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

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.