IL-13, periostin and dipeptidyl-peptidase-4 reveal endotype-phenotype associations in atopic dermatitis

BackgroundThe heterogeneous (endo)phenotypes of atopic dermatitis (AD) require precision medicine. Currently, systemic therapy is recommended to patients with an Eczema Area and Severity Index (EASI) >= 16. Previous studies have demonstrated an improved treatment response to the anti-interleukin (IL)-13 antibody tralokinumab in AD subgroups with elevated levels of the IL-13-related biomarkers dipeptidyl-peptidase (DPP)-4 and periostin. MethodsHerein, 373 AD patients aged >= 12 years were stratified by IL-13(high), periostin(high) and DPP-4(high) endotypes using cross-sectional data from the ProRaD cohort Bonn. "High" was defined as >80th quantile of 47 non-atopic controls. We analyzed endotype-phenotype associations using machine-learning gradient boosting compared to logistic regression. ResultsAtopic dermatitis severity and eosinophils correlated with IL-13 and periostin levels. Correlations of IL-13 with EASI were stronger in patients with increased (rs = 0.482) than with normal (rs = 0.342) periostin levels. We identified eosinophilia >6% and an EASI range of 5.5-17 dependent on the biomarker combination to be associated with increasing probabilities of biomarker(high) endotypes. Also patients with mild-to-low-moderate severity (EASI < 16) featured increased biomarkers (IL-13(high): 41%, periostin(high): 48.4%, DPP-4(high): 22.3%). Herthoge sign (adjusted Odds Ratio (aOR) = 1.89, 95% Confidence Interval (CI) [1.14-3.14]) and maternal allergic rhinitis (aOR = 2.79-4.47) increased the probability of an IL-13(high)-endotype, "dirty neck" (aOR = 2.83 [1.32-6.07]), orbital darkening (aOR = 2.43 [1.08-5.50]), keratosis pilaris (aOR = 2.21 [1.1-4.42]) and perleche (aOR = 3.44 [1.72-6.86]) of a DPP-4(high)-endotype. ConclusionsA substantial proportion of patients with EASI < 16 featured high biomarker levels suggesting systemic impact of skin inflammation already below the current cut-off for systemic therapy. Our findings facilitate the identification of patients with distinct endotypes potentially linked to response to IL-13-targeted therapy.