Although B-cell depleting therapy in rheumatoid arthritis (RA) is clearly effective, response is variable and does not correlate with B cell depletion itself. The B-cell receptor (BCR) repertoire was prospectively analyzed in peripheral blood samples of twenty-eight RA patients undergoing rituximab therapy. Timepoints of achieved BCR-depletion and -repopulation were defined based on the percentage of unmutated BCRs in the repertoire. The predictive value of early BCR-depletion (within one-month post-treatment) and early BCR-repopulation (within 6 months post-treatment) on clinical response was assessed. 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 BCR depletion was not associated with early clinical response but late depleters did show early response. Patients with early 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 BCR repopulation. Our findings indicate that rather than BCR-depletion it is repopulation with unmutated BCRs, possibly from 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.

中文翻译：

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敏感 B 细胞受体库分析显示再增殖与类风湿关节炎中利妥昔单抗的临床反应相关

尽管类风湿性关节炎 (RA) 中的 B 细胞耗竭疗法明显有效，但反应是可变的，并且与 B 细胞耗竭本身无关。对 28 名接受利妥昔单抗治疗的 RA 患者的外周血样本中的 B 细胞受体 (BCR) 进行了前瞻性分析。根据库中未突变 BCR 的百分比定义实现 BCR 耗尽和重新填充的时间点。评估了早期 BCR 耗竭（治疗后 1 个月内）和早期 BCR 重建（治疗后 6 个月内）对临床反应的预测价值。我们观察到利妥昔单抗治疗后外周血 BCR 谱的变化，即克隆扩张增加、克隆多样化减少和突变负荷增加，这些变化持续至治疗后 12 个月，但在第 6 个月开始恢复。早期 BCR 耗竭与早期临床反应，但晚期消耗剂确实显示出早期反应。具有未突变 BCR 的早期再增殖患者在 6 至 12 个月的时间间隔内表现出疾病活动性显着下降。抗药物抗体的产生与更多的 BCR 增殖没有显着相关。我们的研究结果表明，不是 BCR 耗尽，而是未突变的 BCR 重新增殖（可能来自幼稚 B 细胞），从而诱导缓解。这表明患者之间 B 细胞更新的（预先存在的）差异解释了早期临床效果的个体差异。