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Biomarkers in atopic dermatitis—a review on behalf of the International Eczema Council

Open AccessPublished:January 28, 2021DOI:https://doi.org/10.1016/j.jaci.2021.01.013
      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.

      Key words

      Abbreviations used:

      AD (Atopic dermatitis), CCL (Chemokine C-C motif ligand), CTACK (Cutaneous T-cell–attracting chemokine), FDA (Food and Drug Administration), FLG (Filaggrin), GRADE (Grading of Recommendations, Assessment, Development, and Evaluation), IEC (International Eczema Council), MDC (Macrophage-derived chemokine), TARC (Thymus and activation-regulated chemokine)
      Atopic dermatitis (AD) is a complex disorder in which gene-gene and gene-environment interactions contribute to generate a highly heterogeneous clinical phenotype.
      • Bieber 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.
      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.
      • Renert-Yuval Y.
      • Guttman-Yassky E.
      What’s new in atopic dermatitis.
      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.
      • Han 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.
      • Wollenberg 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.
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      • 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).
      • Guttman-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.
      Hence, particularly considering the complexity of AD, there is a need to shift toward precision medicine approaches to improve AD management.

      Biomarkers: definition, subtypes, and other regulatory aspects

      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 approach to assess evidence strength

      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.
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      • 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.
      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.

      Biomarkers in AD international eczema council survey results

      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 experts
      QuestionYes (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 availability
      Why 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 initiation
      Lower 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.

      Types of biomarkers in AD

      Potential biomarkers may be subdivided on the basis of their suggested use.

       Biomarkers differentiating AD from psoriasis

      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]),
      • Garzorz-Stark N.
      • Krause L.
      • Lauffer F.
      • Atenhan A.
      • Thomas J.
      • Stark S.P.
      • et al.
      A novel molecular disease classifier for psoriasis and eczema.
      • He 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.
      • Quaranta 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.
      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 psoriasis
      BiomarkerFull nameFunctional effectAbnormalities
      NOS2Inducible 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 AD
      CCL27/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

       Biomarkers correlating with clinical severity

      These include markers related with general inflammation such as serum lactate dehydrogenase,
      • Vekaria 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.
      • Morishima Y.
      • Kawashima H.
      • Takekuma K.
      • Hoshika A.
      Changes in serum lactate dehydrogenase activity in children with atopic dermatitis.
      • Kou 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.
      • Mizawa M.
      • Yamaguchi M.
      • Ueda C.
      • Makino T.
      • Shimizu T.
      Stress evaluation in adult patients with atopic dermatitis using salivary cortisol.
      C-reactive protein,
      • Vekaria 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.
      along with markers related with allergy (eg, peripheral eosinophil counts).
      • Vekaria 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.
      ,
      • Morishima Y.
      • Kawashima H.
      • Takekuma K.
      • Hoshika A.
      Changes in serum lactate dehydrogenase activity in children with atopic dermatitis.
      ,
      • Thijs J.
      • Krastev T.
      • Weidinger S.
      • Buckens C.F.
      • de Bruin-Weller M.
      • Bruijnzeel-Koomen C.
      • et al.
      Biomarkers for atopic dermatitis: a systematic review and meta-analysis.
      • Kagi M.K.
      • Joller-Jemelka H.
      • Wuthrich B.
      Correlation of eosinophils, eosinophil cationic protein and soluble interleukin-2 receptor with the clinical activity of atopic dermatitis.
      • Ariens L.F.M.
      • van der Schaft J.
      • Bakker D.S.
      • Balak D.
      • Romeijn M.L.E.
      • Kouwenhoven T.
      • et al.
      Dupilumab is very effective in a large cohort of difficult-to-treat adult atopic dermatitis patients: first clinical and biomarker results from the BioDay registry.
      • Kou K.
      • Okawa T.
      • Yamaguchi Y.
      • Ono J.
      • Inoue Y.
      • Kohno M.
      • et al.
      Periostin levels correlate with disease severity and chronicity in patients with atopic dermatitis.
      • Czech W.
      • Krutmann J.
      • Schopf E.
      • Kapp A.
      Serum eosinophil cationic protein (ECP) is a sensitive measure for disease activity in atopic dermatitis.
      Because AD is TH2/TH22-centered, cytokines and chemokines related with these immune pathways and correlated with disease severity in untreated or posttreated tissues (either skin or serum) were also investigated as possible biomarkers (Tables III and IV and Fig 1). Such cytokines include the key TH2 marker IL-13
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.
      ,
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      ,
      • Sanyal 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.
      ,
      • Koning H.
      • Neijens H.J.
      • Baert M.R.
      • Oranje A.P.
      • Savelkoul H.F.
      T cell subsets and cytokines in allergic and non-allergic children, I: analysis of IL-4, IFN-gamma and IL-13 mRNA expression and protein production.
      ,
      • Szegedi K.
      • Lutter R.
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      • Bos J.D.
      • Luiten R.M.
      • Kezic S.
      • et al.
      Cytokine profiles in interstitial fluid from chronic atopic dermatitis skin.
      ,
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      ,
      • Simon D.
      • Vassina E.
      • Yousefi S.
      • Kozlowski E.
      • Braathen L.R.
      • Simon H.U.
      Reduced dermal infiltration of cytokine-expressing inflammatory cells in atopic dermatitis after short-term topical tacrolimus treatment.
      and the key TH22-related cytokine IL-22.
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.
      ,
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      ,
      • Sanyal 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.
      ,
      • Nograles K.E.
      • Zaba L.C.
      • Shemer A.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Kikuchi T.
      • et al.
      IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells.
      ,
      • Gittler J.K.
      • Shemer A.
      • Suarez-Farinas M.
      • Fuentes-Duculan J.
      • Gulewicz K.J.
      • Wang C.Q.
      • et al.
      Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.
      TH2-related chemokines correlated with AD severity include CCL17/thymus and activation-regulated chemokine (TARC),
      • Kou 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.
      ,
      • Mizawa M.
      • Yamaguchi M.
      • Ueda C.
      • Makino T.
      • Shimizu T.
      Stress evaluation in adult patients with atopic dermatitis using salivary cortisol.
      ,
      • Kakinuma T.
      • Nakamura K.
      • Wakugawa M.
      • Mitsui H.
      • Tada Y.
      • Saeki H.
      • et al.
      Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity.
      ,
      • Fujisawa T.
      • Fujisawa R.
      • Kato Y.
      • Nakayama T.
      • Morita A.
      • Katsumata H.
      • et al.
      Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis.
      ,
      • Hijnen D.
      • De Bruin-Weller M.
      • Oosting B.
      • Lebre C.
      • De Jong E.
      • Bruijnzeel-Koomen C.
      • et al.
      Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell-attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis.
      • Jahnz-Rozyk K.
      • Targowski T.
      • Paluchowska E.
      • Owczarek W.
      • Kucharczyk A.
      Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis.
      • Song T.W.
      • Sohn M.H.
      • Kim E.S.
      • Kim K.W.
      • Kim K.E.
      Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis.
      • Nakazato J.
      • Kishida M.
      • Kuroiwa R.
      • Fujiwara J.
      • Shimoda M.
      • Shinomiya N.
      Serum levels of Th2 chemokines, CCL17, CCL22, and CCL27, were the important markers of severity in infantile atopic dermatitis.
      • Fujisawa T.
      • Nagao M.
      • Hiraguchi Y.
      • Katsumata H.
      • Nishimori H.
      • Iguchi K.
      • et al.
      Serum measurement of thymus and activation-regulated chemokine/CCL17 in children with atopic dermatitis: elevated normal levels in infancy and age-specific analysis in atopic dermatitis.
      • van Velsen S.G.
      • Knol M.J.
      • Haeck I.M.
      • Bruijnzeel-Koomen C.A.
      • Pasmans S.G.
      The Self-administered Eczema Area and Severity Index in children with moderate to severe atopic dermatitis: better estimation of AD body surface area than severity.
      • Machura E.
      • Rusek-Zychma M.
      • Jachimowicz M.
      • Wrzask M.
      • Mazur B.
      • Kasperska-Zajac A.
      Serum TARC and CTACK concentrations in children with atopic dermatitis, allergic asthma, and urticaria.
      ,
      • Kataoka Y.
      Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis.
      • Landheer J.
      • de Bruin-Weller M.
      • Boonacker C.
      • Hijnen D.
      • Bruijnzeel-Koomen C.
      • Rockmann H.
      Utility of serum thymus and activation-regulated chemokine as a biomarker for monitoring of atopic dermatitis severity.
      • Ahrens B.
      • Schulz G.
      • Bellach J.
      • Niggemann B.
      • Beyer K.
      Chemokine levels in serum of children with atopic dermatitis with regard to severity and sensitization status.
      • Gu C.Y.
      • Gu L.
      • Dou X.
      Serum levels of thymus and activation-regulated chemokine can be used in the clinical evaluation of atopic dermatitis.
      • Hulshof L.
      • Overbeek S.A.
      • Wyllie A.L.
      • Chu M.
      • Bogaert D.
      • de Jager W.
      • et al.
      Exploring immune development in infants with moderate to severe atopic dermatitis.
      ,
      • Beck L.A.
      • Thaci D.
      • Hamilton J.D.
      • Graham N.M.
      • Bieber T.
      • Rocklin R.
      • et al.
      Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.
      ,
      • Yasukochi Y.
      • Nakahara T.
      • Abe T.
      • Kido-Nakahara M.
      • Kohda F.
      • Takeuchi S.
      • et al.
      Reduction of serum TARC levels in atopic dermatitis by topical anti-inflammatory treatments.
      • Kyoya M.
      • Kawakami T.
      • Soma Y.
      Serum thymus and activation-regulated chemokine (TARC) and interleukin-31 levels as biomarkers for monitoring in adult atopic dermatitis.
      • Gohar M.K.
      • Atta A.H.
      • Nasr M.M.
      • Hussein D.N.
      Serum thymus and activation regulated chemokine (TARC), IL-18 and IL-18 gene polymorphism as associative factors with atopic dermatitis.
      • Bogaczewicz J.
      • Malinowska K.
      • Sysa-Jedrzejowska A.
      • Wozniacka A.
      Medium-dose ultraviolet A1 phototherapy and mRNA expression of TSLP, TARC, IL-5, and IL-13 in acute skin lesions in atopic dermatitis.
      CCL26/eosinophil-attracting chemokine (eotaxin-3),
      • Wen 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.
      ,
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      ,
      • Guttman-Yassky E.
      • Diaz A.
      • Pavel A.B.
      • Fernandes M.
      • Lefferdink R.
      • Erickson T.
      • et al.
      Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.
      ,
      • Kagami S.
      • Kakinuma T.
      • Saeki H.
      • Tsunemi Y.
      • Fujita H.
      • Nakamura K.
      • et al.
      Significant elevation of serum levels of eotaxin-3/CCL26, but not of eotaxin-2/CCL24, in patients with atopic dermatitis: serum eotaxin-3/CCL26 levels reflect the disease activity of atopic dermatitis.
      ,
      • Khattri S.
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      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      ,
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      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      ,
      • Kagami S.
      • Saeki H.
      • Komine M.
      • Kakinuma T.
      • Tsunemi Y.
      • Nakamura K.
      • et al.
      Interleukin-4 and interleukin-13 enhance CCL26 production in a human keratinocyte cell line, HaCaT cells.
      CCL27/CTACK,
      • Song T.W.
      • Sohn M.H.
      • Kim E.S.
      • Kim K.W.
      • Kim K.E.
      Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis.
      ,
      • Nakazato J.
      • Kishida M.
      • Kuroiwa R.
      • Fujiwara J.
      • Shimoda M.
      • Shinomiya N.
      Serum levels of Th2 chemokines, CCL17, CCL22, and CCL27, were the important markers of severity in infantile atopic dermatitis.
      ,
      • Machura E.
      • Rusek-Zychma M.
      • Jachimowicz M.
      • Wrzask M.
      • Mazur B.
      • Kasperska-Zajac A.
      Serum TARC and CTACK concentrations in children with atopic dermatitis, allergic asthma, and urticaria.
      ,
      • Kakinuma T.
      • Saeki H.
      • Tsunemi Y.
      • Fujita H.
      • Asano N.
      • Mitsui H.
      • et al.
      Increased serum cutaneous T cell-attracting chemokine (CCL27) levels in patients with atopic dermatitis and psoriasis vulgaris.
      ,
      • Hon K.L.
      • Leung T.F.
      • Ma K.C.
      • Li A.M.
      • Wong Y.
      • Fok T.F.
      Serum levels of cutaneous T-cell attracting chemokine (CTACK) as a laboratory marker of the severity of atopic dermatitis in children.
      CCL18/pulmonary and activation-regulated chemokine,
      • Esaki 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.
      ,
      • Guttman-Yassky E.
      • Diaz A.
      • Pavel A.B.
      • Fernandes M.
      • Lefferdink R.
      • Erickson T.
      • et al.
      Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.
      ,
      • Hon K.L.
      • Ching G.K.
      • Ng P.C.
      • Leung T.F.
      Exploring CCL18, eczema severity and atopy.
      ,
      • Gittler J.K.
      • Shemer A.
      • Suarez-Farinas M.
      • Fuentes-Duculan J.
      • Gulewicz K.J.
      • Wang C.Q.
      • et al.
      Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.
      and CCL22/macrophage-derived chemokine (MDC).
      • Leung T.F.
      • Ma K.C.
      • Hon K.L.
      • Lam C.W.
      • Wan H.
      • Li C.Y.
      • et al.
      Serum concentration of macrophage-derived chemokine may be a useful inflammatory marker for assessing severity of atopic dermatitis in infants and young children.
      ,
      • Jahnz-Rozyk K.
      • Targowski T.
      • Paluchowska E.
      • Owczarek W.
      • Kucharczyk A.
      Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis.
      ,
      • Kakinuma T.
      • Nakamura K.
      • Wakugawa M.
      • Mitsui H.
      • Tada Y.
      • Saeki H.
      • et al.
      Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis.
      ,
      • Gunther C.
      • Bello-Fernandez C.
      • Kopp T.
      • Kund J.
      • Carballido-Perrig N.
      • Hinteregger S.
      • et al.
      CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells.
      ,
      • Angelova-Fischer I.
      • Hipler U.C.
      • Bauer A.
      • Fluhr J.W.
      • Tsankov N.
      • Fischer T.W.
      • et al.
      Significance of interleukin-16, macrophage-derived chemokine, eosinophil cationic protein and soluble E-selectin in reflecting disease activity of atopic dermatitis--from laboratory parameters to clinical scores.
      ,
      • Furukawa H.
      • Takahashi M.
      • Nakamura K.
      • Kaneko F.
      Effect of an antiallergic drug (Olopatadine hydrochloride) on TARC/CCL17 and MDC/CCL22 production by PBMCs from patients with atopic dermatitis.
      Of note, circulating AD-related biomarkers are found in moderate to severe patients, whereas mild patients may not consistently display upregulation of AD-related biomarkers in their serum.

