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Novel Unconventional Therapeutic Approaches to Atopic Eczema

Novel Unconventional Therapeutic Approaches to Atopic Eczema IntroductionAtopic eczema or atopic dermatitis (AD) is one of the major chronic skin diseases that affects primarily younger age groups. Together with allergic asthma and hay fever, AD belongs to the group of atopic diseases which have a genetically determined overreactivity of the IgE-dependent immune response as common denominator. Accordingly, patients respond to numerous, normally tolerated antigens in their environment, particularly to airborne and to food allergens, with the latter being primarily important in atopic eczema during childhood (fig. 1). Furthermore, eczematous skin changes and associated local and systemic symptoms are elicited and aggravated by numerous nonspecific exogenous environmental factors like changes in temperature and humidity, possibly due to associated disturbances of the epidermal barrier function, changes in lipid metabolism and neurovegetative factors. These changes and in particular the alterations of the immune system may also explain why the cutaneous bacterial flora is increased and why it can aggravate the cutaneous inflammatory reaction [1, 2, 3, 4].Fig. 1Multifactorial elicitation of clinical symptoms in AD.In accordance with the numerous factors that influence the clinical expression and severity of the disease, a great variety of therapeutic modalities are available for patients and physicians to choose from for symptomatic control of the disease. Some of them are highly effective in controlling symptoms, like corticosteroids, cyclosporin and related drugs, but these treatments are potentially associated with serious adverse effects, and patients tend to have a low level of acceptance of these drugs, particularly on long-term use [1, 3, 4, 5, 6, 7]. There is thus a great interest in and a need for alternative treatment modalities.According to recent studies, patients with a low level of disease-specific stress tolerance are particularly prone to turn to alternative therapies [8]. When approached by such patients, dermatologists need to be knowledgeable with regard to the potential value of such treatments in order to provide proper advice. The present review evaluates therefore the relevant published evidence regarding the efficacy of a selected number of alternative treatment options. The selection (table 1) is based on the level of attention given to such treatments by the public media and the associated interest by afflicted persons. Attention is also given to treatments that appeared promising on the basis of their mode of action and their good tolerability.Table 1Selected, recently published, unconventional therapeutic approaches to ADγ-Linolenic-Acid-Containing Plant OilsTherapeutic studies with plant oils were first conducted in 1947 by Hansen et al. [8]since they had found that patients with AD suffer from a disturbance of their lipid metabolism.Unsaturated fatty acids are essential components of cell membranes and can influence receptors, enzymes, ion channels and signal transduction pathways. There are two families of essential fatty acids, the sixfold (n – 6, e.g. linoleic and arachidonic acid) and the threefold (n – 3, e.g. α-linolenic and eicosapentaenoic acid) unsaturated fatty acids. Dihomo-γ-linolenic, arachidonic and eicosapentaenoic acid are precursors of eicosanoids, which can influence numerous inflammatory and immunological processes [9]. After intake of threefold unsaturated fatty acids, these molecules are rapidly incorporated into the cell membranes of various immune and inflammatory cells, including neutrophils and keratinocytes, where they compete with sixfold unsaturated fatty acids as substrates for the cyclooxygenase and lipoxygenase pathways. This results in a diminished production of biologically active leukotrienes and prostaglandins. On this basis, it is assumed that the intake of γ-linolenic acid (9% in primrose oil, 19% in borage oil) reduces the formation of inflammatory lipid mediators in patients with AD.The therapeutic value of γ-linolenic acid for the treatment of AD has been studied in recent years in several placebo-controlled, single- and multicenter studies in adults and children [10, 11, 12, 13]. None showed a statistically significant advantage of γ-linolenic acid treatment over placebo. These studies have been criticized for a number of reasons, mainly with regard to the statistical evaluation of data on the clinical status of the skin and of the associated treatment with corticosteroids during the study so that controversial discussions regarding the value of this treatment have been ongoing for many years [14, 15, 16]. One recently published multicenter, placebo-controlled study with 160 patients treated with borage oil versus a bland oil was aimed at ending this controversy by avoiding previous pitfalls. It also included an objective treatment parameter, namely changes in erythrocyte dihomo-γ-linolenic acid levels [17]. Unfortunately, this study also yielded no unequivocal answers, with clear disparities between different treatment centers and an apparent benefit only in an undefined subgroup. As a point of interest, the placebo effect is remarkable in practically all studies mentioned, underlining the importance of intense medical care for the control of clinical manifestations of this chronic disease.Chinese Herbal TeaThe efficacy of Chinese herbal tea in the treatment of AD was first demonstrated in European patients using double-blind, placebo-controlled, crossover designs and short-time treatment in both children and adults [18, 19, 20]. A highly significant improvement was noted in the treated group regarding subjective parameters like itch, extent of surface involvement and improved sleep. Furthermore, there were no measurable adverse effects, although Chinese tea contains numerous different, potentially cytotoxic components [21]. In fact, there are reports of hypersensitivity reactions, hepato- and nephrotoxicity, cardiomyopathy and respiratory distress syndrome after intake of Chinese tea, including a case with lethal outcome [21, 22, 23].In subsequent long-term open follow-up studies over 1 year by the same group, patients maintaining their treatment clearly benefited, compared to those who did not [24, 25]. Nevertheless, in 2 of the children under long-term treatment, but not in adults, there were significant elevations of liver values. Medical controls (hepatic and renal serum parameters) before and during therapy are therefore indispensable, and treatment is contraindicated in pregnancy and in patients with preexisting liver disease.Therapeutic efficacy, as reported above, was supported by improvement of immunological parameters like a decrease in cutaneous CD23+ macrophages and Langerhans cells and of CD25+ cells as well as decreases in circulating