{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T20:43:06Z","timestamp":1793479386825,"version":"4.5.0"},"reference-count":44,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"unspecified","delay-in-days":15,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare of Japan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"UOEH Grant for Advanced Research","award":["19K17919"],"award-info":[{"award-number":["19K17919"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["RMD Open"],"accepted":{"date-parts":[[2025,12,26]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aimed to develop and validate a prediction model for the future progression of difficult-to-treat rheumatoid arthritis (D2T RA) and support the precise use of biologic and targeted synthetic disease-modifying antirheumatic drugs (b\/tsDMARDs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Data were analysed from 1221 patients with rheumatoid arthritis in the FIRST registry, a multicentre collaborative database, who initiated their first b\/tsDMARD. 25 prediction models for D2T RA were generated using 43 baseline characteristics prior to initiating the first b\/tsDMARD. Model performances were tested. A scoring system based on the selected model was designed and internally validated for use in routine clinical practice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among the 1221 patients, 193 (15.8%) progressed to D2T RA after a median of 54.0 months. These patients had higher tender joint count, global assessment, pain scale, Health Assessment Questionnaire score and Clinical Disease Activity Index score and more frequent coexisting lung disease. Among the machine learning models tested, Lasso logistic regression performed best (area under the curve 0.71), identifying pain scale, erythrocyte sedimentation rate and coexisting lung disease as key predictors. The scoring system based on these predictors demonstrated comparable performance. Among patients identified as high risk for D2T RA by the scoring system, interleukin-6 receptor inhibitors (IL-6Ri) significantly reduced D2T RA progression (relative risk (RR): 0.48).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study developed and validated a scoring system to predict D2T RA progression and identify patients at high risk and suggested the advantages of IL-6Ri. This system may advance precision medicine in RA and may contribute to controlling unmet needs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2025-006544","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T19:15:23Z","timestamp":1768590923000},"page":"e006544","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Predicting the progression of difficult-to-treat rheumatoid arthritis by a machine learning scoring system, from the FIRST registry"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0212-172X","authenticated-orcid":false,"given":"Masanobu","family":"Ueno","sequence":"first","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4003-8842","authenticated-orcid":false,"given":"Koshiro","family":"Sonomoto","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"},{"name":"Department of Clinical Nursing, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0383-1091","authenticated-orcid":false,"given":"Atsushi","family":"Nagayasu","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0266-2342","authenticated-orcid":false,"given":"Takafumi","family":"Aritomi","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ippei","family":"Miyagawa","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"},{"name":"Department of Molecular Targeted Therapeutics, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9693-9263","authenticated-orcid":false,"given":"Satoshi","family":"Kubo","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Todoroki","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"},{"name":"Department of Molecular Targeted Therapeutics, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6484-2360","authenticated-orcid":false,"given":"Yurie","family":"Satoh-Kanda","sequence":"additional","affiliation":[{"name":"The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 Japan, Kitakyushu, Japan"},{"name":"Department of Molecular Targeted Therapeutics, University of Occupational and Environmental Health Japan, Kitakyushu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"2026011611151466000_12.1.e006544.1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab609"},{"key":"2026011611151466000_12.1.e006544.2","doi-asserted-by":"crossref","DOI":"10.1186\/s41232-020-00133-8","article-title":"Rheumatoid arthritis","volume":"40","author":"Tanaka","year":"2020","journal-title":"Inflamm Regen"},{"key":"2026011611151466000_12.1.e006544.3","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217344"},{"key":"2026011611151466000_12.1.e006544.4","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-220973"},{"key":"2026011611151466000_12.1.e006544.5","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaa860"},{"key":"2026011611151466000_12.1.e006544.6","doi-asserted-by":"crossref","first-page":"5247","DOI":"10.1093\/rheumatology\/keab209","article-title":"Characteristics of patients with difficult-to-treat rheumatoid arthritis in clinical practice","volume":"60","author":"Takanashi","year":"2021","journal-title":"Rheumatology (Oxford)"},{"key":"2026011611151466000_12.1.e006544.7","doi-asserted-by":"crossref","first-page":"3866","DOI":"10.1093\/rheumatology\/kead143","article-title":"Characteristics of patients with difficult-to-treat rheumatoid arthritis in a French single-centre hospital","volume":"62","author":"Hecquet","year":"2023","journal-title":"Rheumatology (Oxford)"},{"key":"2026011611151466000_12.1.e006544.8","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1093\/rheumatology\/keac563","article-title":"Early characterization of difficult-to-treat rheumatoid arthritis by suboptimal initial management: a multicentre cohort study","volume":"62","author":"Giollo","year":"2023","journal-title":"Rheumatology (Oxford)"},{"key":"2026011611151466000_12.1.e006544.9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/25785826.2021.1928383","article-title":"Prevalence and predictive factors of difficult-to-treat rheumatoid arthritis: the KURAMA cohort","volume":"45","author":"Watanabe","year":"2022","journal-title":"Immunol Med"},{"key":"2026011611151466000_12.1.e006544.10","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-023-03165-w","article-title":"Unveiling difficult-to-treat rheumatoid arthritis: long-term impact of biologic or targeted synthetic DMARDs from the KOBIO registry","volume":"25","author":"Jung","year":"2023","journal-title":"Arthritis Res Ther"},{"key":"2026011611151466000_12.1.e006544.11","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2022-002842","article-title":"Difficult-to-treat rheumatoid arthritis (D2T RA): clinical issues at early stages of disease","volume":"9","author":"Leon","year":"2023","journal-title":"RMD Open"},{"key":"2026011611151466000_12.1.e006544.12","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1007\/s00296-022-05124-1","article-title":"Clinical characteristics and variants that predict prognosis of difficult-to-treat rheumatoid arthritis","volume":"42","author":"Yoshii","year":"2022","journal-title":"Rheumatol Int"},{"key":"2026011611151466000_12.1.e006544.13","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1007\/s00296-023-05349-8","article-title":"Difficult to treat rheumatoid arthritis in a comprehensive evaluation program: frequency according to different objective evaluations","volume":"43","author":"Garcia-Salinas","year":"2023","journal-title":"Rheumatol Int"},{"key":"2026011611151466000_12.1.e006544.14","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-022-02744-7","article-title":"Preferable outcome of Janus kinase inhibitors for a group of difficult-to-treat rheumatoid arthritis patients: from the FIRST Registry","volume":"24","author":"Ochi","year":"2022","journal-title":"Arthritis Res Ther"},{"key":"2026011611151466000_12.1.e006544.15","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2020-001512","article-title":"Pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis: a systematic literature review informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis","volume":"7","author":"Roodenrijs","year":"2021","journal-title":"RMD Open"},{"key":"2026011611151466000_12.1.e006544.16","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223356"},{"key":"2026011611151466000_12.1.e006544.17","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1093\/mr\/roae049","article-title":"Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis","volume":"34","author":"Nakayama","year":"2024","journal-title":"Mod Rheumatol"},{"key":"2026011611151466000_12.1.e006544.18","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1002\/acr.24596","article-title":"2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis","volume":"73","author":"Fraenkel","year":"2021","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"2026011611151466000_12.1.e006544.19","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s40744-025-00747-9","article-title":"Effective Second-Line b\/tsDMARDs for Patients with Rheumatoid Arthritis Unresponsive to First-Line b\/tsDMARDs from the FIRST Registry","volume":"12","author":"Kanda","year":"2025","journal-title":"Rheumatol Ther"},{"key":"2026011611151466000_12.1.e006544.20","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2024-004987","article-title":"Switching to biological DMARDs versus cycling among JAK inhibitors in patients with rheumatoid arthritis and with inadequate response to JAK inhibitors: from FIRST registry","volume":"11","author":"Miyazaki","year":"2025","journal-title":"RMD Open"},{"key":"2026011611151466000_12.1.e006544.21","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1093\/rheumatology\/keae598","article-title":"Predictors of the effectiveness of first-line CTLA4-Ig in patients with RA: the FIRST registry","volume":"64","author":"Kobayashi","year":"2025","journal-title":"Rheumatology (Sunnyvale)"},{"key":"2026011611151466000_12.1.e006544.22","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s13075-024-03369-8","article-title":"Predictors of functional improvement and pain reduction in rheumatoid arthritis patients who achieved low disease activity with disease-modifying antirheumatic drugs: a retrospective study of the FIRST Registry","volume":"26","author":"Ochi","year":"2024","journal-title":"Arthritis Res Ther"},{"key":"2026011611151466000_12.1.e006544.23","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1093\/rheumatology\/keae334","article-title":"Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST registry","volume":"64","author":"Miyazaki","year":"2025","journal-title":"Rheumatology (Oxford)"},{"key":"2026011611151466000_12.1.e006544.24","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s40744-024-00668-z","article-title":"A Machine Learning Approach for Prediction of CDAI Remission with TNF Inhibitors: A Concept of Precision Medicine from the FIRST Registry","volume":"11","author":"Sonomoto","year":"2024","journal-title":"Rheumatol Ther"},{"key":"2026011611151466000_12.1.e006544.25","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1093\/rheumatology\/kead579","article-title":"Biological\/targeted synthetic DMARDs do not arrest bone loss in patients with rheumatoid arthritis: a multicenter prospective observational study","volume":"63","author":"Sonomoto","year":"2024","journal-title":"Rheumatology (Oxford)"},{"key":"2026011611151466000_12.1.e006544.26","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1007\/s40744-023-00603-8","article-title":"Generation-Dependent Retention Rates and Reasons for Discontinuation of Molecular Targeted Therapies in Patients with Rheumatoid Arthritis: From FIRST Registry","volume":"10","author":"Kubo","year":"2023","journal-title":"Rheumatol Ther"},{"key":"2026011611151466000_12.1.e006544.27","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kead075"},{"key":"2026011611151466000_12.1.e006544.28","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2023-004049","article-title":"CT informs detection and treatment options in rheumatoid arthritis complicated by pulmonary non-tuberculous mycobacterial disease from the FIRST registry","volume":"10","author":"Funada","year":"2024","journal-title":"RMD Open"},{"key":"2026011611151466000_12.1.e006544.29","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1093\/rheumatology\/keab647","article-title":"Prophylaxis against pneumocystis pneumonia in rheumatoid arthritis patients treated with b\/tsDMARDs: insights from 3787 cases in the FIRST registry","volume":"61","author":"Sonomoto","year":"2022","journal-title":"Rheumatology (Oxford)"},{"key":"2026011611151466000_12.1.e006544.30","doi-asserted-by":"crossref","unstructured":"Paudel ML , Shadick N , Weinblatt M , et al . Development and External Validation of a Multivariable Predictive Model for Progression to Difficult\u2010to\u2010Treat Rheumatoid Arthritis in Biologic\u2010Experienced Patients. Arthritis Care Res (Hoboken) 2025. doi:10.1002\/acr.25654","DOI":"10.1002\/acr.25654"},{"key":"2026011611151466000_12.1.e006544.31","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1996.tb02080.x"},{"key":"2026011611151466000_12.1.e006544.32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-9868.2005.00503.x"},{"key":"2026011611151466000_12.1.e006544.33","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.l737","article-title":"Guide to presenting clinical prediction models for use in clinical settings","volume":"365","author":"Bonnett","year":"2019","journal-title":"BMJ"},{"key":"2026011611151466000_12.1.e006544.34","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-025-03645-1","article-title":"Evolution from early to difficult-to-treat rheumatoid arthritis: incidence and risk factors in the ERA uclouvain Brussels cohort","volume":"27","author":"Natalucci","year":"2025","journal-title":"Arthritis Res Ther"},{"key":"2026011611151466000_12.1.e006544.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2012.01.014"},{"key":"2026011611151466000_12.1.e006544.36","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kex012"},{"key":"2026011611151466000_12.1.e006544.37","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2024-226228"},{"key":"2026011611151466000_12.1.e006544.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-00541-7"},{"key":"2026011611151466000_12.1.e006544.39","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000002130"},{"key":"2026011611151466000_12.1.e006544.40","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-018-1614-z","article-title":"Patient-reported outcomes from a randomized phase III trial of sarilumab monotherapy versus adalimumab monotherapy in patients with rheumatoid arthritis","volume":"20","author":"Strand","year":"2018","journal-title":"Arthritis Res Ther"},{"key":"2026011611151466000_12.1.e006544.41","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/art.43014","article-title":"Effectiveness of JAK Inhibitors Compared With Biologic Disease-Modifying Antirheumatic Drugs on Pain Reduction in Rheumatoid Arthritis: Results From a Nationwide Swedish Cohort Study","volume":"77","author":"Eberhard","year":"2025","journal-title":"Arthritis Rheumatol"},{"key":"2026011611151466000_12.1.e006544.42","doi-asserted-by":"crossref","unstructured":"Xie W , Chen T , Xiao S , et al . Difficult-to-treat rheumatoid arthritis (part 1): systematic review and meta-analysis on global prevalence. Ann Rheum Dis 2025. doi:10.1016\/j.ard.2025.10.007","DOI":"10.1016\/j.ard.2025.10.007"},{"key":"2026011611151466000_12.1.e006544.43","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/key208"},{"key":"2026011611151466000_12.1.e006544.44","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2025-006271","article-title":"Strengths and limitations of the EULAR definition for difficult-to-treat rheumatoid arthritis","volume":"11","author":"Nagy","year":"2025","journal-title":"RMD Open"}],"container-title":["RMD Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/rmdopen-2025-006544","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T19:15:32Z","timestamp":1768590932000},"score":1,"resource":{"primary":{"URL":"https:\/\/rmdopen.bmj.com\/lookup\/doi\/10.1136\/rmdopen-2025-006544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,16]]},"published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1136\/rmdopen-2025-006544"],"URL":"https:\/\/doi.org\/10.1136\/rmdopen-2025-006544","relation":{},"ISSN":["2056-5933"],"issn-type":[{"value":"2056-5933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]}}}