      He H, Del Duca E, Diaz A, Kim HJ, Gay-Mimbrera J, Zhang N, et al. Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities [published online ahead of print October 1, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.08.041.

      Table IIIPotential biomarkers reported to strongly and significantly correlate with clinical severity indices of AD (correlation coefficient ≥0.4, P < .05)
      Biomarker (no. of publications)SerumSkin
      AuthorLab methodCorr methodYearCohort (n)AuthorLab methodCorr methodYearCohort (n)
      CCL17/TARC (>20)Kakinuma et al
      • Kakinuma T.
      • Nakamura K.
      • Wakugawa M.
      • Mitsui H.
      • Tada Y.
      • Saeki H.
      • et al.
      Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity.


      Horikawa et al
      • Horikawa T.
      • Nakayama T.
      • Hikita I.
      • Yamada H.
      • Fujisawa R.
      • Bito T.
      • et al.
      IFN-gamma-inducible expression of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 in epidermal keratinocytes and their roles in atopic dermatitis.


      Fujisawa et al
      • Fujisawa T.
      • Fujisawa R.
      • Kato Y.
      • Nakayama T.
      • Morita A.
      • Katsumata H.
      • et al.
      Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis.


      Leung et al
      • Leung T.F.
      • Ma K.C.
      • Hon K.L.
      • Lam C.W.
      • Wan H.
      • Li C.Y.
      • et al.
      Serum concentration of macrophage-derived chemokine may be a useful inflammatory marker for assessing severity of atopic dermatitis in infants and young children.
      Pediatric cohort.


      Hijnen et al
      • Hijnen D.
      • De Bruin-Weller M.
      • Oosting B.
      • Lebre C.
      • De Jong E.
      • Bruijnzeel-Koomen C.
      • et al.
      Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell-attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89


      Jahnz-Rozyk et al
      • Jahnz-Rozyk K.
      • Targowski T.
      • Paluchowska E.
      • Owczarek W.
      • Kucharczyk A.
      Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis.


      Song et al
      • Song T.W.
      • Sohn M.H.
      • Kim E.S.
      • Kim K.W.
      • Kim K.E.
      Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis.
      Pediatric cohort.


      Nakazato et al
      • Nakazato J.
      • Kishida M.
      • Kuroiwa R.
      • Fujiwara J.
      • Shimoda M.
      • Shinomiya N.
      Serum levels of Th2 chemokines, CCL17, CCL22, and CCL27, were the important markers of severity in infantile atopic dermatitis.
      Pediatric cohort.


      Fujisawa et al
      • Fujisawa T.
      • Nagao M.
      • Hiraguchi Y.
      • Katsumata H.
      • Nishimori H.
      • Iguchi K.
      • et al.
      Serum measurement of thymus and activation-regulated chemokine/CCL17 in children with atopic dermatitis: elevated normal levels in infancy and age-specific analysis in atopic dermatitis.
      Pediatric cohort.
      van Velsen et al
      • van Velsen S.G.
      • Knol M.J.
      • Haeck I.M.
      • Bruijnzeel-Koomen C.A.
      • Pasmans S.G.
      The Self-administered Eczema Area and Severity Index in children with moderate to severe atopic dermatitis: better estimation of AD body surface area than severity.
      Pediatric cohort.


      Morita et al
      • Morita E.
      • Takahashi H.
      • Niihara H.
      • Dekio I.
      • Sumikawa Y.
      • Murakami Y.
      • et al.
      Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis.


      Kou et al
      • Kou 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.


      Machura et al
      • Machura E.
      • Rusek-Zychma M.
      • Jachimowicz M.
      • Wrzask M.
      • Mazur B.
      • Kasperska-Zajac A.
      Serum TARC and CTACK concentrations in children with atopic dermatitis, allergic asthma, and urticaria.
      Pediatric cohort.


      Furue et al
      • Furue M.
      • Matsumoto T.
      • Yamamoto T.
      • Takeuchi S.
      • Esaki H.
      • Chiba T.
      • et al.
      Correlation between serum thymus and activation-regulated chemokine levels and stratum corneum barrier function in healthy individuals and patients with mild atopic dermatitis.
      Correlated with TEWL.


      Mizawa et al
      • Mizawa M.
      • Yamaguchi M.
      • Ueda C.
      • Makino T.
      • Shimizu T.
      Stress evaluation in adult patients with atopic dermatitis using salivary cortisol.


      Kataoka
      • Kataoka Y.
      Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis.
      P ≤ .1.


