Atopic dermatitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2] Ogechukwu Hannah Nnabude, MD

Atopic dermatitis is a chronic inflammatory skin disorder that occurs primarily in children, but also affects adults, usually with a personal or family history of atopy including asthma, and allergic rhinitis. Atopic dermatitis presents usually with intense pruritus and is often associated with elevated levels of immunoglobulin E (IgE).

The term atopic dermatitis was first coined by Fred Wise and Marion Sulzberger, American dermatologists, in 1933, and the first widely used diagnostic criteria for atopic dermatitis was published by Jon Hanifin and Georg Rajka, in 1980.

Atopic dermatitis is a chronic inflammatory skin disorder with an immunologic background and occurs in patients with a personal or family history of atopy (i.e. asthma or allergic rhinitis). It is caused by either skin barrier dysfunction or immune dysregulation of the adaptive and innate immune response leading to an enhanced IgE-mediated, systemic Th2 response. The skin barrier is invaded by exogenous substances, including allergens, irritants and microbes; and the tightly packed structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis.

Atopic dermatitis is the result of either skin barrier dysfunction or immune dysregulation due to genetic defects. The most important genetic defect includes mutations in the filaggrin gene (FLG).

Atopic dermatitis is a chronic inflammatory skin disorder, which is indistinguishable from other causes of dermatitis. Atopic dermatitis is usually associated with a personal or family history of atopic diseases including asthma, allergic rhinitis and food allergy. The most common clinically similar dermatitis in infancy is seborrheic dermatitis which includes hyperkeratosis of the scalp, also found in atopic dermatitis.

It now affects 10-20% of children and 1-3% of adults in industrialized countries, and its prevalence there has more than doubled in the past thirty years. Atopic dermatitis incidence is highest during infancy and early childhood. The majority of atopic dermatitis patients have onset of symptoms <5 years of age. The prevalence of atopic dermatitis is approximately 5,000-20,000 cases per 100,000 children worldwide. In 2003, the prevalence of atopic dermatitis was estimated to be 10,700 cases per 100,000 children in the United States.

Atopic dermatitis is a multifactorial, chronic inflammatory skin disease as a result of interactions between various genetic, immune and environmental factors. The most important risk factor for the development of atopic dermatitis is a family history or personal history of atopy including asthma, allergic rhinitis, food allergy.

There is insufficient evidence to recommend routine screening for atopic dermatitis.

The symptoms of atopic dermatitis usually start during the first few years of life, and present with symptoms such as intense pruritus and chronic and relapsing age dependent eczematous lesions. Common complications of atopic dermatitis include super-infection with staphylococcus aureus, herpes simplex virus, and molluscum contagiosum; sleep problems due to intense pruritus, ocular comorbidities, and topical corticosteroids leading to striae formation.

Due to the variable morphology, distribution of skin lesions, and intermittent clinical features, it is very challenging to define the diagnosis of atopic dermatitis. Atopic dermatitis is primarily diagnosed based on the clinical presentation. Currently, the most commonly used criteria worldwide is published by the United Kingdom Working Group and is based upon history, morphology and distribution of eczematous lesions, and clinical features of atopic dermatitis. In patients with atopic dermatitis, to rule out other skin conditions, a histologic examination of a skin biopsy and other laboratory tests (eg, serum immunoglobulin E, potassium hydroxide preparation, patch testing, genetic testing) can be considered.

The most common symptoms of atopic dermatitis include pruritus, distribution of rash in age- specific patters and dry skin. Patients often have a personal or family history of asthma or allergic rhinitis. Patients with atopic dermatitis may report a positive history of cutaneous hyper-reactivity to diverse environmental stimuli and atopic disorders.

Atopic dermatitis is a chronic or relapsing hypersensitive manifestation of the skin. Common physical examination findings of atopic dermatitis include pruritus, eczematous lesions, xerosis and lichenification. The lesions are usually age-specific and can be at various stages of development. The lesions can involve any area of the body in severe cases, but usually, it is uncommon to find lesions in the axillary, gluteal, or groin area.

