Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease driven by loss of immune tolerance, dysregulated nucleic acid sensing and cytokine signaling, abnormal B- and T-cell activation, persistent autoantibody production, and impaired clearance of immune cells and debris. These interconnected abnormalities promote immune-complex formation, complement activation, and multiorgan tissue injury. Recent advances in biologics, small-molecule inhibitors, cellular therapies, and combination regimens reflect an ongoing transition from broad immunosuppression toward mechanism-based treatment. This review summarizes major immunopathogenic mechanisms of SLE and evaluates established and emerging targeted therapeutic strategies according to disease phenotype, trial maturity, efficacy, safety, and principal limitations. The strongest evidence supports type I interferon and B-cell survival blockade, B-cell depletion, and calcineurin–NFAT inhibition, represented by anifrolumab, belimumab, obinutuzumab, and voclosporin. Several Phase 3 programs are evaluating additional TLR, co-stimulatory, FcRn, JAK/TYK2, and B-cell-directed strategies, whereas CD38, BCMA, and cellular therapies remain less mature and require controlled confirmation. Because systemic SLE, lupus nephritis (LN), and cutaneous lupus use distinct populations and outcome measures, efficacy estimates should not be compared directly across phenotypes. Future progress will depend on biomarker-guided patient stratification, rational sequencing of therapy, and careful evaluation of long-term safety, durability, access, and affordability, which may support more personalized treatment in SLE and LN.