Genetic Factors

Genetic factors account for ~90% of susceptibility to early-onset AD , with a significantly higher concordance rate in monozygotic twins (77%) compared to dizygotic twins (15%) . Although the entities in the atopic triad cluster together in families, a parental history of AD is a stronger risk factor for the development of AD than either asthma or allergic rhinitis, supporting the existence of genes specific to AD susceptibility . Genes that encode proteins important to the epidermal barrier and immunologic functions have been implicated in AD pathogenesis ( Table 12.2 ). AD is a complex genetic disease, and both gene–gene and gene–environment interactions have important roles .

Epidermal Barrier Dysfunction

A defective epidermal permeability barrier represents a consistent feature of AD and is evident in the nonlesional as well as lesional skin of affected individuals . A higher level of transepidermal water loss (TEWL), an indicator of barrier dysfunction, on day 2 of life predicts an increased risk of AD at 1 year of age . In addition, the level of TEWL in the nonlesional skin of children with AD correlates with disease severity . Epidermal barrier dysfunction permits an easier entry for irritants, allergens and microbes, which trigger immune responses that include the release of proinflammatory cytokines . In infants, greater TEWL is associated with an increased likelihood of epicutaneous sensitization to aeroallergens, which could potentially play a role in the development of asthma and allergic rhinoconjunctivitis . Factors that contribute to the impaired cutaneous barrier in AD are discussed below.

Immune Dysregulation

The innate and adaptive immune systems play dynamic interrelated roles in the pathogenesis of AD. Acute AD lesions have a predominance of Th2 cytokines, but there is subsequent evolution to a chronic phase characterized by Th1 and Th22 cytokine profiles, as well as variable levels of Th17 cytokines in both acute and chronic AD . The acute phase features IL-4, IL-5, and IL-13; activation of eosinophils and mast cells; and production of allergen-specific IgE . Keratinocyte-derived cytokines including IL-1, thymic stromal lymphopoietin (TSLP), IL-25 (IL-17E), and IL-33 promote a Th2 immune response. Th2 cytokines inhibit expression of major terminal differentiation proteins such as loricrin, filaggrin, and involucrin as well as β-defensin-2/3 antimicrobial peptides .

The Cutaneous Microbiome

The cutaneous microbiome represents a complex and highly diverse community of pathogenic and commensal bacteria, fungi, and viruses that play a critical role in epidermal homeostasis. More than 90% of patients with AD have skin colonized with S. aureus , compared to about 5% of unaffected individuals, presumably reflecting the disrupted acid mantle, decreased antimicrobial peptides (e.g. cathelicidins, defensins), and altered cytokine milieu of AD skin . During AD flares, bacterial diversity decreases and the proportion of the microbiome accounted for by Staphylococcus spp. increases from ~35% to ~90% .

Superantigens can promote the development of a Th2 immune response, and exotoxins with superantigenic properties are produced by up to 65% of the S. aureus strains that colonize AD patients . In addition, the S. aureus δ-toxin stimulates mast cell degranulation and Th2 inflammation . Filaggrin deficiency also increases the susceptibility of keratinocytes to S. aureus α-toxin-induced cytotoxicity .

Alterations in the skin microbiome of AD patients related to the use of cleansers and topical immunomodulatory or antimicrobial agents may have potential effects on cutaneous inflammation and barrier function. In addition, topical administration of coagulase negative Staphylococcus strains with antimicrobial activity has been shown to markedly reduce S. aureus colonization in AD patients , providing the basis for bacteriotherapy as a potential AD treatment.

