{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T07:38:49Z","timestamp":1768635529244,"version":"3.49.0"},"reference-count":35,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2016,10,27]],"date-time":"2016-10-27T00:00:00Z","timestamp":1477526400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"crossref","award":["20385"],"award-info":[{"award-number":["20385"]}],"id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIHR (the Manchester Musculoskeletal Biomedical Research Unit and the Cambridge Biomedical Research Centre)"},{"name":"Wellcome Trust Intermediate Clinical Fellowship","award":["105920\/Z\/14\/Z"],"award-info":[{"award-number":["105920\/Z\/14\/Z"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Genetic variation in <jats:italic>FOXO3<\/jats:italic> (tagged by rs12212067) has been associated with a milder course of rheumatoid arthritis (RA) and shown to limit monocyte\u2010driven inflammation through a transforming growth factor \u03b21\u2013dependent pathway. This genetic association, however, has not been consistently observed in other RA cohorts. We sought to clarify the contribution of <jats:italic>FOXO3<\/jats:italic> to prognosis in RA by combining detailed analysis of nonradiographic disease severity measures with an in vivo model of arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Collagen\u2010induced arthritis, the most commonly used mouse model of RA, was used to assess how <jats:italic>Foxo3<\/jats:italic> contributes to arthritis severity. Using clinical, serologic, and biochemical methods, the arthritis that developed in mice carrying a loss\u2010of\u2010function mutation in <jats:italic>Foxo3<\/jats:italic> was compared with that which occurred in littermate controls. The association of rs12212067 with nonradiographic measures of RA severity, including the C\u2010reactive protein level, the swollen joint count, the tender joint count, the Disease Activity Score in 28 joints, and the Health Assessment Questionnaire score, were modeled longitudinally in a large prospective cohort of patients with early RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Loss of <jats:italic>Foxo3<\/jats:italic> function resulted in more severe arthritis in vivo (both clinically and histologically) and was associated with higher titers of anticollagen antibodies and interleukin\u20106 in the blood. Similarly, rs12212067 (a single\u2010nucleotide polymorphism that increases <jats:italic>FOXO3<\/jats:italic> transcription) was associated with reduced inflammation, both biochemically and clinically, and with lower RA activity scores.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Consistent with its known role in restraining inflammatory responses, <jats:italic>FOXO3<\/jats:italic> limits the severity of in vivo arthritis and, through genetic variation that increases its transcription, is associated with reduced inflammation and disease activity in RA patients, effects that result in less radiographic damage.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39760","type":"journal-article","created":{"date-parts":[[2016,5,24]],"date-time":"2016-05-24T06:48:21Z","timestamp":1464072501000},"page":"2629-2636","source":"Crossref","is-referenced-by-count":31,"title":["Association Between Genetic Variation in <i>FOXO3<\/i> and Reductions in Inflammation and Disease Activity in Inflammatory Polyarthritis"],"prefix":"10.1002","volume":"68","author":[{"given":"Sebastien","family":"Viatte","sequence":"first","affiliation":[{"name":"University of Manchester Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James C.","family":"Lee","sequence":"additional","affiliation":[{"name":"University of Cambridge School of Clinical Medicine Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Fu","sequence":"additional","affiliation":[{"name":"University of Manchester, Manchester, UK, and University College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marion","family":"Esp\u00e9li","sequence":"additional","affiliation":[{"name":"UMR 996, Inflammation, Chemokines, and Immunopathology, INSERM, Universit\u00e9 Paris\u2010Sud, Universit\u00e9 Paris\u2010Saclay Clamart France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Lunt","sequence":"additional","affiliation":[{"name":"University of Manchester Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack N. 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