serum IgE complexes, interleukin 2 receptors and vascular adhesion molecules [26, 27, 28]. It should however be heeded that these changes are only a reflection of clinical improvement and need not be a direct effect of Chinese herbal tea. In contrast to these European studies, a recent double-blind, placebo-controlled, crossover study among Chinese AD patients from Hong Kong failed to show efficacy of Chinese herbal tea therapy over placebo during a 20-week period, except for an improvement of lichenification at visits on week 4 [29]. Ethnic differences may explain these differences. The findings underline however the need for further objective studies of this treatment by several independent centers throughout the world.Reasons for the diverging findings may lie in the complexity of the Chinese herbal preparations which consist of at least 10 plant extracts [21]. There are however reports of antiphlogistic, antimicrobial, immunological and sedative effects of the Chinese tea ingredients which can partly also be demonstrated with cells of normal subjects studied in vitro [21, 27, 28, 30]. Individual components also exhibited corticosteroid-like activities since the metabolization of cortisol by 11γ-hydroxysteroid dehydrogenase is inhibited [31].In summary, treatment of AD with Chinese tea is a pharmacological and potentially toxic therapy, with numerous possible long-term side effects. The view held by many patients that ‘natural’ therapy is harmless is thus a misconception. Its efficacy also needs confirmation by independent study centers in different parts of the world.Elimination DietsDietetic measures for the treatment of AD are described in numerous case reports and also in larger studies. The therapeutic value of elimination diets, particularly of cow’s milk, is undoubted in infants and their lactating mothers with verified food allergy, based on double-blind, placebo-controlled provocation tests [32, 33, 34]. However, not all test-positive allergens produce also eczematous changes, and the long-term value of their elimination has been questioned as well since the clinical benefit could not be maintained during a 1-year follow-up treatment [35].The situation is even more difficult with the so-called pseudoallergens, agents that have clinical effects like ordinary allergens but without involvement of the immune system and thus without production of specific IgE antibodies.The clinical value of avoiding pseudoallergens like food additives and natural aromas in the diet has so far been demonstrated in urticaria [36]. In one recent study with a diet that avoided only artificial additives like preservatives and food colorings, no effect on AD symptomatology was observed [37]. On the other hand, another study involving 50 AD patients and a diet that in addition avoided natural aromas, clinical improvement was noted, together with a decrease in serum eosinophil cationic protein levels in 23 of 41 evaluable patients [38]. Subsequent unblinded oral provocation tests resulted in worsening of the eczema in 19 of the responding patients, and further double-blind, placebo-controlled oral provocation tests in 6 of these patients resulted also in a precipitation of the eczema [38]. Overall, food additives and natural aromas play thus a minor role in a subgroup of patients with AD. Avoidance of such agents can therefore only be recommended after demonstration of their clinical relevance in individual patients by reproduction of the lesions in double-blind placebo-controlled oral provocation.Other dietetic measures, proposed for various subgroups of patients, are less well evaluated. One such approach involves the avoidance of metal ions. In an open study of 27 patients with severe AD and positive patch or oral provocation tests to metal salts, two thirds of the patients noted marked or moderate improvement of their skin condition on a low-metal diet and after removal of metals from their teeth [39]. There is furthermore a report of a child with marked improvement of its AD when avoiding sodium-rich water, with worsening of the skin condition on reexposition [40]. The pathomechanisms are thought to be related to a reduction of gastrointestinal permeability [41]. Obviously, controlled studies are needed before incorporating this treatment into clinical practice.Taken together, until now there has been no generally favored type of diet for all patients with AD. An exception are elimination diets in selected patients with proven food allergy or pseudoallergy. Diagnostic measures should only be initiated by experienced physicians on the basis of a thorough medical history, positive skin tests or specific serum IgE and double-blind, placebo-controlled provocation testing. When approached regarding the possible institution of special diets, a physician should also consider that avoidance of essential foods might have harmful effects on growing children and might cause imbalance of normal physiology and metabolism. Finally, it should be kept in mind that severe dietary restrictions can markedly reduce the quality of life of the patient.Paramedical Therapeutic MeasuresWith a general interest in electromagnetic and other waves as a cause of allergological symptoms in recent years, bioresonance treatment has been proposed in 1994 as an effective treatment for allergic diseases, with a supposedly 83% incidence of improvement [42]. The theory implies that electromagnetic waves of the body are conducted via cables to an instrument which recognizes electromagnetic wave patterns, normalizes them and then sends the latter back to the patient via another electrode.The biophysical activity of such instruments has been shown to have numerous built-in systematic faults, and treatment is very expensive. Nevertheless, one double-blind, placebo-controlled study (sham treatment) in 32 children with AD has so far been conducted. The design involved a 4-week treatment and an 8-month follow-up period. During the study and at its end, no efficacy of treatment over placebo could be demonstrated [43].ConclusionTaken together, none of the alternative treatment options discussed here and available so far demonstrate clear, unequivocal evidence of efficacy, and some have in addition serious adverse effects or represent a psychological burden to the patient. Nevertheless, until the pathogenesis of AD is clarified and disease-specific basic alterations can be rectified or their clinical impact improved, the search for alternative, unconventional treatments must be accepted and should be continued since it may provide not only relief to the patient, but also new venues to the understanding of AD. The value of unconventional treatments should however be subjected to critical testing, as is done for newly developed drugs by the pharmaceutical industry, both regarding efficacy and reasons of safety. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Dermatology Karger

