{"markup":"\u003C?xml version=\u00221.0\u0022 encoding=\u0022UTF-8\u0022 ?\u003E\n    \u003Chtml version=\u0022HTML+RDFa+MathML 1.1\u0022\n    xmlns:content=\u0022http:\/\/purl.org\/rss\/1.0\/modules\/content\/\u0022\n    xmlns:dc=\u0022http:\/\/purl.org\/dc\/terms\/\u0022\n    xmlns:foaf=\u0022http:\/\/xmlns.com\/foaf\/0.1\/\u0022\n    xmlns:og=\u0022http:\/\/ogp.me\/ns#\u0022\n    xmlns:rdfs=\u0022http:\/\/www.w3.org\/2000\/01\/rdf-schema#\u0022\n    xmlns:sioc=\u0022http:\/\/rdfs.org\/sioc\/ns#\u0022\n    xmlns:sioct=\u0022http:\/\/rdfs.org\/sioc\/types#\u0022\n    xmlns:skos=\u0022http:\/\/www.w3.org\/2004\/02\/skos\/core#\u0022\n    xmlns:xsd=\u0022http:\/\/www.w3.org\/2001\/XMLSchema#\u0022\n    xmlns:mml=\u0022http:\/\/www.w3.org\/1998\/Math\/MathML\u0022\u003E\n  \u003Chead\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_itu2PgFdrjV-docKmLK8Jn5oXe_05RgvQh73eOhI_mE.js\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_at_symbol.js?nzngld\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_article_reference_popup.js?nzngld\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/js\/js_I8yX6RYPZb7AtMcDUA3QKDZqVkvEn35ED11_1i7vVpc.js\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\n(function(i,s,o,g,r,a,m){i[\u0022GoogleAnalyticsObject\u0022]=r;i[r]=i[r]||function(){(i[r].q=i[r].q||[]).push(arguments)},i[r].l=1*new Date();a=s.createElement(o),m=s.getElementsByTagName(o)[0];a.async=1;a.src=g;m.parentNode.insertBefore(a,m)})(window,document,\u0022script\u0022,\u0022\/\/www.google-analytics.com\/analytics.js\u0022,\u0022ga\u0022);ga(\u0022create\u0022, \u0022UA-15605596-27\u0022, {\u0022cookieDomain\u0022:\u0022auto\u0022});ga(\u0022set\u0022, \u0022page\u0022, location.pathname + location.search + location.hash);ga(\u0022send\u0022, \u0022pageview\u0022);ga(\u0027create\u0027, \u0027UA-189672-26\u0027, \u0027auto\u0027, {\u0027name\u0027: \u0027hwTracker\u0027});\r\nga(\u0027hwTracker.send\u0027, \u0027pageview\u0027);\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022\u003E\n\u003C!--\/\/--\u003E\u003C![CDATA[\/\/\u003E\u003C!--\njQuery.extend(Drupal.settings, {\u0022basePath\u0022:\u0022\\\/\u0022,\u0022pathPrefix\u0022:\u0022\u0022,\u0022highwire\u0022:{\u0022markup\u0022:[{\u0022requested\u0022:\u0022full-text\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;12\\\/9\\\/26\u0022},{\u0022requested\u0022:\u0022long\u0022,\u0022variant\u0022:\u0022full-text\u0022,\u0022view\u0022:\u0022full\u0022,\u0022pisa\u0022:\u0022spmdc;12\\\/9\\\/26\u0022}],\u0022ac\u0022:{\u0022spmdc;12\\\/9\\\/26\u0022:{\u0022access\u0022:{\u0022reprint\u0022:true,\u0022full\u0022:true},\u0022pisa_id\u0022:\u0022spmdc;12\\\/9\\\/26\u0022,\u0022atom_uri\u0022:\u0022\u0022,\u0022jcode\u0022:\u0022spmdc\u0022}}},\u0022googleanalytics\u0022:{\u0022trackOutbound\u0022:1,\u0022trackMailto\u0022:1,\u0022trackDownload\u0022:1,\u0022trackDownloadExtensions\u0022:\u00227z|aac|arc|arj|asf|asx|avi|bin|csv|doc(x|m)?|dot(x|m)?|exe|flv|gif|gz|gzip|hqx|jar|jpe?g|js|mp(2|3|4|e?g)|mov(ie)?|msi|msp|pdf|phps|png|ppt(x|m)?|pot(x|m)?|pps(x|m)?|ppam|sld(x|m)?|thmx|qtm?|ra(m|r)?|sea|sit|tar|tgz|torrent|txt|wav|wma|wmv|wpd|xls(x|m|b)?|xlt(x|m)|xlam|xml|z|zip\u0022,\u0022trackUrlFragments\u0022:1},\u0022ajaxPageState\u0022:{\u0022js\u0022:{\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/jquery.cluetip.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.hoverIntent.js\u0022:1,\u0022sites\\\/all\\\/libraries\\\/cluetip\\\/lib\\\/jquery.bgiframe.min.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_at_symbol.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/highwire\\\/highwire\\\/plugins\\\/highwire_markup_process\\\/js\\\/highwire_article_reference_popup.js\u0022:1,\u0022sites\\\/all\\\/modules\\\/contrib\\\/google_analytics\\\/googleanalytics.js\u0022:1,\u00220\u0022:1}}});\n\/\/--\u003E\u003C!]]\u003E\n\u003C\/script\u003E\n\u003Clink 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\u003EThis article discusses studies of Janus kinase (JAK) inhibitors in the treatment of patients with rheumatoid arthritis. JAK inhibitors have short half-lives and can be administered orally once or twice daily. As of 2012, more than 50 clinical trials of JAK inhibitors have been completed or are ongoing. Also reviewed is the role of new orally bioavailable kinase inhibitors in the treatment of RA, and whether therapy will be influenced by their efficacy, safety profile, cost, and ability to be used with RA-related medications.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERheumatoid Arthritis\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003EJAK Inhibition in RA\u003C\/h2\u003E\n         \u003Cp id=\u0022p-2\u0022\u003EThe Janus kinase (JAK) tyrosine kinase family consists of small intracellular molecules that are required for cytokine and growth factor signaling. Four members of the JAK family have been identified: JAK1, JAK2, JAK3, and Tyk2. JAK1 and JAK2 mediate the signals of cytokine targets in inflammatory diseases, such as rheumatoid arthritis (RA), while JAK3 is primarily involved in T cell-mediated immune function.