      Landheer et al
      • Landheer J.
      • de Bruin-Weller M.
      • Boonacker C.
      • Hijnen D.
      • Bruijnzeel-Koomen C.
      • Rockmann H.
      Utility of serum thymus and activation-regulated chemokine as a biomarker for monitoring of atopic dermatitis severity.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89


      Ahrens et al
      • Ahrens B.
      • Schulz G.
      • Bellach J.
      • Niggemann B.
      • Beyer K.
      Chemokine levels in serum of children with atopic dermatitis with regard to severity and sensitization status.
      Pediatric cohort.


      Gu et al
      • Gu C.Y.
      • Gu L.
      • Dou X.
      Serum levels of thymus and activation-regulated chemokine can be used in the clinical evaluation of atopic dermatitis.


      Hulshof et al
      • Hulshof L.
      • Overbeek S.A.
      • Wyllie A.L.
      • Chu M.
      • Bogaert D.
      • de Jager W.
      • et al.
      Exploring immune development in infants with moderate to severe atopic dermatitis.
      Pediatric cohort.
      E

      E

      E

      E

      E

      E

      E

      E

      E

      E

      E

      E

      E

      E

      NA

      NA

      E

      E

      E

      L
      S

      P

      S

      S

      S

      P

      S

      S

      S

      P/S

      S

      S

      S

      S

      S

      NA

      S

      S

      S

      S
      2001

      2002

      2002

      2003

      2004

      2005

      2006

      2008

      2009

      2010

      2010

      2012

      2012

      2012

      2013

      2014

      2014

      2015

      2015

      2018
      40

      52

      29

      20

      177

      43

      157

      34

      27

      60

      33

      121

      26

      61

      30

      96

      320

      128

      73

      41
      Morita et al
      • Morita E.
      • Takahashi H.
      • Niihara H.
      • Dekio I.
      • Sumikawa Y.
      • Murakami Y.
      • et al.
      Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis.
      Correlated with SCORAD components and not with the total SCORAD.
      (LS-TS)

      McAleer et al
      • McAleer M.A.
      • Jakasa I.
      • Hurault G.
      • Sarvari P.
      • McLean W.H.I.
      • Tanaka R.J.
      • et al.
      Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell-related immunity and angiogenesis.
      Pediatric cohort.
      (NL-TS)

      He et al

      He H, Del Duca E, Diaz A, Kim HJ, Gay-Mimbrera J, Zhang N, et al. Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities [published online ahead of print October 1, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.08.041.

      (LS-B)
      IF

      ECL

      PCR
      S

      S

      P
      2010

      2019

      2020
      33

      66

      61
      CCL22/MDC (>10)Kakinuma et al
      • Kakinuma T.
      • Nakamura K.
      • Wakugawa M.
      • Mitsui H.
      • Tada Y.
      • Saeki H.
      • et al.
      Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis.


      Fujisawa et al
      • Fujisawa T.
      • Fujisawa R.
      • Kato Y.
      • Nakayama T.
      • Morita A.
      • Katsumata H.
      • et al.
      Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis.


      Leung et al
      • Leung T.F.
      • Ma K.C.
      • Hon K.L.
      • Lam C.W.
      • Wan H.
      • Li C.Y.
      • et al.
      Serum concentration of macrophage-derived chemokine may be a useful inflammatory marker for assessing severity of atopic dermatitis in infants and young children.
      Pediatric cohort.


      Jahnz-Rozyk et al
      • Jahnz-Rozyk K.
      • Targowski T.
      • Paluchowska E.
      • Owczarek W.
      • Kucharczyk A.
      Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis.


      Gunther et al
      • Gunther C.
      • Bello-Fernandez C.
      • Kopp T.
      • Kund J.
      • Carballido-Perrig N.
      • Hinteregger S.
      • et al.
      CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells.


      Angelova-Fischer et al
      • Angelova-Fischer I.
      • Hipler U.C.
      • Bauer A.
      • Fluhr J.W.
      • Tsankov N.
      • Fischer T.W.
      • et al.
      Significance of interleukin-16, macrophage-derived chemokine, eosinophil cationic protein and soluble E-selectin in reflecting disease activity of atopic dermatitis--from laboratory parameters to clinical scores.


      Hashimoto et al
      • Hashimoto S.
      • Nakamura K.
      • Oyama N.
      • Kaneko F.
      • Tsunemi Y.
      • Saeki H.
      • et al.
      Macrophage-derived chemokine (MDC)/CCL22 produced by monocyte derived dendritic cells reflects the disease activity in patients with atopic dermatitis.


      Nakazato et al
      • Nakazato J.
      • Kishida M.
      • Kuroiwa R.
      • Fujiwara J.
      • Shimoda M.
      • Shinomiya N.
      Serum levels of Th2 chemokines, CCL17, CCL22, and CCL27, were the important markers of severity in infantile atopic dermatitis.
      Pediatric cohort.


      Wen et al
      • Wen 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.
      P ≤ .1.


      Brunner et al
      • Brunner P.M.
      • He H.
      • Pavel A.B.
      • Czarnowicki T.
      • Lefferdink R.
      • Erickson T.
      • et al.
      The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
      Pediatric cohort.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89


      McAleer et al
      • McAleer M.A.
      • Jakasa I.
      • Hurault G.
      • Sarvari P.
      • McLean W.H.I.
      • Tanaka R.J.
      • et al.
      Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell-related immunity and angiogenesis.
      Pediatric cohort.
      E

      E

      E

      E

      E

      E

      E
      Performed on monocyte-derived circulating dendritic cells.


      E

      ECL

      O

      ECL
      S

      S

      S

      P

      P

      P

      NA

      S

      P

      S

      S
      2002

      2002

      2003

      2005

      2005

      2006

      2006

      2008

      2018

      2019

      2019
      45

      29

      20

      43

      36

      21

      11

      34

      15

      30

      47
      Tintle et al
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.


      Suarez-Farinas et al
      • Suarez-Farinas M.
      • Tintle S.J.
      • Shemer A.
      • Chiricozzi A.
      • Nograles K.
      • Cardinale I.
      • et al.
      Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
      (LS/NL-B)

      Wen et al
      • Wen 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.
      (NL-B)
      PCR

      PCR

      PCR
      S

      S

      P
      2011

      2011

      2018
      12

      15

      12
      IgE (>10)Tsuboi et al
      • Tsuboi H.
      • Kouda K.
      • Takeuchi H.
      • Takigawa M.
      • Masamoto Y.
      • Takeuchi M.
      • et al.
      8-hydroxydeoxyguanosine in urine as an index of oxidative damage to DNA in the evaluation of atopic dermatitis.
      Log2(IgE) was correlated with SCORAD.


      Yoshizawa et al
      • Yoshizawa Y.
      • Nomaguchi H.
      • Izaki S.
      • Kitamura K.
      Serum cytokine levels in atopic dermatitis.


      Kaminishi et al
      • Kaminishi K.
      • Soma Y.
      • Kawa Y.
      • Mizoguchi M.
      Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease.
      Log2(IgE) was correlated with SCORAD.


      Jahnz-Rozyk et al
      • Jahnz-Rozyk K.
      • Targowski T.
      • Paluchowska E.
      • Owczarek W.
      • Kucharczyk A.
      Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis.


      Aral et al
      • Aral M.
      • Arican O.
      • Gul M.
      • Sasmaz S.
      • Kocturk S.A.
      • Kastal U.
      • et al.
      The relationship between serum levels of total IgE, IL-18, IL-12, IFN-gamma and disease severity in children with atopic dermatitis.
      Pediatric cohort.


      Salomon and Baran
      • Salomon J.
      • Baran E.
      The role of selected neuropeptides in pathogenesis of atopic dermatitis.


      Wu et al
      • Wu K.G.
      • Li T.H.
      • Chen C.J.
      • Cheng H.I.
      • Wang T.Y.
      Correlations of serum interleukin-16, total IgE, eosinophil cationic protein and total eosinophil counts with disease activity in children with atopic dermatitis.
      Pediatric cohort.


      Suarez-Farinas et al
      • Suarez-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.


      Zedan et al
      • Zedan K.
      • Rasheed Z.
      • Farouk Y.
      • Alzolibani A.A.
      • Bin Saif G.
      • Ismail H.A.
      • et al.
      Immunoglobulin E, interleukin-18 and interleukin-12 in patients with atopic dermatitis: correlation with disease activity.
      Pediatric cohort.


      Glatz et al
      • Glatz M.
      • Buchner M.
      • von Bartenwerffer W.
      • Schmid-Grendelmeier P.
      • Worm M.
      • Hedderich J.
      • et al.
      Malassezia spp.-specific immunoglobulin E level is a marker for severity of atopic dermatitis in adults.


      Rosinska-Wieckowicz et al
      • Rosinska-Wieckowicz A.
      • Czarnecka-Operacz M.
      • Adamski Z.
      Selected immunological parameters in clinical evaluation of patients with atopic dermatitis.


      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      Log2(IgE) was correlated with SCORAD.


      Wen et al
      • Wen 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.


      Sanyal et al
      • Sanyal 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.
      IRMA

      NA

      FEIA

      E

      N

      E

      F

      E

      E

      E

      F

      E

      E

      E
      P

      S

      P

      P

      S

      P/S

      P

      P

      NA

      S

      S

      P

      P

      S
      1998

      2002

      2002

      2005

      2006

      2008

      2011

      2013

      2015

      2015

      2016

      2017

      2018

      2019
      17

      26

      20

      43

      20

      49

      48

      42

      50

      67

      102

      25

      15

      15
      NA
      CCL22/MDC (>10)Kakinuma et al
      • Kakinuma T.
      • Nakamura K.
      • Wakugawa M.
      • Mitsui H.
      • Tada Y.
      • Saeki H.
      • et al.
      Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis.


      Fujisawa et al
      • Fujisawa T.
      • Fujisawa R.
      • Kato Y.
      • Nakayama T.
      • Morita A.
      • Katsumata H.
      • et al.
      Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis.


