2439 A New Era in the Treatment of Systemic Juvenile Idiopathic Arthritis Christy Sandborg, M.D., and Elizabeth D. Mellins, M.D. Advances in understanding the biology of in- flammation have spurred drug development and revolutionized the care of both adults and chil- dren with rheumatic diseases. Among the most dramatic examples of this progress are the clin- ical trials, reported by Ruperto et al. 1 and De Benedetti et al. 2 in this issue of the Journal, of two different biologic agents the interleukin-1 in- hibitor, canakinumab, and the interleukin-6 inhibitor, tocilizumab for the treatment of systemic juvenile idiopathic arthritis (JIA). These studies represent the culmination of work begun in small, but encouraging studies involving pa- tients with systemic JIA who received treatment with interleukin-1 or interleukin-6 inhibitors. 3-5
Previously, there were no effective therapies for children and young adults with systemic JIA, particularly those with severe disease, despite successful management of other types of JIA with methotrexate and tumor necrosis factor inhibitors. The distinctive clinical and immuno- logic features of systemic JIA have long been recognized, but it is the striking responsiveness to antiinterleukin-1 and antiinterleukin-6 that convinced pediatric rheumatologists that the immunobiology of systemic JIA was unique among JIA subsets. Systemic JIA and its adult counterpart, adult-onset Stills disease, are char- acterized by a distinct pattern of rapid onset of daily high temperatures, rash, elevated inflam- matory markers, and arthritis, resulting in vari- able degrees of severe systemic disease and de- structive arthritis. Systemic JIA lacks the classic features of autoimmune disease, such as autoan- tibodies and HLA associations, and cells of the innate immune system are strongly implicated in this disease. These findings support reclassi- fication of systemic JIA as an autoinflammatory disease. 6 The successful design and performance of the trials of both agents is laudable, given the severity of illness in eligible patients, the ethical challenges of placebo-controlled pediatric stud- ies, and the rarity of systemic JIA. Each study had an initial randomized, placebo-controlled phase with the same primary end point (absence of fever and a JIA American College of Rheuma- tology [ACR] 30 response, indicating improve- ment of 30% or more in at least three of the six core criteria for JIA and worsening of more than 30% in no more than one of the criteria). With both agents, the primary end point for the pla- cebo-controlled phase was reached in more than 80% of the study participants within the first 2 to 6 weeks, and the number of participants who had even greater improvement was remarkable. At 12 weeks, 71% of the patients who received tocilizumab had absence of fever and a JIA ACR 70 response (defined as improvement of 70% or more in at least three of the six core criteria for JIA and worsening of more than 30% in no more than one of the criteria), versus 8% of those in the placebo group. In the randomized, placebo- controlled phase of the canakinumab study (trial 1), 67% of the patients treated with canakinumab had a JIA ACR 70 response and absence of fever at 4 weeks, as compared with 2% of those in the placebo group. The studies of both agents had open-label phases that showed sustained JIA ACR 30 responses in more than 70% of patients as well as the ability of patients to undergo glucocorticoid tapering. Af- ter the open-label phase, the canakinumab study had a third phase with a patient-friendly ran- domized withdrawal design as an additional test of efficacy. The safety profiles of canakinumab and toci- lizumab are difficult to assess, given the severe underlying disease of the study participants, the high percentage of patients with previous expo- sure to biologic agents, and the relatively short periods of exposure to placebo. As both groups of investigators recognize, the therapeutic ben- efits of these biologic agents will need to be weighed against the apparent risks of infection, neutropenia, and liver dysfunction. The macro- phage activation syndrome developed in a small number of patients in both the placebo and ac- tive-treatment groups in these trials, but an un- derstanding of the overall effect of the agents on the macrophage activation syndrome will re- quire additional study. Cytokine blockade may The New England Journal of Medicine Downloaded from nejm.org on May 24, 2013. For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved. The new engl and journal o f medicine n engl j med 367;25 nejm.org december 20, 2012 2440 create an imbalance in the cytokine network, thereby driving or unmasking previously un- common complications. The occurrence of pul- monary hypertension in one patient who re- ceived canakinumab and in two who received tocilizumab is notable, in light of a recent re- port of a significantly increased frequency of pulmonary hypertension in children with sys- temic JIA treated with a number of different therapies, including antiinterleukin-1 and anti interleukin-6. 