{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:10:50Z","timestamp":1793383850318,"version":"4.5.0"},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T00:00:00Z","timestamp":1707177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To investigate the prevalence of poly\u2010refractory rheumatoid arthritis (RA) defined as failure of all biological (b)\/targeted synthetic (ts)\u2010disease\u2010modifying drugs (DMARDs). To further investigate whether patients with persistent inflammatory refractory RA (PIRRA) and noninflammatory refractory RA (NIRRA), determined by objective ultrasound (US) synovitis, have distinct clinical phenotypes in both EULAR difficult\u2010to\u2010treat RA (D2T\u2010RA) and poly\u2010refractory RA groups.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A cross\u2010sectional study of 1,591 patients with RA on b\/tsDMARDs that evaluated D2T\u2010RA criteria and subclassified as poly\u2010refractory if inefficacy\/toxicity to at least one drug of all classes. PIRRA was defined if US synovitis in one or more swollen joint and NIRRA if absent. Univariate tests and multivariate logistic regression were conducted to investigate factors associated with poly\u2010refractory, PIRRA, and NIRRA phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>122 of 1,591 were excluded due to missing data. 247 of 1,469 (16.8%) had D2T\u2010RA and only 40 of 1,469 (2.7%) poly\u2010refractory RA. This latter group had higher disease activity score 28 C\u2010reactive protein (CRP) (median 5.4 vs 5.02, <jats:italic>P<\/jats:italic> &lt;\u20090.05), CRP levels (median 13 vs 5 mg\/l, <jats:italic>P<\/jats:italic> &lt;\u20090.01), and smoking (ever) rates (20% vs 4%, <jats:italic>P<\/jats:italic> &lt;\u20090.01) compared with other D2T patients. Smoking was associated with poly\u2010refractory RA (odds ratio 5.067, 95% CI 1.774\u201314.472, <jats:italic>P<\/jats:italic> =\u20090.002). Of 107 patients with D2T\u2010RA with recent US, 61 (57%) were PIRRA and 46 (43%), NIRRA. Patients with NIRRA had elevated body mass index (median 30 vs 26, <jats:italic>P<\/jats:italic> &lt;\u20090.001) and higher fibromyalgia prevalence (15% vs 3%, <jats:italic>P<\/jats:italic> &lt;\u20090.05), lower swollen joint count (median: 2 vs 5, <jats:italic>P<\/jats:italic> &lt;\u20090.001), and lower CRP levels (5 vs 10, <jats:italic>P<\/jats:italic> &lt;\u20090.01).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Only 2.7% of D2T\u2010RA failed all classes of b\/tsDMARDs. Among D2T\u2010RA, less than 60% had objective signs of inflammation, representing a target for innovative strategies.<\/jats:p><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art42767-toc-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42767","type":"journal-article","created":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T20:47:21Z","timestamp":1701982041000},"page":"510-521","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["<scp>Poly\u2010Refractory<\/scp> Rheumatoid Arthritis: An Uncommon Subset of Difficult to Treat Disease With Distinct Inflammatory and Noninflammatory Phenotypes"],"prefix":"10.1002","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0075-5895","authenticated-orcid":false,"given":"Paula","family":"David","sequence":"first","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM) University of Leeds  Leeds United\u00a0Kingdom"},{"name":"Sheba Medical Center\u2010 Tel Hashomer  Ramat Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Di Matteo","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM) University of Leeds  Leeds United\u00a0Kingdom"},{"name":"Leeds Teaching Hospitals NHS Trust  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Or","family":"Hen","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM) University of Leeds  Leeds United\u00a0Kingdom"},{"name":"Sheba Medical Center\u2010 Tel Hashomer  Ramat Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouvik","family":"Dass","sequence":"additional","affiliation":[{"name":"Leeds Teaching Hospitals NHS Trust  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Marzo\u2010Ortega","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM) University of Leeds  Leeds United\u00a0Kingdom"},{"name":"Leeds Teaching Hospitals NHS Trust  Leeds United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Wakefield","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM) University of Leeds  Leeds United\u00a0Kingdom"},{"name":"Leeds Teaching Hospitals NHS Trust  Leeds United 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