INTRODUCTION Atopic dermatitis (AD) is a chronic inflammatory skin condition that appears to involve a genetic defect in the proteins

s supporting the epidermal barrier. Atopy, referring to "out of place", describes a group of disorders that include eczema, asthma, and allergic rhinitis [1]. However such a link between AD and asthma and hay fever has been called into question and is now controversial [2-4]. (See "Risk factors for asthma", section on 'Atopy'.) The terms "dermatitis" and "eczema" are frequently used interchangeably. When the term "eczema" is used alone, it usually refers to atopic dermatitis (atopic eczema). "Eczematous" also connotes some crusting, serous oozing, or blister formation as opposed to mere erythema. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of atopic dermatitis are reviewed here. The treatment of atopic dermatitis, the impact of staphylococcus aureus and other microbes on atopic dermatitis, the role of allergy in atopic dermatitis, and a review of other types of dermatitis are discussed separately. (See "Treatment of atopic dermatitis (eczema)" and "Management of severe refractory atopic dermatitis (eczema)" and "Role of allergy in atopic dermatitis (eczema)" and "Overview of dermatitis".) EPIDEMIOLOGY Atopic dermatitis affects approximately 5 to 20 percent of children worldwide [5]. The prevalence of atopic dermatitis in the United States is around 17 percent [6]. The incidence of atopic dermatitis appears to be increasing. It may occur in any race or geographic location, although there appears to be a higher incidence in urban areas and developed countries, especially western societies [7]. The vast majority of atopic dermatitis has an onset before age five years, and prevalence data in children show a slight female to male preponderance (1.3 to 1) [8]. PATHOGENESIS Two major models currently exist to explain the pathogenesis of atopic dermatitis. The predominant model describes atopic dermatitis as a result of impaired epidermal barrier function due to intrinsic structural and functional abnormalities in the skin. In this model, the disease evolves from the outside in, with an abnormal epidermal barrier as the primary defect [9]. The second and traditional model views atopic dermatitis as primarily an immune function disorder in which Langerhans cells, T-cells and immune effector cells modulate an inflammatory response to environmental

factors. While widely accepted for years, there is now little support that AD is the result of allergies [2-4]. Epidermal permeability barrier The epidermis is the first line of defense between the body and the environment. An intact epidermis keeps environmental irritants, allergens, and microbes from entering the body [10]. Permeability of the epidermis is determined by complex interactions of differentiated keratinocytes on the surface of the skin called corneocytes and groups of structural proteins, such as filaggrin, regulatory, enzymes and lipids [11]. Any disruption of these components through inherited defects, trauma, decreased humidity, alteration of pH, and infection can interfere with the ability of the epidermis to function as an effective barrier. Disruption allows antigenic and irritant agents to penetrate the barrier and come into contact with immune cells, leading to the release of proinflammatory mediators [11]. This can then produce the clinical and pathologic findings of dermatitis. Hydration of the epidermis is a key factor in maintaining an intact barrier. Corneocytes have the ability to bind three times their weight in water. This water binding is mediated by surface lipids, primarily ceramides, and proteins of the corneocyte cell envelope, filaggrin and involucrin. (See "Contact dermatitis in children".) Atopic dermatitis is characterized by decreased ceramides due to upregulation of sphingomyelin deacylase [11], leading to decreased water binding. Atopic skin has a compromised ability to maintain water; this can be measured by assessing the transepidermal water loss (TEWL), which is increased in atopic skin [10]. Even clinically normal skin in an atopic individual has increased water loss and altered barrier function. Dry skin (xerosis) results in pruritus which induces scratching (itch-scratch cycle) and superficial trauma which results in release of proinflammatory mediators triggering inflammation [12]. The less the water binding in AD skin, the worse the dermatitis [13]. Several studies discussed below have discovered genetic defects in key components involved in establishing the epidermal permeability barrier. Filaggrin Filaggrin is encoded by the (FLG) gene on the 1q21 epidermal differentiation complex. Filaggrin is a protein that is produced by differentiating keratinocytes that functions to aggregate keratin filaments into a cytoskeleton that, in combination with other components, comprise the cornified cell envelope [11]. Mutations of filaggrin have been demonstrated to cause ichthyosis vulgaris, the most common inherited disorder of keratinization. Ichthyosis vulgaris is characterized by many of the features that are included in the diagnostic criteria for AD including dry skin, keratosis pilaris, and palmar hyperlinearity [14]. (See 'Diagnosis' below.) Ichthyosis vulgaris is also associated with a higher risk of AD.

