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No. 67 Skin |
Table 1. Diagnostic criteria for atopic eczema published in 1982 • Eczematous skin lesions • Pruritus • Typical localization (according to age) • Stigmata of atopic constitution • Personal or family history of atopic diseases • IgE-mediated allergic sensitization Epidemiology Atopic eczema occurs throughout the world and is a major health problem. In industrialized countries today, an estimated 10–20% of children and 1–3% of adults are affected. In 60% of the cases, atopic eczema begins in the first year of life (usually after the first month), in 30% in the following 4 years. Atopic eczema tends to be more severe in young children, with periods of remission appearing more frequently as the patient grows older. The outcome of atopic eczema is difficult to predict, but in about one-third of patients the disease will resolve during childhood, while in the remaining two-thirds it tends to persist or will reoccur in adolescence (fig. 1).
There is clear epidemiological evidence that the prevalence of atopic eczema has increased at least two- to threefold in the past few decades. The reasons remain unclear, but hypotheses include increased awareness of the disease, improved diagnostics, increased genetic susceptibility, psychosocial influences, allergen exposure, decreased immune system stimulation, increased prevalence of an underlying disease, antiallergic therapy and environmental pollution [2]. There seems to be good evidence that factors characteristic of a 'modern western society' now play an important role in the development of allergy. With improved hygiene, the immature immune system of the young is less stimulated and, in particular, less challenged by severe parasitic infections. This may mean that the IgE present as a major defense mechanism is now directed against harmless environmental substances such as pollen, house dust mite or animal dander. Investigations in Swiss, Austrian, German, Australian and Finnish children who grew up in farmhouses with heavy exposure to farm animals and endotoxin showed less allergies than in children living in the same area but not in a farmhouse. Gastrointestinal infections also seem to play an important role: studies from Italy with military recruits showed lower rates of gastrointestinal infections in allergic individuals. Another environmental factor may be pollution. For the indoor environment, tobacco smoke has been shown to increase the risk of developing atopic diseases, especially when women smoke during pregnancy and lactation. For atmospheric pollutants such as diesel exhaust particles, in vitro studies with different cell populations showed a shift of the T cell response towards the T helper 2 (Th2) secretion pattern. Epidemiological studies comparing similar ethnic groups living under different conditions (e.g. people in East and West Germany after reunification who had lived in different air pollution profiles) have given further support to this idea, but the precise mechanisms underlying the rise in prevalence are still not known and are the subject of intense investigations. Other changes in recent decades that have altered our exposure to allergens include the energy-saving insulation of houses, wall-to-wall carpeting and new and 'exotic' foods. Nevertheless, we still cannot satisfactorily answer the question as to why allergies are on the increase, and further research is needed not only to identify the most important factors, but also to distinguish between causal and adjuvant/enhancing factors, and to identify protective influences. We must know what the causative factors are to both counteract the rising prevalence of atopic diseases and inform the population of effective measures of prevention. Whereas atopic eczema was once a disease of childhood, in many cases it now continues into adulthood, and at the beginning of the new millennium we are faced with the prospect of increasing numbers of adults needing treatment for this disease. Clinical manifestations In atopic eczema, typical patterns of skin reactions occur in the different age groups, in all cases accompanied by intense pruritus. In infants, atopic eczema involves mainly the scalp, face and extensoral sides of the arms and legs (fig. 2) whereas in older children (fig. 3, 4) and adults, it is primarily found in the flexural folds of the extremities as well as on the skin of hands, feet and neck. In infancy, the disease tends to be more acute, with vesicles over erythematous skin and a serous exudate. As the children get older, the eczema turns dry and the skin shows lichenification, the epidermis turning leathery and thick as a response to scratching. The dominant feature in adults is often excoriated prurigo nodules, i.e. persistently erupting, highly itchy papules that the sufferer scratches. Patients with long-standing atopic eczema frequently display a chronic form of the disease with a dry, lichenificated skin and eczematous lesions localized to the flexural folds. The skin barrier is permanently impaired and exposure to exogenous irritants or allergens can trigger acute exacerbations of the disease. As these descriptions imply, many of the skin lesions seen in atopic eczema, such as erythema, papules or vesicles, can be explained as the consequence of intensive pruritus followed by scratching [4].
Atopic eczema is accompanied by a number of typical stigmata which are summarized in table 2.
