Age of onset defines two distinct profiles of atopic dermatitis in adults

Background: The incidence of adult-onset atopic dermatitis (AOAD) is increasing. However, the unique characteristics of AOAD compared to pediatric-onset AD persisting into adulthood (POAD) are underexplored, hampering the development of targeted-therapeutics for this growing population. We thus assessed the profile of AOAD in skin and blood compared to that of POAD. Methods: We collected skin biopsies and blood from adults with AOAD, POAD, and healthy controls (n = 15 in each group). Skin samples were analyzed by RNA sequencing, qRT-PCR, and immunohistochemistry, and Olink Proseek multiplex assay was used to identify the serum proteomic profile. Results: Compared to healthy controls, both AOAD and POAD showed cutaneous immune and barrier dysregulations with a shared Th2/Th22 hyperactivation. Overall, POAD showed greater inflammation in lesional skin, with more prominent expression of Th2/Th17/Th22 markers (CCL17/22, S100A8/9, IL-36A, PI3/Elafin, DEFB4) in POAD compared to AOAD (p-value <.05). In contrast, higher Th1-(IFN-γ, IL-2, IL-15, CCL5) upregulation and Th1-skewing were seen in AOAD. The epidermal barrier was also more compromised in POAD, with greater epidermal hyperplasia and lower expression of markers related to terminal differentiation, lipids, and cell adhesion. In parallel with increased rates of cardiovascular comorbidities, AOAD demonstrated many more significantly dysregulated proteins in serum (n = 148) compared to POAD (n = 86), including pro-inflammatory and cardiovascular-risk markers. Th1-related products showed significant correlations between their skin and blood expressions only in AOAD subjects. Conclusion: Age-of-onset delineates two distinct endophenotypes in adult AD potentially suggesting the need for broader (beyond Th2) therapeutic targeting in AOAD.