Chapter 14. Atopic Dermatitis (Atopic Eczema)

Atopic dermatitis (AD) is a chronically relapsing skin disease that occurs most commonly during early infancy and childhood. It is frequently associated with abnormalities in skin barrier function, allergen sensitization, and recurrent skin infections. There is no single distinguishing feature of AD or a diagnostic laboratory test. Thus, the diagnosis is based on the constellation of clinical findings listed in Table 14-1.1

Since the 1960s, there has been a more than threefold increase in the prevalence of AD.2 AD is a major public health problem worldwide, with a prevalence in children of 10–20% in the United States, Northern and Western Europe, urban Africa, Japan, Australia, and other industrialized countries.3 The prevalence of AD in adults is approximately 1–3%. Interestingly, the prevalence of AD is much lower in agricultural regions of countries such as China and in Eastern Europe, rural Africa, and Central Asia. However, the most recent data from the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three study confirms that AD is a disease with high prevalence, affecting patients in both developed and developing countries.4 There is also a female preponderance for AD, with an overall female/male ratio of 1.3:1.0.

The basis for this increased prevalence of AD is not well understood. However, wide variations in prevalence have been observed within countries inhabited by similar ethnic groups, suggesting that environmental factors are critical in determining disease expression. Some of the potential risk factors that may be associated with the rise in atopic disease include small family size, increased income and education both in whites and blacks, migration from rural to urban environments, and increased use of antibiotics, that is, the so-called Western lifestyle.5,6 This has resulted in the “hygiene hypothesis” that allergic diseases might be prevented by “infection in early childhood transmitted by unhygienic contact with older siblings.”7 Given the increase in autoimmune diseases such as diabetes, abnormalities in T regulatory cells have also been implicated.

AD is a highly pruritic inflammatory skin disease that results from complex interactions between genetic susceptibility genes resulting in a defective skin barrier, defects in the innate immune system, and heightened immunologic responses to allergens and microbial antigens.8

Decreased Skin Barrier Function

AD is associated with a marked decrease in skin barrier function due to the downregulation of cornified envelope genes (filaggrin and loricrin), reduced ceramide levels, increased levels of endogenous proteolytic enzymes, and enhanced transepidermal water loss.9,10 Addition of soap and detergents to the skin raises its pH, thereby increasing activity of endogenous proteases, leading to further breakdown of epidermal barrier function. The epidermal barrier may also be damaged by exposure to exogenous proteases from house dust mites and Staphylococcus aureus (S. aureus). This is worsened by the lack of certain endogenous protease inhibitors in atopic skin. These epidermal changes likely contribute to increased allergen absorption into the skin and microbial colonization. Because epicutaneous, as compared to systemic or airway, sensitization to allergen results in higher level allergic immune responses, decreased skin barrier function could act as a site for allergen sensitization and predispose such children to the development of food allergy and respiratory allergy.11

Immunopathology of Atopic Dermatitis

Clinically unaffected skin of AD patients manifests mild epidermal hyperplasia and a sparse perivascular T cell infiltrate.12 Acute eczematous skin lesions are characterized by marked intercellular edema (spongiosis) of the epidermis. Dendritic antigen-presenting cells [e.g., Langerhans cells (LCs), macrophages] in lesional and, to a lesser extent, in nonlesional skin of AD exhibit surface-bound immunoglobulin E (IgE) molecules. A sparse epidermal infiltrate consisting primarily of T lymphocytes is also frequently observed.

In the dermis of the acute lesion, there is an influx of T cells with occasional monocyte-macrophages. The lymphocytic infiltrate consists predominantly of activated memory T cells bearing CD3, CD4, and CD45 RO (suggesting previous encounter with antigen). Eosinophils are rarely present in acute AD. Mast cells are found in normal numbers in different stages of degranulation.

Chronic lichenified lesions are characterized by a hyperplastic epidermis with elongation of the rete ridges, prominent hyperkeratosis, and minimal spongiosis. There is an increased number of IgE-bearing LCs in the epidermis, and macrophages dominate the dermal mononuclear cell infiltrate. Mast cells are increased in number but are generally fully granulated. Neutrophils are absent in AD skin lesions even in the setting of increased S. aureus colonization and infection. Increased numbers of eosinophils are observed in chronic AD skin lesions. These eosinophils undergo cytolysis with release of granule protein contents into the upper dermis of lesional skin. Eosinophil-derived extracellular major basic protein can be detected in a fibrillar pattern associated with the distribution of elastic fibers throughout the upper dermis. Eosinophils are thought to contribute to allergic inflammation by the secretion of cytokines and mediators that augment allergic inflammation and induce tissue injury in AD through the production of reactive oxygen intermediates and release of toxic granule proteins.

Cytokines and Chemokines

Atopic skin inflammation is orchestrated by the local expression of proinflammatory cytokines and chemokines.12 Cytokines such as tumor necrosis factor-α (TNF-α) and interleukin 1 (IL-1) from resident cells [keratinocytes, mast cells, dendritic cells (DCs)] bind to receptors on the vascular endothelium, activating cellular signaling pathways, which leads to the induction of vascular endothelial cell adhesion molecules. These events initiate the process of tethering, activation, and adhesion to vascular endothelium followed by extravasation of inflammatory cells into the skin. Once inflammatory cells have infiltrated into the skin, they respond to chemotactic gradients established by chemokines that emanate from sites of injury or infection.

Acute AD is associated with the production of T helper 2 type (Th2) cytokines, notably IL-4 and IL-13,13 which mediate immunoglobulin isotype switching to IgE synthesis and upregulate expression of adhesion molecules on endothelial cells. The important role that Th2 cytokines play in the skin's inflammatory response is supported by the observation that transgenic mice genetically engineered to overexpress IL-4 in their skin develop inflammatory pruritic skin lesions similar to AD, suggesting that local skin expression of Th2 cytokines plays a critical role in AD. There has also been considerable interest in IL-31, which is a novel Th2 cytokine that induces severe pruritus and dermatitis in experimental animals. IL-31 has also been found to be increased in AD skin and serum levels of IL-31 correlate with severity of skin disease.14

In chronic AD, there is an increase in the production of IL-5, which is involved in eosinophil development and survival. Increased production of granulocyte macrophage colony-stimulating factor in AD inhibits apoptosis of monocytes, thereby contributing to the persistence of AD.15 The maintenance of chronic AD also involves production of the Th1-like cytokines IL-12 and IL-18, as well as several remodeling-associated cytokines, including IL-11 and transforming growth factor-1.16

The skin-specific chemokine, cutaneous T cell-attracting chemokine [CTACK; CC chemokine ligand 27 (CCL27)], is highly upregulated in AD and preferentially attracts skin homing cutaneous lymphoid antigen (CLA)+ CC chemokine receptor 10+ (CCR10+) T cells into the skin.17 CCR4 expressed on skin homing CLA+ T cells can also bind to CCL17 on the vascular endothelium of cutaneous venules. Selective recruitment of CCR4-expressing Th2 cells is mediated by macrophage-derived chemokine and thymus and activation-regulated cytokine, both of which are increased in AD. Severity of AD has been linked to the magnitude of thymus and activation-regulated cytokine levels. In addition, chemokines such as fractalkine, interferon (IFN)-γ-inducible protein 10, and monokine induced by IFN-γ are strongly upregulated in keratinocytes and result in Th1-cell migration toward epidermis, particularly in chronic AD. Increased expression of the CC chemokines, macrophage chemoattractant protein-4, eotaxin, and RANTES (regulated on activation, normal T cell expressed and secreted) contribute to infiltration of macrophages, eosinophils, and T cells into both acute and chronic AD skin lesions.

