96 CHAPTER 5 Abstract Background Although B-cell depleting therapy in rheumatoid arthritis (RA) is clearly effective, response is variable and does not correlate with B cell depletion itself. Methods The B-cell receptor (BCR) repertoire was prospectively analyzed in peripheral blood samples of twenty-eight RA patients undergoing rituximab therapy. Timepoints of achieved depletion and repopulation were defined based on the percentage of unmutated BCRs in the repertoire. The predictive value of early depletion (within one-month post-treatment) and early repopulation (within 6 months post-treatment) on clinical response was assessed. Results We observed changes in the peripheral blood BCR repertoire after rituximab treatment, i.e., increased clonal expansion, decreased clonal diversification and increased mutation load which persisted up to 12 months after treatment, but started to revert at month 6. Early B-cell depletion was not associated with early clinical response but late depleters did show early response. Patients with early B-cell repopulation with unmutated BCRs showed a significant decrease in disease activity in the interval 6 to 12 months. Development of anti-drug antibodies non-significantly correlated with more B-cell repopulation. Conclusion Our findings indicate that rather than depletion it is repopulation with unmutated, possibly naïve B cells which induces remission. This suggests that (pre-existing) differences in B-cell turnover between patients explain the interindividual differences in early clinical effect.
RkJQdWJsaXNoZXIy MTk4NDMw