Most Common Allergic Diseases: Historical Reflections in Understanding Bergmann K-C, Ring J (eds): History of Allergy. Chem Immunol Allergy. Basel, Karger, 2014, vol 100, pp 81–96 DOI: 10.1159/000358606

Atopic Dermatitis/Atopic Eczema

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Daniel Wallach a · Alain Taïeb b a

Department of Dermatology, Hôpital Tarnier-Cochin, Paris, and b Department of Dermatology and Pediatric Dermatology, National Reference Centre for Rare Skin Disorders, Hôpital St. André, Bordeaux, France

Atopic dermatitis was described in 1933 but exists since antiquity. We review descriptions of a childhood skin disease compatible with our modern diagnosis of atopic dermatitis, in ancient medicine and in nineteenth century dermatology texts. We identify Hebra’s prurigo and Besnier’s diathetic prurigo as forerunners of atopic dermatitis, the latter being a synthesis of infantile eczema and prurigo. The pathogenic theories which link atopic dermatitis to humoralistic medicine, to digestive diseases, to allergy may have had consequences on today’s reluctance to consider atopic dermatitis as a skin disorder, the treatment of which relies mainly on topicals. © 2014 S. Karger AG, Basel

Atopic dermatitis is one of the most prevalent skin disorders. It is estimated that approximately 10% of young children receive a diagnosis of atopic dermatitis [1], and in some individuals the disease persists into adulthood. Severe atopic dermatitis is a burdensome disease, with painful repercussions on the daily life of the patient and his or her family, and significant economic consequences [2].

Atopic dermatitis is relatively easy to diagnose and is well known by dermatologists, as well as general practitioners and pediatricians. Even the lay public is aware of the main clinical features of atopic dermatitis as an eczema involving infants. In spite of its prevalence, ease of diagnosis and the availability of efficient treatments, atopic dermatitis still remains a mysterious disease, and many aspects of atopic dermatitis knowledge are controversial. A huge amount of literature is available, reflecting diverse, if not contradictory opinions, which may be confusing. Recently, two comprehensive textbooks have gathered and attempted to synthesize recent publications [3, 4]; one of these textbooks contains a historical text by ourselves [5]. The goal of this chapter is to review the historical aspects of atopic dermatitis in order to understand not only the ancient descriptions and conceptions of the disease, but also to find explanations for our current difficulties with the understanding and management of atopic dermatitis. When looking at the historical aspects of the disease that we today call atopic dermatitis or atopic eczema, the question of semantics is unavoidable. One can identify three levels of complexity in analyzing the meaning of the terms we use: (1) the sigDownloaded by: Fudan University Library 61.129.42.15 - 5/12/2015 10:56:12 PM

Abstract

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dermatitis will be one of the controversies we will examine. To add to the confusion, even the atopic nature – in the sense of associated immunoglobulin (Ig) E sensitization – of atopic dermatitis is questioned [8]. For these and many more reasons, atopic dermatitis is a fascinating disease, and hundreds of papers are written every year on this topic. In 2004, we edited a book, in French, on the history of atopic dermatitis [9]. This book, which contains hundreds of references, forms the basis of this chapter, enriched with additional reflections.

Chronological Agenda Atopic dermatitis has existed since antiquity, but was only described in 1933. For didactic purposes, we will divide the history of atopic dermatitis (an anachronism when it refers to pre-1933) into four periods: – ancient medicine, from antiquity to 1800: descriptions compatible with atopic dermatitis can be found in ancient texts; – clinical dermatology, from 1800 to 1933: dermatologists describe diseases which resemble atopic dermatitis, under different denominations, including eczemas and prurigos; infantile eczema and Besnier’s prurigo appear as the most faithful forereunners of atopic dermatitis; – immunologic medicine, from 1933 to 2006: discoveries in immunology and allergology allow the definition of atopic dermatitis as a special form of hypersensitivity; – cutaneous medicine, since 2006: progress in genetics focuses on the importance of the epidermis in the pathophysiology of atopic dermatitis. In spite of all these achievements, in 2011, our understanding of atopic dermatitis is far from complete.

Atopic Dermatitis before 1800 Atopic dermatitis was described and named in 1933 by Fred Wise and Marion Sulzberger [10]. Before 1933, however, the dermatological literature

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nificance of ancient medical terms, which have long been vague and indefinite; (2) translation problems, from Greek and Latin into current languages, and between current vernacular languages, and (3) current controversies about the meaning of medical terms. In order to avoid too many citations, we will only indicate briefly how the three terms – ‘atopic’, ‘dermatitis’ and ‘eczema’ – can be considered as specifically controversial. Atopic derives from the Greek ‘a-topos’, and means a strange disease without a precise place, a disease with no known place in the medical nosology. This word was coined in 1923 to designate a special state of immunologic hypersensitivity; it is selfmysterious. Dermatitis is an inflammation of the skin. Many diseases can be included under this heading, such as urticaria, lichen planus, psoriasis, pemphigoid and eczema. Some authors use dermatitis as a synonym for eczema, as indicated in the title of this chapter. For other authors, dermatitis indicates an inflammation of the dermis, separate from eczema, which is primarily an inflammation of the epidermis. Eczema was defined by Bateman in 1813 and has a rather precise meaning for the majority of dermatologists (clinical vesicles, microscopic spongiosis). The word eczema is often used as a synonym for dermatitis and would probably be a well-accepted denomination since the general public has always considered the disease called atopic dermatitis to be an eczema, as it is identical to infantile eczema. However, eczema is also a controversial term and it is possible to find in the literature such contradictory statements about eczema that some authors wish to see this term disappear from the dermatologic nomenclature [6]. Therefore, we are left with a ‘strange’ inflammation of controversial denomination. To add disturbing arguments to this brief review into the uncertainties of medical semantics would render the place of atopic dermatitis in allergic diseases (and with it the justification of this chapter of the book) very questionable. Atopic dermatitis indeed is not an allergic disease in the sense that the clinical manifestations are usually not directly induced by contact with an allergen [7]; the place of allergic factors in atopic

