Atopic Eczema Between Rationality and Irrationality

Atopic eczema is one of the most common chronic inflammatory skin diseases, and its incidence is increasing—doubling in each of the past few decades. In Great Britain and Scandinavian countries, point prevalence was determined to be between 9.7% and 23%.^{1 - 2}

There are several risk factors associated with atopic eczema. Socioeconomic factors are of importance. The disease is more frequent in urban areas compared with rural areas, and in cities, a higher prevalence is observed among higher socioeconomic classes. Atopic eczema presents features of a "civilization disease," with the highest prevalence in highly industrialized countries. Indoor climates in highly insulated buildings support the growth of dust mites and molds, and high concentrations of noxae are common. There are also the decrease in infections and improved living conditions in highly industrialized countries. Other possible contributory factors include changes in nutrition and a decrease in infant breast-feeding. Furthermore, the prognosis ofinfantile atopic eczema is worse than previously assumed, with a persistence rate of 40% to 60% after puberty.³ Another important risk factor is respiratory allergy; 40% to 60% of all persons with atopic eczema have respiratory allergies.

The following review presents pathophysiological concepts of atopic eczema that are based on the interaction between genetic predisposition and environmental influences, and that provide a scientific foundation for a concept-oriented, rational treatment of the disease. Rational treatment of disease is based on a pathophysiological concept and/or is of proven scientific efficacy.

Treatment of atopic eczema is a matter of intensive controversy between rational academic medicine and irrational, alternative complementary medicine more than any other skin disease. Some proponents of complementary medicine and their followers deliberately disregard the fact that excellent results can be obtained today with the methods of academic medicine, using an integrated, holistic therapeutic approach. Moreover, drugs and therapeutic modalities in academic medicine are almost without exception of natural origin (Table 1). Thus, conventional medicine implements principles of natural medicine without the need of an ideological or pseudophilosophical justification. The only purely "chemical" synthetic drugs used in the treatment of atopic eczema are the antihistamines; however, they are one of the best-tolerated classes of drugs in dermatology and medicine.

Patients with atopic eczema, and their parents, often seek complementary treatments from obscure healers and physicians, many of whom use unproven and unvalidated diagnostic and therapeutic procedures. Unfortunately, this withholds from patients (frequently children) the excellent treatment options available in conventional medicine and results in unnecessary long-term suffering. While some alternative healers often follow simplistic and irrational treatment concepts, I present an integrated therapeutic concept implementing holistic principles as it is used with some variations in most leading departments of dermatology in the Western world. The excellent treatment results routinely obtained with this rational approach make these alternative therapies appear redundant and harmful because they withhold effective treatment modalities.

Atopic eczema is characterized by a highly complex pathophysiology.^{4 - 7} The disease has a genetic basis, but its expression is modified by a broad spectrum of exogenous manifestation factors. Many pathophysiological factors have been postulated, of which the following are considered the most important at present:

The cause of the irritability of atopic skin is not completely understood. Xerosis may be a consequence of a disturbance in epidermal lipid metabolism (deficient δ-6-desaturase) and a consequent skin barrier disruption.

The cellular immune deficiency of atopy is reflected by frequent cutaneous infections. Cutaneous infections with herpes simplex or papillomaviruses⁸ and staphylococci, among others, are common. Defective T-suppressor function is regarded as a possible cause of increased IgE production.

Atopy is defined as familiar sensitivity of skin and mucous membranes toward environmental factors with enhanced IgE synthesis and/or altered nonspecific reactivity. An important characteristic of atopic diathesis is the tendency to recognize ubiquitous environmental factors such as pollen, house dust mites, or certain foods as allergens and to develop specific IgE antibodies against them. However, approximately 20% of patients with atopy show normal total serum IgE levels and lack specific sensitization against inhalant and food allergens as evidenced by negative IgE and prick test results. On the other hand, highly elevated IgE levels can be present without clinical manifestatons of atopy and eczema. Currently, analogous to the concept of asthma, dermatologists are favoring the concept of an endogenous, intrinsic atopic eczema without IgE involvement and an exogenous allergic atopic eczema (Figure 1).⁹ However, the demonstration of IgE receptors on the surface of Langerhans cells, the antigen presenting cells of the epidermis, has shed new light on the role of IgE in atopic eczema.¹⁰ These receptors bind inhalant allergens (eg, house dust mites) in the epidermis and evoke a delayed-type contact hypersensitivity reaction, which is of diagnostic use in the newly developed atopy patch test.¹¹ The fact that IgE causes an eczema-type reaction rather than the classic urticarial reaction challenges the dogma of IgE-mediated immediate hypersensitivity reactions. The concept of IgE bound with Langerhans cells provides important therapeutic consequences concerning allergen elimination and environmental control.

