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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.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\u003EThe four Janus kinases (JAKs), JAK1, JAK2, JAK3, and Tyk2, are essential components of the signaling pathway of certain cytokines [O\u0027Shea JJ et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013]. This article reviews the role of JAKs in inflammation and JAK inhibitor efficacy and toxicity, the clinical data for tofacitinib, as well as discusses kinase inhibition in development, baricitinib, which strongly inhibits JAK1 and JAK2.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERheumatoid Arthritis\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERheumatology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERheumatoid Arthritis\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EThe four Janus kinases (JAKs), JAK1, JAK2, JAK3, and Tyk2, are essential components of the signaling pathway of certain cytokines [O\u0027Shea JJ et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2013]. John J. O\u0027Shea, MD, National Institutes of Health, Bethesda, Maryland, USA, reviewed the role of JAKs in inflammation and JAK inhibitor efficacy and toxicity. JAKs transduce the signal from extracellular cytokines binding their transmembrane receptors by transferring phosphates from adenosine triphosphate (ATP) to substrates. JAKs are enzymes that mediate signal transduction. Many enzymes bind ATP but structural differences among these kinases provide different targets for specific kinase inhibitors. Dr. O\u0027Shea pointed out that for any new kinase inhibitor, it is now possible to test its activity against all 518 protein kinases in the human kinome to determine specificity.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EJAK inhibitors block only the type I and II cytokine receptors, which are dependent on Jaks for signal transduction. Type I and II receptor ligands include many interleukins (ILs), interferons (IFNs), and other molecules involved in the pathogenesis of rheumatoid arthritis (RA) and other autoimmune diseases; these also are relevant to the side effects of JAK inhibitors. Because JAK2 is essential for the function of erythropoietin, thrombopoeitin, and colony-stimulating factors, among other effectors, cytopenias are known to occur with first generation JAK inhibitors. Other possible toxicities include serious infections (eg, tuberculosis and herpes zoster), and increased lipids, which are of unknown significance. Dr. O\u0027Shea mentioned that more selective JAK inhibitors are in development for a variety of autoimmune diseases. These are summarized in \u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIain B. McInnes, PhD, University of Glasgow, Glasgow, Scotland, United Kingdom, continued the discussion by reviewing the clinical data for tofacitinib, the first-in-class United States Food and Drug Administration (FDA)-approved JAK inhibitor. Tofacitinib mainly inhibits JAK3 and JAK1. The primary outcome measures for the registration trials included American College of Rheumatology 20% improvement response criteria (ACR20), Health Assessment Questionnaire Disability Index (HAQ-DI), Disease Activity Score (DAS28)\u0026lt;2.6, ACR 70% improvement response criteria (ACR70), and modified total Sharp score. The trial designs were similar, and those for Sync, Standard, and Scan are shown in \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E.\u003C\/p\u003E\u003Cdiv id=\u0022T1\u0022 class=\u0022table pos-float\u0022\u003E\u003Cdiv class=\u0022table-inline\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022\/\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/13847\/expansion?postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022 html=\u00221\u0022 fragment=\u0022#\u0022 external=\u00221\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/13847\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_figures%2Chighwire_math%2Chighwire_inline_linked_media\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13847\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETable 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-5\u0022 class=\u0022first-child\u0022\u003ESpecific JAK Inhibitors in Development for Autoimmune Diseases\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/18\/31\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Tofacitinib: Phase 3 Studies of 1 to 2 Year Duration\u0026#x2014;ORAL Sync, Standard, and Scan\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-683474257\u0022 data-figure-caption=\u0022Tofacitinib: Phase 3 Studies of 1 to 2 Year Duration\u0026#x2014;ORAL Sync, Standard, and Scan\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/18\/31\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/18\/31\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/18\/31\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13846\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-8\u0022 class=\u0022first-child\u0022\u003ETofacitinib: Phase 3 Studies of 1 to 2 Year Duration\u2014ORAL Sync, Standard, and Scan\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EDMARD=disease-modifying antirheumatic drug; IR=nonresponder; MTX=methotrexate.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from IB McInnes, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-9\u0022\u003EPatients were randomly assigned to 5 or 10 mg tofacitinib BID or placebo. Crossover was allowed at Month 3 for patients assigned to placebo whose disease did not respond; at Month 6 all patients assigned to placebo crossed over to active therapy. In Sync, Standard, and Scan, patients receiving either dose of tofacitinib had significantly improved ACR20, HAQ-DI, and DAS28 scores at Month 6, and the response was dose-dependent [Kremer J et al. \u003Cem\u003EAnn Intern Med\u003C\/em\u003E 2013; van Vollenhoven RF et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012; van der Heijde D et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2011 (abstr 2592)].