The diagnosis of atopic dermatitis remains clinical as there is no reliable bio-marker that can differentiate atopic dermatitis from other skin diseases.

There are no routinely diagnostic studies for atopic dermatitis, but in selected patients to rule out other skin conditions, a histologic examination of a skin biopsy and other laboratory tests (eg, serum immunoglobulin E, potassium hydroxide preparation, patch testing, genetic testing) can be considered.

The mainstay of treatment for atopic dermatitis depends upon the severity of the disease and is treated with a combination of conservative and medical therapy. The goals of treatment include the elimination of aggravating factors, skin barrier function repair, maintaining skin hydration, and pharmacologic treatment of skin inflammation. Pharmacologic medical therapies for atopic dermatitis can be classified according to several severity scales( (i.e SCORAD index, the Eczema Area, and Severity Index (EASI), and the Patient-Oriented Eczema Measure POEM).

Primary prevention applies to patients with a history of other atopic diseases and have not been diagnosed with atopic dermatitis yet. Its primary goal is to reduce the risk of developing atopic dermatitis in the future. Approaches to reduce the development of atopic dermatitis in children usually include the minimization of antibiotics administration in infants and infections in infants.

Secondary prevention involves protecting and restoring the epidermal skin barrier function including abstaining from using soap, cosmetics, dyes, fragrances, and detergents, washing new clothes before wearing them, avoiding frequent and sudden climate changes, using air humidifiers in winters, avoiding excessive exposure to UV radiation and using SPF sunscreens, regular application of emollients every 6 hours, and stress-reducing therapy

There has been no discussion on the cost-effectiveness of therapy for atopic dermatitis, however, in a retrospective study, the utilization of health care and treatment costs annually were higher for patients with atopic dermatitis than for controls without atopic dermatitis and was associated with the severity of the disease.

A more novel form of treatment involves exposure to broad or narrow-band ultraviolet light. UV radiation exposure has been found to have a localized immunomodulatory effect on affected tissues, and may be used to decrease the severity and frequency of flares. In particular, Meduri et al. have suggested that the usage of UVA1 is more effective in treating acute flares, whereas narrow-band UVB is more effective in long-term management scenarios. However, UV radiation has also been implicated in various types of skin cancer, and thus UV treatment is not without risk.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

In 1933, atopic dermatitis was first coined by two American dermatologists, Fred Wise and Marion Sulzberger. The first study on the clinical features of asthma as well as allergic rhinitis and genetics was performed by Cooke and Vander in 1916. An association of higher serum IgE levels was published by Bruno Wüthrich in 1978.

• One of the very first traces of the relationship between allergies and genetic factors was described by Hippocrates.^[1]
• In 1816, Willan and Bateman described a disease, “Porrigo larvalis,” which is identified as one of the earliest descriptions of atopic dermatitis.^[2][3][4]
• The first systemic study on the clinical features of asthma as well as allergic rhinitis and genetics was performed by Cooke and Vander in 1916.^[5]
• The association between heritable hypersensitivity to allergens in patients with asthma and hay fever and atopic dermatitis was made in 1923 by Arthur Coca and Robert Cooke.^[6][7]
• The term atopic dermatitis was first coined from the Greek word, atopos, by Fred Wise and Marion Sulzberger, American dermatologists, in 1933. Fred Wise and Marion Sulzberger enhanced Arthur Coca and Robert Cooke’s concept to include the description of atopic dermatitis.^{[3][8][9][10]}
• A paper reporting a patient with atopic dermatitis was published by Bruno Wüthrich in 1978, demonstrating on average higher serum IgE levels compared with controls.^[11]
• The first widely used diagnostic criteria for atopic dermatitis was published by Jon Hanifin and Georg Rajka, in 1980.^[12]
• Hanifin and Rajka’s criteria was modified by Williams et al. in 1997, to develop the UK Working Party criteria, in which an individual must have itchy skin for 12 months along with other features.^[13]
• In 2006, filaggrin gene mutations were first implicated in the pathogenesis of atopic dermatitis by Palmer et al.^[14]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