Disease Course

AD has a broad clinical spectrum that varies depending upon the age of the patient. It is divided into infantile, childhood, and adolescent/adult stages ( Fig. 12.3 ). In each stage, patients may develop acute, subacute, and chronic eczematous lesions, all of which are intensely pruritic and often excoriated. Acute lesions predominate in infantile AD and are characterized by edematous, erythematous papules and plaques that may exhibit vesiculation, oozing, and serous crusting. Subacute eczematous lesions display erythema, scaling, and variable crusting. Chronic lesions, which typify adolescent/adult AD, present as thickened plaques with lichenification as well as scale; prurigo nodule-like lesions can also develop (see below). Perifollicular accentuation and small, flat-topped papules (papular eczema) are particularly common in patients with African or Asian heritage. In any stage of AD, a generalized exfoliative erythroderma may develop in the most severely affected patients (see Ch. 10 ). All types of AD lesions can leave postinflammatory hyper-, hypo-, or occasionally depigmentation upon resolution ( Fig. 12.4 ).

Distribution patterns of atopic dermatitis (AD) and regional variants.

*May be the only manifestation of AD in adults. ^† Not to be confused with nummular eczema occurring outside the setting of AD.

Postinflammatory hypopigmentation in atopic dermatitis.

Infantile AD (age <2 years) typically develops after the second month of life, often initially appearing as edematous papules and pap­ulovesicles on the cheeks, with sparing of the central face; the lesions may evolve to form large plaques with oozing and crusting ( Fig. 12.5 ). The scalp, neck, extensor aspects of the extremities, and trunk may also be involved, usually with sparing of the diaper area ( Fig. 12.6 ). In the first 6 months of life, the face is affected in >90% of patients with AD . Young infants may attempt to relieve itch through rubbing movements against their bedding, whereas older infants are better able to directly scratch affected areas.

Infantile atopic dermatitis on the face.

A Erythema with scale-crust on the cheeks. Note the sparing of the central face. B More severe, widespread facial dermatitis with accentuation of scale-crust around the mouth.

A, Courtesy, Julie V Schaffer, MD.

Infantile atopic dermatitis on the extensor arms.

Chronic diffuse involvement of the extensor arms with scaling and hyperpigmentation. Note the follicular prominence on the trunk.

In childhood AD (age 2 to 12 years) , the lesions tend to be less exudative and often become lichenified. The classic sites of predilection are the antecubital and popliteal fossae (flexural eczema) ( Fig. 12.7 ). Other common locations include the wrists, hands, ankles, feet, neck, and eyelids, although any area can be involved ( Fig. 12.8 ). Xerosis typically becomes pronounced and widespread.

Flexural atopic dermatitis in a child.

The popliteal fossa is a typical location. Note the excoriations.

Courtesy, Julie V Schaffer, MD.

Extensive atopic dermatitis in a child.

Excoriations, crusting, and lichenification are evident.

Adult/adolescent AD (age >12 years) also features subacute to chronic, lichenified lesions, and involvement of the flexural folds typically continues ( Fig. 12.9 ). However, the clinical picture may also change. Adults with AD frequently present with chronic hand dermatitis that has both endogenous and exogenous components ( Fig. 12.10 ), while others have primarily facial dermatitis ( Fig. 12.11 ), often with severe eyelid involvement (see below). Patients who have suffered from continuous AD since childhood are more likely to have extensive disease that is resistant to treatment. Such individuals may also have severe excoriations and chronic papular skin lesions because of habitual scratching and rubbing ( Fig. 12.12A ).

Chronic atopic dermatitis.

A Lichenification, scale, and punctate excoriations in the antecubital fossae. B Coalescing papules and lichenification on the ankle due to chronic scratching and rubbing. C Thick eczematous plaques with excoriation on the dorsal hand and wrist.

A, C, Courtesy, Julie V Schaffer, MD; B, Courtesy, Antonio Torrelo, MD.

Atopic dermatitis with severe chronic hand involvement.

Note the marked lichenification.

Courtesy, Julie V Schaffer, MD.

Severe atopic dermatitis with facial involvement in an adult.

Atopic dermatitis variants.

A Chronic papular lesions resulting from habitual rubbing and scratching in the setting of longstanding disease. B Prurigo lesions presenting as firm, dome-shaped papules and nodules with central hemorrhagic crust. C Nummular plaques with oozing and crusting on the legs.