\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EIn two other Phase 3 studies, ORAL Step (with methotrexate) and ORAL Solo (monotherapy), patients were randomly assigned to tofacitinib 5 or 10 mg BID, or to placebo. At Month 3, all patients on placebo were randomly assigned to tofacitinib 5 or 10 mg BID. Results for these trials were similar to those for the other Phase 3 trials [Burmester GR et al. \u003Cem\u003ELancet\u003C\/em\u003E 2012; Fleischmann R et al. \u003Cem\u003EN Engl J Med\u003C\/em\u003E 2012]. In the ORAL Solo trial, tofacitinib was associated with less fatigue and improved sleep compared with placebo [Strand V et al. \u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2011 (abstr 88)]. Responses in open-label extension therapy was maintained over 3 years. When compared with methotrexate, tofacitinib was associated with higher ACR70 rates over 12 months [Lee E et al. \u003Cem\u003EArth Rheum\u003C\/em\u003E (abstr 2486)], although in the current pharmacoeconomic environment, it is unlikely that tofacitinib would be used before methotrexate.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EOver 4000 patients were involved in the registration trials, with about 7000 patient-years of exposure for the safety analysis. The rate of serious infection was about 3 per 100 patient-years, and was higher in patients receiving tofacitinib, particularly those who were aged \u0026gt;65 years, had diabetes, or were taking steroids or tofacitinib 10 mg. Infection was also associated with decreased lymphocyte counts, so tofacitinib should not be given to patients with a lymphocyte count \u0026lt;0.5 \u00d7 103\/mm\u003Csup\u003E3\u003C\/sup\u003E. The rate of herpes zoster was higher than expected, so vaccination before the start of therapy is recommended. Tofacitinib was not associated with rate of malignancy higher than that reported in patients with RA, who are reported to have a higher rate of lymphoma than the general population [Curtis J et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2013 (abstr 802)]. Lipid levels were increased at both doses of tofacitinib. However, less-atheroprotective components of high-density lipoprotein (HDL) decreased, and cardiovascular outcomes are similar for treatment with adalimumab, tofacitinib, or placebo [McInnes J et al. EULAR 2012 (abstr AB0160)]. Patients whose low-density lipoprotein (LDL) cholesterol increases can be treated with statins.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EJoel M. Kremer, MD, Albany Medical College, Albany, New York, USA, concluded the session by discussing kinase inhibition in development, baricitinib, which strongly inhibits JAK1 and JAK2. Because of the JAK2 inhibition, side effects show a dose-dependent decrease in hemoglobin. In a Study in Participants With Rheumatoid Arthritis on Background Methotrexate [JADA; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01185353\u0026amp;atom=%2Fspmdc%2F13%2F18%2F31.atom\u0022\u003ENCT01185353\u003C\/a\u003E], although LDL increased with baricitinib, the number of particles decreased over 12 weeks of treatment; atherogenic very small particles decreased and protective large particles increased. HDL increased, and was also associated with protective particle size [Kremer J et al. \u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2013 (abstr THU0226)]. At 52 weeks of treatment on extension, responses were seen, although nonresponders were removed from the trial. Hemoglobin changes did occur, as did herpes zoster. One death due to myocardial infarction occurred, and the majority of patients experienced treatment-emergent adverse events [Taylor P et al. \u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2013 (abstr OP0047)].\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EOnly early data are available for the other drugs in development, including GLPG0634 which targets JAK1; VX509, which targets JAK3; and ASP015K, which targets JAK1 and JAK2, and as shown in \u003Ca id=\u0022xref-table-wrap-1-2\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E, trials are planned or ongoing.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EAlthough JAK inhibitors are promising agents for autoimmune diseases, more research is needed to determine the right dose and schedule for any given patient. For each new agent it will be important to determine what other kinases in addition to JAKs are inhibited and the effect on efficacy and safety. There are multiple possible approaches to inhibit JAK targets, and the ideal JAK inhibitor with the best efficacy and toxicity profile for the treatment of RA has not been identified. Long-term trials will be necessary to determine the optimum dose and schedule for particular patients, but the large number of potential JAK inhibitors already identified suggests there will be future options for patients with RA whose disease does not respond to currently available treatments.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 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\/13\/18\/31.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_figures.js?nzo6r1\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo6r1\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_tables.js?nzo6r1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}