Background/Purpose: A phase characterized by the presence of specific autoantibodies and arthralgias in the absence of clinically evident synovial inflammation often precedes the onset of rheumatoid arthritis (RA). However, only a subset of these RA-risk individuals will develop active disease in the short term.¹ Recent findings show that dominant B-cell receptor (BCR) clones in peripheral blood can accurately predict imminent onset of arthritis in these RA-risk individuals.² To validate the predictive role of BCR clones in peripheral blood in RA-risk individuals and explore it in more detail in a larger cohort.

Methods: The BCR repertoire in peripheral blood was analysed using next-generation BCR sequencing in a prospective cohort study of 129 RA-risk individuals from Reade. Like earlier, BCR clones expanded beyond 0.5% of the total repertoire were labelled highly expanded clones (HECs), shortly referred to as dominant BCR clones, and individuals were labelled BCR-positive if peripheral blood at study baseline showed ≥ 5 dominant BCR clones.

Results: We confirmed that the number of dominant BCR clones in peripheral blood at baseline is increased in RA-risk individuals who develop arthritis within 3 years, compared to RA-risk individuals who do not (10.5 ± 5.2 vs. 2.0 ± 2.4; mean ±SD; p<0.0001). Within 3 years none of the BCR-negative RA-risk individuals developed arthritis, while 32 (71%) of the BCR-positive individuals did (estimated RR: 120.1; 95%-CI: 7.5 – 1917; p<0.0001). Using a logistic regression the BCR clone test performed significantly better in predicting development of arthritis in comparison with the Risk Rule Model, a test consisting of clinical parameters (DAIC= 14.91).³

A higher number of BCR clones was associated with an even higher risk of arthritis, even when this analysis was restricted to the BCR-positive group (Spearman R, p=0.019). When we divided the BCR clone positive individuals into two equal groups (5-8 HECs: n=23 and ≥ 9 HECs: n=22 ) cox proportional hazard analysis showed a significantly higher risk of arthritis at 3 years in the BCR-high versus BCR-medium group (log-rank test p=0.006). Having 9 or more HECs corresponded with a positive predictive value of 91% (20 in 22).

Conclusion: High short-term risk of rheumatoid arthritis is predicted by a high number of dominant BCR clones at baseline. Among the 17% high-risk individuals 91% (20 in 22) developed arthritis within 3 years, after a median follow-up of 16 months. Our data support therapeutic intervention in this high-risk group.

References

¹Bos, WH et al. Ann. Rheum. Dis. 2010;69:490-4, ²Tak, PP et al. Ann. Rheum. Dis. 2017;76: 1924-30, ³van de Stadt, LA et al. Ann. Rheum. Dis. 2013;72:1920-6