Novel Unconventional Therapeutic Approaches to Atopic Eczema

Worm, Margitta; Henz, Beate M.
Dermatology , Volume 201 (3): 5 – Jan 1, 2000
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Publisher
Karger
Copyright
© 2000 S. Karger AG, Basel
ISSN
1018-8665
eISSN
1421-9832
DOI
10.1159/000018487
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Abstract

IntroductionAtopic eczema or atopic dermatitis (AD) is one of the major chronic skin diseases that affects primarily younger age groups. Together with allergic asthma and hay fever, AD belongs to the group of atopic diseases which have a genetically determined overreactivity of the IgE-dependent immune response as common denominator. Accordingly, patients respond to numerous, normally tolerated antigens in their environment, particularly to airborne and to food allergens, with the latter being primarily important in atopic eczema during childhood (fig. 1). Furthermore, eczematous skin changes and associated local and systemic symptoms are elicited and aggravated by numerous nonspecific exogenous environmental factors like changes in temperature and humidity, possibly due to associated disturbances of the epidermal barrier function, changes in lipid metabolism and neurovegetative factors. These changes and in particular the alterations of the immune system may also explain why the cutaneous bacterial flora is increased and why it can aggravate the cutaneous inflammatory reaction [1, 2, 3, 4].Fig. 1Multifactorial elicitation of clinical symptoms in AD.In accordance with the numerous factors that influence the clinical expression and severity of the disease, a great variety of therapeutic modalities are available for patients and physicians to choose from for symptomatic control of the disease. Some of them are highly effective in controlling symptoms, like corticosteroids, cyclosporin and related drugs, but these treatments are potentially associated with serious adverse effects, and patients tend to have a low level of acceptance of these drugs, particularly on long-term use [1, 3, 4, 5, 6, 7]. There is thus a great interest in and a need for alternative treatment modalities.According to recent studies, patients with a low level of disease-specific stress tolerance are particularly prone to turn to alternative therapies [8]. When approached by such patients, dermatologists need to be knowledgeable with regard to the potential value of such treatments in order to provide proper advice. The present review evaluates therefore the relevant published evidence regarding the efficacy of a selected number of alternative treatment options. The selection (table 1) is based on the level of attention given to such treatments by the public media and the associated interest by afflicted persons. Attention is also given to treatments that appeared promising on the basis of their mode of action and their good tolerability.Table 1Selected, recently published, unconventional therapeutic approaches to ADγ-Linolenic-Acid-Containing Plant OilsTherapeutic studies with plant oils were first conducted in 1947 by Hansen et al. [8]since they had found that patients with AD suffer from a disturbance of their lipid metabolism.Unsaturated fatty acids are essential components of cell membranes and can influence receptors, enzymes, ion channels and signal transduction pathways. There are two families of essential fatty acids, the sixfold (n – 6, e.g. linoleic and arachidonic acid) and the threefold (n – 3, e.g. α-linolenic and eicosapentaenoic acid) unsaturated fatty acids. Dihomo-γ-linolenic, arachidonic and eicosapentaenoic acid are precursors of eicosanoids, which can influence numerous inflammatory and immunological processes [9]. After intake of threefold unsaturated fatty acids, these molecules are rapidly incorporated into the cell membranes of various immune and inflammatory cells, including neutrophils and keratinocytes, where they compete with sixfold unsaturated fatty acids as substrates for the cyclooxygenase and lipoxygenase pathways. This results in a diminished production of biologically active leukotrienes and prostaglandins. On this basis, it is assumed that the intake of γ-linolenic acid (9% in primrose oil, 19% in borage oil) reduces the formation of inflammatory lipid mediators in patients with AD.The therapeutic value of γ-linolenic acid for the treatment of AD has been studied in recent years in several placebo-controlled, single- and multicenter studies in adults and children [10, 11, 12, 13]. None showed a statistically significant advantage of γ-linolenic acid treatment over placebo. These studies have been criticized for a number of reasons, mainly with regard to the statistical evaluation of data on the