{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:02:09Z","timestamp":1791403329825,"version":"4.3.3"},"reference-count":237,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T00:00:00Z","timestamp":1771545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that leads to progressive joint destruction, extra-articular manifestations, disability, and increased mortality. Early detection, particularly in seronegative patients, remains challenging because current diagnostic criteria based on joint involvement, serology, and acute-phase reactants may fail to identify disease at its earliest stages. Epigenetic mechanisms, including DNA and RNA methylation, histone modifications, and non-coding RNAs (ncRNAs), provide a dynamic interface between genetic predisposition and environmental triggers in RA pathogenesis. Peripheral blood (plasma, serum, and cellular fractions) is an accessible, minimally invasive source for monitoring systemic molecular alterations over time. To capture the latest evidence, we performed a structured literature search using curated keywords covering RA, epigenetic mechanisms, DNA and RNA methylation, m6A, histone modifications, miRNAs, lncRNAs, circRNAs, and blood-based fractions (peripheral blood mononuclear cells (PBMCs), plasma, serum, whole blood). Emerging data indicate that blood-based epigenetic signatures not only reflect disease activity but also hold promise as prognostic biomarkers, predictors of treatment response, and tools for personalized therapeutic strategies. In this review, we synthesize current knowledge on blood-based epigenetic alterations in RA, focusing on DNA methylation, histone modifications, and multiple classes of ncRNAs, including less widely studied species such as piRNAs, snoRNAs, Y-RNAs, snRNAs, and tRNA-derived fragments, with an emphasis on studies published between 2020 and 2025. We highlight the translational potential of multilayered epigenetic signatures as innovative diagnostic and prognostic tools that could advance early detection and guide precision-medicine approaches in RA.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1753808","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:40:55Z","timestamp":1771569655000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Blood-based epigenetic biomarkers in rheumatoid arthritis: current knowledge and future perspectives"],"prefix":"10.3389","volume":"17","author":[{"given":"Agnieszka","family":"Mo\u0142o\u0144","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Kubis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"\u017burawska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Cie\u015bla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965","article-title":"The pathogenesis of rheumatoid arthritis","volume":"365","author":"McInnes","year":"2011","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01525-8","article-title":"Rheumatoid arthritis","volume":"402","author":"Di Matteo","year":"2023","journal-title":"Lancet Lond Engl"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nature01661","article-title":"Evolving concepts of rheumatoid arthritis","volume":"423","author":"Firestein","year":"2003","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00648.x","article-title":"The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis","volume":"223","author":"Noss","year":"2008","journal-title":"Immunol Rev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60008-8","article-title":"Rheumatoid arthritis","volume":"373","author":"Klareskog","year":"2009","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584","article-title":"2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology\/European League Against Rheumatism collaborative initiative","volume":"62","author":"Aletaha","year":"2010","journal-title":"Arthritis Rheum"},{"key":"B8","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1002\/art.30100","article-title":"Classification of rheumatoid arthritis: Comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology\/European League Against Rheumatism criteria","volume":"63","author":"van der Linden","year":"2011","journal-title":"Arthritis Rheum"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.143560","article-title":"Performance of the 2010 ACR\/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort","volume":"70","author":"Cader","year":"2011","journal-title":"Ann Rheum Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/art.33348","article-title":"The clinical picture of rheumatoid arthritis according to the 2010 American College of Rheumatology\/European League Against Rheumatism criteria: Is this still the same disease","volume":"64","author":"de Hair","year":"2012","journal-title":"Arthritis Rheum"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.140741","article-title":"Genetic factors for the severity of ACPA-negative rheumatoid arthritis in 2 cohorts of early disease: A genome-wide study","volume":"42","author":"de Rooy","year":"2015","journal-title":"J Rheumatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-203130","article-title":"What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? 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