{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:01:43Z","timestamp":1790182903677,"version":"4.1.0"},"reference-count":25,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"unspecified","delay-in-days":84,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2026,8,5]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background\/objectives<\/jats:title>\n                    <jats:p>Despite major advances in rheumatoid arthritis (RA) management, a substantial proportion of patients evolve to difficult-to-treat RA (D2T-RA). We estimated the probability of progression to D2T-RA and assessed whether the initial choice of biological\/targeted synthetic disease-modifying antirheumatic drugs (b\/tsDMARDs) is associated with this risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analysed 675 patients with established RA from the first consultation through all b\/tsDMARD lines to the last follow-up or D2T-RA classification. Kaplan-Meier, log-rank and multivariable Cox regression analyses were performed to identify factors associated with D2T-RA progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of the 675 patients (mean follow-up of 217.1\u00b1131.16 months), 126 (18.7%) fulfilled the D2T-RA criteria. Tumour necrosis factor inhibitor (TNFi) accounted for most first-line and second-line treatments (81.0% and 53.2%). In the post-2000 subcohort (498 patients), no significant difference in D2T-RA risk was observed between TNFi and non-TNFi starters nor between TNFi-cycling or other mechanism of action (MoA)-switching strategies. Glucocorticoid exposure was independently associated with increased risk (HR 2.47, 95%\u2009CI 1.38 to 4.42) and delayed b\/tsDMARD initiation with decreased hazard (HR 0.990, 95%\u2009CI 0.98 to 0.996).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this observational cohort, initial MoA choice was not associated with D2T-RA progression. Disease severity markers appeared more prominent than treatment strategies in driving refractory evolution. Validation in a prospective\/randomised setting is required before potential transition into clinical practice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2026-007098","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:11:44Z","timestamp":1790179904000},"page":"e007098","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Association between initial treatment strategy and progression to difficult-to-treat rheumatoid arthritis (D2T-RA): evidence from a 20-year-old real-world cohort"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4542-1048","authenticated-orcid":false,"given":"C\u00e9cile","family":"Van Mullem","sequence":"first","affiliation":[{"name":"Rheumatology Department, Cliniques universitaires Saint-Luc, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Natalucci","sequence":"additional","affiliation":[{"name":"Rheumatology Department, Cliniques universitaires Saint-Luc, Brussels, Belgium"},{"name":"P\u00f4le de pathologies rhumatismales syst\u00e9miques et inflammatoires (RUMA), Institut de Recherche Exp\u00e9rimentale et Clinique (IREC), Universit\u00e9 catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Avramovska","sequence":"additional","affiliation":[{"name":"Rheumatology Department, Cliniques universitaires Saint-Luc, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Sokolova","sequence":"additional","affiliation":[{"name":"P\u00f4le de pathologies rhumatismales syst\u00e9miques et inflammatoires (RUMA), Institut de Recherche Exp\u00e9rimentale et Clinique (IREC), Universit\u00e9 catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9ment","family":"Triaille","sequence":"additional","affiliation":[{"name":"Rheumatology Department, Cliniques universitaires Saint-Luc, Brussels, Belgium"},{"name":"P\u00f4le de pathologies rhumatismales syst\u00e9miques et inflammatoires (RUMA), Institut de Recherche Exp\u00e9rimentale et Clinique (IREC), Universit\u00e9 catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Durez","sequence":"additional","affiliation":[{"name":"Rheumatology Department, Cliniques universitaires Saint-Luc, Brussels, Belgium"},{"name":"P\u00f4le de pathologies rhumatismales syst\u00e9miques et inflammatoires (RUMA), Institut de Recherche Exp\u00e9rimentale et Clinique (IREC), Universit\u00e9 catholique de Louvain, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"2026092309101793000_12.3.e007098.1","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1016\/j.autrev.2017.10.002","article-title":"The management of first-line biologic therapy failures in rheumatoid arthritis: current practice and future perspectives","volume":"16","author":"Favalli","year":"2017","journal-title":"Autoimmun Rev"},{"key":"2026092309101793000_12.3.e007098.2","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.autrev.2019.05.007","article-title":"Challenges in the treatment of rheumatoid arthritis","volume":"18","author":"Conigliaro","year":"2019","journal-title":"Autoimmun Rev"},{"key":"2026092309101793000_12.3.e007098.3","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2019-216655"},{"key":"2026092309101793000_12.3.e007098.4","doi-asserted-by":"crossref","unstructured":"Favalli EG , Biggioggero M , Marchesoni A , et al . 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