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EJoel M. Kremer, MD, Albany Medical College, Albany, New York, USA, discussed studies of JAK inhibitors in the treatment of patients with RA. JAK inhibitors have short half-lives and can be administered orally once or twice daily. As of 2012, more than 50 clinical trials of JAK inhibitors have been completed or are ongoing. Ruxolitinib is the first United States Food and Drug Administration-approved JAK inhibitor to be indicated for the treatment of myelofibrosis. A JAK1\/2 inhibitor, ruxolitinib also has been tested in Phase 2 studies for RA. Other JAK inhibitors that are under investigation in RA include baricitinib, tofacitinib (CP-690,550), VX-509, and GLPG0634 (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E).\u003C\/p\u003E\n         \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\/14238\/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\/14238\/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\/14238\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-4\u0022 class=\u0022first-child\u0022\u003EJAK Inhibitors Under Investigation.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-5\u0022\u003ETofacitinib is a relatively selective JAK1\/2\/3 inhibitor that has been studied as monotherapy [Fleischmann et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2012] and combined with disease-modifying antirheumatic drugs (DMARDs) [Kremer et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2012]. In the Phase 2b dose-ranging study [Fleischmann et al. \u003Cem\u003EArthritis Rheum\u003C\/em\u003E 2012], patients were randomized to 1, 3, 5, 10, or 15 mg oral tofacitinib twice daily for 24 weeks, placebo for 24 weeks, or adalimumab 40 mg every other week for 12 weeks, followed by tofacitinib 5 mg twice daily for 12 weeks. The safety results showed that transaminase values were increased in the 5- and 10-mg tofacitinib groups, low-density lipoprotein cholesterol was increased in 29% of patients in the 5-mg group and 36% of patients in the 10-mg group; 6 patients experienced a confirmed 50% increase in serum creatinine, and 6 patients experienced confirmed severe anemia. A Phase 2 study of tofacitinib plus methotrexate demonstrated sustained efficacy at 5, 10, and 15 mg twice daily over 24 weeks.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EThe Phase 2 data on tofacitinib supported investigation of the 5- and 10-mg doses in several Phase 3 monotherapy and combination therapy trials. The ORAL Scan trial [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00960440\u0026amp;atom=%2Fspmdc%2F12%2F9%2F26.atom\u0022\u003ENCT00960440\u003C\/a\u003E] evaluated tofacitinib 5 and 10 mg in combination with methotrexate (n=750). The 1-year interim analysis showed that at 6 months, the primary endpoint of ACR20 was achieved by 61.8% of tofacitinib 10 mg patients and 51.5% of tofacitinib 5 mg patients versus 25.3% of placebo patients (p\u0026lt;0.00001; \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). Patients who were treated with tofacitinib 10 mg versus placebo had significantly greater reductions in HAQ-DI at 3 months (p\u0026lt;0.0001), and a greater percentage of patients achieved DAS28\u20134 (ESR) scores \u0026lt;2.6 at 6 months (p\u0026lt;0.0001). In a secondary analysis, both 5- and 10-mg tofacitinib doses were superior to placebo in the percentage of patients without radiographic progression.\u003C\/p\u003E\n         \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\/12\/9\/26\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u00221-Year Interim Analysis: ORAL Scan.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1318167053\u0022 data-figure-caption=\u00221-Year Interim Analysis: ORAL 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\/12\/9\/26\/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\/12\/9\/26\/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\/12\/9\/26\/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\/14235\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\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003E1-Year Interim Analysis: ORAL Scan.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EIn the ORAL Step study [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00856544\u0026amp;atom=%2Fspmdc%2F12%2F9%2F26.atom\u0022\u003ENCT00856544\u003C\/a\u003E] of tofacitinib plus methotrexate (n=400), ACR20 response rates were significantly higher with tofacitinib 5 mg (p\u22640.05) and 10 mg (p\u0026lt;0.0001) versus placebo at 3 months.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EThe Phase 3 trials of tofacitinib have demonstrated consistent efficacy and adverse events profiles. Tofacitinib is furthest along in the development process, but other JAK targets may offer a better efficacy\/toxicity profile.\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-2\u0022\u003E\n         \u003Ch2 class=\u0022\u0022\u003ESmall-Molecule Kinase Inhibitors in RA Treatment\u003C\/h2\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThe role of new orally bioavailable kinase inhibitors in the treatment of RA will be influenced by their efficacy, safety profile, cost, and ability to be used with RA-related medications. Iain B. McInnes, PhD, University of Glasgow, Glasgow, Scotland, United Kingdom, reviewed the available data on the use of these novel agents in the management of RA.