{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T16:07:55Z","timestamp":1779120475035,"version":"3.51.4"},"reference-count":21,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"unspecified","delay-in-days":47,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005865","name":"Mochida Memorial Foundation for Medical and Pharmaceutical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005865","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Precision Medicine in Rheumatoid Arthritis"},{"name":"JSPS KAKENHI","award":["24K11609"],"award-info":[{"award-number":["24K11609"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2026,4,16]]},"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Randomised controlled trials (RCTs) use restrictive eligibility criteria, raising concerns about external validity for heterogeneous routine-care populations. We aimed to characterise real-world patients with rheumatoid arthritis who would be ineligible for phase III RCTs, to evaluate their outcomes on biological\/targeted synthetic disease-modifying anti-rheumatic drugs (b\/tsDMARDs) in routine care and to assess how eligibility status influences comparative effectiveness estimates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analysed 5462 patients who initiated b\/tsDMARDs between 2003 and 2023. RCT ineligibility was defined using common phase III trial exclusions (eg, renal\/hepatic impairment). Outcomes were treatment persistence and Clinical Disease Activity Index remission at 26 weeks. Comparative effectiveness across drug classes was estimated using propensity score weighting, stratified by RCT eligibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Overall, 39.7% (2167\/5462) met at least one RCT exclusion criterion and ineligible patients had higher baseline disease activity and worse functional status. However, after propensity score adjustment for clinical characteristics, remission rates did not differ between groups (24.0% vs 23.2%; OR 0.90; 95%\u2009CI 0.78 to 1.04). The proportion ineligible differed by b\/tsDMARDs, highest with interleukin 6 inhibitors (47.4%) and CTLA4-Ig (45.1%) and lowest with Janus kinase (JAK) inhibitors (31.0%). In the RCT-eligible cohort, remission with JAK inhibitors exceeded that with tumour necrosis factor inhibitors (OR 1.39; 95%\u2009CI 1.09 to 1.76), consistent with head-to-head RCTs. In the RCT-ineligible cohort, this advantage was attenuated and no longer statistically significant (OR 1.24; 95%\u2009CI 0.81 to 1.91).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Approximately 40% of routine-care patients would be RCT ineligible. Although these patients achieved comparable adjusted outcomes, between-drug differences were smaller than in trial-eligible populations. Real-world comparative analysis should therefore consider composition and calendar time when interpreting treatment effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2026-006825","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:15:30Z","timestamp":1779117330000},"page":"e006825","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Impact of trial exclusion criteria on real-world comparative effectiveness of targeted therapies in rheumatoid arthritis: the FIRST Registry"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9693-9263","authenticated-orcid":false,"given":"Satoshi","family":"Kubo","sequence":"first","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0807-7139","authenticated-orcid":false,"given":"Yoshiya","family":"Tanaka","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"},{"name":"Department of Molecular Targeted Therapies, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5692-3881","authenticated-orcid":false,"given":"Yusuke","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3022-1317","authenticated-orcid":false,"given":"Hiroaki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6220-1233","authenticated-orcid":false,"given":"Hidenori","family":"Sakai","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8247-6595","authenticated-orcid":false,"given":"Ryuichiro","family":"Kanda","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4163-9356","authenticated-orcid":false,"given":"Yuya","family":"Fujita","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0212-172X","authenticated-orcid":false,"given":"Masanobu","family":"Ueno","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuyuki","family":"Todoroki","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"},{"name":"Department of Molecular Targeted Therapies, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ippei","family":"Miyagawa","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"},{"name":"Department of Molecular Targeted Therapies, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2209-8454","authenticated-orcid":false,"given":"Shingo","family":"Nakayamada","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"2026051808152632000_12.2.e006825.1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.13103"},{"key":"2026051808152632000_12.2.e006825.2","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1093\/rheumatology\/kead257","article-title":"Exclusion of older adults from randomized controlled trials in rheumatoid arthritis","volume":"63","author":"Ma\u0144ko","year":"2024","journal-title":"Rheumatology (Oxford)"},{"key":"2026051808152632000_12.2.e006825.3","doi-asserted-by":"crossref","first-page":"e674","DOI":"10.1016\/S2666-7568(22)00186-6","article-title":"Comparing clinical trial population representativeness to real-world populations: an external validity analysis encompassing 43\u2008895 trials and 5\u2008685\u2008738 individuals across 989 unique drugs and 286 conditions in 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