Overview of atopic dermatitis Avena-Woods, Carmela
The American journal of managed care
23, Številka:
8 Suppl
Journal Article
Recenzirano
Atopic dermatitis (AD), also known as atopic eczema, is a chronic relapsing inflammatory skin condition. Incidence of AD has increased 2- to 3-fold in industrialized nations, impacting approximately ...15% to 20% of children and 1% to 3% of adults worldwide. AD has a wide-ranging impact on a patient's quality of life and the burden from direct and indirect costs (approximately $37.7 billion in out-of-pocket costs) is shared by the families and caregivers of patients with AD. This article reviews the epidemiology, burden of disease, pathophysiology, and diagnostic criteria important for early diagnosis and treatment. New insights related to the genetic, immunologic, and environmental impacts of AD have created new treatment opportunities. Nonpharmacologic and pharmacologic interventions are discussed, with an emphasis on emerging treatments for AD. Healthcare providers play an important role in the management of AD to improve economic and clinical outcomes. Treatment strategies need to be individualized with a strong emphasis on patient education and self-management strategies to optimize outcomes and reduce unnecessary costs associated with the management of AD.
Epidemiology of adult atopic dermatitis Sacotte, Ryan, BS; Silverberg, Jonathan I., MD, PhD, MPH
Clinics in dermatology,
09/2018, Letnik:
36, Številka:
5
Journal Article
Recenzirano
Abstract Atopic dermatitis (AD) is driven by a complex gene–environment interaction. Many of the risk factors and genetic underpinning previously observed for pediatric AD may not apply to adult ...atopic dermatitis, suggesting that these may largely be different disorders. Whereas AD is classically thought of as a pediatric disease, recent studies have shown high rates of disease in adults as well. Risk factors for persistence of childhood-onset AD, as well as adult-onset AD, are reviewed. Adults with AD are particularly vulnerable to exogenous insults from the outside environment, including climate, ultraviolet exposure, pollution, irritants and pruritogens, and microbes. Finally, adult AD is associated with a substantial health care burden, with increased utilization, direct and indirect costs of care, and lost work productivity.
Atopic dermatitis is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. Although the pathogenesis of atopic dermatitis is ...not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis. Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence. More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis. However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified δ-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by δ-toxin depended on phosphoinositide 3-kinase and calcium (Ca(2+)) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced δ-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of δ-toxin. Skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by δ-toxin was abrogated in Kit(W-sh/W-sh) mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify δ-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.
New treatments in atopic dermatitis Puar, Neha; Chovatiya, Raj; Paller, Amy S
Annals of allergy, asthma, & immunology,
01/2021, Letnik:
126, Številka:
1
Journal Article
Recenzirano
Odprti dostop
To discuss the efficacy and safety of novel and emerging topical and systemic therapeutic agents for atopic dermatitis (AD).
The review of the published literature was performed using the PubMed ...database, published abstracts and virtual presentations from scientific meetings, posted results on ClinicalTrials.gov, and data from industry press releases.
Primary manuscripts with trial results, case reports, case series, clinical trial data from ClinicalTrials.gov, and articles highlighting expert perspectives on management of AD were selected.
Emerging topical and systemic therapies primarily target the type 2 immune pathway. Moreover, 2 newer targeted medications are now approved by the Food and Drug Administration for both children and adults, crisaborole 2% ointment and dupilumab, with several others in the therapeutic pipeline. New directions in developing topical medications include Janus kinase inhibitors, tapinarof (an aryl hydrocarbon receptor agonist), and agents to correct microbial dysbiosis. In addition to the subcutaneously injected monoclonal antibody targeting the interleukin (IL) 4 receptor (dupilumab), other biologics targeting IL-13, IL-31, IL-33, OX40, and thymic stromal lymphopoietin are currently being tested. Oral Janus kinase inhibitors are showing outstanding efficacy and no serious safety signs, but safety concerns remain.
Given the tremendous burden of AD on physical, mental, and social health, the need is high to develop new, targeted therapies. Advances in our understanding of AD pathogenesis have paved the way toward the development of new therapies that promise to revolutionize our management of AD. Future research will focus on long-term efficacy and safety and creating predictive models for choosing best management options on a personalized basis.
