Eczema (E), Atopic Eczema (AE) and Atopic Dermatitis (AD)
Posted: July 2004
Updated: May 2008
Prof. Johannes Ring and Prof. Ulf Darsow
Johannes Ring, PhD, Dr.med.Dr.phil. and Ulf Gerrit Darsow, PD MD
Department of Dermatologie und Allergologie Biederstein
Biedersteiner Strasse 29
Ulf Darsow is General Secretary of the European Task Force Atopic Dermatitis
Eczema (E) (also called atopic dermatitis (AD)) is an inflammatory, chronically relapsing, non-contagious and extremely pruritic skin disease. The discussion about pathogenesis of this disease is mirrored by the different names that it has been given ("prurigo Besnier," "neurodermitis," "endogenous eczema," etc.). Atopy is a strikingly common finding in these patients. The Nomenclature Task Force of the European Academy of Allergology and Clinical Immunology (EAACI) proposed the term the Atopic Eczema/Dermatitis Syndrome (AEDS) for this disease, since IgE is not a prerequisite in all patients. The World Allergy Organization 2003 Nomenclature Task force recommended that under the umbrella term dermatitis, eczema is now the agreed term to replace the transitional term atopic eczema/dermatitis syndrome (AEDS). Atopic eczema is eczema with demonstrable IgE association
With a prevalence of 2-5% (in children and young adults approximately 10%), atopic eczema is one of the most commonly seen dermatoses. The "atopic diseases" E, allergic bronchial asthma and allergic rhinoconjunctivitis are familiar. A multifactorial trait, with gene loci on several chromosomes, has been proposed by different groups. The concordance of AE in monzygotic twins is 75-85%, in dizygotic twins 30%. The genetic predisposition exerts its effects in an immunological and organ-specific fashion. In addition environmental factors can work to increase or reduce the development of allergies. The first and most important step is exposure to an allergen. The long and often incomplete progression from genetic susceptibility via IgE-mediated hypersensitivity to hyperrreactivity of skin and mucosa, and finally the manifestations of an allergic disease, is modulated by environmental factors.
Modern molecular genetics has made it possible to couple certain gene loci with different clinical phenotypes. The search for an atopy gene has made it clear that E is inherited in a polygenenic fashion with many genes involved and even provided evidence for genomic imprinting, as maternal influences exceed paternal. Genomic regions linked to E show only limited overlap with asthma, but some coincide with psoriasis susceptibility regions, such a region on chromosome 1 is known as the epidermal differentiation complex, which is a cluster of genes and gene families expressed in the terminally differentiating epithelium. In 2006, a breakthrough in the genetics of E was achieved with the identification of loss-of-function mutations within the EDC gene filaggrin, which cause ichthyosis vulgaris and confer a substantial risk to develop E, especially early-onset with persistent sensitization. Filaggrin is an important protein in the formation of the epidermal barrier through binding to and aggregation of the keratin cytoskeleton. These findings underline the importance of the skin barrier in preventing allergic responses and give rise to the concept that the primary defect in E is a failure of skin barrier function allowing abnormally enhanced cutaneous presentation of antigens, allergens and chemicals to the immune system.
In many patients with eczema, IgE-mediated allergic reactions play a pathophysiological role. However there are also patients in whom nonspecific factors such as irritants or psychosomatic influence appear to be of major importance. Careful allergy diagnosis is thus mandatory in patients with E. The clinical relevance of a given allergic sensitization should be evaluated in each individual.
Often beginning with the clinical sign known as "cradle cap" after the first 8-12 weeks of life, the disease spreads to face and extensor sides of arms and legs of toddlers, showing extensive oozing and crusting. Later on, the typical preferential pattern with eczematous skin lesions of flexures, neck and hands develops, accompanied by dry skin, both as a subjective impression and as measurable transepidermal water loss. Lichenification is a result of scratching and rubbing, and in adults this may also result in excoriated nodules, the "prurigo form" of E. New exacerbations often start without obvious symptoms except increased itching (sometimes localized). This is followed by erythema, papules and infiltration. Acute E is histopathologically characterized by acanthosis, hyperkeratosis, parakeratosis, spongiosis, exocytosis and a sparse lymphohistiocytic infiltrate. Chronic lichenified lesions show acanthosis, hyperkeratosis, parakeratosis, dense dermal mononuclear infiltrate, increase in mast cell and capillary numbers, enlargement of capillary walls with endothelial hyperplasia, and fibrosis. However, these features are not specific for E. Accordingly, eczematous rashes of different origin are the main differential diagnosis for E.
As there is no laboratory marker specific for the disease, "stigmata" and minimal manifestations of E have been found to have diagnostic significance. The clinical diagnosis may be established by finding four of the criteria listed in Table 1.
Increased IgE production, role of allergy
IgE antibodies and positive Atopy Patch Test have been found in the majority of adult patients with AE. The inflammatory infiltrate in AE lesions mainly consists of CD4+ T lymphocytes, and a correlation with disease activity can be shown by the proportion of activated and unactivated CD4+ cells. In the early lesions Th2 cells predominate, later in the more chronic phase Th1 cells prevail.
More than in other allergic diseases, E is characterized by increased serum IgE levels.. T cells play a major role in regulation of IgE production. The Th2 subtype secreting the cytokines IL-4, IL-5 and IL-13 is most important, working via the MHC-II and T-cell receptor, and with co-stimulatory molecules to induce an isotype switch in B cells to produce IgE. While Th2 reactions are crucial for triggering reactions, in chronic skin lesions Th1 reaction patterns can be observed.