Atopic Dermatitis/Atopic Eczema

most prevalent of infantile diseases, that these lesions are a way of evacuating sick humors, and that it is wiser not to treat them in order to avoid more severe, even lethal, diseases. One can, however, try and modify the wet nurse’s diet, or ask for another wet nurse. In his Traité des tumeurs et des ulcères (1759), Jean Astruc (1684–1766) describes in detail infantile milky crusts, secondary to the milk and its influence on the sebaceous glands. He differentiates stick crusts with little pruritus, probably infantile seborrheic dermatitis, from wet crusts with violent pruritus, probably atopic dermatitis. Jean-Louis Alibert (1768–1837), the founder of French dermatology, described tinea mucosa (teigne muqueuse) as an oozing and violent disease not to be mistaken for the trivial milky crusts. In his Description des maladies de la peau observées à l’hôpital SaintLouis et exposition des meilleures méthodes suivies pour leur traitement, published in 1806, he gave detailed reports of 4 infants with tinea mucosa. One of these patients (Joseph Buisseret, aged 20 months) became ill after his wet nurse’s husband was taken to jail. In spite of these precise and lively clinical descriptions, it is difficult to find forerunners of atopic dermatitis in Alibert’s classifications of diseases. In his 1829 classification, very famous for its illustration of the ‘tree of the dermatoses’, the mucous tinea became the mucous achore, which belongs to the branch of tinea, the third group of dermatoses. The fourth group, the ‘dartres’, includes herpes (in the old sense), and one of these herpes, ‘herpes squamosus madidans’, is considered to be an eczema. Alibert indicated that this kind of ‘dartre’ alternates with dyspnea and asthma, which is a clue for diagnosing atopic dermatitis. However, the corresponding illustration was not convincing. Prurigos, which belong to another group, may also have included cases of atopic dermatitis. Therefore, we can say that Alibert observed genuine cases of atopic dermatitis, described them and mentioned their relation with asthma, but his nosological conceptions and personal vocabulary innovations prevented him from a logical classification. To summarize, dermatologists prior to the scientific era had precisely described cases which fit well into the modern criteria for atopic dermatitis that we will detail below: a frequent, cephalic oozing (ulcerated) skin condition of infants, with violent pruritus.

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contained many clinical descriptions compatible with the modern diagnosis of atopic dermatitis. Atopic dermatitis has probably existed since antiquity. Mier [11] attracted attention to a text by Suetonius, clearly describing cutaneous and respiratory atopic symptoms in Emperor Augustus. From antiquity to 1800, skin disorders were not particularly looked at because the skin was considered one of the emunctories of the human body. Skin eruptions, especially oozing ones, were viewed as a salutary way of elimination of noxious or vitiated humors. With this conception, the individuality of skin diseases was not important, and it was dangerous to try and heal them. This Hippocratic humoralist conception of skin diseases was prevalent until at least the 19th century and is still present in today’s popular culture, as well as some alternative medicines. A few authors, however, paid special attention to the skin and its disorders. The first book committed to skin diseases was published in 1572 in Venice. It reported the oral lessons of Girolamo Mercuriali (1530–1606) and was recently translated into English [12] and French [13]. For the purpose of this chapter, we have selected Mercuriali’s book as a good example of the ancient conceptions of skin diseases. Following Galen, Mercuriali classified skin disorders into two groups: the ones involving the head (hair and scalp, and less importantly the face), and the ones involving the remainder of the body. The ninth chapter of the cephalic dermatoses is called ‘achores and favus’. Achores, a term close to tinea or to head ulcerations, designates oozing cephalic dermatoses, which are particularly frequent in children. This is attributed to the need to eliminate humors accumulated during intrauterine life. Mercuriali here describes an itchy cephalic dermatosis in infants, where one can recognize atopic dermatitis. Similar precise descriptions of pruriginous dermatoses in infants, starting or predominating on the head, can be found in all the books of authors of this ‘pre-Willanist’ era, including Turner, Astruc and Alibert. In A Treatise of Diseases Incident to the Skin, written in English and published in 1714, Daniel Turner (approx. 1667–1741) mentions crusts and scabies (pruritus) in infants. He indicates that it is one of the

Atopic Dermatitis in Willanist Dermatology

The eczema is characterized by an eruption of small vesicules, on various parts of the skin, usually set close or crowded together, with little or no inflammation round their bases, and unattended by fever. It is not contagious. This eruption is generally the effect of irritation, whether internally or externally applied, and is occasionally produced by a great variety of irritants, in persons whose skin is constitutionally very irritable.

Considering the fact that almost 200 years later there is still controversy concerning the definition of eczema, it is interesting to point out that Bateman clearly indicated that eczemas may have external and internal causes, and occur in predisposed individuals. However, the eczemas described by Bateman are eczema solare (sunburn), eczema impetiginodes (close to impetigo) and eczema rubrum (probably mercurial dermatitis and other drug reactions). All are of external origin and none of Bateman’s eczemas resemble atopic dermatitis. In the writings of Willan and Bateman, there is nothing like a chronic, infantile eczema. The reason they did not describe atopic dermatitis can be found in their epistemological way of thinking. For them, one disease must have one elementary lesion, and atopic dermatitis has many lesions: vesicles, papules, scales, pustules and erythema. Therefore, it cannot be found under only one heading in Willan’s and Bateman’s works. A careful reading of Willan’s and Bateman’s writings, innovatively illustrated by engravings [15], shows that diseases compatible with the modern diagnosis of atopic dermatitis can be found in four different chapters: ‘Strophulus’, ‘Lichens’ and ‘Pruri-

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Fig. 1. Porrigo larvalis Willan has been identified as one of the earliest faithful descriptions and representations of atopic dermatitis [16]. Instead of the well-known initial picture, we chose to show this plate to pay tribute to the most beautiful dermatological atlas ever published. The illustrators, Anton Elfinger (1821–1864) and Carl Heitzmann (1836–1896), were gifted painters and physicians. Hebra describes chronic eczemas according to their localization. In scalp eczema, he alludes to the old porrigos and achores, for which he proposes the synonyms eczema impetiginosum and porrigo larvalis Willan. As seen here, the term ‘head and scalp’ clearly includes the face.