A, Courtesy, Thomas Bieber, MD, and Caroline Bussmann, MD; B, C, Courtesy, Antonio Torrelo, MD.

Senile AD (age >60 years) is characterized by marked xerosis. Most of these patients do not have the lichenified flexural lesions typical of AD in children and younger adults.

AD has a profound adverse impact on the quality of life of affected children and adults, with intense pruritus and stigmatization often resulting in sleep disturbances, psychological distress, social isolation, disrupted family dynamics, and impaired functioning at school or work. Children with AD experience greater impairment in their quality of life than those with diabetes mellitus or epilepsy .

Regional Variants of Atopic Dermatitis

Several regional variants of AD can occur in isolation or together with the classic age-related patterns of involvement described above (see Fig. 12.3 ). The face is a frequent location for site-specific manifestations. Eczema of the lips, referred to as cheilitis sicca , is common in AD patients, especially during the winter ( Fig. 12.13A ). It is characterized by dryness (“chapping”) of the vermilion lips, sometimes with peeling and fissuring, and may be associated with angular cheilitis. Patients try to moisten their lips by licking, which in turn may irritate the skin around the mouth, resulting in so-called lip-licker’s eczema. Another common feature of childhood AD is ear eczema , presenting as erythema, scaling, and fissures under the earlobe and in the retroauricular area, sometimes in association with bacterial superinfection. Eyelid eczema can represent the only manifestation of AD, especially in adults. In contrast to eyelid eczema due to other causes, it is characterized by lichenification of the periorbital skin.

Regional variants of atopic dermatitis.

A Atopic cheilitis involving both the vermilion lip and surrounding skin (lip licker’s eczema). B Nipple eczema in an adolescent.

Courtesy, Julie V Schaffer, MD.

“Head and neck dermatitis” represents a variant of AD that typically occurs after puberty and primarily involves the face, scalp, and neck. When older children and teenagers present with this form of AD, it usually persists into adulthood. Malassezia yeasts, which are members of the skin microbiome in the head and neck area, may be an aggravating factor for this presentation , and systemic antifungal treatment with itraconazole or fluconazole may be of benefit.

Eczema variants also occur in acral sites. Juvenile plantar dermatosis presents with “glazed” erythema, scale, and fissuring on the balls of the feet and plantar aspect of the toes in children with AD (see Ch. 13 ). Atopic hand eczema (see Fig. 12.10 ) affects ~60% of adults with AD and may be the only manifestation of the condition. FLG mutations are associated with increased likelihood of hand eczema in children and adults , and frequent exposure to water and other irritants in household or occupational settings represents another risk factor. Atopic hand eczema typically involves the volar wrists and dorsum of the hands. The palms and sides of the fingers may develop the deep-seated vesicles of dyshidrotic eczema (see Ch. 13 ).

The prurigo form of AD favors the extensor aspects of the extremities and is characterized by firm, dome-shaped papules and nodules with central scale-crust, similar to prurigo nodularis lesions in non-atopic patients ( Fig. 12.12B ). Nummular (discoid) lesions also tend to develop on the extremities in children and adults with AD, appearing as coin-shaped eczematous plaques, usually 1 to 3 cm in diameter and often with prominent oozing and crusting ( Fig. 12.12C ). They are similar in appearance to nummular dermatitis occurring outside the setting of atopy (see Ch. 13 ). Frictional lichenoid eruption has a predilection for atopic children and presents as multiple small, flat-topped, pink to skin-colored papules on the elbows and (less often) knees and dorsal hands. Lastly, chronic nipple eczema can develop in children and adults with AD ( Fig. 12.13B ).

