Biomarkers in atopic dermatitis—a review on behalf of the International Eczema Council
Authors: Yael Renert-Yuval, Jacob P. Thyssen, Robert Bissonnette, Thomas Bieber, Kenji Kabashima, DirkJan Hijnen, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2021)

Atopic dermatitis (AD) is a common yet complex skin disease, posing a therapeutic challenge with increasingly recognized different phenotypes among variable patient populations. Because therapeutic response may vary on the basis of heterogeneous clinical and molecular phenotypes, a shift toward precision medicine approaches may improve AD management. Herein, we will consider biomarkers as potential instruments in the toolbox of precision medicine in AD and will review the process of biomarker development and validation, the opinion of AD experts on the use of biomarkers, types of biomarkers, encompassing biomarkers that may improve AD diagnosis, biomarkers reflecting disease severity, and those potentially predicting AD development, concomitant atopic diseases, or therapeutic response, and current practice of biomarkers in AD. We found that chemokine C-C motif ligand 17/thymus and activation-regulated chemokine, a chemoattractant of TH2 cells, has currently the greatest evidence for robust correlation with AD clinical severity, at both baseline and during therapy, by using the recommendations, assessment, development, and evaluation approach. Although the potential of biomarkers in AD is yet to be fully elucidated, due to the complexity of the disease, a comprehensive approach taking into account both clinical and reliable, AD-specific biomarker evaluations would further facilitate AD research and improve patient management. Atopic dermatitis (AD) is a common yet complex skin disease, posing a therapeutic challenge with increasingly recognized different phenotypes among variable patient populations. Because therapeutic response may vary on the basis of heterogeneous clinical and molecular phenotypes, a shift toward precision medicine approaches may improve AD management. Herein, we will consider biomarkers as potential instruments in the toolbox of precision medicine in AD and will review the process of biomarker development and validation, the opinion of AD experts on the use of biomarkers, types of biomarkers, encompassing biomarkers that may improve AD diagnosis, biomarkers reflecting disease severity, and those potentially predicting AD development, concomitant atopic diseases, or therapeutic response, and current practice of biomarkers in AD. We found that chemokine C-C motif ligand 17/thymus and activation-regulated chemokine, a chemoattractant of TH2 cells, has currently the greatest evidence for robust correlation with AD clinical severity, at both baseline and during therapy, by using the recommendations, assessment, development, and evaluation approach. Although the potential of biomarkers in AD is yet to be fully elucidated, due to the complexity of the disease, a comprehensive approach taking into account both clinical and reliable, AD-specific biomarker evaluations would further facilitate AD research and improve patient management. Atopic dermatitis (AD) is a complex disorder in which gene-gene and gene-environment interactions contribute to generate a highly heterogeneous clinical phenotype.1Bieber T. Traidl-Hoffmann C. Schappi G. Lauener R. Akdis C. Schmid-Grendlmeier P. Unraveling the complexity of atopic dermatitis: the CK-CARE approach towards precision medicine.Allergy. 2020; 75: 2936-2938Crossref PubMed Scopus (4) Google Scholar This heterogeneity likely reflects yet-to-be-defined mechanisms, coupled with clinical relevance we are only beginning to grasp. Progress in our understanding of the role of microbiome, epidermal barrier function, and different cytokines and other immune mediators underlying the chronic AD inflammation has led to an unprecedented number of new compounds in clinical development, for both the topical and systemic therapy of AD.2Renert-Yuval Y. Guttman-Yassky E. What's new in atopic dermatitis.Dermatol Clin. 2019; 37: 205-213Abstract Full Text Full Text PDF PubMed Google Scholar However, thus far none of the therapeutic approaches can be considered a magic bullet, or a "one-size-fits-all" agent. When using stringent end points such as percent of patients reaching investigator's global assessment 0/1 with a 2-grade decrease or Eczema Area and Severity Index-90 in a monotherapy study design (ie, without adding topical/systemic anti-inflammatory medications), it appears that both biologics that specifically target cytokines or their receptors and broad-acting Janus kinase inhibitors fail to fully control AD in most patients.3Han Y. Chen Y. Liu X. Zhang J. Su H. Wen H. et al.Efficacy and safety of dupilumab for the treatment of adult atopic dermatitis: a meta-analysis of randomized clinical trials.J Allergy Clin Immunol. 2017; 140: 888-891.e6Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 4Wollenberg A. Howell M.D. Guttman-Yassky E. Silverberg J.I. Kell C. Ranade K. et al.Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb.J Allergy Clin Immunol. 2019; 143: 135-141Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 5Simpson E.L. Flohr C. Eichenfield L.F. Bieber T. Sofen H. Taieb A. et al.Efficacy and safety of lebrikizumab (an anti-IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: a randomized, placebo-controlled phase II trial (TREBLE).J Am Acad Dermatol. 2018; 78: 863-871.e11Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 6Guttman-Yassky E. Silverberg J.I. Nemoto O. Forman S.B. Wilke A. Prescilla R. et al.Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study.J Am Acad Dermatol. 2019; 80: 913-921.e9Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Hence, particularly considering the complexity of AD, there is a need to shift toward precision medicine approaches to improve AD management. Biomarkers have always existed for different purposes in medicine, principally as a diagnostic tool. However, AD diagnosis and treatment, as opposed to many other chronic diseases, relies completely on clinical scores rather than biochemical markers. Thus, a reliable biomarker will reduce observatory differences. Herein, we will consider biomarkers as potential instruments in the toolbox of precision medicine in AD. Biomarkers may have tremendous implications in prevention strategies and, most importantly, in strategies used for the development of upcoming new compounds on the background of stringent regulatory landscapes. In this regard, the definition of a biomarker given by regulatory organizations is particularly helpful but obviously not universal. The Food and Drug Administration (FDA) has adopted a rather broad definition: "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." The FDA also adds the following comment: "Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. A biomarker is not an assessment of how an individual feels, functions, or survives." Interestingly, the European Medicines Agency has another, more restrictive definition: "A biological molecule found in blood, other body fluids, or tissues that can be used to follow body processes and diseases in humans and animals." In the process of biomarker discovery, one should distinguish between the kind of biologic material (or its origin) on one hand and the purpose/value of the biomarker on the other hand. For the first group, a wide range of biologic material can be used such as (1) genomic information (eg, specific gene sequences or epigenetic modification of genes), (2) transcriptomic profiles obtained by analysis of mRNA and miRNA, (3) proteins such as cytokines and other mediators from body fluids (whole blood, serum, plasma, tissue fluids) or tape stripping, and (4) morphological information (immunohistochemical staining and pictures thereof). This is to be distinguished from the purpose/value of biomarkers with 7 different subtypes as defined by the FDA-NIH Biomarker Working Group (www.ncbi.nlm.nih.gov/books/NBK326791/): (1) susceptibility/risk, (2) diagnostic, (3) monitoring/severity, (4) prognostic, (5) predictive, (6) pharmacodynamic/response, and (7) safety. All these subtypes could potentially be of importance in the context of the management of AD. Unfortunately, the literature and the classical understanding thereof in the scientific community has generated the idea that a biomarker can be easily described and used in the context of disease management. In reality, bringing a given biomarker from discovery to clinical practice and regulatory acceptance in clinical development and/or as a companion diagnostic is a rather complex procedure, widely underestimated by most scientists, which is often comparable to a drug development process. There are several crucial steps in the evolution of a biomarker before it reaches the status of qualification in clinical practice. In a nutshell, the life of a biomarker starts with its discovery, which can be either by chance or the product of a hypothesis-driven biomarker discovery program based on a patient registry collecting high-quality phenotypical data linked to a biobank with several hundreds of specimens from these patients. The next step is a first (internal) analytical and clinical validation in a limited number of clinical cases. Thereafter, the biomarker must undergo another (external) validation step, ideally from independent institutions, using a large cohort of patients where the reproducibility is key. Once this goal of internal and external validation is reached, the biomarker is subjected to a complex process of regulatory qualification, which is supported by a number of guidance documents from the regulatory agencies (FDA, European Medicines Agency). Thus, developing a newly discovered biomarker to the stage of an accepted companion diagnostic for the management of a disease is a complex and demanding process. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach offers a system for rating quality of evidence, with a structured process for developing and presenting evidence summary.7Guyatt G. Oxman A.D. Akl E.A. Kunz R. Vist G. Brozek J. et al.GRADE guidelines, 1: introduction—GRADE evidence profiles and summary of findings tables.J Clin Epidemiol. 2011; 64: 383-394Abstract Full Text Full Text PDF PubMed Scopus (3344) Google Scholar Herein, we searched for AD-related publications that included correlation analysis and found a significant (P < .05) correlation coefficient of greater than or equal to 0.4 between AD clinical severity and blood/skin potential biomarkers, both at baseline and during various AD treatments, and across both pediatric and adult patients. Biomarkers that were found to robustly correlate with AD clinical severity in more than 3 publications were included in this review. Next, we summarized these findings using the GRADE approach, in which accumulated evidence per each potential biomarker (separated by pediatric and adults, and at baseline and during topical and systemic treatments) was graded on the basis of strength of the overall published data, given our inclusion threshold. The International Eczema Council (IEC) consists of more than 