gos’ contain three varieties of the papules (order I), and ‘Porrigo’ contains one of the pustular dermatoses (order V). Porrigo larvalis (fig. 1) is considered by many as one of the best forerunners of atopic dermatitis. The Latin word porrigo is very close to the ancient vague terms ‘tinea’, ‘favus’ and ‘achores’, and designates an oozing and crusty scalp eruption. Larvalis means ‘similar to the mask of a ghost’, or ‘frightening’. Porrigo larvalis is similar to the milky crusts (or milky tinea) of many ancient authors. Ancient terminology is a difficult problem, and the majority of the terms used before Willan to describe dermatoses are impossible to understand or to translate into modern dermatological descriptions. Fortunately, starting with Willan, dermatological books included atlases with drawings, engravings and paintings of the diseases described in words. Even though modern dermatologists may be unable to understand ancient words, they are able to look at ancient images and to make diagnoses. The position of a modern dermatologist looking at an ancient picture is very similar to his or her position as a teleder-

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Robert Willan (1757–1812) and his talented pupil Thomas Bateman (1778–1821) created clinical dermatology by giving precise descriptions of elementary lesions, a concept created in 1776 by Jacob Plenck (1735–1807), and classifying skin diseases according to these elementary lesions. In this truly revolutionary approach, skin diseases were defined by their primary lesion. For example, psoriasis is scaly and pemphigus is bullous. But what is atopic dermatitis? In Willan and Bateman’s [14] classification, eczema is precisely described in the order of vesicles. Thomas Bateman is credited with the first definition of eczemas:

majority of cases, the general health and the moral and intellectual qualities are unaffected, as illustrated by this photograph of Maurice, a 10-month-old patient of Prof. Degos.

matologist, or as an expert indicating, with his or her own undetailed criteria, whether a given patient has atopic dermatitis or not. Accordingly, we recently asked 31 experts in pediatric dermatology to examine selected ancient pictures in order to identify the first images of atopic dermatitis in the dermatological literature. Consensus could be reached to indicate that the first three iconographic representations of atopic dermatitis are strophulus confertus (Willan, 1796), lichen agrius (Willan, 1796) and porrigo larvalis (included in Willan’s works, but formally described by Bateman in 1816) [16]. Hidden among papular and pustular diseases, absent from eczema descriptions, atopic dermatitis was present, but was not identified as a single skin disease by dermatology pioneers. The method used by Willan and Bateman for diagnosing skin diseases and for classifying them was soon adopted by the majority of dermatologists [17]. Rayer (1793–1867), in the first edition of his influential Treatise [18], proposed to distinguish acute and chronic eczemas. Chronic eczemas are clearly different from the three categories of Bateman’s eczemas, but Rayer does not insist on any infantile form. In the second edition of Treatise [19], however, Rayer gives a detailed description of scalp eczema, a synonym for mucous tinea Alibert and por-

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Atopic Dermatitis as a Diathetic Prurigo According to Willan and Bateman’s classification, prurigos are one of the three varieties of papules, but no prurigo is predominantly a pediatric disease. The infantile papules are included in the strophulus. The nosological status of prurigos changed when Ferdinand von Hebra (1816–1880), head of Viennese dermatology and considered to be the leader of European (world) dermatology during the second half of the 19th century, described prurigo not only as a lesion, but also as a disease [21]. Hebra’s prurigo (‘prurigo mihi’) is essentially a papular disease. These papules are severely pruriginous. Hebra’s prurigo is a lifelong disease, which follows the patient ‘to his

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Fig. 2. Infantile eczema is a rather stereotyped condition. In the

rigo larvalis Willan. The onset of this chronic eczema is between 3 and 8 months of age and it is violently pruriginous. One of the best descriptions of infantile eczema must be credited to Erasmus Wilson (1809–1884), delivered at the 1856 Meeting of the British Medical Association. His lecture and the subsequent publication in the British Medical Journal were so successful that he wrote the same description again many times, including in his 1870 lectures on eczema [20]. He asserted that infantile eczema (synonyms: crusta lactea, tinea lactea, porrigo larvalis, tinea mucosa, tinea granulata) commences at 4–6 weeks of age and its cause resides in the mother’s milk. To support this assumption, Wilson reported the case of a mother who, distressed by the death of her husband, transmitted eczema to her child. In this case, which is similar to the one described by Alibert and cited above, one can see that at this time not only nutriments, bacteria and allergens, but also emotions, were considered to be transmitted by the milk. Wilson indicated that many different types of lesions can be seen in infantile eczema, which was not limited to a vesicular disease. These included ‘erythema, lichen, strophulus, eczema, impetigo, pityriasis, psoriasis’, all of them ‘on the same skin and in gross defiance of the order, genera and species of the Plenckio-Willanean method of classification’ [20]. Figure 2 shows the well-known typical aspect of infantile eczema.

Fig. 4. Ernest Besnier (1831–1909) was the leader of French dermatology between 1890 and 1900. He was the first editor of La pratique dermatologique, the first French multi-author textbook, published in 1900. Diathetic prurigo, described by Besnier in 1892, is identical to atopic dermatitis.

matologists were never comfortable with the diagnosis of Hebra’s prurigo and thought that this typical and precisely described form was very rare. They invented the term ‘French variety’ for these atypical cases, probably identical to Besnier’s prurigo. The photograph was taken on March 12, 1902, Hôpital Broca, Dr. Brocq’s department.

grave’ and there is no mention of infantile forms or of a pediatric predominance. The distribution of lesions is characteristic and Hebra insisted on the involvement of the extensor parts of the limbs. The folds, including the elbows, are ‘almost always unaffected’. Hebra’s prurigo has always been considered as a severe, rare disease, and French and British dermatologists, although acknowledging the talent and authority of the Viennese master, often indicated that they saw very few genuine cases [22] (fig. 3). Another disease named prurigo was described in 1892 by Besnier (1831–1909; fig. 4), under the name diathetic prurigo [23]; more precisely, ‘paroxystic