As patients with E are prone to develop a variety of infectious diseases of fungal, viral or bacterial origin like candidosis, eczema herpeticum (Kaposi´s varicelliform eruption), or staphylococcal impetigo, defective cellular immunity has been suspected. However, the hypothesis of a lower prevalence of T cell-mediated contact allergy in E has been questioned. Greater prevalence rates of contact allergy are found in E patients than in a normal population. Rather, these patients show a different contact allergen spectrum compared to individuals lacking the atopic constitution (metal allergy more frequent; lanolin, fragrance, etc. less frequent).
Autonomic nervous system dysregulation
In response to different pharmacological stimuli, a substantial proportion of patients with E shows a decreased α-adrenergic and an increased β-adrenergic or cholinergic reactivity. Clinically, the white dermatographism and some psychosomatic interactions may partially be explained by this imbalance, which also gives rise to enhanced releasability of vasoactive mediators, e.g., histamine and leukotrienes, after appropriate stimulation.
Food allergy and other non-allergic food hypersensitivity
An exacerbation of E by foods in food allergic patients (atopic eczema) has been repeatedly reported, with the vast majority of cases seen in children. This should be considered in the management of E when there is a history of food allergy, or when conventional treatment measures are ineffective. Whereas the IgE-mediated reactions are the most common ones, a non-immunological hypersensitivity reaction to food additives can also worsen E in some cases. An appropriate diagnosis of the suspected food allergy should be made.
Some patients with eczema suffer exacerbations of their skin lesions after contact with certain aeroallergens, e.g., house dust mite, pollen or animal dander, and improve after appropriate avoidance strategies have been applied. In certain patients, eczematous skin lesions can be induced by epicutaneous patch testing with aeroallergens, e.g. house dust mite. The term "atopy patch test" (APT) has been proposed for this test procedure.
The clinical appearance of eczematous inflamed lesions emerging on dry, scaling skin is suggestive of an impairment of skin barrier function. An enhanced transepidermal water loss (TEWL) and reduced skin surface water content are physical parameters that directly reflect this impaired barrier function. The barrier function is maintained by the stratum corneum which forms a continuous sheet of alternating squamae, which are protein-enriched corneocytes embedded in an intercellular matrix, consisting mainly of non-polar lipids which have developed as lamellar sheets. Even uninvolved skin of E patients is characterized by distinct differences in skin surface lipid composition, especially in the ceramide fraction.
Profound changes in cutaneous flora occur in some patients with E and the pathogenic importance of microbial organisms is recognized. Among these, Malassezia furfur and Staphylococcus aureus seem to play a major role. S. Aureus is responsible for a known, very often quite dramatic complication of E, named "impetiginised E," requiring systemic antibacterial treatment, and in addition S. aureus may act as a persistent allergen stimulating IgE antibody production, or as an irritant with inflammatory potency when colonizing atopic skin. The inflammatory reaction may be caused by enterotoxin production, possibly with superantigen effects. More than 50% of S. aureus isolates cultured from patients with E have the ability to produce these enterotoxins. It is speculated that staphyloccocal superantigens, when released within the epidermis, cause a marked immune stimulation. The ability of staphylococcal enterotoxin B to elicit dermatitis after application to intact normal or intact atopic skin has been shown. It is likely that reduced innate immune responses, eg, reduced formation of antimicrobial peptides like defensins, give rise to increased microbial colonization.
Severity of pruritus in E has been described as directly related to severity of depressive symptoms. Increased itch and sweating in lichenified skin areas, following emotional stimuli, can be recorded by psychophysiological methods. Investigations of parent-child relationships have shown different emotional responses from diseased children when compared to controls. Increased "fear scores" on personality questionnaires of patients with E have been reported by different investigators. It is uncertain whether these findings have any impact on the etiology of eczema, as they may also result from the prolonged process of coping with chronic disease experienced by the patient and his/her family. Stressful emotional events have been shown to precede the deterioration of eczematous symptoms, not to follow them. Partner conflict situations in the parents are associated with a higher risk for E in the offspring. Further investigations in the field of psychoneuroimmunology may shed light on the reasons for the contradictory results.
The concept of patient management of eczema is based on patient education, which aims to achieve a constant cooperation between physician and patient in the treatment of this chronic disease, and to address also the psychological aspects of eczema. "Eczema school" programs have been successfully introduced in many countries.
Symptomatic treatment includes frequent use of emollients to restore disturbed epidermal barrier, oil baths and topical application of moisturizers, e.g., urea. Anti-inflammatory treatment uses topical steroids and calcineurin inhibitors, antiseptics, wet-wrap dressings in acute cases, and oral antihistamines. UV therapy, especially the long-wave UVA modality, has proven helpful in many patients. If indicated, topical antifungal treatment (for head and neck dermatitis) or systemic antibiotics (for treatment of impetiginization) are also given. In severe cases the use of systemic immunosuppressives, eg, cyclosporine is indicated.
Recommendations for primary prevention in children at risk for atopic diseases propose breast feeding up to 4 months and late introduction of solid foods. Guidelines recommend avoidance of allergens (eg, mites, pets) although this is an area of controversy. In manifest E trigger factors that have been identified should be avoided, or specific allergen avoidance strategies may be applied (e.g., dietary changes, encasing bedding against house dust mite allergen, removal of pets from the home, climate therapy at sea level or high altitude etc.). Prevention of drying of the skin of predisposed patients by creams and emollients is useful to protect against relapsing disease. Pharmacological prevention by intermittent use of anti-inflammatory topicals (steroids, calcineurin inhibitors) is under discussion and may be an option in the future.
Ring, J, Ruzicka, T, Przybilla B (Eds). Handbook of Atopic Eczema, 2nd Edition, Springer, Berlin, New York (2006)