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.