106 CHAPTER 5 Figure 4 | Repopulation is associated with improvement of disease activity shortly after and possibly with anti-drug antibodies development A) Boxplot showing the changes in DAS28-score between the month 6 and month 12 after treatment in early or late repopulating patients. Boxplots show the median and 25th and 75th interquartile, error bars show the range, and single data points are depicted in grey (** p ≤ 0.01, using unpaired t-test). B) Barplot showing the correlation between anti-drugs antibodies (ADA) development and repopulation within 12 months of treatment. Discussion Using UMI-based adaptive immune receptor repertoire (AIRR) sequencing in RA patients undergoing rituximab treatment we show that deletion and recurrence of the unmutated BCRs, associated with the naive repertoire, proved a sensitive marker for depletion and repopulation. Using this parameter, we find a correlation between repopulation and clinical improvement shortly after, strongly suggesting that it might be the repopulation, rather than the depletion, that has a dampening role on disease activity. In this study we monitored unmutated clonotypes in the BCR repertoire with quantitative UMI-based sequencing to sensitively follow the dynamics of B cell depletion and repopulation in rituximab treated patients. Using this method, we observed that repopulation of the BCR repertoire within 6 months of treatment did correlate with significantly better disease amelioration in the subsequent period, between month 6 and 12 post treatment, compared to patients that did achieve repopulation later or not at all (p-value < 0.01). This observation was not explained by a difference in disease activity at 6 months between the two groups (p-value = 0.92) nor by a 2nd cycle of treatment. This might indicate that it is in fact the repopulation following rituximab – rather than depletion itself - that is able to “re-set” the (pathological) B cell compartment, leading to temporal improvement of the disease activity. In this context, the ability to promptly recognize the start of B cell repopulation after
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