Background/Purpose: 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 analyze 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 analyzed using RNA-based next-generation BCR sequencing. BCR clones that were expanded beyond 0.5% of the total repertoire were labeled dominant. The relative risk for onset of arthritis was assessed, using a cut-off of presence of 5 or more 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 BCR positive if peripheral blood at study entry showed 5 or more dominant BCR clones.

Results: Both in the test and validation cohort, the presence of 5 or more 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). Figure A and B show the arthritis-free survival curves of BCR negatives (black) and BCR positives (red) for the test and validation cohort respectively. After adjustment 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.