Atopic Dermatitis: Epidemiology, Pathogenesis, and Therapeutic Advances

Atopic dermatitis is one of the most prevalent inflammatory skin diseases. It usually develops in childhood and can persist into adulthood; less commonly, it begins in middle age or old age.

The disorder is characterized by localized, pruritic, and recurrent eczema, often with seasonal fluctuations.

Many patients also have allergic asthma, allergic rhinoconjunctivitis, food allergies, and other immediate hypersensitivity (type 1) allergies.

The disease was described and named atopic dermatitis in the 1930s, "atopic" reflecting the Greek word atopos ("placeless") to indicate the frequent and concomitant occurrence of IgE-mediated hypersensitivity reactions, such as asthma.1  

Atopic dermatitis remains the preferred term for the disorder, but others have been used, including atopic eczema, neurodermatitis, atopic dermatitis, and most commonly, eczema.

The prevalence and incidence of atopic dermatitis have increased in the past decades.2,3 The Global Burden of Disease study showed a prevalence of 15 to 20% among children and up to 10% among adults, making Atopic dermatitis is the 15th most common non-fatal disease and the skin disorder with the highest burden of disease, in terms of disability-adjusted life years.4  

In a retrospective study, healthcare utilization and annual treatment costs were higher for patients with atopic dermatitis than for matched controls without atopic dermatitis and were associated with disease severity.5  

Both sexes are affected, and the prevalence varies between races and ethnic groups.6,7 For example, in the United States, the prevalence is higher among black children (19.3%) than among white children (16.1% ). 8 The increasing prevalence in industrialized and high-income countries has been tentatively attributed to environmental factors such as exposure to air pollution and household hygiene products.

The clinical features of atopic dermatitis vary depending on age, disease stage, ethnicity, and geographic location. Typical acute lesions in white patients and in black patients are circumscribed patches of eczema; The erythema is more frequently violaceous or even invisible in black patients.

The lesions are characterized by papules, papulovesicles, edema, crusting and peeling, with hyperpigmentation or hypopigmentation of the lesions after healing.

In severe atopic dermatitis, areas of eczema merge into larger regions of widespread redness of the skin (erythroderma).

In children, eczema may be widespread over the body, affecting the head, face, cheeks, and arms and legs, with frequent involvement of the ventral side of the wrists and trunk.9 Contrary to previous assumptions, Often the area of ​​skin covered by the diaper is also involved.9  

With increasing patient age, lesions tend to be more circumscribed and confined to the arms and legs, mainly the popliteal flexor areas and the hands, legs and feet, neck and periocular region. Rates of hand and foot dermatitis are higher among adults than children.9

The appearance of the lesions also varies in relation to ethnic group and geographic region.9 Phenotypes have been proposed that are more common in white, black, or Asian patients, 9-11, but these findings need to be confirmed. For example, lesions on the trunk are found in all races and ethnic groups, but are more clearly demarcated and more common in Asians. 9-11

Pruritus is a characteristic of atopic dermatitis,9 and the intensity of itching generally corresponds to the severity of the disease.12 Pruritus is aggravated by stress, sweating from physical activity, or environmental heat and humidity . , as well as contact with woolen clothing.12

Itching-related scratching induces excoriation, bleeding, or hemorrhagic crusting. Persistent scratching leads to lichenification, as well as prurigo nodularis, which is characterized by widespread, severely itchy nodules.

Patients with atopic dermatitis have a range of associated clinical signs, such as rarefaction of the lateral eyebrows (Hertoghe’s sign) or increased density and depth of the palmar folds (hyperlinear palms).9 In the majority of patients (75% ), areas of dry skin (xerosis) occur, even during remission of eczema.9

The presence of these signs helps establish the diagnosis of atopic dermatitis, but their absence does not rule it out. Atopic dermatitis has a fluctuating and chronic course. However, the aforementioned clinical signs and chronic scratching-related lesions, such as lichenifications, persist during periods when eczema is inactive.

Chronic and relapsing eczema, severe pruritus, clinical signs, coexisting medical conditions, and dermatological complications of atopic dermatitis lead to a decreased quality of life for patients and their families. These symptoms cause sleep disorders and decreased productivity at work or school, with detrimental effects on emotional and social life.13 Depression, anxiety, and suicide have been associated with long-term atopic dermatitis.14

The clinical diagnosis of atopic dermatitis is based on the morphological characteristics and distribution of skin lesions, the presence of clinical signs, and a characteristic medical history.15 A list of 23 clinical signs and symptoms of atopic dermatitis was published by Hanifin and Rajka in 1980 and is still used as a reference in clinical research. The American Academy of Dermatology has established core characteristics used to diagnose the disease (Table).15

The severity of atopic dermatitis can be quantified with the use of multi-item scoring tools such as the Eczema Area and Severity Index (EASI) and the Scoring Scale for Atopic Dermatitis (SCORAD); both are used in practice and in clinical trials.16 The EASI evaluates the severity of redness, thickness, excoriation and lichenification and the percentage of skin involvement in four body areas (head, trunk, arms and legs). The scores are added, for an overall score ranging from 0 to 72.