Associated Features

Pruritus

Intense pruritus is a hallmark of AD. The itch is often worse in the evening and may be exacerbated by exogenous factors such as sweating or wool clothing. Rubbing and scratching in response to pruritus can initiate flares or exacerbate existing dermatitis, explaining why AD is known as the “itch that rashes”. Excoriations (linear or punctate) are frequently present, providing evidence of scratching ( Fig. 12.14 ; see Figs 12.7–12.9 ). With repeated rubbing and scratching, the skin becomes thickened and leathery with exaggerated skin markings, referred to as lichenification (see Figs 12.9 and 12.10 ).

Associated features of atopic dermatitis.

See Table 12.3 .

Inset of hand: Courtesy, Jean L Bolognia, MD.

Atopic stigmata

Physical findings other than dermatitis that are frequently observed in patients with AD are presented in Table 12.3 and Figs 12.15–12.17 .

Table 12.3

Associated features of atopic dermatitis (“atopic stigmata”).

AD, atopic dermatitis. See Fig. 12.14 .

ASSOCIATED FEATURES OF ATOPIC DERMATITIS (“ATOPIC STIGMATA”)
Xerosis	• Important feature that is present in most patients with AD • Often most prominent on the lower legs; may be generalized • Dry skin with fine scale in areas without clinically apparent inflammation • Typically worse during the winter • Impaired epidermal barrier function from decreased water content in the stratum corneum leads to easier entry of irritants, which can promote pruritus and initiate an inflammatory response
Ichthyosis vulgaris	• Autosomal semidominant disorder with incomplete penetrance caused by mutations in the filaggrin gene ( FLG ; see text and Ch. 57 ) • ~15% of patients with AD have moderate-to-severe ichthyosis vulgaris; conversely, >50% of patients with ichthyosis vulgaris have AD • Excessive fine, whitish to brown scaling that favors the lower legs (especially the shins) and spares the flexures
Keratosis pilaris	• Common condition that affects >40% of patients with AD and ~75% of those with ichthyosis vulgaris • Onset typically in childhood; may improve after puberty (especially facial involvement) • Affects the lateral aspect of the upper arms, thighs, and lateral cheeks (especially in children) > trunk and extensor aspects of the distal extremities • Keratotic follicular papules, often with a rim of erythema (see Fig. 12.16A ) or a background of patchy erythema (especially on the cheeks) • The keratosis pilaris rubra (KPR) variant features numerous tiny, “grain-like” follicular papules superimposed on prominent confluent erythema (see Fig. 12.16B ); often widespread on face & ears > trunk & proximal extremities, and tends to persist after puberty; presence of erythema rather than hyperpigmentation differentiates KPR from erythromelanosis follicularis faciei et colli, and a lack of atrophy in KPR differentiates it from keratosis pilaris atrophicans (see Ch. 38 ) • Keratolytic agents and topical retinoids are sometimes used to decrease the hyperkeratotic component, but the benefit is limited and these agents can be irritating, especially in AD patients; treatment with vascular lasers (e.g. pulsed dye laser) can sometimes improve associated erythema
Palmar and plantar hyperlinearity	• Increased prominence of the palmar and, less often, plantar creases • Associated with ichthyosis vulgaris and FLG mutations
Dennie–Morgan lines	• Symmetric, prominent horizontal fold(s) (single or double) just beneath the margin of the lower lid, originating at or near the inner canthus and extending one-half to two-thirds the width of the lid
Periorbital darkening (“allergic shiners”)	• Skin around the eyes appears gray to violet–brown, while the rest of the facial skin is rather pale • Periorbital edema and lichenification may also be seen
Anterior neck folds	• Horizontal folds across the middle of the anterior neck
Hertoghe sign	• Absence or thinning of the lateral eyebrows
White dermographism	• Stroking the skin leads to a white streak that reflects excessive vasoconstriction • Most apparent on the forehead • Midfacial pallor and a delayed blanch response represent additional manifestations of aberrant vascular reactivity in patients with atopic dermatitis
Follicular prominence	• “Goose bump-like” appearance of the skin, most often on the trunk (see Fig. 12.6 ) • More commonly observed in children with darkly pigmented skin

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