Targeting CD38 Across Autoimmune and Plasma Cell-Driven Immune-Mediated Diseases: Rationale, Clinical Evidence, and Emerging Therapeutic Landscape.

Autoimmune diseases remain a major cause of chronic morbidity despite substantial advances in targeted immunomodulatory therapies. In many autoantibody-mediated conditions, disease refractoriness and relapse are driven by long-lived plasma cells, which are largely resistant to conventional immunosuppression and upstream B cell-directed strategies. CD38, a surface molecule highly expressed on plasmablasts and plasma cells and functionally involved in immunometabolic regulation, has emerged as a promising therapeutic target to overcome this limitation. Clinical interest in anti-CD38 therapy has been catalyzed by experience in plasma cell dyscrasias, where anti-CD38 monoclonal antibodies induce rapid and profound depletion of antibody-secreting cells. Over recent years, accumulating reports and early-phase studies have explored the repurposing of CD38-directed therapies in severe, treatment-refractory autoimmune diseases. The most compelling evidence has emerged in lupus nephritis and immune thrombocytopenia, with additional proof-of-concept data in autoimmune cytopenias and plasma cell-driven renal disorders such as immunoglobulin light chain (AL) amyloidosis. These experiences suggest that targeting CD38 can lead to meaningful clinical and immunological improvement, often accompanied by rapid reductions in pathogenic autoantibody production. However, the current evidence base remains heterogeneous and largely derived from small cohorts, case series, and early-phase trials, and important questions remain regarding durability of response, optimal treatment strategies, and long-term safety, particularly with respect to hypogammaglobulinemia and infection risk. We summarize the biological rationale for CD38 targeting in autoimmunity and plasma cell-driven immune-mediated diseases, critically appraise the emerging clinical evidence across disease settings, and discuss key challenges and future directions for integrating plasma cell-directed therapies into immunological disease management.