ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacoepidemiology
This article is part of the Research TopicAdvancing Medication Safety in the Real World: Multidisciplinary Strategies for Preventing Harm and Improving OutcomesView all 4 articles
Genetic Pharmacoepidemiology of JAK Inhibitors in Chronic Immune-Mediated Skin Diseases: Implications for Precision Therapy and Medication Safety
Provisionally accepted
- Zhujiang Hospital, Southern Medical University, Guangzhou, China
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Background This study aims to investigate the associations between genetically proxied JAK inhibition and various disease outcomes and adverse effects, providing insights into therapeutic efficacy and potential side effects for immune-mediated skin diseases (IMIDs). Methods Using Mendelian Randomization (MR), we analyzed genetic proxies for JAK1, JAK2, JAK3, and TYK2 inhibition. Data from the UK Biobank (N = 361,194) and FinnGen (N = 453733) were utilized to explore associations with nine autoimmune skin diseases, and twelve adverse outcomes, including tuberculosis, non-melanoma skin cancer, lung cancer, and pulmonary embolism. A systematic review of randomized controlled trials (RCTs) on JAK inhibitors in IMIDs was performed to complement the genetic evidence, focusing on safety outcomes. Results: Summary-data-based MR (SMR) analysis revealed that genetically proxied loss of function mutation of TYK2 was linked to psoriasis(OR = 0.673, 95% CI = 0.512–0.884, p = 0.004), aligning with clinical evidence. Safety analyses yielded genetically supported, hypothesis-generating signals with effect sizes close to unity, including associations between JAK2 inhibition and pulmonary embolism (OR = 0.998, p =0.035) and tuberculosis (OR = 1.004, p =0.013), as well as TYK2 inhibition and malignant non-melanoma skin cancer (OR = 1.006, p =0.047), and lung cancer (OR = 1.002, p =0.029). These findings should be interpreted cautiously and do not constitute definitive evidence of drug-induced adverse effects. The systematic review partially confirmed the safety of JAK inhibitors in IMIDs. Conclusions: This study supports TYK2 inhibition as a targeted therapy for psoriasis and provides hypothesis-generating genetic evidence for additional target–disease and target–safety associations that warrant further validation.
Keywords: Genetic pharmacoepidemiology, immune-mediated inflammatory skin diseases, Janus kinase (JAK) inhibitors, Pharmacovigilance and Drug Safety, Summary-data-based Mendelian Randomization (SMR)
Received: 03 Nov 2025; Accepted: 21 Jan 2026.
Copyright: © 2026 Zhang, Qu, Luo, Liang, Jiang, Zhu, Wu and Bao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Weijia Bao
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