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Fig. 3. Hebra’s prurigo in a 4-year-old (French variety). French der-

and chronic polymorphous and pruriginous dermatoses, Hebra’s prurigo type’. In this communication to the French Society of Dermatology, Besnier, helped by his resident Sabouraud, described a disease in three young men which began in early infancy and was mainly a pruritus. Pruritus came first and lesions followed. Besnier’s prurigo was, so to say, a ‘pruritic diathesis, a diathetic prurigo’. This denomination is very significant because Besnier, like the majority of dermatologists of his time (in opposition to Hardy and Bazin) did not think that diatheses really exist. At an early age, the lesions which follow pruritus in Besnier’s prurigo are non-specific. It may be ‘infantile erythema, urticaria, pseudo-lichen, or one of the eczematisations or lichenisations…’. Besnier did not relate his prurigo to infantile eczema, but he related it to asthma and hay fever, and differentiated it from the narrow description of Hebra’s prurigo. The French dermatologists of these times, including Besnier, Brocq and Vidal, wrote many pages about eczemas, prurigos, lichens and pruriginous dermatoses. However, since a picture is worth a thousand words, it is appropriate to examine figure 5, which represents the nebula of cutaneous reactions according to Louis Brocq (1856–1928), one of the smartest of the dermatology clinicians. Accord-

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Fig. 5. The turning point in the history of atopic dermatitis was the discovery that infantile eczema and some prurigos are in fact the same disease. This discovery was anticipated by some clinicians at the end of the 19th century and is well illustrated in this graphic representation of Brocq’s conception of cutaneous reactions. The pruritic reactions are situated to the right of the double dotted line. Brocq’s main idea was that clinical entities are linked with one another by ‘faits de passage’ (transitions) which are represented by ‘corridors’. The width of the corridors represents the frequency of

these transitions and their length represents the closeness between the entities. We have added a circle to point out the nosological position of Besnier’s prurigo, the forerunner of atopic dermatitis. It is rightly positioned between eczemas and prurigos, especially the severe prurigo Hebra, synonym of prurigo ferox. Short, wide corridors indicate the closeness of these entities. By contrast, the corridor between Besnier’s prurigo and mycosis fungoides is both long and narrow, indicating that these entities are rather distant, although some relationship may exist.

ing to Brocq, skin diseases are not separated, but linked by many ‘faits de passage’ (transitions), represented by the corridors between the circles. As clearly indicated on the figure, diathetic prurigo (Besnier’s prurigo) is situated between eczemas (true eczemas) and prurigos, rather close to Hebra’s prurigo, the most severe form of prurigos. Indeed, it was necessary to link infantile eczema and chronic prurigo to conceive such a disease as atopic dermatitis. A few years earlier, J. Hutchinson had suggested

such a link when indicating that severe cases of infantile eczema, persisting into adulthood, are similar to Hebra’s prurigo [24].

Before the years of Index Medicus and Medline, The Year Book of Dermatology was a publication most awaited for. Once a year, experts analyzed the

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Atopic Dermatitis/Atopic Eczema

Birth of Atopic Dermatitis

York and studied in Geneva and in Zurich with Bruno Bloch, a pioneer in cutaneous allergy. Back in the USA, he was associated with Fred Wise, his mentor and friend. Sulzberger was professor of dermatology in New York from 1949 to 1961, and in San Francisco from 1964 to 1970. He was one of the most brilliant and influential of American dermatologists. His contribution to the history of atopic dermatitis is unique – he denominated and described the disease, and indicated the main criteria and the clinical course. Twenty years later, he discovered the efficacy of topical corticosteroids.

international literature. In the 1933 edition, Fred Wise and Marion Sulzberger (fig. 6) tried to simplify the problem of eczemas [7]. They commented on Rost’s early and late ‘exudative eczematoids’ and their link to allergy, and on Ormsby’s discussion of neurodermatitis (Brocq) and lichenification, similar to Vidal’s lichen simplex chronicus. In an illuminating footnote, Wise and Sulzberger indicated that from this confused and confusing group of diseases, ‘at least one is now emerging as a fairly distinct and clear-cut entity. This is probably best called atopic dermatitis.’ As soon as they denominated atopic dermatitis, Wise and Sulzberger indicated the nine qualities, or criteria, of this condition: (1) atopic family history; (2) antecedent infantile eczema; (3) localizations: creases of elbows and knees, neck, chest, face and mainly eyelids; (4) a grayish/brownish coloration of the skin; (5) the absence of true vesicles, both clinically and histologically;

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Fig. 6. Marion Baldur Sulzberger (1895–1983) was born in New

(6) vasomotor instability or irritability; (7) negativity of patch tests to contact irritants; (8) many positive reactions of immediate wheal type to scratch or intradermal testing; (9) presence of many reagins in the blood serum. Immediate allergy, or atopic hypersensitivity, was therefore the main argument for isolating atopic dermatitis from other chronic eczemas, and skin tests were considered as a valuable scientific diagnostic test for this condition. An earlier attempt to link skin manifestations to constitutional disturbances, including food reactions and respiratory disorders, had been proposed by Czerny with the concept of ‘exsudative diathesis’ (1905), but it lacked the biological support that skin and blood tests brought to establish the allergic nature of atopic dermatitis [25]. Consequently, the logical treatment of atopic dermatitis was the elimination of all foods and all inhalants that gave positive reactions. Atopy had been defined in 1923 as a type of inherited hypersensitivity to environmental allergens, different from anaphylaxis and hypersensitivity to infection [26]. Other chapters in this book will give a detailed account of the history of the discovery of allergic phenomena. Richet and Portier discovered anaphylaxis to toxic substances in 1902, von Pirquet described allergy to infectious antigens in 1906. In 1909, Smith described positive tests in a patient allergic to buckwheat, and in 1912 Schloss described hypersensitivity to egg in a child with urticaria. In 1916, Blackfan [27] published the first article on skin tests in children with eczema. Considering the fact that many patients with asthma had infantile eczema, he thought it would be ‘of interest to determine the frequency of proteins reactions in eczema, to see if a relation existed between the disease and protein sensitization…’. Indeed, in a group of 27 patients with eczema, including 18 infants, he found a majority of positive tests: 21 to egg white, 17 to cow’s milk, 10 to human milk, 7 to horse serum and 6 to meat extract. In a control group, no test was positive. In older children and adults, the removal of the food that gave positive tests improved some patients. However, this was not the case in infants exposed to the dangers of unnecessary avoidance diets. So, the discrepancy between the positivity of skin tests and