The autonomous dysregulation of atopy¹² can be explained by an imbalance of the β-adrenergic and cholinergic system and manifests clinically as a paradoxical vasoconstriction on mechanical stimulation of skin (white dermographism). One of the consequences of altered reactivity of autonomous transmitter molecules may be the enhanced release of inflammatory mediators from leukocytes and mast cells. These mediators exert proinflammatory and immunoregulatory (suppressive) effects.

The enhanced "releasibility" of histamine, leukotrienes, and other inflammatory mediators is an important factor underlying cutaneous inflammation and the minimal cellular immune deficiency in atopic eczema.⁴

The psychosomatic influence in atopic eczema has been recognized and accepted for a long time, and has led to the term neurodermatitis. Stress is a provocation factor in atopic eczema and its effects are probably mediated by neuropeptides. Current psychoneuroimmunological research focuses on the modulation of immune functions by neural factors.¹³ Mast cell innervation and modulation of Langerhans cell function by neuropeptides¹⁴ have been demonstrated recently.

The therapeutic strategy in atopic eczema must take the complexity of its pathophysiology into consideration. I favor a concept that integrates various treatments that are aimed at the respective pathophysiological factors (Figure 2). Conversely, simplistic therapeutic approaches that emphasize just 1 pathogenetic model (eg, food allergy or psychosomatic aspects) are necessarily inaccurate and harmful to the patient because they withhold important therapeutic options. These simple pathogenetic models disregard the multifactorial pathogenesis of atopic eczema and often show characteristics of an ideology rather than a disease model based on medical science. The therapeutic concepts resulting thereof are defended by their advocates and believers with a quasi-religious zealousness rather than by a sound pathophysiological basis. Frequently, however, economic motives are hidden behind the auratic myths of alternative medicine.

Family and twin studies provide clear evidence of a genetic basis of the disease.⁴ The highest risk exists when both parents are involved (70%). Respiratory allergy represents another important risk factor. Maternal imprinting (higher risk of inheritance from mother than father) may be due to intrauterine immune reactions or allergens and noxae in breast milk. The mode of inheritance is complex and suggestive of polygenic inheritance. No correlation was found for atopic eczema with asthma genes on chromosome 11q13. The research focuses on atopy genes coding for subunits of the high-affinity IgE receptor or involving IgE and cytokine production. Recently, genetic polymorphisms in mast cell chymase have been identified as possible risk factors in atopic eczema,¹⁵ but not asthma or allergic rhinitis.

In addition to genetic predisposition, exogenous provocation factors influence manifestation of the disease, its course, and localization.^{1 ,4} The influence of environmental factors characterizes atopic eczema as one of the most frequent environmental dermatoses and one of the most important environmental diseases.¹⁶ In public opinion, the increase in environmental diseases in general and allergies in particular is due to "chemistry," which is synonymous to "bad," as opposed to "nature," which is equal to "good." It should be made clear, however, that most allergens and provocation factors of atopy are not chemical compounds but of natural origin, such as house dust mites, molds, foods, pollen, and penicillin. Stress also plays a decisive role. Contrary to widespread belief, chemical food additives such as preservatives and dyes play a minimal role in the provocation of pruritus.¹⁷

The identification of provocation factors by appropriate diagnostic procedures is the prerequisite for an individualized treatment approach. The multimodal triggering mechanisms make simplistic "recipes" not useful in the treatment of patients with atopic eczema.

The disturbed epidermal barrier facilitates the penetration of ubiquitous contact allergens present in the domestic milieu or workplace, such as nickel, balsam of Peru, and latex. Allergens in skin care products and topically used drugs such as fragrances, preservatives in vehicles, or topical preparations should be considered. Paradoxically, glucocorticosteroids are increasingly being recognized as contact allergens.¹⁸ Irritants play an important role in domestic and occupational settings, eg, disinfectants and solvents. Intolerance to wool is a stigma of atopy.