Key Cell Types in Atopic Dermatitis Skin

Antigen-Presenting Cells

DCs play an important role in detecting environmental allergens or pathogens via pattern recognition receptors such as toll-like receptors (TLR). AD skin contains two types of high-affinity, IgE receptor-bearing (FcϵR) myeloid DCs: (1) LCs and (2) inflammatory dendritic epidermal cells (IDECs). IgE-bearing LCs appear to play an important role in cutaneous allergen presentation to IL-4-producing Th2 cells.18 In this regard, IgE-bearing LCs from AD skin lesions, but not LCs that lack surface IgE, are capable of presenting allergens to T cells. These results suggest that cell-bound IgE on LCs facilitates capture and internalization of allergens into LCs before their processing and antigen presentation to T cells. IgE-bearing LCs that have captured allergen likely activate memory Th2 cells in atopic skin, but they may also migrate to the lymph nodes to stimulate naïve T cells there to further expand the pool of systemic Th2 cells. Stimulation of FcϵRI on the surface of LCs by allergens induces the release of chemotactic signals and recruitment of precursor cells of IDECs and T cells in vitro. Stimulation of FcϵRI on IDECs leads to the release of proinflammatory signals, which contribute to amplification of the allergic immune response.

In contrast to other inflammatory skin diseases, such as allergic contact dermatitis or psoriasis vulgaris, very low numbers of plasmacytoid DCs (pDCs), which play an important role in host defense against viral infections, can be detected within the AD skin lesion.19 pDCs in the peripheral blood of patients with AD have been shown to bear the trimeric variant of FcϵRI on their cell surface, which is occupied by IgE molecules. The modified immune function of pDCs of patients with AD after FcϵRI-mediated allergen stimulation might contribute to a local deficiency of type I IFNs, thereby contributing to increased susceptibility of AD patients toward viral skin infections such as eczema herpeticum.20

T Cells

Skin homing memory T cells play an important role in the pathogenesis of AD, particularly during the acute phase of illness. This concept is supported by the observation that primary T-cell immunodeficiency disorders are frequently associated with eczematous skin lesions that clear after successful bone marrow transplantation.21 Furthermore, in animal models of AD, the eczematous rash does not occur in the absence of T cells. In addition, treatment with topical calcineurin inhibitors (TCIs), which target activated T cells, significantly reduces the clinical skin rash of AD.22

Several studies have demonstrated the presence of Th2-like T cells in acute AD that produce cytokines that enhance allergic skin inflammation. During the chronic phase of AD, there is a switch to Th1-like cells that primarily produce IFN-γ. These Th1-like cells induce the activation and apoptosis of keratinocytes.23 Recently, T regulatory (Treg) cells have been described as a further subtype of T cells that have immunosuppressive function and cytokine profiles distinct from both Th1 and Th2 cells.24 Treg cells are able to inhibit the development of both Th1 and Th2 responses. Mutations in a nuclear factor expressed in Treg cells, FoxP3, result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome characterized by elevated serum IgE, food allergy, and dermatitis that may be eczematous or psoriasiform. A deficiency of resident Treg cells has also been reported in AD skin.25 Interestingly, staphylococcal superantigens subvert Treg cell function and may thereby augment skin inflammation.26

There has also been considerable interest in the role of Th17 cells in the immunopathogenesis of AD.27 These cells produce inflammatory cytokines such as IL-17 and are thought to play a role in host defense by inducing keratinocytes to produce antimicrobial peptides as well as promote neutrophil chemotaxis. Th17 cells are increased in the skin lesions of autoimmune diseases, such as psoriasis, where they may promote inflammatory responses, including neutrophil infiltration but also reduce skin infection.28 Compared to psoriasis, AD skin lesions have significantly fewer T cells expressing IL-17, but increased numbers of IL-4+ cells.29 Furthermore, it has been found that the Th2 cytokines, IL-4 and IL-13, inhibit IL-17 induced generation of antimicrobial peptides.30 Interestingly, an independent increase of IL-22 expressing cells, originally thought to be produced by Th17 cells, can be found in AD skin and it has been suggested that these may contribute to epidermal hyperplasia.31

Keratinocytes

Keratinocytes play a critical role in the augmentation of atopic skin inflammation. AD keratinocytes secrete a unique profile of chemokines and cytokines after exposure to proinflammatory cytokines. This includes high levels of RANTES after stimulation with TNF-α and IFN-γ.32 They are also an important source of thymic stromal lymphopoietin (TSLP), which activates DCs to prime naïve T cells to produce IL-4 and IL-13 (i.e., promotes Th2 cell differentiation).33 The importance of TSLP in AD pathogenesis is supported by the observation that mice genetically manipulated to overexpress TSLP in the skin develop AD-like skin inflammation. Skin-derived TSLP is also thought to trigger the development of asthma.34,35

Keratinocytes are critical to the skin's innate immune responses, expressing Toll-like receptors, producing proinflammatory cytokines and antimicrobial peptides (such as human β defensins and cathelicidins) in response to tissue injury or invading microbes.36 Several studies have now demonstrated that AD keratinocytes produce reduced amounts of antimicrobial peptides and this may predispose such individuals to skin colonization and infection with S. aureus, viruses, and fungi. However, this defect appears to be acquired as the result of Th2-cytokine (IL-4, IL-10, and IL-13) mediated inhibition of TNF-α and IFN-γ-induced antimicrobial peptide generation.

Genetics

AD is a complex disease that is familially transmitted with a strong maternal influence.37 Genome-wide linkage studies of families with AD have implicated chromosomal regions that overlap with other inflammatory skin diseases such as psoriasis. Together with candidate gene studies, these have provided interesting insights into the pathogenesis of AD. Although many genes are likely to be involved in the development of AD, there has been particular interest in the potential role of skin barrier/epidermal differentiation genes and immune response/host defense genes.

