Targeted therapies in pemphigus vulgaris: Emerging horizons beyond rituximab

Pemphigus vulgaris is a potentially life-threatening autoimmune blistering disorder driven by pathogenic IgG autoantibodies targeting desmoglein 3 and 1. While rituximab has transformed management-achieving complete remission off-therapy in 70-90% of patients-approximately 20-30% of patients relapse or fail to respond, defining a critical unmet need. The key drivers of rituximab-refractory disease include post-depletion B-cell repopulation fuelled by elevated BAFF and APRIL, persistence of long-lived plasma cells in bone marrow niches that evade anti-CD20 depletion, IgG4-dominant autoantibodies requiring high complement-dependent cytotoxicity, innate immune amplification via Fcγ-receptor signalling and human anti-chimeric antibody formation neutralizing the drug itself. This review critically evaluates five emerging targeted therapeutic classes addressing these mechanisms. Next-generation anti-CD20 monoclonal antibodies-ofatumumab, ocrelizumab, obinutuzumab and veltuzumab-offer enhanced effector functions, reduced immunogenicity and subcutaneous delivery for rituximab-intolerant or HACA-positive patients, though evidence remains at case and cohort level. BAFF/APRIL pathway inhibitors, principally telitacicept and ianalumab, target the B-cell survival axis elevated post-rituximab and show promise in pemphigus case reports and extrapolated phase 2/3 systemic lupus erythematosus data. Bruton tyrosine kinase inhibitors, particularly rilzabrutinib, demonstrated rapid disease control and meaningful steroid-sparing effects in phase 2 trials, though the pivotal PEGASUS phase 3 trial did not meet its primary endpoint. FcRn antagonists, led by efgartigimod, achieve 60-70% reduction in circulating IgG within weeks without broad immunosuppression; the phase 3 ADDRESS trial missed its primary endpoint, likely due to corticosteroid confounding rather than biological inefficacy. Finally, DSG3-CAAR T-cell therapy represents the most transformative approach-antigen-specific elimination of pathogenic anti-Dsg3 B cells while preserving normal humoral immunity-with early phase 1 data awaited. Rational combination strategies and refined trial designs will be essential to translate the biological promise of these next-generation agents into clinical practice for patients with refractory pemphigus.