Inhalant allergens penetrate the disturbed epidermal barrier in patients with atopic eczema and cause contact allergic reactions. Seasonal exacerbations in the intensity of atopic eczema can often be explained by contact with pollen (eg, atopic lid eczema). The most important indoor allergens are house dust mites, and, less frequently, molds. Most intensive contact with house dust mites occurs in bed, where elimination measures should primarily be applied. Furry pets, particularly cats, represent another source of allergens, and their presence in the home should be discouraged with high-risk patients. The atopy patch test is a new diagnostic procedure that should facilitate identification of contact reaction—inducing inhalant allergens in the future.¹¹

Food constituents can lead to an exacerbation of atopic eczema via immunologic (allergic) or nonimmunologic mechanisms. Antigenic food proteins can penetrate the disturbed epidermal barrier particularly during occupational exposure, and provoke atopic eczema via a contact urticarial reaction. In contrast to infants and small children, the role of nutritive factors in adults with atopy is considered negligible. Patients allergic to birch pollen complain of symptoms on the lips and oral mucosa after ingestion of fresh fruits, vegetables, and nuts (oral allergy syndrome), but exacerbation of atopic eczema has not been observed.

Ninety percent of patients with atopic eczema have skin that is colonized by Staphyloccocus aureus. The induction of atopic eczema can occur via anti–Staphyloccocus IgE or by superantigen stimulation of the T-cell response.¹⁹ Head, neck, and shoulder dermatitis is caused by infection with Pityrosporum ovale, eliciting both immediate and late-type allergic reactions. This variant of atopic eczema is amenable to antimycotic treatment. Viral infections (eg, herpes simplex virus, human papillomavirus, and mollusca contagiosa) can be viewed as a consequence rather than cause of atopic eczema.

Psychological factors are accepted as a provocation factor in atopic eczema. Occupational and familial stress can trigger an attack of atopic eczema. On the other hand, maladaptation to the disease may contribute to the perpetuation and to its becoming chronic. Triggering of disease exacerbations by stressful events is observed by approximately half of patients with atopic eczema.

Seasonal fluctuations are typical provocation factors of atopic eczema. In winter, exsiccation of skin and the indoor microclimate in inadequately ventilated rooms contribute to disease exacerbation. In summer and sunny climates, spontaneous remission of atopic eczema is frequently observed, although heat and sweating may worsen the skin condition. Relapses during spring or summer may point to a role of inhalant allergens.

Knowledge of the complex pathophysiology of atopic eczema can be translated into a rational, integrated therapeutic strategy (Table 2). The multiplicity of provocation factors necessitates a highly individualized therapeutic approach. Contrary to claims from some practitioners of alternative medicine whose prophets generally follow a strategy based on ideologically fixed, simple disease models, academic medicine is, therefore, inherently "holistic." It is a perversion of facts that alternative medicine practitioners claim a holistic approach to disease management for themselves and a narrow perspective with organ-oriented specialists for academic medicine. Such proponents of alternative dietary treatment approaches, for example, certainly apply a much less holistic approach than broad-based university departments, and their dietary interventions generally lack a scientific basis and are implemented without appropriate allergological evaluation.

In the following, I review the basic principles of rational, integrated, and holistic therapy of atopic eczema, which are used with various modifications in most university clinics and other dermatological centers in the Western world. The treatment is stage adapted and occurs in gradual, stepwise increases and intensities (Table 3). The therapeutic decisions are based on severity and extensiveness of the dermatosis as well as individual response to treatment.²⁰ The therapy is arranged in 3 strategic levels: (1) elimination of individual trigger factors, (2) stage-adapted individualized symptomatic treatment, and (3) generation of coping strategies.

The support by specialists trained in psychosomatic medicine is quite helpful in the long-term management of the disease (level 3).

All patients with atopic eczema are treated with basic therapy and most experience a satisfactory response with the use of simple, convenient methods. Only in severe cases of eczema and in patients who do not respond to basic therapy are further diagnostic and therapeutic measures justified.

