{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:47:27Z","timestamp":1791859647771,"version":"4.3.4"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of inflammation through cell death and proinflammatory cytokine production. This multicenter, randomized, double-blind (sponsor-unblinded), placebo-controlled, experimental medicine study evaluated the safety, pharmacokinetics (PK), and preliminary efficacy of GSK2982772, a RIPK1 inhibitor, in moderate to severe rheumatoid arthritis (RA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with moderate to severe RA who had received \u226512\u2009weeks\u2019 stable-dose conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy were randomized (2:1) to GSK2982772 60\u2009mg or placebo orally 2 or 3 times daily for 84\u2009days. Safety, PK, disease activity, joint damage, and pharmacodynamic (PD) biomarkers were assessed at days 43 and 85.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 52 patients were randomized (placebo, 18; GSK2982772, 34). Adverse events (AEs) were reported in 13 (72%)\u00a0in patients in the placebo group (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u20093 b.i.d;\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u200910 t.i.d.) and 20 (61%) in the GSK2982772 group (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u20093 b.i.d;\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u200917 t.i.d.). All treatment-related AEs were mild\/moderate, except one severe case of alopecia areata at day 49 and retinal vein thrombosis at day 66 (which led to withdrawal from the study) in patients receiving GSK2982772 t.i.d. Disease Activity Score in 28 Joints\u2013C-reactive protein (DAS28-CRP) scores, ACR20\/50\/70 response, and rates of low disease activity and remission were similar between placebo and GSK2982772 arms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results suggest that inhibition of RIPK1 activity at the GSK2982772 exposure levels evaluated do not translate into meaningful clinical improvement of RA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                      Identifier:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT02858492\">NCT02858492<\/jats:ext-link>\n                      . Registered 8 August 2016.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-021-02468-0","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T03:04:35Z","timestamp":1615863875000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["A randomized, placebo-controlled experimental medicine study of RIPK1 inhibitor GSK2982772 in patients with moderate to severe rheumatoid arthritis"],"prefix":"10.1186","volume":"23","author":[{"given":"Kathleen","family":"Weisel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Berger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Thorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Peterfy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Siddall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Tompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilia","family":"Quattrocchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan W.","family":"Burriss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul Peter","family":"Tak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,16]]},"reference":[{"key":"2468_CR1","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1002\/1529-0131(200012)43:12<2619::AID-ANR1>3.0.CO;2-V","volume":"43","author":"PP Tak","year":"2000","unstructured":"Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum. 2000;43:2619\u201333.","journal-title":"Arthritis Rheum"},{"issue":"Suppl 5","key":"2468_CR2","doi-asserted-by":"publisher","first-page":"v22","DOI":"10.1093\/rheumatology\/kes115","volume":"51","author":"P Emery","year":"2012","unstructured":"Emery P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment. Rheumatology (Oxford). 2012;51(Suppl 5):v22\u201330.","journal-title":"Rheumatology (Oxford)"},{"key":"2468_CR3","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.mayocp.2017.05.009","volume":"92","author":"CA Wijbrandts","year":"2017","unstructured":"Wijbrandts CA, Tak PP. Prediction of response to targeted treatment in rheumatoid arthritis. Mayo Clin Proc. 2017;92:1129\u201343.","journal-title":"Mayo Clin Proc"},{"key":"2468_CR4","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","volume":"388","author":"JS Smolen","year":"2016","unstructured":"Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023\u201338.","journal-title":"Lancet."},{"key":"2468_CR5","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1056\/NEJM200103223441207","volume":"344","author":"EH Choy","year":"2001","unstructured":"Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907\u201316.","journal-title":"N Engl J Med"},{"key":"2468_CR6","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1016\/j.pharmthera.2007.10.001","volume":"117","author":"D Tracey","year":"2008","unstructured":"Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244\u201379.","journal-title":"Pharmacol Ther"},{"key":"2468_CR7","doi-asserted-by":"publisher","first-page":"15671","DOI":"10.1073\/pnas.95.26.15671","volume":"95","author":"VJ Palombella","year":"1998","unstructured":"Palombella VJ, Conner EM, Fuseler JW, Destree A, Davis JM, Laroux FS, et al. Role of the proteasome and NF-kappaB in streptococcal cell wall-induced polyarthritis. Proc Natl Acad Sci U S A. 1998;95:15671\u20136.