      Leung et al
      • Leung T.F.
      • Ma K.C.
      • Hon K.L.
      • Lam C.W.
      • Wan H.
      • Li C.Y.
      • et al.
      Serum concentration of macrophage-derived chemokine may be a useful inflammatory marker for assessing severity of atopic dermatitis in infants and young children.
      Pediatric cohort.


      Jahnz-Rozyk et al
      • Jahnz-Rozyk K.
      • Targowski T.
      • Paluchowska E.
      • Owczarek W.
      • Kucharczyk A.
      Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis.


      Gunther et al
      • Gunther C.
      • Bello-Fernandez C.
      • Kopp T.
      • Kund J.
      • Carballido-Perrig N.
      • Hinteregger S.
      • et al.
      CCL18 is expressed in atopic dermatitis and mediates skin homing of human memory T cells.


      Angelova-Fischer et al
      • Angelova-Fischer I.
      • Hipler U.C.
      • Bauer A.
      • Fluhr J.W.
      • Tsankov N.
      • Fischer T.W.
      • et al.
      Significance of interleukin-16, macrophage-derived chemokine, eosinophil cationic protein and soluble E-selectin in reflecting disease activity of atopic dermatitis--from laboratory parameters to clinical scores.


      Hashimoto et al
      • Hashimoto S.
      • Nakamura K.
      • Oyama N.
      • Kaneko F.
      • Tsunemi Y.
      • Saeki H.
      • et al.
      Macrophage-derived chemokine (MDC)/CCL22 produced by monocyte derived dendritic cells reflects the disease activity in patients with atopic dermatitis.


      Nakazato et al
      • Nakazato J.
      • Kishida M.
      • Kuroiwa R.
      • Fujiwara J.
      • Shimoda M.
      • Shinomiya N.
      Serum levels of Th2 chemokines, CCL17, CCL22, and CCL27, were the important markers of severity in infantile atopic dermatitis.
      Pediatric cohort.


      Wen et al
      • Wen 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.
      P ≤ .1.


      Brunner et al
      • Brunner P.M.
      • He H.
      • Pavel A.B.
      • Czarnowicki T.
      • Lefferdink R.
      • Erickson T.
      • et al.
      The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
      Pediatric cohort.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89


      McAleer et al
      • McAleer M.A.
      • Jakasa I.
      • Hurault G.
      • Sarvari P.
      • McLean W.H.I.
      • Tanaka R.J.
      • et al.
      Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell-related immunity and angiogenesis.
      Pediatric cohort.
      E

      E

      E

      E

      E

      E

      E
      Log2(IgE) was correlated with SCORAD.


      E

      ECL

      O

      ECL
      S

      S

      S

      P

      P

      P

      NA

      S

      P

      S

      S
      2002

      2002

      2003

      2005

      2005

      2006

      2006

      2008

      2018

      2019

      2019
      45

      29

      20

      43

      36

      21

      11

      34

      15

      30

      47
      Tintle et al
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.


      Suarez-Farinas et al
      • Suarez-Farinas M.
      • Tintle S.J.
      • Shemer A.
      • Chiricozzi A.
      • Nograles K.
      • Cardinale I.
      • et al.
      Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
      (LS/NL-B)

      Wen et al
      • Wen 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.
      (NL-B)
      PCR

      PCR

      PCR
      S

      S

      P
      2011

      2011

      2018
      12

      15

      12
      Eosinophils/ECP (>10)Mukai et al
      • Mukai H.
      • Noguchi T.
      • Kamimura K.
      • Nishioka K.
      • Nishiyama S.
      Significance of elevated serum LDH (lactate dehydrogenase) activity in atopic dermatitis.


      Czech et al
      • Czech W.
      • Krutmann J.
      • Schopf E.
      • Kapp A.
      Serum eosinophil cationic protein (ECP) is a sensitive measure for disease activity in atopic dermatitis.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89


      Kagi et al
      • Kagi M.K.
      • Joller-Jemelka H.
      • Wuthrich B.
      Correlation of eosinophils, eosinophil cationic protein and soluble interleukin-2 receptor with the clinical activity of atopic dermatitis.


      Halmerbauer et al
      • Halmerbauer G.
      • Frischer T.
      • Koller D.Y.
      Monitoring of disease activity by measurement of inflammatory markers in atopic dermatitis in childhood.
      Pediatric cohort.


      Tsuboi et al
      • Tsuboi H.
      • Kouda K.
      • Takeuchi H.
      • Takigawa M.
      • Masamoto Y.
      • Takeuchi M.
      • et al.
      8-hydroxydeoxyguanosine in urine as an index of oxidative damage to DNA in the evaluation of atopic dermatitis.


      Yoshizawa et al
      • Yoshizawa Y.
      • Nomaguchi H.
      • Izaki S.
      • Kitamura K.
      Serum cytokine levels in atopic dermatitis.


      Raap et al
      • Raap U.
      • Weissmantel S.
      • Gehring M.
      • Eisenberg A.M.
      • Kapp A.
      • Folster-Holst R.
      IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis.
      Pediatric cohort.


      Kaminishi et al
      • Kaminishi K.
      • Soma Y.
      • Kawa Y.
      • Mizoguchi M.
      Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease.


      Angelova-Fischer et al
      • Angelova-Fischer I.
      • Hipler U.C.
      • Bauer A.
      • Fluhr J.W.
      • Tsankov N.
      • Fischer T.W.
      • et al.
      Significance of interleukin-16, macrophage-derived chemokine, eosinophil cationic protein and soluble E-selectin in reflecting disease activity of atopic dermatitis--from laboratory parameters to clinical scores.


      Morishima et al
      • Morishima Y.
      • Kawashima H.
      • Takekuma K.
      • Hoshika A.
      Changes in serum lactate dehydrogenase activity in children with atopic dermatitis.


      Wu et al
      • Wu K.G.
      • Li T.H.
      • Chen C.J.
      • Cheng H.I.
      • Wang T.Y.
      Correlations of serum interleukin-16, total IgE, eosinophil cationic protein and total eosinophil counts with disease activity in children with atopic dermatitis.
      Pediatric cohort.


      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.


      Chen et al
      • Chen Y.L.
      • Gutowska-Owsiak D.
      • Hardman C.S.
      • Westmoreland M.
      • MacKenzie T.
      • Cifuentes L.
      • et al.
      Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis.
      C

      RIA

      RIA

      RIA

      C

      NA

      IC

      C

      FEIA

      C

      FEIA

      C

      NA
      NA

      S

      S

      K

      P

      S

      S

      P

      P

      S

      P

      P

      S
      1990

      1992

      1992

      1997

      1998

      2002

      2012

      2002

      2006

      2010

      2011

      2017

      2019
      30

      19

      37

      20

      17

      26

      60

      20

      21

      58

      48

      25

      12
      NA
      IL-22 (>5)Nograles et al
      • Nograles K.E.
      • Zaba L.C.
      • Shemer A.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Kikuchi T.
      • et al.
      IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells.


      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      F

      EMD
      LRA

      P
      2009

      2017
      12

      25
      Tintle et al
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.
      (LS-B)
      P ≤ .1.


      Suarez-Farinas et al
      • Suarez-Farinas M.
      • Tintle S.J.
      • Shemer A.
      • Chiricozzi A.
      • Nograles K.
      • Cardinale I.
      • et al.
      Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
      (LS/NL-B)

      Esaki et al
      • Esaki 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.
      Pediatric cohort.
      Correlated with TEWL.
      (LS-B)

      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      (LS/NL-B)

      Wen et al
      • Wen 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.
      (NL-B)
      P ≤ .1.


      Sanyal et al
      • Sanyal 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.
      (LS-B)
      PCR

      PCR

      PCR

      PCR

      PCR

      PCR
      S

      S

      P

      P

      P

      S
      2011

      2011

      2016

      2017

      2018

      2019
      12

      12

      19

      25

      15

      15
      IL-13 (>5)Koning et al
      • Koning H.
      • Neijens H.J.
      • Baert M.R.
      • Oranje A.P.
      • Savelkoul H.F.
      T cell subsets and cytokines in allergic and non-allergic children, I: analysis of IL-4, IFN-gamma and IL-13 mRNA expression and protein production.
      Pediatric cohort.


      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      E

      E
      S

      P
      1997

      2017
      15

      25
      Tintle et al
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.
      (LS-B)
      P ≤ .1.


      Suarez-Farinas et al
      • Suarez-Farinas M.
      • Tintle S.J.
      • Shemer A.
      • Chiricozzi A.
      • Nograles K.
      • Cardinale I.
      • et al.
      Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
      (LS-B)

      Szegedi et al
      • Szegedi K.
      • Lutter R.
      • Res P.C.
      • Bos J.D.
      • Luiten R.M.
      • Kezic S.
      • et al.
      Cytokine profiles in interstitial fluid from chronic atopic dermatitis skin.
      (LS-ISF)

      Wen et al
      • Wen 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.
      (NL-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Diaz A.
      • Pavel A.B.
      • Fernandes M.
      • Lefferdink R.
      • Erickson T.
      • et al.
      Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.
      Pediatric cohort.
      Correlated with pruritus.
      (LS-TS)

      Sanyal et al
      • Sanyal 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.
      (LS/NL-B)

      He et al

      He H, Del Duca E, Diaz A, Kim HJ, Gay-Mimbrera J, Zhang N, et al. Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities [published online ahead of print October 1, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.08.041.

      (LS-B)
      PCR

      PCR

      L

      PCR

      PCR

      PCR

      PCR
      S

      S

      P/S

      P

      S

      S

      P
      2011

      2011

      2015

      2018

      2019

      2019

      2020
      12

      12

      16

      15

      21

      15

      61
      IL-18 (>5)Hon et al
      • Hon K.L.
      • Leung T.F.
      • Ma K.C.
      • Wong C.K.
      • Wan H.
      • Lam C.W.
      Serum concentration of IL-18 correlates with disease extent in young children with atopic dermatitis.
      Pediatric cohort.