Loss-of-function mutations in FLG, which encodes the epidermal barrier protein, filaggrin, have been demonstrated to be a major predisposing factor for AD,38 as well as ichthyosis vulgaris, a common keratinizing disorder associated with AD (Figs. 14-1 and 14-2). Patients with filaggrin null mutations often have early onset, severe eczema, high level allergen sensitization, and develop asthma later in childhood. Of note, the filaggrin gene is found on chromosome 1q21 that contains genes (including loricrin and S100 calcium-binding proteins) in the epidermal differentiation complex, known to be expressed during terminal differentiation of the epidermis. DNA microarray analyses have demonstrated upregulation of S100 calcium-binding proteins and downregulation of loricrin and filaggrin in AD. Candidate gene approaches have also implicated variants in the SPINK5 gene, which is expressed in the uppermost epidermis where its product, LEKT1, inhibits two serine proteases involved in desquamation and inflammation (stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme). Stratum corneum tryptic enzyme and stratum corneum tryptic enzyme expression is increased in AD, suggesting that an imbalance of protease versus protease inhibitor activity may contribute to atopic skin inflammation.9

These observations establish a key role for impaired skin barrier function in the pathogenesis of AD, as impaired skin barrier formation allows increased transepidermal water loss and, importantly, increased entry of allergens, antigens, and chemicals from the environment resulting in skin inflammatory responses. It is important to note that these filaggrin mutations, and likely other mutations affecting the skin barrier, can occur in clinically normal individuals, and in patients with ichthyosis vulgaris without clinical evidence of skin inflammation. The majority of patients with AD outgrow their inflammatory skin disease by adolescence. Thus, AD is a complex trait that involves interactions between multiple gene products requiring environmental factors and the immune response to result in the final clinical phenotype. Chromosome 5q31-33 contains a clustered family of functionally related cytokine genes—IL-3, IL-4, IL-5, IL-13, and granulocyte macrophage colony-stimulating factor—which are expressed by Th2 cells. A case control comparison has suggested a genotypic association between the T allele of the 590C/T polymorphism of the IL-4 gene promoter region with AD. Because the T allele is associated with increased IL-4 gene promoter activity when compared to the C allele, this suggests that genetic differences in transcriptional activity of the IL-4 gene influence AD predisposition. In addition, an association of AD with a gain-of-function mutation in the α subunit of the IL-4 receptor has been reported, providing further support of the concept that IL-4 gene expression plays a role in AD. Functional mutations in the promoter region of the CC chemokines, RANTES, and eotaxin, as well as variants in IL-13, the α subunit of the high affinity cell surface receptor for IgE (FcϵR1) found on basophils and mast cells suggest an overlapping of genetic basis with other atopic diseases.

Recent studies demonstrating a significant association between TSLP gene polymorphisms and AD provide further support for the importance of Th2 polarization in this disease.37 The involvement of T cell γ interferon and IL-18 genes support the role of CD4+ T cells and dysregulation of Th1 genes in the pathophysiology of AD. As well, reports of AD association with polymorphisms of the NOD1 gene, which encodes cytosolic pathogen recognition receptor and toll-like receptors, suggest an important role for host defense genes in the pathogenesis of AD. The reader is referred to Chapter 10 and reference 35 for a detailed discussion of the genetics of AD.

Basis of Pruritus in Atopic Dermatitis

Pruritus is a prominent feature of AD, manifested as cutaneous hyperreactivity and scratching following exposure to allergens, changes in humidity, excessive sweating, and low concentrations of irritants. Control of pruritus is important because mechanical injury from scratching can induce proinflammatory cytokine and chemokine release, leading to a vicious scratch–itch cycle perpetuating the AD skin rash. The mechanisms of pruritus in AD are poorly understood. Allergen-induced release of histamine from skin mast cells is not an exclusive cause of pruritus in AD, because H1 antihistamines are not effective in controlling the itch of AD.39 However, recent studies demonstrating a potential role for H4 receptors in skin pathobiology suggests that histamine may play a contributory role.40 However, the observation that treatment with topical corticosteroids and calcineurin inhibitors is effective at reducing pruritus suggests that the inflammatory cells play an important role in pruritus.41,42 Molecules that have been implicated in pruritus include T-cell-derived cytokines such as IL-31, stress-induced neuropeptides, and proteases which can act on protease-activated receptors, eicosanoids, and eosinophil-derived proteins.43,44 The reader is referred to Chapter 103 for a detailed discussion of the pathophysiology of pruritus.

The diagnosis of AD is based on the constellation of clinical features summarized in Table 14-1. AD typically begins during infancy. Approximately 50% of patients develop this illness by the first year of life and an additional 30% between the ages of 1–5 years. Between 50–80% of patients with AD develop allergic rhinitis or asthma later in childhood. Many of these patients outgrow their AD as they are developing respiratory allergy.

Cutaneous Lesions

Intense pruritus and cutaneous reactivity are cardinal features of AD. Pruritus may be intermittent throughout the day but is usually worse in the early evening and night. Its consequences are scratching, prurigo papules (Fig. 14-3), lichenification (Fig. 14-4), and eczematous skin lesions. Acute skin lesions are characterized by intensely pruritic, erythematous papules associated with excoriation, vesicles over erythematous skin, and serous exudate (Fig. 14-5). Subacute dermatitis is characterized by erythematous, excoriated, scaling papules (Fig. 14-6). Chronic AD is characterized by (1) thickened plaques of skin, (2) accentuated skin markings (lichenification), and (3) fibrotic papules (prurigo nodularis; Fig. 14-7). In chronic AD, all three stages of skin reactions frequently coexist in the same individual. At all stages of AD, patients usually have dry, lackluster skin.

The distribution and skin reaction pattern vary according to the patient's age and disease activity. During infancy, the AD is generally more acute and primarily involves the face (Fig. 14-8), scalp, and the extensor surfaces of the extremities (Fig. 14-9). The diaper area is usually spared. In older children, and in those who have long-standing skin disease, the patient develops the chronic form of AD with lichenification and localization of the rash to the flexural folds of the extremities (Fig. 14-10). AD often subsides as the patient grows older, leaving an adult with skin that is prone to itching and inflammation when exposed to exogenous irritants. Chronic hand eczema may be the primary manifestation of many adults with AD (Fig. 14-11). Other associated features of AD are listed in Table 14-1.

Laboratory Tests

Laboratory testing is not needed in the routine evaluation and treatment of uncomplicated AD. Serum IgE levels are elevated in approximately 70–80% of AD patients. This is associated with sensitization against inhalant and food allergens and/or concomitant allergic rhinitis and asthma.8 In contrast, 20–30% of AD patients have normal serum IgE levels. This subtype of AD has a lack of IgE sensitization against inhalant or food allergens. However, some of these patients may possess IgE sensitization against microbial antigens such as S. aureus toxins, and Candida albicans or Malassezia sympodialis can be detected. As well, some of these patients show positive reactions using the atopy patch test despite negative immediate skin tests.

The majority of patients with AD also have peripheral blood eosinophilia. Patients with AD have increased spontaneous histamine release from basophils. These findings likely reflect a systemic Th2 immune response in AD especially those patients who have elevated serum IgE levels. Importantly, the peripheral blood skin homing CLA+ T cells in AD expressing either CD4 or CD8 spontaneously secrete IL-5 and IL-13, which functionally prolong eosinophil survival and induce IgE synthesis.