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2468_CR8","doi-asserted-by":"publisher","first-page":"13859","DOI":"10.1073\/pnas.95.23.13859","volume":"95","author":"AV Miagkov","year":"1998","unstructured":"Miagkov AV, Kovalenko DV, Brown CE, Didsbury JR, Cogswell JP, Stimpson SA, et al. NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci U S A. 1998;95:13859\u201364.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2468_CR9","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/ng.874","volume":"43","author":"M Matmati","year":"2011","unstructured":"Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, et al. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet. 2011;43:908\u201312.","journal-title":"Nat Genet"},{"key":"2468_CR10","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/nrm3683","volume":"14","author":"D Ofengeim","year":"2013","unstructured":"Ofengeim D, Yuan J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol. 2013;14:727\u201336.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2468_CR11","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1038\/cdd.2014.126","volume":"22","author":"F Humphries","year":"2015","unstructured":"Humphries F, Yang S, Wang B, Moynagh PN. RIP kinases: key decision makers in cell death and innate immunity. Cell Death Differ. 2015;22:225\u201336.","journal-title":"Cell Death Differ"},{"key":"2468_CR12","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.semcdb.2014.07.013","volume":"35","author":"W Zhou","year":"2014","unstructured":"Zhou W, Yuan J. Necroptosis in health and diseases. Semin Cell Dev Biol. 2014;35:14\u201323.","journal-title":"Semin Cell Dev Biol"},{"key":"2468_CR13","doi-asserted-by":"publisher","first-page":"15009","DOI":"10.1038\/cddiscovery.2015.9","volume":"1","author":"SB Berger","year":"2015","unstructured":"Berger SB, Harris P, Nagilla R, Kasparcova V, Hoffman S, Swift B, et al. Characterization of GSK'963: a structurally distinct, potent and selective inhibitor of RIP1 kinase. Cell Death Discov. 2015;1:15009.","journal-title":"Cell Death Discov."},{"key":"2468_CR14","doi-asserted-by":"publisher","first-page":"5476","DOI":"10.4049\/jimmunol.1400499","volume":"192","author":"SB Berger","year":"2014","unstructured":"Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol. 2014;192:5476\u201380.","journal-title":"J Immunol"},{"key":"2468_CR15","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1084\/jem.20141130","volume":"212","author":"B Boisson","year":"2015","unstructured":"Boisson B, Laplantine E, Dobbs K, Cobat A, Tarantino N, Hazen M, et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med. 2015;212:939\u201351.","journal-title":"J Exp Med"},{"key":"2468_CR16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041238","volume":"7","author":"MA O\u2019Donnell","year":"2012","unstructured":"O\u2019Donnell MA, Hase H, Legarda D, Ting AT. NEMO inhibits programmed necrosis in an NF\u03baB-independent manner by restraining RIP1. PLoS One. 2012;7:e41238.","journal-title":"PLoS One"},{"key":"2468_CR17","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1038\/nature09816","volume":"471","author":"B Gerlach","year":"2011","unstructured":"Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature. 2011;471:591\u20136.","journal-title":"Nature."},{"key":"2468_CR18","doi-asserted-by":"crossref","unstructured":"Raghav SK, Gupta B, Agrawal C, Chaturvedi VP, Das HR. Expression of TNF-alpha and related signaling molecules in the peripheral blood mononuclear cells of rheumatoid arthritis patients. Mediators Inflamm. 2006;2006:12682.","DOI":"10.1155\/MI\/2006\/12682"},{"key":"2468_CR19","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41419-019-1735-6","volume":"10","author":"J Hou","year":"2019","unstructured":"Hou J, Ju J, Zhang Z, Zhao C, Li Z, Zheng J, et al. Discovery of potent necroptosis inhibitors targeting RIPK1 kinase activity for the treatment of inflammatory disorder and cancer metastasis. Cell Death Discov. 2019;10:493.","journal-title":"Cell Death Discov"},{"key":"2468_CR20","doi-asserted-by":"publisher","first-page":"14436","DOI":"10.1073\/pnas.1409389111","volume":"111","author":"JE Roderick","year":"2014","unstructured":"Roderick JE, Hermance N, Zelic M, Simmons MJ, Polykratis A, Pasparakis M, et al. Hematopoietic RIPK1 deficiency results in bone marrow failure caused by apoptosis and RIPK3-mediated necroptosis. Proc Natl Acad Sci U S A. 2014;111:14436\u201341.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2468_CR21","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1182\/blood-2018-05-847335","volume":"133","author":"PN Wagner","year":"2019","unstructured":"Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, et al. Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Blood. 2019;133:107\u201320.","journal-title":"Blood."