Atopic dermatitis is a chronic inflammatory skin disorder with an immunologic background and occurs in patients with a personal or family history of atopy (i.e. asthma or allergic rhinitis). It is caused by either a skin barrier dysfunction or immune dysregulation of the adaptive and innate immune response leading to an enhanced IgE-mediated, systemic Th2 response. The skin barrier is invaded by exogenous substances, including allergens, irritants and microbes; and the tightly packed structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis.

The normal physiology of atopic dermatitis can be understood as follows:

Epidermal barrier function:

• Epidermis: It directly interfaces with the environment and acts as the 1st line of defense. It is primarily dependent on the structure and composition of the most outermost layer of the skin, i.e. stratum corneum. It protects the body from irritants, allergens, microbes, and pathogens from invading the skin as well as preventing the excess water loss. The epidermis consists of:^[1]
  • Tightly packed corneocytes layers in the stratum corneum
  • Intercellular lipid bilayers
  • Corneocytes layers embedded in the extracellular matrix derived from lipid lamellae
  • Natural moisturizing factors (NMF), maintaining the water retention in the stratum corneum
  • Antimicrobial peptides
• Filaggrin proteins: It is encoded by filaggrin gene FLG on chromosome 1q21 (contains the genes of the epidermal differentiation complex (EDC)) and is the main component required to form corneocytes in the stratum corneum.^[2][3]
  • Pro-filaggrin is required for the formation of dense cytoplasmic granules, which along with other proteins, forms the corneocytes that acts as a primary unit for the barrier function of the skin.
  • Pro-filaggrin undergoes extensive phosphorylation and dephosphorylation, to produce filaggrin monomers to interact and aggregate with the keratin filaments and permits extensive crosslinking, to form a highly insoluble keratin matrix.^[4]
  • The degraded products of filaggrin protein are one of the major components of natural moisturizing factors (NMF), which prevents excess water loss from the stratum corneum.
  • The degraded products of filaggrin protein also maintain the acidic pH of the stratum corneum, required to regulate the activity of enzymes.
• Proteins related to tight junctions: These transmembrane proteins are present in the stratum granulosum of the epidermis and come together to form tight junctions which includes the claudin-1, occludin, junctional adhesion molecule.^[5]
• Other proteins: Filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, transglutaminase-3 are also part of skin barrier related proteins.^[6]

Immune response:

• Cutaneous immune response: Acts as the first-line barrier and constitutes the rapid response mechanism to the invading allergen or pathogen.^[7] It recognizes the microbes through receptors known as pattern recognition receptors (PRRs). The cutaneous immune response includes the following 4 elements:^[8]
  • Physical: Stratum corneum and the tight junctions in stratum granulosum forms the physical barrier. The maintenance and repair of epithelial barriers are mediated through the activation of PRRs by the innate immune system.^[9]
  • Chemical: Chemical constitutes antimicrobial proteins including antimicrobial peptides (AMPs), S100 proteins, cytokines as well as chemokines, innate lymphoid cells group 2 (ILC-2), toll-like receptors (TLRs), keratinocytes, filaggrin degraded products, and neutrophils.^[10][11]
  • Microbiome: The microbiome consists of skin-resident normal microbial flora including bacteria, fungi, and viruses. It provides protection against invading microbes and pathogens, and modulates the balance between inflammation and immune responses.^[12]
  • Immunological: Immune response includes both non-specific and immediate response (innate immunity) and highly specific and late response (adaptive immunity).
• Adaptive Immune response:^[7]
  • The character and magnitude of the adaptive immune system is determined by the innate immune response by interactions with the epidermal elements and activation of TLRs.^[13]
• Thymic stromal lymphopoietin:
  • Thymic stromal lymphopoietin (TSLP) is considered as a master switch for allergic inflammation, and is highly expressed by epithelial cells and epidermal keratinocytes.^[14][15]
  • It is an IL-7-like cytokine, which stimulates the differentiation of naïve T helper cells into inflammatory Th2 cells.^[16]

