Disruption of memory B-cell trafficking by belimumab in patients with systemic lupus erythematosus.

Abstract

Autoreactive memory B cells (MBCs) contribute to chronic and progressive courses in autoimmune diseases like SLE. The efficacy of belimumab (BEL), the first approved biologic treatment for SLE and LN, is generally attributed to depletion of activated naïve B cells and inhibition of B-cell activation. BEL's effect on MBCs is currently unexplained. We performed an in-depth cellular and transcriptomic analysis of BEL's impact on the blood MBC compartment in patients with SLE. A retrospective meta-analysis was conducted, pooling flow cytometry data from four randomized trials involving 1245 patients with SLE treated with intravenous BEL or placebo. Then, extensive MBC phenotyping was performed using high-sensitivity flow cytometry in patients with mild/moderate SLE and severe SLE/LN treated with subcutaneous BEL. Finally, transcriptomic characterization of surging MBCs was performed by single-cell RNA sequencing. In BEL-treated patients, a significant increase in circulating MBCs, in a broad range of MBC subsets, was established at week 2, gradually returning to baseline by week 52. The increase was most prominent in patients with higher SLE disease activity, serologically active patients and patients aged ≤18 years. MBCs had a non-proliferating phenotype with a prominent decrease in activation status and downregulation of numerous migration genes. Upon BEL initiation, an increase of MBCs was firmly established. In the small cohort investigated, circulating MBCs were de-activated, non-proliferative and demonstrated characteristics of disrupted lymphocyte trafficking, expanding on our understanding of the therapeutic mechanism of B-cell-activating factor inhibition by BEL. ClinicalTrials.gov, http://clinicaltrials.gov, NCT00071487, NCT00410384, NCT01632241, NCT01649765, NCT03312907, NCT03747159.