Diagnostic criteria for atopic eczema were first published by Hanifin and Rajka in 1980 [5] and included four major features and many associated findings. The major features are (1) pruritus, (2) facial and extensor eczema in infants and children or flexural eczema in adults, (3) chronic or relapsing dermatitis, (4) a personal or family history of atopic diseases. Other diagnostic criteria for atopic eczema are the 'UK Refined Criteria', the 'Millennium Criteria' and the criteria mentioned above (table 1). The SCORAD index (severity scoring of atopic dermatitis) was developed by the Task Force on Atopic Dermatitis to assess the intensity of atopic eczema [6]. This method enables the clinician to calculate an intensity index taking into account the extent of the disease as well as the characteristics and prominence of the skin lesions. Subjective symptoms such as pruritus and loss of sleep are also included. Patients with atopic eczema are prone to bacterial, fungal and viral infections of the skin which can significantly exacerbate the disease [7]. Staphylococcus aureus is particularly frequent on atopic skin, and can cause pyoderma, folliculitis and honey-colored crusting accompanied by regional lymphadenopathy (fig. 5). Common superficial fungal infections are mostly caused by Trichophyton rubrum and Malassezia furfur. Infections with herpes simplex virus are also seen frequently and can lead to the serious complication of eczema herpeticum, a febrile condition which occurs when the virus disseminates cutaneously. Similar skin eruptions can be seen after smallpox vaccination, and are called eczema vaccinatum.
A rare but potentially life-threatening complication is exfoliative dermatitis which can occur in patients with extensive skin involvement and is usually caused by bacterial or viral superinfection leading to generalized redness, scaling, crusting, lymphadenopathy and fever. Complications are not limited to the skin but can also affect other organs like the eye where chronic blepharitis and atopic keratoconjunctivitis are frequently seen. More severe ocular complications include atopic keratoconus and cataracts. Pathophysiology Atopic eczema is closely linked genetically to allergic asthma and allergic rhinoconjunctivitis. The disease occurs in families, with a marked maternal influence on susceptibility. In 60% of patients with atopic eczema, the family history for atopic diseases is positive. A gene likely to be associated with atopic eczema of early infancy is localized on chromosome 3q21. This region encodes the costimulatory molecules CD80 and CD86. Further searching for candidate genes has revealed a linkage to loci on chromosomes 1q21, 17q25 and 20p which were not known to be related to the development of atopic diseases but had been linked to psoriasis. Thus these genes may influence skin inflammation independently of allergic mechanisms. Total and specific serum IgE are often highly elevated in patients with atopic eczema, as revealed in a recent study which found antibodies to house dust mites in the serum of 95% of patients with atopic eczema compared to 42% for asthmatic subjects. Beside house dust mite, specific IgE antibodies are frequently directed against common aeroallergens such as cat dander, pollen or, in childhood, against foods like hen's egg and cow's milk. The degree of sensitization to aeroallergens is related to the severity of atopic eczema. Nevertheless, sensitization is not always of clinical relevance, and provocation tests are needed to confirm their importance for the development of atopic eczema. Here, the atopy patch test is a valuable tool to identify allergens able to elicit eczematous skin lesions in the individual patient (fig. 6) [8]. In this test, type I allergens are applied epicutaneously to uninvolved skin of patients with atopic eczema for 48 h and the skin reaction is evaluated at the time of their removal and again 24 h later. In healthy individuals or patients with solely respiratory allergies, the atopy patch test is rarely positive. The patch test is proof of the concept that aeroallergens can trigger and maintain atopic eczema, and the finding of IgE and IgE receptors on epidermal Langerhans cells casts new light on the pathogenesis of the disease.
In patients with atopic eczema, activated T cells infiltrate the skin and induce apoptosis of keratinocytes which leads to spongiosis, an intercellular edema of the epidermis and a typical histopathological finding of the disease. The pattern of T cell activation is biphasic: early in the development of eczematous skin lesions, Th2 cells dominate with increased interleukin (IL)-4 and IL-13 expression, with a shift to Th1 in more chronic disease, and a cytokine profile comprising IL-5, IL-12, interferon-gamma and granulocyte-macrophage colony-stimulating factor. Although IgE-mediated allergies are important in the majority of patients with atopic eczema (extrinsic atopic eczema), in some patients, no increased serum IgE levels or type I allergies can be found. The term intrinsic atopic eczema was coined for this group. Recently, IgE autoantibodies against human epidermal proteins (Hom s 1) were found in some patients with atopic eczema. Thus one hypothesis for the evolution of atopic eczema over time could be (1) a Th2 reaction responsible for the initial triggering, (2) Th1-mediated inflammation for chronic lesions leading to finally (3) an autoimmune pathomechanism for perpetuation of severe cases which are therapy resistant and in which allergen avoidance strategies no longer help. In atopic eczema the skin is dry and rough with reduced levels of surface lipids and ceramides. Transepidermal water loss is increased as the barrier function in eczema patients is impaired in noninvolved and, even more, in eczematous skin. These changes are likely to increase the permeability of the skin to exogeneous substances such as allergens, leading to elevated cutaneous sensitization rates and subsequently to an enhanced Th2 response. The interaction between dryness of the skin and pruritus which in turn leads to scratching and further skin lesions is complex (fig. 7). The disturbed barrier function renders the skin more vulnerable to irritants which can cause inflammation and enhance pruritus. Investigations into the quality of pruritus using a component analysis of atopic itch in the 'Eppendorf Itch Questionnaire' identified specific patterns of a 'compulsive' character to atopic pruritus. Many patients taking action against the itching sensation, e.g. by scratching, describe it as a pleasurable experience. To break this itch-scratch cycle, an effective antipruritogenic therapy needs to be combined with patient education. Studies to visualize the perception of itch in the central nervous system have been performed by positron emission tomography (fig. 8) and showed activation patterns of sensory and large motor areas in the cortex reflecting movements to counteract the pruritus; the activation of further areas showed involvement of the limbic cortex, perhaps suggesting emotional processing of itch sensations. In the skin, new receptor systems such as vanilloid, opioid and cannabinoid receptors have been identified on sensory nerve fibers. These receptors may modulate itch and therefore represent future targets for antipruritic agents.