Criteria and Scores in the Contemporary Era Neither the skin or blood tests which helped the individualization of atopic dermatitis nor the discovery of an increase of circulating IgE in the 1960s [30] proved to be pathognomonic, or even very helpful for the diagnosis of atopic dermatitis. Although the majority of physicians had no major problem in diagnosing atopic dermatitis, precise clinical criteria were felt necessary for epidemiological and clinical research, as well as for communication between dermatologists, immunologists, allergists and pediatricians from different countries, who were still using different denominations. Jon Hanifin (USA) and Georg Rajka (Norway), who had

Atopic Dermatitis/Atopic Eczema

worked independently on this topic, organized an international symposium in Oslo in June, 1979. In a short article, one of the most frequently cited of the dermatological literature, they proposed clinical criteria for atopic dermatitis [31]. Although Hanifin and Rajka’s criteria are based on personal experience and informal discussions, and have never been formally validated, they have been widely accepted and used in the majority of the works published in the last 30 years. According to Hanifin and Rajka, a diagnosis of atopic dermatitis is certain if a patient has 3 or more of 4 major features, and 3 or more of 21 minor features. The major criteria are (abridged text): – pruritus – typical eczema, according to age (flexural in adults…) – chronicity – personal or family history of atopy The minor criteria are: – xerosis – ichthyosis/keratosis pilaris – immediate skin reactivity – elevated serum IgE – early age of onset – tendency toward cutaneous infections (Staphylococcus aureus and Herpes simplex) – non-specific hand and foot dermatitis – nipple eczema – cheilitis – conjunctivitis – Dennie-Morgan fold – keratoconus – cataracts – orbital darkening – facial pallor/facial erythema – pityriasis alba – anterior neck folds – itch when sweating – intolerance to wool and lipid solvents – perifollicular accentuation – food intolerance – influence of environmental/emotional factors – white dermographism Hanifin and Rajka’s criteria were found to be relevant for clinical research, but they required derma-

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the consequences of food intake or food exclusion was noted as soon as tests were performed. This remark is of paramount importance. In 1921, Prausnitz and Küstner demonstrated that allergy can be transferred by serum and so, when Wise and Sulzberger described atopic dermatitis in 1933, they could consider skin and blood tests as reliable criteria for this new condition, the main criteria to differentiate atopic dermatitis from other eczematoid dermatoses. Soon afterwards, Hill and Sulzberger [28] gave a precise description of the evolution of atopic dermatitis, indicating clearly that the hypersensitivity to proteins was the link unifying different clinical aspects: eczema in infants, neurodermatitis in children, and the numerous denominations of what is now called atopic dermatitis in adults (prurigos, among others). The denomination of atopic dermatitis was rapidly adopted by American and British dermatologists. In France, it was long considered to be an Anglicism, and Degos, leader of French dermatology until the 1970s, always spoke of constitutional eczema. In Germany, the term ‘neurodermitis’ was long favored. When Nexmand [29], in 1948, wrote a thesis on this disease in Copenhagen, he preferred to call it Besnier’s prurigo, explaining that it was not an eczema, not always atopic (although he favored an allergic pathogenesis) and always pruriginous.

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turbance. The SCORAD index has been widely accepted and used, although other indexes are also used (e.g. EASI), resulting in somewhat disturbing confusion [34].

Will Semantic Discussions End? The progressive abandonment of immunological criteria in the diagnosis of atopic dermatitis paralleled the observation that many patients did not have atopic biologic criteria, i.e. positive immediate skin tests and elevated circulating IgE. Many authors questioned the adequacy of the terms ‘atopic’ and ‘dermatitis’. They proposed separating atopic dermatitis into an extrinsic and an intrinsic form, the latter lacking atopic stigmata. Others, skeptical of an atopic disease without atopy, preferred to speak of an atopiform dermatitis. The Task Force for Nomenclature of the European Academy of Allergology and Clinical Immunology proposed in 2001 to replace atopic dermatitis with ‘atopic eczema/dermatitis syndrome’ (AEDS), which could be allergic or non-allergic. Allergic AEDS is further divided into IgE-associated and non-IgE-associated forms [35]. The World Allergy Organization made a somewhat different proposal 3 years later, in which eczema is considered to be one of the dermatitis, and divided into atopic eczema and non-atopic eczema [36]. No doubt the discussions will continue, and no doubt there is also a clear advantage, at least from the bibliographic point of view, to consider that atopic dermatitis is a pragmatically useful, if not very precise, denomination.

Pathogenic Theories and Their Therapeutic Consequences Atopic dermatitis is a complicated disease. In the chapter on atopic dermatitis of the first edition of Dermatology in General Medicine, issued in 1971, Sulzberger [37] represents a multifactorial chain of causation which does not prioritize any of the 10 factors cited (fig. 7). However, the majority of authors tend to favor an etiological hypothesis and to recommend therapy according to their preferred hypothesis.

