Abstract
Abstract
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.