Genetic pharmacoepidemiology of JAK inhibitors in chronic immune-mediated skin diseases: implications for precision therapy and medication safety

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 = 453,733) 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. Conclusion: 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.