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tological skills. They were considered later to be too complicated to be used in a primary care setting, and in 1994 a British Working Group headed by Hywel Williams elaborated the criteria using an epidemiological methodology. Thirty-two physicians examining 224 patients established and validated diagnostic criteria for atopic dermatitis based on the presence and frequency of 13 symptoms and 18 signs. The main conclusion of this impressive work [32] was that the diagnosis of atopic dermatitis requires pruritus, or ‘an itchy skin condition’; no atopic dermatitis can exist without pruritus. In addition to this compulsory criterion, the patient must have 3 or more of the following criteria: (1) history of flexural involvement, (2) visible flexural dermatitis, (3) history of a generalized dry skin, (4) history of asthma or hay fever and (5) onset of rash before the age of 2 years. There is a historical sense in comparing these three sets of criteria for atopic dermatitis. Wise and Sulzberger’s 1933 criteria can be considered allergists’ criteria, in which one third of the criteria relate to skin or blood tests. Hanifin and Rajka’s 1979 criteria are those of dermatologists – none of the major criteria and only 2 of the 21 minor criteria are related to immunological data. Williams’ 1994 criteria are those of epidemiologists – immunological skin and blood tests have disappeared and the diagnosis requires no dermatological skills; all the criteria can be obtained by interview or questionnaire, except one (visible flexural dermatitis), which can be established by a non-physician health professional or a caring mother. Atopic dermatitis is a polymorphous disease and, in addition to ascertaining the diagnosis, it is helpful for clinical research as well as everyday practice to gather some information on the severity of the disease. In 1990, Alain Taïeb and Jean-François Stalder co-ordinated 29 specialists from 9 European countries in a European Task Force on Atopic Dermatitis [33]. Through expert discussions on clinical photographs, consensus meetings and statistician expertise, this group was able to set up a score called SCORAD (scoring atopic dermatitis) following a suggestion by A. Oranje. The SCORAD index takes into account the intensity of the lesions and the extent of the disease, as well as pruritus and sleep dis-

1 10 Sweat retention

Genetics defects

2

Susceptible targets (skinĂlungsĂH\HV

3 Allergens (inhaled, ingested, HWF

9

4 Scratching other trauma

Heat KXPLGLW\ exercise

8

Humoralistic Theories and Reluctance to Treat The Hippocratic conception of a beneficial oozing, allowing the elimination of vitiated humors, was the main cause of contemplative medicine or a refusal to try and heal eczematous eruptions [38]. This was the attitude of the majority of French dermatologists until the middle of the 20th century, in contrast with the position of Viennese dermatologists who favored a local cause and a local therapy. Not only did French dermatologists advise to respect the eruptions, but they also invented ways to increase them. The so-called serous bloodletting was used for this purpose from 1870 until at least 1924 [39]. We hypothesize that modern controversies about the use of water [40], topical corticosteroids [41] and topical immunomodulators [42] are due in part to the persistence of such a Hippocratic thinking in the lay public and some alternative practitioners, as well as in some mainstream physicians.

Digestive Theories and Diet Atopic dermatitis begins a few weeks after birth and in the majority of patients stops before the age of 2 years. This special timing, which seems incom-

Atopic Dermatitis/Atopic Eczema

5

7

Alkalis, detergents

Infections, local or distant focal

6

3V\FKLF stresses

patible with a genetic disease or an infectious disease, suggested to many physicians that it could be due to milk, the only food taken at this age. This belief led to much contradictory therapeutic advice. The psychological stress and the physical health of the wet nurse was implicated. Human and animal milk were compared and their supposed influence on the health of children was questioned. Marfan, a leading French pediatrician, taught that infantile eczema is linked to digestive disturbances [43]. The nervous component of eczema was also attributed to dyspepsia. When biochemistry developed, the content of the milk in fat, sugar and proteins was studied, and many attempts were made to modify the milk. The pediatric and the dermatologic literature contain hundreds of dietetic advices, none of which have ever proved useful. The positivity of skin tests to food (milk and mainly egg) in children with atopic dermatitis but no digestive symptom has never been clearly understood. Some authors considered they had no causal relationship, others advised the suppression from the diet of foods which were tested positive. However, the advantage of food avoidance has never been clearly established [44, 45], and some cases of severe malnutrition resulted from unwise food evictions [46].

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Fig. 7. In the first edition of Fitzpatrick’s famous textbook, Dermatology in General Medicine, published in 1971, Marion B. Sulzberger [37] represents the etiology of atopic dermatitis as a chain of 10 elements, without hierarchy between them.

Temperature changes

2

At the end of the 19th century, medicine could rely not only on clinical grounds, but also on modern biologic discoveries. The discovery of microscopic parasites, including bacteria, by Pasteur and other researchers led to the belief that all diseases had a microbial cause. Paul Gerson Unna (1850– 1929) described seborrheic eczema and was a talented advocate of the microbial (parasitic) cause of all eczemas [47]. This theory was much discussed at the 1900 Paris International Congress, and the complexity of eczemas, the non-specificity of the morococcus described by Unna, and the difficult interpretations of inoculation experiments led the majority of dermatologists to reject the microbial theory of eczemas. The skin of patients with atopic dermatitis is almost constantly colonized by S. aureus [48], but the meaning of this colonization is not fully understood. Staphylococci are rarely the cause of clinical superinfection. They are believed to trigger eczema flareups, possibly by a superantigenic mechanism [49]. The interest of anti-infectious treatments for the management of atopic dermatitis, however, remains controversial [50]. The severe varicelliform eruption identified by Kaposi and Juliusberg in the 19th century is a specific consequence of vaccinia or herpes inoculation on the skin of atopic individuals [51]. It is currently believed that the reason for atopic individuals’ cutaneous susceptibility to staphylococcal and herpetic infections lies in a defect of innate immunity, one of the constituents of the barrier function of the epidermis [52]. The relationship between micro-organisms and atopy is even more complex. The hygiene hypothesis proposed by Strachan [53] in 1989 postulates that a lack of contacts with bacteria in early childhood could favor an orientation of the immune system towards Th2-related responses, including allergy and auto-immunity. This hypothesis could theoretically explain the apparent recent increase in prevalence of atopic diseases in westernized countries. One of the aspects of the complex interaction between microorganisms and allergy is the influence of the gut mi-

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croflora on the development of digestive and systemic immunity, and the tendency to Th2-oriented, allergic-type responses. A much-publicized clinical trial indicated that probiotics could prevent allergy in newborns at risk [54]. Such favorable results, however, could not be reproduced and this topic remains controversial.