Table 14-1 lists the clinical features of AD. Of the major features, pruritus and chronic or remitting eczematous dermatitis with typical morphology and distribution are essential for diagnosis. Other features, including allergy or elevated IgE, are variable, and some of the “associated features” in the table may not be useful discriminators of individuals with AD from the unaffected general population. Various diagnostic criteria have been proposed to assist with clinical diagnosis, definition of patients for clinical studies, and epidemiologic population studies.45 A refined list of diagnostic criteria suitable for epidemiologic studies has been derived and validated by workers in the United Kingdom.46

Box 14-1 lists a number of inflammatory skin diseases, immunodeficiencies, skin malignancies, genetic disorders, infectious diseases, and infestations that share symptoms and signs with AD. These should be considered and ruled out before a diagnosis of AD is made. Infants presenting in the first year of life with failure to thrive, diarrhea, a generalized scaling erythematous rash, and recurrent cutaneous and/or systemic infections should be evaluated for severe combined immunodeficiency syndrome. Wiskott–Aldrich syndrome is an X-linked recessive disorder characterized by cutaneous findings almost indistinguishable from AD (see Chapter 143). It is associated with thrombocytopenia, variable abnormalities in humoral and cellular immunity, and recurrent severe bacterial infections. The hyper-IgE syndrome is characterized by elevated serum IgE levels, defective T-cell function, recurrent deep-seated bacterial infections, including cutaneous abscesses due to S. aureus and/or pruritic skin disease due to S. aureus pustulosis, or by recalcitrant dermatophytosis. A papulopustular eruption of the face and scalp may be seen in early life. Although S. aureus is an important pathogen in this disorder, infection with other bacteria, viruses, and fungi may occur, particularly when patients are on chronic antistaphylococcal antibiotic prophylaxis. Hyper-IgE is most commonly an autosomal dominant disorder due to mutations in STAT3, which also features pneumonia with pneumatocele formation, dental anomalies with retained primary teeth, bone fractures, and osteopenia. Autosomal recessive forms of hyper-IgE syndrome show severe eosinophilia, recurrent viral and bacterial infections, an increased risk of autoimmune disease, and serious neurologic manifestations, but not the pneumatoceles and dental or skeletal defects. To date, deficiencies of Tyk2 and dedicator of cytokinesis 8 protein (DOCK8) deficiency have been found, leading to a global defect in T-cell activation.47

It is important to recognize that an adult who presents with an eczematous dermatitis with no history of childhood eczema, respiratory allergy, or atopic family history may have allergic contact dermatitis. A contact allergen should be considered in any patient whose AD does not respond to appropriate therapy. Of note, contact allergy to topical glucocorticoids and TCIs has been reported in patients with chronic dermatitis. In addition, cutaneous T-cell lymphoma must be ruled out in any adult presenting with chronic dermatitis poorly responsive to topical glucocorticoid therapy. Ideally, biopsies should be obtained from three separate sites, because the histology may show spongiosis and cellular infiltrate similar to AD. Eczematous dermatitis has been also reported with human immunodeficiency virus as well as with a variety of infestations such as scabies. Other conditions that can be confused with AD include psoriasis, ichthyoses, and seborrheic dermatitis.

Ocular Problems

Eye complications associated with severe AD can lead to significant morbidity. Eyelid dermatitis and chronic blepharitis are commonly associated with AD and may result in visual impairment from corneal scarring. Atopic keratoconjunctivitis is usually bilateral and can have disabling symptoms that include itching, burning, tearing, and copious mucoid discharge. Vernal conjunctivitis is a severe bilateral recurrent chronic inflammatory process associated with papillary hypertrophy, or cobblestoning of the upper eyelid conjunctiva. It usually occurs in younger patients and has a marked seasonal incidence, often in the spring. The associated intense pruritus is exacerbated by exposure to irritants, light, or sweating. Keratoconus is a conical deformity of the cornea believed to result from chronic rubbing of the eyes in patients with AD and allergic rhinoconjunctivitis. Cataracts were reported in the early literature to occur in up to 21% of patients with severe AD. However, it is unclear whether this was a primary manifestation of AD or the result of the extensive use of systemic and topical glucocorticoids, particularly around the eyes. Indeed, more recent studies suggest that routine screening for cataracts in patients with AD may not be productive unless there is concern about potential side effects from steroid therapy.

Infections

AD can be complicated by recurrent viral skin infections that may reflect local defects in T-cell function.48 The most serious viral infection is herpes simplex (see Chapter 193), which can affect patients of all ages, resulting in Kaposi varicelliform eruption or eczema herpeticum. After an incubation period of 5–12 days, multiple, itchy, vesiculopustular lesions erupt in a disseminated pattern; vesicular lesions are umbilicated, tend to crop, and often become hemorrhagic and crusted (Fig. 14-12). Punched out and extremely painful erosions result. These lesions may coalesce to large, denuded, and bleeding areas that can extend over the entire body.

Although smallpox infections have been eradicated worldwide since the late 1970s, threats of bioterrorism (with smallpox and other infectious agents) have made nations reconsider their policies toward initiating vaccination programs. In AD patients, smallpox vaccination (or even exposure to vaccinated individuals) (see Chapter 195) may cause a severe widespread eruption (called eczema vaccinatum) that appears very similar to eczema herpeticum. Thus, in patients with AD, vaccination is contraindicated unless there is a clear risk of smallpox. In addition, decisions regarding vaccination of family members should take into consideration the potential of eczema vaccinatum in household contacts.

Superficial fungal infections are also more common in atopic individuals and may contribute to the exacerbation of AD. Patients with AD have an increased prevalence of Trichophyton rubrum infections compared to nonatopic controls. There has been particular interest in the role of M. sympodialis (Pityrosporum ovale or P. orbiculare) in AD. M. sympodialis is a lipophilic yeast (see Chapters 188 and 189) commonly present in the seborrheic areas of the skin. IgE antibodies against M. furfur are commonly found in AD patients and most frequently in patients with head and neck dermatitis. In contrast, IgE sensitization to M. sympodialis is rarely observed in normal controls or asthmatics. Positive allergen patch-test reactions to this yeast have also been demonstrated. The potential importance of M. sympodialis as well as other dermatophyte infections is further supported by the reduction of AD skin severity in such patients after treatment with antifungal agents.

S. aureus is found in more than 90% of AD skin lesions. Honey-colored crusting, folliculitis, and pyoderma are indicators of secondary bacterial skin infection, usually due to S. aureus, that requires antibiotic therapy. Regional lymphadenopathy is common in such patients. The importance of S. aureus in AD is supported by the observation that patients with severe AD, even those without overt infection, can show clinical response to combined treatment with antistaphylococcal antibiotics and topical glucocorticoids. Although recurrent staphylococcal pustulosis can be a significant problem in AD, deep-seated S. aureus infections occur rarely and should raise the possibility of an immunodeficiency syndrome such as hyper-IgE syndrome. Methicillin-resistant S. aureus has become an increasingly important pathogen in patients with AD.49

Hand Dermatitis

Patients with AD often develop nonspecific, irritant hand dermatitis. It is frequently aggravated by repeated wetting and by washing of the hands with harsh soaps, detergents, and disinfectants. Atopic individuals with occupations involving wet work are prone to develop an intractable hand dermatitis in the occupational setting. This is a common cause of occupational disability.

Exfoliative Dermatitis

Patients with extensive skin involvement may develop exfoliative dermatitis (see Chapter 23). This is associated with generalized redness, scaling, weeping, crusting, systemic toxicity, lymphadenopathy, and fever. Although this complication is rare, it is potentially life threatening. It is usually due to superinfection, for example, with toxin-producing S. aureus or herpes simplex infection, continued irritation of the skin, or inappropriate therapy. In some cases, the withdrawal of systemic glucocorticoids used to control severe AD may be a precipitating factor for exfoliative erythroderma.