clinical status of the skin and of the associated treatment with corticosteroids during the study so that controversial discussions regarding the value of this treatment have been ongoing for many years [14, 15, 16]. One recently published multicenter, placebo-controlled study with 160 patients treated with borage oil versus a bland oil was aimed at ending this controversy by avoiding previous pitfalls. It also included an objective treatment parameter, namely changes in erythrocyte dihomo-γ-linolenic acid levels [17]. Unfortunately, this study also yielded no unequivocal answers, with clear disparities between different treatment centers and an apparent benefit only in an undefined subgroup. As a point of interest, the placebo effect is remarkable in practically all studies mentioned, underlining the importance of intense medical care for the control of clinical manifestations of this chronic disease.Chinese Herbal TeaThe efficacy of Chinese herbal tea in the treatment of AD was first demonstrated in European patients using double-blind, placebo-controlled, crossover designs and short-time treatment in both children and adults [18, 19, 20]. A highly significant improvement was noted in the treated group regarding subjective parameters like itch, extent of surface involvement and improved sleep. Furthermore, there were no measurable adverse effects, although Chinese tea contains numerous different, potentially cytotoxic components [21]. In fact, there are reports of hypersensitivity reactions, hepato- and nephrotoxicity, cardiomyopathy and respiratory distress syndrome after intake of Chinese tea, including a case with lethal outcome [21, 22, 23].In subsequent long-term open follow-up studies over 1 year by the same group, patients maintaining their treatment clearly benefited, compared to those who did not [24, 25]. Nevertheless, in 2 of the children under long-term treatment, but not in adults, there were significant elevations of liver values. Medical controls (hepatic and renal serum parameters) before and during therapy are therefore indispensable, and treatment is contraindicated in pregnancy and in patients with preexisting liver disease.Therapeutic efficacy, as reported above, was supported by improvement of immunological parameters like a decrease in cutaneous CD23+ macrophages and Langerhans cells and of CD25+ cells as well as decreases in circulating serum IgE complexes, interleukin 2 receptors and vascular adhesion molecules [26, 27, 28]. It should however be heeded that these changes are only a reflection of clinical improvement and need not be a direct effect of Chinese herbal tea. In contrast to these European studies, a recent double-blind, placebo-controlled, crossover study among Chinese AD patients from Hong Kong failed to show efficacy of Chinese herbal tea therapy over placebo during a 20-week period, except for an improvement of lichenification at visits on week 4 [29]. Ethnic differences may explain these differences. The findings underline however the need for further objective studies of this treatment by several independent centers throughout the world.Reasons for the diverging findings may lie in the complexity of the Chinese herbal preparations which consist of at least 10 plant extracts [21]. There are however reports of antiphlogistic, antimicrobial, immunological and sedative effects of the Chinese tea ingredients which can partly also be demonstrated with cells of normal subjects studied in vitro [21, 27, 28, 30]. Individual components also exhibited corticosteroid-like activities since the metabolization of cortisol by 11γ-hydroxysteroid dehydrogenase is inhibited [31].In summary, treatment of AD with Chinese tea is a pharmacological and potentially toxic therapy, with numerous possible long-term side effects. The view held by many patients that ‘natural’ therapy is harmless is thus a misconception. Its efficacy also needs confirmation by independent study centers in different parts of the world.Elimination DietsDietetic measures for the treatment of AD are described in numerous case reports and also in larger studies. The therapeutic value of elimination diets, particularly of cow’s milk, is undoubted in infants and their lactating mothers with verified food allergy, based on double-blind, placebo-controlled provocation tests [32, 33, 34]. However, not all test-positive allergens produce also eczematous changes, and the long-term value of their elimination has been questioned as well since the clinical benefit could not be maintained during a 1-year follow-up treatment [35].The situation is even more difficult with the so-called pseudoallergens, agents that have clinical effects like ordinary allergens but without involvement