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Systemic juvenile idiopathic arthritis has shown "striking responsiveness" to two biological modifiers, canakinumab and tocilizumab, in new studies reported in NEJM.
The “striking responsiveness” of systemic juvenile idiopathic arthritis (JIA) to a pair of biological modifiers is a “dramatic” example of how biology has revolutionized the treatment of rheumatic disease, says an editorial in the current New England Journal of Medicine by Christy Sandborg MD and Elizabeth D. Mellins MD of the Stanford University Department of Pediatrics.
The editorial accompanies a pair of phase III trials (with open-label continuation) of the interleukin-1 (IL-1) inhibitor canakinumab, and the interleukin-6 (IL-6) inhibitor tocilizumab, for systemic JIA. In both studies, more than 80% of the participants reached the primary end point, ACR30 with no fever, within the first 6 weeks.
The number of participants with an even greater improvement was “remarkable,” they say. At 12 weeks, 71% of patients on tocilizumab reached ACR70, with no fever, versus 8% of those on placebo. At 4 weeks, 67% of patients on canakinumab reached ACR70, with no fever, versus 2% of placebo subjects.
With canakinumab, significant numbers of patients reached ACR100 and inactive disease. The results were sustained over a lengthy open label phase. Glucorticoids were reduced or eliminated in significant numbers of patients.
The safety profiles are difficult to assess, given the severe underlying disease and the study design. They apparently include infection, neutropenia, and liver dysfunction. Patients in both the treatment and placebo groups developed macrophage activation syndrome. Pulmonary hypertension in 3 treated patients is a concern. Registries will be needed to follow long-term and rare adverse events.
The similar response to both drugs suggests that IL-1 and IL-6 are on the same regulatory pathway in systemic JIA. However, some patients respond only to IL-1 inhibitors, others only to IL-6 inhibitors, some to neither. There may be different subsets of disease; windows of therapeutic opportunity or inflammatory “escape” pathways may also differ.
These trials signal a new era not only for the treatment of systemic JIA, but for autoinflammatory diseases generally, and for our understanding of the regulation of inflammation, the editorial concludes.
(Mellins disclosed support from Genentech and Novartis for attending a meeting.)
1. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med (2012) 367:2385-2395 Full Text http://www.nejm.org/doi/full/10.1056/NEJMoa1112802
2. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med (2012) 367:2396-2406 Full Text http://www.nejm.org/doi/full/10.1056/
3. C. Sandborg and E.D. Mellins, A new era in the treatment of systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2439-2440 Full Text http://www.nejm.org/doi/full/10.1056/NEJMe12