BACKGROUND

Bullous pemphigoid (BP) is a common immunobullous disease that mainly affects older people; however, the molecular pathogenesis of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in BP is not fully understood.

OBJECTIVES

To characterize the immune profiles of and the key JAK/STAT pathway in patients with BP. The clinical efficacy of JAK inhibition in patients with BP was also assessed.

METHODS

Skin transcriptome profiling, measurement of plasma cytokine/chemokine levels, and an in vitro T-cell activation and JAK inhibitor (JAKi) blocking assay were performed for patients with BP. The clinical improvement in steroid-resistant patients with BP treated with JAKi was evaluated.

RESULTS

Fifty patients with BP and 31 healthy donor individuals were enrolled in this study. JAK3 and STAT3 mRNA levels were increased in skin lesions from patients with BP. BP-related inflammatory-mediated cytokines/chemokines, including interleukin 5, CCL22, CCL17, CCL18, matrix metalloproteinase 9 and granzyme B, were significantly elevated in patients with BP compared with the healthy donors (all P < 0.001). An in vitro T-cell activation and JAKi blocking assay revealed that tofacitinib (JAK1/3i) and ritlecitinib (JAK3i) had better inhibitory effects than upadacitinib on granzyme B and CCL17 in patients with BP. Eight patients with steroid-resistant BP were treated with oral tofacitinib. Of these patients, five had a rapid reduction in their Bullous Pemphigoid Disease Area Index (from 104.2 to 34.8) within 5 weeks.

CONCLUSIONS

JAK3i can attenuate JAK3/STAT3-mediated inflammatory factors, providing an alternative treatment strategy for patients with refractory BP in combination with low-dose steroids.