Breakthroughs in the Pathogenesis and Phenotypic Presentation of Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that affects 6% to 13% of children and up to 10% of adults in the United States.^1,2 This condition commonly emerges in childhood, with up to 85% of patients experiencing onset before the age of 5 years.³ Clinically, AD presents acutely as wet, erythematous vesicles with crusting and chronically as hyperpigmented, dry, lichenified papules with excoriations. Phenotypic presentation varies by age and other patient factors.^4,5 Considerable morbidity in AD stems from intense pruritus, often causing sleep impairment, social embarrassment, and psychological anguish.^1,6

The foundation of AD treatment involves the maintenance of skin integrity through utilization of hydrating topical therapies in addition to avoiding provoking or irritating factors such as stress, sweat, and fragrant detergents.⁷ Anti-inflammatory medications are utilized during exacerbations, while systemic immunosuppressive medications are typically reserved for profound refractory cases.⁷ Antimicrobial treatments may be utilized as well, depending on the severity of both colonization and overall disease.⁷ The diverse assortment of therapeutic targets in AD is attributable to the heterogenous nature of the disease when considering its complex pathogenesis and phenotypic presentations. Recognition of such evolving pathogenesis and various phenotypic presentations of AD has important implications for immunotherapy and future treatments. This article aims to discuss the recent developments and discoveries in the pathogenesis and phenotypic presentations of AD. 

Pathogenesis of AD
The “atopic march” describes the progression between various atopic and allergic conditions starting with AD in infanthood, asthma in childhood, and allergic rhinitis in adulthood.^3,8,9 The pathogenesis of atopic disorders is a multifactorial culmination of complex interactions between immunologic, environmental, and genetic factors.⁹ Among the numerous genes associated with AD, a complete loss of function (null) mutation in the FLG gene encoding for filaggrin, an epidermal barrier protein synthesized by keratinocytes, poses the strongest genetic risk for skin barrier dysfunction and increased transepidermal water loss, facilitating the development of AD (Table 1).^3,4,10-15 Cytokines also play a pivotal role in the pathogenesis of AD; type 2 helper T cell (T_H2) cytokines are present in both acute and chronic disease states, while T_H1 cytokines contribute solely to chronic disease states.^9,16  

Recently, additional cytokines such as IL-17, IL-24, IL-25 (also known as IL-17E), and IL-31 are postulated to play a role in the pathogenesis of AD (Figure).^17-19 Significantly higher levels of IL-17 and IL-23 and lower levels of IL-10 are seen in children with AD as compared with healthy controls; higher levels of IL-17 and IL-23 are associated with increased disease severity.²⁰ Additionally, IL-24 and IL-25 downregulate filaggrin synthesis in the skin, linking inflammation with impaired function of the skin barrier independently of an underlying FLG gene mutation.^18,21 IL-25 also has a reciprocal regulatory relationship with endothelin 1 in the epidermis, supporting a histamine-independent pruritus in AD.²² Additionally, IL-25 induces T_H2 cytokines and eosinophilia and increases levels of IgE via direct and indirect stimulation of T_H2 cells.¹⁸ Chemokines produced by epidermal Langerhans cells and dermal dendritic cells also induce T_H2 cytokine production.^23,24 IL-24 attenuates IL-17A-dependent neutrophil recruitment in response to Staphylococcus aureus skin infection, thus contributing to skin barrier dysfunction.²¹ Interactions between IL-31 and its receptor also play an important role in the pathogenesis of AD, in addition to being a major causative factor of the often severe pruritus associated with the disease.^19,25,26  

Susceptibility to skin infection by S aureus is a pathogenic feature of AD; the microbe can be isolated from more than 90% of affected adult patients, with a positive correlation between relative S aureus abundances and severe AD flares.^9,27,28 In a murine model with intact immunity and a lack of skin barrier dysfunction, S aureus strains isolated from AD lesions during a severe flare induced epidermal hyperplasia and skin inflammation through cutaneous infiltration of T_H2 and T_H17 cells, neutrophils, and eosinophils.^28,29 Therefore, S aureus can induce and worsen skin inflammation without an underlying breach of skin barrier, although human studies are necessary for further validation.^28,29 Adult patients with AD concomitantly colonized by S aureus have a phenotype and endotype associated with more severe disease, stronger allergen sensitization, more pronounced barrier disruption, increased serum levels of lactate dehydrogenase, and greater type 2 immune system deviation with higher levels of multiple type 2 biomarkers (total IgE, eosinophil counts, CCL17, and periostin) than noncolonized patients with AD.^5,30 Alternate bacterial organisms are also implicated in the pathogenesis of AD.⁹ Diminished numbers and/or alternate strains of common skin commensal bacteria including gram negatives (Roseomonas mucosa) and coagulase-negative gram positive bacteria (Staphylococcus epidermis and Staphylococcus hominis) capable of producing antimicrobial peptides contribute to flares and superinfections in AD.^9,31,32 Recent discoveries regarding the microbiome of AD suggest immune dysregulation associated with AD may follow an “outside in” construct in which the inflammatory cascade of AD is triggered by an abnormal skin barrier.^9,33 This is in contrast to the “inside out” hypothesis in which barrier dysfunction via alterations in filaggrin production is triggered by underlying cutaneous inflammation.^9,33

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

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 T_H2/T_H22-skewing cytokine profile with attenuated T_H1 and T_H17 activation compared with European Americans with AD.^38,41 Upregulation of T_H22 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 T_H17 and T_H22 cytokine profile than European American extrinsic AD.^35,37,44 The T_H22 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

Conclusion
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 www.DrScore.com 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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