      Aral et al
      • Aral M.
      • Arican O.
      • Gul M.
      • Sasmaz S.
      • Kocturk S.A.
      • Kastal U.
      • et al.
      The relationship between serum levels of total IgE, IL-18, IL-12, IFN-gamma and disease severity in children with atopic dermatitis.
      Pediatric cohort.


      Park and Youn
      • Park D.S.
      • Youn Y.H.
      Clinical significance of serum interleukin-18 concentration in the patients with atopic dermatitis [in Korean].


      Kou et al
      • Kou 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.


      Zedan et al
      • Zedan K.
      • Rasheed Z.
      • Farouk Y.
      • Alzolibani A.A.
      • Bin Saif G.
      • Ismail H.A.
      • et al.
      Immunoglobulin E, interleukin-18 and interleukin-12 in patients with atopic dermatitis: correlation with disease activity.
      Pediatric cohort.


      Suwarsa et al
      • Suwarsa O.
      • Adi S.
      • Idjradinata P.
      • Sutedja E.
      • Avriyanti E.
      • Asfara A.
      • et al.
      Interleukin-18 correlates with interleukin-4 but not interferon-gamma production in lymphocyte cultures from atopic dermatitis patients after staphylococcal enterotoxin B stimulation.
      E

      E

      NA

      E

      E

      E
      S

      S

      NA

      S

      NA

      P
      2004

      2006

      2007

      2012

      2015

      2017
      19

      20

      65

      121

      50

      20
      Inoue et al
      • Inoue Y.
      • Aihara M.
      • Kirino M.
      • Harada I.
      • Komori-Yamaguchi J.
      • Yamaguchi Y.
      • et al.
      Interleukin-18 is elevated in the horny layer in patients with atopic dermatitis and is associated with Staphylococcus aureus colonization.
      (LS/NL-TS)

      McAleer et al
      • McAleer M.A.
      • Jakasa I.
      • Hurault G.
      • Sarvari P.
      • McLean W.H.I.
      • Tanaka R.J.
      • et al.
      Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell-related immunity and angiogenesis.
      Correlated with SCORAD components and not with the total SCORAD.
      Pediatric cohort.
      (NL-TS)

      Pavel et al
      • Pavel A.B.
      • Zhou L.
      • Diaz A.
      • Ungar B.
      • Dan J.
      • He H.
      • et al.
      The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature.
      (LS-B)
      E

      ECL

      O
      S

      S

      S
      2011

      2019

      2020
      95

      66

      20
      CCL27/CTACK (>5)Kakinuma et al
      • Kakinuma T.
      • Saeki H.
      • Tsunemi Y.
      • Fujita H.
      • Asano N.
      • Mitsui H.
      • et al.
      Increased serum cutaneous T cell-attracting chemokine (CCL27) levels in patients with atopic dermatitis and psoriasis vulgaris.


      Hon et al
      • Hon K.L.
      • Leung T.F.
      • Ma K.C.
      • Li A.M.
      • Wong Y.
      • Fok T.F.
      Serum levels of cutaneous T-cell attracting chemokine (CTACK) as a laboratory marker of the severity of atopic dermatitis in children.
      Correlated with SCORAD components and not with the total SCORAD.
      Pediatric cohort.


      Hijnen et al
      • Hijnen D.
      • De Bruin-Weller M.
      • Oosting B.
      • Lebre C.
      • De Jong E.
      • Bruijnzeel-Koomen C.
      • et al.
      Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell-attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89


      Song et al
      • Song T.W.
      • Sohn M.H.
      • Kim E.S.
      • Kim K.W.
      • Kim K.E.
      Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis.
      Pediatric cohort.


      Nakazato et al
      • Nakazato J.
      • Kishida M.
      • Kuroiwa R.
      • Fujiwara J.
      • Shimoda M.
      • Shinomiya N.
      Serum levels of Th2 chemokines, CCL17, CCL22, and CCL27, were the important markers of severity in infantile atopic dermatitis.
      Pediatric cohort.


      Machura et al
      • Machura E.
      • Rusek-Zychma M.
      • Jachimowicz M.
      • Wrzask M.
      • Mazur B.
      • Kasperska-Zajac A.
      Serum TARC and CTACK concentrations in children with atopic dermatitis, allergic asthma, and urticaria.
      Pediatric cohort.
      E

      E

      E

      E

      E

      E
      S

      S

      S

      S

      S

      S
      2003

      2004

      2004

      2006

      2008

      2012
      50

      37

      76

      157

      34

      26
      S100A7/12 (>5)Suarez-Farinas et al
      • Suarez-Farinas M.
      • Tintle S.J.
      • Shemer A.
      • Chiricozzi A.
      • Nograles K.
      • Cardinale I.
      • et al.
      Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
      (LS-B)

      Tintle et al
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.
      (LS-B)
      P ≤ .1.


      Suarez-Farinas et al
      • Suarez-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.
      (LS-B)

      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      (LS+/NL-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Diaz A.
      • Pavel A.B.
      • Fernandes M.
      • Lefferdink R.
      • Erickson T.
      • et al.
      Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.
      Pediatric cohort.
      (LS-TS)

      Sanyal et al
      • Sanyal 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.
      (LS-B)

      He et al

      He H, Del Duca E, Diaz A, Kim HJ, Gay-Mimbrera J, Zhang N, et al. Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities [published online ahead of print October 1, 2020]. J Allergy Clin Immunol. https://doi.org/10.1016/j.jaci.2020.08.041.

      (LS-B)
      PCR

      PCR

      PCR

      PCR

      PCR

      PCR

      PCR
      S

      S

      P

      P

      S

      S

      P
      2011

      2011

      2013

      2017

      2019

      2019

      2020
      12

      12

      7

      25

      21

      15

      61
      E-selectin (>5)Morita et al
      • Morita H.
      • Kitano Y.
      • Kawasaki N.
      Elevation of serum-soluble E-selectin in atopic dermatitis.


      Yamashita et al
      • Yamashita N.
      • Kaneko S.
      • Kouro O.
      • Furue M.
      • Yamamoto S.
      • Sakane T.
      Soluble E-selectin as a marker of disease activity in atopic dermatitis.


      Wolkerstorfer et al
      Pediatric cohort.
      • Wolkerstorfer A.
      • Savelkoul H.F.
      • de Waard van der Spek F.B.
      • Neijens H.J.
      • van Meurs T.
      • Oranje A.P.
      Soluble E-selectin and soluble ICAM-1 levels as markers of the activity of atopic dermatitis in children.


      Angelova-Fischer et al
      • Angelova-Fischer I.
      • Hipler U.C.
      • Bauer A.
      • Fluhr J.W.
      • Tsankov N.
      • Fischer T.W.
      • et al.
      Significance of interleukin-16, macrophage-derived chemokine, eosinophil cationic protein and soluble E-selectin in reflecting disease activity of atopic dermatitis--from laboratory parameters to clinical scores.


      Brunner et al
      • Brunner P.M.
      • Suarez-Farinas M.
      • He H.
      • Malik K.
      • Wen H.C.
      • Gonzalez J.
      • et al.
      The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins.


      Brunner et al
      • Brunner P.M.
      • He H.
      • Pavel A.B.
      • Czarnowicki T.
      • Lefferdink R.
      • Erickson T.
      • et al.
      The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
      Pediatric cohort.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89
      E

      E

      E

      E

      O

      O
      NA

      K

      S

      P

      S

      S
      1995

      1997

      2003

      2006

      2017

      2019
      23

      53

      15

      21

      59

      30
      MMP12 (>5)Brunner et al
      • Brunner P.M.
      • Suarez-Farinas M.
      • He H.
      • Malik K.
      • Wen H.C.
      • Gonzalez J.
      • et al.
      The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins.


      Brunner et al
      • Brunner P.M.
      • He H.
      • Pavel A.B.
      • Czarnowicki T.
      • Lefferdink R.
      • Erickson T.
      • et al.
      The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
      Pediatric cohort.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89


      He et al
      • He 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.
      O

      O

      O
      S

      S

      P
      2017

      2019

      2020
      59

      30

      71
      Suarez-Farinas et al
      • Suarez-Farinas M.
      • Tintle S.J.
      • Shemer A.
      • Chiricozzi A.
      • Nograles K.
      • Cardinale I.
      • et al.
      Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
      (LS-B)

      Suarez-Farinas et al
      • Suarez-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.
      (LS-B)

      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      (NL-B)

      Pavel et al
      • Pavel A.B.
      • Renert-Yuval Y.
      • Wu J.
      • Del Duca E.
      • Diaz A.
      • Lefferdink R.
      • et al.
      Tape-strips from early-onset pediatric atopic dermatitis highlight disease abnormalities in non-lesional skin.
      Pediatric cohort.
      Correlated with pruritus.
      (NL-TS)
      PCR

      PCR

      PCR

      R
      S

      P

      P

      S
      2011

      2013

      2017

      2020
      12

      7

      25

      19
      LDH (>5)Mukai et al
      • Mukai H.
      • Noguchi T.
      • Kamimura K.
      • Nishioka K.
      • Nishiyama S.
      Significance of elevated serum LDH (lactate dehydrogenase) activity in atopic dermatitis.


      Tsuboi et al
      • Tsuboi H.
      • Kouda K.
      • Takeuchi H.
      • Takigawa M.
      • Masamoto Y.
      • Takeuchi M.
      • et al.
      8-hydroxydeoxyguanosine in urine as an index of oxidative damage to DNA in the evaluation of atopic dermatitis.


      Morishima et al
      • Morishima Y.
      • Kawashima H.
      • Takekuma K.
      • Hoshika A.
      Changes in serum lactate dehydrogenase activity in children with atopic dermatitis.


      Kou et al
      • Kou 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.