Allergological Theories, Hyposensitization and Allergen Eviction In non-atopic allergic diseases, for example in allergic contact dermatitis, the introduction of the allergen induces the lesions. Its responsibility can be further proved by skin tests which reproduce the lesions, and its eviction eradicates the symptoms. In atopic dermatitis, there are many positive skin tests and elevated circulating IgE against many substances. However, the significance of these allergological data is not clear. They do not point to an external causation (allergens), but rather to an internal condition (atopy, also called the atopic diathesis). The true nature of the interaction between internal (genetic) and external (environmental) factors has never been understood in atopic dermatitis, leaving all physicians and patients experimenting with their own belief of these mysterious relationships. The discovery of elevated IgE blood levels in atopic dermatitis [30] stimulated the hope that this could represent a faithful biologic diagnostic test. IgE is indeed important in the pathophysiology of atopy, and its presence on Langerhans cells of atopic individuals is also an important discovery [55], but these are non-specific findings which cannot be used as diagnostic tests. Elevated IgE against dietary allergens, skin tests, scratch tests, prick tests, intradermal tests and the more recent atopy epidermal patch tests were never considered a convincing proof of the allergens’ responsibility. Double-blind placebo-controlled oral food challenges have been advocated as the gold standard for food allergy in conditions such as atopic dermatitis [56], yet are seldom performed. Children with atopic dermatitis and digestive symptoms could possibly benefit from a digestive investigation. However, for the majority of children with atopic

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Parasitic/Bacteriological Dimension of Eczema

Fear of Treatment Side Effects At the beginning of the 20th century, infantile eczema was known among pediatric diseases for a lethal threat through the rapid death of eczematous children when they were hospitalized. Eczema has been long considered a contra-indication to hospital admission because of the frequency of a syndrome consisting of apparent improvement of the skin condition coupled with pallor, high fever and death. Some authors thought that the cause of death was the rapidity with which eczema had improved, and many theories were discussed. The infectious nature of this syndrome was claimed by Hutinel and Rivet [57] and became evident after the use of antibiotics in the 1950s. Since the report by Sulzberger and Witten [58] in 1952, it has become well established that topical corticosteroids are highly efficient in the treatment of atopic dermatitis. In acute, early eczema, daily applications stop the oozing and bring an almost complete resolution in a few days. Maintenance treatment (currently called proactive therapy) prevents relapses in the majority of cases. Safety is excellent with careful use of topical corticosteroids. In spite of this truly revolutionary progress, many children are not adequately treated and this is probably the cause of many chronic evolutions and complications. The reason for this underutilization of an efficient treatment has been identified as a corticophobia, or topical corticophobia. It is mainly due to an overestimation of the side effects of corticosteroids and confusion between the safety of oral and topical corticosteroids. Corticophobia [41] is a widespread problem that should be solved by a more careful attention to patients’ beliefs and wishes in order to increase their confidence in physicians and scientific medicine. Atopy schools and workshops for therapeutic education are the mod-

Atopic Dermatitis/Atopic Eczema

ern answer to this sequel of the humoralistic way of thinking [59]. Topical immunomodulators were recently developed as a new class of anti-inflammatory topical drugs [60]. They were widely accepted, partly due to the reluctance to use topical corticosteroids in the long term, particularly in children and on the face or areas of thin skin, such as the eyelids. In February 2005, the Food and Drug Administration recommended ‘black box’ warnings for these drugs because of concern of potential increased risk of skin cancer and lymphoma. This issue is still controversial [61]. This warning and the following controversy can be viewed by clinicians and patients as an additional argument for fearing efficient treatments.

2

Neuropsychological Considerations Psychological factors have long been recognized as important triggers of atopic dermatitis flares. The wet nurses’ or nursing mothers’ stresses were considered to be the cause of milk modifications, inducing eruptions. The link between psychologic or psychiatric events, however, is difficult to rationalize and little attention has been paid to a psychiatric approach in the dermatological literature. Brocq, who created the term ‘neurodermitis/névrodermite’, and his contemporary dermatologists discussed the importance of the nervous system in pruritus, prurigos and lichenifications. Some even advocated the removal of cerebrospinal fluid by spinal tap for the treatment of prurigos [62], although this produced irregular results. Psychology-based treatments are less aggressive, if not easier to evaluate. The attention to the psychological and sociological consequences of chronic diseases has recently led to the concept of quality of life scores. Atopic dermatitis is a condition which severely impairs quality of life. Some quality of life scales are valid for all diseases, some are specific for skin diseases in general, some are specific for atopic dermatitis [63], and some also evaluate the consequences of atopic dermatitis on the quality of life of family members. The neurological pathogenesis of pruritus is another component of the link between atopic dermatitis and the central nervous system [64].

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dermatitis there is usually no digestive clinical disease and investigation of sensitization to food is left to severe cases. Hyposensitizations are similarly useless, with the occasional exception of food allergy symptoms, and are rarely employed for eczema itself.

Szentivanyi [65] proposed that a relative blockade in β-adrenergic responses could explain immediate respiratory and cutaneous allergy. Abnormalities in the functions of many immunological cells, such as T cell subpopulations, B cells, antigen-presenting cells, eosinophils and basophils, have been described in atopic dermatitis. One unifying explanation has been proposed: the increase in phosphodiesterase activity [66].

Dermatological Approach and Topical Therapy It is clear from the above considerations that until recently the skin itself played a small role, if any, in the attempts to understand the pathophysiology of atopic dermatitis. Humoralist physicians believing in the importance of humors, pediatricians believing in the importance of diet and immunologists believing in the importance of circulating IgE had little consideration for the skin itself, not to speak of the stratum corneum, the outer layer of the epidermis, commonly considered as being made of ‘dead’ cells. Things began to change in the 1990s with hypotheses speculating on the importance of the epidermal barrier in epicutaneous allergenic sensitization and possibly other aspects of atopic dermatitis [67, 68]. Dryness of the skin is one of the most important minor criteria of atopic dermatitis. Epidermal abnormalities had been described which could explain this dryness, such as a decreased level of ceramides [69] or an abnormality in the metabolism of essential fatty acids [70]. These biochemical discoveries led to numerous trials of topical or oral interventions on the metabolism of epidermal lipids, with conflicting results. We have not reported the numerous genetic studies which have led to the identification of many loci and candidate genes linked and associated with atopic dermatitis. Some of them code for molecules of acquired immunity, including interleukins 4 and 5, their receptors, and chains of IgE receptors. The most significant genetic discovery, however, was

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made in 2006 when an Irish-Scottish team headed by I. McLean discovered that mutations in the filaggrin gene are a major predisposing factor for atopic dermatitis [71]. It was later demonstrated that filaggrin mutations are correlated with the severity of atopic dermatitis and, more importantly, with respiratory atopy, including asthma [72]. A new paradigm thus emerged, which gives priority to the epidermis in the pathophysiology of cutaneous and respiratory atopy. Recent experimental work has shown that skin barrier defects such as filaggrin deficiency or proteases hyperactivity can induce the epidermal production of TSLP (thymic stromal lymphopoietin), a cytokine inducing an asthmatic phenotype [73]. This is a contemporary area of research which is not yet part of history. We wish to underline, however, that this epidermal pathogenesis of atopy already has therapeutic implications [74], including the important role of emollient therapy to maintain the epidermal homeostasis, prevent allergenic transepidermal penetration and the subsequent induction of inflammation.