It is understood that atopic dermatitis is the result of either skin barrier dysfunction or immune dysregulation.^[17]

Epidermal barrier dysfunction (outside-in hypothesis):^[18]

• The major factors causing abnormal skin barrier include loss-of-function mutations in the filaggrin gene (FLG) resulting in:^[19][20][21]
  • Filaggrin protein deficiency^[22]
  • Tight junction abnormalities^[23]
  • More alkaline surface pH^[24]
  • Microbial colonization
  • Altered protease activity in the stratum corneum^[25]

• Skin barrier abnormalities lead to the increased permeability of the epidermis.
  • This leads to entry of antigens or pathogens resulting in microbial colonization, most notably by staphylococcus aureus and herpes simplex virus (HSV).
  • This sequence of events results in the production of inflammatory cytokines and impaired production of antimicrobial peptides.^[26]

• Skin barrier abnormalities also lead to increased trans-epidermal water loss, and decreased levels of ceramides and water binding.^[27][3]

• Severe atopic dermatitis has been associated with higher levels of trans-epidermal water loss.^[28]

Immune dysregulation (inside-out’ hypothesis):^[29]

• Innate immune response:
  • Pathogens or tissue damage activate pattern recognition receptors including toll-like receptors (TLRs), which further induces a release of inflammatory mediators, including AMPs, cytokines, and chemokines.^[30]
  • Defective cutaneous innate immune-mediated epidermal barrier repair and maintenance may alter skin-resident normal microbial flora and lead to severe inflammation as demonstrated with atopic dermatitis patients colonized with staphylococcus aureus.^[31]
  • In intact skin barrier, antimicrobial peptides (AMPs) are regulated by cytokines, IL-17, and IL- 22, which are secreted by Th17 and Th22 cells. This effect is suppressed in patients with atopic dermatitis.^[32]
• Adaptive immune response:
  • Increased allergen penetration through the damaged epidermis leading to a Th2-type milieu is thought to explain the critical link between the barrier defect of atopic dermatitis patients with FLG mutations and Th2 polarization.^[33]
  • Enhanced expression of Th2, Th17, and Th22 cytokines, characterize the acute initiation of atopic dermatitis lesions.^[34][3]
  • Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and IL-22) by:^[35][3]
    • Stimulating epidermal hyperplasia
    • Inhibiting the expression of terminal keratinocyte differentiation genes (eg, FLG, loricrin, involucrin)
    • Suppressing the production of AMPs
• Thymic stromal lymphopoietin:
  • Defective skin barrier and enhanced epidermal protease activity, which is reported in atopic dermatitis, promote TSLP production and Th2 response, leading to atopic dermatitis-like inflammation.^[36]
  • TSLP polymorphisms have been linked to the severity of atopic dermatitis.
  • TSLP genetic variants are associated with atopic dermatitis and eczema herpeticum.^[37]
  • In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis.^[38]

Recent studies have established a strong genetic association of atopic dermatitis. Twin studies have indicated high heritability of atopic dermatitis with a concordance rate of 72–86 % for monozygotic twins compared with 21–23 % for dizygotic twins.^[39]

Genes involved in the pathogenesis of atopic dermatitis include:^[40]

Conditions associated with atopic dermatitis:

• Atopic triad ^[3]
  • Atopic dermatitis
  • Allergic rhinitis
  • Asthma
• Food-induced urticaria/anaphylaxis
• Ichthyosis vulgaris
• Ocular comorbidities
  • Atopic keratoconjunctivitis
  • Vernal keratoconjunctivitis
• Wiskott-Aldrich syndrome
  • Thrombocytopenia
  • Eczema (atopic dermatitis)
  • Recurrent infections
• Hyper-IgE syndrome:
  • Eczema (atopic dermatitis)
  • High serum IgE
  • Recurrent cold abscesses
• Anemia
• Psychiatric disorders
  • Depression
  • Anxiety
  • Suicidal ideations
  • Attention deficit hyperactivity disorder
• Angina pectoris

On gross pathology, characteristic findings of atopic dermatitis include:^[48]

• Acute atopic dermatitis:
  • Erythema
  • Edema
  • Vesiculation with oozing
• Chronic atopic dermatitis:
  • Lichenified plaques
  • Prominent skin markings

On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:^[49]

• Acute vesicular lesions:
  • Epidermal psoriasiform hyperplasia
  • Marked intercellular edema with spongiotic vesiculation
  • Marked perivenular infiltrate
  • Epidermal infiltrate, consisting predominately of a lymphohistiocytic infiltrate in the dermis
• Chronic lichenified plaque:
  • Hyperkeratosis
  • Psoriasiform hyperplasia
  • Dyskeratosis
  • Marked thickening of the papillary dermis
  • Minimal intercellular edema

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

Atopic dermatitis (AD) is a chronic inflammatory skin disorder which primarily occurs as a result of various genetics, immune or environmental factors. Other causes leading to development or aggravation of atopic dermatitis include infection, hygiene hypothesis, climate and cigarette smoking.

• Genetics:
  • Filaggrin gene encodes proteins which are involved in the epidermal proliferation and differentiation of cytokines.^[1][2]
  • Loss-of-function mutations in the filaggrin gene (FLG) causes epidermal barrier dysfunction.
• Infection:
  • In atopic dermatitis, patient’s skin is often colonized by staphylococcus aureus and herpes simplex virus.^[2]
  • It acts as a super antigen and thought to cause the flare up of atopic dermatitis.

List the causes of the disease in alphabetical order:

• Filaggrin gene mutation
• Family or personal history of atopic diseases:
  • Asthma
  • Allergic rhinitis
• Infection by staphylococcus aureus and herpes simplex virus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

Atopic dermatitis is a chronic inflammatory skin disorder, which is indistinguishable from other causes of dermatitis. Atopic dermatitis is usually associated with personal or family history of atopic diseases including asthma, allergic rhinitis and food allergy. The most common clinically similar dermatitis in infancy is seborrheic dermatitis which includes hyperkeratosis of the scalp, also found in atopic dermatitis.

Atopic dermatitis should be differentiated from allergic contact dermatitis, iirritant contact dermatitis, seborrheic dermatitis, psoriasis, lichen simplex chronicus, ichthyosis vulgaris, nummular dermatitis (discoid eczema), netherton’s syndrome, and dermatitis herpetiformis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

Atopic dermatitis is a multifactorial, chronic inflammatory skin disease as a result of interactions between various genetic, immune, and environmental factors. The most important risk factor for the development of atopic dermatitis is a family history or personal history of atopy including asthma, allergic rhinitis, food allergy.

The most potent risk factor in the development of atopic dermatitis is a family history or personal history of atopy.

• Common risk factors in the development of atopic dermatitis include:
  • Family history of atopic dermatitis or other atopy^[1]
    • 70% of atopic dermatitis patients have a positive family history of atopic diseases
    • Risk of developing atopic dermatitis is 2- to 3-fold higher in children with 1 atopic parent ^[2]
    • Risk of developing atopic dermatitis is 3- to 5-fold higher in children with both atopic parents ^[3]
  • Loss of function mutations in the filaggrin (FLG) gene^[4]
    • Risk for earlier-onset atopic dermatitis
    • Risk for severe and persistent atopic dermatitis
  • Personal history of atopy (asthma, allergic rhinitis, food allergy) ^[5]
  • Environmental factors predisposing individuals to the development of atopic dermatitis include:^[6]
    • Temperature (colder climates with low humidity)
    • Ultraviolet radiation
    • Air pollution
    • Water hardness
    • Household hygiene

