Patients with atopic dermatitis (AD) have an abnormal skin barrier and are frequently colonized by S. aureus. In this study we investigated if S. aureus penetrates the epidermal barrier of subjects ...with AD and sought to understand the mechanism and functional significance of this entry. S. aureus was observed to be more abundant in the dermis of lesional skin from AD patients. Bacterial entry past the epidermis was observed in cultured human skin equivalents and in mice but was found to be increased in the skin of cathelicidin knockout and ovalbumin-sensitized filaggrin mutant mice. S. aureus penetration through the epidermis was dependent on bacterial viability and protease activity, because killed bacteria and a protease-null mutant strain of S. aureus were unable to penetrate. Entry of S. aureus directly correlated with increased expression of IL-4, IL-13, IL-22, thymic stromal lymphopoietin, and other cytokines associated with AD and with decreased expression of cathelicidin. These data illustrate how abnormalities of the epidermal barrier in AD can alter the balance of S. aureus entry into the dermis and provide an explanation for how such dermal dysbiosis results in increased inflammatory cytokines and exacerbation of disease.
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease and a growing health concern, especially in children, because of its high prevalence and associated low quality of life. ...Genetic predisposition, environmental triggers, or interactions between them contribute to the pathophysiology of AD. Therefore, it is very important to identify and control risk factors from the environment in susceptible subjects for successful treatment and prevention. Both indoor and outdoor air pollution, which are of increasing concern with urbanization, are well-known environmental risk factors for asthma, whereas there is relatively little evidence in AD. This review highlights epidemiologic and experimental data on the role of air pollution in patients with AD. Recent evidence suggests that a variety of air pollutants, such as environmental tobacco smoke, volatile organic compounds, formaldehyde, toluene, nitrogen dioxide, and particulate matter, act as risk factors for the development or aggravation of AD. These air pollutants probably induce oxidative stress in the skin, leading to skin barrier dysfunction or immune dysregulation. However, these results are still controversial because of the low number of studies, limitations in study design, inaccurate assessment of exposure and absorption, and many other issues. Further research about the adverse effects of air pollution on AD will help to expand our understanding and to establish a better strategy for the prevention and management of AD.
Atopic dermatitis (AD) is a paradigmatic chronic inflammatory skin disease characterized by a complex pathophysiology and a wide spectrum of the clinical phenotype. Despite this high degree of ...heterogeneity, AD is still considered a single disease and usually treated according to the “one-size-fits-all” approach. Thus more tailored prevention and therapeutic strategies are still lacking. As for other disciplines, such as oncology or rheumatology, we have to approach AD in a more differentiated way (ie, to dissect and stratify the complex clinical phenotype into more homogeneous subgroups based on the endophenotype panel of biomarkers) with the aim to refine the management of this condition. Because we are now entering the era of personalized medicine, a systems biology approach merging the numerous clinical phenotypes with robust (ie, relevant and validated) biomarkers will be needed to best exploit their potential significance for the future molecular taxonomy of AD. This approach will not only allow an optimized prevention and treatment with the available drugs but also hopefully help assign newly developed medicinal products to those patients who will have the best benefit/risk ratio.
Abrocitinib, an oral, once-daily Janus kinase 1 selective inhibitor, was effective and well tolerated in a phase 3 monotherapy trial of patients with moderate-to-severe atopic dermatitis (AD).
To ...investigate the efficacy and safety of abrocitinib in adolescents and adults with moderate-to-severe AD in an identically designed trial.
This phase 3, double-blinded, placebo-controlled, parallel-group randomized clinical trial included patients 12 years or older with a clinical diagnosis of moderate-to-severe AD for at least 1 year and inadequate response to topical medications given for at least 4 weeks within 6 months. Patients were enrolled from 115 centers in Australia, Bulgaria, Canada, China, Czechia, Germany, Hungary, Japan, South Korea, Latvia, Poland, United Kingdom, and the United States from June 29, 2018, to August 13, 2019. Data were analyzed from September 13 to October 25, 2019.
Patients were randomly assigned (2:2:1) to receive once-daily oral abrocitinib in 200- or 100-mg doses or placebo for 12 weeks.
The coprimary end points were the proportion of patients achieving Investigator Global Assessment (IGA) response (ie, clear 0 or almost clear 1, with improvement of ≥2 grades) and the proportion of patients achieving at least 75% improvement in Eczema Area and Severity Index score (EASI-75) at week 12. Key secondary end points included the proportion of patients achieving a Peak Pruritus Numerical Rating Scale (PP-NRS) response (ie, improvement of ≥4 points) at week 12. Other secondary end points included the proportion of patients achieving at least 90% improvement in EASI score (EASI-90). Safety was assessed via adverse events and laboratory monitoring.