100 councilors and associates (https://www.eczemacouncil.org/), all experts in AD. Before the IEC meeting at the Society of Investigative Dermatology meeting in 2019 in Chicago, an invitation to an internet-based survey on biomarkers for AD was sent by email to all IEC councilors and associates to examine their opinion regarding biomarkers in AD (Table I; for detailed questions, see this article's Online Repository at www.jacionline.org). Monkey survey software was used for data collection. Overall, the experts believe AD is a heterogeneous disease with at least 3 different phenotypes, that biomarkers may help to stratify patients by phenotypes and improve patient management and treatment compliance, and that future developments should focus on their use as predictors of therapeutic response.Table IResults of the biomarkers survey by IEC AD expertsQuestionYes (N)No (N)Follow-up questions (N)Do you think that AD is a heterogeneous disease?97.52% (41)2.38% (1)How many different AD phenotypes are there? (38)•>3 types of different AD phenotypes (92.7%)•<3 (7.3%)How would you stratify AD phenotypes? (38)•Combining clinical features and biomarkers (92.7%)•Only clinical features (7.3%)Which groups of biomarkers should be used for patients' stratification? (36)•Blood biomarkers (70%)•Skin biomarkers (genomics/transcriptomics) (50%)•Proteomics (28%)•Genomics and transcriptomics in tape-strips (28%)•Physiological properties (eg, TEWL and Raman spectroscopy) (25%)Are you using blood tests/biomarkers for the diagnosis of AD?29.55% (13)70.45% (31)Which are you using? (13)•IgE (100%)•Eosinophils (92.3%)•Other (FLG, LDH, CCL17/TARC) (30.8%)Do you think that blood tests/biomarkers are useful for assessing the severity of AD?59.09% (25)40.91% (18)Why not?•Lack of reliability, validity, and commercial availabilityWhy yes?•Improve selection of patients for specific therapies or in clinical trials•Improve comparability of clinical trials•Allow better follow-up tool in daily practice•Improve compliance of patients and patient encouragement.Could blood test/biomarkers be useful for assessing treatment compliance?76.74% (33)23.26% (10)Which biomarkers would you suggest? (17)•CCL17/TARC (52.9%)•IgE (47.1%)•p-EASI (formula containing CCL17/TARC, sIL-2R, IL-22) (35.3%)•Eosinophils (35.3%)•IL-13 (23.5%)•Other markers (CCL22, CCL26, sIL-2R, and IL-22—selected by <23.5%)How would you prioritize the needs for blood test/biomarkers?Top-rated development priorities: (40)•Biomarkers predicting treatment response, either in general, by identification of AD endo/phenotypes to predict treatment response, or by identifying responders to a particular drug before treatment initiationLower priority for development:•The use of biomarkers for disease severity, treatment response, diagnosis, and the development of less-invasive biomarkers (all ranked almost equally)EASI, Eczema Area and Severity Index; LDH, lactate dehydrogenase; TEWL, transepidermal water loss. Open table in a new tab EASI, Eczema Area and Severity Index; LDH, lactate dehydrogenase; TEWL, transepidermal water loss. Potential biomarkers may be subdivided on the basis of their suggested use. Some biomarkers seem to reliably distinguish between AD and psoriasis (namely NOS2 and chemokine C-C motif ligand [CCL]27/cutaneous T-cell–attracting chemokine [CTACK]),8Garzorz-Stark N. Krause L. Lauffer F. Atenhan A. Thomas J. Stark S.P. et al.A novel molecular disease classifier for psoriasis and eczema.Exp Dermatol. 2016; 25: 767-774Crossref PubMed Scopus (27) Google Scholar, 9He H. Bissonnette R. Wu J. Diaz A. Saint-Cyr Proulx E. Maari C. et al.Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis.J Allergy Clin Immunol. 2021; 147: 199-212Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 10Quaranta M. Knapp B. Garzorz N. Mattii M. Pullabhatla V. Pennino D. et al.Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema.Sci Transl Med. 2014; 6244ra90Crossref PubMed Scopus (116) Google Scholar thus potentially improving the diagnosis and management of patients with psoriasiform dermatitis (Table II).Table IIBiomarkers as disease classifiers, potentially improving diagnosis by differentiating AD and psoriasisBiomarkerFull nameFunctional effectAbnormalitiesNOS2Inducible nitric oxidase synthaseCatalyzing the production of nitric oxide, a toxic defense molecule against infections, and a regulator of functional activity, growth, and death of immune cells including T cells, antigen-presenting cells, mast cells, neutrophils, and natural killer cellsUpregulated in psoriasis, downregulated in ADCCL27/CTACKChemokine (C-C motif) ligand 27/cutaneous T-cell–attracting chemokineExpressed by keratinocytes. Mediates the migration of lymphocytes into the skin by binding to CCR10Upregulated in AD, downregulated in psoriasis Open table in a new tab These include markers related with general inflammation such as serum lactate dehydrogenase,11Vekaria A.S. Brunner P.M. Aleisa A.I. Bonomo L. Lebwohl M.G. Israel A. et al.Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity.F1000Res. 2017; 6: 1712PubMed Google Scholar, 12Morishima Y. Kawashima H. Takekuma K. Hoshika A. Changes in serum lactate dehydrogenase activity in children with atopic dermatitis.Pediatr Int. 2010; 52: 171-174Crossref PubMed Scopus (0) Google Scholar, 13Kou K. Aihara M. Matsunaga T. Chen H. Taguri M. Morita S. et al.Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis.Arch Dermatol Res. 2012; 304: 305-312Crossref PubMed Scopus (48) Google Scholar, 14Mizawa M. Yamaguchi M. Ueda C. 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