      Mizawa et al
      • Mizawa M.
      • Yamaguchi M.
      • Ueda C.
      • Makino T.
      • Shimizu T.
      Stress evaluation in adult patients with atopic dermatitis using salivary cortisol.


      Kataoka
      • Kataoka Y.
      Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis.
      P ≤ .1.


      Olesen et al
      • Olesen C.M.
      • Holm J.G.
      • Norreslet L.B.
      • Serup J.V.
      • Thomsen S.F.
      • Agner T.
      Treatment of atopic dermatitis with dupilumab: experience from a tertiary referral centre.
      NANA

      P

      S

      S

      S

      NA

      S
      1990

      1998

      2010

      2012

      2013

      2014

      2019
      80

      17

      58

      121

      30

      96

      43
      NA
      CCL18/PARC (≥5)Hon et al
      • Hon K.L.
      • Ching G.K.
      • Ng P.C.
      • Leung T.F.
      Exploring CCL18, eczema severity and atopy.
      Pediatric cohort.
      EP2011108Suarez-Farinas et al
      • Suarez-Farinas M.
      • Tintle S.J.
      • Shemer A.
      • Chiricozzi A.
      • Nograles K.
      • Cardinale I.
      • et al.
      Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities.
      (NL-B)

      Gittler et al
      • Gittler J.K.
      • Shemer A.
      • Suarez-Farinas M.
      • Fuentes-Duculan J.
      • Gulewicz K.J.
      • Wang C.Q.
      • et al.
      Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.
      (NL-B)

      Esaki et al
      • Esaki 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.
      Pediatric cohort.
      (LS-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Diaz A.
      • Pavel A.B.
      • Fernandes M.
      • Lefferdink R.
      • Erickson T.
      • et al.
      Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.
      Pediatric cohort.
      Correlated with pruritus.
      (LS-TS)
      PCR

      PCR

      PCR

      PCR
      S

      S

      P

      S
      2011

      2012

      2016

      2019
      12

      10

      19

      21
      Eotaxin-3/CCL26 (≥5)Kagami et al
      • Kagami S.
      • Kakinuma T.
      • Saeki H.
      • Tsunemi Y.
      • Fujita H.
      • Nakamura K.
      • et al.
      Significant elevation of serum levels of eotaxin-3/CCL26, but not of eotaxin-2/CCL24, in patients with atopic dermatitis: serum eotaxin-3/CCL26 levels reflect the disease activity of atopic dermatitis.


      Wen et al
      • Wen 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.
      E

      ECL
      S

      P
      2003

      2018
      30

      15
      Zhou et al
      • Zhou 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.
      (LS-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Diaz A.
      • Pavel A.B.
      • Fernandes M.
      • Lefferdink R.
      • Erickson T.
      • et al.
      Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.
      Pediatric cohort.
      Correlated with TEWL.
      P ≤ .1.
      (LS-TP)
      PCR

      PCR
      S

      S
      2019

      2019
      27

      21
      IL-19 (≥5)Oka et al
      • Oka T.
      • Sugaya M.
      • Takahashi N.
      • Nakajima R.
      • Otobe S.
      • Kabasawa M.
      • et al.
      Increased interleukin-19 expression in cutaneous T-cell lymphoma and atopic dermatitis.


      Konrad et al
      • Konrad R.J.
      • Higgs R.E.
      • Rodgers G.H.
      • Ming W.
      • Qian Y.W.
      • Bivi N.
      • et al.
      Assessment and clinical relevance of serum IL-19 levels in psoriasis and atopic dermatitis using a sensitive and specific novel immunoassay.
      P ≤ .1.
      E

      E
      S

      S
      2017

      2019
      21

      124
      Esaki et al
      • Esaki 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.
      Pediatric cohort.
      (LS-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Diaz A.
      • Pavel A.B.
      • Fernandes M.
      • Lefferdink R.
      • Erickson T.
      • et al.
      Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis.
      Pediatric cohort.
      (LS-TS)
      P ≤ .1.


      Pavel et al
      • Pavel A.B.
      • Renert-Yuval Y.
      • Wu J.
      • Del Duca E.
      • Diaz A.
      • Lefferdink R.
      • et al.
      Tape-strips from early-onset pediatric atopic dermatitis highlight disease abnormalities in non-lesional skin.
      Pediatric cohort.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.89
      (LS-TS)
      P ≤ .1.
      PCR

      PCR

      R
      P

      S

      S
      2016

      2019

      2020
      19

      21

      19
      B, Skin biopsy; C, cell count; Corr, correlation; ECP, eosinophil cationic protein; E, ELISA; ECL, electrochemiluminescence immunoassay; EMD, Erenna immunoassay; F, flow cytometry; FEIA, fluorescent enzyme immunoassays; IC, ImmunoCap system; IF, immunofluorescence; IRMA, immunoradiometric assay; ISF, interstitial fluid; K, Kendall rank correlation; L, Luminex; LDH, lactate dehydrogenase; LRA, linear regression analysis; LS, lesional; N, nephelometric method; NA, not applicable/available; NL, nonlesional; O, OLINK proteomics; PARC, pulmonary and activation-regulated chemokine; R, RNA-sequencing; RIA, ECP radioimmunoassay; SCORAD, SCORing of Atopic Dermatitis; TEWL, transepidermal water loss; TS, tape-strips.
      Correlated with SCORAD components and not with the total SCORAD.
      Pediatric cohort.
      Correlated with Six Area, Six Sign AD/body surface area/Leicester severity score/scoring system as described by Costa et al.
      • Costa C.
      • Rilliet A.
      • Nicolet M.
      • Saurat J.H.
      Scoring atopic dermatitis: the simpler the better?.
      § Correlated with TEWL.
      P ≤ .1.
      Performed on monocyte-derived circulating dendritic cells.
      # Log2(IgE) was correlated with SCORAD.
      ∗∗ Correlated with pruritus.
      Table IVPotential biomarkers reported to strongly and significantly correlate with clinical therapeutic response in AD (correlation coefficient ≥0.4, P < .05)
      Biomarker (no. of publications)SerumSkin
      AuthorLab methodCorr methodYearCohort (n)AuthorLab methodCorr methodYearCohort (n)
      CCL17/TARC (>5)Furukawa et al
      • Furukawa H.
      • Takahashi M.
      • Nakamura K.
      • Kaneko F.
      Effect of an antiallergic drug (Olopatadine hydrochloride) on TARC/CCL17 and MDC/CCL22 production by PBMCs from patients with atopic dermatitis.


      Kwon et al
      • Kwon Y.S.
      • Oh S.H.
      • Wu W.H.
      • Bae B.G.
      • Lee H.J.
      • Lee M.G.
      • et al.
      CC chemokines as potential immunologic markers correlated with clinical improvement of atopic dermatitis patients by immunotherapy.


      Beck et al
      • Beck L.A.
      • Thaci D.
      • Hamilton J.D.
      • Graham N.M.
      • Bieber T.
      • Rocklin R.
      • et al.
      Dupilumab treatment in adults with moderate-to-severe atopic dermatitis.
      Correlated with pruritus.


      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      P ≤ .1.
      E

      E

      E

      ECL
      NA

      LRA

      NA

      P
      2004

      2010

      2014

      2017
      15

      20

      55

      25
      Khattri et al
      • Khattri S.
      • Shemer A.
      • Rozenblit M.
      • Dhingra N.
      • Czarnowicki T.
      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      (LS-B, P)

      Koppes et al
      • Koppes S.A.
      • Brans R.
      • Ljubojevic Hadzavdic S.
      • Frings-Dresen M.H.
      • Rustemeyer T.
      • Kezic S.
      Stratum corneum tape stripping: monitoring of inflammatory mediators in atopic dermatitis patients using topical therapy.
      (LS-TS)

      Pavel et al
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      (LS-B)
      PCR

      E

      PCR
      S

      S

      S
      2014

      2016

      2019
      19

      21

      36
      MDC/CCL22 (>5)Furukawa et al
      • Furukawa H.
      • Takahashi M.
      • Nakamura K.
      • Kaneko F.
      Effect of an antiallergic drug (Olopatadine hydrochloride) on TARC/CCL17 and MDC/CCL22 production by PBMCs from patients with atopic dermatitis.


      Kwon et al
      • Kwon Y.S.
      • Oh S.H.
      • Wu W.H.
      • Bae B.G.
      • Lee H.J.
      • Lee M.G.
      • et al.
      CC chemokines as potential immunologic markers correlated with clinical improvement of atopic dermatitis patients by immunotherapy.
      E

      E
      NA

      LRA
      2004

      2010
      15

      20
      Khattri et al
      • Khattri S.
      • Shemer A.
      • Rozenblit M.
      • Dhingra N.
      • Czarnowicki T.
      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      (LS-B)

      Pavel et al
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      (LS-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Bissonnette R.
      • Ungar B.
      • Suarez-Farinas M.
      • Ardeleanu M.
      • Esaki H.
      • et al.
      Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
      (LS-B)
      P ≤ .1.
      PCR

      PCR

      PCR
      S

      S

      S
      2014

      2019

      2019
      19

      36

      54
      IL-13 (≥5)Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      EP201725Khattri et al
      • Khattri S.
      • Shemer A.
      • Rozenblit M.
      • Dhingra N.
      • Czarnowicki T.
      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      (LS-B)

      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      (LS-B)

      Pavel et al
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      (LS-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Bissonnette R.
      • Ungar B.
      • Suarez-Farinas M.
      • Ardeleanu M.
      • Esaki H.
      • et al.
      Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
      (LS-B)
      P ≤ .1.
      PCR

      PCR

      PCR

      PCR
      S

      P

      S

      S
      2014

      2017

      2019

      2019
      19

      25

      36

      54
      S100A7/8/12 (≥5)Tintle et al
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.
      (LS-B)
      P ≤ .1.


      Khattri et al
      • Khattri S.
      • Shemer A.
      • Rozenblit M.
      • Dhingra N.
      • Czarnowicki T.
      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      (LS-B)

