Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich rheumatoid arthritis, pre-rheumatoid arthritis and systemic lupus erythematosus

Abstract

Abstract Autoantibodies play a significant role in the progression and pathogenesis of many autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). No studies have analyzed the expression of plasma cell/plasmablast genes during RA disease progression and the potential of an anti-CD38 antibody in depleting plasma cells and plasmablasts for efficacy in autoimmunity. Therefore, we interrogated the rationale of daratumumab, an anti-CD38 monoclonal antibody, as a potential therapeutic in RA and SLE. RNA-Seq analysis of synovial biopsies from various stages of RA disease development shows that plasma cell/plasmablast-related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up-regulated in synovial biopsies from arthralgia, undifferentiated arthritis, early RA and established RA compared to healthy and osteoarthritis controls. In addition, flow cytometry analysis reveals highest CD38 expression on plasma cells and plasmablasts compared to natural killer cells, classical dendritic cell (DC), plasmacytoid DC, and T cells, in peripheral blood of healthy control, SLE and RA donors. We show that IGJ expression mRNA strongly correlates with the number of plasma cell/plasmablast in SLE patient PBMCs. Most importantly, IGJ mRNA down-regulation correlates with daratumumab-mediated depletion of these cells ex vivo. The data indicates a potential use of IGJ mRNA as a surrogate pharmacodynamic biomarker in clinical testing of daratumumab. Taken together, our data provides rationale for daratumumab in the treatment of RA and SLE.