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Bead\u2010based multiplex flow immunoassay detected IgG autoantibodies against joint\u2010related peptides relevant in arthritis models. Principal component analysis was used to identify subgroups and univariable regression analyses to characterize the performance of autoantibodies with significance for patients with RA negative for anti\u2013cyclic citrullinated peptide (anti\u2010CCP) and rheumatoid factor (RF), that is, the seronegative RA diagnosis (SeNe) test. Multivariable logistic regression identified autoantibodies with the strongest discriminative power between cases and controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Autoantibody profiles revealed three distinct presymptomatic subgroups, suggesting early immune heterogeneity. The SeNe test was associated with symptom onset within 2.5 years in 13% of anti\u2010CCP and RF\u2010negative individuals. Specificity for RA versus OA was 97% (95% confidence interval, 95%\u201399%). An improved version (SeNe 2.0) identified 16% of anti\u2010CCP and RF\u2010negative presymptomatic individuals with 98% specificity versus population controls. Two of five SeNe 2.0 autoantibodies were associated with the presymptomatic state in the multivariable model, including RF and anti\u2010CCP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These novel biomarkers can identify presymptomatic, seronegative individuals at high risk of RA onset and support their recruitment into trials for personalized prevention. Additionally, they distinguish early seronegative RA from OA with high specificity.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70184-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70184","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:31:47Z","timestamp":1776421907000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Autoantibodies to Joint\u2010Related Peptides Are Associated With Onset of Rheumatoid Arthritis in Presymptomatic Seronegative Individuals"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5644-8216","authenticated-orcid":false,"given":"Outi","family":"Sareila","sequence":"first","affiliation":[{"name":"Medical Inflammation Research, Department of Medical Biochemistry and Biophysics Karolinska Institutet  Stockholm Sweden"},{"name":"Medical Inflammation Research, Department of Medical Biochemistry and Microbiology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7071-4699","authenticated-orcid":false,"given":"Linda","family":"Johansson","sequence":"additional","affiliation":[{"name":"Public Health and Clinical Medicine, Rheumatology Ume\u00e5 University  Ume\u00e5 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