Two well characterized loss of function FLG mutations (R501X and 2282del4) have been shown to be responsible for moderate-severe ichthyosis vulgaris in those who carry two mutant alleles and mild disease in those with only one copy of the allele. One study examined the occurrence of AD in individuals with known mutations of the FLG (R501X and 2282del4) and ichthyosis vulgaris. AD was found in higher frequency in those who had two mutated FLG alleles compared with those with one, and AD was completely absent in family members who had no copies of the mutated FLG [15]. A number of independent studies in Ireland, Scotland, Denmark, and Japan corroborate these results [15-21]. Many authorities now cite filaggrin defects as the major cause of atopic dermatitis [2-4]. Spink 5 Spink 5 is a serine protease inhibitor (Kazal-type 5 serine protease inhibitor) that is deficient in Netherton's syndrome (a rare autosomal recessive disorder characterized by severe atopic dermatitis). Spink 5 inhibits a well characterized protease stratum corneum chymotryptic enzyme (SCCE) that is involved in cleaving the intercellular attachments between corneocytes in normal desquamation process. Decreased Spink 5 results in upregulated SCCE function and increased cleavage of intercellular attachments and reduced corneocyte cohesion and compromised barrier function [11]. Epicutaneous sensitization Introduction of environmental allergens, irritants, and microbes through a defective barrier results in an interaction with immune surveillance cells, such as the Langerhans' cell, an antigen presenting cell. This theory may also help explain why not all patients with AD have elevated IgE levels. Patients with mild to moderate AD have much lower, or normal, IgE levels compared to individuals with severe AD, and more exposure to environmental antigens [11]. This finding suggests that the allergic Th2 driven axis of the immune system results from epidermal barrier dysfunction, and introduction of environmental antigens. Immune hypersensitivity Another theory explaining the pathogenesis of AD proposes that the immune system is responsible for atopic disorders [22]. AD in this view may represent a cutaneous sign of a systemic disorder that is characterized by food allergy, asthma, and allergic rhinitis [1]. The discovery that defects in the filaggrin protein lead to a dysfunctional epidermal barrier and that this is the primary cause of atopic dermatitis has made this theory less plausible. Emphasis is now placed on the study of the epidermal barrier dysfunction as it relates to the abnormal epidermal architecture and how the immune system responds to the barrier failure.

Genetics Most experts believe that AD has a genetic basis. A genetic basis is suggested by the following:

Twins studies have found concordance rates of 80 percent for monozygotic twins compared to 20 percent for dizygotic twins [17,23,24]. Chromosome studies have suggested that the trait for atopy may be inherited via a maternal gene located on chromosome 11 [25]; clinical studies demonstrate a higher risk for atopy if a child's mother rather than father has atopy [26,27]. Linkage on chromosome 3q21, 1q21, 17q25, and 20p also have been reported; all of these loci correspond closely with known psoriasis loci [28,29].

