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Etanercept effective in about half of refractory SOJRA cases

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About half the children with refractory systemic onset juvenile rheumatoid arthritis (SOJRA) treated with the TNF-antagonist etanercept (Enbrel, Immunex and Wyeth) appear to respond, a survey of US pediatric rheumatologists has found. This finding, together with preliminary reports of successful treatment with the interleukin-6 (IL-6) blocker MRA (still in clinical trials; Roche and Chugai) and the interleukin-1 antagonist anakinra (Kineret, Amgen), suggest that TNF may not be the driving proinflammatory cytokine in this disease and that TNF blockade may not be the optimal therapeutic approach.

Although SOJRA is the least common form of juvenile rheumatoid arthritis, it is often the most challenging to manage, comments an accompanying editorial in the May 2005 issue of the Journal of Rheumatology. Between 25% and 35% of systemic patients develop severe erosive arthritis and extra-articular complications, including life-threatening serositis or macrophage activation syndrome (MAS). However, it is difficult to identify on onset those patients with poor prognoses, making treatment decisions challenging, it comments. At present, etanercept is a third-line agent in the standard care of SOJRA, following methotrexate as second-line after traditional treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. Disease flares seen even in good responders The survey was conducted by Dr Yukiko Kimura (Joseph Sanzari Children’s Hospital, Hackensack University Medical Center, NJ), working with researchers at other US centers. The team sent out a standardized questionnaire to 122 pediatric rheumatologists in the US, although less than a quarter replied, supplying information on 100 children with SOJRA, of whom 82 had analyzable data.Of the 82 patients, 48 (59%) were female, with a mean age at disease onset of 4.25+3.73 years (range 0.25-17). The authors note that the patient who was 17 at disease onset would be categorized as adult-onset Still’s disease rather than SOJRA, but “because the 2 diseases are virtually identical aside from the differences in ages at onset, we included him in the analysis.” The mean disease duration before initiation of etanercept was 5.18+4.2 years, and the mean duration of etanercept treatment was 24.8+12.3 months. All patients initially received the standard dose of 0.4 mg/kg twice weekly subcutaneously, but 29 patients went on to receive higher doses subsequently. The majority of patients (54%) had poor or limited responses, and flares occurred in 45% of all patients, the authors report. Good or excellent responses were seen in 46%, and most of them were able to discontinue corticosteroids, which is “an important finding in these patients with refractory disease,” the authors comment. However, even among the responders, more than one quarter had flares while on etanercept therapy. Also, the drug did not prevent the occurrence of MAS during a disease flare in 2 patients, 1 of whom had initially been an excellent responder, they note. Etanercept was not thought to be the cause of MAS, but the fact that 2 children developed it “underscores the failure of etanercept to prevent disease flares in patients.” Kimura et al comment that although the results are limited by the retrospective design of the study, which subjects it to ascertainment bias, they are consistent with other recently published studies, such as that of Quartier et al, who found that SOJRA patients were less responsive to etanercept and more likely to experience flares compared with patients with other types of JRA. “TNF blockade may not be the optimal therapeutic approach for children with treatment-resistant SOJRA,” they conclude. New approaches show promise The accompanying editorial reviews growing evidence suggesting that in active SOJRA the driving proinflammatory cytokine is IL-6 rather than TNF. It highlights clinical results with the anti-IL-6 receptor monoclonal antibody (MRA), including a small open-label trial that was “very encouraging, with complete remission in 10 out of 11 patients.” There have also been anecdotal reports about “excellent response” with the interleukin-1 antagonist anakinra in SOJRA, including many patients who had failed on etanercept. Both of these approaches have been reported previously by rheumawire. Clinical trials in SOJRA with both products are expected to start shortly, the editorial notes. The outcomes of these future biological-therapy trials may influence how the current findings on etanercept are viewed, it adds: as a glass that is half full (nearly half the children respond) or half empty (only about half of the children respond). Kimura commented to rheumawire: “Treatments aimed at IL-1 and IL-6 inhibition show great promise in the treatment of SOJRA. There have been several case reports in the literature regarding the efficacy of anakinra in patients who have failed other agents. The reports from Japan regarding MRA (anti-IL-6) are also quite exciting, and so we eagerly await the results of a larger study from Japan, as well as hopefully clinical trials here in the US.” He does not have any personal experience with anti-IL-6 but has used anakinra and says: “While there are patients with SOJRA who respond nicely to it, there are others who do not respond. So while there is great potential for these biologic therapies, we will need to await results of larger randomized trials testing these therapies in SOJRA before we will have a true sense of their efficacy.”As for what to use currently, Kimura comments: “The results of our paper show that about half of the patients responded to etanercept, so it is certainly worth trying in patients who have failed other therapies. Anakinra certainly has potential in this disease, and because there seems to be improved efficacy of this biologic compared with etanercept, there are pediatric rheumatologists who would try this medication before trying etanercept.”(Source: Journal of Rheumatology: Joint and Bone: May 2005.)


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Posted On: 18 May, 2005
Modified On: 16 January, 2014

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