131 B-cells during preclinical phase of rheumatoid arthritis uals is fundamentally altered due to effective B cell depletion for up to 6 months after a single infusion of rituximab, which is underlined by a decrease in the number of clones, an increase in number and impact of dominant clones, a decrease in the diversity of the BCRh repertoire and a subsequent increase of unmutated BCR clones, suggesting re-establishment of the repertoire after B cell repopulation. This re-establishment of the repertoire is best visible between 6 and 12 months post RTX-infusion. This is the first time that the effects of RTX are studied in RA-risk individuals. The findings are in line with previous studies conducted in established RA [15]. The RTX-group and placebo-group were very similar in baseline characteristics, but due to the nature of the study, all participants were vaccinated at the screening visit and subsequently received methylprednisolone (MPNS) at the baseline visit prior to the intervention (i.e. RTX or placebo). To evaluate this effect, we established a novel cohort of at-risk individuals with similar inclusion criteria: baseline clinical and clonal characteristics were comparable between all RA-risk individuals although an increased CRP or signs of subclinical synovitis on ultrasound were not necessary for inclusion. When comparing both groups during follow-up, similar dynamics were seen, suggesting that the effect of MPNS or vaccination is limited or worn-off shortly after screening in the PRAIRI-placebo-group. Unfortunately, no BCRh repertoire related parameters that would potentially associate with RA development could be distinguished in the peripheral blood. In sub-analyses, comparing developers with non-developers in both the PRAIRI-placebo-group and untreated group, the impact and number of dominant clones were comparable throughout follow-up timepoints. In addition, when comparing the RA developers versus RA non-developers in the RTX-treated group, we also did not find any peripheral blood BCRh repertoire parameters that could distinguish both groups. However, it should be noted that this not preclude such differences in other tissues, e.g. in lymphoid tissues such as lymph nodes (LNs) and bone marrow (BM). This could explain the ability of RTX to delay the onset of RA in RA-risk individuals. Such a hypothesis is in line with a previous report that showed changes in various B cell subsets in lymphoid tissues of RA patients treated with RTX [16]. Therefore, future studies aimed at unravelling the effect of RTX treatment on the BCR repertoire in LNs and BM during the RA-risk phase are needed. A possible explanation for the lack of association of peripheral blood repertoire with onset of arthritis might lie in the observation that the BCRh repertoire is subject to major changes over time. Dominant clones varied from time point to time 6
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