Biomarkers in atopic dermatitis

Atopic dermatitis (AD) is a complex and highly heterogeneous inflammatory skin disease. Given the highly heterogeneous character of AD, it is unlikely that every patient will respond equally to a particular treatment. The recent introduction of novel targeted therapies for AD has driven the need for patient stratification based on immunologic biomarkers. We have reviewed the use of different types of biomarkers as potential tools in the movement toward personalized medicine in AD, comprising different ways of endotyping patients with AD based on immunologic profiles and predictive biomarkers. The application of biomarkers will result in better characterization and stratification of patients and allow better comparison of current and new treatments. The ultimate goal will be to switch from the current generalized “one-drug-fits-all” management to more personalized “patient endotype–specific” management. Atopic dermatitis (AD) is a complex and highly heterogeneous inflammatory skin disease. Given the highly heterogeneous character of AD, it is unlikely that every patient will respond equally to a particular treatment. The recent introduction of novel targeted therapies for AD has driven the need for patient stratification based on immunologic biomarkers. We have reviewed the use of different types of biomarkers as potential tools in the movement toward personalized medicine in AD, comprising different ways of endotyping patients with AD based on immunologic profiles and predictive biomarkers. The application of biomarkers will result in better characterization and stratification of patients and allow better comparison of current and new treatments. The ultimate goal will be to switch from the current generalized “one-drug-fits-all” management to more personalized “patient endotype–specific” management. Atopic dermatitis (AD) is a common though complex and highly heterogeneous inflammatory skin disease. Its pathophysiology is thought to be the result of both genetic and environmental factors, resulting in immunologic and barrier dysfunctions.1Eyerich K. Novak N. Immunology of atopic eczema: overcoming the Th1/Th2 paradigm.Allergy. 2013; 68: 974-982Crossref PubMed Scopus (236) Google Scholar The current treatment guidelines for AD focus mainly on disease severity measured by using clinical scores; they do not take the individual pathogenesis of the disease into account. Given the highly heterogeneous character of AD, it is unlikely that every patient will respond equally to a particular treatment. The recent introduction of novel targeted therapies for AD has driven the need for patient stratification based on immunologic biomarkers. The increased use of biomarkers in AD research will result in objective outcome measures allowing better comparison of current and new treatments. Furthermore, biomarkers may provide us with a better understanding of the pathogenesis of AD and enable better characterization and stratification of patients with AD, further enabling more personalized clinical care. According to the US Food and Drug Administration, a biomarker is “a defined characteristic that is measured as an indicator of normal biologic processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.” Biomarkers can be broadly separated into 2 categories (Fig 1, A). The first category comprises biomarkers that are used to identify persons at risk of developing a disease (screening biomarkers), patients with active disease (diagnostic biomarkers), disease recurrence or progression in patients who have the disease (prognostic biomarkers), and the populations of patients that are most likely to benefit from a given therapy (predictive biomarkers). The second category includes biomarkers for monitoring treatment effects (disease severity biomarkers) and possible side effects (pharmacodynamics biomarkers) (Fig 1). Biomarkers can be defined not only from genomics, transcriptomics, and proteomics (such as cytokines and chemokines) data but also from morphologic information (eg, immunohistochemical staining).2Renert-Yuval Y. Thyssen J.P. Bissonnette R. Bieber T. Kabashima K. Hijnen D. et al.Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council.J Allergy Clin Immunol. 2021; 147: 1174-1190.e1Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Moreover, they can be measured in different sample types, such as blood, saliva, and urine, or in tissue samples, including skin biopsy samples and tape strips. Although many different potential biomarkers have been identified for AD, none of them has yet been implemented in daily practice. Clinical characteristics such as age of onset, persistence of disease after childhood, and presence of other atopic diseases such as allergic rhinitis and asthma have been used to divide AD into different disease phenotypes.3Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine.Allergy. 