Atopic Dermatitis Endotypes Research Articles

Diagnostic and prognostic value of biomarkers in atopic dermatitis for assessing its endotypes, phenotypes, and treatment efficacy

Atopic dermatitis is a highly heterogeneous disease that usually requires a tailored approach to therapy. Recent studies have described a variety of biomarkers linked to diverse pathophysiological aspects of atopic dermatitis. Furthermore, they have provided encouraging evidence supporting high clinical importance of these biomarkers as promising tools for personalized diagnosis, assessment of disease severity, and monitoring of treatment efficacy. This review aims to provide a comprehensive summary of research progress on atopic dermatitis biomarkers, their diagnostic and prognostic value, as well as the benefits they might potentially offer not only for determining the disease endotype, but also for developing novel management strategies. The implementation of easily accessible and simple methods to measure atopic dermatitis biomarkers into clinical practice is an ambitious task for allergologists and dermatologists. A detailed overview of currently available data will allow us to identify the most important trajectories for future research in this area that will promote the concept of personalized atopic dermatitis therapy, reduce the disease burden, and improve the quality of life of patients.

How Do Classical Subtypes Correspond to Endotypes in Atopic Dermatitis?

Since atopic dermatitis (AD) is a heterogeneous condition, the subtyping of AD is a crucial issue. The classical subtypes of AD are represented by extrinsic and intrinsic subtypes, European-American and Asian subtypes, and adult and pediatric subtypes. While the subtyping of AD was historically conducted based on the phenotype, recent findings on the mechanisms of AD have revealed the importance of the endotype, which can characterize individual patients more accurately. Considering the current development of AD therapies, AD endotyping is a prerequisite for a personalized therapeutic choice. Endotypes of AD can be stratified from different viewpoints, including cytokine expression patterns, allergen properties, epidermal barrier conditions, ceramide variation, the involvement of innate immunity, and serum biomarkers. Among them, the cytokine-based endotype seems to be the most useful one and is categorized into type 2 cytokine (IL-4, IL-13 and IL-31)-high, type 1 cytokine (IFN-γ)-high, and/or type 3 cytokine (IL-22 and IL-17)-high, or mixed subtypes. Recently proposed biomarker endotyping aims at individualized treatment options, although the daily clinical use of endotypes is a future issue. To better understand the endotypes for clinicians, attempts to adjust each of the classical subtypes to endotypes are required. This review will discuss the correspondence of the classical subtypes to the various endotypes that have recently been proposed.

43946 Neutralization of IL-13 by tralokinumab improves atopic dermatitis endotypes characterized by S. aureus colonization

43946 Neutralization of IL-13 by tralokinumab improves atopic dermatitis endotypes characterized by S. aureus colonization

Moderate to severe atopic dermatitis in children: focus on systemic Th2 cytokine receptor antagonists and Janus kinase inhibitors.

Atopic dermatitis (AD) is a lifelong disease that markedly impairs quality of life. AD is considered a starting point of the "atopic march," which begins at a young age and may progress to systemic allergic diseases. Moreover, it is strongly associated with comorbid allergic and inflammatory diseases including arthritis and inflammatory bowel disease. Understanding the pathogenesis of AD is essential for the development of targeted therapies. Epidermal barrier dysfunction, immune deviation toward a T helper 2 proinflammatory profile, and microbiome dysbiosis play important roles via complex interactions. The systemic involvement of type 2 inflammation, wheather acute or chronic, and whether extrinsic or intrinsic, is evident in any type of AD. Studies on AD endotypes with unique biological mechanisms have been conducted according to clinical phenotypes, such as race or age, but the endotype for each phenotype, or endophenotype, has not yet been clearly identified. Therefore, AD is still being treated according to severity rather than endotype. Infancy-onset and severe AD are known risk factors leading to atopic march. In addition, up to 40% of adult AD are cases of infancy-onset AD that persist into adulthood, and these are often accompanied by other allergic diseases. Therefore, early intervention strategies to identify high-risk infants and young children, repair an impaired skin barrier, and control systemic inflamation may improve long-term outcomes in AD patients. However, to the best of our knowledge, no study has evaluated the effectiveness of early intervention on atopic march using systemic therapy in high-risk infants. This narrative review addresses the latest knowledge of systemic treatment, including Th2 cytokine receptor antagonists and Janus kinase inhibitors, for children with moderate to severe AD that is refractory to topical treatment.

