JAK/STAT signalling pathway is involved in the immune mechanism of Bullous pemphigoid

Abstract Background Bullous Pemphigoid (BP) is a common immune bullous disease, mainly affecting the elderly. However, the molecular pathogenesis of the JAK/STAT pathway in BP is not fully understood. Objective To characterize immune profiles and the key JAK/STAT pathway in BP patients. The clinical efficacy of the JAKi for BP patients was also assessed. Methods Skin transcriptome profile, plasma cytokine/chemokine levels, and in vitro T cell activation and JAKi blocking assay for BP patients were performed. Clinical improvement for steroid-resistant BP patients treated with JAK inhibitors was evaluated. Results A total of fifty BP patients as well as thirty-one healthy individuals were enrolled. The mRNA expression levels of JAK3 and STAT3 were increased in skin lesions from the BP patients. The BP-related inflammatory-mediated cytokines/chemokines such as IL-5, CCL22, TARC/CCL17, PARC/CCL18, MMP9, and Granzyme B (P values <10-3-10-5) were elevated in the BP patients compared with those in the healthy control. In vitro T cell activation and JAKi blocking assay revealed that tofacitinib (JAK1/3i) and ritlecitinib (JAK3i) had better inhibitory effects than upadacitinib for granzyme B and TARC secretions in BP patients. Eight steroid-resistant BP patients were treated with oral tofacitinib. Among these patients, five patients had a rapid reduction in their Bullous Pemphigoid Disease Area Index (BPDAI) from 104.2 to 34.8 within five weeks. Conclusions JAK3 inhibitors can attenuate JAK3/STAT3-mediated inflammatory factors, providing an alternative treatment strategy for refractory BP patients in combination with low-dose steroids.