2012; 67: 1475-1482Crossref PubMed Scopus (90) Google Scholar However, clinical phenotypes do not necessarily relate to, or give insights into, the underlying disease mechanisms, and they might be less suitable than molecular markers for defining those subpopulations of patients with AD that are the best candidates for various treatments. It has become increasingly clear that not only is AD heterogeneous based on clinical characteristics but also that different underlying pathophysiologic processes can be seen in different subgroups of patients. Because of this heterogeneity, it is unlikely that newly developed biologic drugs targeting specific components of the immune system will be effective in all patients with AD. Thus, defining disease endotypes based on the most important pathophysiologic mechanisms at the cellular and molecular levels driving the disease has become an important development for stratification of patients with AD. Predictive biomarkers can subsequently be used to identify and select the specific endotype that will respond to a targeted treatment (Fig 2). Several ways of endotyping patients with AD have been described (Table I4Thijs J.L. Strickland I. Bruijnzeel-Koomen C. Nierkens S. Giovannone B. Csomor E. et al.Moving toward endotypes in atopic dermatitis: identification of patient clusters based on serum biomarker analysis.J Allergy Clin Immunol. 2017; 140: 730-737Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 5Bakker D.S. Nierkens S. Knol E.F. Giovannone B. Delemarre E.M. van der Schaft J. et al.Confirmation of multiple endotypes in atopic dermatitis based on serum biomarkers.J Allergy Clin Immunol. 2021; 147: 189-198Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 6Sims J.T. Chang C.Y. Higgs R.E. Engle S.M. Liu Y. Sissons S.E. et al.Insights into adult atopic dermatitis heterogeneity derived from circulating biomarker profiling in patients with moderate-to-severe disease.Exp Dermatol. 2021; 30: 1650-1661Crossref PubMed Scopus (12) Google Scholar, 7Möbus L. Rodriguez E. Harder I. Boraczynski N. Szymczak S. Hubenthal M. et al.Blood transcriptome profiling identifies 2 candidate endotypes of atopic dermatitis.J Allergy Clin Immunol. 2022; 150: 385-395Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 8He H. Li R. Choi S. Zhou L. Pavel A. Estrada Y.D. et al.Increased cardiovascular and atherosclerosis markers in blood of older patients with atopic dermatitis.Ann Allergy Asthma Immunol. 2020; 124: 70-78Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 9Zhou L. Leonard A. Pavel A.B. Malik K. Raja A. Glickman J. et al.Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.J Allergy Clin Immunol. 2019; 144: 144-156Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 10Wen H.C. Czarnowicki T. Noda S. Malik K. Pavel A.B. Nakajima S. et al.Serum from Asian patients with atopic dermatitis is characterized by TH2/TH22 activation, which is highly correlated with nonlesional skin measures.J Allergy Clin Immunol. 2018; 142: 324-328.e11Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 11Suarez-Farinas M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar, 12Martel B.C. Litman T. Hald A. Norsgaard H. Lovato P. Dyring-Andersen B. et al.Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis.Exp Dermatol. 2016; 25: 453-459Crossref PubMed Scopus (51) Google Scholar, 13Esaki H. Brunner P.M. Renert-Yuval Y. Czarnowicki T. Huynh T. Tran G. et al.Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin.J Allergy Clin Immunol. 2016; 138: 1639-1651Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 14Noda S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar, 15Chan T.C. Sanyal R.D. Pavel A.B. Glickman J. Zheng X. Xu H. et al.Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features.J Allergy Clin Immunol. 2018; 142: 1013-1017Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 16Sanyal R.D. Pavel A.B. Glickman J. Chan T.C. Zheng X. Zhang N. et al.Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation.Ann Allergy Asthma Immunol. 2019; 122: Full Text Full Text PDF PubMed Scopus Google Scholar, P.M. Pavel A.B. S. Leonard A. Malik K. S. et in patients with atopic dermatitis tissue responses to Allergy Clin 2019; Full Text Full Text PDF PubMed Scopus Google Scholar, N. E. C. Kim L. P. et skin tape identifies novel characteristics of the atopic dermatitis disease Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Y. H. et of the barrier are a for atopic PubMed Scopus Google Scholar, A. D. A. et but other in patients with atopic Dermatol. PubMed Scopus Google Scholar, with skin and allergic PubMed Scopus Google have to endotype AD using a by the immunologic of subgroups based on specific patient such as treatment P.M. Pavel A.B. S. Leonard A. Malik K. S. et in patients with atopic dermatitis tissue responses to Allergy Clin 2019; Full Text Full Text PDF PubMed Scopus Google Scholar intrinsic or extrinsic M. Dhingra N. Gittler J. Shemer A. Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (348) Google B.C. Litman T. Hald A. Norsgaard H. Lovato P. Dyring-Andersen B. et al.Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis.Exp Dermatol. 