Evaluating and comparing the clinical characteristics between adult-onset and childhood-onset atopic dermatitis in an Asian clinical cohort.

Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin conditions. We aimed to describe the clinical features of adult-onset and childhood-onset AD in a multi-ethnic Asian population. A retrospective study was performed of 188 patients with AD managed at a tertiary skin institution in Singapore. Patient demographics, clinical features and disease scores were analysed. Clinical features related to pigmentary changes, such as orbital darkening and Dennie-Morgan folds were more prevalent among childhood-onset AD patients than in adult-onset AD patients. Similarly, features related to prolonged scratching or friction, such as anterior neck folds, perifollicular accentuation and infra-auricular/infranasal fissuring were also more prevalent in childhood-onset AD patients. Disease scores such as SCORAD and EASI were not different between patients with childhood versus adult-onset disease. There were significant differences in clinical features between childhood-onset and adult-onset AD. Certain features are related to pigmentary changes and might be more accentuated in patients with skin of colour. Further studies are needed to understand how the different features might be clinically significant and related to the various AD endotypes and disease trajectories.

Serum biomarker-based endotypes of atopic dermatitis in China and prediction for efficacy of dupilumab.

Atopic dermatitis (AD) is a highly heterogeneous disease clinically and biologically. Serum biomarkers have been utilized for endotype identification and have the potential to be predictors for treatment. To explore the serum biomarker-based endotypes of Chinese patients with AD and to identify biomarkers for prediction of the efficacy of dupilumab. Sera from 125 patients with moderate-to-severe AD and 60 normal controls (NC) were analysed for 24 cytokines/chemokines using the magnetic Luminex assay. After the patients received 16 weeks of dupilumab treatment, the efficacy was evaluated, and blood eosinophils, serum immunoglobulin (Ig) E and biomarkers were measured. Chinese patients with moderate-to-severe AD were characterized by T-helper (Th)2-dominant serum biomarkers that were mixed with differentially increased Th1-, Th17- and Th22-type cytokines/chemokines, and it was mainly Th2-type serum biomarkers that were positively correlated with disease severity and eosinophil counts. Adult (but not adolescent or elderly) patients with AD showed a consistent and more significant increase of biomarkers across different types of inflammation. The patients were grouped into two clusters by unsupervised k-means analysis, which were differentially associated with inflammation. Treatment with dupilumab decreased the levels of most cytokines/chemokines analysed. While there was no difference between the two clusters in the efficacy of dupilumab, baseline levels of CD25/soluble interleukin (sIL)-2Rα, IL-31 and IL-36β were identified as predictive factors associated with the efficacy. Our study revealed two inflammation-related endotypes of Chinese patients with AD based on serum biomarkers. High levels of CD25/sIL-2Rα, IL-31 and IL-36β might predict good efficacy of dupilumab treatment.

The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective.

Atopic dermatitis (AD) is one of the most common, chronic inflammatory skin diseases with a significant physical, emotional and socioeconomic burden. In recent years the understanding of AD pathogenesis has expanded from the Th2-centred perspective, with the recognition of the involvement of other immune axes. In different AD endotypes, influenced by environment, genetics and race, transcriptomic profiles have identified differing contributions of multiple immune axes such as, Th17, Th22 and Th1. The enriched pathogenic model of AD has catalysed the development of numerous biologic therapies targeting a range of key molecules implicated in disease progression. Currently, dupilumab and tralokinumab, which both target the Th2 pathway, are the only approved biologic therapies for AD in the United States and Europe. New biologic therapies in development, however, target different Th2-pathway molecules along with cytokines in other immune axes, including Th17 and Th22, offering promise for varied treatments for this heterogeneous disease. As the biologic pipeline advances, the integration into clinical practice and approval of these experimental biologics may provide more effective, tailored therapeutic solutions and illuminate on the pathologic processes of AD across a broader, more diverse patient population.

Immunopathogenesis of Atopic Dermatitis: Focus on Interleukins as Disease Drivers and Therapeutic Targets for Novel Treatments.

