Dual BAFF/APRIL inhibition with telitacicept in systemic lupus erythematosus and IgA nephropathy: pharmacological rationale, clinical efficacy, and safety on female fertility preservation.

Background: Systemic lupus erythematosus (SLE) and IgA nephropathy (IgAN) are immune-mediated renal disorders characterized by aberrant B-cell activation. While SLE shows a striking female predominance, IgAN is more prevalent in males; nonetheless, both conditions typically peak the during reproductive years. Their pathogenesis involves distinct molecular drivers: SLE is mediated by specific autoantibodies, whereas IgAN is initiated by galactose-deficient IgA1 (Gd-IgA1) acting as a primary antigen that elicits immune complex deposition. Conventional immunosuppressive therapies are effective but limited by non-selective toxicity, particularly in women of reproductive age. Telitacicept, a first-in-class recombinant transmembrane activator and CAML interactor (TACI)-fragment crystallizable (Fc) fusion protein, simultaneously neutralizes B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), offering a targeted pharmacological strategy. Methods: This narrative review synthesizes evidence from randomized controlled trials, real-world studies, and mechanistic investigations to evaluate the pharmacological rationale, clinical efficacy, and safety profile of telitacicept in SLE and IgAN, with particular attention to its steroid-sparing effects and endocrine safety. Results: Dual inhibition of BAFF and APRIL by telitacicept suppresses pathological B-cell maturation and plasma cell survival, leading to marked reductions in antigen Gd-IgA1 and associated immune complexes, proteinuria, and disease activity, alongside stabilization of renal function. Clinical trials and real-world data demonstrate robust efficacy in both refractory IgAN and active SLE/lupus nephritis, with sustained complement recovery and favorable tolerability. Importantly, available clinical data indicate no direct gonadotoxic effects, with preserved ovarian reserve markers and hypothalamic-pituitary-gonadal axis function, distinguishing telitacicept from cytotoxic immunosuppressants. Conclusion: Telitacicept represents a pharmacologically rational, targeted immunomodulator that combines effective disease control with a favorable safety profile. Its dual BAFF/APRIL inhibition and steroid-sparing properties support its potential role as a long-term therapeutic option for patients with SLE and IgAN, particularly women requiring sustained disease control who seek to minimize systemic toxicity and safeguard ovarian reserve.