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 (TH2) cytokines are present in both acute and chronic disease states, while TH1 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 TH2 cytokines and eosinophilia and increases levels of IgE via direct and indirect stimulation of TH2 cells.18 Chemokines produced by epidermal Langerhans cells and dermal dendritic cells also induce TH2 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 TH2 and TH17 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