Atopic dermatitis is a chronic, recurrent inflammatory skin disorder manifesting by eczematous lesions and intense pruritus. Atopic dermatitis develops primarily as a result of an epidermal barrier defect and immunological imbalance. Advances in understanding these pathogenetic hallmarks, and particularly the complex role of interleukins as atopic dermatitis drivers, resulted in achieving significant therapeutic breakthroughs. Novel medications involve monoclonal antibodies specifically blocking the function of selected interleukins and small molecules such as Janus kinase inhibitors limiting downstream signaling to reduce the expression of a wider array of proinflammatory factors. Nevertheless, a subset of patients remains refractory to those treatments, highlighting the complexity of atopic dermatitis immunopathogenesis in different populations. In this review, we address the immunological heterogeneity of atopic dermatitis endotypes and phenotypes and present novel interleukin-oriented therapies for this disease.

The Dawn of a New Era in Atopic Dermatitis Treatment.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, and the condition is typified by barrier dysfunction and immune dysregulation. Recent studies have characterized various phenotypes and endotypes of AD and elucidated the mechanism. Numerous topical and systemic narrow targeting therapies for AD have been developed according to these findings. Topical medications, including Janus kinase (JAK) inhibitors, phosphodiesterase 4 inhibitors, and the aryl hydrocarbon receptor agonist tapinarof, are effective and safe for AD compared to topical corticosteroids. Oral JAK inhibitors and monoclonal antibodies targeting interleukin (IL)-4, IL-13, IL-31, IL-33, OX40, thymic stromal lymphopoietin, and sphingosine 1-phosphate signaling have displayed outstanding efficacy against moderate-to-severe AD. We are currently in a new era of AD treatment.

Atopic dermatitis endotypes: knowledge for personalized medicine.

Endotypes are clinically relevant phenotypes that can be explained by molecular mechanisms, and are defined to predict the development, progression, prognosis and responses to treatment on the individual level. This review summarizes atopic dermatitis phenotypes, endotypes and their potential application for personalized medicine. Atopic dermatitis can be classified into several phenotypes according to disease courses that likely have common pathophysiology. The genotype is important to define endotypes, but the value of genotype alone remains somewhat limited in most atopic dermatitis patients. Recent studies have demonstrated that atopic dermatitis phenotypes according to ethnicity or age can be classified into endotypes based on the dominant immunologic markers, that is TH1/TH2/TH17/TH22 cells. Newly developed biologic agents targeting specific cytokines show therapeutic potential in a personalized medicine approach. Cytokine-based endotypes in different age groups or ethnic groups have contributed to expanding our understanding of atopic dermatitis. Recent biologics or small molecules can be used for more personalized treatment of atopic dermatitis. Further research using integrated multiomic analysis is needed to define a more detailed classification of endotypes and provide endotype-driven targeted therapies for personalized medicine.

Longitudinal Atopic Dermatitis Endotypes: An Atopic March Paradigm That Includes Black Children

Longitudinal Atopic Dermatitis Endotypes: An Atopic March Paradigm That Includes Black Children

Longitudinal atopic dermatitis endotypes: An atopic march paradigm that includes Black children

The atopic march has been studied mostly in White populations, biasing our current paradigms. We sought to define the atopic march in Black and White children and explore mechanisms for racial differences. Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (n= 601), we assessed longitudinal sensitization, food allergy (FA), allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), Scoring for Atopic Dermatitis (SCORAD), transepidermal water loss, skin filaggrin (FLG) expression, exposures, and genetic heritability to define AD progression endotypes in Black and White children. White MPAACH children were more likely to be sensitized to aero and food allergens (P= .0001) and over 3 times more likely to develop FA and/or allergic rhinitis (AR) without asthma risk (P< .0001). In contrast, Black children were over 6 times more likely to proceed to high asthma risk without FA, sensitization, or AR (P< .0001). White children had higher lesional and nonlesional transepidermal water loss (both P< .001) as well as decreased nonlesional keratinocyte FLG expression (P= .02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier and less sensitization, FA, and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR, and sensitization. The observed racial differences are likely due in part to increased genetic heritability for asthma risk and harmful environmental exposures in Black children. Collectively, our findings provide a new paradigm for an atopic march that is inclusive of Black children.

Molecular Mechanisms of Atopic Dermatitis Pathogenesis.

Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. Acharacteristic feature is persistent itching of the skin. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life of patients and their families. The disease emerges as a social problem by increasing indirect costs, such as visiting a doctor, absenteeism from work and school, and avoiding social interactions. Thepathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, anddisruption of the skin’s microbial balance. The numerous complex changes at thegenetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. Emerging therapies rely on the action of specific molecules involved in the disease’s pathogenesis. It may be the starting point for the individualization of atopic dermatitis treatment. This paper will try to present some molecular mechanisms of atopic dermatitis and their clinical implications.

Janus kinase inhibitors for atopic dermatitis: a promising treatment modality.

Atopic dermatitis (AD) is chronic, pruritic, inflammatory skin disease that affects a significant portion of the population in industrialized nations. For nonresponders to conventional therapies, AD can significantly reduce sleep quality and quality of life. AD pathogenesis is multifactorial and involves multiple immune pathways, with recent evidence of T helper (Th)2, Th17 and Th22 axis attenuation in various AD endotypes and racial subtypes. Inhibition of the conserved Janus kinase (JAK) signalling pathway represents a promising therapeutic avenue to reduce the activation of multiple proinflammatory mediators involved in AD pathogenesis. JAK inhibitors exist in both oral and topical forms with variable specificity for the receptor tyrosine kinases JAK1, JAK2, JAK3 and tyrosine kinase 2. Oral formulations include abrocitinib, upadacitinib, baricitinib and gusacitinib, and are most appropriate for patients with moderate to severe AD. Emerging topical formulation in development include ruxolitinib and deglocitinib, which may be used in patients with localized AD and also adjunctively with systemic therapy in patients with more severe disease. With observed rapidity in itch relief and accompanying dramatic reduction in inflammatory lesion count, JAK inhibitors represent a promising new treatment to revolutionize the management of AD.

Genomic and phenotypic characterization of Investigator Global Assessment (IGA) scale-based endotypes in atopic dermatitis

To the Editor: Atopic dermatitis (AD) is a heritable and heterogeneous inflammatory chronic skin disorder that makes the “one size fits all” therapeutic approach suboptimal for patients.1,2 Using decision tree/supervised learning of extensive clinical, molecular, and genetic data, we aimed to define distinct AD endotypes. Deep phenotyping and whole-genome sequencing were performed on samples obtained from participants of Evaluating the Effects of Tradipitant vs. Placebo in Atopic Dermatitis (EPIONE), a randomized, placebo-controlled phase III study in patients with severe pruritus comprising mild (23%), moderate (64%), and severe (13%) AD, as determined by the validated Investigator Global Assessment (IGA) for Atopic Dermatitis scale.

Confirmation of multiple endotypes in atopic dermatitis based on serum biomarkers

Atopic dermatitis (AD) is a highly heterogeneous disease, both clinically and biologically, whereas patients are still being treated according to a "one-size-fits-all" approach. Stratification of patients into biomarker-based endotypes is important for future development of personalized therapies. Our aim was to confirm previously defined serum biomarker-based patient clusters in a new cohort of patients with AD. A panel of 143 biomarkers was measured by using Luminex technology in serum samples from 146 patients with severe AD (median Eczema Area and Severity Index= 28.3; interquartile range= 25.2-35.3). Principal components analysis followed by unsupervised k-means cluster analysis of the biomarker data was used to identify patient clusters. Aprediction model was built on the basis of a previous cohort to predict the 1 of the 4 previously identified clusters to which the patients of our new cohort would belong. Cluster analysis identified 4 serum biomarker-based clusters, 3 of which (clusters B, C, and D) were comparable to the previously identified clusters. Cluster A(33.6%) could be distinguished from the other clusters as being a "skin-homing chemokines/IL-1R1-dominant" cluster, whereas cluster B (18.5%) was a "TH1/TH2/TH17-dominant" cluster, cluster C (18.5%) was a "TH2/TH22/PARC-dominant" cluster, and cluster D (29.5%) was a "TH2/eosinophil-inferior" cluster. Additionally, by using a prediction model based on our previous cohort we accurately assigned the new cohort to the 4 previously identified clusters by including only 10 selected serum biomarkers. We confirmed that AD is heterogeneous at the immunopathologic level and identified 4 distinct biomarker-based clusters, 3 of which were comparable with previously identified clusters. Cluster membership could be predicted with a model including 10 serum biomarkers.