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003ESeveral tumor necrosis factor (TNF) inhibitors have demonstrated efficacy in RA trials, including etanercept, infliximab, adalimumab, certolizumab, and golimumab. Abatacept, rituximab, and tocilizumab have been shown to improve ACR responses in RA patients who had an inadequate response to TNF inhibitors. Many of these agents are associated with of serious adverse events and infections [Singh J et al. \u003Cem\u003ECochrane Database Syst Rev\u003C\/em\u003E 2011] (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E). Data from several registries demonstrate an increased relative risk of infection shortly after the start of TNF inhibitor treatment [Askling J et al. \u003Cem\u003ECurr Opin Rheum\u003C\/em\u003E 2008]. Several randomized clinical trials found an increased risk of cancer in patients who were treated with anti-TNF therapies, with ORs ranging from 1.3 to 3.3.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F2\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\/12\/9\/26\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Adverse Event\/Serious Infection Profiles.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1318167053\u0022 data-figure-caption=\u0022Adverse Event\/Serious Infection Profiles.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/9\/26\/F2.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\/12\/9\/26\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\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\/12\/9\/26\/F2.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\/14237\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 2.\u003C\/span\u003E \n               \u003Cp id=\u0022p-12\u0022 class=\u0022first-child\u0022\u003EAdverse Event\/Serious Infection Profiles.\u003C\/p\u003E\n            \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with permission from I.B. McInnes, PhD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-13\u0022\u003EPatients with RA often have comorbidities, including cardiovascular disease, insulin resistance, low bone mineral density, and depression. Greenberg et al. [\u003Cem\u003EAnn Rheum Dis\u003C\/em\u003E 2011] reported that compared with nonbiologic disease-modifying antirheumatic drugs (DMARDs), the HRs for cardiovascular risk are 0.39 (95% CI, 0.19 to 0.82) with anti-TNF treatment and 0.94 (95% CI, 0.49 to 1.80) with methotrexate. With no treatment as a reference, treatment with prednisone yielded HR=1.78 (95% CI, 1.06 to 2.96) with \u0026lt;7.5 mg daily and HR=2.62 (95% CI, 1.29 to 5.31) with \u22657.5 mg daily.\u003C\/p\u003E\n         \u003Cp id=\u0022p-14\u0022\u003EWith rigorous application of current medicines and advanced strategies, new therapies for RA have the potential to improve symptoms, signs, and function; reduce or eliminate damage; have an acceptable safety profile; have widespread patient endorsement; and increase adherence to target-based strategic approaches. These therapies could provide greater convenience, increased remission potential, cost-effectiveness, and\/or durability.\u003C\/p\u003E\n         \u003Cp id=\u0022p-15\u0022\u003ETreatment strategies that are currently in development for RA include targeting DAMPs\/PAMPs and other innate receptors, cytokines (eg, GM-CSF receptor, IL-17A, BlyS), protease-activated receptors (eg, PAR2), complement (eg, C5), kinase inhibitors (eg, SYK, JAK, BTK, PI3K), post-translational modification (eg, PADI4), and autoreactivity (eg, T-cell, \u03b2-cell). The most advanced kinase targets in RA are JAK and SYK. Both modulate inflammation and damage and are undergoing investigation in Phase 3 trials. Thus far, the efficacy datasets are encouraging. However, safety datasets will be a major driver in clinical decision-making. Additionally, questions remain about the effect of kinase inhibitors on comorbidities. Other factors that will affect the adoption of these new agents include patients\u0027 preferences (parenteral vs oral therapeutics) and cost-effectiveness.\u003C\/p\u003E\n         \u003Cp id=\u0022p-16\u0022\u003EConsiderations for introducing kinase inhibitors in practice include comparing their tolerability and safety, efficacy, ease of administration, cost, predictability of responses, and pathological rationale with other treatments that are used in specific settings: premethotrexate (vs methotrexate, triple therapy), postmethotrexate inadequate response (IR; vs TNF inhibitor or other mechanism of action), and post-TNF inhibitor-IR (vs other biologic mechanism of action).\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\/9\/26.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?nzngld\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?nzngld\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?nzngld\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}