Many AD patients have filaggrin mutations. Findings in several atopic dermatitis populations (Japanese, Scottish, Irish, and EuropeanAmerican) have identified filaggrin (FLG) mutations linked to the epidermal differentiation complex on chromosome 1q21 [15-18]. Filaggrin mutations are found in AD but not in asthma [20]. Staphylococcus aureus Staphylococcus aureus colonization may play a role in the development of atopic dermatitis. (See "Treatment of atopic dermatitis (eczema)", section on 'Staphylococcus aureus'.) CLINICAL MANIFESTATIONS Atopic dermatitis occurs in the first year of life in 60 percent of cases, and by the age of 5 years in nearly 85 percent of cases. Atopic dermatitis will clear in nearly 40 percent of patients by adulthood [30-32]. There are three age-group stages of atopic dermatitis: infantile (from infancy to 2 years old), childhood (from 2 years old to 12 years old) and the adult stage for those older than 12 years [30]. Virtually all patients report dry skin [31-33]. The infantile stage may present with pruritic, red, scaly, and crusted lesions on the extensor surfaces and cheeks or scalp (picture 1A-C). There is usually sparing of the diaper area (picture 2) [30]. Acute lesions can include vesicles (picture 3) and there can be serous exudates and crusting in severe cases. The childhood stage is characterized by less exudation and often demonstrates lichenified plaques in a flexural distribution, especially of the antecubital and popliteal fossae, volar aspect of the wrists, ankles, and neck (picture 4A-D) [30]. The adult stage of atopic dermatitis is considerably more localized and lichenified and has a similar distribution to the childhood stage, or may be primarily located on the hands and feet [30]. Adult AD is characterized by thickened skin, increased skin markings (lichenification), and excoriated and fibrotic papules (picture 5). In adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly involved (picture 6); other common sites include the face, wrists, and forearms (picture 7). In severe cases, any area of the body can be involved, although it is uncommon to see lesions in the axillary, gluteal, or groin area; lesions in these locations should prompt consideration of other diagnoses such as psoriasis. The presence of pustules within areas of dermatitis suggests secondary infection with Staphylococcus aureus. DIAGNOSIS Atopic dermatitis is diagnosed by observing its representative clinical features. The United Kingdom working group

on AD published criteria for diagnosing atopic dermatitis that include the following [31]:

Evidence of itchy skin, including the report by a parent of a child rubbing or scratching.

In addition to itchy skin, three or more of the following are needed to make the diagnosis:

History of skin creases being involved. These include: antecubital fossae, popliteal fossae, neck, areas around eyes, fronts of ankles. The presence of generally dry skin within the past year. Symptoms beginning in a child before the age of two years. This criterion is not used to make the diagnosis in a child who is under four years old. Visible evidence of dermatitis involving flexural surfaces. For children under four years old, this criterion is met by dermatitis affecting the cheeks or forehead and outer aspects of the extremities.

The UK working group's analysis excluded allergy criteria as originally proposed by Hanifin and Rajka. The UK working group data have been validated by investigators from the Netherlands [33]. Laboratory testing, including IgE levels, are not used routinely in the evaluation of patients with suspected atopic dermatitis, and are not currently recommended. When the diagnosis is uncertain, we suggest that patients be referred to a specialist (eg, dermatologist, allergist). DIFFERENTIAL DIAGNOSIS The differential diagnosis of atopic dermatitis includes other eczematous disorders such as contact dermatitis (picture 8), seborrheic dermatitis (picture 9), and drug reactions (picture 10). (See "Overview of dermatitis".) In infants, considerations include psoriasis (picture 11), scabies (picture 12), Wiskott-Aldrich syndrome, hyperimmunoglobulin E syndrome (picture 13), nutritional deficiencies, acrodermatitis enteropathica (picture 14) and Netherton's syndrome. (See "Epidemiology, pathophysiology, clinical manifestations, and diagnosis of psoriasis" and "Scabies" and "Wiskott-Aldrich syndrome" and "Hyperimmunoglobulin E syndrome" and "Zinc deficiency and supplementation in children and adolescents".) INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Atopic dermatitis (eczema)".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics. SUMMARY AND RECOMMENDATIONS Atopic dermatitis (AD) is a chronic inflammatory skin condition that appears to involve a genetic defect in the proteins supporting the epidermal barrier. Disruption of the barrier results in inflammation of the skin. (See 'Introduction' above.) The diagnosis of atopic dermatitis is generally based on its typical clinical presentation (see 'Clinical manifestations' above:

Most patients have manifestations of atopic dermatitis by age five to seven years. In children, acute skin lesions that appear as intensely pruritic erythematous patches with papules and some crusting can be seen on the face, scalp, extremities, or trunk; diaper areas are usually spared. The skin lesions in older individuals with more chronic disease are characterized by thickened skin, increased skin markings (lichenification), and excoriated and fibrotic papules. In adults, the flexural areas (neck, antecubital fossae, and popliteal fossae) are most commonly involved. We suggest not performing routine laboratory testing in patients felt clinically to have atopic dermatitis. When the diagnosis is uncertain, we suggest that patients be referred to a specialist (eg, dermatologist, allergist). (See 'Diagnosis' above.) The differential diagnosis of atopic dermatitis includes other eczematous disorders such as contact dermatitis, seborrheic dermatitis, and drug reactions. (See 'Differential diagnosis' above.)

