Clinical Phenotype Transition in Pemphigus May Suggest Undertreatment with Rituximab: Findings from a Retrospective...

Introduction: Pemphigus is an autoimmune bullous disease caused by autoantibodies against desmoglein (DSG) 1 and/or 3 and comprises two main subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). PV affects the skin and/or mucosa and includes two forms: mucocutaneous PV (mcPV; anti-DSG1 and anti-DSG3) and mucosal PV (mPV; anti-DSG3). PF, characterized by anti-DSG1 autoantibodies, is limited to the skin. Pemphigus is effectively treated with rituximab, a B-cell-depleting therapy. However, about half of patients relapse, with a subset exhibiting a shift in clinical subtype following relapse, known as clinical phenotype transition. This study aimed to investigate clinical phenotype transition in relapsed pemphigus patients following rituximab treatment.

A single-centre, exploratory retrospective cohort study was conducted, reviewing the medical records of patients with pemphigus who received at least one treatment cycle of rituximab between December 2006 and December 2023. Clinical and immunological data were collected at several time points during the first cycle of rituximab treatment.

A total of 109 patients were included, of whom 44% (48/109) achieved sustained complete remission, while 56% (61/109) experienced relapse. Among the 61 patients who relapsed, 26% (16/61) experienced a clinical phenotype transition. All had an initial diagnosis of mcPV. Among these, 75% (12/16) transitioned from mcPV to mPV and 25% (4/16) from mcPV to PF. Clinical phenotype transitioned patients often remained seropositive for anti-DSG3 at clinical remission, a pattern not observed in patients who did not experience a clinical phenotype transition.

Clinical phenotype transition was observed exclusively in mcPV patients, suggesting that such changes do not represent a true alteration in disease subtype but rather reflect persistent activity of the same pathogenic autoantibody due to suboptimal B-cell depletion, suggesting undertreatment with rituximab. These findings support the need to refine rituximab treatment regimens to achieve complete B-cell depletion, reduce relapse rates, and optimize long-term disease control in pemphigus.