The onset of seropositive rheumatoid arthritis (RA) is preceded by the presence of specific autoantibodies in the absence of synovial inflammation. Only a subset of these at-risk individuals will develop clinical disease. This impedes efforts to implement early interventions that may prevent onset of clinical disease. Here we analyse whether clonal changes in the B-cell receptor (BCR) repertoire can reliably predict onset of clinical disease.Methods
In a prospective cohort study in 21 individuals at-risk for RA, the BCR repertoire of paired peripheral blood and synovial tissue samples was analysed using next-generation BCR sequencing. BCR clones that were expanded beyond 0.5% of the total repertoire were labelled dominant. The relative risk for onset of arthritis was assessed, using a cut-off of presence of ≥5 dominant BCR clones. Findings in peripheral blood were validated in an independent prospective cohort of 50 at-risk individuals. Based on the test cohort, individuals in the validation cohort were considered positive if peripheral blood at study entry showed ≥5 dominant BCR clones.Results
Both in the test and validation cohort, the presence of ≥5 dominant BCR clones in peripheral blood was significantly associated with arthritis development (validation cohort relative risk (RR) 6.3, 95% confidence interval (CI) 2.7–15, p<1*10-4). Even when adjusted for the recently described clinical prediction rule the association remained intact (relative risk 5.0, 95% CI 1.2–20, p=0.024). When individuals developed arthritis, dominant BCR clones disappeared from peripheral blood and appeared in synovial tissue, suggesting a direct role of these clones in disease pathogenesis.Conclusion
Dominant BCR clones in peripheral blood predict onset of clinical symptoms of RA in at-risk individuals with high accuracy. Our data suggest that during onset of RA these clones shift from peripheral blood to target tissue.