AbstractBackgroundTranscriptome analyses of vesicular hand eczema (VHE) indicated a large overlap with atopic dermatitis (AD). However, differentially expressed genes (DEGs) that differentiate VHE from AD are unknown.ObjectiveTo identify distinctive transcriptional features of VHE in comparison to AD.MethodsWe re‐analysed RNA sequencing data of 10 lesional palmar VHE epidermal biopsies and performed DEG analyses. We adjusted the obtained DEG results of 57 lesional whole AD skin biopsies of the upper extremities or trunk to our criteria. Up‐ and down‐regulated DEGs in both skin diseases, VHE‐only, AD‐only, and opposite regulated DEGs were identified. Enrichment analyses and Chi‐squared tests were conducted to test for differences in gene set enrichment between both skin diseases.ResultsComparing 3028 DEGs in VHE (1645 up; 1383 down) with 5391 DEGs in AD (3842 up; 1549 down), revealed 1516 shared DEGs (1179 up; 337 down) and 1512 DEGs unique to VHE (466 up, 1046 down). Interferon signalling and necroptosis were significantly more prominent in VHE compared to AD. Downregulated genes identified only in VHE (like DNASE1L2, KRT2, KRT9 and KRT25) indicate an aberrant epidermal differentiation.ConclusionOur study indicates a common pathophysiology between VHE and AD, but also reveals transcriptional differences between VHE and AD.