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. 2025 Aug 18;193(3):521-531.
doi: 10.1093/bjd/ljaf219.

Janus kinase/signal transducer and activator of transcription signalling pathway is involved in the immune mechanism of bullous pemphigoid

Hsin-Yu Chung  1 , Chun-Bing Chen  1   2   3   4   5   6   7   8   9 , Hua-En Lee  1   4   7 , Chun-Wei Lu  1   7   8 , Wei-Ti Chen  1   7 , Rosaline Chung-Yee Hui  1   7 , Min-Hui Chi  1   4   7 , Ya-Ching Chang  1   7 , Pei-Chi Lo  1 , Chuang-Wei Wang  1   2   3   4   5 , Wen-Hung Chung  1   2   3   4   5   7   9   10   11   12   13   14
Affiliations

Janus kinase/signal transducer and activator of transcription signalling pathway is involved in the immune mechanism of bullous pemphigoid

Hsin-Yu Chung et al. Br J Dermatol. .

Abstract

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.

Plain language summary

Bullous pemphigoid (or ‘BP’ for short) is a common disease that mainly affects older people. In Asia, approximately 1 individual in 100 has BP. How BP develops at a molecular level is still unknown. It may involve a cellular pathway called the ‘JAK/STAT’ pathway. In this study, we aimed to find out immune profiles and the key JAK/STAT pathway in patients with BP. The effectiveness of medications called ‘JAK inhibitors’ in patients with BP was also investigated. We analysed a variety of things in patients with BP. This included which genes were active in their skin and the levels of certain proteins in their blood. We also carried out laboratory testing to find out how JAK inhibitors work in patients BP. Improvements in patients with difficult-to-treat BP taking JAK inhibitors were evaluated. Fifty people with BP and 31 people without the disease took part. The expression of genes called ‘JAK3’ and ‘STAT3’ were much higher in skin lesions from patients with BP. We found that factors involved in the JAK3/STAT3 signalling pathway were activated. Certain inflammation-related proteins associated with BP were higher in patients with BP. In lab tests, we found that drugs called tofacitinib and ritlecitinib were better at blocking two of these proteins in BP. Eight patients with steroid-resistant BP took tofacitinib. Five of these patients had a rapid improvement in their disease within 5 weeks. Our findings suggest that JAK3 inhibitors can reduce the levels of inflammation-related factors in BP. When combined with low-dose steroids, JAK inhibitors are an option for patients with difficult-to-treat BP.

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Conflict of interest statement

Conflicts of interest: The authors declare no conflicts of interest.

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