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GRAPHICS

Atopic dermatitis: infantile

Confluent erythema, microvesiculation, scaling, and crusting on the face, with similar involvement (to a lesser degree) on the trunk and arms. The facial involvement is more severe due to easier access to scratching; the baby is squeezing the breast skin to relieve the intense pruritus. Reproduced with permission from: Fitzpatrick, TB, Johnson, RA, Wolff, K, et al (Eds). Color Atlas and Synopsis of Clinical Dermatology, 3rd ed, McGraw-Hill, New York, 1997. Copyright McGraw-Hill.

Atopic dermatitis: infantile

Confluent erythema, mircovesiculation, papules, crust, and scale of a young Asian infant; the shoulders are relatively spared, being protected from scratching by clothing. Reproduced with permission from: Fitzpatrick, TB, Johnson, RA, Wolff, K, et al (Eds). Color Atlas and Synopsis of Clinical Dermatology, 3rd ed, McGraw-Hill, New York, 1997. Copyright McGraw-Hill.

Atopic dermatitis - infantile

Pruritic, hyperpigmented patches are present on the face of this infant with atopic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Atopic dermatitis - infantile

The diaper area is relatively spared in this infant with widespread atopic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Atopic dermatitis

Acute atopic dermatitis of the hand with intense erythema and vesicles. Reproduced with permission from: Williams, W. Atopic Dermatitis. New Engl J Med 2005; 352:2314. Copyright 2005 Massachusetts Medical Society.

Atopic dermatitis

Hyperpigmented, slightly scaly patches and lichenified plaques are present in the popliteal fossae of this patient with atopic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Atopic dermatitis

Severe atopic dermatitis in a 12-year-old girl showing in the typical location of the popliteal fossae. Note the oozing of serous fluid from the most involved areas, plus the papular component and erythema. Courtesy of Scott Walsh, MD, FRPCP.

Flexural atopic dermatitis

Typical appearance of atopic dermatitis in flexural areas of the legs. Courtesy of James C Shaw, MD.

Atopic dermatitis

Numerous erythematous papules are present on the hands of this patient with atopic dermatitis. Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Atopic dermatitis

Chronic atopic dermatitis with lichenification (skin thickening and enhancement of skin markings) and scaling on the front of the ankle. Reproduced with permission from: Williams, W. Atopic Dermatitis. New Engl J Med 2005; 352:2314. Copyright 2005 Massachusetts Medical Society.

Atopic dermatitis

A slightly lichenified, erythematous patch and excoriations are present in the antecubital fold. Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Papular eczema

Scattered inflammatory papules are present among lichenified, eczematous plaques in this patient with papular eczema. Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.

Allergic contact dermatitis

Allergic contact dermatitis is characterized by an erythematous, papular dermatitis with indistinct margins, distributed in areas of exposure. Courtesy of James C Shaw, MD.

Seborrheic dermatitis

Seborrheic dermatitis is characterized by erythema and scale, with some pruritus. The most common areas of involvement on the face are the lateral sides of the nose and the nasolabial folds, eyebrows and glabella. Courtesy of James C Shaw, MD.

Photoallergic eruption

Photoallergic eruptions are characterized by widespread eczema, in this case on the back of the hands. Courtesy of Andrew Samel, MD.

Plaque type psoriasis

Plaque type psoriasis is characterized by erythematous plaques with sharply defined margins that are raised above the surrounding normal skin. A thick silvery scale is usually present. Courtesy of James C Shaw, MD.

Interdigital lesions of scabies

The essential lesion is a small, erythematous, nondescript papule. Courtesy of John T Crissey, MD.

Severe eczema in an infant with the hyperimmunoglobulin E syndrome

Acrodermatitis enteropathica

Acrodermatitis enteropathica in an infant. Moist erythematous plaques are present on the cheeks and buttocks. The buttock lesions are typically symmetric. Courtesy of Robert Sidbury, MD.