      Pavel et al
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      (LS-B)

      Bissonnette et al
      • Bissonnette R.
      • Pavel A.B.
      • Diaz A.
      • Werth J.L.
      • Zang C.
      • Vranic I.
      • et al.
      Crisaborole and atopic dermatitis skin biomarkers: an intrapatient randomized trial.
      Correlated with Leicester severity score/Investigator’s Static Global Assessment.
      (LS-B)

      Guttman-Yassky et al
      • Guttman-Yassky E.
      • Bissonnette R.
      • Ungar B.
      • Suarez-Farinas M.
      • Ardeleanu M.
      • Esaki H.
      • et al.
      Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
      (LS-B)
      PCR

      PCR

      PCR

      PCR

      PCR
      S

      S

      S

      S

      S
      2011

      2014

      2019

      2019

      2019
      12

      19

      36

      40

      54
      IL-22 (>3)Tintle et al
      • Tintle S.
      • Shemer A.
      • Suarez-Farinas M.
      • Fujita H.
      • Gilleaudeau P.
      • Sullivan-Whalen M.
      • et al.
      Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.
      (LS-B)

      Khattri et al
      • Khattri S.
      • Shemer A.
      • Rozenblit M.
      • Dhingra N.
      • Czarnowicki T.
      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      (LS-B)

      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      (LS/NL-B)

      Pavel et al
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      (LS-B)
      PCR

      PCR

      PCR

      PCR
      S

      S

      P

      S
      2011

      2014

      2017

      2019
      12

      19

      25

      36
      CCL13/MCP-4 (>3)Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      ECPP201725Hamilton et al
      • Hamilton J.D.
      • Suarez-Farinas M.
      • Dhingra N.
      • Cardinale I.
      • Li X.
      • Kostic A.
      • et al.
      Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.
      (LS-B)
      P ≤ .1.


      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      (NL-B)

      Pavel et al
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      (LS-B)

      He et al
      • He H.
      • Olesen C.M.
      • Pavel A.B.
      • Clausen M.L.
      • Wu J.
      • Estrada Y.
      • et al.
      Tape-strip proteomic profiling of atopic dermatitis on dupilumab identifies minimally invasive biomarkers.
      (LS-TS)
      PCR

      PCR

      PCR

      O
      P

      P

      S

      S
      2014

      2017

      2019

      2020
      18

      25

      36

      26
      Eotaxin-3/CCL26 (≥3)Hamilton et al
      • Hamilton J.D.
      • Suarez-Farinas M.
      • Dhingra N.
      • Cardinale I.
      • Li X.
      • Kostic A.
      • et al.
      Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis.
      (LS-B)

      Khattri et al
      • Khattri S.
      • Shemer A.
      • Rozenblit M.
      • Dhingra N.
      • Czarnowicki T.
      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      (LS-B)

      Pavel et al
      • Pavel A.B.
      • Song T.
      • Kim H.J.
      • Del Duca E.
      • Krueger J.G.
      • Dubin C.
      • et al.
      Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
      (LS-B)
      PCR

      PCR

      PCR
      P

      S

      S
      2014

      2014

      2019
      18

      19

      36
      CCL18/PARC (≥3)Guttman-Yassky et al
      • Guttman-Yassky E.
      • Bissonnette R.
      • Ungar B.
      • Suarez-Farinas M.
      • Ardeleanu M.
      • Esaki H.
      • et al.
      Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
      ES201954Khattri et al
      • Khattri S.
      • Shemer A.
      • Rozenblit M.
      • Dhingra N.
      • Czarnowicki T.
      • Finney R.
      • et al.
      Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology.
      (LS-B)

      Ungar et al
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      (LS/NL-B)
      PCR

      PCR
      S

      P
      2014

      2017
      19

      25
      B, Skin biopsy; Corr, correlation; E, ELISA; ECL, electrochemiluminescence immunoassay; LRA, linear regression analysis; LS, lesional; N, nephelometric method; NL, nonlesional; PARC, pulmonary and activation-regulated chemokine; TS, tape-strips.
      Correlated with pruritus.
      P ≤ .1.
      Correlated with Leicester severity score/Investigator’s Static Global Assessment.
      Figure thumbnail gr1
      Fig 1Potential biomarkers for AD in nonlesional and lesional AD skin (using both biopsies and tape-strips, top) as well as circulating potential biomarkers in blood of patients with AD (bottom). LDH, Lactate dehydrogenase.
      Barrier-related potential biomarkers, including filaggrin (FLG), loricrin, and natural moisturizing factor, may inversely correlate with disease severity.
      • Kezic S.
      • O’Regan G.M.
      • Lutter R.
      • Jakasa I.
      • Koster E.S.
      • Saunders S.
      • et al.
      Filaggrin loss-of-function mutations are associated with enhanced expression of IL-1 cytokines in the stratum corneum of patients with atopic dermatitis and in a murine model of filaggrin deficiency.
      Because of the complexity of AD pathogenesis, a few reports modeled a combination of biomarkers to better reflect molecular changes correlating with clinical severity.
      • Hulshof L.
      • Overbeek S.A.
      • Wyllie A.L.
      • Chu M.
      • Bogaert D.
      • de Jager W.
      • et al.
      Exploring immune development in infants with moderate to severe atopic dermatitis.
      ,
      • Ungar B.
      • Garcet S.
      • Gonzalez J.
      • Dhingra N.
      • Correa da Rosa J.
      • Shemer A.
      • et al.
      An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease.
      ,
      • Thijs J.L.
      • Drylewicz J.
      • Fiechter R.
      • Strickland I.
      • Sleeman M.A.
      • Herath A.
      • et al.
      EASI p-EASI: utilizing a combination of serum biomarkers offers an objective measurement tool for disease severity in atopic dermatitis patients.
      The current evidence from the literature, including only those reports in which a significant and robust correlation between AD clinical severity and a tissue biomarker was found (r ≥ 0.4; P < .05), is summarized using the GRADE approach in Table V.
      • Guyatt 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.
      Table VGRADE evidence profile: Accumulated data on potential biomarkers correlating with disease severity in AD
      Based on Tables III and IV, only studies with a significant positive correlation with a correlation coefficient of ≥0.4 were included.
      Biomarker

      No. of studies; No. of subjects included
      Weighted average of correlation strength (r)
      Based on Tables III and IV, only studies with a significant positive correlation with a correlation coefficient of ≥0.4 were included.
      LimitationInconsistencyIndirectness/ imprecision/publication biasOverall evidence for biomarker generalizability (highest achieved)
      Biomarkers correlating with severity in nontreated adult AD
       CCL17/TARC

      14; 1,136
      0.58No serious limitations for blood; for skin— limited number of studies were found by our criteriaNot all studies correlated the biomarker with EASI or SCORAD as scores for AD clinical severityNo serious indirectness or imprecision; no publication bias detectedVery high (in blood)
       IgE

      11; 421
      0.62No serious limitationsNo serious inconsistency among these reports, but IgE levels are not consistently correlated with AD severity in multiple other reportsNo serious indirectness or imprecision; no publication bias detectedHigh
       CCL22/MDC

      9; 227
      0.62No serious limitations for blood; for skin— limited evidence exists by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedHigh (in blood)
       LDH

      7; 445
      0.52No serious limitationsNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedHigh
       IL-18

      5; 321
      0.63No serious limitationsVariable laboratory methods in skinNo serious indirectness or imprecision; no publication bias detectedHigh
       Eosinophils/ ECP

      9; 253
      0.6No serious limitationsVariable laboratory methods were reported. Different aspects of eosinophil upregulation/activation were analyzedNo serious indirectness or imprecision; no publication bias detectedModerate-high
       IL-22

      7; 116
      0.52Sparse reports in blood, with limited number of patientsVariable laboratory methods in bloodNo serious indirectness or imprecision; no publication bias detectedModerate (in skin)
       IL-13

      6; 144
      0.54Sparse data in blood by our criteria. Limited number of patients in both skin and blood studiesVariable laboratory methods in bloodNo serious indirectness or imprecision; no publication bias detectedModerate (in skin)
       E-selectin

      4; 159
      0.53No serious limitationsLaboratory and correlation methods and variedNo serious indirectness or imprecision; no publication bias detectedModerate
       MMP12

      5; 174
      0.46No serious limitations for skin. Only proteomic data were reported in blood by our criteriaLaboratory and correlation methods and variedNo serious indirectness or imprecision; no publication bias detectedModerate
       S100A7/12

      6; 132
      0.49No serious limitationsNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate
       CCL27/CTACK

      2; 126
      0.59Limited evidence in blood, no evidence in skin by our criteriaDifferent AD severity scores were usedNo serious indirectness or imprecision; no publication bias detectedModerate-low (in blood)
       CCL26/eotaxin-3

      3; 72
      0.53Very limited data in skinNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate-low (in blood)
       CCL18/ PARC

      2; 22
      0.63Very limited data in adult skin; no data from adult blood by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedLow
       IL-19

      2; 136
      0.59No data were reported in adult skin by our criteria. The largest study in adult blood only achieved P < .1No serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedLow (in blood)
      Biomarkers correlating with severity in nontreated pediatric AD
       CCL17/TARC

      9; 559
      0.56No serious limitations in blood. No data were reported in pediatric skin by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedHigh (in blood)
       CTACK/CCL27

      4; 254
      0.66No serious limitations in blood. No data were reported in pediatric skin by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedHigh (in blood)
       IgE, 3; 118

      IL-18, 4; 155,

      CCL22/MDC, 4; 131
      0.76, 0.64, 0.46 (respectively)Limited number of studies by our criteria. For CCL22/MDC, correlation was found only in bloodNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate-high (in blood)
       E-selectin,