Skin Care. Dermatologic treatment of individuals with atopy is based on the care of dry, xerotic skin; left untreated, it can lead to the disruption of the epidermal barrier and to pruritus, scratching, eczema, and infection. The care involves the use of "greasy" topical preparations ("the fatter the better"), avoidance of aggressive cleansing procedures, the use of bath oils, and adequate clothing.

Glucocorticosteroids. Topical glucocorticosteroids are the most valuable and important drugs in the treatment of eczema. A widespread fear of this class of compounds ("corticophobia") is unsubstantiated and irrational. It is partly due to adverse effects caused by long-term high-dose systemic treatment and inexpert use by nondermatologists. On the other hand, this fear is promoted by healers and zealots whose Kassandra calls are motivated by economic interests aimed at selling alternative treatments to insecure patients. The use of topical glucocorticosteroids is conceivably the most natural treatment modality because they are a natural component of the human body. Since their introduction in the 1950s, this substance class has been continuously improved. New steroid derivatives with improved risk-benefit ratio²¹ display a low atrophogenic potential despite high anti-inflammatory activity (Figure 3). Low atrophogenicity was shown by exact ultrasonographic measurement of skin thickness even with long-term use and in children and infants. Nonetheless, glucocorticosteroids should be used judiciously and only intermittently. The choice of an individual preparation depends on the strength required, the skin condition, and the location of the lesion. Chronic lichenified lesions necessitate the use of different topical preparations than those used for acute inflammation. Glucocorticosteroids have profoundly improved the quality of life in patients with atopic eczema, but their reputation has suffered from inexpert use. Other valuable drugs used in medicine, such as digitalis or insulin, can kill the patient if inappropriately dosed, but their benefit remains uncontested. Although no such serious harmful effects have been demonstrated for topical glucocorticosteroids, it is astonishing for rational physicians how vigorously these compounds are rejected by many physicians and their insecure patients despite the lack of effective alternatives. Nonsteroidal topical preparations preferred by many pediatricians show little clinical efficacy and possess a sensitizing and photosensitizing potential. The traditional use of tars is marked by low anti-inflammatory efficacy and reduced cosmetic acceptability due to smell and color.

To withhold glucocorticosteroid treatment from patients with atopic eczema constitutes, in my opinion, a deliberate withholding of appropriate medical care and deliberate bodily injury to the patient.

Antihistamines. The improvement of pruritus, the main agonizing symptom of atopic eczema, by treatment with antihistamines interrupts the vicious circle of pruritus-scratching-eczema-pruritus, and profoundly improves the quality of life of those suffering from the disease. Classic, sedating antihistamines are drugs with an extremely favorable risk-safety profile, and their use in sufficient doses should be strongly encouraged. Frequently, the doses prescribed are suboptimal. By stepwise dose increases, an adaptation to the sedating effects can often be achieved. Modern, nonsedating antihistamines offer an advantage for persons who are employed or who have to drive. The efficacy of nonsedating antihistamines in atopic eczema has been confirmed in controlled trials recently. The sedating effect of classic antihistamines is beneficial in severe cases, during in-patient treatment, and for sleep disturbances caused by the tormenting pruritus.

Insufficient response to basic therapy justifies additional diagnostic and therapeutic measures.²⁰ Of importance are systematic diagnostic procedures to identify individual trigger effects and their elimination.

Contact Allergens and Irritants. Contact allergens are encountered at home, eg, in clothing and in skin care and skin therapy products, and in occupational settings. Counseling of patients with atopy with regard to the choice of occupation and the measures of skin care to be taken in the workplace are important tasks of occupational dermatology.

Inhalant Allergens. Environmental control measures may be indicated for relevant indoor allergens, particularly house dust mites. Pets are an avoidable source of allergens. The question of specific hyposensitization in atopic eczema, in contrast to respiratory allergies, is unsettled.

Climate. Certain climatic zones at high altitudes or at the seaside may improve atopic eczema by various mechanisms. Reduction of allergen concentration, sunlight exposure, and psychological factors may contribute to the beneficial effects of climatotherapy, which only recently became the focus of scientific evaluation.

Infections. The pathogenic role of staphylococci can be reduced by appropriate treatment particularly if impetiginization is clinically evident. In head, neck, and shoulder dermatitis, antimycotic azole derivatives may be indicated.