The Mechanisms of Atopic Dermatitis to Asthma in Children (MPAACH) Cohort: Novel Atopic Dermatitis Endotypes

The Mechanisms of Atopic Dermatitis to Asthma in Children (MPAACH) Cohort: Novel Atopic Dermatitis Endotypes

Phenotypes and endotypes of atopic dermatitis: Clinical implications

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, characterized by a complex pathophysiology and a variety of clinical phenotypes. However, heterogeneous clinical phenotypes are generally not considered in treating AD. To date, phenotypes and endotypes have been proposed to classify AD mainly based on differences in age, IgE, severity, race, skin barrier dysfunction, immune (Th2/Th17/Th22) polarization, and skin microbiome. Various biologics to target polarized immune pathways, including dupilumab, have been newly developed for the personalized treatment of moderate-to-severe AD. Further understand ing of AD pathophysiology and identification of novel biomarkers will not only allow clinically useful stratification of AD and but also achieve precision medicine for the prevention and treatment of AD. (Allergy Asthma Respir Dis 2020;8:9-14)

Atopic Dermatitis Endotypes Based on Allergen Sensitization, Reactivity to Staphylococcus aureus Antigens, and Underlying Systemic Inflammation

Atopic dermatitis (AD) is a chronic inflammatory disease with significant local and systemic inflammation and barrier disruption. AD is associated with increased risk of allergen sensitization and skin colonization by Staphylococcus aureus. The heterogeneity of AD is unknown, and its complexity suggests its subdivision into several endotypes. To evaluate allergy-driven endotypic differences in patients with AD and identify proteomic signatures to distinguish between inflammatory responses. To perform proteomic profiling of allergen sensitivity, antibody levels to S aureus antigens, and circulating inflammatory mediators to characterize AD subsets in 76 subjects with moderate to severe AD and 39 healthy controls (HCs). Sera were collected from 76 subjects with moderate to severe AD and 39 HCs with no history of skin disease. Serum was tested for levels of total serum immunoglobulin E (IgE) and allergen-specific IgE using a panel of 119 allergens as well as IgE antibodies against Saureus antigens, and was profiled for more than 1100 proteins by SOMAscan to detect differential expression of inflammatory mediators. Total serum IgE levels were significantly (P < .001) elevated in subjects with AD versus controls. A greater percentage of subjects with AD were allergic compared with HCs, and patients with AD tested positive to a greater number of allergens than did HCs. IgE was upregulated across 4 allergen subsets (food, perennial, seasonal, and mixed), and each allergen subset was associated with a distinct inflammatory signature marked by a specific suite of upregulated proteins. Finally, IgE antibodies against S aureus toxic shock syndrome toxin-1 were significantly upregulated in subjects with seasonal allergy (P= .0430) and perennial allergy (P= .00032). Overall, this study addresses the heterogeneity of AD by characterizing subsets of AD on the basis of allergen sensitization. It also demonstrates the differential systemic inflammation and S aureus-specific antibody responses associated with the allergenic endotypes. These unique proteomic signatures may be valuable for precise disease characterization and subsequent personalized treatment.

Transcriptional control and transcriptomic analysis of lipid metabolism in skin barrier formation and atopic dermatitis (AD)

ABSTRACTIntroduction: Atopic dermatitis (AD) is a multifactorial ailment associated with barrier breach and intense systemic inflammation. Several studies over the years have shown the complex interplay of a large number of factors in governing the progression and outcome of AD. In addition to the diverse types of AD resulting due to variation in the intrinsic mechanisms giving rise to AD such as single nucleotide polymorphisms (SNPs), epigenetic alterations or transcriptional changes, extrinsic factors such as age, ancestry, ethnicity, immunological background of the subject, the interactions of the subject with environmental stimuli and existing microbiome in the periphery surrounding the subject account for further heterogeneity in the clinical manifestations of the disease.Areas covered: Here we have selectively discussed transcriptional regulation of genes associated with skin lipid metabolism in the context of AD. Transcriptional control and transcriptomic changes are just one face of this multifaceted disease known to affect humans and a detailed study concerning those will enable us to develop targeted therapies to deal with the disease.Expert opinion: Large-scale integration of different omics approaches (genomics, epigenomics, transcriptomics, lipidomics, proteomics, metabolomics, effect of exposome) will help identify the potential candidate gene(s) associated with the development of various endotypes of AD.