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Persistent DNA damage in tissues is known to drive a senescent microenvironment, genomic instability and ultimately chronic inflammation. Here, we determined cellular DNA damage and repair capacity within synovial tissue from rheumatoid arthritis (RA) patients and individuals at risk of developing RA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the presence of senescence-associated DNA damage in synovial biopsies and synovial fibroblasts obtained during different phases of RA. Histone 2A is phosphorylated (\u03b3H2AX) at the site of a double-stranded DNA break where DNA repair proteins are recruited and is therefore a proxy measurement for DNA damage. In this study, we employed immunofluorescence staining for \u03b3H2AX on synovial tissue sections and cultured synovial fibroblasts alongside quantitative PCR for a panel of DNA repair proteins.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrated the presence of DNA damage in both synovial fibroblasts and T cells during the preclinical, RA-risk phase of disease. Furthermore, cultured synovial fibroblasts from RA-risk individuals and RA patients exhibited increased DNA damage and a reduced capacity for DNA repair compared with synovial fibroblasts from control individuals. Finally, treatment with senolytic drugs partially restored the DNA damage repair capacity in RA and RA-risk synovial fibroblasts in vitro.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings reveal persistent DNA damage in the preclinical phase of RA in both synovial tissue and fibroblasts, suggesting a role in disease progression. The partial restoration of DNA repair in synovial fibroblasts by senolytic treatment highlights its potential therapeutic target for preventative therapy in RA-risk individuals.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/rmdopen-2025-005774","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T11:35:17Z","timestamp":1769081717000},"page":"e005774","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["RA-risk synovium exhibits DNA damage coupled with impaired DNA repair in fibroblasts"],"prefix":"10.1136","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-2501","authenticated-orcid":false,"given":"Aoife M","family":"O\u2019Byrne","sequence":"first","affiliation":[{"name":"Department of Rheumatology & Clinical Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"},{"name":"Laboratory for Experimental Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tineke A","family":"de Jong","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna F","family":"Semmelink","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemek M","family":"Krawczyk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron A","family":"Hoebe","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-878X","authenticated-orcid":false,"given":"Marleen","family":"van de Sande","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University of Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3346-8921","authenticated-orcid":false,"given":"Lisa","family":"van Baarsen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology & Clinical Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"},{"name":"Laboratory for Experimental Immunology, Amsterdam UMC Locatie AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"2026012203351047000_12.1.e005774.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1004965"},{"key":"2026012203351047000_12.1.e005774.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.02.006"},{"key":"2026012203351047000_12.1.e005774.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.11.009"},{"key":"2026012203351047000_12.1.e005774.4","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.105759"},{"key":"2026012203351047000_12.1.e005774.5","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202254"},{"key":"2026012203351047000_12.1.e005774.6","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.132662"},{"key":"2026012203351047000_12.1.e005774.7","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213678"},{"key":"2026012203351047000_12.1.e005774.8","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature12873","article-title":"Genetics of rheumatoid arthritis contributes to biology and drug discovery","volume":"506","author":"Okada","year":"2014","journal-title":"Nature New Biol"},{"key":"2026012203351047000_12.1.e005774.9","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1076"},{"key":"2026012203351047000_12.1.e005774.10","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214539"},{"key":"2026012203351047000_12.1.e005774.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06708-y"},{"key":"2026012203351047000_12.1.e005774.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0939-8"},{"key":"2026012203351047000_12.1.e005774.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0378-1"},{"key":"2026012203351047000_12.1.e005774.14","doi-asserted-by":"crossref","unstructured":"Mizoguchi F , Slowikowski K , Marshall JL , et al . 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