{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T06:33:14Z","timestamp":1768890794643,"version":"3.49.0"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T00:00:00Z","timestamp":1756339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00c3\u00a5det","doi-asserted-by":"publisher","award":["2019-01035"],"award-info":[{"award-number":["2019-01035"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007212","name":"V\u00c3\u00a4stra G\u00c3\u00b6talandsregionen","doi-asserted-by":"publisher","award":["ALF-GBG-717541"],"award-info":[{"award-number":["ALF-GBG-717541"]}],"id":[{"id":"10.13039\/100007212","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003849","name":"IngaBritt och Arne Lundbergs Forskningsstiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003849","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>To determine whether baseline CD4<jats:sup>+<\/jats:sup> T helper (Th) cell subset proportions in blood may serve as predictive biomarkers for achieving remission 48 weeks after initiating CTLA-4Ig, anti-tumor necrosis factor (TNF), or anti-interleukin 6 receptor (IL6R) treatment in patients with early rheumatoid arthritis (eRA).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This study included 60 untreated eRA patients from the larger randomized treatment trial NORD-STAR. They were treated with methotrexate (MTX) combined with either CTLA-4Ig (n\u2009=\u200917), anti-TNF (n\u2009=\u200922), or anti-IL6R (n\u2009=\u200921). Disease activity was assessed by clinical disease activity index (CDAI), C-reactive protein, and erythrocyte sedimentation rate. The primary outcome was remission (CDAI\u2009\u2264\u20092.8) at week 48, and the secondary outcomes were time to reach remission or sustained remission during the 48-week follow-up. CD4<jats:sup>+<\/jats:sup> T cell subset proportions were analyzed fresh by flow cytometry at baseline and at 24 and 48 weeks.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>In CTLA-4Ig\u2009+\u2009MTX-treated patients, baseline Th2 together with PD1<jats:sup>+<\/jats:sup> T follicular helper (TFh) cell proportions predicted CDAI remission at week 48 (AUC: 0.986, 95% CI 0.94\u20131.0). Survival analysis revealed that patients with Th2 proportions below 16.8% or PD1<jats:sup>+<\/jats:sup> TFh proportions above 7.6% at baseline were more likely to achieve remission (log-rank <jats:italic>p\u2009=\u2009<\/jats:italic>0.002 and <jats:italic>p\u2009=\u2009<\/jats:italic>0.007, respectively), and sustained remission (log-rank <jats:italic>p\u2009=\u2009<\/jats:italic>0.01 and p\u2009=\u20090.001, respectively), over the 48-week follow-up. CD4<jats:sup>+<\/jats:sup> T cell subset proportions did not predict remission in patients treated with anti-TNF\u2009+\u2009MTX or anti-IL6R\u2009+\u2009MTX. Only CTLA-4Ig treatment reduced PD1<jats:sup>+<\/jats:sup> TFh and PD1<jats:sup>neg<\/jats:sup> TFh fractions after 48 weeks.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Circulating Th2 and PD1<jats:sup>+<\/jats:sup> TFh cell proportions at baseline may serve as predictive biomarkers for achieving CDAI remission after 48 weeks of CTLA-4Ig treatment in eRA.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0330823","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T17:27:32Z","timestamp":1756402052000},"page":"e0330823","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Low Th2 and high PD1+ TFh cells in blood predict remission after CTLA-4Ig treatment for 48 weeks in early rheumatoid 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Dis"},{"issue":"3","key":"pone.0330823.ref022","first-page":"455","article-title":"Presence of anti-cyclic citrullinated peptide antibodies is associated with better treatment response to abatacept but not to TNF inhibitors in patients with rheumatoid arthritis: a meta-analysis","volume":"38","author":"E Alemao","year":"2020","journal-title":"Clin Exp Rheumatol"},{"issue":"11","key":"pone.0330823.ref023","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1136\/annrheumdis-2011-201109","article-title":"Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the \u201cOrencia and Rheumatoid Arthritis\u201d registry","volume":"71","author":"JE Gottenberg","year":"2012","journal-title":"Ann Rheum Dis"},{"issue":"12","key":"pone.0330823.ref024","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1136\/ard-2024-226024","article-title":"Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial","volume":"83","author":"K Lend","year":"2024","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"pone.0330823.ref025","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.4049\/jimmunol.181.3.1767","article-title":"IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4","volume":"181","author":"DT Avery","year":"2008","journal-title":"J Immunol"},{"issue":"1","key":"pone.0330823.ref026","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.immuni.2010.12.012","article-title":"Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion","volume":"34","author":"R 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cell origin","volume":"7","author":"K Raza","year":"2005","journal-title":"Arthritis Res Ther"},{"issue":"12","key":"pone.0330823.ref030","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1172\/JCI7739","article-title":"IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion","volume":"105","author":"E Lubberts","year":"2000","journal-title":"J Clin Invest"},{"key":"pone.0330823.ref031","doi-asserted-by":"crossref","first-page":"11596","DOI":"10.1038\/ncomms11596","article-title":"Th2 and eosinophil responses suppress inflammatory arthritis","volume":"7","author":"Z Chen","year":"2016","journal-title":"Nat Commun"},{"issue":"10","key":"pone.0330823.ref032","doi-asserted-by":"crossref","first-page":"2660","DOI":"10.1016\/j.jid.2022.03.013","article-title":"T Helper 2 IL-4\/IL-13 Dual Blockade with Dupilumab Is Linked to Some Emergent T Helper 17\u2012Type Diseases, Including Seronegative Arthritis and 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