Reviews and feature articleDeciphering the complexities of atopic dermatitis: Shifting paradigms in treatment approaches
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.