Comment on: “Apremilast for Oral Mucosal‐Predominant Resistant Pemphigus Vulgaris: A Promising Adjunctive Treatment”

The study by Zhang et al. (2025) makes a significant contribution by exploring apremilast as an adjunctive therapy for mucosal-predominant resistant pemphigus vulgaris (PV), a clinical presentation that remains challenging to clinicians despite significant advances in immunobiological techniques. The authors' emphasis on oral lesions as a major determinant of morbidity and quality of life is both relevant and timely, underscoring the urgent need for better management strategies in mucosal PV. The rationale for investigating phosphodiesterase-4 (PDE4) inhibition in autoimmune disorders has been supported by prior evidence across several mucocutaneous diseases, including Behçet's disease and chronic oral ulcerations (Chung et al. 2025). In this context, the study's finding of a reduction in PDAI scores and anti-DSG3 titers strengthens the possibility that PDE4 inhibition can modulate autoantibody-driven disruption of desmosomal adhesion. While the study design was non-randomized and the sample size limited (n = 5), these constraints are understandable when dealing with rare or low-prevalence diseases. Nevertheless, the absence of a comparator arm, such as placebo or rituximab maintenance, limits the strength of causal interpretation and may magnify placebo or corticosteroid co-therapy effects (Joly et al. 2017). The focus on patients' refractory to standard immunosuppressive regimens is commendable, but larger randomized controlled trials will be essential to more accurately define apremilast's clinical impact, including its potential disease-modifying properties and corticosteroid-sparing role. In addition, the 32-week follow-up period, while sufficient to observe initial remission, may not fully capture the long-term relapse dynamics typical of mucosal PV, where immune memory and DSG3 autoantibody oscillations can persist for years (De et al. 2025). The discussion presented by Zhang et al. (2025) is precisely interesting, linking the cAMP-Epac1-Rap1-plakoglobin pathway to the restoration of DSG3-dependent adhesion. This aligns well with recent in vitro findings demonstrating cAMP-mediated stabilization of desmosomal junctions and Rap1-driven epithelial integrity (Sigmund et al. 2025). However, without molecular corroboration from lesional biopsies or immunostaining before and after therapy, these mechanistic insights remain speculative. Incorporating immunofluorescence quantification of DSG3 expression or RNA-seq-based transcriptomic profiling in future studies would strengthen the biological basis of this proposed mechanism. Additionally, the pharmacokinetics of apremilast in inflamed oral mucosa remain poorly understood, a crucial knowledge gap that may influence dosage optimization for mucosal-dominant autoimmune diseases. Despite these limitations, the study meaningfully advances therapeutic understanding in PV, particularly given its reassuring safety profile, consistent with prior dermatologic literature (Delvaux et al. 2024). In conclusion, we would like to acknowledge and congratulate Zhang et al. (2025) for pioneering this pilot investigation, which opens both mechanistic and therapeutic avenues for mucosal-predominant PV. Their investigation highlights the importance of multi-center randomized trials and translational research that correlate clinical findings with molecular immunopathogenesis, ultimately helping to establish PDE4 inhibition as a viable immunomodulatory strategy in PV management. Rajiv Gandhi Gopalsamy: conceptualization, investigation, writing – original draft, visualization, validation, data curation, formal analysis. Lucas Alves da Mota Santana: conceptualization, investigation, writing – original draft, validation, visualization, formal analysis, data curation. Virgínia Kelma dos Santos Silva: supervision, validation, visualization, writing – review and editing. Eduardo Morato de Oliveira: validation, visualization, writing – review and editing, supervision. Juliana Batista Melo da Fonte: validation, visualization, writing – review and editing, supervision. Lysandro Pinto Borges: validation, visualization, writing – review and editing, supervision. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.