{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:08:18Z","timestamp":1790082498132,"version":"4.0.1"},"reference-count":25,"publisher":"BMJ","issue":"1","funder":[{"DOI":"10.13039\/100009857","name":"Regeneron Pharmaceuticals, Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009857","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100013995","name":"Sanofi Genzyme","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100013995","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2018,2,15]]},"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Interleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6R\u03b1. In TARGET (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT01709578\">NCT01709578<\/jats:ext-link>), a phase 3 study in adults with moderate-to-severe RA and inadequate response or intolerance to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150\u2009mg every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) significantly reduced disease activity versus placebo plus csDMARDs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Circulating levels of biomarkers associated with synovial inflammation (matrix metalloproteinase 3 (MMP-3), collagen type I MMP-cleaved fragment (C1M), collagen type III MMP-cleaved fragment (C3M)), myeloid (soluble intercellular adhesion molecule 1 (sICAM-1), IL-8 and calprotectin) and lymphoid activation (chemokine, CXC motif, ligand 13 (CXCL13), CXCL10, B cell-activating factor) and bone remodelling (receptor activator of nuclear factor-\u03baB ligand (RANKL), osteoprotegerin and osteocalcin) were evaluated in patients from a TARGET substudy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Sarilumab significantly decreased C1M, C3M, CXCL13, MMP-3 and total RANKL levels at week 24 versus placebo; some markers were significantly suppressed at week 2 and normalised to levels in healthy controls. Levels of sICAM-1 were predictive of disease activity score by C-reactive protein and clinical disease activity index low disease activity (LDA) response in the sarilumab 200\u2009mg q2w group at week 12. A trend was observed in which patients with lower sICAM-1 levels at baseline had better response compared with patients with higher sICAM-1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Sarilumab plus csDMARDs decreased circulating biomarkers of synovial inflammation and bone resorption; sICAM-1 was predictive of achieving LDA with sarilumab.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"NCT01709578\" ext-link-type=\"clintrialgov\" specific-use=\"clinicaltrial post-results\">NCT01709578<\/jats:ext-link>; Post-results.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2017-000607","type":"journal-article","created":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T08:40:17Z","timestamp":1521016817000},"page":"e000607","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study"],"prefix":"10.1136","volume":"4","clinical-trial-number":[{"clinical-trial-number":"nct01709578","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01709578","registry":"10.18810\/clinical-trials-gov","type":"postResults"},{"clinical-trial-number":"nct01709578","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct00106522","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Cem","family":"Gabay","sequence":"first","affiliation":[{"name":"University Hospitals of Geneva, Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Msihid","sequence":"additional","affiliation":[{"name":"Sanofi R&D, Chilly-Mazarin, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Zilberstein","sequence":"additional","affiliation":[{"name":"Sanofi R&D, Bridgewater, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Paccard","sequence":"additional","affiliation":[{"name":"Sanofi R&D, Chilly-Mazarin, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Lin","sequence":"additional","affiliation":[{"name":"Sanofi Genzyme, Bridgewater, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil M H","family":"Graham","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Boyapati","sequence":"additional","affiliation":[{"name":"Regeneron Pharmaceuticals, Inc, Tarrytown, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2018,3,14]]},"reference":[{"key":"2025090312204387000_4.1.e000607.1","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X10378372"},{"key":"2025090312204387000_4.1.e000607.2","doi-asserted-by":"publisher","DOI":"10.2146\/ajhp070449"},{"key":"2025090312204387000_4.1.e000607.3","first-page":"1510","article-title":"Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid","volume":"24","author":"Desgeorges","year":"1997","journal-title":"J Rheumatol"},{"key":"2025090312204387000_4.1.e000607.4","doi-asserted-by":"publisher","DOI":"10.1007\/BF00307733"},{"key":"2025090312204387000_4.1.e000607.5","first-page":"2069","article-title":"Soluble interleukin 6 (IL-6) receptor and IL-6 levels in serum and synovial fluid of patients with different arthropathies","volume":"24","author":"Us\u00f3n","year":"1997","journal-title":"J Rheumatol"},{"key":"2025090312204387000_4.1.e000607.6","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.4049\/jimmunol.145.10.3297","article-title":"IL-6 is produced by osteoblasts and induces bone resorption","volume":"145","author":"Ishimi","year":"1990","journal-title":"J Immunol"},{"key":"2025090312204387000_4.1.e000607.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.24.11924"},{"key":"2025090312204387000_4.1.e000607.8","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.5.1461"},{"key":"2025090312204387000_4.1.e000607.9","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(02)00915-8"},{"key":"2025090312204387000_4.1.e000607.10","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ken363"},{"key":"2025090312204387000_4.1.e000607.11","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1186\/s13075-016-1132-9","article-title":"Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY","volume":"18","author":"Boyapati","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"2025090312204387000_4.1.e000607.12","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/art.39944","article-title":"Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors","volume":"69","author":"Fleischmann","year":"2017","journal-title":"Arthritis Rheumatol"},{"key":"2025090312204387000_4.1.e000607.13","doi-asserted-by":"publisher","DOI":"10.1186\/ar4555"},{"key":"2025090312204387000_4.1.e000607.14","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-203923"},{"key":"2025090312204387000_4.1.e000607.15","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0040362","article-title":"Biomarkers of good EULAR response to the B cell depletion therapy in all seropositive rheumatoid arthritis patients: clues for the pathogenesis","volume":"7","author":"Ferraccioli","year":"2012","journal-title":"PLoS One"},{"key":"2025090312204387000_4.1.e000607.16","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s13075-016-0995-0","article-title":"Baseline CXCL10 and CXCL13 levels are predictive biomarkers for tumor necrosis factor inhibitor therapy in patients with moderate to severe rheumatoid arthritis: a pilot, prospective study","volume":"18","author":"Han","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"2025090312204387000_4.1.e000607.17","doi-asserted-by":"publisher","DOI":"10.1186\/ar2419"},{"key":"2025090312204387000_4.1.e000607.18","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1002\/art.39093","article-title":"Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study","volume":"67","author":"Genovese","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"2025090312204387000_4.1.e000607.19","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204405"},{"key":"2025090312204387000_4.1.e000607.20","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Statist Soc B"},{"key":"2025090312204387000_4.1.e000607.21","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1080\/13696998.2016.1275653","article-title":"Outcomes of tumor necrosis factor inhibitor cycling versus switching to a disease-modifying anti-rheumatic drug with a new mechanism of action among patients with rheumatoid arthritis","volume":"20","author":"Chastek","year":"2017","journal-title":"J Med Econ"},{"key":"2025090312204387000_4.1.e000607.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2012.01.004"},{"key":"2025090312204387000_4.1.e000607.23","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-200198"},{"key":"2025090312204387000_4.1.e000607.24","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-008-0870-8"},{"key":"2025090312204387000_4.1.e000607.25","doi-asserted-by":"publisher","DOI":"10.1002\/art.23417"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2017-000607","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T19:20:57Z","timestamp":1756927257000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2017-000607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,3,14]]},"published-print":{"date-parts":[[2018,3]]}},"alternative-id":["10.1136\/rmdopen-2017-000607"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2017-000607","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3]]}}}