204 Abrocitinib reverses the altered immune and skin barrier phenotype in skin biopsies from patients with moderate-to-severe atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterised by cytokine activation and barrier dysfunction. Abrocitinib is a Janus kinase 1-selective inhibitor approved for treatment of moderate-to-severe AD. This post hoc analysis of the phase 2b trial JADE MOA (NCT03915496) examined the effect of abrocitinib on AD biomarker expression using skin biopsies. Adult patients were randomly assigned to receive abrocitinib (200 mg/100 mg) or placebo (12 weeks). Punch biopsies were collected from lesional skin at baseline and weeks 2, 4, and 12 and from nonlesional skin at baseline and week 12; samples were analyzed with RNA sequencing to identify differentially expressed genes (DEGs; fold change >2, false discovery rate <0.05). Correlations between DEGs and clinical severity as assessed by Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA) scores were determined using Spearman correlations. Using skin biopsies from 46 patients, 2264 DEGs were identified across treatment arms and timepoints, including 2260 in the abrocitinib arms. Progressive and dose-dependent modulation of AD-related biomarkers in lesional skin was observed with abrocitinib at either dose, including genes associated with general inflammation (MMP12), hyperplasia (KRT16, S100A7/8/9/12), Th1 (IFNG, CXCL9/10/11), Th2 (IL-13/10/4R/7R, CCL13/17/18), and Th17/22 (IL-22/36A/36G, CCL20, S100A7/8/9/12) mediated inflammation, barrier markers (LOR, CLDN8/23) and negative regulators (IL-34/37). Following treatment with abrocitinib 200 mg, statistically significant and positive correlations were observed between changes in EASI and IGA scores and markers of T-cell activation (IL-2RA), Th2 (IL-13/4R, OX40, CCL18) and Th1 inflammation (OASL, IFNGR1) and Th17/Th22/epidermal hyperplasia (S100A7/8/9, IL-22; r>0.4; P<0.005); negative correlations were observed with barrier markers (FABP7, DGAT2, CDH10/20, CLDN1) and the negative regulator IL-37 (r<−0.4; P<0.05). These results indicate that abrocitinib induces statistically significant and dose-dependent changes in the expression of biomarkers linked to inflammation and epidermal barrier dysfunction in lesional AD skin, which correlate with improvements in disease severity.