Blood-based epigenetic biomarkers in rheumatoid arthritis: current knowledge and future perspectives.

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.