{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:43:00Z","timestamp":1790628180792,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:00:00Z","timestamp":1590710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000194","name":"Nova Scotia Health Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000194","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009415","name":"IWK Health Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009415","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000032","name":"Institute of Infection and Immunity","doi-asserted-by":"publisher","award":["THC 135230"],"award-info":[{"award-number":["THC 135230"]}],"id":[{"id":"10.13039\/501100000032","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2020,7]]},"abstract":"\n Objective<\/jats:title>\n \n Rheumatoid arthritis (\n RA<\/jats:styled-content>\n ) is a chronic inflammatory disease mediated through complex immunologic pathways. Among\n RA<\/jats:styled-content>\n patients receiving low\u2010dose methotrexate (\n MTX<\/jats:styled-content>\n ) monotherapy, approximately one\u2010half exhibit a meaningful clinical response within the first 6 months of starting treatment. Whether baseline immune phenotypes differ between subsequent\n MTX<\/jats:styled-content>\n responders and nonresponders is unknown. This study utilized comprehensive T cell immunophenotyping to identify specific immunologic pathways associated with\n MTX<\/jats:styled-content>\n \u2010nonresponsive joint inflammation in patients with\n RA<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In total, 32 patients with recent\u2010onset\n RA<\/jats:styled-content>\n were treated with\n MTX<\/jats:styled-content>\n therapy. After 6 months, 15 patients were categorized as responders and 17 as nonresponders. Comprehensive blood T cell immunophenotyping, using multiparameter immunofluorescence flow cytometry analyses, was performed at baseline and following 6 months of treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Baseline measures of disease activity (Disease Activity Score in 28 joints [\n DAS<\/jats:styled-content>\n 28], C\u2010reactive protein level, and erythrocyte sedimentation rate) did not differ between\n MTX<\/jats:styled-content>\n responders and nonresponders following\n MTX<\/jats:styled-content>\n treatment. Frequencies of\n CD<\/jats:styled-content>\n 4+ and\n CD<\/jats:styled-content>\n 8+ T cells were skewed to favor higher\n CD<\/jats:styled-content>\n 4:\n CD<\/jats:styled-content>\n 8 T cell ratios in\n MTX<\/jats:styled-content>\n responders compared to nonresponders (\n P<\/jats:italic>\n < 0.05). The proportion of inducible costimulator\u2013expressing Treg cells was significantly greater among\n MTX<\/jats:styled-content>\n nonresponders. Interleukin\u201013 (\n IL<\/jats:styled-content>\n \u201013)\u2013producing, but not interferon\u2010\u03b3\u2013 or\n IL<\/jats:styled-content>\n \u201017\u2013producing,\n CD<\/jats:styled-content>\n 4+ effector memory T (Tem) cells were significantly more frequent in\n MTX<\/jats:styled-content>\n nonresponders (\n P<\/jats:italic>\n < 0.05). The ratio of\n IL<\/jats:styled-content>\n \u201013+:\n IL<\/jats:styled-content>\n \u201017+ Tem cells among\n CD<\/jats:styled-content>\n 4+ Tem cells was 1.9\u2010fold higher in\n MTX<\/jats:styled-content>\n nonresponders compared to responders (\n P<\/jats:italic>\n < 0.05). Both the\n CD<\/jats:styled-content>\n 4:\n CD<\/jats:styled-content>\n 8 T cell ratio and the frequency of\n IL<\/jats:styled-content>\n \u201013+\n CD<\/jats:styled-content>\n 4+ Tem cells correlated with changes in the\n DAS<\/jats:styled-content>\n 28 score following\n MTX<\/jats:styled-content>\n treatment, whereas T cell expression of immune checkpoint inhibitor markers (\n CTLA<\/jats:styled-content>\n \u20104, programmed death 1, and T cell immunoglobulin and mucin domain\u2013containing protein 3) did not differ between\n MTX<\/jats:styled-content>\n responders and nonresponders.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We observed a bias toward type 2\u2013polarized T cell inflammatory responses in the peripheral blood of\n MTX<\/jats:styled-content>\n \u2010nonresponsive\n RA<\/jats:styled-content>\n patients. Targeting the\n IL<\/jats:styled-content>\n \u201013+\n CD<\/jats:styled-content>\n 4+ T cell pathway could be a new therapeutic strategy in\n RA<\/jats:styled-content>\n patients whose disease remains resistant to\n MTX<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.41223","type":"journal-article","created":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T07:29:19Z","timestamp":1581319759000},"page":"1091-1102","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Association of a Type 2\u2013Polarized T Cell Phenotype With Methotrexate Nonresponse in Patients With Rheumatoid Arthritis"],"prefix":"10.1002","volume":"72","author":[{"given":"Drew","family":"Slauenwhite","sequence":"first","affiliation":[{"name":"IWK Health Centre and Dalhousie University Halifax Nova Scotia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah 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