The natural history of AD is not completely known because studies have been flawed in terms of inadequate sample size, an unclear definition of remission, inadequate length of follow-up, selection bias in the initial cohort, and excessive loss of patients to follow-up. Nevertheless, although the outcome of AD may be difficult to predict in any given individual, the disease generally tends to be more severe and persistent in young children. Periods of remission appear more frequently as the patient grows older. Spontaneous resolution of AD has been reported to occur after age 5 years in 40–60% of patients affected during infancy, particularly if their disease is mild. Although earlier studies suggested that approximately 84% of children outgrow their AD by adolescence, more recent studies have reported that AD disappears in approximately 20% of children followed from infancy until adolescence, but becomes less severe in 65%. In addition, more than one-half of adolescents treated for mild dermatitis may experience a relapse of disease as adults. Filaggrin mutations have been associated with higher rates of persistent atopic dermatitis into later childhood and adulthood.50 Importantly, for occupational counseling, adults whose childhood AD has been in remission for a number of years may present with hand dermatitis, especially if daily activities require repeated hand wetting. The following predictive factors correlate with a poor prognosis for AD: widespread AD in childhood, associated allergic rhinitis and asthma, family history of AD in parents or siblings, early age at onset of AD, being an only child, and very high serum IgE levels.

Successful treatment of AD requires a systematic, multipronged approach that incorporates education about the disease state, skin hydration, pharmacologic therapy, and the identification and elimination of flare factors such as irritants, allergens, infectious agents, and emotional stressors (Fig. 14-13).51,52 Many factors lead to the symptom complex characterizing AD. Thus, treatment plans should be individualized to address each patient's skin disease reaction pattern, including the acuity of the rash, and the trigger factors that are unique to the particular patient. In patients refractory to conventional forms of therapy, alternative anti-inflammatory and immunomodulatory agents may be necessary.53

Topical Therapy

Cutaneous Hydration

Patients with AD have abnormal skin barrier function with increased transepidermal water loss and decreased water content and dry skin (xerosis) contributing to disease morbidity by the development of microfissures and cracks in the skin, which serve as portals of entry for skin pathogens, irritants, and allergens. FLG gene mutations have also been shown to result in decreased epidermal levels of natural moisturizing factor.54 This problem can become aggravated during the dry winter months and in certain work environments. Warm soaking baths for approximately 10 minutes followed by the application of an occlusive emollient or topical medication to retain moisture can give such patients excellent symptomatic relief. Bathing without emollient use may result in drier skin.55 Use of an effective emollient combined with hydration therapy helps to restore and preserve the stratum corneum barrier, and may decrease the need for topical glucocorticoids. Moisturizers are available in the form of lotions, creams, or ointments. Some lotions and creams may be irritating due to added preservatives, solubilizers, and fragrances. Lotions containing water may be drying due to an evaporative effect.

Hydrophilic ointments can be obtained in varying degrees of viscosity according to the patient's preference. Occlusive ointments are sometimes not well tolerated because of interference with the function of the eccrine sweat ducts and the induction of folliculitis. In these patients, less occlusive agents should be used.

Topical therapy to replace abnormal epidermal lipids, improve skin hydration, and decrease skin barrier dysfunction may be useful therapeutically. Studies have shown benefits of topical preparations with distinct compositions of lipids and ceramides, as well as a nonsteroidal cream containing palmitamide MEA, an essential fatty acid, and a hydrolipidic cream with glycyrrhetinic acid (MAS063ADP).56,57 Further clinical studies to define the benefits relative to traditional moisturizers and topical anti-inflammatory agents will be helpful.

Hydration, by baths or wet dressings, promotes transepidermal penetration of topical glucocorticoids. Dressings may also serve as an effective barrier against persistent scratching, allowing more rapid healing of excoriated lesions.58 Wet dressings, or “wet wraps” are recommended for use on severely affected or chronically involved areas of dermatitis refractory to therapy.59 However, overuse of wet dressings may result in maceration of the skin complicated by secondary infection. Wet dressings or baths also have the potential to promote drying and fissuring of the skin if not followed by topical emollient use. Thus, wet dressing therapy is reserved for poorly controlled AD and should be closely monitored by a physician.

Topical Anti-Inflammatory Therapy

A recent study looked at TEWL, as well as several other parameters of epidermal barrier including stratum corneum hydration and dye penetration.60 The authors found improvement in all parameters when AD patients were treated with both a topical steroid (betamethasone valerate 0.1% cream) and a topical calcineurin inhibitor (pimecrolimus 1% cream) applied to paired lesions of the upper extremities. Electron microscopic evaluation of barrier structure showed prevalently ordered stratum corneum lipid layers and regular lamellar body extrusion in the calcineurin inhibitor-treated skin but inconsistent extracellular lipid bilayers and only partially filled lamellar bodies in the steroid-treated skin. Both treatments normalized epidermal differentiation and reduced epidermal hyperproliferation. Both anti-inflammatory therapies increased expression of filaggrin and involucrin in the skin. Betamethasone valerate was superior in reducing clinical symptoms and epidermal proliferation, but twice daily use over the 3-week period of the study led to epidermal thinning. The authors concluded that since pimecrolimus improved the epidermal barrier and did not cause cutaneous atrophy, it might be more suitable for long-term treatment of AD. However, the finding that the topical steroid was more effective in reducing clinical symptoms and inflammation supports the use of topical steroids for acute intervention of AD flares.

Topical Glucocorticoid Therapy

Topical glucocorticoids are the cornerstone of treatment for anti-inflammatory eczematous skin lesions. Because of potential side effects, most physicians use topical glucocorticoids only to control acute exacerbations of AD. However, recent studies suggest that once control of AD is achieved with a daily regimen of topical glucocorticoid, long-term control can be maintained in a subset of patients with twice weekly applications of topical fluticasone to areas that have healed but are prone to developing eczema.61

Patients should be carefully instructed in the use of topical glucocorticoids to avoid potential side effects. The potent fluorinated glucocorticoids should be avoided on the face, the genitalia, and the intertriginous areas. A low-potency glucocorticoid preparation is generally recommended for these areas. Patients should be instructed to apply topical glucocorticoids to their skin lesions and to use emollients over uninvolved skin. Failure of a patient to respond to topical glucocorticoids is sometimes due in part to an inadequate supply. It is important to remember that it takes approximately 30 g of cream or ointment to cover the entire skin surface of an adult once. To treat the entire body twice daily for 2 weeks requires approximately 840 g (2 lb) of topical glucocorticoids.

There are seven classes of topical glucocorticoids, ranked according to their potency based on vasoconstrictor assays. Because of their potential side effects, the ultrahigh-potency glucocorticoids should be used only for very short periods of time and in areas that are lichenified but not on the face or intertriginous areas. The goal is to use emollients to enhance skin hydration and low-potency glucocorticoids for maintenance therapy. Midpotency glucocorticoids can be used for longer periods of time to treat chronic AD involving the trunk and extremities. Newer formulations of topical steroids include gel formulations without alcohol bases that moisturize skin, and solutions, oils, foams, and shampoos that may be useful on hair-bearing surfaces.

