Atopic dermatitis endotypes and implications for targeted therapeutics

doi:10.1016/j.jaci.2018.10.032

Journal of Allergy and Clinical Immunology

Volume 143, Issue 1, January 2019, Pages 1-11

https://doi.org/10.1016/j.jaci.2018.10.032 Get rights and content

Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional “one-size-fits-all” therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation.

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 T_H17 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, T_H2 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 T_H2 AD endotype.124, 125 Disease improvement was accompanied by reversal of both immune and barrier abnormalities.126, 127, 128 The efficacy of other T_H2 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 T_H2 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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