Reviews and feature articleAtopic dermatitis endotypes and implications for targeted therapeutics
Section snippets
Acute versus chronic AD
AD is characterized clinically by acute and chronic stages. Acute (new onset, within 72 hours) lesions are usually erythematous, wet, and highly inflammatory, turning lichenified, dry, thick, and hyperpigmented in patients with chronic disease.14, 15, 16 Comparing the skin profile of nonlesional, acute, and chronic AD skin17 showed both barrier and immune disparities between disease stages. Chronic lesions are more hyperplastic and proliferative, with increased keratin 16 mRNA expression and
Intrinsic versus extrinsic AD
AD can be classified according to IgE levels into extrinsic and intrinsic subgroups. The classic (80%) extrinsic phenotype is characterized by high total and environmental serum IgE levels, eosinophilia, personal and family atopic background, and greater rate of filaggrin (FLG) mutation.18, 19, 20 Despite a similar clinical presentation, patients with intrinsic AD (20%) have normal IgE levels; have female predominance; show delayed disease onset and preserved barrier function, as measured based
AD in European American versus Japanese and Korean patients
Endotyping AD according to different ethnic backgrounds is critical for establishing disease biomarkers and nurturing precision therapeutic approaches. Although AD prevalence in European American (EA) adults is approximately 3% to 4%,29, 30 it is substantially greater in Asian countries (7% to 10%).31, 32, 33
Studying the Asian AD endotype, Koga et al34 showed increased TH17 frequencies in blood and acute lesions of Japanese patients with AD, both of which are associated with AD severity. These
Pediatric versus adult AD
Morphology and distribution of AD lesions differ between age groups, with face, trunk, and extensor limb inflammatory involvement in infants and young children and lichenified, chronic, dry, and flexural distribution in adults.64 These changes might derive from background endotype skewing over time. Thus it is crucial to define those changes to tailor adequate treatments.65
Early life is a critical period for immune development. At birth, most T cells are naive, developing gradually into memory
AD features vary according to the patient's FLG status
It is now recognized that AD pathogenesis is driven by a combination of immune dysregulation and impaired epidermal barrier integrity.84, 85, 86, 87 The primary defect that initiates the atopic cycle is still not clear; however, the general concept is that a skin barrier defect facilitates allergen penetration, leading to innate immune activation, Langerhans cells migration to regional lymph nodes, TH2 production, and promotion of B-cell IgE switch, with T cells recirculating back to the skin
Staphylococcus aureus–colonized patients with AD have a unique phenotype and endotype
The vast majority of patients with AD are colonized and/or infected with S aureus, with emerging methicillin-resistant S aureus strains presenting a therapeutic challenge.116, 117, 118 Complex interaction exists between S aureus and its related toxins and the immune dysregulation and barrier impairment seen in patients with AD.119 Sequencing of the cutaneous microbial structure showed that although normal skin flora is characterized by a diverse collection of bacteria, patients with AD harbor a
Endotype-based targeted therapeutic approaches
There are multiple medications in the therapeutic pipeline for AD (Table I).123 The recently US Food and Drug Administration–approved IL-4 receptor mAb that blocks IL-4 and IL-13, dupilumab, specifically targets the TH2 AD endotype.124, 125 Disease improvement was accompanied by reversal of both immune and barrier abnormalities.126, 127, 128 The efficacy of other TH2 antagonists is yet to be determined (eg, anti–IL-13/tralokinumab and lebrikizumab/NCT02347176/NCT02340234 and anti-thymic stromal
Concluding remarks
Current inclusion criteria for AD clinical trials are mostly based on disease severity rather than AD phenotyping. An attempt to define the patient's endotype before treatment should be made to optimize therapeutic responses moving toward precision medicine based on the different clinical and molecular disease subsets. Although TH2 axis activation seems to be a universal trait across the AD spectrum, it still might be the case that other or additional cytokine targeting will be highly effective
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