Conclusion Atopic dermatitis is a complex disease. Many of the theoretical and practical unsolved questions are enlightened by a consideration of the medical doctrines that have been prevalent in Western medicine since antiquity. The humoralist doctrine led to the belief that skin eruptions should not be treated. The allergological doctrine implies that hypersensitivity is the cause of the eczematous eruptions. A more dermatological approach leads to a pragmatic synthesis of epidermal defects, including the permeability barrier and innate immunity, atopic hypersensitivity, and the interaction between the nervous system and the skin.

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Other Hypotheses

References

Atopic Dermatitis/Atopic Eczema

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50 Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS: Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 2009;123:e808–e814. 51 Barton RL, Brunsting LA: Kaposi’s varicelliform eruption. Arch Derm Syph 1944; 50: 99–104. 52 Hata TR, Gallo RL: Innate immunity in atopic dermatitis; in Bieber T, Leung DYM (eds): Atopic Dermatitis, ed 2. New York, Informa Healthcare, 2009, pp 101–119. 53 Strachan DP: Hay fever, hygiene, and household size. BMJ 1989;299:1259–1260. 54 Kalliomäki M, Salminen S, Arvilommi H, Kero P, Koskinen P, Isolauri E: Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001;357:1076–1079. 55 Bruynzeel-Koomen C, van Wichen DF, Toonstra J, Berrens L, Bruynzeel PL: The presence of IgE molecules on epidermal Langerhans cells in patients with atopic dermatitis. Arch Dermatol Res 1986; 278: 199–205. 56 Sampson HA, McCaskill CC: Food hypersensitivity and atopic dermatitis: evaluation of 113 patients. J Pediatr 1985;107:669–675. 57 Hutinel V, Rivet L: Septicémies graves au cours des affections cutanées des jeunes enfants. Arch Méd Enfants 1909;12:1–20. 58 Sulzberger MB, Witten VH: The effect of topically applied compound F in selected dermatoses. J Invest Dermatol 1952; 19: 101–102. 59 Staab D, Diepgen TL, Fartasch M, Kupfer J, Lob-Corzilius T, Ring J, Scheewe S, Scheidt R, Schmid-Ott G, Schnopp C, Szczepanski R, Werfel T, Wittenmeier M, Wahn U, Gieler U: Age related, structured educational programmes for the management of atopic dermatitis in children and adolescents: multicentre, randomised controlled trial. BMJ 2006;332:933–938.

60 Ruzicka T, Bieber T, Schöpf E, Rubins A, Dobozy A, Bos JD, Jablonska S, Ahmed I, Thestrup-Pedersen K, Daniel F, Finzi A, Reitamo S: A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997;337:816–821. 61 Ring J, Möhrenschlager M, Henkel V: The US FDA ‘black box’ warning for topical calcineurin inhibitors: an ongoing controversy. Drug Saf 2008;31:185–198. 62 Thibierge G: Ponction lombaire dans les dermatoses prurigineuses. CR du Xe congrès français de médecine. Paris, Masson, 1910. 63 Whalley D, McKenna SP, Dewar AL, Erdman RA, Kohlmann T, Niero M, Cook SA, Crickx B, Herdman MJ, Frech F, Van Assche D: A new instrument for assessing quality of life in atopic dermatitis: international development of the Quality of Life Index for Atopic Dermatitis (QoLIAD). Br J Dermatol 2004;150:274–283. 64 Tominaga M, Ogawa H, Takamori K: Possible roles of epidermal opioid systems in pruritus of atopic dermatitis. J Invest Dermatol 2007;127:2228–2235. 65 Szentivanyi A: The beta-adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 1968;42:203–232. 66 Hanifin JM, Chan SC: Monocyte phosphodiesterase abnormalities and dysregulation of lymphocyte function in atopic dermatitis. J Invest Dermatol 1995; 105(suppl 1):84S–88S. 67 Ogawa H, Yoshiike T: A speculative view of atopic dermatitis: barrier dysfunction in pathogenesis. J Dermatol Sci 1993; 5: 197– 204.

68 Taieb A: Hypothesis: from epidermal barrier dysfunction to atopic disorders. Contact Dermatitis 1999;41:177–180. 69 Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano: Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? J Invest Dermatol 1991;96:523–526. 70 Melnik BC, Plewig G: Is the origin of atopy linked to deficient conversion of omega6-fatty acids to prostaglandin E1? J Am Acad Dermatol 1989;21:557–563. 71 Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O’Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH: Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38: 441– 446. 72 Weidinger S, O’Sullivan M, Illig T, Baurecht H, Depner M, Rodriguez E, Ruether A, Klopp N, Vogelberg C, Weiland SK, McLean WH, von Mutius E, Irvine AD, Kabesch M: Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol 2008;121:1203–1209. 73 Demehri S, Morimoto M, Holtzman MJ, Kopan R: Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol 2009;7:e1000067. 74 Elias PM: Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Ann Dermatol 2010;22:245–254.

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Dr. Daniel Wallach Department of Dermatology Hôpital Tarnier-Cochin 89, rue d’Assas FR–75006 Paris (France) E-Mail dwallach @ noos.fr

atopic eczema.

Atopic dermatitis was described in 1933 but exists since antiquity. We review descriptions of a childhood skin disease compatible with our modern diag...
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