LAUSR

Inhibitors of the IL-13 pathway, such as dupilumab and tralokinumab, are licensed to treat atopic diseases such as eczema and asthma. Musculoskeletal adverse events that resemble enthesitis and psoriatic arthritis (PsA) after dupilumab initiation have been reported, but evidence is limited to case reports and spontaneous pharmacovigilance with uncertain causal inference. Naturally occurring genetic variation in drug targets can provide insight into their potential adverse effects. We used population-level data to investigate whether genetically proxied IL-13 inhibition (IL-13i) increases risk of PsA and other spondyloarthritis-related diseases. Dupilumab is recognised to reduce eosinophil count in clinical studies; we therefore used it as the biomarker of IL-13i. We instrumented IL-13i using missense (protein coding) variants within the IL13 gene that are associated with circulating eosinophil count at genome-wide significance (p < 5x10-8) in a study of 563,946 individuals. Outcome genetic associations were taken from studies of PsA, psoriasis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis and iritis. To examine instrument validity, we used atopic eczema and asthma as positive control outcomes, and rheumatoid arthritis as a negative control. We used the ratio method, with estimates scaled to per standard deviation (SD ∼0.14x109/L) reduction in eosinophil count. One missense variant, rs20541, was selected to proxy IL-13i. Genetically proxied IL-13i was associated with increased risk of PsA (OR 37.39; 95%CI 11.52, 121.34), psoriasis (OR 20.08; 4.38, 92.01), Crohn’s disease (OR 3.49; 1.38, 8.81), but not ulcerative colitis, ankylosing spondylitis or iritis. IL-13i was associated with reduced risk of positive control outcomes, but not with the negative control (Table 1). Genetically proxied IL-13 inhibition is associated with increased risk of PsA, psoriasis and Crohn’s disease, which may be a class effect relevant to other IL-13i that are not yet reported to have Th17-type adverse events. These findings are compatible with the hypothesis that Th2 cytokines IL-4/-13 may act as a restraint toward Th17-type disease activation in some organs. Clinicians assessing adverse events after dupilumab initiation should be aware of incident PsA and related features. This study demonstrates the value of MR in evaluating rare adverse events in the study of drug safety. Disclosure S. Zhao: None. K.L. Hyrich: None. Z.Z.N. Yiu: None. A. Barton: None. J. Bowes: None.