An EASI score of 7 or less is considered to indicate mild disease, 8 to 21 moderate, 22 to 50 severe, and 51 to 72 very severe. The SCORAD score takes into account more types of lesions and body areas than the EASI score and is calculated based on the area of ​​skin affected and the severity of redness, swelling, oozing, crusting, lichenification, and dryness, evaluated separately for the head and neck, arms and legs, anterior trunk, back and genitals.

The score includes patient-reported symptom severity based on two 100-point visual analog scales, one for sleep loss and one for pruritus. The total score ranges from 0 to 103, with a score of 25 or less indicating mild disease, 26 to 50 moderate disease, and 51 to 103 severe disease.16

Patients with atopic dermatitis are at risk of "atopic march ," the sequential development of allergic disorders, including food allergies (especially in children), allergic rhinitis, rhinoconjunctivitis, and asthma.17

This apparent induction of allergies has been considered to be related to leakage of the skin barrier, penetration of allergens and a predisposition of the immune system to react to allergens with a type 2 (Th2) CD4 + T cell response and production. subsequent production of antibodies by B cells.

Patients of any age with atopic dermatitis are at risk of developing bacterial, viral, or fungal skin infections due to skin barrier defects, bacterial skin colonization (especially by Staphylococcus aureus ), and an alteration of the skin microbiome.18,19

Common skin infections in patients with atopic dermatitis are infections induced by S. aureus (impetigo and abscesses), eczema herpeticum related to herpes simplex virus 1, and molluscum contagiosum infection.18,20,21 Fungal infections such as candidiasis of skin or nails.19

Due to skin infections, patients with atopic dermatitis are at higher risk of life-threatening systemic infections (e.g., osteomyelitis, septic arthritis, and endocarditis) than patients who do not have atopic dermatitis, although such complications are rare.18 22

Other disorders that have been associated to varying degrees with atopic dermatitis include inflammatory bowel disease and rheumatoid arthritis. A cardiovascular risk has been suggested, but estimates of this risk have varied. 14.23

Interactions between genetic and environmental factors, skin barrier dysfunction, microbial imbalance, immune dysregulation, and environmental triggers of skin inflammation play a role in the pathogenesis of atopic dermatitis. 24-26

Inflammation is thought to be initiated by disruption of the epidermal barrier and activation of inflammatory epidermal dendritic cells and innate lymphoid cells, which attract and interact with invading Th2 cells.

The proximate mechanism of eczematous lesions is related to inflammation related to the deregulation of Th2 cells.26 Activated T cells release cytokines into the skin, mainly interleukin-4, interleukin-13 and interleukin-31, which activate the Janus kinase (JAK). Cytokines promote inflammation, pruritus, and the production of antigen-specific IgE by activation of B cells and plasma cells.

Studies have identified other immunoendotypes, such as those associated with activation of other helper T cell pathways (i.e., Th1, Th17, and Th22), partly associated with race/ethnicity.11 For example, activation of Th2 and Th17 pathways were reported in Asian patients, while in patients of European ancestry, there is especially activation of the Th2 pathway.

Activation of the Th1 and Th17 pathways is also absent in black patients with atopic dermatitis.8 These differences may explain the diverse manifestations of eczematous lesions depending on race or ethnic group. However, targeting mediators and cytokines in the Th2 pathway appears to be the most promising individualized approach to treatment.27-29

Among the genetic factors that promote skin barrier dysfunction, mutations in the filaggrin ( FLG ) gene have become the most prominent, affecting 30 to 50% of white patients.25

Filaggrin, which is produced by the epidermal keratinocytes of the upper layer, promotes the production of natural moisturizing factors and the lipid matrix, which acts by keeping the keratinocytes together in the stratum corneum. A loss-of-function mutation in FLG leads to the formation of an altered skin barrier and increased transepidermal water loss, resulting in dry skin.

The lack of skin lipids also reduces the production of epidermal antimicrobial peptides, leading to an increase in microbial dysbiosis.25,26 This alteration in the skin barrier makes it possible for allergens to penetrate the skin and induces allergic sensitization.

Environmental factors influence the predisposition and worsening of atopic dermatitis. Established factors include extreme temperatures, exposure to ultraviolet radiation, exposure to air pollution (through activation of the epidermal aryl hydrocarbon receptor), increased water hardness, and increased frequency of household products.24

The last of these factors refers to the "hygiene hypothesis" , which proposes that increased cleanliness leads to decreased incidence of infections in Western countries, which is associated with increasing incidence of allergic and autoimmune diseases. , including atopic dermatitis.24

A study of the skin microbiome in patients with atopic dermatitis has shown that it is predominantly colonized by pathogenic S. aureus . 24 This change in the microbiome, together with reduced production of epidermal antimicrobial peptides, may have clinical implications for the development of impetigo and skin abscesses in areas of eczema.

