{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T03:02:48Z","timestamp":1784516568047,"version":"3.55.0"},"reference-count":71,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background and Objectives: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which persistent synovial inflammation and joint damage are influenced not only by immune dysregulation but also by environmental, genetic, and epigenetic factors. Vitamin D is a secosteroid hormone and has emerged as a key immunomodulatory hormone, with reported effects on innate and adaptive immune responses, with potential relevance to RA clinical activity and treatment. This narrative review synthesizes mechanistic and clinical evidence enlightening vitamin D\u2019s immunomodulatory role in RA pathogenesis and management. Methods: A comprehensive literature search was carried out on PubMed and MEDLINE databases using Medical Subject Headings (MeSH) terms: \u201cVitamin D\u201d, \u201cCholecalciferol\u201d, \u201cArthritis, Rheumatoid\u201d, \u201cSeasons\u201d, \u201cEpigenomics\u201d, \u201cDNA Methylation\u201d, and \u201cTherapy\u201d. The narrative review highlights evidence published mainly in the last 5 years on the link between vitamin D and RA, focusing on epigenetic interactions, circannual rhythms, and therapeutic implications. Results: Emerging data suggest that vitamin D-related epigenetic mechanisms (e.g., DNA methylation, histone acetylation, and microRNA regulation) and genetic polymorphisms have been associated with disease susceptibility and treatment outcomes. Latitude and seasonal fluctuations in serum 25-hydroxyvitamin D levels correlate with variations in RA disease activity, although results remain heterogeneous across studies. Overall, the available evidence supports an association between vitamin D deficiency and greater RA disease activity, while its adequate supplementation has been associated with improvements in inflammatory markers and selected clinical outcomes, especially when tailored to baseline status and individual risk factors, such as limited dietary intake and sunlight exposure. Conclusions: Current evidence emphasizes the need for further studies using standardized methods and larger, geographically diverse cohorts to define how best to leverage seasonal vitamin D variations in RA management, considering also the range of concomitant epigenetic modifiers that may influence the effects of vitamin D on the management of RA patients.<\/jats:p>","DOI":"10.3390\/nu18142359","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T02:32:08Z","timestamp":1784514728000},"page":"2359","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Vitamin D on Epigenetics, Seasonality, and Management of Rheumatoid Arthritis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1395-3611","authenticated-orcid":false,"given":"Orlando","family":"Izzo","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4732-0306","authenticated-orcid":false,"given":"Emanuele","family":"Gotelli","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"AOM\u2014IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6970-0983","authenticated-orcid":false,"given":"Elvis","family":"Hysa","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Campitiello","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Paolino","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"AOM\u2014IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5125-0200","authenticated-orcid":false,"given":"Carmen","family":"Pizzorni","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"AOM\u2014IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Soldano","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3674-4880","authenticated-orcid":false,"given":"Alberto","family":"Sulli","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"AOM\u2014IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Ghent University Hospital, University of Ghent, 9000 Ghent, Belgium"},{"name":"Department of Internal Medicine, Ghent University Hospital, University of Ghent, 9000 Ghent, Belgium"},{"name":"Unit for Molecular Immunology and Inflammation, Flemish Institute for Biotechnology, Inflammation Research Center, 9052 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-0932","authenticated-orcid":false,"given":"Maurizio","family":"Cutolo","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Rheumatology, Division of Rheumatology, Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genova, 16132 Genova, Italy"},{"name":"AOM\u2014IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1001\/jama.2018.13103","article-title":"Diagnosis and Management of Rheumatoid Arthritis: A Review","volume":"320","author":"Aletaha","year":"2018","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid 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