Background/Purpose: Belimumab (BEL), a recombinant human monoclonal antibody directed against B-cell activating factor (BAFF), is the first approved biological agent for patients (pts) with active systemic lupus erythematosus (SLE) and lupus nephritis (LN). BEL inhibits primary humoral immune responses by depleting naïve B cells that are dependent on BAFF for their survival while secondary humoral immune responses by memory B cells (MBCs) remain intact. Indeed, some studies reported an increase of circulating MBCs following neutralisation of BAFF. So far, these effects of BEL on the MBC compartment in SLE pts have not been investigated.

This study aimed to establish the dynamics of circulating MBCs in pts with SLE treated with BEL and to perform an in-depth analysis of the impact of BEL on the MBC compartment.

Methods: First, a retrospective meta-analysis was performed by pooling individual patient (pt) MBC flow cytometry data from 1245 pts with SLE treated with BEL 10 mg/kg IV or placebo (PBO) from four randomised clinical trials (NCT00071487, NCT00410384 [BLISS-76], NCT01632241 [EMBRACE], NCT01649765 [PLUTO]). Second, extensive B-cell subset phenotyping was performed prospectively by employing high-sensitivity flow cytometry (HSFC) based on EuroFlow protocolsin pts with active SLE (from the BLISS-BELIEVE trial [NCT03312907]) and with severe SLE/LN (from the SynBioSe-2 trial [NCT03747159]) treated with BEL. Additionally, in-depth characterisation of surging MBCs in circulation was performed by single-cell RNA sequencing (scRNA-seq).

Results: By comparing BEL-treated with PBO-treated pts with SLE, a substantial increase in circulating MBC counts was established 4 weeks after BEL initiation, gradually returning to baseline by Week 52. The increase of MBCs was most prominent in BEL-treated pts with higher SLE disease activity (SLE Disease Activity Index >9), serologically active pts (dsDNA positive and/or low complement levels) and with younger age (below 18 years). HSFC established that the increase was non-specific and observed in a broad range of MBC subclasses peaking as early as 2 weeks after BEL initiation. Subsequent scRNA-seq analysis of the emerging MBCs revealed a non-proliferating phenotype with a prominent decrease in activation status. In these circulating MBCs, a large amount of migration and adhesion genes were downregulated suggesting that the accumulation of MBCs following BEL treatment was related to their impaired cell-cell adhesion, disrupting cell-trafficking and preventing extravasation.

Conclusion: After initiation of BEL treatment, a substantial increase of circulating MBCs was firmly established and was most notable in pts with severe, serologically active SLE/LN. The surge of circulating MBCs appeared to be associated with disrupted lymphocyte trafficking of MBCs, thereby suggesting a new potential therapeutic mechanism of BEL on MBCs in SLE. These findings have important implications to our understanding and consequent improvement of B-cell targeted treatment strategies in pts with active SLE and LN, as MBC accumulation in circulation might allow for more efficient targeting of the B-cell compartment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/belimumab-disrupts-memory-b-cell-trafficking-in-patients-with-systemic-lupus-erythematosus/