2016; 25: 453-459Crossref PubMed Scopus (51) Google Scholar and or patient pediatric adult patients with H. Brunner P.M. Renert-Yuval Y. Czarnowicki T. Huynh T. Tran G. et al.Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin.J Allergy Clin Immunol. 2016; 138: 1639-1651Abstract Full Text Full Text PDF PubMed Scopus (273) Google P.M. H. Pavel A.B. Czarnowicki T. R. T. et al.The blood of pediatric atopic dermatitis shows and is from adult Dermatol. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar older H. Li R. Choi S. Zhou L. Pavel A. Estrada Y.D. et al.Increased cardiovascular and atherosclerosis markers in blood of older patients with atopic dermatitis.Ann Allergy Asthma Immunol. 2020; 124: 70-78Abstract Full Text Full Text PDF PubMed Scopus (51) Google L. Leonard A. Pavel A.B. Malik K. Raja A. Glickman J. et al.Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.J Allergy Clin Immunol. 2019; 144: 144-156Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar and African Asian and H.C. Czarnowicki T. Noda S. Malik K. Pavel A.B. Nakajima S. et al.Serum from Asian patients with atopic dermatitis is characterized by TH2/TH22 activation, which is highly correlated with nonlesional skin measures.J Allergy Clin Immunol. 2018; 142: 324-328.e11Abstract Full Text Full Text PDF PubMed Scopus (39) Google S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (410) Google R.D. Pavel A.B. Glickman J. Chan T.C. Zheng X. Zhang N. et al.Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation.Ann Allergy Asthma Immunol. 2019; 122: Full Text Full Text PDF PubMed Scopus Google Scholar The of are in of on endotyping clusters of patients with AD with a specific of inflammatory et J.L. Strickland I. Bruijnzeel-Koomen C. Nierkens S. Giovannone B. Csomor E. et al.Moving toward endotypes in atopic dermatitis: identification of patient clusters based on serum biomarker analysis.J Allergy Clin Immunol. 2017; 140: 730-737Abstract Full Text Full Text PDF PubMed Scopus (106) Google of clusters of patients with AD with a specific of inflammatory et D.S. Nierkens S. Knol E.F. Giovannone B. Delemarre E.M. van der Schaft J. et al.Confirmation of multiple endotypes in atopic dermatitis based on serum biomarkers.J Allergy Clin Immunol. 2021; 147: 189-198Abstract Full Text Full Text PDF PubMed Scopus (41) Google AD et J.T. Chang C.Y. Higgs R.E. Engle S.M. Liu Y. 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Cardinale I. de Guzman Strong C. et al.Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.J Allergy Clin Immunol. 2013; 132: 361-370Abstract Full Text Full Text PDF PubMed Scopus (348) Google of and in intrinsic AD compared with in extrinsic et B.C. Litman T. Hald A. Norsgaard H. Lovato P. Dyring-Andersen B. et al.Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis.Exp Dermatol. 2016; 25: 453-459Crossref PubMed Scopus (51) Google higher of TH17 cytokines and and and markers than et H. Brunner P.M. Renert-Yuval Y. Czarnowicki T. Huynh T. Tran G. et al.Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin.J Allergy Clin Immunol. 2016; 138: 1639-1651Abstract Full Text Full Text PDF PubMed Scopus (273) Google Asian AD a specific endotype et S. Suarez-Farinas M. Ungar B. Kim S.J. de Guzman Strong C. Xu H. et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.J Allergy Clin Immunol. 2015; 136: 1254-1264Abstract Full Text Full Text PDF PubMed Scopus (410) Google Chinese AD a specific endotype et T.C. Sanyal R.D. Pavel A.B. Glickman J. Zheng X. Xu H. et al.Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features.J Allergy Clin Immunol. 2018; 142: 1013-1017Abstract Full Text Full Text PDF PubMed Scopus (64) Google African American AD is characterized by and TH17 et R.D. Pavel A.B. Glickman J. Chan T.C. Zheng X. Zhang N. et al.Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation.Ann Allergy Asthma Immunol. 2019; 122: Full Text Full Text PDF PubMed Scopus Google in patients with AD tissue responses to et P.M. Pavel A.B. S. Leonard A. Malik K. 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E. of drugs in atopic dermatitis by clinical and molecular measures.J Allergy Clin 2020; Full Text Full Text PDF PubMed Scopus Google Scholar that have been to to targeted in AD based on biomarkers the presence of skin for treatment with P.M. Pavel A.B. S. Leonard A. Malik K. S. et in patients with atopic dermatitis tissue responses to Allergy Clin 2019; Full Text Full Text PDF PubMed Scopus Google Scholar and serum of the markers and for A. E. C. C. et and of in adult patients with to atopic dermatitis (AD) Dermatol. 2017; A. E. C. K. et of atopic dermatitis with an Allergy Clin Immunol. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar data from clinical in patients with AD do not or D. Bieber T. et for the treatment of moderate-to-severe atopic dermatitis: from the Dermatol. 2021; PubMed Scopus Google A. A. E. M. C. J.P. et for moderate-to-severe atopic dermatitis: from and Dermatol. 