7 To address the challenge of eval- uating long-term and infrequent adverse events that occur with these therapies, new approaches are needed, such as consolidated disease regis- tries designed to evaluate safety signals in the context of the underlying disease and exposure to multiple agents. It is interesting that the participants in these trials had marked similarities in the magnitude and timing of their responses, suggesting that interleukin-1 and interleukin-6 may be in the same pathway in systemic JIA. In contrast, there is anecdotal evidence that some patients have a response to antiinterleukin-1 but not to anti interleukin-6, and vice versa, which is consistent with the complexity of proinflammatory cyto- kine networks. 8 The partial or absent responses in a significant minority of patients in the trials of both canakinumab and tocilizumab suggest that genetic or environmental factors may result in different subsets of systemic JIA. Alternative- ly, there may be an early therapeutic window of opportunity during which higher response rates can be achieved, 9 or inflammatory escape pathways may be activated because of the pres- ence of these inhibitors. The search for the most proximal step that can be targeted in the in- flammatory cascade will undoubtedly continue. Despite important remaining questions about regulation of inflammation, the pathogenesis of systemic JIA, and appropriate interventions, there is no doubt that the agents tested in these trials signal a new era in the treatment of sys- temic JIA and will shed light on the mecha- nisms driving this enigmatic disorder. Contin- ued investigation of systemic JIA is likely to inform our understanding of other multigenic autoinflammatory diseases a growing cate- gory that now includes type 2 diabetes and in- flammatory bowel disease as well as our un- derstanding of the regulation of inflammation. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Department of Pediatrics, Stanford University School of Medicine, Stanford, CA. 1. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396-406. 2. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2385-95. 3. Pascual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset ju- venile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005;201:1479-86. 4. Verbsky JW, White AJ. Effective use of the recombinant inter- leukin 1 receptor antagonist anakinra in therapy resistant sys- temic onset juvenile rheumatoid arthritis. J Rheumatol 2004; 31:2071-5. 5. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Ar- thritis Rheum 2005;52:818-25. 6. Mellins ED, Macaubas C, Grom AA. Pathogenesis of sys- temic juvenile idiopathic arthritis: some answers, more ques- tions. Nat Rev Rheumatol 2011;7:416-26. 7. Kimura YW, Haroldsom JE, Lee KL, et al. Pulmonary hyper- tension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hobo- ken) 2012 November 8 (epub ahead of print). 8. Schmitz ML, Weber A, Roxlau T, Gaestel M, Kracht M. Signal integration, crosstalk mechanisms and networks in the function of inflammatory cytokines. Biochim Biophys Acta 2011;1813: 2165-75. 9. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first- line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multi- center series. Arthritis Rheum 2011;63:545-55. DOI: 10.1056/NEJMe1212640 Copyright 2012 Massachusetts Medical Society. Aquaretic Treatment in Polycystic Kidney Disease Rudolf P. Wthrich, M.D., and Changlin Mei, M.D. Autosomal dominant polycystic kidney disease (ADPKD), the most common hereditary kidney disease, progresses relentlessly to end-stage kid- ney disease before the age of 60 years in half the affected patients. One in 10 patients undergoing dialysis has ADPKD. The disease is characterized by prominent cystic enlargement of the kidneys, which is often associated with episodes of pain, The New England Journal of Medicine Downloaded from nejm.org on May 24, 2013. For personal use only. No other uses without permission. Copyright 2012 Massachusetts Medical Society. All rights reserved.