of the immune system and thus without production of specific IgE antibodies.The clinical value of avoiding pseudoallergens like food additives and natural aromas in the diet has so far been demonstrated in urticaria [36]. In one recent study with a diet that avoided only artificial additives like preservatives and food colorings, no effect on AD symptomatology was observed [37]. On the other hand, another study involving 50 AD patients and a diet that in addition avoided natural aromas, clinical improvement was noted, together with a decrease in serum eosinophil cationic protein levels in 23 of 41 evaluable patients [38]. Subsequent unblinded oral provocation tests resulted in worsening of the eczema in 19 of the responding patients, and further double-blind, placebo-controlled oral provocation tests in 6 of these patients resulted also in a precipitation of the eczema [38]. Overall, food additives and natural aromas play thus a minor role in a subgroup of patients with AD. Avoidance of such agents can therefore only be recommended after demonstration of their clinical relevance in individual patients by reproduction of the lesions in double-blind placebo-controlled oral provocation.Other dietetic measures, proposed for various subgroups of patients, are less well evaluated. One such approach involves the avoidance of metal ions. In an open study of 27 patients with severe AD and positive patch or oral provocation tests to metal salts, two thirds of the patients noted marked or moderate improvement of their skin condition on a low-metal diet and after removal of metals from their teeth [39]. There is furthermore a report of a child with marked improvement of its AD when avoiding sodium-rich water, with worsening of the skin condition on reexposition [40]. The pathomechanisms are thought to be related to a reduction of gastrointestinal permeability [41]. Obviously, controlled studies are needed before incorporating this treatment into clinical practice.Taken together, until now there has been no generally favored type of diet for all patients with AD. An exception are elimination diets in selected patients with proven food allergy or pseudoallergy. Diagnostic measures should only be initiated by experienced physicians on the basis of a thorough medical history, positive skin tests or specific serum IgE and double-blind, placebo-controlled provocation testing. When approached regarding the possible institution of special diets, a physician should also consider that avoidance of essential foods might have harmful effects on growing children and might cause imbalance of normal physiology and metabolism. Finally, it should be kept in mind that severe dietary restrictions can markedly reduce the quality of life of the patient.Paramedical Therapeutic MeasuresWith a general interest in electromagnetic and other waves as a cause of allergological symptoms in recent years, bioresonance treatment has been proposed in 1994 as an effective treatment for allergic diseases, with a supposedly 83% incidence of improvement [42]. The theory implies that electromagnetic waves of the body are conducted via cables to an instrument which recognizes electromagnetic wave patterns, normalizes them and then sends the latter back to the patient via another electrode.The biophysical activity of such instruments has been shown to have numerous built-in systematic faults, and treatment is very expensive. Nevertheless, one double-blind, placebo-controlled study (sham treatment) in 32 children with AD has so far been conducted. The design involved a 4-week treatment and an 8-month follow-up period. During the study and at its end, no efficacy of treatment over placebo could be demonstrated [43].ConclusionTaken together, none of the alternative treatment options discussed here and available so far demonstrate clear, unequivocal evidence of efficacy, and some have in addition serious adverse effects or represent a psychological burden to the patient. Nevertheless, until the pathogenesis of AD is clarified and disease-specific basic alterations can be rectified or their clinical impact improved, the search for alternative, unconventional treatments must be accepted and should be continued since it may provide not only relief to the patient, but also new venues to the understanding of AD. The value of unconventional treatments should however be subjected to critical testing, as is done for newly developed drugs by the pharmaceutical industry, both regarding efficacy and reasons of safety.

Journal

Dermatology – Karger

Published: Jan 1, 2000

Keywords: Atopic eczema; =γ-Linolenic acid; Chinese herbal tea; Elimination diet; Pseudoallergy; Bioresonance

There are no references for this article.