Therapy, patient education and prevention The efficient treatment of atopic eczema must include attempts to restore the disturbed epidermal barrier by cutaneous hydration. Effective skin moisturizers are available in the form of creams, lotions and ointments and should be used on a regular basis by a patient, especially during disease-free intervals when the skin appears to be unaffected. Oil baths can also be used to improve the condition of the skin and preserve epidermal integrity. Eczematous skin lesions are treated with topical or systemic antiinflammatory, antipruritic and antimicrobial drugs. Other therapeutic options include phototherapy and climatherapy (fig. 9).
Less direct but no less important aspects of treatment include the identification and avoidance of triggering factors (i.e. following an accurate allergy diagnosis), and the psychological guidance and education of the patient. In acute exacerbations of the disease, topical glucocorticoids are usually employed. However, two topical immunomodulators, tacrolimus and pimecrolimus, were recently put on the market. These substances inhibit calcineurin phosphatase, lower intracellular signaling and inhibit transcription of multiple proinflammatory cytokines. Both agents have been used successfully to treat atopic eczema without the side-effects, such as skin atrophy, associated with topical glucocorticoids. It is still too early to say, though, what position these new drugs will ultimately occupy in the management of atopic eczema. Since eczematous skin is prone to bacterial, fungal and viral infections, antimicrobial agents (especially against S. aureus) are often needed in the therapy of exacerbated atopic eczema. To achieve control of the atopic itch, systemic antihistamines can be helpful. For the patient to carry out useful avoidance strategies and improve his or her ability to deal with the disease, new approaches in patient education have been introduced. In Germany, a special education program has been initiated to increase the patients' understanding of the disease so that they can achieve a higher level of independence and self-determination. Physicians, nurses, psychologists and dieticians are also trained within the program to meet the special needs of patients with atopic eczema. Efforts are also underway to spread information about measures of allergy prevention at a population-based level: in Germany, for example, the Government has encouraged the formation of a network of organizations working in the field. This interdisciplinary group is generating evidence-based guidelines for allergy prevention which will be distributed on a national and international level to increase awareness and ensure that the right steps will be taken in the prevention of allergic diseases. If these guidelines are followed, effective prevention, which will decrease the number of allergic individuals, may be within reach. To identify susceptible individuals who will especially benefit from preventive measures, epidemiological and experimental studies are underway with the long-term aim of delivering tailor-made prevention. One promising approach in the field of diagnosis is the use of the atopy patch test to confirm the clinical relevance of individual allergens and thus customize the therapeutic concept to the patient's needs. Despite new developments in pathophysiology, treatment and prophylaxis, some of which have been outlined here, atopic eczema continues to seriously impair the quality of life of millions of people, and remains a major challenge for modern medicine requiring further epidemiological, experimental and clinical research.
  Johannes Ring, MD, PhD, is director and chairman of the Department of Dermatology and Allergy Biederstein of the Technical University Munich, Germany. He is also President of the Collegium Internationale Allergologicum (CIA) and President-Elect of the European Academy of Dermatology and Venereology (EADV). He is involved in basic, clinical and epidemiological research programs concerning atopic diseases, and has published several textbooks on allergy and atopic eczema, while also being editor of the Karger book series Chemical Immunology and Allergy.
Johannes Huss-Marp, MD, is a Research Fellow in the Center for Allergy and Environment (ZAUM – Zentrum Allergie und Umwelt GSF/TUM) at the Department of Dermatology and Allergy Biederstein of the Technical University Munich. He undertakes research on atopic eczema and skin physiology, with a particular focus on the role of environmental factors.
Prof. Dr. Johannes Ring, MD, PhD Klinik u. Poliklinik f. Dermatologie u. Allergologie am Biederstein Technische Universität München Biedersteiner Str. 29 D–80802 München Germany Homepage: www.derma-allergie.med.tu-muenchen.de Email: Johannes.Ring@lrz.tu-muenchen.de Dr. Johannes Huss-Marp, MD Klinik u. Poliklinik f. Dermatologie u. Allergologie am Biederstein Technische Universität München Biedersteiner Str. 29 D–80802 München Germany Homepage: www.derma-allergie.med.tu-muenchen.de Email: Huss-marp@lrz.tum.de |
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