{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:07:09Z","timestamp":1792598829189,"version":"4.5.0"},"reference-count":100,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Rheumatoid arthritis (RA) has traditionally been managed after the onset of clinically apparent synovitis; however, accumulating evidence indicates that disease-related immune abnormalities precede clinical diagnosis by several years. This preclinical phase is characterized by systemic autoimmunity, early musculoskeletal symptoms, and subclinical inflammation in genetically and environmentally susceptible individuals. In this review, we summarize current concepts regarding the pathogenesis, risk stratification, and therapeutic interception of preclinical RA. Particular attention is given to the mucosal origin hypothesis and to the roles of immunosenescence, peripheral helper T cells, and fibroblast-like synoviocytes in early disease evolution. Recent advances in clinical, serological, and imaging-based risk stratification have improved the identification of individuals at high risk of progression to clinical RA, and emerging intervention trials have shown that selected therapies may delay disease onset or reduce early inflammatory burden. Although complete prevention of RA has not yet been achieved, these findings support a paradigm shift from the treatment of established RA toward earlier, risk-adapted intervention before irreversible joint damage occurs. Future efforts should focus on refining predictive biomarkers, optimizing the timing and intensity of intervention, and establishing safe, individualized preventive strategies.<\/jats:p>","DOI":"10.3390\/jcm15093283","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T09:55:39Z","timestamp":1777370139000},"page":"3283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Preclinical Rheumatoid Arthritis: Pathogenesis, Risk Stratification, and Therapeutic Interception"],"prefix":"10.3390","volume":"15","author":[{"given":"Yukina Mizuno","family":"Yokoyama","sequence":"first","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"},{"name":"Department of Rheumatology, Daido Hospital, Nagoya 457-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1089-5296","authenticated-orcid":false,"given":"Ryu","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8992-1805","authenticated-orcid":false,"given":"Mayu","family":"Shiomi","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuhei","family":"Ishihara","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Katsushima","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-5816","authenticated-orcid":false,"given":"Kazuo","family":"Fukumoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichiro","family":"Haji","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Daido Hospital, Nagoya 457-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinsuke","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motomu","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Osaka Metropolitan University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Smolen, J.S., Edwards, C.J., Konzett, V., Laskou, F., Aletaha, D., Caporali, R., Dorner, T., Hyrich, K.L., Mateus, E., and Pope, J.E. 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