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editorials

n engl j med 367;25 nejm.org december 20 , 2012 2439

A New Era in the Treatment of Systemic Juvenile IdiopathicArthritis

Christy Sandborg, M.D., and Elizabeth D. Mellins, M.D.

Advances in understanding the biology of in-flammation have spurred drug development andrevolutionized the care of both adults and chil-dren with rheumatic diseases. Among the mostdramatic examples of this progress are the clin-ical trials, reported by Ruperto et al. 1 and DeBenedetti et al. 2 in this issue of the Journal, of twodifferent biologic agents the interleukin-1 in-hibitor, canakinumab, and the interleukin-6inhibitor, tocilizumab for the treatment ofsystemic juvenile idiopathic arthritis (JIA). Thesestudies represent the culmination of work begunin 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 forchildren and young adults with systemic JIA,particularly those with severe disease, despitesuccessful 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 beenrecognized, but it is the striking responsivenessto antiinterleukin-1 and antiinterleukin-6 thatconvinced pediatric rheumatologists that theimmunobiology of systemic JIA was uniqueamong JIA subsets. Systemic JIA and its adultcounterpart, adult-onset Stills disease, are char-acterized by a distinct pattern of rapid onset ofdaily 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 classicfeatures of autoimmune disease, such as autoan-tibodies and HLA associations, and cells of theinnate immune system are strongly implicatedin this disease. These findings support reclassi-

fication of systemic JIA as an autoinflammatorydisease. 6

The successful design and performance ofthe trials of both agents is laudable, given theseverity of illness in eligible patients, the ethicalchallenges of placebo-controlled pediatric stud-ies, and the rarity of systemic JIA. Each studyhad an initial randomized, placebo-controlledphase 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 sixcore criteria for JIA and worsening of more than30% in no more than one of the criteria). Withboth agents, the primary end point for the pla-cebo-controlled phase was reached in more than80% of the study participants within the first2 to 6 weeks, and the number of participants whohad even greater improvement was remarkable.At 12 weeks, 71% of the patients who receivedtocilizumab had absence of fever and a JIA ACR70 response (defined as improvement of 70% ormore in at least three of the six core criteria for

JIA and worsening of more than 30% in no morethan one of the criteria), versus 8% of those inthe placebo group. In the randomized, placebo-controlled phase of the canakinumab study(trial 1), 67% of the patients treated withcanakinumab had a JIA ACR 70 response andabsence of fever at 4 weeks, as compared with2% of those in the placebo group. The studiesof both agents had open-label phases thatshowed sustained JIA ACR 30 responses in morethan 70% of patients as well as the ability ofpatients to undergo glucocorticoid tapering. Af-ter the open-label phase, the canakinumab studyhad a third phase with a patient-friendly ran-domized withdrawal design as an additional testof efficacy.

The safety profiles of canakinumab and toci-lizumab are difficult to assess, given the severeunderlying disease of the study participants, thehigh percentage of patients with previous expo-sure to biologic agents, and the relatively shortperiods of exposure to placebo. As both groupsof 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 smallnumber of patients in both the placebo and ac-tive-treatment groups in these trials, but an un-derstanding of the overall effect of the agentson the macrophage activation syndrome will re-quire additional study. Cytokine blockade may

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n engl j med 367;25 nejm.org december 20 , 20122440

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 receivedtocilizumab is notable, in light of a recent re-port of a significantly increased frequency ofpulmonary hypertension in children with sys-temic JIA treated with a number of differenttherapies, including antiinterleukin-1 and antiinterleukin-6. 7 To address the challenge of eval-uating long-term and infrequent adverse eventsthat occur with these therapies, new approachesare needed, such as consolidated disease regis-tries designed to evaluate safety signals in thecontext of the underlying disease and exposureto multiple agents.

It is interesting that the participants in thesetrials had marked similarities in the magnitudeand timing of their responses, suggesting thatinterleukin-1 and interleukin-6 may be in thesame pathway in systemic JIA. In contrast, thereis anecdotal evidence that some patients have aresponse to antiinterleukin-1 but not to antiinterleukin-6, and vice versa, which is consistent

with the complexity of proinflammatory cyto-kine networks. 8 The partial or absent responsesin a significant minority of patients in the trialsof both canakinumab and tocilizumab suggestthat genetic or environmental factors may resultin different subsets of systemic JIA. Alternative-ly, there may be an early therapeutic window ofopportunity during which higher response ratescan be achieved, 9 or inflammatory escapepathways may be activated because of the pres-ence of these inhibitors. The search for the mostproximal step that can be targeted in the in-flammatory cascade will undoubtedly continue.

Despite important remaining questions aboutregulation of inf lammation, the pathogenesis ofsystemic JIA, and appropriate interventions,

there is no doubt that the agents tested in thesetrials 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 toinform our understanding of other multigenicautoinflammatory 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 withthe full text of this article at NEJM.org.

From the Department of Pediatrics, Stanford University Schoolof Medicine, Stanford, CA.

1. Ruperto N, Brunner HI, Quartier P, et al. Two randomizedtrials 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. Randomizedtrial 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. Roleof 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 eff icacyof humanized recombinant anti-interleukin-6 receptor antibodyin children with systemic-onset juvenile idiopathic arthrit is. 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 insystemic 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. Signalintegration, crosstalk mechanisms and networks in the functionof inflammatory cytokines. Biochim Biophys Acta 2011;1813:2165-75.9. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as f irst-line disease-modifying therapy in systemic juvenile idiopathicarthritis: report of forty-six patients from an international multi-center series. Arthritis Rheum 2011;63:545-55.DOI: 10.1056/NEJMe1212640Copyright 2012 Massachusetts Medical Societ y.

Aquaretic Treatment in Polycystic Kidney DiseaseRudolf P. Wthrich, M.D., and Changlin Mei, M.D.

Autosomal dominant polycystic kidney disease(ADPKD), the most common hereditary kidneydisease, progresses relentlessly to end-stage kid-ney disease before the age of 60 years in half the

affected patients. One in 10 patients undergoingdialysis has ADPKD. The disease is characterizedby prominent cystic enlargement of the kidneys,

which is often associated with episodes of pain,

The New England Journal of MedicineDownloaded from nejm.org on May 24, 2013. For personal use only. No other uses without permission.

Copyright 2012 Massachusetts Medical Society. All rights reserved.