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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EMedication use patterns in systemic juvenile idiopathic arthritis (sJIA) are changing gradually and reflect significant treatment variability. Data from recent Phase 3 clinical trials of 2 biologic inhibiting agents, tocilizumab and canakinumab, may prompt further changes in treatment choices in the future, as these 2 agents show impressive response rates [Yokota S et al \u003Cem\u003ELancet\u003C\/em\u003E 2008; De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2010; De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011; Brunner HI et al. ACR 2012 Abstract 759].\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EArthritis\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EMedication use patterns in systemic juvenile idiopathic arthritis (sJIA) are changing gradually and reflect significant treatment variability. Data from recent Phase 3 clinical trials of 2 biologic inhibiting agents, tocilizumab and canakinumab, may prompt further changes in treatment choices in the future, as these 2 agents show impressive response rates [Yokota S et al \u003Cem\u003ELancet\u003C\/em\u003E 2008; De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2010; De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011; Brunner HI et al. ACR 2012 Abstract 759].\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EsJIA is difficult to treat, as patients are often refractory to conventional antiarthritis therapies such as methotrexate and tumor necrosis factor (TNF) inhibitors, and many sJIA patients have been corticosteroid-dependent, said Yukiko Kimura, MD, Joseph M. Sanzari Children\u0027s Hospital at Hackensack University Medical Center, Hackensack, New Jersey, USA, in her overview of current sJIA practices. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) is examining how pediatric rheumatologists are treating sJIA. The research network has 304 members from 92 sites in the United States and Canada. A survey was conducted in April 2010 regarding treatment choices of CARRA pediatric rheumatologists that had a 46% response rate. It revealed that corticosteroid-containing regimens were the most common choice of treatment, followed by methotrexate and an interleukin (IL)-1 inhibitor [DeWitt EM et al. \u003Cem\u003EArthritis Care Res (Hoboken)\u003C\/em\u003E 2012]. The least popular choices in 2010 were IL-6 inhibitors, TNF inhibitors, and calcineurin inhibitors. Dr. Kimura noted that these results were obtained prior to the approval of tocilizumab (an IL-6 receptor inhibitor) for the treatment of sJIA.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EFor initial therapy, respondents were most likely to choose prednisone and intravenous pulse corticosteroids followed by methotrexate. For refractory patients (defined as those who did not respond after 3 months of therapy), an IL-1 inhibitor and an IL-6 inhibitor gained popularity. However, more recent surveys and data have shown a shift in treatment patterns.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003ECARRA established a prospective registry of pediatric rheumatic diseases that began collecting data in May 2010. As of November 2012, more than 8000 patients from 60 US sites have been enrolled in the registry. Dr. Kimura examined which medications the 418 patients with sJIA who had enrolled in the registry had ever used during their disease course. More than 80% had ever taken corticosteroids, more than 70% had been on methotrexate, \u223c60% a TNF inhibitor, and \u223c50% an IL-1 inhibitor.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EHowever, looking at current use, the CARRA registry data show that the use of biologics, especially IL-1 and IL-6 inhibitors, has increased over the past 3 years, accompanied by a decrease in the use of disease-modifying antirheumatic drugs (DMARDs). In addition, over time more clinicians have started using a biologic as monotherapy for treatment of sJIA, and fewer are using only a DMARD.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003ERonald Laxer, MD, The University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada, discussed recent data with IL-1 and IL-6 inhibiting agents. Data regarding anakinra, a recombinant molecule that competitively binds the IL-1 receptor site to prevent signal transduction, show an excellent early response is particularly effective in some patients and may reduce the need for corticosteroids. However, anakinra may be less effective in some patients. Of those who do respond, there is sometimes a loss of response over time [Quartier P et al. \u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2011]. It also seems to be less effective in younger patients and in those with polyarthritis [Pascual V et al. \u003Cem\u003EJ Exp Med\u003C\/em\u003E 2005; Gattorno M et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2008; Lequerr\u00e9 T et al. \u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2008; Nigrovic PA et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003ECanakinumab is a humanized monoclonal antibody given subcutaneously once every 4 weeks. It acts by binding IL-1\u03b2 in the circulation to prevent its binding with the receptor. Tocilizumab is a humanized monoclonal antibody against the IL-6 receptor. Dr. Laxer said canakinumab and tocilizumab have each been studied in short-term, randomized clinical trials demonstrating rapid response with acceptable safety in the short term.\u003C\/p\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ETocilizumab\u003C\/h2\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EData from a 12-week randomized placebo-controlled study of tocilizumab versus placebo demonstrated superiority for the primary endpoint of an adapted American College of Rheumatology (aACR) pediatric 30 (Ped30) combined with absence of fever at 12 weeks (85.3% vs 24.3%; p\u0026lt;0.0001) [De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2010]. Secondary endpoint responses of an aACR50\/70\/90 were also significantly greater in the tocilizumab group (85.3% vs 10.8%, 70.7% vs 8.1%, and 37.3% vs 5.4%, respectively; p\u0026lt;0.0001 for all).