},{"key":"2468_CR22","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s12967-019-1809-3","volume":"17","author":"J Jhun","year":"2019","unstructured":"Jhun J, Lee SH, Kim SY, Ryu J, Kwon JY, Na HS, et al. RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis. J Transl Med. 2019;17:84.","journal-title":"J Transl Med"},{"key":"2468_CR23","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1021\/acs.jmedchem.6b01751","volume":"60","author":"PA Harris","year":"2017","unstructured":"Harris PA, Berger SB, Jeong JU, Nagilla R, Bandyopadhyay D, Campobasso N, et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J Med Chem. 2017;60:1247\u201361.","journal-title":"J Med Chem"},{"key":"2468_CR24","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.365","volume":"5","author":"K Weisel","year":"2017","unstructured":"Weisel K, Scott NE, Tompson DJ, Votta BJ, Madhavan S, Povey K, et al. Randomized clinical study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor GSK2982772 in healthy volunteers. Pharmacol Res Perspect. 2017;5:e00365.","journal-title":"Pharmacol Res Perspect"},{"key":"2468_CR25","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1002\/art.27584","volume":"62","author":"D Aletaha","year":"2010","unstructured":"Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology\/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569\u201381.","journal-title":"Arthritis Rheum"},{"key":"2468_CR26","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1136\/ard.2010.139550","volume":"70","author":"MGH van de Sande","year":"2011","unstructured":"van de Sande MGH, Gerlag DM, Lodde BM, van Baarsen LGM, Alivernini S, Codullo V, et al. Evaluating antirheumatic treatments using synovial biopsy: a recommendation for standardisation to be used in clinical trials. Ann Rheum Dis. 2011;70:423\u20137.","journal-title":"Ann Rheum Dis"},{"key":"2468_CR27","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/1477-7525-1-79","volume":"1","author":"K Webster","year":"2003","unstructured":"Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) measurement system: properties, applications, and interpretation. Health Qual Life Outcomes. 2003;1:79.","journal-title":"Health Qual Life Outcomes"},{"issue":"5 Suppl 85","key":"2468_CR28","first-page":"S65","volume":"32","author":"PL van Riel","year":"2014","unstructured":"van Riel PL. The development of the disease activity score (DAS) and the disease activity score using 28 joint counts (DAS28). Clin Exp Rheumatol. 2014;32(5 Suppl 85):S65\u201374.","journal-title":"Clin Exp Rheumatol"},{"key":"2468_CR29","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1002\/art.22552","volume":"57","author":"American College of Rheumatology Committee to Reevaluate Improvement Criteria","year":"2007","unstructured":"American College of Rheumatology Committee to Reevaluate Improvement Criteria. A proposed revision to the ACR20: the hybrid measure of American College of Rheumatology response. Arthritis Rheum. 2007;57:193\u2013202.","journal-title":"Arthritis Rheum"},{"key":"2468_CR30","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.3899\/jrheum.161433","volume":"44","author":"M \u00d8stergaard","year":"2017","unstructured":"\u00d8stergaard M, Peterfy CG, Bird P, Gandjbakhch F, Glinatsi D, Eshed I, et al. The OMERACT rheumatoid arthritis magnetic resonance imaging (MRI) scoring system: updated recommendations by the OMERACT MRI in Arthritis Working Group. J Rheumatol. 2017;44:1706\u201312.","journal-title":"J Rheumatol"},{"key":"2468_CR31","doi-asserted-by":"publisher","first-page":"R131","DOI":"10.1186\/ar3861","volume":"14","author":"CG Peterfy","year":"2012","unstructured":"Peterfy CG, DiCarlo JC, Olech E, Bagnard MA, Gabriele A, Gaylis N. Evaluating joint-space narrowing and cartilage loss in rheumatoid arthritis by using MRI. Arthritis Res Ther. 2012;14:R131.","journal-title":"Arthritis Res Ther"},{"key":"2468_CR32","first-page":"167","volume":"30","author":"B Bruce","year":"2003","unstructured":"Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of its history, issues, progress, and documentation. J Rheumatol. 2003;30:167\u201378.","journal-title":"J Rheumatol"},{"key":"2468_CR33","doi-asserted-by":"crossref","unstructured":"Cohen S, Tuckwell K, Katsumoto TR, Zhao R, Lee C, Berman A, et al. Fenebrutinib compared to placebo and adalimumb in patients with inadequate response to either methotrexate therapy or prior TNF therapy: phase 2 study. American College of Rheumatology annual meeting; November 8\u201313, 2019; Atlanta, GA. Abstract OP0025.","DOI":"10.1136\/annrheumdis-2019-eular.4469"},{"key":"2468_CR34","doi-asserted-by":"crossref","unstructured":"Combe B, Kivitz A, Tanaka Y, van der Heijde D, Matzkies F, Bartok B, et al. Efficacy and safety of filgotinib for patients with rheumatoid arthritis with inadequate response to methotrexate: FINCH1 primary outcome results. American College of Rheumatology annual meeting; November 8\u201313, 2019; Atlanta, GA. Abstract LB0001.","DOI":"10.1136\/annrheumdis-2019-eular.8676"},{"key":"2468_CR35","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1136\/annrheumdis-2016-210094","volume":"76","author":"M Dougados","year":"2017","unstructured":"Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76:88\u201395.","journal-title":"Ann Rheum Dis"},{"key":"2468_CR36","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1056\/NEJMoa1109071","volume":"367","author":"R Fleischmann","year":"2012","unstructured":"Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012;367:495\u2013507.","journal-title":"N Engl J Med"},{"key":"2468_CR37","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1002\/art.41032","volume":"71","author":"R Fleischmann","year":"2019","unstructured":"Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III, double-blind, randomized controlled trial. Arthritis Rheum. 