Reviews and feature article
Deciphering the complexities of atopic dermatitis: Shifting paradigms in treatment approaches

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Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. It often precedes the development of food allergy and asthma. Recent insights into AD reveal abnormalities in terminal differentiation of the epidermal epithelium leading to a defective stratum corneum, which allows enhanced allergen penetration and systemic IgE sensitization. Atopic skin is also predisposed to colonization or infection by pathogenic microbes, most notably Staphylococcus aureus and herpes simplex virus. Causes of this abnormal skin barrier are complex and driven by a combination of genetic, environmental, and immunologic factors. These factors likely account for the heterogeneity of AD onset and the severity and natural history of this skin disease. Recent studies suggest prevention of AD can be achieved through early interventions to protect the skin barrier. Onset of lesional AD requires effective control of local and systemic immune activation for optimal management. Early intervention might improve long-term outcomes for AD and reduce the systemic allergen sensitization that leads to associated allergic diseases in the gastrointestinal and respiratory tract.

Section snippets

Multifunctional role of filaggrin

The robust association of loss-of-function mutations in the skin barrier gene encoding filaggrin (FLG) with risk of AD has focused attention on the important role of epithelial barrier dysfunction in patients with this skin disease.28, 29 Patients with filaggrin mutations have been found to have dry skin and early-onset AD that is more persistent and often associated with asthma, food allergy, and microbial infection.30, 31, 32 Recent studies suggest that stratification of patients with versus

Implications of AD pathobiology for general management approaches

Patients with established AD have a combination of skin barrier dysfunction and skin inflammation driving their skin disease. Therefore keys to the successful management of AD should include skin hydration and skin barrier repair, topical anti-inflammatory medications (topical corticosteroids or calcineurin inhibitors), control of infection, and elimination of factors (including allergens, irritants, and emotional triggers) that might exacerbate the scratch-itch cycle. Treatment should use a

Prevention of AD by early intervention

Because current treatment approaches are not curative, there is considerable interest in studying approaches to prevent AD.97 The use of probiotic therapy or bacterial lysates early in the course of illness to prevent AD remains an area of active investigation,98, 99, 100 but results have been inconsistent. This might be due to lack of standardization of the bacterial preparations or lack of biomarkers to identify which AD phenotype would benefit from this approach.

The potential contribution of

Clinical phenotypes of AD

AD is primarily defined by clinical criteria.107 However, there is increasing recognition that AD is a complex syndrome with multiple causes and mechanistic pathways that clinically can be distinguished by age of onset, severity of illness, racial modifiers, response to therapy, and triggers (including infections, allergens, stress, and irritant threshold). Table II lists some of the major clinical phenotypes of AD.15, 16 These phenotypes often have overlapping features but contain dominant

Defining endotypes in patients with AD

The importance of eventually defining endotypes in patients with AD is that these new subtypes can be used in clinical study design and drug development to target therapies to patients most likely to benefit from a mechanism-based treatment. In the future, AD might be stratified by genotype and biomarkers reflecting immune polarization to complement their clinical phenotype. As noted in Table I, filaggrin genotyping defines AD subsets with different mechanistic pathways. Importantly, the

Concluding comments: The translational revolution in AD

AD presents a large unmet need for more effective topical and systemic therapeutics. In addition to TH2 antagonists (ie, anti–IL-4 receptor/dupilumab), the key role of thymic stromal lymphopoietin receptor signaling125, 126 and IL-22,127 as studied in clinical trials with agents targeting thymic stromal lymphopoietin, TH22, and TH17/IL-23, will be of interest. Selection of immune-targeted therapeutics for patients with different degrees of disease severity or recognized AD phenotypes should not

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    Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

    This work was funded in part by the National Institutes of Health/National Institute of Allergy and Infectious Diseases Atopic Dermatitis Research Network (contract HHSN272201000020C), NIAMS grant AR41256 and the Colorado CTSA/CCTSI grant UL1 RR025780 from NCRR/NIH and UL1 TR000154 from NIH/NCATS. Additionally, D.Y.M.L. wishes to acknowledge the Edelstein Family Foundation for their generous support of his work.

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