Genetically proxied IL-6 receptor inhibition is associated with increased risk of atopic dermatitis.

Background: Dermatitis has been reported after initiation of IL-6 receptor (IL-6R) inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signaling. However, causality remains unclear. As the indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD.
Objective: Our aim was to examine the association between IL-6Ri and risk of AD.
Methods: To genetically mimic IL-6Ri, we selected single-nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein at genome-wide significance among 343,524 individuals. Genetic data were obtained from 10,788 individuals with AD and 30,047 controls of European ancestry. We used inverse variance-weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated by using 13,473 Finnish and 2,385 East Asian individuals with AD. The results from 3 independent analyses were pooled by meta-analysis.
Results: Genetically proxied IL-6Ri was associated with increased risk of AD (odds ratio [OR] = 1.78 per 4.4-mg/L reduction in C-reactive protein level [95% CI = 1.28-2.48] [P = 6.5 × 10 ^-4 ]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [P = 1.57 × 10 ^-7 ]) and Eastern Asian data (OR = 1.68 [95% CI = 1.12-2.54] [P = .013]). Meta-analysis of 3 independent populations (OR = 1.89 [95% CI = 1.57-2.28] [P = 2.68 × 10 ^-11 ]) showed no evidence of heterogeneity (P = .65). We found no statistical evidence for pleiotropy or genetic confounding.
Conclusion: This genetic investigation provides consistent evidence (across independent multiancestry populations) that IL-6R signaling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases.
Competing Interests: Disclosure statement Supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (grant NIHR203308), as well as by an NIHR Clinical Lectureship (to S.S.Z.) and Versus Arthritis (grants 21173, 21754, and 21755). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)