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Breakthroughs in the Pathogenesis and Phenotypic Presentation of Atopic Dermatitis

Breakthroughs in the Pathogenesis and Phenotypic Presentation of Atopic Dermatitis

Phenotypic Presentations of AD
Historically, AD is divided into two distinct phenotypes utilizing IgE as a clinical biomarker, distinguishing “intrinsic” (non-IgE-associated) from “extrinsic” (IgE-associated, allergen-specific IgE) AD (Table 2).16,34 Additionally, phenotypic presentation differs in acute vs chronic AD as well as in infantile, childhood, adolescent/adult, and elderly AD.35 AD in infants and young children commonly presents with involvement of the face and extensor surfaces, while lesions in older children, adolescents, and adults often involve the hands, head, and flexural surfaces, with a higher likelihood of extensive lesions in patients with long-standing disease.35 In children as young as 3 years, differing AD phenotypes are distinguishable based on age of onset and diagnosis, total leukocyte and eosinophil counts, levels of C-reactive protein, and total levels of IgE, with higher levels of leukocytes, eosinophils, and IgE associated with greater sensitization to food allergens, increased transepidermal water loss, and a more severe disease state, similar to the extrinsic AD phenotype.36 However, the classification of AD as strictly extrinsic or intrinsic may be overly simplified to fully represent the diverse phenotypes associated with AD.36 Stratification of AD phenotypes based on age of onset allows for identification of patients at greatest risk of ongoing chronic inflammation and presents the opportunity for implementation of early interventions with the goal of a targeted approach to prevention.35

Table 2

AD can be further classified phenotypically based on ethnicity. Clinical presentation of AD varies among different ethnicities and is underrepresented in the literature for nonwhite ethnic groups.5,37 Prevalence of AD is higher in African American populations, affecting up to 19% of children.38 In African American adults, AD commonly presents with a lichenoid appearance in patients with heavy pigmentation and is more likely to be resistant to treatment due to a potentially delayed diagnosis and subsequently more severe disease, as increased severity of AD at time of diagnosis is associated with persistence of disease.36-40 African Americans with AD have a greater propensity for a more severe disease course and may have a higher propensity for extensor involvement, lichenification, and prurigo nodularis.37,40 They also have have higher levels of serum IgE than European American and Asian patients; lesions in these patients have greater numbers of dendritic cells with the high affinity IgE receptor (Fc-RI+), indicative of a stronger inflammatory infiltration.41 African American patients also have a TH2/TH22-skewing cytokine profile with attenuated TH1 and TH17 activation compared with European Americans with AD.38,41 Upregulation of TH22 may account for the unusual lichenified phenotype often present in African American patients with AD, as IL-22 induces epidermal hyperplasia and proliferation of keratinocytes.42 Additionally, only 5.8% of children of African descent with AD have any variant of an FLG gene mutation vs 27.5% of white children.43 This challenges the applicability of the “outside in” hypothesis in this patient population.33 Lastly, underlying social factors influencing access to health care may also account for differences in prevalence and severity of AD when comparing these patient populations. 

AD also has a higher prevalence in Asian populations, affecting 7% to 10% of adults.44-46 Phenotypically, AD presents in Asians as a mix of the clinical features of AD common to European Americans, such as erythematous excoriated patches, and some of the clinical features common to psoriasis, including increased epidermal hyperplasia, parakeratosis, and focal hypogranulosis.44 Unique features of AD in Asian populations include more clearly demarcated lesions than those of European American patients, along with more prominent lichenification and scaling.44 Asian AD also differs from AD seen in European Americans on both a histologic and molecular level.47 Loss-of-function FLG gene mutations associated with Asian AD are unique to each Asian subpopulation and are different from the common FLG null gene mutations associated with European AD populations.47,48 One of the most prevalent FLG null gene mutations in European patients, R501X, is infrequently found in Asian and African patients.47,49,50 The 3321delA FLG null gene mutation is present in multiple Asian populations, including Japanese, Chinese, Korean, Taiwanese, and Singaporean, but it has not been identified in European patients with AD.48,49,51 Additionally, Korean, Japanese, and Chinese extrinsic AD shows a greater degree of epidermal hyperplasia, parakeratosis, and a stronger TH17 and TH22 cytokine profile than European American extrinsic AD.35,37,44 The TH22 leaning cytokine profiles present in both Asian and African American patients with AD suggests that anti-IL-22 treatment may be especially efficacious in these patient populations.5

AD is a heterogenous inflammatory skin condition associated with various phenotypic presentations according to age, ethnicity, chronicity of disease, FLG mutation status, IgE levels, and underlying molecular and immune mechanisms.5 Consideration of the evolving pathogenesis and unique phenotypic features of individual disease creates the potential for improved disease treatments via targeted therapies. Consideration of patient characteristics, phenotypes, and updates in pathogenesis may facilitate better disease understanding and has the potential to drive improved therapeutic strategies.

Ms Heron is a medical student and research associate at the Center for Dermatology Research in the department of dermatology at Wake Forest School of Medicine in Winston-Salem, NC. Ms Ghamrawi is a medical student and research associate at the Center for Dermatology Research in the department of dermatology at Wake Forest School of Medicine. Dr Feldman is with the Center for Dermatology Research and the departments of dermatology, pathology, and social sciences & health policy at Wake Forest University School of Medicine and the department of dermatology at the University of Southern Denmark, Odense, Denmark.

Disclosure: Dr Feldman has received research, speaking, and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, AbbVie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate, and National Psoriasis Foundation. He is founder and majority owner of and founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. The remaining authors have no relevant financial relationships.

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