125 B-cells during preclinical phase of rheumatoid arthritis a trend towards re-establishment to the pre-treatment diversity at 12 months after treatment (Figure 1F). In summary, RTX causes a quantitative and qualitative change in the BCRh repertoire during the pre-clinical phase of RA. Depletion of the BCR repertoire can be observed at 6 months after single rituximab infusion. From that point onwards re-establishment of the BCR repertoire in peripheral blood occurs, progressing to a normal repertoire 12 months after treatment. Figure 1 | Influence of rituximab on the BCRh repertoire in RA-risk individuals Dot plots of (A) the number of BCRh clones, (B) the absolute number of dominant BCRh clones (clonal size ≥ 0.5% of the total repertoire), and (C) impact of the dominant BCRh-clones on the total BCRh repertoire in all RA-risk individuals randomized in the rituximab-arm (n=38). (D) Dot plots of the top 25 clonal overlap between the screening visit and various timepoints after rituximab treatment. (E) Percentage of unmutated BCRh clones in the repertoire at various timepoints before and after treatment. (F) Simpsons index to measure the diversity of the BCR repertoires at various timepoints. dot plots show median and interquartile range and analysed with Kruskall Wallis test. * p value <0.01, ** p value <0.001, *** p value <0.0001 The BCR repertoire is comparable between RA developers and non-developers in the RTX treated group We next investigated whether the effect of rituximab on the BCRh repertoire during the at-risk phase was different in individuals that eventually developed RA when compared to non-developers. We did not see any significant association in the number of BCRh clones, number and impact of dominant BCR clones, and the progression or non-progression to arthritis (Figure 2A-2C). 6
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