Integrative Multiomics Approaches Identify Biomarkers Associated With Progression From Arthralgia to Rheumatoid Arthritis

OBJECTIVE: Arthralgia, an early manifestation preceding definite rheumatoid arthritis (RA), represents a critical window to identify high-risk individuals and implement timely interventions. However, the immunopathologic mechanisms underlying the transition from arthralgia to established RA remain incompletely defined. METHODS: We employed a multiomics strategy integrating peripheral immune cell phenotyping, serum proteomics, and autoantibody profiling to investigate the immunopathologic 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 (at-risk individuals, 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 Treg cells and a lower Treg/Th17 cell ratio, with related changes persisting into early RA. Serum proteomics revealed upregulation of C5, α-1-B glycoprotein, RPUSD4, WDR87, and FUBP2, which showed inverse associations with Treg cells. 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 nonconverters were comparable, whereas longitudinal paired analyses revealed a reduction in Treg cells and Treg/Th17 cell ratio. Treg/Th17 cell ratio (area under the curve [AUC] 0.734) outperformed anti-cyclic citrullinated peptide (CCP; AUC 0.611) in discriminating ARI from SLA, particularly in patients who are anticitrullinated peptide antibodies negative (AUC 0.729). Combining Treg cells, anti-CCP and Treg/Th17 cell ratio improved classification performance (AUC 0.783). CONCLUSION: These findings delineate a critical transition from reversible immune dysregulation to established autoimmunity along the arthralgia-RA continuum, suggesting that Treg cell-related dysregulation may be associated with progression toward persistent inflammatory arthritis.