact mechanisms remain largely unknown, the use of anakinra, an IL-1ra, as a therapy in RA was effective and safe (39). Treg cells highly express CTLA-4, which controls the suppressive function of Treg cells (40). "
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    ABSTRACT: Regulatory T (Treg) cells are essential for normal immune surveillance systems, and their dysfunction leads to development of diseases, such as autoimmune disorders. CD4(+)CD25(+) Treg cells are well-known suppressive cells, which express the transcription factor Foxp3, are indispensable for the maintenance of immune self-tolerance and homeostasis by suppressing aberrant or excessive immune response. Other Foxp3(-) Treg cells include Tr1, Th3, CD8(+)CD28(-/-), and Qa1-restricted T cells; however, the contribution of these Treg cells to self-tolerance, immune homeostasis as well as preventing autoimmunity is not well defined. Here, we discuss the phenotypes and function of Foxp3(+) Treg cells and the potential use of such Treg cells against rheumatoid arthritis (RA). Of note, even though most expanded populations of Foxp3(+) Treg cells exhibit suppressive activity, tissue-associated or antigen-specific Treg cells appear superior in suppressing local autoimmune disorders such as RA. In addition, utilizing tissue-associated Foxp3(+) Treg cells from stem cells may stable Foxp3 expression and avoid induction of a potentially detrimental systemic immunosuppression.
    Frontiers in Oncology 08/2014; 4:209. DOI:10.3389/fonc.2014.00209
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    • "Microarray analysis of PBMCs of sJIA patients in the ANAJIS trial showed significant upregulation of innate immunity and underexpression of adaptive immunity gene modules before treatment, similar to our Dallas sJIA cohort. The ANAJIS trial was a small multicenter, randomized, double blind, placebo-controlled trial done to study efficacy of Anakinra in treatment-resistant sJIA patients with active disease [75]. The 24 patients in this study were steroid-dependent with a minimum of six month disease duration. "
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    ABSTRACT: Blood gene expression profiling has led to major advances in the field of rheumatology over the last few decades. Specifically, DNA microarray technology has been integral in increasing our knowledge of key players in the pathogenesis of some rare pediatric rheumatic diseases. Our group, using microarray analysis, identified the interferon (IFN) gene signature in pediatric systemic lupus erythematosus (SLE) and has published data that suggest high doses of intravenous corticosteroid treatment may have benefit over strictly oral regimens. Additionally, DNA microarray technology led to our discovery that the interleukin (IL)-1 gene signature is associated with systemic juvenile idiopathic arthritis (sJIA) and to the use of IL-1 blockade with anakinra in this disease. We also reported the biologic rationale for use of anakinra early in the disease course. Anakinra is now being used as first-line treatment in sJIA in multiple centers. Herein, we review how information obtained from blood gene expression profiling has changed our clinical practice.
    Pediatric Rheumatology 05/2014; 12(1):16. DOI:10.1186/1546-0096-12-16 · 1.61 Impact Factor
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    • "The first indication that IL-1 blockade may be promising in children with sJIA was provided by Verbsky and White, who successfully treated two children with anakinra [62]. Since then, multiple additional case series have confirmed its effectiveness [63-65], as have RCTs of all three agents [39,44,46]. Anakinra appears to be of greater benefit to the systemic, rather than the articular, features of sJIA when not used at disease onset/diagnosis [64,65]; this topic will be discussed further below. "
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    ABSTRACT: A generation ago, children with arthritis faced a lifetime of pain and disability. Today, there are a multitude of treatment options, including a variety of biologics targeting key cytokines and other inflammatory mediators. While non-steroidal anti-inflammatory drugs and corticosteroids were once the mainstay of therapy, they are now largely used as bridge or adjunctive therapies. Among the conventional disease-modifying anti-rheumatic drugs, methotrexate remains first-line therapy for most children with juvenile idiopathic arthritis (JIA) due to its long track record of safety and effectiveness in the management of peripheral arthritis. Sulfasalazine and leflunomide may also have a secondary role. The tumor necrosis factor inhibitors (TNFi) have shown tremendous benefit in children with polyarticular JIA and likely in enthesitis-related arthritis and psoriatic JIA as well. There may be additional benefit in combining TNFi with methotrexate. Abatacept and tocilizumab also appear to benefit polyarticular JIA; the role of rituximab remains unclear. For the treatment of systemic JIA, while the TNFi are of less benefit, blockade of interleukin-1 or interleukin-6 is highly effective. Additionally, interleukin-1 blockade appears to be effective treatment of macrophage activation syndrome, one of the most dangerous complications of JIA; specifically, anakinra in combination with cyclosporine and corticosteroids may obviate the need for cytotoxic approaches. In contrast, methotrexate along with the TNFi and abatacept are effective agents for the management of uveitis, another complication of JIA. Overall, the biologics have demonstrated an impressive safety record in children with JIA, although children do need to be monitored for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of malignancy. Finally, there may be a window of opportunity during which children with JIA will demonstrate most optimal responses to aggressive therapy, underscoring the need for rapid diagnosis and initiation of treatment.
    Pediatric Rheumatology 04/2014; 12(1):13. DOI:10.1186/1546-0096-12-13 · 1.61 Impact Factor
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