\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003ELonger-term data provide insights into efficacy over time. For tocilizumab, a 2-year open-label follow-up showed continuing increases in the aACR Ped30\/50\/70\/90 responses over time [De Benedetti F et al. ACR 2011 Abstract L12]. Sixty percent of tocilizumab recipients were able to stop steroids by Week 104 of the study.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ECanakinumab\u003C\/h2\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EAn aACR Ped30 at Day 15 was the primary endpoint of a 4-week randomized, placebo-controlled study of canakinumab given as a single subcutaneous dose [Ruperto N et al. \u003Cem\u003EPediatr Rheumatol\u003C\/em\u003E 2011]. In total, 83.7% of the canakinumab group reached the primary endpoints versus 9.8% of the placebo group (p\u0026lt;0.0001). Canakinumab was also superior for the secondary endpoints of aACR Ped50 (67.4% vs 4.9%) and aACR Ped100 (32.6% vs 0.0%; both p\u0026lt;0.001). aACR Ped30\/50 responses with canakinumab remained significantly higher than with placebo at Day 29 (79.1% vs 9.8%, and 76.7% vs 4.9%, respectively; p\u0026lt;0.001 for both) [Brunner HI et al. ACR 2012 Abstract 759]. The data suggest that a response to canakinumab may occur earlier than with tocilizumab.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EThirty-two week open-label data with canakinumab revealed an ACR30 response in 76% of patients, an ACR70 in 63%, and an ACR100 in 34% [Quartier et al. \u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2012].\u003C\/p\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EIn the short-term studies, there were 4 serious adverse events (AEs) in 3 patients randomized to tocilizumab (varicella, septic arthritis, and urticarial\/angioedema) [De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011], and 2 serious AEs in patients randomized to canakinumab (varicella and macrophage activation syndrome), although Dr. Laxer noted high rates of AEs among the placebo groups in both trials and that 2 serious AEs occurred in the placebo group of the canakinumab trial [Ruperto N et al. \u003Cem\u003EPediatr Rheumatol\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-3\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EEarly Use of Biologics\u003C\/h2\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EVery early use of biologics is advocated by Timothy Beukelman, MD, MSCE, University of Alabama at Birmingham, Birmingham, Alabama, USA, who said that steroid-sparing therapy should be a goal of treatment for patients with systemic arthritis. AEs such as Cushing\u0027s syndrome, growth suppression, and impaired glucose tolerance are common with glucocorticoids and perhaps even anticipated. Methotrexate is often used as a steroid-sparing therapy, but its efficacy in this regard and its utility in resolving systemic features is questionable [Woo P et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2000]. In fact, the ACR 2011 Recommendations for the Treatment of JIA state that methotrexate is \u201cinappropriate for initial management of patients with active fever and without arthritis\u201d [Beukelman T et al. \u003Cem\u003EArthritis Care Res (Hoboken)\u003C\/em\u003E 2011].\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003EOn the other hand, early interventions with IL-1 and IL-6 inhibiting agents for systemic JIA are nearing what Dr. Beukelman referred to as a \u201cmagic bullet.\u201d The typical ACR response at 3 months in randomized controlled trials of biologics for the treatment of rheumatoid arthritis is ACR20 in approximately 60% of patients, ACR50 in approximately 40%, and an ACR70 in approximately 20%. In an open-label phase of a randomized, controlled trial of etanercept for the treatment of polyarticular JIA, the ACR70 response was 36% [Lovell DJ et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2000].\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EIn contrast, the ACR70 response at 3 months in the blinded phase of a clinical trial of tocilizumab for the treatment of sJIA was 71% [De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2010], and in an open-label extension of this study, the ACR70 response improved to 87% at 12 months [De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011]. A similar ACR70 response of 62% was achieved with canakinumab at 8 months (during glucocorticoid taper) in an open-label phase for the treatment of sJIA [Brunner HI et al. ACR 2012 Abstract 759].\u003C\/p\u003E\n         \u003Cp id=\u0022p-17\u0022\u003EA notion that IL-1 inhibition is not a good target for synovitis in sJIA is not substantiated by the data, according to Dr. Beukelman. Anakinra improved the number of active joints versus placebo at 1 month in a clinical trial of 24 patients [Quartier P et al. \u003Cem\u003EAnn Rhuem Dis\u003C\/em\u003E 2011], and in a clinical trial of canakinumab, the median number of active joints decreased from 10 to 1 during the first 2 months of open-label use in 177 patients [Brunner HI et al. ACR 2012 Abstract 759].\u003C\/p\u003E\n         \u003Cp id=\u0022p-18\u0022\u003EIn clinical trials of sJIA with a polyarticular course and without active systemic features, typical ACR30 responses at 12 to 16 weeks with the older biologic agents (anakinra, etanercept, and abatacept) are in the range of 65% to 75% [Lovell DJ et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2000; Ruperto N et al. \u003Cem\u003ELancet\u003C\/em\u003E 2008; Ilowite N et al. \u003Cem\u003EClin Rheumatol\u003C\/em\u003E 2009]. Data are absent with cankinumab on JIA with polyarticular course without systemic features, while the data with tocilizumab have shown ACR70 responses of 88.5% (ages 2 to 5; n=26), 88.1% (ages 6 to 12; n=42), and 85.7% (ages 13 to 17; n=35) at 52 weeks [De Benedetti F et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011].\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/19\/27.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzn5pp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}