T‐cell engagers in autoimmune rheumatic diseases: From concept to clinical practice

B-cell depletion has transformed the therapeutic landscape of rheumatic autoimmune diseases and has firmly established B cells as key drivers of immune-mediated pathology.Since the introduction of anti-CD20 therapy, substantial advances have been made in understanding the role of B cells in disease pathogenesis and in exploiting their therapeutic potential.However, accumulating evidence indicates that conventional B-cell depletion is often incomplete, with significant amounts of residual B-cell populations persisting in lymphoid tissues and inflamed organs, potentially contributing to refractory diseases and relapse.1,2 These observations have led to the concept of deep B-cell depletion, which aims to achieve more complete and sustained elimination of pathogenic B-cell compartments.This strategy is currently being explored using CAR T-cell or T-cell engager (TCE) therapies that target B-cell antigens such as CD19, CD20 or BCMA.These approaches have shown encouraging results across several severe autoimmune diseases in first case series and small monocentric clinical trials.[3][4][5][6][7] Beyond improved clinical efficacy, deep B-cell depletion offers important insights into disease mechanisms and raises the possibility of inducing immune reset 3,4 leading to durable clinical remission.Autologous CAR T-cell therapy, however, requires leukapheresis, individualised manufacturing, lymphodepleting chemotherapy and specialised infrastructure.3 TCEs offer an off-the-shelf alternative by simultaneously binding CD3 on endogenous T cells and lineage-specific antigens on B cells or plasma cells, thereby inducing targetcell cytotoxicity.8 Their standardised availability and short pharmacological persistence permit dose adaptation or interruption, 5 but loss of protective humoral immunity with increased risk of infection 5-7 and systemic T-cell activation causing cytokine release syndrome (CRS) 5-7 remain significant concerns.Initial evidence for the efficacy of TCEs in rheumatology came from six patients with multidrug-refractory rheumatoid arthritis treated with low-dose CD19×CD3