“Genomic and phenotypic characterization of Investigator Global Assessment (IGA) scale based endotypes in atopic dermatitis”

Abstract

Background: Atopic dermatitis (AD) is a heritable and heterogeneous inflammatory chronic skin disorder. Utilizing decision tree/ supervised learning of extensive clinical, molecular and genetic data, we aimed to define distinct AD endotypes. Methods: Deep phenotyping and whole-genome sequencing was performed on samples obtained from participants of EPIONE, a phase III study in AD patients with severe pruritus: mild (23%) to moderate (64%) and severe (13%) as determined by validated Investigator Global Assessment scale for Atopic dermatitis (vIGA-ADTM). Three categories of analysis were performed: clinical associations, lab value associations (EOS, IgE, cytokines) and genetic analysis of whole-genome sequencing data Results: Based on a decision tree, we found that mild AD presents with fewer lesions with mild erythema and minimal induration/papulation or oozing/crusting. In contrast, severe AD presents with a larger number of erythematous lesions associated with significant induration/papulation or oozing/crusting. We observe significant differences between severity and eosinophil counts (p < 0.001), IgE (p < 0.001) and Filaggrin (FLG) LOF frequency (OR 2.3 CI 1.6-3.2 p < 0.0001) as well as interleukin pathway genes, specifically IL5RA variants differentiating the groups. Conclusion: Our results suggest significant differences between severity groups across a number of features appear to constitute distinct endotypes with likely distinct causative factors. Differing underlying pathophysiologies indicate endotype knowledge is critical to help guide therapeutic approaches to AD.

Neurokinin‐1 receptor antagonist tradipitant has mixed effects on itch in atopic dermatitis: results from EPIONE, a randomized clinical trial

“…It is possible that the immediate and robust improvements observed in the mild AD subgroup were seen not only because of different levels of cutaneous inflammation between AD severities but also because of distinct AD endotypes including different clinical manifestations, molecular levels and genetic associations. 10 The concept of different endotypes in AD underlines the need for targeted therapeutics in different AD disease types. 11 Itch related to nerve hypersensitivity causes increased scratching which worsens eczema and induces excoriations.…”