Factors which influence topical glucocorticoid potency and side effects include the molecular structure of the compound, the vehicle, the amount of medication applied, the duration of application, occlusion, as well as host factors, including age, body surface area and weight, skin inflammation, anatomic location of treated skin, and individual differences in cutaneous or systemic metabolism. Side effects from topical glucocorticoids are directly related to the potency ranking of the compound and the length of use, so it is incumbent on the clinician to balance the need for a more potent steroid with the potential for side effects. In addition, ointments have a greater potential to occlude the epidermis, resulting in enhanced systemic absorption when compared to creams. Side effects from topical glucocorticoids can be divided into local side effects and systemic side effects resulting from suppression of the hypothalamic–pituitary–adrenal axis. Local side effects include the development of striae, skin atrophy, perioral dermatitis, and acne rosacea. The potential for potent topical glucocorticoid to cause adrenal suppression is greatest in infants and young children. Several topical steroid formulations have been specifically tested for safety and received specific US Federal Drug Administration (FDA) approval for use in younger children such as desonide hydrogel and nonethanolic foam, fluocinolone acetonide oil, and fluticasone 0.05% cream.62–65 Mometasone cream and ointment are approved for children aged 2 years and older.

Because normal-appearing skin in AD shows evidence of immunologic dysregulation, the use of topical corticosteroids as maintenance therapy has been reported in several controlled studies.66 Once control of AD with a once daily regimen was achieved, long-term control could be maintained with twice weekly application of fluticasone to previously involved areas. Given recent insights into skin barrier and immunologic abnormalities and colonization of normal-appearing skin in AD by S. aureus, it is important to appreciate that proactive therapy is an attempt to control residual disease, not just application of an active drug to nonaffected skin.67

Topical Calcineurin Inhibitors

Topical tacrolimus and pimecrolimus have been developed as nonsteroidal immunomodulators.68 Tacrolimus ointment 0.03% has been approved for intermittent treatment of moderate to severe AD in children aged 2 years and older, with tacrolimus ointment 0.1% approved for use in adults; pimecrolimus cream 1% is approved for treatment of patients aged 2 years and older with mild–moderate AD. Both drugs have proven to be effective with a good safety profile for treatment up to 4 years with tacrolimus ointment69 and up to 2 years with pimecrolimus cream.70 A frequently observed side effect with TCIs is a transient burning sensation of the skin. Importantly, treatment with TCIs is not associated with skin atrophy,71 thus they are particularly useful for the treatment of areas such as the face and intertriginous regions. Ongoing surveillance and recent reports have not shown a trend for increased frequency of viral superinfections, especially eczema herpeticum.72 The long-term safety of TCIs has not been established. Rare cases of skin malignancy and lymphoma have been reported with topical tacrolimus, though the level of data quality and applicability of these reports was judged low in the report of a scientific consensus conference.73 Importantly, a case-control study of a large database that identified a cohort of 293,253 patients with AD found no increased risk of lymphoma with the use of TCIs.74 Twice to three times weekly maintenance therapy using tacrolimus ointment has also been reported in both adults and children with AD.75,76

Identification and Elimination of Triggering Factors

General Considerations

Patients with AD are more susceptible to irritants than are unaffected individuals. Thus, it is important to identify and eliminate aggravating factors that trigger the itch–scratch cycle. These include soaps or detergents, contact with chemicals, smoke, abrasive clothing, and exposure to extremes of temperature and humidity. Alcohol and astringents found in toiletries are drying. When soaps are used, they should have minimal defatting activity and a neutral pH. New clothing may be laundered before wearing to decrease levels of formaldehyde and other added chemicals. Residual laundry detergent in clothing may be irritating. Using a liquid rather than powder detergent and adding a second rinse cycle facilitates removal of the detergent.

Recommendations regarding environmental living conditions should include temperature and humidity control to avoid problems related to heat, humidity, and perspiration. Every attempt should be made to allow children to be as normally active as possible. Certain sports, such as swimming, may be better tolerated than other sports involving intense perspiration, physical contact, or heavy clothing and equipment, but chlorine should be rinsed off immediately after swimming and the skin lubricated. Although ultraviolet (UV) light may be beneficial to some patients with AD, sunscreens should be used to avoid sunburn. However, because sunscreens can be irritants, care should be used to identify a nonirritating product.

Specific Allergens

Foods and aeroallergens such as dust mites, animal danders, molds, and pollens have been demonstrated to exacerbate AD. Potential allergens can be identified by taking a careful history and carrying out selective skin-prick tests or specific serum IgE levels. Negative skin tests or serum tests for allergen-specific IgE have a high predictive value for ruling out suspected allergens. However, a normal total serum IgE level does not rule out the possibility of allergen-specific IgE being present. Positive skin or in vitro tests, particularly to foods, often do not correlate with clinical symptoms and should be confirmed with controlled food challenges and elimination diets. Avoidance of foods implicated in controlled challenges results in clinical improvement. Extensive elimination diets, which in some cases can be nutritionally deficient, are rarely, if ever, required, because even with multiple positive skin tests, the majority of patients react to three or fewer foods on controlled challenge. In dust mite-allergic patients with AD, prolonged avoidance of dust mites has been found to result in improvement of their skin disease. Avoidance measures include use of dust mite-proof encasings on pillows, mattresses, and box springs; washing bedding in hot water weekly; removal of bedroom carpeting; and decreasing indoor humidity levels with air conditioning. Because there are many triggers contributing to the flares of AD, attention should be focused on identifying and controlling the flare factors that are important to the individual patient. Infants and young children are more likely to have food allergies, whereas older children and adults are more likely to be sensitive to environmental aeroallergens. Contact allergens have been increasingly recognized in AD. A recent study found that of children with relevant positive reactions, 34% had a diagnosis of AD.77

Emotional Stressors

Although emotional stress does not cause AD, it often exacerbates the illness. AD patients often respond to frustration, embarrassment, or other stressful events with increased pruritus and scratching. In some instances, scratching is simply habitual and less commonly associated with significant secondary gain. Psychological evaluation or counseling should be considered in patients who have difficulty with emotional triggers or psychological problems, contributing to difficulty in managing their disease. It may be especially useful in adolescents and young adults who consider their skin disease disfiguring. Relaxation, behavioral modification, or biofeedback may be helpful in patients with habitual scratching.58

Infectious Agents

Antistaphylococcal antibiotics are very helpful in the treatment of patients who are heavily colonized or infected with S. aureus.78 Cephalosporins or penicillinase-resistant penicillins (dicloxacillin, oxacillin, or cloxacillin) are usually beneficial for patients who are not colonized with resistant S. aureus strains. Because erythromycin-resistant Staphylococci are common, erythromycin and newer macrolide antibiotics are usually of limited utility. Topical antimicrobials such as mupirocin, fusidic acid, or more recently retapamulin offers some utility in the treatment of impetiginized lesions. A Cochrane Database analysis of interventions for impetigo found that topical mupirocin and topical fusidic acid are equal to or more effective than oral treatment for patients with limited disease and that fusidic acid and mupirocin are of similar efficacy.79 Patients should be cautioned against using topical antibiotics in an “as-needed” manner that can lead to resistant organisms.80

Use of neomycin topically can result in development of allergic contact dermatitis as neomycin is among the more common allergens causing contact dermatitis. However, in patients with extensive superinfection, a course of systemic antibiotics is most practical. Methicillin-resistant Staphylococci may require culture and sensitivity testing to assist in appropriate antibiotic selection. Baths with dilute sodium hypochlorite (bleach) may also benefit AD patients with superinfected eczema, especially those with recurrent MRSA, although they can occasionally be irritating. Of note, a controlled study of twice weekly bleach baths for 3 months showed clinical benefit, although skin colonization by S. aureus did not disappear, even when combined with intranasal mupirocin 5 days each month.81