Pruritus in atopic dermatitis is based on signaling between pruritogens released by keratinocytes, mast cells and immune cells (T cells and eosinophils) and small sensory nerve fibers in the skin. Pruritogens comprise Th2 cytokines (especially interleukin-4, -13, and -31), thymic stromal lymphopoietin (a proinflammatory cytokine derived from the epithelium), histamine, proteases, and neuropeptides. These pruritogens bind to receptors on sensory fibers of the C nerve and Aδ nerve fibers in the epidermis and dermis, which sense itch and pain.

Patients with atopic dermatitis often report painful sensations including burning and stinging, as well as itching, in eczematous skin regions.30 Most pruritogens bind to nonhistaminergic nerve fibers. A small subset (<5%) of skin C nerve fibers are sensitive to histamine; However, blocking histamine 1 receptors with antihistamines has not controlled pruritus.

Consequently, guidelines do not recommend histamine 1 receptor antihistamines for the control of pruritus.31

Pruritogens are released not only by inflammation but also by scratching. This could result in hypersensitization of nerve fibers due to the itch-scratch cycle, a hypothesis that is consistent with patient reports of increased pruritus after scratching to relieve itch. 32,33

The interleukin4α receptor subunit is expressed in itch-sensitive nerve fibers and can hypersensitize to itch upon continuous stimulation with interleukin-4.34 This could partly explain the itch-scratch cycle and the rapid benefit of JAK1 and JAK2 inhibition and interleukin-4α receptor pathways.

Therapy for atopic dermatitis is selected according to the clinical stage of the disease (mild, moderate, or severe), the extent of body surface area involved, age, coexisting conditions and medications taken by the patient, severity of pruritus, the degree to which the quality of life is disabling, and the patient’s goals.35,36

For all stages of the disease, including eczema-free intervals, general measures such as the use of emollients (with or without antipruritic agents) and avoidance of infections and triggers are recommended.

When eczema occurs, the use of topical immunosuppressive therapies is recommended as a first approach. Crisaborole, a phosphodiesterase-4 inhibitor, has recently been approved for the treatment of atopic dermatitis in the United States, but is not available in all countries.

For moderate eczema, ultraviolet phototherapy can be used, but it is not used in children and young adults due to the potential for developing skin cancer with prolonged use.

For severe atopic dermatitis, various conventional systemic immunosuppressive methods such as glucocorticoids, cyclosporine or methotrexate were used. However, these agents do not target specific sites of immune dysregulation in atopic dermatitis and can lead to serious adverse effects, including liver and kidney dysfunction.

Regarding the coronavirus disease 2019 (Covid-19) pandemic, most dermatological societies, including the American Academy of Dermatology, recommend that patients with atopic dermatitis continue receiving systemic immunosuppressive therapy unless they have a positive test result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with a positive test can restart systemic immunosuppressive therapy after recovery from Covid-19.40

There have been advances in the development of Th2-targeted therapies. Promising agents are interleukin-4, -13, -22, and -31 receptor monoclonal antibodies, phosphodiesterase-4 inhibitors, and JAK inhibitors (topical and systemic), most of which have been tested in phase-in trials. 2-3.

In a comparative study, the interleukin-4 antibody dupilumab and the JAK inhibitor abrocitinib were associated with reductions in signs and symptoms of atopic dermatitis when compared with placebo; Abrocitinib was superior to dupilumab in reducing itch at 2 weeks, but the two drugs otherwise had similar results.41

Adverse effects such as skin infections or worsening asthma require careful evaluation of the future use of these new therapies in sensitive populations (children) and in patients with typical complications of atopic dermatitis.

For example, many patients have long-term functionally impaired conjunctivitis with dupilumab therapy, especially when combined with seasonal allergic conjunctivitis. JAK inhibitors carry a risk of thromboembolism and cancer42 and may be associated with respiratory tract infections, shingles infection, headache, nausea, diarrhea, and decreased white blood cells.43

Atopic dermatitis is a serious skin disease, particularly in children. Geographic and race or ethnic group variations, as well as complex pathogenesis, have impeded the development of targeted therapies.

Pruritus associated with the disorder affects quality of life and is a focus of treatment and a determinant of treatment effectiveness, as well as a major concern in the development of new medications to treat atopic dermatitis.

Board. Diagnostic Criteria for Atopic Dermatitis according to the American Academy of Dermatology

The essential characteristics are those necessary for the diagnosis of atopic dermatitis. The important features are those seen in most cases, adding support to the diagnosis. The associated characteristics suggest the diagnosis, but are too nonspecific to be used in the definition or detection of atopic dermatitis for clinical purposes and epidemiological studies. Th2 denotes T helper cell type 2 and Th17 is the type 17 helper cell.

†Monitoring IgE levels is not recommended for routine assessment of disease severity.