      2; 45
      0.45Limited evidence in pediatric blood; no data from pediatric skin by our criteriaVariable laboratory methodsNo serious indirectness or imprecision; no publication bias detectedModerate-low (in blood)
       Eosinophils/ ECP

      3; 128
      0.71Limited number of studies by our criteriaVariable laboratory methodsNo serious indirectness or imprecision; no publication bias detectedModerate-low
       CCL18/PARC

      3; 148
      0.47Limited number of studies by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate-low
       IL-22, 1; 19

      IL-13, 1; 21

      S100A7/12,

      1; 21
      NAVery limited number of studies and subjects in pediatric skin; no evidence in pediatric blood by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedLow (in skin)
       MMP12

      2; 49
      0.5Very limited number of studies and subjects in both skin and blood by our criteriaIn blood, correlation was found with body surface area. In skin, correlation was found with pruritusNo serious indirectness or imprecision; no publication bias detectedLow
       IL-19

      3; 59
      0.43Limited evidence in pediatric skin; no evidence in pediatric blood by our criteria. Tape-stripped pediatric skin only achieved P < .1No serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedLow (in skin)
      Biomarkers showing decreased levels in correlation with clinical improvement in longitudinal, topical treatment studies
       CCL17/TARC,

      CCL22/MDC,

      1; 20 (for both)
      NALimited data and only with an emollient. Correlation was found only in patients with moderate ADNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedLow
      Baseline CCL22/MDC expression in skin correlated with future clinical improvement in a report analyzing data across multiple studies (using both topical and systemic therapies) at various time points.108
       S100A7/8/12

      1; 40
      NALimited data and only with crisaboroleUnlike other potential biomarkers, correlation was found with Investigator’s Static Global Assessment and not EASI/SCORADNo serious indirectness or imprecision; no publication bias detectedLow
      Biomarkers showing decreased levels in correlation with clinical improvement in longitudinal, systemic treatment studies
       CCL17/TARC

      6; 170
      0.55No serious limitationsDuring dupilumab treatment, biomarker reduction was correlated with pruritusNo serious indirectness or imprecision; no publication bias detectedModerate-high (in blood)
       CCL13/MCP-4,

      5; 130,

      IL-13, 5; 159,

      CCL22/MDC, 4; 124
      0.54, 0.56, 0.49 (respectively)Sparse data in blood by our criteriaDuring dupilumab treatment, correlation with biomarker reduction only achieved P < .1. For CCL13/MCP-4, variable laboratory methods were reportedNo serious indirectness or imprecision; no publication bias detectedModerate-high (in skin)
      Baseline CCL22/MDC expression in skin correlated with future clinical improvement in a report analyzing data across multiple studies (using both topical and systemic therapies) at various time points.108
       S100A7/8/12

      4; 121
      0.54No serious limitationsNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate
       IL-22

      4; 92
      0.56Limited evidence in skin; no evidence in bloodNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate-low
       CCL18/PARC

      3; 98
      0.56Limited evidence in skin; sparse evidence in blood by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate-low
       CCL26/ eotaxin-3

      3; 73
      0.62No evidence in blood by our criteriaNo serious inconsistencyNo serious indirectness or imprecision; no publication bias detectedModerate-low (in skin)
      EASI, Eczema Area and Severity Index; ECP, eosinophil cationic protein; LDH, lactate dehydrogenase; NA, not applicable because only 1 report was included by our criteria; PARC, pulmonary and activation-regulated chemokine; SCORAD, SCORing of Atopic Dermatitis.
      Based on Tables III and IV, only studies with a significant positive correlation with a correlation coefficient of ≥0.4 were included.
      Baseline CCL22/MDC expression in skin correlated with future clinical improvement in a report analyzing data across multiple studies (using both topical and systemic therapies) at various time points.
      • Glickman J.W.
      • Dubin C.
      • Renert-Yuval Y.
      • Dahabreh D.
      • Kimmel G.W.
      • Auyeung K.
      • et al.
      Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation.

       Biomarkers that failed to show consistent correlation with severity

      Although total serum IgE levels (particularly in extrinsic AD)
      • Vekaria 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.
      ,
      • Kou 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.
      ,
      • Jahnz-Rozyk K.
      • Targowski T.
      • Paluchowska E.
      • Owczarek W.
      • Kucharczyk A.
      Serum thymus and activation-regulated chemokine, macrophage-derived chemokine and eotaxin as markers of severity of atopic dermatitis.
      ,
      • Yoshizawa Y.
      • Nomaguchi H.
      • Izaki S.
      • Kitamura K.
      Serum cytokine levels in atopic dermatitis.
      ,
      • Salomon J.
      • Baran E.
      The role of selected neuropeptides in pathogenesis of atopic dermatitis.
      • Wu K.G.
      • Li T.H.
      • Chen C.J.
      • Cheng H.I.
      • Wang T.Y.
      Correlations of serum interleukin-16, total IgE, eosinophil cationic protein and total eosinophil counts with disease activity in children with atopic dermatitis.
      • Suarez-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.
      ,
      • Glatz M.
      • Buchner M.
      • von Bartenwerffer W.
      • Schmid-Grendelmeier P.
      • Worm M.
      • Hedderich J.
      • et al.
      Malassezia spp.-specific immunoglobulin E level is a marker for severity of atopic dermatitis in adults.
      ,
      • Sanyal 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.
      ,
      • Laske N.
      • Niggemann B.
      Does the severity of atopic dermatitis correlate with serum IgE levels?.
      • Shaheen M.A.
      • Attia E.A.
      • Louka M.L.
      • Bareedy N.
      Study of the role of serum folic acid in atopic dermatitis: a correlation with serum IgE and disease severity.
      • Neuber K.
      • Schwartz I.
      • Itschert G.
      • Dieck A.T.
      Treatment of atopic eczema with oral mycophenolate mofetil.
      are elevated in AD, these are not consistently correlated with disease severity or only weakly correlated,
      • Morishima Y.
      • Kawashima H.
      • Takekuma K.
      • Hoshika A.
      Changes in serum lactate dehydrogenase activity in children with atopic dermatitis.
      ,
      • Aral M.
      • Arican O.
      • Gul M.
      • Sasmaz S.
      • Kocturk S.A.
      • Kastal U.
      • et al.
      The relationship between serum levels of total IgE, IL-18, IL-12, IFN-gamma and disease severity in children with atopic dermatitis.
      ,
      • Furukawa H.
      • Takahashi M.
      • Nakamura K.
      • Kaneko F.
      Effect of an antiallergic drug (Olopatadine hydrochloride) on TARC/CCL17 and MDC/CCL22 production by PBMCs from patients with atopic dermatitis.
      ,
      • Thijs J.L.
      • Knipping K.
      • Bruijnzeel-Koomen C.A.
      • Garssen J.
      • de Bruin-Weller M.S.
      • Hijnen D.J.
      Immunoglobulin free light chains in adult atopic dermatitis patients do not correlate with disease severity.
      and in dupilumab studies, responses of patients with AD are regardless of their baseline IgE levels.
      • Hamilton J.D.
      • Ungar B.
      • Guttman-Yassky E.
      Drug evaluation review: dupilumab in atopic dermatitis.
      Thus, it is likely that IgE is a bystander in AD pathogenesis, rather than a treatment target.
      • Heil P.M.
      • Maurer D.
      • Klein B.
      • Hultsch T.
      • Stingl G.
      Omalizumab therapy in atopic dermatitis: depletion of IgE does not improve the clinical course—a randomized, placebo-controlled and double blind pilot study.
      ,
      • Holm J.G.
      • Agner T.
      • Sand C.
      • Thomsen S.F.
      Omalizumab for atopic dermatitis: case series and a systematic review of the literature.
      Although periostin is implicated in the pathogenesis of AD and was suggested as a potential AD biomarker by some reports, evidence for a correlation with disease severity is weak.
      • Kou K.
      • Okawa T.
      • Yamaguchi Y.
      • Ono J.
      • Inoue Y.
      • Kohno M.
      • et al.
      Periostin levels correlate with disease severity and chronicity in patients with atopic dermatitis.
      ,
      • Uysal P.
      • Birtekocak F.
      • Karul A.B.
      The relationship between serum TARC, TSLP and POSTN levels and childhood atopic dermatitis.
      ,
      • Sung M.
      • Lee K.S.
      • Ha E.G.
      • Lee S.J.
      • Kim M.A.
      • Lee S.W.
      • et al.
      An association of periostin levels with the severity and chronicity of atopic dermatitis in children.
      Curiously, despite some reports on the correlation of the “itch cytokine,” IL-31, with disease severity,
      • Raap U.
      • Weissmantel S.
      • Gehring M.
      • Eisenberg A.M.
      • Kapp A.
      • Folster-Holst R.
      IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis.
      ,
      • Raap U.
      • Wichmann K.
      • Bruder M.
      • Stander S.
      • Wedi B.
      • Kapp A.
      • et al.
      Correlation of IL-31 serum levels with severity of atopic dermatitis.
      more evidence is accumulating on the lack of such correlation.
      • Kyoya M.
      • Kawakami T.
      • Soma Y.
      Serum thymus and activation-regulated chemokine (TARC) and interleukin-31 levels as biomarkers for monitoring in adult atopic dermatitis.
      ,
      • Ozceker D.
      • Bulut M.
      • Ozbay A.C.
      • Dilek F.
      • Koser M.
      • Tamay Z.
      • et al.
      Assessment of IL-31 levels and disease severity in children with atopic dermatitis.
      • Neis M.M.
      • Peters B.
      • Dreuw A.
      • Wenzel J.
      • Bieber T.
      • Mauch C.
      • et al.
      Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis.
      • Nygaard U.
      • Hvid M.
      • Johansen C.
      • Buchner M.
      • Folster-Holst R.
      • Deleuran M.
      • et al.
      TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis.