{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,12]],"date-time":"2026-11-12T18:13:03Z","timestamp":1794507183675,"version":"4.9.1"},"reference-count":31,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"unspecified","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N026977\/1"],"award-info":[{"award-number":["MR\/N026977\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,3,21]]},"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Huge advances in rheumatoid arthritis (RA) treatment mean an increasing number of patients now achieve disease remission. However, long-term treatments can carry side effects and associated financial costs. In addition, some patients still experience painful and debilitating disease flares, the mechanisms of which are poorly understood. High rates of flare and a lack of effective prediction tools can limit attempts at treatment withdrawal. The BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (BIO-FLARE) experimental medicine study was designed to study flare and remission immunobiology. Here, we present the clinical outcomes and predictors of drug-free remission and flare, and develop a prediction model to estimate flare risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design, setting and participants<\/jats:title>\n                    <jats:p>BIO-FLARE was a multicentre, prospective, single-arm, open-label experimental medicine study conducted across seven National Health Service Trusts in the UK. Participants had established RA in clinical remission (disease activity score in 28 joints with C reactive protein (DAS28-CRP)&lt;2.4) and were receiving methotrexate, sulfasalazine or hydroxychloroquine (monotherapy or combination).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>The intervention was disease-modifying anti-rheumatic drug cessation, followed by observation for 24 weeks or until flare, with clinical and immune monitoring.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Outcome measures<\/jats:title>\n                    <jats:p>The primary outcome measure was the proportion of participants experiencing a confirmed flare, defined as DAS28-CRP\u22653.2 or DAS28-CRP\u22652.4 twice within 2 weeks, and time to flare. Exploratory predictive modelling was also performed using multivariable Cox regression to understand risk factors for flare.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>121 participants were recruited between September 2018 and December 2020. Flare rate by week 24 was 52.3% (95% CI 43.0 to 61.7), with a median (IQR) time to flare of 63 (41\u201396) days. Female sex, baseline methotrexate use, anti-citrullinated peptide antibody level and rheumatoid factor level were associated with flare. An exploratory prediction model incorporating these variables allowed estimation of flare risk, with acceptable classification (C index 0.709) and good calibration performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The rate of flare was approximately 50%. Several baseline clinical parameters were associated with flare. The BIO-FLARE study design provides a robust experimental medicine model for studying flare and remission immunobiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>ISRCTN registry 16371380<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-092478","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T05:09:18Z","timestamp":1744261758000},"page":"e092478","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Clinical predictors of flare and drug-free remission in rheumatoid arthritis: preliminary results from the prospective BIO-FLARE experimental medicine study"],"prefix":"10.1136","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4302-0899","authenticated-orcid":false,"given":"Fiona","family":"Rayner","sequence":"first","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"},{"name":"Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1699-4348","authenticated-orcid":false,"given":"Shaun","family":"Hiu","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK"},{"name":"Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Melville","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2387-4918","authenticated-orcid":false,"given":"Theophile","family":"Bigirumurame","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Anderson","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Dyke","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, NIHR Birmingham Biomedical Research Centre, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Kerrigan","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"McGucken","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Prichard","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohadeseh Shojaei","family":"Shahrokhabadi","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharien M U","family":"Hilkens","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D","family":"Buckley","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, NIHR Birmingham Biomedical Research Centre, Birmingham, UK"},{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain B","family":"McInnes","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Fai","family":"Ng","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"},{"name":"Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Goodyear","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Teare","sequence":"additional","affiliation":[{"name":"Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Filer","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, NIHR Birmingham Biomedical Research Centre, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1802-7311","authenticated-orcid":false,"given":"Stefan","family":"Siebert","sequence":"additional","affiliation":[{"name":"Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK"},{"name":"NHS Greater Glasgow and Clyde, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Raza","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, NIHR Birmingham Biomedical Research Centre, Birmingham, UK"},{"name":"Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur","family":"Pratt","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"},{"name":"Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth F","family":"Baker","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"},{"name":"Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Isaacs","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK"},{"name":"Musculoskeletal Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"2025081404165217000_15.4.e092478.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965"},{"key":"2025081404165217000_15.4.e092478.2","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.semarthrit.2020.02.011","article-title":"The impact of a disease flare during tapering of DMARDs on the lives of rheumatoid arthritis patients","volume":"50","author":"van Mulligen","year":"2020","journal-title":"Semin Arthritis Rheum"},{"key":"2025081404165217000_15.4.e092478.3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1093\/rheumatology\/kez224","article-title":"Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis","volume":"59","author":"Smolen","year":"2020","journal-title":"Rheumatology (Oxford)"},{"key":"2025081404165217000_15.4.e092478.4","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206411"},{"key":"2025081404165217000_15.4.e092478.5","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223356"},{"key":"2025081404165217000_15.4.e092478.6","doi-asserted-by":"crossref","DOI":"10.1016\/j.jaut.2019.06.009","article-title":"Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study","volume":"105","author":"Baker","year":"2019","journal-title":"J Autoimmun"},{"key":"2025081404165217000_15.4.e092478.7","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204016"},{"key":"2025081404165217000_15.4.e092478.8","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-212423"},{"key":"2025081404165217000_15.4.e092478.9","doi-asserted-by":"crossref","DOI":"10.1186\/s41927-021-00194-3","article-title":"BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study","volume":"5","author":"Rayner","year":"2021","journal-title":"BMC Rheumatol"},{"key":"2025081404165217000_15.4.e092478.10","doi-asserted-by":"crossref","DOI":"10.1186\/s12916-014-0241-z","article-title":"Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD Statement","volume":"13","author":"Collins","year":"2015","journal-title":"BMC Med"},{"key":"2025081404165217000_15.4.e092478.11","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204920"},{"key":"2025081404165217000_15.4.e092478.12","first-page":"vi16","article-title":"The new ACR\/EULAR remission criteria: rationale for developing new criteria for remission","volume":"51 Suppl 6","author":"Bykerk","year":"2012","journal-title":"Rheumatology (Oxford)"},{"key":"2025081404165217000_15.4.e092478.13","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v045.i05"},{"key":"2025081404165217000_15.4.e092478.14","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0258(19960229)15:4<361::AID-SIM168>3.0.CO;2-4"},{"key":"2025081404165217000_15.4.e092478.15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jclinepi.2019.09.016","article-title":"Validation of clinical prediction models: what does the \u201ccalibration slope\u201d really measure?","volume":"118","author":"Stevens","year":"2020","journal-title":"J Clin Epidemiol"},{"key":"2025081404165217000_15.4.e092478.16","doi-asserted-by":"publisher","DOI":"10.1177\/0962280213497434"},{"key":"2025081404165217000_15.4.e092478.17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/art.42347","article-title":"American College of Rheumatology\/EULAR Remission Criteria for Rheumatoid Arthritis: 2022 Revision","volume":"75","author":"Studenic","year":"2023","journal-title":"Arthritis Rheumatol"},{"key":"2025081404165217000_15.4.e092478.18","doi-asserted-by":"crossref","DOI":"10.1136\/rmdopen-2020-001220","article-title":"DMARD-free remission as novel treatment target in rheumatoid arthritis: A systematic literature review of achievability and sustainability","volume":"6","author":"Verstappen","year":"2020","journal-title":"RMD Open"},{"key":"2025081404165217000_15.4.e092478.19","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1111\/1756-185X.13888","article-title":"Six-month flare risk after discontinuing long-term methotrexate treatment in patients having rheumatoid arthritis with low disease activity","volume":"23","author":"Lee","year":"2020","journal-title":"Int J Rheum Dis"},{"key":"2025081404165217000_15.4.e092478.20","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.141520"},{"key":"2025081404165217000_15.4.e092478.21","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.068247"},{"key":"2025081404165217000_15.4.e092478.22","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208138"},{"key":"2025081404165217000_15.4.e092478.23","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1093\/rheumatology\/kex340","article-title":"The risk of individual autoantibodies, autoantibody combinations and levels for arthritis development in clinically suspect arthralgia","volume":"56","author":"Ten Brinck","year":"2017","journal-title":"Rheumatology (Oxford)"},{"key":"2025081404165217000_15.4.e092478.24","doi-asserted-by":"publisher","DOI":"10.1002\/art.22380"},{"key":"2025081404165217000_15.4.e092478.25","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-206047"},{"key":"2025081404165217000_15.4.e092478.26","doi-asserted-by":"publisher","DOI":"10.1002\/art.27692"},{"key":"2025081404165217000_15.4.e092478.27","doi-asserted-by":"crossref","DOI":"10.1136\/bmjopen-2019-031467","article-title":"Relapse in rheumatoid arthritis patients undergoing dose reduction and withdrawal of biologics: are predictable factors more relevant than predictive parameters? An observational prospective real-life study","volume":"9","author":"Vittecoq","year":"2019","journal-title":"BMJ Open"},{"key":"2025081404165217000_15.4.e092478.28","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keab107"},{"key":"2025081404165217000_15.4.e092478.29","doi-asserted-by":"crossref","DOI":"10.1186\/s13075-021-02599-4","article-title":"Treatment patterns in rheumatoid arthritis patients newly initiated on biologic and conventional synthetic disease-modifying antirheumatic drug therapy and enrolled in a North American clinical registry","volume":"23","author":"Mease","year":"2021","journal-title":"Arthritis Res Ther"},{"key":"2025081404165217000_15.4.e092478.30","doi-asserted-by":"publisher","DOI":"10.1002\/art.30634"},{"key":"2025081404165217000_15.4.e092478.31","doi-asserted-by":"crossref","first-page":"e767","DOI":"10.1016\/S2665-9913(21)00220-4","article-title":"Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial","volume":"3","author":"Tascilar","year":"2021","journal-title":"Lancet Rheumatol"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2024-092478","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T14:28:03Z","timestamp":1755181683000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2024-092478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,4,9]]},"published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1136\/bmjopen-2024-092478"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2024-092478","relation":{"has-part":[{"id-type":"doi","id":"https:\/\/doi.org\/10.1136\/bmjopen-2024-092478.supp1","asserted-by":"subject"}]},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]}}}