2021; PubMed Scopus Google Scholar are data that endotypes respond to different and current biomarkers are not yet in the specific endotype that will respond to a targeted treatment. with patients in the other 2 patients stratified into the and clusters in of et J.L. Strickland I. Bruijnzeel-Koomen C. Nierkens S. Giovannone B. Csomor E. et al.Moving toward endotypes in atopic dermatitis: identification of patient clusters based on serum biomarker analysis.J Allergy Clin Immunol. 2017; 140: 730-737Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar and et D.S. Nierkens S. Knol E.F. Giovannone B. Delemarre E.M. van der Schaft J. et al.Confirmation of multiple endotypes in atopic dermatitis based on serum biomarkers.J Allergy Clin Immunol. 2021; 147: 189-198Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar of the levels of 2 cytokines and by using skin et that of patients with AD a inflammatory N. E. C. Kim L. P. et skin tape identifies novel characteristics of the atopic dermatitis disease Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar patients be the most candidates for including D. Bieber T. R. et treatment in with moderate-to-severe atopic PubMed Scopus Google Scholar A. E. C. K. et of atopic dermatitis with an Allergy Clin Immunol. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar and C. Bieber T. H. A. et and of in with moderate-to-severe atopic dermatitis by a Dermatol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar by the biomarkers and as predictive biomarkers for A. E. C. C. et and of in adult patients with to atopic dermatitis (AD) Dermatol. 2017; A. E. C. K. et of atopic dermatitis with an Allergy Clin Immunol. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar are in to treatment the different stratified into the 2 endotypes might need a such as the E. D. H.C. K. et in with to atopic dermatitis: from a Allergy Clin Immunol. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar Bissonnette R. Zhang C. et and of for patients with atopic dermatitis: a 2 clinical Dermatol. 2019; PubMed Scopus Google Scholar and E. A. R. et in adult patients with moderate-to-severe atopic dermatitis: a 2 Dermatol. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar in the endotype by et L. Rodriguez E. Harder I. Boraczynski N. Szymczak S. Hubenthal M. et al.Blood transcriptome profiling identifies 2 candidate endotypes of atopic dermatitis.J Allergy Clin Immunol. 2022; 150: 385-395Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar might benefit more from such as or the which is in a of the used skin biopsy samples to endotyping in AD. Because of skin biopsy samples are to use in clinical and as as in pediatric Y. Thyssen J.P. Bissonnette R. Bieber T. Kabashima K. Hijnen D. et al.Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council.J Allergy Clin Immunol. 2021; 147: 1174-1190.e1Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Although the skin is the of AD, of disease might be only into skin and biomarker might be a more to a disease as AD to J.L. Strickland I. Bruijnzeel-Koomen C. Nierkens S. Giovannone B. Knol E.F. et al.Serum biomarker profiles that atopic dermatitis is a Allergy Clin Immunol. 2018; Full Text Full Text PDF PubMed Scopus (41) Google P.M. Suarez-Farinas M. H. Malik K. H.C. J. et al.The atopic dermatitis blood is characterized by in inflammatory and cardiovascular risk 2017; PubMed Scopus Google Scholar the use of serum has effective in different immunologic endotypes of AD as as in disease J.L. Strickland I. Bruijnzeel-Koomen C. Nierkens S. Giovannone B. Csomor E. et al.Moving toward endotypes in atopic dermatitis: identification of patient clusters based on serum biomarker analysis.J Allergy Clin Immunol. 2017; 140: 730-737Abstract Full Text Full Text PDF PubMed Scopus (106) Google M. M. J. et persistence of atopic dermatitis in using clinical and serum 2020; PubMed Scopus (12) Google J.L. J. R. Strickland I. A. et a of serum biomarkers an objective for disease severity in atopic dermatitis Allergy Clin Immunol. 2017; 140: Full Text Full Text PDF PubMed Scopus Google Scholar, J.L. J. Bruijnzeel-Koomen C. Giovannone B. Knol E.F. de et disease severity in atopic dermatitis patients with 2019; Google Scholar, van der Schaft J. D.S. D. T. et is effective in a of adult atopic dermatitis first clinical and biomarker from the 2020; PubMed Scopus Google Scholar Because of blood biomarkers might be to or and side AD is toward an of more targeted the application of biomarkers will result in better characterization and stratification of patients and allow better comparison of current and new treatments. Given the of targeting specific it is important to patients based on the most important immunologic of AD to them based on clinical the ultimate goal of a for of treatment it is to to a in which a of biomarkers are to treatment and can be for use in daily practice. The ultimate goal will be to switch from the current generalized “one-drug-fits-all” management to more personalized “patient endotype–specific” management.