Psychological Factors. The importance of psychological factors must be taken into consideration in the integrated therapeutic model. Many university departments offer psychosomatic counseling to patients with intermediate to severe atopic eczema and this service is readily accepted by most patients. The therapeutic spectrum encompasses relaxation techniques, behavioral therapy to reduce scratching, autogenous training, psychoanalytic approaches, and others in the setting of individual, family, or group therapy.

Diet. The controversial concept of food provocation in atopic eczema has recently received renewed interest and acceptance from the scientific community owing to carefully performed controlled studies in the United States²² and Great Britain.²³ Results of these studies show that in a selected pediatric population, a double-blind, placebo-controlled provocation with a few allergenic foods led to an exacerbation of atopic eczema,²² and a double-blind elimination diet led to its improvement.²³

It is estimated that dietary intervention is indicated in about 10% to 15% of young children with atopic eczema, but only in rare instances in adults. The following principles should be implemented:

Before prescribing a dietary regimen, its risks should be taken into consideration:

The critical and considerate use of dietary measures is nevertheless justified, and many clinical departments have incorporated food allergy testing procedures and dietary consulting into their therapeutic concept. Diagnostics of food intolerance reactions is a highly complex field, and few departments have the complete spectrum of diagnostic procedures including the gold standard, oral provocation testing, at their disposal. In most patients with multiple food allergies, negative results of open provocation tests may suffice to demonstrate the tolerance to long-withheld foods.

Because of unsolved diagnostic problems in food allergy testing, most patients should be offered an empirical elimination diet,²⁴ avoiding the frequent allergens of milk, eggs, nuts, and fish. This seemingly simple diet is already difficult enough for many patients to comply with and requires the cooperation of professional diet assistants since these allergens are present in hidden form in many foods. Besides nutritional allergens, irritating foods such as citrus fruits should be avoided. Food dyes and preservatives are rare trigger factors, particularly in adults.²⁵ Restrictive oligoantigenic diets are warranted only in severe cases unresponsive to empirical elimination diets. Elemental diets carrying the risk of malnutrition should be reserved for exceptional cases.

Ultraviolet treatment is gaining increasing importance. In large dermatological centers, most patients with intermediate to severe atopic eczema receive some form of UV therapy.²⁶ The exact knowledge of its indications, contraindications, short- and long-term risks, and performance requires a high degree of experience and training that can be obtained only in specialized dermatological centers. There is concern about the increasing tendency to perform UV treatment by nondermatologists or nonmedical professionals for profit or other reasons. The widespread use of UV therapy by nonspecialists will automatically result in an increased incidence of severe adverse effects and long-term sequelae, including photocarcinogenesis, and will prove ultimately harmful to patients. The establishment and strict enforcement of quality-control criteria and legal regulations in UV use as that exist for ionizing radiation is imperative to prevent abuse of the technology and subsequent harm to patients.

In cases of acute atopic eczema, long-wave UV-A (UV-A 1) may be an alternative to glucocorticosteroid therapy, but its long-term safety, particularly in children, is not yet established. With conventional broad spectrum UV-A and UV-B lamps or their combination, the stabilization of glucocorticosteroid- or UV-A 1– induced remission can be obtained, and a steroid-sparing effect achieved. Narrowband 311-nm UV-B irradiation is a new promising modality. In severe cases, psoralen–UV-A treatment may be required. Recently, extracorporeal photochemotherapy has yielded good results in uncontrolled pilot studies in severe cases resistant to conventional therapy.²⁷ Efficacy of UV treatment is due to immunomodulatory effects of UV radiation.

The pathophysiology of atopic eczema is characterized both by an immune deficiency and by exaggerated immune responses. This poses the question of whether an immunostimulatory or immunosuppressive approach to therapy is more appropriate. Despite a sound rationale (inhibition of IgE production in vitro), the use of immunomodulators such as interferon-γ has met with limited success at best. Therefore, current interest concentrates on the use of immunosuppressive agents. The prototype drug cyclosporine leads to a rapid remission of signs and symptoms of atopic eczema.^{28 - 29} Quality-of-life parameters show improvement as well, and remain improved after discontinuation of treatment. Long-term remission may be achieved with low-dose maintenance treatment. Severe atopic eczema that is unresponsive to conventional therapy is the main indication for treatment with cyclosporine, which is probably the most potent modality in such cases. The spectrum of adverse effects is analogous to those of psoriasis, but the risk of cutaneous infection needs more consideration in the setting of atopic eczema. Drug interactions and exclusion of patients with risk factors are further aspects to be considered. The combination of UV treatment with cyclosporine is prohibited due to an increased risk of photocarcinogenesis. The introduction of cyclosporine can be regarded as a breakthrough in the treatment of severe eczema, and its efficacy and safety have been recently demonstrated in children.³⁰ However, great need exists for the development of topical, nonsteroidal drugs in moderate to intermediate atopic eczema.

