Xiang Li,1 Juan Zhang,2 Lian Zhang,1 Hongzhi Gu,1 Zhifang Zhai,1 Mingwang Zhang1 

1Department of Dermatology, The First Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of China; 2Department of Pediatrics, Zhuzhou Central Hospital, Zhuzhou, Hunan, People’s Republic of China

Correspondence: Zhifang Zhai, Department of Dermatology, The First Affiliated Hospital of Army Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People’s Republic of China, Email zhaizf1004@163.com Mingwang Zhang, Department of Dermatology, The First Affiliated Hospital of Army Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing, 400038, People’s Republic of China, Email mingwangzhang2@tmmu.edu.cn

Abstract: Pemphigus vulgaris (PV), a life-threatening autoimmune blistering disorder mediated by pathogenic anti-desmoglein antibodies, manifests clinically with extensive cutaneous and mucosal vesicles, bullae, and erosions. While corticosteroids remain first-line therapy, a substantial subset of patients develop refractory disease requiring advanced therapies. Tofacitinib, an oral Janus kinase (JAK) 1/3 inhibitor, demonstrates broad immunomodulatory effects through interference with cytokine signaling pathways. We report the case of a 50-year-old male with recalcitrant PV who achieved sustained remission following adjunctive tofacitinib therapy. Combination therapy with tofacitinib (5 mg twice daily) and prednisone (60 mg/day) enabled successful corticosteroids withdrawal within 5 months, achieving complete clinical remission (PDAI=0) and serological improvement (Dsg1/Dsg3 antibodies reduced by 64.5%/75.8%). Longitudinal immunohistochemistry (IHC) revealed attenuated phospho-STAT3 and phospho-STAT6 in post-treatment lesional skin compared to baseline. Proteomic profiling of PV lesions (n=3) versus healthy controls (n=3) identified 198 differentially expressed proteins (fold change > 1.5, p< 0.05), with KEGG pathway analysis revealing predominant enrichment in JAK-STAT signaling, IL-17-mediated inflammation, and lymphocyte differentiation pathways. Independent validation in an expanded cohort (5 PV vs 5 controls) confirmed constitutive JAK-STAT hyperactivation: phospho-STAT3 (7.2± 1.64 vs 1± 0, p< 0.001) and phospho-STAT6 (9.6± 1.34 vs 1.2± 0.45, p< 0.001) were markedly elevated in untreated PV lesions. These findings posit tofacitinib as a promising steroid-sparing agent in PV management, potentially through multimodal inhibition of pathogenic cytokine networks. Large-scale randomized controlled trials are warranted to validate these observations.

Keywords: pemphigus vulgaris, JAK-STAT pathway, tofacitinib, targeted immunotherapy, proteomic profiling