97 B-cell repopulation after rituximab in rheumatoid arthritis Background The introduction of the B-cell depleting agent rituximab constituted a major revolution in the treatment of autoimmune diseases, which renewed interest in the role of B cells in autoimmunity. In Rheumatoid Arthritis (RA), an autoimmune disease that affects the peripheral joints, pathological studies show a prominent role for B cells in at least a subset of patients. A larger influx of B cells in the synovial tissue has been associated with autoantibody positivity, but also with more radiographic disease progression [1]. This suggests that treatment efficacy might be tightly linked to the contribution of the B-cell compartment in disease pathogenesis. Although rituximab is clearly effective in certain autoimmune diseases, on the individual level clinical response may vary and is difficult to predict. One of the factors thought to contribute to this variability is the timing and depth of B cell depletion, which has been shown to be very patient specific [2,3]. However, the extent of B-cell depletion does not correlate evidently with clinical response [4]. This might be due to the fact that our tools are relatively insensitive in monitoring B-cell levels in depleted patients, thus detecting repopulation of B cells too late to prevent disease relapse. And in fact, earlier studies confirmed that in rituximab-treated patients high sensitivity techniques are needed to successfully detect B cell signals when conventional flow cytometry fails [2,3]. Hence, there is a clear need for a more sensitive, quantitative diagnostic tool that is able to spot B-cell repopulation very early. If indeed this shows a link with disease progression, this might guide clinicians to adapt therapy accordingly. In a new prospective cohort of RA patients undergoing rituximab therapy, we used adaptive immune receptor repertoire (AIRR) sequencing to analyze B-cell depletion and repopulation dynamics at the clonal level. We confirmed previously reported effects of rituximab treatment on the peripheral blood B-cell receptor (BCR) repertoire. Furthermore, using BCR repertoire analysis we were able to find a link between B-cell repopulation and clinical efficacy, thus shedding more light on the mechanism behind rituximab efficacy in RA. Methods Patients and Samples Thirty-one patients previously diagnosed with RA according to the 2010 ACR/EULAR criteria, who were about to start with rituximab treatment were included in the ABIRISK consortium multicentric clinical study (NCT02116504) whose primary ob5
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