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

Laura Maintz; Thomas Welchowski; Nadine Herrmann; Juliette Brauer; Claudia Traidl-Hoffmann; Regina Havenith; Svenja Müller; Claudio Rhyner; Anita Dreher; Matthias Schmid; Thomas Bieber; CK-CARE study group

doi:10.1111/all.15647

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

Allergy. 2023 Jan 17. doi: 10.1111/all.15647. Online ahead of print.

Authors

Laura Maintz^{1

2}, Thomas Welchowski^{2

3}, Nadine Herrmann^{1

2}, Juliette Brauer^{1

2}, Claudia Traidl-Hoffmann^{2

4

5}, Regina Havenith^{1

2}, Svenja Müller^{1

2}, Claudio Rhyner^{2

6}, Anita Dreher^{2

6}, Matthias Schmid³, Thomas Bieber^{1

2

6}; CK-CARE study group

Collaborators

CK-CARE study group:
Thomas Bieber, Peter Schmid-Grendelmeier, Claudia Traidl-Hoffmann, Cezmi Akdis, Roger Lauener, Marie-Charlotte Brüggen, Claudio Rhyner, Nadine Herrmann, Laura Maintz, Eugen Bersuch, Anita Dreher, Avidan Neumann, Gertrud Hammel, Ellen D Renner, Daria Luschkova, Claudia C V Lang, Matthias Reiger

Affiliations

¹ Department of Dermatology and Allergy, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany.
² Christine Kühne Center for Allergy Research and Education Davos (CK-CARE), Herman-Burchard-Str. 1, 7265, Davos, Switzerland.
³ Department of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany.
⁴ Environmental Medicine, Faculty of Medicine, University of Augsburg, Stenglinstraße 2, Augsburg, Germany.
⁵ Institute of Environmental Medicine, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Augsburg, Germany.
⁶ Davos Biosciences, Herman-Burchard-Str. 1, 7265, Davos, Switzerland.

PMID: 36647778
DOI: 10.1111/all.15647

Abstract

Background: The 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.

Methods: Herein, 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 >80^th quantile of 47 non-atopic controls. We analyzed endotype-phenotype associations using machine-learning gradient boosting compared to logistic regression.

Results: AD 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.

Conclusions: A 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.

Keywords: atopic dermatitis; biomarker; endotype; interleukin-13; tralokinumab.