A total of 391 patients (229 male 58.6%; mean SD age, 35.1 15.1 years) were included in the analysis; of these, 155 received abrocitinib, 200 mg/d; 158, abrocitinib, 100 mg/d; and 78, placebo. Among patients with available data at week 12, greater proportions of patients in the 200- and 100-mg abrocitinib groups vs the placebo group achieved IGA (59 of 155 38.1% and 44 of 155 28.4% vs 7 of 77 9.1%; P < .001) and EASI-75 (94 of 154 61.0% and 69 of 155 44.5% vs 8 of 77 10.4%; P < .001), greater estimated proportions achieved PP-NRS (55.3% 95% CI, 47.2%-63.5% and 45.2% 95% CI, 37.1%-53.3% vs 11.5% 95% CI, 4.1%-19.0%; P < .001), and/or greater proportions achieved EASI-90 (58 of 154 37.7% and 37 of 155 23.9% vs 3 of 77 3.9%) responses. Adverse events were reported for 102 patients (65.8%) in the 200-mg group, 99 (62.7%) in the 100-mg group, and 42 (53.8%) in the placebo group; serious adverse events were reported for 2 patients (1.3%) in the 200-mg group, 5 (3.2%) in the 100-mg group, and 1 (1.3%) in the placebo group. Decreases in platelet count (2 1.3%) and laboratory values indicating thrombocytopenia (5 3.2%) were reported in the 200-mg group.
Monotherapy with once-daily oral abrocitinib was effective and well tolerated in adolescents and adults with moderate-to-severe AD.
ClinicalTrials.gov Identifier: NCT03575871.
Atopic dermatitis (AD) is a common complex disease that frequently follows a chronic relapsing course and affects the quality of life of patients and families in a significant manner. New insights ...into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Patients with AD have a unique predisposition to colonization or infection by a number of microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. A multipronged approach directed at healing or protecting the skin barrier and addressing the immune dysregulation is necessary to improve the likelihood of successful outcomes.
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Genetic predisposition, epidermal barrier disruption, and dysregulation of the immune system are some of the critical ...components of AD. An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization. Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the development of AD. New insights into the pathophysiology of AD have focused on epidermal lipid profiles, neuroimmune interactions, and microbial dysbiosis. Newer therapeutic strategies focus on improving skin barrier function and targeting polarized immune pathways found in AD. Further understanding of AD pathophysiology will allow us to achieve a more precision medicine approach to the prevention and the treatment of AD.
The type 2 cytokines IL-4 and IL-13 promote not only atopic dermatitis (AD) but also the resolution of inflammation. How type 2 cytokines participate in the resolution of AD is poorly known.
Our aim ...was to determine the mechanisms and cell types governing skin inflammation, barrier dysfunction, and resolution of inflammation in a model of AD.
Mice that exhibit expression of IL-4, IL-13, and MCPT8 or that could be depleted of basophils or eosinophils, be deficient in IL-4 or MHC class II molecules, or have basophils lacking macrophage colony-stimulating factor (M-CSF) were treated with calcipotriol (MC903) as an acute model of AD. Kinetics of the disease; keratinocyte differentiation; and leukocyte accumulation, phenotype, function, and cytokine production were measured by transepidermal water loss, histopathology, molecular biology, or unbiased analysis of spectral flow cytometry.
In this model of AD, basophils were activated systemically and were the initial and main source of IL-4 in the skin. Basophils and IL-4 promoted epidermal hyperplasia and skin barrier dysfunction by acting on keratinocyte differentiation during inflammation. Basophils, IL-4, and basophil-derived M-CSF inhibited the accumulation of proinflammatory cells in the skin while promoting the expansion and function of proresolution M2-like macrophages and the expression of probarrier genes. Basophils kept their proresolution properties during AD resolution.
Basophils can display both beneficial and detrimental type 2 functions simultaneously during atopic inflammation.
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As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with ...pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies.
Background Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which ...skin barrier function is disrupted in patients with AD remains unclear. Objectives Taking into account the fact that the TH 2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. Methods We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. Results IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. Conclusion STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
The “epithelial barrier hypothesis” proposes that the exposure to various epithelial barrier–damaging agents linked to industrialization and urbanization underlies the increase in allergic diseases. ...The epithelial barrier constitutes the first line of physical, chemical, and immunological defense against environmental factors. Recent reports have shown that industrial products disrupt the epithelial barriers. Innate and adaptive immune responses play an important role in epithelial barrier damage. In addition, recent studies suggest that epithelial barrier dysfunction plays an essential role in the pathogenesis of the atopic march by allergen sensitization through the transcutaneous route. It is evident that external factors interact with the immune system, triggering a cascade of complex reactions that damage the epithelial barrier. Epigenetic and microbiome changes modulate the integrity of the epithelial barrier. Robust and simple measurements of the skin barrier dysfunction at the point‐of‐care are of significant value as a biomarker, as recently reported using electrical impedance spectroscopy to directly measure barrier defects. Understanding epithelial barrier dysfunction and its mechanism is key to developing novel strategies for the prevention and treatment of allergic diseases. The aim of this review is to summarize recent studies on the pathophysiological mechanisms triggered by environmental factors that contribute to the dysregulation of epithelial barrier function.
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