{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T20:44:03Z","timestamp":1793479443874,"version":"4.5.0"},"reference-count":36,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"content-version":"unspecified","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Pancretan Health Organization"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2024,1,4]]},"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Characterisation of the long-term outcome of patients with \u2018difficult to treat\u2019 (D2T) rheumatoid arthritis and factors contributing to its evolution are unknown. Herein, we explored the heterogeneity and contributing factors of D2T long-term outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients included from a prospective single centre cohort study. The EULAR definition of D2T was applied. Longitudinal clustering of functional status (modified Health Assessment Questionnaire (mHAQ)) and disease activity (Disease Activity Score-28 (DAS28)) were assessed using latent-class trajectory analysis. Multiple linear mixed models were used to examine the impact of comorbidities and their clusters on the long-term outcome.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>251 out of 1264 patients (19.9%) were identified as D2T. Younger age, fibromyalgia, osteoarthritis, DAS28-erythrocyte sedimentation rate (ESR) at first biological or targeted synthetic disease-modifying antirheumatic drug (b\/ts-DMARD) initiation and failure to reduce DAS28-ESR scores within the first 6 months of b\/ts-DMARD therapy were significant predictors of patients becoming D2T. Long-term follow-up (total of 5872 person-years) revealed four groups of functional status evolution: 18.2% had stable, mildly compromised mHAQ (mean 0.41), 39.9% had gradual improvement (1.21\u20130.87) and two groups had either slow deterioration or stable significant functional impairment (HAQ&gt;1). Similarly, four distinct groups of disease activity evolution were identified. Among the different clusters of comorbidities assessed, presence of \u2018mental-health and pain-related illnesses\u2019 or \u2018metabolic diseases\u2019 had significant contribution to mHAQ worsening (p&lt;0.0001 for both) and DAS28 evolution (p&lt;0.0001 and p=0.018, respectively).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>D2T patients represent a heterogeneous group in terms of long-term disease course. Mental-health\/pain-related illnesses as well as metabolic diseases contribute to long-term adverse outcomes and should be targeted in order to optimise the prognosis of this subset of rheumatoid arthritis.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/rmdopen-2023-003808","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T12:55:28Z","timestamp":1705668928000},"page":"e003808","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":29,"title":["Patterns of comorbidities differentially affect long-term functional evolution and disease activity in patients with \u2018difficult to treat\u2019 rheumatoid arthritis"],"prefix":"10.1136","volume":"10","author":[{"given":"Antonios","family":"Bertsias","sequence":"first","affiliation":[{"name":"Rheumatology, Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6966-1304","authenticated-orcid":false,"given":"Irini D","family":"Flouri","sequence":"additional","affiliation":[{"name":"Rheumatology, Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Argyro","family":"Repa","sequence":"additional","affiliation":[{"name":"Rheumatology, Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nestor","family":"Avgoustidis","sequence":"additional","affiliation":[{"name":"Rheumatology, Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Kalogiannaki","sequence":"additional","affiliation":[{"name":"Rheumatology, Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Pitsigavdaki","sequence":"additional","affiliation":[{"name":"Rheumatology, Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Heraklion, Crete, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5299-1406","authenticated-orcid":false,"given":"George","family":"Bertsias","sequence":"additional","affiliation":[{"name":"Rheumatology, Clinical Immunology and Allergy Department, School of Medicine, University of Crete, Heraklion, Crete, Greece"},{"name":"Laboratory of Autoimmunity-Inflammation, Institute of Molecular Biology and Biotechnology, Heraklion, 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