Autoantibodies to Joint-Related Peptides Are Associated With Onset of Rheumatoid Arthritis in Presymptomatic...

To identify autoantibodies in presymptomatic individuals that associate with the onset of rheumatoid arthritis (RA) and to distinguish early RA from osteoarthritis (OA), particularly in individuals lacking classic RA serologic markers.

We analyzed serum and plasma from three cohorts: presymptomatic individuals who later developed RA (n = 518), a subset of these at RA diagnosis (n = 241), matched population controls (n = 530), and patients with OA (n = 287). Bead-based multiplex flow immunoassay detected IgG autoantibodies against joint-related peptides relevant in arthritis models. Principal component analysis was used to identify subgroups and univariable regression analyses to characterize the performance of autoantibodies with significance for patients with RA negative for anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF), that is, the seronegative RA diagnosis (SeNe) test. Multivariable logistic regression identified autoantibodies with the strongest discriminative power between cases and controls.

Autoantibody profiles revealed three distinct presymptomatic subgroups, suggesting early immune heterogeneity. The SeNe test was associated with symptom onset within 2.5 years in 13% of anti-CCP and RF-negative individuals. Specificity for RA versus OA was 97% (95% confidence interval, 95%-99%). An improved version (SeNe 2.0) identified 16% of anti-CCP and RF-negative presymptomatic individuals with 98% specificity versus population controls. Two of five SeNe 2.0 autoantibodies were associated with the presymptomatic state in the multivariable model, including RF and anti-CCP.

These novel biomarkers can identify presymptomatic, seronegative individuals at high risk of RA onset and support their recruitment into trials for personalized prevention. Additionally, they distinguish early seronegative RA from OA with high specificity.