Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by severe pruritus and typical age-specific clinical picture (scaly, and oozing plaques on the forehead and face, neck, hands, and flexural area) and is frequently associated with other genetic predisposed atopic diseases such as asthma and/or allergic rhinitis. The prevalence of AD is rather high, mostly involving children, and affects 2% to 5% of the general population with 10% to 20% or more occurrences in infants and children and 1% to 3% in adults. There is wide variation in the prevalence of AD in different populations of the world, and it appears to be increasing.

The course of the disease is characterized by exacerbations and remissions that cannot always be etiologically explained. Complete remission has been estimated to occur in one third of patients after 2 years of age and in another one third after 5 years of age. However, many patients with infantile AD or juvenile AD experience discomforts up to their adult age.

Self-healing, the susceptibility to allergy, and the characteristic immune profile of lesional skin and peripheral blood are hallmarks of AD. They, together with the two different types of AD (intrinsic and extrinsic), require new definitions and reassessments. According to the recent findings of a search for susceptibility genes, it appears that nonatopic dermatitis should be considered a distinct entity of childhood eczema. The affected youngsters show dry ichthyosiform and eczematous skin changes at an early age with absence of sensitization to common allergens, and 33% of them should be clear of skin lesions by the age of 5 years of age without skin lesions.

The terminology of AD is controversial, with many different names used in different countries, among them neurodermitis, flexural eczema, Besnier’s prurigo, constitutionalis atopica, and atopic eczema. Johansson and colleagues and the European Academy of Allergology and Clinical Immunology (EAACI) proposed a new term, “atopic eczema/dermatitis syndrome” (AEDS), which was divided into nonallergic and allergic types, the latter applying to immunoglobulin (Ig) E-associated allergic AEDS. They revised the nomenclature of AD and atopy and called only the IgEassociated forms of the diseases true AD. It is hoped that the term “eczema” will replace the current term AD.

Several genetic analyses have identified different chromosome regions with a linkage to AD features: Th2 cell cytokine genes on 5q31-33, on 1q21, 3q21, 17q25, and 20p which are closely related to some major psoriasis loci. Further genetic regions associated with AD features include gene polymorphisms, activator of transcription (STAT)-6; the proximal promoter of regulated on activation, T-cell expressed and secreted (RANTES); interleukin (IL)-4, IL-4 Rα; and transforming growth factor (TGF)-β. An association of one region intron 2 polymorphisms (rs 324011) with total serum IgE and a STAT-6 risk haplotype for elevated IgE in white adults was also proven. Candidate genes found in regions (3q21, 5q31-33, and 11q13) code for various immunomodulators, including costimulatory proteins (CD80 and CD86) involved in T-cell activation (3q21); IL-3, 4, 5, and 11; granulocyte-macrophage colony-stimulating factor (GM-CSF) (5q31-33); and the beta subunit of the high-affinity IgE receptors (11q13). Finally, a genetic linkage was shown to contribute to immunologic abnormalities of AD pathogenesis. Atopic constitution is more frequently transmitted by maternal inheritance.

AD is frequently associated with immunodeficiency (selective IgA and IgM). Numerous factors are implicated in the onset of the disease. Hyperimmunoglobulinemia E is characteristic of atopic diseases; however, AD is also a consequence of immune response type IV. The cells infiltrating the skin are predominated by Th2 cell types that produce IL-4/IL-10/IL-13 and enable differentiation of B lymphocytes and production of IgE and eosinophilia. It has been demonstrated that Langerhans cells (LCs), dendritic cells (DC) of the dermis, and peripheral blood monocytes of atopic patients can bind monomeric IgE via high-affinity IgE receptors (FcεRI), representing allergen-binding molecules on antigen-presenting cells. In the same way, they translate and present the allergen to T lymphocytes. Mastocytes also play a major role in the genesis of AD, via allergen stimulation of the secretion of mediators (histamine, prostaglandins, and cytokines including IL-3, IL-4, IL-5, IL-6, and tumor necrosis factor alpha [TNF-α]). Thus, the function of suppressor
(CD8) lymphocytes is impaired due to the underlying gene defect. There are activated Th1 cells with increased production of interferon (IFN)-γ in acute AD skin lesions binding to keratinocytes and, consequently, inflammatory skin changes in the disease. A relative imbalance between Th1 and Th2 subsets of CD4 + T cells producing cytokines are indicative of prominent immune disorders in AD. Autoreactivity to human proteins in patients with AD has been postulated as a decisive pathogenetic factor for AD. Several investigations have looked into the question of whether the stress-inducible enzyme, manganese superoxide dismutase (MnSOD) of human and fungal origin, might act as an autoallergen in AD. The findings on T cells with regulatory features as well as on IgE-mediated autoreactivity will give insight into the defective tolerance of AD patients. Imbalance of Th1 and Th2 in AD depends on polymorphism in the IL-18 gene on peripheral mononuclear cells, which reacts after stimulation with superantigens through upregulation of IL-18 and downregulation of IL-12. Substance P, nerve growth factor (NGF), and vasoactive intestinal polypeptides (VIP) are increased in the blood of AD patients. Cytokines and chemokines are also key factors in the pathogenesis of AD.

