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Clinically, the period before RA onset can be divided into an asymptomatic and a symptomatic risk phase. Published visual representations of RA development often display the maturation of the autoimmune response occurring in the symptomatic risk phase or relatively short before RA development, but evidence underlying this notion is limited. To obtain more detailed insights into the time sequence of immune processes in the asymptomatic and symptomatic risk stages of RA development, we interpreted the current available literature against the level of evidence, as longitudinal studies with repeated measurements in patients are needed for a robust conclusion on temporal sequences. Regarding the development of ACPA-positive disease, maturation of the systemic autoimmune response seems to occur approximately 5-years before diagnosis, but the autoimmune response is stable during the symptomatic risk phase and progression to RA. Known genetic and environmental factors have a different effect in both risk phases. Less is known about the development of ACPA-negative RA, the symptomatic risk phase lasts longer than for ACPA-positive RA, but here too the maturation of the autoimmunity seems to take place mainly in the asymptomatic phase. Based on this, we have proposed a new picture of RA development. This knowledge can guide the choice of treatment targets in future trials aimed at preventing RA.<\/jats:p>","DOI":"10.1136\/rmdopen-2024-005377","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T04:10:20Z","timestamp":1746677420000},"page":"e005377","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Time sequence of autoimmune processes in the trajectory to rheumatoid arthritis development: what do we know?"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2126-7922","authenticated-orcid":false,"given":"Judith W","family":"Heutz","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9618-6414","authenticated-orcid":false,"given":"Ren\u00e9 E M","family":"Toes","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8572-1437","authenticated-orcid":false,"given":"Annette H M","family":"van der Helm-van Mil","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands"},{"name":"Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"key":"2025090312345559000_11.2.e005377.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-023-01035-y"},{"key":"2025090312345559000_11.2.e005377.2","doi-asserted-by":"crossref","first-page":"e214","DOI":"10.1016\/S2665-9913(20)30445-8","article-title":"The autoimmune response as a potential target for tolerance induction before the development of rheumatoid arthritis","volume":"3","author":"Toes","year":"2021","journal-title":"Lancet Rheumatol"},{"key":"2025090312345559000_11.2.e005377.3","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nrrheum.2018.10","article-title":"The B cell response to citrullinated antigens in the development of rheumatoid arthritis","volume":"14","author":"Scherer","year":"2018","journal-title":"Nat Rev Rheumatol"},{"key":"2025090312345559000_11.2.e005377.4","article-title":"Regulatory CD4+ T-Cell Subsets and Anti-Citrullinated Protein Antibody Repertoire","volume":"11","author":"Janssen","year":"2016","journal-title":"Potential Biomarkers for Arthritis Development in Seropositive Arthralgia Patients? 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