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Epigenetic modifications such as DNA methylation (DNAm) have been described as potential mediators in gene-environment interactions, contributing to immune system dysregulation. Emerging evidence suggests that DNAm profiles also predict therapeutic responses in autoimmune diseases. This study aims to identify epigenetic biomarkers and epigenetic-driven gene expression changes associated with JIA clinical activity.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We reanalyzed a publicly available dataset of 44 JIA patients, with whole-genome DNAm and gene expression from CD4\u2009+\u2009T cells measured at two points: at anti-TNF therapy withdrawal (T<jats:sub>0<\/jats:sub>) and eight months later (T<jats:sub>end<\/jats:sub>). At T<jats:sub>end<\/jats:sub>, 30 patients maintained inactive disease (ID) while 14 did not (NO ID). We investigated differences between ID and NO ID patients in the epigenetic mutation load and various epigenetic clocks through linear regression models, and prioritized genomic regions with significantly higher number of epimutations in NO ID patients through machine learning.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>We found a higher mutation load in NO ID than ID patients, both at T<jats:sub>0<\/jats:sub> and at T<jats:sub>end<\/jats:sub>, with the differences at T<jats:sub>end<\/jats:sub> reaching statistical significance (<jats:italic>p<\/jats:italic>\u2009=\u20090.02). In contrast, we found no evidence of association between epigenetic clocks and JIA clinical activity. Using a multi-omic approach, we identified a List of candidate epigenetically-driven differentially expressed genes, 80 up-regulated and 77 down-regulated, in NO ID patients. Finally, comparing our candidate gene list with the Connectivity Map database, we identified new candidate potential therapeutic targets. Key findings were validated in independent datasets: DNAm profiles from CD4\u2009+\u2009T cells (56 JIA patients, 57 controls) and transcriptomic data from PBMCs of JIA patients with active or inactive disease, confirming dysregulation of pathways such as <jats:italic>TNF-\u03b1 signaling via NF-kB<\/jats:italic> and <jats:italic>TGF-\u03b2 signaling<\/jats:italic> among others.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We described a significant association of epigenetic mutations with JIA clinical activity, indicating that epigenetic changes might precede clinical symptoms and may serve as biomarkers for early disease monitoring. Further, our results shed light on biomolecular mechanisms of JIA, supporting the development of more effective treatments.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s10020-025-01348-6","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T12:42:05Z","timestamp":1758804125000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Stochastic epigenetic mutation profiles as biomarkers of clinical activity in juvenile idiopathic arthritis: a multi-omic machine learning approach for gene prioritization"],"prefix":"10.1186","volume":"31","author":[{"given":"Giacomo","family":"Cavalca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Vergani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Cangelosi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Consolaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Gattorno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Ravelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Munro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Novakovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Uva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Fiorito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,25]]},"reference":[{"key":"1348_CR1","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/s41590-018-0276-y","volume":"20","author":"D Aran","year":"2019","unstructured":"Aran D, Looney AP, Liu L, Wu E, Fong V, Hsu A, et al. 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