Integrative Multi‐omics Approaches Identify Biomarkers Associated with Progression from Arthralgia to Rheumatoid Arthritis

BACKGROUND: Arthralgia, an early manifestation preceding definite rheumatoid arthritis (RA), represents a critical window to identify high-risk individuals and implement timely interventions. However, the immunopathological mechanisms underlying the transition from arthralgia to established RA remain incompletely defined. METHODS: We employed a multi-omics strategy integrating peripheral immune cell phenotyping, serum proteomics, and autoantibody profiling to investigate the immunopathological continuum from preclinical to established RA. A prospective cohort of 346 patients with recent-onset arthralgia was enrolled. Participants included healthy controls, self-limiting arthralgia (SLA), arthralgia at risk of RA (ARI), early RA, and established RA. RA development in ARI was ascertained through 24-month follow-up. RESULTS: Compared with SLA, ARI showed immune dysregulation, including reduced Tregs and a lower Treg/Th17 ratio, with related changes persisting into early RA. Serum proteomics revealed upregulation of C5, A1BG, RPUSD4, WDR87 and FUBP2, which showed inverse associations with Tregs. Autoantibody profiling identified stage-specific reactivity, with ARI showing elevated antibodies against stress-related proteins. Within 24 months, 18.4% of ARI progressed to RA (converters). Baseline immunophenotypic differences between converters and non-converters were comparable, while longitudinal paired analyses revealed a reduction in Tregs and Treg/Th17 ratio. Treg/Th17 ratio (AUC = 0.734) outperformed anti-CCP (AUC = 0.611) in discriminating ARI from SLA, particularly in ACPA-negative patients (AUC = 0.729). Combining Tregs, anti-CCP and Treg/Th17 ratio improved classification performance (AUC = 0.783). CONCLUSIONS: These findings delineate a critical transition from reversible immune dysregulation to established autoimmunity along the arthralgia-RA continuum, suggesting that Treg-related dysregulation may be associated with progression toward persistent inflammatory arthritis.