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

CK-CARE study group

doi:10.1111/all.15647

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

CK-CARE study group

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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

Original language	English
Pages (from-to)	1554-1569
Number of pages	16
Journal	Allergy: European Journal of Allergy and Clinical Immunology
Volume	78
Issue number	6
DOIs	https://doi.org/10.1111/all.15647
State	Published - Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

Funding

We thank the Christine Kühne‐Center for Allergy Research and Education (CK‐CARE), Davos, Switzerland, for funding of the study. The study, Laura Maintz, Thomas Welchowski, Juliette Brauer, Regina Havenith, Svenja Müller, Ellen Renner, Claudio Rhyner and Anita Dreher were supported by or are employees of CK‐CARE. We also thank LEO pharma GmbH, Germany, for covering the costs of biomarker analysis for this study. The funding sources did not participate in study design and conduct, nor in the data collection, management, analysis and interpretation, nor in preparation, review or approval of the manuscript nor in the decision to submit the article for publication. We are grateful to all our study participants, Anna Sophie Kläschen, Nina Evertz, Lisa Braun, and Veronika Ralser‐Isselstein for their help in recruitment of participants in this study, and Sylvia Schnautz, Simone Willms, Helene Kirins, Jolien Oosterveer, and Anja Heider for excellent technical assistance. We are thankful to Beate Rückert for her work with the CK‐CARE biobank and all other co‐workers of the prospective longitudinal study investigating the remission phase in patients with atopic dermatitis and other allergy‐associated diseases (ProRaD). Open Access funding enabled and organized by Projekt DEAL. We thank the Christine Kühne-Center for Allergy Research and Education (CK-CARE), Davos, Switzerland, for funding of the study. The study, Laura Maintz, Thomas Welchowski, Juliette Brauer, Regina Havenith, Svenja Müller, Ellen Renner, Claudio Rhyner and Anita Dreher were supported by or are employees of CK-CARE. We also thank LEO pharma GmbH, Germany, for covering the costs of biomarker analysis for this study. The funding sources did not participate in study design and conduct, nor in the data collection, management, analysis and interpretation, nor in preparation, review or approval of the manuscript nor in the decision to submit the article for publication. We are grateful to all our study participants, Anna Sophie Kläschen, Nina Evertz, Lisa Braun, and Veronika Ralser-Isselstein for their help in recruitment of participants in this study, and Sylvia Schnautz, Simone Willms, Helene Kirins, Jolien Oosterveer, and Anja Heider for excellent technical assistance. We are thankful to Beate Rückert for her work with the CK-CARE biobank and all other co-workers of the prospective longitudinal study investigating the remission phase in patients with atopic dermatitis and other allergy-associated diseases (ProRaD). Open Access funding enabled and organized by Projekt DEAL.

Funders	Funder number
LEO pharma GmbH
Christine Kühne – Center for Allergy Research and Education

Keywords

atopic dermatitis
biomarker
endotype
interleukin-13
tralokinumab

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10.1111/all.15647

Cite this

@article{d89497814d4b41b59d188933f537230d,

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

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-13high, periostinhigh and DPP-4high 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. Results: Atopic 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 biomarkerhigh endotypes. Also patients with mild-to-low-moderate severity (EASI < 16) featured increased biomarkers (IL-13high: 41%, periostinhigh: 48.4%, DPP-4high: 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-13high-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-4high-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",

author = "{CK-CARE study group} and Laura Maintz and Thomas Welchowski and Nadine Herrmann and Juliette Brauer and Claudia Traidl-Hoffmann and Regina Havenith and Svenja M{\"u}ller and Claudio Rhyner and Anita Dreher and Matthias Schmid and Thomas Bieber and Peter Schmid-Grendelmeier and Cezmi Akdis and Roger Lauener and Br{\"u}ggen, {Marie Charlotte} and Eugen Bersuch and Avidan Neumann and Gertrud Hammel and Renner, {Ellen D.} and Daria Luschkova and Lang, {Claudia C.V.} and Matthias Reiger",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.",

year = "2023",

month = jun,

doi = "10.1111/all.15647",

language = "אנגלית",

volume = "78",

pages = "1554--1569",

journal = "Allergy: European Journal of Allergy and Clinical Immunology",

issn = "0105-4538",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "6",

}

TY - JOUR

T1 - IL-13, periostin and dipeptidyl-peptidase-4 reveal endotype-phenotype associations in atopic dermatitis

AU - CK-CARE study group

AU - Maintz, Laura

AU - Welchowski, Thomas

AU - Herrmann, Nadine

AU - Brauer, Juliette

AU - Traidl-Hoffmann, Claudia

AU - Havenith, Regina

AU - Müller, Svenja

AU - Rhyner, Claudio

AU - Dreher, Anita

AU - Schmid, Matthias

AU - Bieber, Thomas

AU - Schmid-Grendelmeier, Peter

AU - Akdis, Cezmi

AU - Lauener, Roger

AU - Brüggen, Marie Charlotte

AU - Bersuch, Eugen

AU - Neumann, Avidan

AU - Hammel, Gertrud

AU - Renner, Ellen D.

AU - Luschkova, Daria

AU - Lang, Claudia C.V.

AU - Reiger, Matthias

PY - 2023/6

Y1 - 2023/6

N2 - 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-13high, periostinhigh and DPP-4high 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. Results: Atopic 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 biomarkerhigh endotypes. Also patients with mild-to-low-moderate severity (EASI < 16) featured increased biomarkers (IL-13high: 41%, periostinhigh: 48.4%, DPP-4high: 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-13high-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-4high-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.

AB - 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-13high, periostinhigh and DPP-4high 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. Results: Atopic 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 biomarkerhigh endotypes. Also patients with mild-to-low-moderate severity (EASI < 16) featured increased biomarkers (IL-13high: 41%, periostinhigh: 48.4%, DPP-4high: 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-13high-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-4high-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.

KW - atopic dermatitis

KW - biomarker

KW - endotype

KW - interleukin-13

KW - tralokinumab

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JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

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ER -

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

Abstract

Bibliographical note

Funding

Keywords

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