Integrated multi‑omics defines immune programmes underlying progression to rheumatoid arthritis in anti-citrullinated protein antibody positive individuals with arthralgia and palindromic rheumatism

Integrated multi‑omics defines immune programmes underlying progression to rheumatoid arthritis in anti-citrullinated protein antibody positive individuals with arthralgia and palindromic rheumatism. | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Integrated multi‑omics defines immune programmes underlying progression to rheumatoid arthritis in anti-citrullinated protein antibody positive individuals with arthralgia and palindromic rheumatism. Leon Chang, Fareeha Tariq, Amreen Azeem, Daniel Clayton, Kierran Flack, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9108192/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Rheumatoid arthritis (RA) develops through a prolonged preclinical phase in which systemic immune dysregulation precedes joint inflammation. To clarify the molecular programmes driving divergent outcomes in anti-citrullinated protein antibody (ACPA) positive individuals, we performed integrated multi‑omics profiling of 192 ACPA+ at‑risk individuals, including those with arthralgia and palindromic rheumatism (PR). Analyses across genomic, transcriptomic, proteomic, and functional modalities revealed broad innate‑immune activation relative to healthy controls. Genetic risk factors, including shared epitope alleles and rare germline variants in inflammation‑related pathways, distinguished future progressors from non‑progressors, while clonal haematopoiesis contributed to a latent factor associated with progression. Multi‑omics factor analysis identified an innate‑dominant immune programme associated with delayed progression, with adaptive‑immune interactions accelerating the transition to RA. Distinct interferon‑enriched and cytokine‑driven latent factors characterised PR, indicating unique immune programmes associated with this episodic phenotype, even when measured between flares. These findings define coordinated immune programmes in ACPA+ individuals with arthralgia and PR that precede the development of clinical RA, providing a framework for biomarker development and targeted RA prevention strategies. Health sciences/Diseases/Immunological disorders Health sciences/Diseases Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SuppFigS1.png Supplementary Figure 1 SuppFigS2.png Supplementary Figure 2 SuppTableS1BaselineDemographicsSummary.docx Supplementary Table 1 SuppTableS2Panels.docx Supplementary Table 2 SuppTableS3germlinevariantsarthralgiaprogressors.docx Supplementary Table 3 SuppTableS4germlineexomewide.docx Supplementary Table 4 SuppTableS5somaticCH.docx Supplementary Table 5 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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