Herpes simplex can provoke recurrent dermatitis and may be misdiagnosed as S. aureus infection. The presence of punched-out erosions, vesicles, and/or infected skin lesions that do not respond to oral antibiotics should initiate a search for herpes simplex. This can be diagnosed by a Giemsa-stained Tzanck smear of cells scraped from the vesicle base, direct immunofluorescence assay, polymerase chain reaction identification of herpes genetic material, or by viral culture. For infection suspected to be caused by herpes simplex, topical anti-inflammatory agents might be discontinued, at least temporarily. Antiviral treatment for cutaneous herpes simplex infections is of critical importance in the patient with widespread AD because life-threatening dissemination has been reported. Acyclovir, 400 mg three times daily for 10 days or 200 mg four times daily for 10 days by oral administration (or an equivalent dosage of one of the newer antiherpetic medications), is useful in adults with herpes simplex confined to the skin. Intravenous treatment may be necessary for severe disseminated eczema herpeticum. The dosage should be adjusted according to weight in children.

Dermatophyte infections can complicate AD and may contribute to exacerbation of disease activity. Patients with dermatophyte infection or IgE antibodies to Malassezia may benefit from a trial of topical or systemic antifungal therapy.

Pruritus

The treatment of pruritus in AD should be directed primarily at the underlying causes. Reduction of skin inflammation and dryness with topical glucocorticoids and skin hydration, respectively, often symptomatically reduce pruritus. Inhaled and ingested allergens should be eliminated if documented to cause skin rash in controlled challenges. Systemic antihistamines act primarily by blocking the H1 receptors in the dermis, thereby ameliorating histamine-induced pruritus. However, histamine is only one of many mediators that can induce pruritus of the skin. Therefore, certain patients may derive minimal benefit from antihistaminic therapy. Some antihistamines are also mild anxiolytics and may offer symptomatic relief through tranquilizing and sedative effects. Studies of newer, nonsedating antihistamines show variable results in the effectiveness of controlling pruritus in AD, although they may be useful in the subset of AD patients with concomitant urticaria or concurrent allergic rhinitis.

Because pruritus is usually worse at night, the sedating antihistamines, for example, hydroxyzine or diphenhydramine, may offer an advantage with their soporific side effects when used at bedtime. Doxepin hydrochloride has both tricyclic antidepressant and H1- and H2-histamine receptor-blocking effects. It can be used in doses of 10–75 mg orally at night or up to 75 mg bid in adult patients. If nocturnal pruritus remains severe, short-term use of a sedative to allow adequate rest may be appropriate. Treatment of AD with topical antihistamines is generally not recommended because of potential cutaneous sensitization. However, short-term (1 week) application of topical 5% doxepin cream has been reported to reduce pruritus without sensitization. Of note, sedation is a side effect of widespread application of doxepin cream, and allergic contact dermatitis has been reported.

Tar Preparations

Coal tar preparations may have antipruritic and anti-inflammatory effects on the skin, although usually not as pronounced as those of topical glucocorticoids.82 Tar preparations may be useful in reducing the potency of topical glucocorticoids required in chronic maintenance therapy of AD. Newer coal tar products have been developed that are more acceptable with respect to odor and staining of clothes than some older products. Tar shampoos can be beneficial for scalp dermatitis and are often helpful in reducing the concentration and frequency of topical glucocorticoid applications. Tar preparations should not be used on acutely inflamed skin, because this often results in skin irritation. Side effects associated with tars include folliculitis and photosensitivity. There is a theoretic risk of tar being a carcinogen based on observational studies of workers using tar components in their occupations; however, epidemiologic studies do not confirm similar outcomes when used topically.83

Phototherapy

Natural sunlight is frequently beneficial to patients with AD. However, if the sunlight occurs in the setting of high heat or humidity, thereby triggering sweating and pruritus, it may be deleterious to patients. Broadband UVB, broadband UVA, narrowband UVB (311 nm), UVA-1 (340 to 400 nm), and combined UVAB phototherapy can be useful adjuncts in the treatment of AD. Investigation of the photoimmunologic mechanisms responsible for therapeutic effectiveness indicates that epidermal LCs and eosinophils may be targets of UVA phototherapy, with and without psoralen, whereas UVB exerts immunosuppressive effects via blocking of function of antigen-presenting LCs and altered keratinocyte cytokine production. Photochemotherapy with psoralen and UVA light may be indicated in patients with severe, widespread AD, although studies comparing it with other modes of phototherapy are limited. Short-term adverse effects with phototherapy may include erythema, skin pain, pruritus, and pigmentation. Long-term adverse effects include premature skin aging and cutaneous malignancies (see Chapters 237 and 238 for detailed discussion of phototherapy and photochemotherapy, respectively).

Hospitalization

AD patients who appear erythrodermic or who have widespread severe skin disease resistant to outpatient therapy should be hospitalized before considering systemic alternative therapies (see section “Systemic Therapy”). In many cases, removing the patient from environmental allergens or emotional stresses, intense patient education, and assurance of compliance with therapy results in a sustained improvement in their AD. Clearing of the patient's skin during hospitalization also allows the patient to undergo allergen skin testing and appropriately controlled provocative challenges to correctly identify or rule out potential allergens.

Systemic Therapy

Systemic therapies discussed below were reviewed in a consensus conference.53

Systemic Glucocorticoids

The use of systemic glucocorticoids, such as oral prednisone, is rarely indicated in the treatment of chronic AD. Some patients and physicians prefer the use of systemic glucocorticoids to avoid the time-consuming skin care involving hydration and topical therapy. However, the dramatic clinical improvement that may occur with systemic glucocorticoids is frequently associated with a severe rebound flare of AD after the discontinuation of systemic glucocorticoids. Short courses of oral glucocorticoids may be appropriate for an acute exacerbation of AD whereas other treatment measures are being instituted. If a short course of oral glucocorticoids is given, it is important to taper the dosage and to begin intensified skin care, particularly with topical glucocorticoids and frequent bathing followed by application of emollients to prevent rebound flaring of AD.

Cyclosporine

Cyclosporine is a potent immunosuppressive drug that acts primarily on T cells by suppressing cytokine transcription. The drug binds to cyclophilin, an intracellular protein, and this complex, in turn, inhibits calcineurin, a molecule required for initiation of cytokine gene transcription. Multiple studies demonstrate that both children and adults with severe AD, refractory to conventional treatment, can benefit from short-term cyclosporine treatment. Various oral-dosing regimens have been recommended: 5 mg/kg has generally been used with success in short-term and long-term (1 year) use, whereas some authorities advocate body-weight-independent daily dosing of adults with 150 mg (low dose) or 300 mg (high dose) daily of cyclosporine microemulsion. Treatment with cyclosporine is associated with reduced skin disease and an improved quality of life (see Chapter 233 for further discussion). Discontinuation of treatment may result in rapid relapse of skin disease, although some patients may have sustained remission. Elevated serum creatinine or more significant renal impairment and hypertension are specific side effects of concern with cyclosporine use.