Atopic dermatitis (AD) is a chronic or chronically relapsing, eczematous, severely pruritic skin disorder mostly associated with IgE elevation and skin barrier dysfunction due to decreased filaggrin ...expression. The lesional skin of AD exhibits Th2- and Th22-deviated immune reactions that are progressive during disease chronicity. Th2 and Th22 cytokines further deteriorate the skin barrier by inhibiting filaggrin expression. Some IgEs are reactive to self-antigens. The IgE autoreactivity may precipitate the chronicity of AD. Upon activation of the ORAI1 calcium channel, atopic epidermis releases large amounts of thymic stromal lymphopoietin (TSLP), which initiates the Th2 and Th22 immune response. Th2-derived interleukin-31 and TSLP induce an itch sensation. Taken together, TSLP/Th2/Th22 pathway is a promising target for developing new therapeutics for AD. Enhancing filaggrin expression using ligands for the aryl hydrocarbon receptor may also be an adjunctive measure to restore the disrupted barrier function specifically for AD.
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Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the ...downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.
To the Editor: Atopic dermatitis (AD) is a multifactorial skin disease with skin barrier damage, progressive sensitization to environmental antigens, and TH2-skewed mediated systemic immune ...response.1 Synthesis of filaggrin and filaggrin-like stratum corneum proteins is reduced both on lesional and on nonlesional skin of patients with AD irrespective of their FLG genotype.2 Staphylococcus aureus colonization of lesional skin in AD has been identified by traditional bacteriological sampling methods.3 We characterized, in comparison with healthy adults, a cohort of patients with AD in terms of AD phenotype, severity, FLG genotype, transepidermal water loss (TEWL), hydration index (HI), pH, pyrrolidone carboxylic acid (PCA) levels, and S aureus density on lesional and nonlesional skin. The 4 FLG mutations most prevalent in the European population (p.R501X, c.2282del4, p.S3247X, and p.R2447X) were investigated.2 For statistical analysis (SAS version 8.2 Windows; SAS, Cary, NC), the following variables were included as potential predictive factors of AD severity in bivariable and multivariable logistic regression analyses: HI, pH, PCA, TEWL measurements, Staphylococcal skin density, and FLG gene mutations.
Atopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have ...highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic “atopic (allergic) march.” In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function.
Animal studies have suggested that transient receptor potential ion channels and G-protein coupled receptors play important roles in itch transmission. TRPV3 gain-of-function mutations have been ...identified in patients with Olmsted syndrome, which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of protease-activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis, whereas their inhibition attenuated scratching and inflammatory responses in mouse atopic dermatitis models. These results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in atopic dermatitis.
IL-22 is potentially a pathogenic cytokine in patients with atopic dermatitis (AD), but the molecular effects of IL-22 antagonism have not been defined in human subjects.
We sought to evaluate the ...cellular and molecular effects of IL-22 blockade in tissues from patients with moderate-to-severe AD.
We assessed lesional and nonlesional skin from 59 patients with moderate-to-severe AD treated with anti–IL-22 (fezakinumab) versus placebo (2:1) using transcriptomic and immunohistochemistry analyses.
Greater reversal of the AD genomic profile was seen with fezakinumab versus placebo, namely 25.3% versus 10.5% at 4 weeks (P = 1.7 × 10−5) and 65.5% versus 13.9% at 12 weeks (P = 9.5 × 10−19), respectively. Because IL-22 blockade showed clinical efficacy only in patients with severe AD, we used baseline median IL-22 mRNA expression to stratify for high (n = 30) and low (n = 29) IL-22 expression groups. Much stronger mean transcriptomic improvements were seen with fezakinumab in the IL-22–high drug-treated group (82.8% and 139.4% at 4 and 12 weeks, respectively) than in the respective IL-22–high placebo-treated group (39.6% and 56.3% at 4 and 12 weeks) or the IL-22–low groups. Significant downregulations of multiple immune pathways, including TH1/CXCL9, TH2/CCL18/CCL22, TH17/CCL20/DEFB4A, and TH22/IL22/S100A's, were restricted to the IL-22–high drug group (P < .05). Consistently, tissue predictors of clinical response were mostly genes involved in T-cell and dendritic cell activation and differentiation.
This is the first report showing a profound effect of IL-22 blockade on multiple inflammatory pathways in AD. These data, supported by robust effects in patients with high IL-22 baseline expression, suggest a central role for IL-22 in AD, indicating the need for a precision medicine approach for improving therapeutic outcomes in patients with AD.
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