Various immunosuppressant drugs with a cyclosporinelike mechanism of action and improved topical efficacy are currently in clinical development. Most experience has been accumulated with the macrolide immunosuppressants tacrolimus (FK-506) and ascormycin (SDZ-ASM 981). In a short-term trial,³¹ tacrolimus showed an exceedingly high efficacy that led to marked improvement after 3 days of treatment. No adverse effects have been observed in short-term treatment, and clinical studies evaluating the long-term effects of the drug are under way. Available evidence³² suggests that tacrolimus and similar immunosuppressants may become the most important development in the treatment of atopic eczema and may change the practice of dermatology in the years to come.

The disturbed epidermal barrier function and other characteristics of atopic eczema have been linked to altered metabolism of unsaturated fatty acids.³³ This assumption provides the rationale for the treatment with essential fatty acids such as dihomogammalinolenic acid. It is characterized by a low incidence of side effects but also by low efficacy. High doses administered over prolonged periods may yield better results but are impractical in children who would have to swallow large numbers of capsules.

The antieczematous efficacy of traditional Chinese herbal medicine was confirmed by British dermatologists.³⁴ The identification of the active constituents and toxicological aspects are subjects of investigations. Unfortunately, some preparations of Chinese herbs caused a toxic reaction with fatal outcome. Batches of Chinese herbal preparations have been shown to contain toxins such as heavy metals and to have been adulterated with western drugs such as corticosteroids.^{35 - 36} These experiences show the potentials and dangers of phytotherapeutic products that, contrary to popular belief, do not represent harmless natural remedies. In rational medicine, plant products have been in use for centuries, eg, digitalis in internal medicine and psoralens in dermatology. In addition, established drugs and promising new natural remedies, such as the mold products penicillin and the immunosuppressive macrolides are being developed by conventional medicine without ideological boldasis on their natural origin.

Methods such as bioresonance, treatment with one's own blood or urine, and cleansing of the colon and intestines using enemas, are particularly popular among alternative medicine professionals and self-help groups, but they lack valid scientific basis³⁷ and should be strictly refuted. These methods should be clearly marked what they are: as quackery.

The prevention of atopic eczema is an integral part of a holistic approach and can be accomplished at various stages. In the prenatal phase, reduction of maternal smoking reduces the risk of allergy. In infants, prolonged breast-feeding in high-risk children in combination with a hypoallergenic diet of the mother is recommended.³⁸ Passive smoking in young children is associated with increased risk of allergic diseases. Avoidance of allergens such as house dust mites and pets should be considered. In young adults, occupational consulting may reduce the risk of atopic disease.

This review shows that an integrated therapeutic concept that deals with all aspects of the complex pathophysiology of atopic eczema holds the best promise for an individualized successful treatment strategy. Alternative therapeutic approaches based on simplistic disease theories disregard the multimodal aspects of the disease and are, therefore, insufficient and inadequate. I have shown the absurdity of the polarization between conventional medicine, which is presumably organ fixed and chemically oriented, and alternative medicine with its holistic and natural claims. Academic medicine uses complex, holistic strategies with widespread use of natural remedies (Table 1) without an ideological zealousness. The practice of alternative medicine that disregards the complex, holistic, and individual nature of the disease and uses simple therapies based on prefixed ideology and claims rather than sound scientific evidence is most harmful to patients seeking treatment for a troubling disease. The dichotomy between conventional and alternative medicine thus reflects the contrast between rational, scientific medicine and irrational quackery based on unvalided claims, superstition, and quasi-religious belief.

Accepted for publication July 2, 1998.

Reprints: Thomas Ruzicka, MD, Department of Dermatology, Heinrich-Heine-University of Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany.