Longitudinal integrated proteomic and metabolomic skin changes in atopic dermatitis patients treated with dupilumab.

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Inhibition of IL-4/IL-13 driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD). To assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment. Skin tape strip (STS) were collected from lesional/non-lesional skin of 20 AD patients during 16-week dupilumab treatment and from 20 healthy volunteers (HV) followed for 16-weeks. STS extracts were examined by LC-MS proteomic analysis and targeted metabolomics. Approximately 2,500 individual proteins were identified in STS extracts. 490 proteins were present in ≥80% of AD and HV skin samples and differentially expressed in AD skin. 249 proteins were significantly reduced (cluster 1) and 136 were significantly increased (cluster 2) in AD skin (both p<0.0001 compared to HV). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes and actin filament proteins. Significant increase in cluster 1 and significant inhibition in cluster 2 proteins expression was achieved in AD skin by 16-weeks of dupilumab treatment (p<0.0001 for both, compared to baseline) and approached HV skin levels. These improvements were also revealed in differential metabolite changes in STS extracts, including amino acids, nucleotide breakdown products and antioxidants. Longitudinal integrated assessment of the skin proteome and metabolome in AD patients treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. Identified changes were linked to improvements in clinical AD skin assessments, including TEWL and disease severity. Mass spectrometry analysis identifies molecular improvements in skin protein and metabolite composition in AD patients and their relationship to targeted suppression of IL-4/IL-13 signaling by dupilumab treatment and clinical response. The study performed longitudinal sampling and analysis of skin samples of AD patients treated by dupilumab and provided evaluation of structural and inflammatory protein components of skin barrier, skin metabolites and their changes on treatment.