Genetically proxied IL-13 inhibition is associated with risk of psoriatic disease: Mendelian randomization study

Objective: Inhibitors of the IL-13 pathway, such as dupilumab, are licensed for atopic dermatitis and asthma. Adverse events that resemble psoriatic disease after dupilumab initiation have been reported, but evidence is limited to case reports with uncertain causality. We aimed to investigate whether genetically mimicked IL-13 inhibition (IL-13i) is associated with risk of psoriatic arthritis (PsA) and psoriasis.

Methods: We instrumented IL-13i using a protein-coding variant in the IL13 gene, rs20541, that is associated with circulating eosinophil count (biomarker of IL-13i) at genome-wide significance in a study of 563,946 individuals. Outcome genetic data were taken from studies of PsA, psoriasis, and related spondylarthritis traits in up to 10,588 cases and 209,287 controls. Colocalization analysis was performed to examine genetic confounding. We additionally used circulating immunoglobulin E (IgE) as a biomarker to test whether associations were replicated, both in the test and in an independent genetic dataset. We also replicated analyses using individual-level data from the UK Biobank.

Results: Genetically proxied IL-13i was associated with increased risk of PsA (OR 37.39; 95%CI 11.52, 121.34; p=1.64x10^-9), psoriasis (OR 20.08; 4.38, 92.01; p=1.12x10^-4). No consistent associations were found for Crohn’s disease, ulcerative colitis, ankylosing spondylitis or iritis. Colocalization showed no strong evidence for genetic confounding for psoriatic disease. Results were replicated using circulating IgE for the exposure, using independent outcome data, and using individual-level data.

Conclusion: We provide supportive genetic evidence that IL-13i is linked to increased risk of PsA and psoriasis. Physicians prescribing IL-13 inhibitors should be vigilant for these adverse events.