2019;71:1788\u2013800.","journal-title":"Arthritis Rheum"},{"key":"2468_CR38","doi-asserted-by":"publisher","first-page":"253","DOI":"10.7326\/0003-4819-159-4-201308200-00006","volume":"159","author":"J Kremer","year":"2013","unstructured":"Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159:253\u201361.","journal-title":"Ann Intern Med"},{"key":"2468_CR39","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1002\/art.33419","volume":"64","author":"JM Kremer","year":"2012","unstructured":"Kremer JM, Cohen S, Wilkinson BE, Connell CA, French JL, Gomez-Reino J, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012;64:970\u201381.","journal-title":"Arthritis Rheum"},{"key":"2468_CR40","doi-asserted-by":"publisher","first-page":"2303","DOI":"10.1016\/S0140-6736(19)30419-2","volume":"393","author":"JS Smolen","year":"2019","unstructured":"Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet. 2019;393:2303\u201311.","journal-title":"Lancet."},{"key":"2468_CR41","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1056\/NEJMoa1608345","volume":"376","author":"PC Taylor","year":"2017","unstructured":"Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen ML, Gonzaga JR, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376:652\u201362.","journal-title":"N Engl J Med"},{"key":"2468_CR42","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1002\/art.37816","volume":"65","author":"D van der Heijde","year":"2013","unstructured":"van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65:559\u201370.","journal-title":"Arthritis Rheum"},{"key":"2468_CR43","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1056\/NEJMoa1112072","volume":"367","author":"RF van Vollenhoven","year":"2012","unstructured":"van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garc\u00eda Meijide JA, Wagner A, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367:508\u201319.","journal-title":"N Engl J Med"},{"key":"2468_CR44","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1128\/MCB.01225-12","volume":"33","author":"B Lamothe","year":"2013","unstructured":"Lamothe B, Lai Y, Xie M, Schneider MD, Darnay BG. TAK1 is essential for osteoclast differentiation and is an important modulator of cell death by apoptosis and necroptosis. Mol Cell Biol. 2013;33:582\u201395.","journal-title":"Mol Cell Biol"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02468-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13075-021-02468-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13075-021-02468-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T03:06:22Z","timestamp":1615863982000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/s13075-021-02468-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,16]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["2468"],"URL":"https:\/\/doi.org\/10.1186\/s13075-021-02468-0","relation":{},"ISSN":["1478-6362"],"issn-type":[{"value":"1478-6362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,16]]},"assertion":[{"value":"21 October 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was conducted in accordance with Good Clinical Practice, the International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines, and local laws and regulations. The protocol and amendments were approved by an institutional review board (IRB) at each study site, and blinded safety data were reviewed by a safety review team. Each patient provided written informed consent prior to treatment initiation.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"KW, SB, EQ, SW, and PPT are former employees of and stockholders in GlaxoSmithKline (GSK).KT is an employee of GSK.PCT reports personal consultant fees from GSK and grants from Celgene, Galapagos, and Eli Lilly. He also reports personal fees from AbbVie, Galapagos, Gilead, GSK, Eli Lilly, and Pfizer.CP received nonfinancial support from GSK. He is an employee of and stockholder in Spire Sciences Inc. which received research funding from GSK to conduct the study. He reports consulting or personal fees from AbbVie, Acerta Therapeutics, Five Prime, Genentech, Modern Bioscience, Myriad, Novartis, Roche, Set Point, and Vorso and speakers fees from Amgen and Bristol\u00a0Myers Squibb.HS, DT, and SWB are employees of and hold stock options in GSK.JW reports personal fees and nonfinancial support from AbbVie, Medac, and Pfizer, and personal fees from Fraunhofer Institute, Gilead, GSK, Janssen-Cilag, Medac, Novartis, and Pfizer.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"85"}}