Antimetabolites

Mycophenolate mofetil is a purine biosynthesis inhibitor used as an immunosuppressant in organ transplantation, which has been used for treatment of refractory inflammatory skin disorders (see Chapter 233). Open-label studies report that short-term oral mycophenolate mofetil, 2 g daily, as monotherapy results in clearing of skin lesions in adults with AD resistant to other treatment, including topical and oral steroids and psoralen and UVA light. The drug has generally been well tolerated with the exception of one patient developing herpes retinitis that may have been secondary to this immunosuppressive agent. Dose-related bone marrow suppression has also been observed. Similar results were previously reported in another open study of ten patients with a mean reduction in the SCORAD (SCORing Atopic Dermatitis) index of 68% in all ten patients. Of note, not all patients benefit from treatment. Therefore, the medication should be discontinued if patients do not respond within 4 to 8 weeks. Dose finding and well-controlled studies are needed for this drug.

Methotrexate is an antimetabolite with potent inhibitory effects on inflammatory cytokine synthesis and cell chemotaxis. Methotrexate has been used for adult AD patients with recalcitrant disease, although controlled trials are lacking. Dosing more frequently than the typical weekly dosing for psoriasis has been advocated.84 In open-label studies, initial improvement was observed after a period ranging from 2 weeks to 3 months (mean 9.95 weeks +/– 3.17).

Azathioprine is a purine analog with anti-inflammatory and antiproliferative effects. It has been used for severe AD, and several controlled trials have been reported in adults and children.85,86 Myelosuppression is a significant adverse effect. Thiopurine methyl transferase levels may predict individuals at risk.87

Other Therapies

Interferon-γ

IFN-γ is known to suppress IgE responses and downregulate Th2 cell proliferation and function. Several studies of patients with AD, including a multicenter, double-blind, placebo-controlled trial88 and two long-term open trials,89,90 have demonstrated that treatment with recombinant human IFN-γ results in clinical improvement. Reduction in clinical severity of AD correlated with the ability of IFN-γ to decrease total circulating eosinophil counts. Influenza-like symptoms are commonly observed side effects early in the treatment course.

Omalizumab

Treatment of patients with severe AD and elevated serum IgE levels with monoclonal anti-IgE has shown lack of efficacy in three adult patients91 and significant improvement in three adolescent patients.92 In an open study of 11 adult patients with high IgE levels treated with anti-IgE, some patients had very good clinical improvement, others had none and several had worsening of their AD based on change in SCORAD.93 To date, specific markers have not been found to identify potential responders.

Allergen Immunotherapy

Unlike allergic rhinitis and extrinsic asthma, immunotherapy with aeroallergens has not proven to be efficacious in the treatment of AD. There are anecdotal reports of both disease exacerbation and improvement. A recent study of specific immunotherapy over 12 months in adults with AD sensitized to dust mite allergen showed improvement in SCORAD as well as reduction in topical steroid use.94 However, well-controlled studies are still required to determine the role for immunotherapy with this disease. More recently, a controlled study with sublingual immunotherapy showed benefit in a subset of children with AD sensitized to dust mite allergen.95 This data need to be reproduced in a larger pediatric population, given the natural history of AD.

Extracorporeal Photopheresis

Extracorporeal photopheresis consists of the passage of psoralen-treated leukocytes through an extracorporeal UVA light system. Clinical improvement in skin lesions associated with reduced IgE levels has been reported in a few patients with severe, resistant AD who were treated with extracorporeal photopheresis and topical glucocorticoids.96

Probiotics

Perinatal administration of the probiotic Lactobacillus rhamnosus strain GG was shown to reduce the incidence of AD in at-risk children during the first 2 years of life.97 Mothers were given either placebo or Lactobacillus GG daily for 4 weeks before delivery and then either the mother (if breast-feeding) or the infant continued with daily therapy for 6 months. In a follow-up study, the same group assessed the persistence of potential to prevent AD at 4 years.98 The results suggest that the preventive effect of Lactobacillus GG on AD could extend beyond infancy.

In a second study, children with AD treated with two Lactobacillus strains for 6 weeks experienced improvement of their eczema compared to placebo-treated patients, although their SCORAD index did not change significantly.99 The treatment response was found to be more pronounced in patients with positive skin-prick tests and elevated IgE levels. Another study of children with moderate to severe AD treated for 8 weeks with L. fermentum in a placebo-controlled study showed persistent improvement in SCORAD at 16 weeks.100 These studies suggest that probiotics, or at least some Lactobacillus strains, may have preventative, lasting effects on the incidence of AD in a subset of patients. More research into subgroups of responders, optimal therapy [route (i.e., directly to infant or via mother's milk); length of treatment; strain of Lactobacillus], as well as mechanisms involved is clearly needed.101

A recent meta-analysis found a modest role for probiotics in children with moderately severe disease in reducing SCORAD (mean change from baseline, –3.01; 95% confidence interval, –5.36 to –0.66; P = .01).102 Duration of probiotic administration, age, and type of probiotic used did not affect outcomes. Another meta-analysis found that current evidence is more convincing for probiotics’ efficacy in prevention, rather than treatment of AD in children.103 In contrast to earlier studies, supplementation with Lactobacillus GG during pregnancy and early infancy neither reduced the incidence of AD nor altered the severity of AD in affected children, but was associated with increased rate of recurrent episodes of wheezy bronchitis.104 A Cochrane review concluded that probiotics are not an effective treatment for eczema in children and that probiotic treatment carries a small risk of adverse events.105

Chinese Herbal Medications

Several placebo-controlled clinical trials have suggested that patients with severe AD may benefit from treatment with traditional Chinese herbal therapy (see Chapter 241). They had significantly reduced skin disease and decreased pruritus. However, the beneficial response of Chinese herbal therapy is often temporary, and effectiveness may wear off despite continued treatment. The possibility of hepatic toxicity, cardiac side effects, or idiosyncratic reactions remains a concern. The specific ingredients of the herbs also remain to be elucidated and some preparations have been found to be contaminated with corticosteroids. At present, Chinese herbal therapy for AD is considered investigational.

Oral Vitamin D

A pilot randomized, double-blind placebo-controlled study looked at the benefit of oral vitamin D supplementation in children with AD from February to March in Boston.106 Eleven pediatric patients primarily with mild AD were treated with either vitamin D (1,000 IU ergocalciferol) or placebo once daily for a month. IGA score improved in four of six subjects in the vitamin D group (80%), as compared to one of five subjects in the placebo group (p = 0.04). In addition, there was a greater reduction in EASI score in the vitamin D, as compared to the placebo group, although the difference was not statistically significant. In addition, in a controlled study, 14 healthy subjects and 14 subjects with AD were supplemented with 4,000 IU per day of oral vitamin D3 (cholecalciferol) for 3 weeks.107 Expression of the AMP cathelicidin was significantly increased in the skin biopsies of AD lesions, as compared to those in healthy skin or uninvolved AD skin, suggesting a role for oral vitamin D in improving innate immune responses in AD patients.108

Education may be considered as a therapeutic intervention for the management of atopic dermatitis.51,52 Intensive disease education has been shown in randomized, controlled trials to improve subjective quality-of-life and objective eczema severity scores.109 Intensive education may include comprehensive “center-based” patient/family teaching, written “handouts,” and care plans, patient/family support groups, and Internet-accessed media. Several resources available online are listed in Table 14-2.