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Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, which exhibits multiple B cell abnormalities including expanded populations of memory B cells and elevated levels of autoantibodies. Belimumab is a monoclonal antibody targeting the B cell cytokine BAFF (a.k.a. BLyS), approved for the treatment of SLE. Methods: In this prospective cohort study, B cells from peripheral blood of 23 SLE patients initiating belimumab treatment and followed longitudinally for up to three years, were assessed using mass cytometry. Findings: B cells decreased during the study period, with a rapid decrease of both naïve and CD11c+CD21− B cells at the first follow-up visit, followed by a continuous reduction at subsequent follow-ups. In contrast, plasma cells and switched memory B cells remained stable throughout the study. The observed immunological changes correlated with early, but not late, clinical improvements. Moreover, high baseline B cell counts were predictive of failure to attain low disease activity. In summary, our data unveiled both rapid and gradual later therapy-associated alterations of both known and unforeseen B cell phenotypes. Interpretation: Our results suggest that evaluation of B cell counts might prove useful prior to initiation of belimumab treatment and that early treatment evaluation and discontinuation might underestimate delayed clinical improvements resultant of late B cell changes. Keywords: Systemic lupus erythematosus, Biologics, BLyS, Mass cytometry, CyTOF

This manuscript is a companion paper to Amara et al. [1]. Data shown here include detailed clinical characteristics from anonymized patients, the Ig subclass data generated from B cells sorted from four individual patients, tables detailing variable gene region sequences from sorted cells linked to the patient information and the sequence yields from individual patients. Furthermore a URL link to the RNAseq datasets submitted to GEO is included. Keywords: B cells, FcRL4, Rheumatoid arthritis, IRTA1