Rheumatology Advance Access originally published online on August 18, 2006
Rheumatology 2006 45(11):1448-1449; doi:10.1093/rheumatology/kel301
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Successful treatment of refractory polyarticular juvenile idiopathic arthritis with rituximab
Rheumatology Research Unit, Addenbrooke's Hospital, Cambridge University Teaching Hospitals NHS, Foundation Trust, Cambridge, UK.
Correspondence to: Dr A. J. K. Östör, Rheumatology Research Unit, Box 194, E6, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. E-mail: andrew.ostor{at}addenbrookes.nhs.uk
SIR, Juvenile idiopathic arthritis (JIA), being the most common chronic musculoskeletal disease of childhood, has a prevalence estimated to be 1 in 1000 children [1]. Up to 10% of these remain severely disabled in adulthood [2]. Numerous disease-modifying anti-rheumatic drugs (DMARDs) have been trialled with varying success in JIA, and therefore additional therapeutic targets have been investigated. Pro-inflammatory cytokines have been implicated in the pathogenesis of JIA especially tumour necrosis factor-
(TNF-), interleukin-1 (IL-1) and IL-6. Biological agents that directly target these cytokines such as etanercept [3], infliximab [4], anakinra [5] and tocilizumab [6] have, therefore, been used in JIA with promising results.
In addition to cytokine blockade, research arousing considerable interest in inflammatory arthritis is B-cell-targeted therapy. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been successfully used in patients with rheumatoid arthritis (RA) [7]. Accordingly, we investigated the safety and efficacy of rituximab in a young adult with a history of rheumatoid factor (RF) negative polyarticular JIA.
A 26-yr-old woman was first diagnosed with JIA at the age of 8 yrs. Laboratory findings at presentation revealed anti-nuclear antibody positivity but absence of RF. Numerous DMARDs were initiated in an attempt to achieve symptomatic control including methotrexate, sulphasalazine, myocrisin, minocycline and ciclosporin. All of these, however, were discontinued owing to intolerable side effects or poor efficacy. Frequent flares of arthritis were controlled with high-dose corticosteroid treatment; however, the patient developed Cushing's syndrome and osteoporotic fractures. Her course was further complicated by the need for bilateral hip replacements at the age of 21 yrs.
With limited therapeutic options, Alemtuzumab (Campath 1-H), a lymphocytic monoclonal antibody used primarily in the treatment of chronic lymphocytic leukaemia, was trialled in 1993. Despite suggestions of efficacy in a range of immune-mediated diseases, our patient did not respond to this agent. In 1999, the TNF- antagonist etanercept was commenced, which led to a vast improvement in the signs and symptoms of disease and quality of life for 4 yrs. The development of uveitis and worsening arthritis in 2003 prompted a change to infliximab therapy. This second anti-TNF- agent induced rapid remission of both the joint and eye manifestations of disease, although its efficacy waned after 2 yrs. It was eventually terminated after the development of multi-drug-resistant septic osteomyelitis of the mandible following dental extraction. Adalimumab was next employed, and although this third anti-TNF- agent showed an initial biochemical response, there was no clinical benefit.
Based on pathogenic considerations, disease control was attempted with rituximab. Two months after stopping adalimumab, two infusions of rituximab 1 g on day 1 and day 15 were administered, with intravenous methylprednisolone 100 mg given prior. Concomitant treatment consisted of mycophenolate mofetil, hydroxychloroquine and prednisolone 7.5 mg daily. At the time of infusion, the patient was wheelchair-bound with 24 tender and 15 swollen joints and a disease activity score 28 (DAS28) of 8.32. Erythrocyte sedimentation rate (ESR) was 88 mm/h, and there were no detectable autoantibodies. Rituximab was well tolerated, and within 6 weeks, the patient's DAS28 score had fallen to 4.22, with a corresponding reduction in ESR to 5 mm/h (Fig. 1), enabling corticosteroid dose reduction. A marked functional improvement was reflected in her renewed ability to walk and drive. Review at 3 months showed maintenance of disease remission with a DAS28 of 3.97 paralleling the depletion of circulating B-cells.
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Originally approved for the treatment of B-cell lymphomas, rituximab has been investigated in a variety of immune-mediated conditions in which B-lymphocytes are thought to play a role including open-label studies of systemic lupus erythematosus, idiopathic thrombocytopaenic purpura, Wegener's granulomatosis and dermatomyositis [8]. The most convincing evidence of efficacy, however, comes from studies in RA with significant clinical improvements when used either as a single agent or in combination with methotrexate or cyclophosphamide [7].
That rituximab was successful in our case of polyarticular JIA strongly supports the hypothesis that B-cells play a role in the pathogenesis of the disorder. This would seem intuitive since this subset of JIA shares many features consistent with RA. Although studies suggest that response to rituximab in RA is related to RF positivity, treatment was beneficial in our patient despite the absence of autoantibodies. This would indicate that loss of B-cell tolerance is not the only B-cell process operating in JIA. It is now known that B-lymphocytes have much broader functions within the immune system, including T-cell activation and cytokine synthesis [9]. Disruption of these tightly regulated processes may lead to autoimmune disease.
To our knowledge, this is the first reported case of the successful treatment of JIA with rituximab. Specific B-cell depletion may represent a true alternative to conventional immunosuppressive therapy in the treatment of refractory polyarticular JIA, and we encourage further investigation in this area.
A.O. has received honoraria and travel grants as well as research support from Schering Plough, Wyeth, Abbott and Roche Pharmaceuticals. J.G. has received research support and honoraria from various pharmaceutical companies, and also served as a consultant.
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