Comprehensive proteome profiling of molecular endotypes in Japanese adults with moderate-to-severe atopic dermatitis.

Introduction: Atopic dermatitis (AD) is an inflammatory skin disease that is heterogeneous in clinical presentation and biological mechanisms. Several studies have suggested biomarker-defined molecular endotypes in AD. This study aimed to characterize potential endotypes in Japanese patients with moderate-to-severe AD and comprehensively evaluate their circulating protein profiles to better understand disease etiology. Methods: Serum samples from Japanese patients with moderate-to-severe AD (n = 73) enrolled in a phase 3 study of baricitinib (BREEZE-AD2; NCT03334422) and samples from healthy controls (n = 15) were analyzed using the Olink Explore 1536 assay. Patient clusters were identified through k-means clustering. Differential expression analysis and weighted gene co-expression network analysis were performed for in-depth examination of proteomic profiles. Results: Two patient clusters, characterized by high (AD_HI) and low (AD_LO) inflammatory profiles, were found to be stable and reproducible. Canonical AD inflammatory mediators-including interleukin (IL)-13, IL-19, pulmonary and activation-regulated chemokine (PARC), thymus and activation-regulated chemokine (TARC), chemokine (C-C motif) ligand (CCL)22, CCL26, and CCL27-were upregulated in both clusters, with greater upregulation in the AD_HI cluster. Additionally, proteins not typically associated with AD-related inflammation were upregulated in AD_HI patients. The AD_HI cluster was associated with protein networks representing a range of immune and non-immune pathways. Dysregulated protein signatures associated with the AD_HI cluster were also correlated with skin-based disease severity scores. Conclusion: This study characterizes the circulating proteome and clinical characteristics across putative molecular endotypes in AD. The findings corroborate current knowledge on AD pathophysiology and suggest other axes of dysregulation in a subset of patients with AD. These results may support the development of personalized therapeutic approaches.