• Less common risk factors in the development of atopic dermatitis include:
  • Infections
    • Children who are frequently exposed to infections, carry an increased probability of developing atopic dermatitis and other allergic diseases.^[7]
    • During pregnancy, exposure to antibiotics and infections is a crucial risk factor for the development of atopic march diseases.^[8]
  • House renovation
    • Mothers who have been living in a renovated areas during pregnancy has increased risk of developing atopic diseases in the children.^[9]
  • Vaccination
    • Recent published studies has observed a significantly higher risk of asthma and atopic diseases in non-vaccinated children vs vaccinated children.^[10]
  • High domestic water calcium carbonate levels in infancy^[11]
  • Higher level of parental education^[12]
  • Living in urban areas^[13]
  • Exposure to antibiotics in infancy^[14]
  • Active and passive exposure to tobacco^[15]
  • Itching causes scratching which leads to dysfunction of the epidermal skin barrier.
    • Risk factors which aggravate itching include sweating, dry skin, emotional stress, hot water, and certain foods.
  • Stress can result into increased levels of glucocorticosteroids in blood, which further leads to dysfunction of skin barrier by affecting the integrity and adhesion of the stratum corneum.^[16]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

There is insufficient evidence to recommend routine screening for atopic dermatitis.

There is insufficient evidence to recommend routine screening for atopic dermatitis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogechukwu Hannah Nnabude, MD; Shalinder Singh, M.B.B.S.[2]

The symptoms of atopic dermatitis usually start during the first few years of life, and present as intense pruritus and chronic and relapsing age dependent eczematous lesions. Common complications of atopic dermatitis include super-infection with staphylococcus aureus, herpes simplex virus, and molluscum contagiosum; sleep problems due to intense pruritus, ocular comorbidities, and striae formation due to long term use of topical corticosteroids.

• The symptoms of atopic dermatitis usually start during the first few years of life, and present as intense pruritus and chronic and relapsing age dependent eczematous lesions.^[1]
• The majority of infants and children with atopic dermatitis usually grow out of the disease during childhood.^[2]
• In severe cases, atopic dermatitis continues or relapses in adulthood.^[3]
• The natural history of atopic dermatitis can be categorized into various subtypes according to the clinical features.
  • The most common subtype was characterized by the early onset of atopic dermatitis (<2 years) and persistent until adulthood.^[4]
• In the sequence of atopy march diseases, atopic dermatitis is the first to commence during infancy, followed by allergic rhinitis, food allergy and asthma later in life.^[5]
• Atopic dermatitis is a life long disease with periods of waxing and waning eczematous skin lesions.^[6]

• Common complications of atopic dermatitis include:
  • Super-infection
    • Staphylococcus aureus^[7][8]
    • Herpes simplex virus ( Kaposi varicelliform eruption or eczema herpeticum) – occurs in <3% of patients
    • Molluscum contagiosum
  • Sleep problems due to intense pruritus
  • Ocular comorbidities
    • Atopic keratoconjunctivitis^[9]
    • Vernal keratoconjunctivitis^[10]
    • Keratoconus
    • Infectious keratitis
    • Blepharitis
  • Topical corticosteroids can lead to striae formation
  • Atopy march: Other atopic disorders such as allergic rhinitis, food allergy and asthma^[8]
  • Depression, anxiety and suicidality are among long-term complications of atopic dermatitis.^[1]

• Atopic dermatitis is a chronic disease with varying subtypes.^[11]
• The presence of severe atopic dermatitis and early atopic sensitization is associated with a particularly poor prognosis.^[12]
• Mortality is unusual in atopic dermatitis.