There is a Th2 cytokine profile of IL-4, IL-5, and IL-13 in the skin in the acute phase of AD, while Th1/0 with IFN-γ, IL-12, and GM-CSF prevail in the chronic phase. There is significant coordination between AD disease activity and skin eosinophilic cationic protein (ECP) deposition. Moreover, ECP and IL-16 are elevated in the acute AD phase, and IL-10 plays an important immunoregulatory role in atopic as well as nonatopic eczema. In lesional AD skin, there are two types of the high-affinity receptors for IgE-bearing myeloid dendritic cells (DC) (i.e., LCs and inflammatory dendritic epidermal cells [IDECs]), each of which displays a different function in the pathophysiology of AD. Specifically, LCs play a predominant role in the initiation of the allergic immune response and conversion of prime naïve T cells into T cells of the Th2 type with high amounts of IL-4. Furthermore, stimulation of high-affinity receptors for IgE on the surface of LCs by allergens induces the release of chemotactic signals and recruitment of IDECs and T cells in vitro. Stimulation of high-affinity IgE receptors (FcεRI) on IDECs leads to the release of high amounts of proinflammatory signals, which contribute to the allergic immune response. Keratinocytes play a role in innate immunity by expressing toll-like receptors and by producing antimicrobial peptides in response to invading microbes. AD keratinocytes secrete a unique profile of chemokines and cytokines. Apoptosis of keratinocytes is a crucial event in the formation of eczema (spongiosis in AD). The expression of different immunologic parameters has been studied in AD patients since immune dysregulation is a possible key defect in AD. Regulatory T cells (Tregs) or Th3 cells (CD25+/CD4+) can suppress Th1 as well as Th2 cells. Superantigens of Staphylococcus aureus cause defects in Tregs function and promote the skin inflammation. Autoallergens (e.g., Homs 1-5 and DSF 70) are atopy-related autoantigens (ARA) in the setting of AD and other atopic diseases. IgE autoreactivity appears very early (during the first year of life) and is associated with flares in AD. Adhesion molecules may play an important role in the homing of T-cell subsets into allergen-exposed skin of atopic individuals. High expressions of adhesion molecules, especially intracellular adhesion molecules (ICAM)-1 and ICAM-3, E-selectin, and L-selectin, in skin lesions of AD patients revealed that they may play an important role in the pathogenesis of AD and may be of clinical relevance for the management of AD. AD is a product of an interaction between various susceptibility genes, host and environmental factors, infectious agents, defects in skin barrier function, and immunologic responses.

AD is characterized by dry skin and increased transepidermal water loss even in nonlesional skin, and fewer ceramides in the cornified envelope of lesional and nonlesional skin are found in AD patients. Changes in the stratum corneum pH in AD skin may impair lipid metabolism in the skin. Such alterations allow the penetration of and increase susceptibility to irritants and allergens, triggering the inflammatory response, cutaneous hyperreactivity, inflammation, and skin damage characteristic of AD. Filaggrin deficiency leads to mild or severe ichthyosis vulgaris. Impaired keratinocyte differentiation and barrier formation allow increased transepidermal water loss and the entry of allergens, antigens, and chemicals from the environment in AD.

The importance of environmental factors in the development of AD has been increasing. The majority (40% to 65%) of AD patients experience deterioration in the winter, probably due to decreased humidity of the air outdoors (due to cold) as well as indoors due to heating. The aggravation by sun exposure is probably due to a nonspecific intolerance of heat caused by impaired function of sweating in affected skin and induction of itch sweating. Outdoor pollution seems to be one of the major causes of the dramatic increase of atopy in recent years. Chemical compounds and exhaust particles as well as pollen are released into the air and may have indirect effects on the allergic sensitization. AD is major contributing factor to occupational irritant or allergic contact dermatitis. Irritants, such as soaps, detergents, and disinfectants, and prolonged exposure to water have an excitatory effect on the impaired barrier layer of atopic skin. Daily washing with soap and water or noxious agent may elicit an irritant contact reaction in atopic individuals. Saliva frequently induces perioral eczema. Contact with wool is a common trigger of irritant contact dermatitis in AD. Other textiles, especially synthetics or dyed fabrics, are sometimes incriminated. Tobacco smoke is also a potent irritator of atopic skin. Nutritive allergens are primarily important in AD in children. The most common allergens in children are egg whites, cow’s milk, peanuts, soya, shellfish, and flour. The prevalence of food allergy in AD varies widely from 25% to 60% according to different studies. There are also
nonspecific irritant reactions predominantly to acid fruit (citrus fruit, tomatoes) and salty or spicy foods. Aggravation of eczema may also be provoked by food additives.

Among airborne allergens, the most important are grass, weeds, and tree pollen allergens, animal epidermis, dander allergens, and house-dust mites. Airborne allergy in AD varies widely according to different studies. Great attention has been paid to skin colonization and infection with S. aureus. This bacterium can be isolated in nostrils and intertriginous regions in 5% to 15% of normal individuals but is found in 64% to 100% of skin lesions in AD patients. It influences the course of the disease via different mechanisms: exotoxins, enzymes, superantigen, and protein A. Bacterial toxins act as superantigens aligned along MHC II and can directly stimulate massive T-cell proliferation. This discovery has entailed introduction in AD treatment of antistaphylococcal antibiotics. Malassezia furfur (Pityrosporum ovale) yeast may produce positive skin prick reactions in a higher rate (49%) in patients with AD of the head, scalp, and neck region. It can also be detected in the serum (specific IgE to P. ovale) and can provoke positive patch-test reaction. M. furfur can induce an eczematous reaction in sensitized AD patients and may be a trigger factor for AD. Patients with AD do not have a major deficiency in defending against viruses. However, some viral skin infections can have a dramatic course. Kaposi’s herpetiform (Figs. 10-1 and 10-2

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