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Keywords:

  • allergen-specific IgE;
  • atopic eczema;
  • atopiform dermatitis;
  • atopy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

Please cite this paper as: Atopic eczema or atopiform dermatitis. Experimental Dermatology 2010.

Abstract:  Age period prevalence of atopic eczema (AE), a very common skin disease, has increased during the past decennia. This expansion seems to be ending in wealthy countries, while an increase is observed in developing nations, for which there is no firm explanation. Recent steps in understanding AE are the detection of skin barrier related filaggrin null mutations in approximately 25% of patients and the recognition of IL-31 as a molecule possibly involved in the itch (pruritus). Also interesting are the recognition of thymus and activation-regulated chemokine (TARC) and proliferating-inducing ligand (APRIL), as being associated with AE severity and activity. Immunocentric and corneocentric views on pathogenesis (the inside-outside paradigm) and the diagnostic entity atopiform dermatitis (AFD) are discussed here. We emphasize that diagnosing AE is not simple but challenging. We accentuate that a diagnosis of AE is only possible when there is allergen-specific IgE. Advice as to the need for elimination of allergens and adjustment of lifestyle are only proficient in patients having atopy and true AE, not in those having AFD.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

Atopic eczema (AE) is a very common disease which is known under many different names, such as constitutional eczema, neurodermitis, and allergic eczema. The semantics have been thoroughly described in ‘Histoire de la dermatite atopique’ by Wallach, Taïeb, and Tilles (1). The word ‘Allergie’ (‘allergy’) is over 100 years old, introduced by Von Pirquet (2), while the word ‘atopy’ dates from 1922 (3), quite well before IgE was recognized (4). Presence of IgE on cutaneous mast cells was then identified and its binding to Langerhans cells in AE was first described in 1986 (5). Functional subpopulations of human T cells, with the principal role for type 2 T cells in central immune organ IgE production, were first revealed in 1990 (6,7). This short early history illustrates how central IgE is in the atopy syndrome.

AE is part of this syndrome, in which patients may develop allergic asthma, rhinitis, conjunctivitis, food allergy, allergic contact urticaria, and AE in any order and in any combination over time. Production of allergen-specific IgE is the inner characteristic of the syndrome. In the world of dermatology, this is not a generally accepted concept. Patients having the clinical phenotype of AE, but without detectable allergen-specific IgE, have been given different diagnoses including non-allergic eczema and intrinsic AE, as opposed to extrinsic AE where allergen-specific IgE is present. We have suggested using the term atopiform dermatitis (AFD) in these cases, clearly indicating that it has the clinical phenotype of AE, but there is no atopy (8). In clinical practice, the term intrinsic AE is hardly in use. We hope that the term AFD will be more acceptable.

The term ‘atopy march’ is in use to describe the common pattern in which patients develop AE early in life, asthma in youth, and rhinitis in adulthood (9). A pathway in time related to the eczema itself is that patients have, to begin with, an abnormal skin barrier leading to eczema, followed by allergen penetration and sensitization, ending with IgE-mediated autosensitisation to non-atopic auto-allergens (10). This hypothetical model of changes in reactivity over time in AE needs to be further substantiated.

Pruritus, visible as excoriations and prurigo lesions, is the major symptom. Pruritus is so dominant that AE is also known as ‘the itch that rashes’. There is no laboratory-test based diagnosis possible today. Histopathology is supportive but not definitive. For clinicians, it is difficult to give a precise definition of this disease that has so many different clinical phenotypes, is characterized by such a large variety in severity, and is so unpredictable in its natural course in the individual patient. In addition, there are a substantial number of entities to be considered in a differential diagnosis (see online Supporting Information, Table S1). Therefore, uniform diagnostic criteria are necessary.

In this paper, definitions of AE and AFD, diagnostic criteria, epidemiology, distribution patterns, aetiology and prevention and management will be described.

Definitions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

AE has a wide spectrum of dermatological manifestations and there is disagreement about its definition. The requirements of a disease definition are that it should result in an optimum discrimination; it should be easy to remember and to use, correspond to the current clinical concept of the disease and be acceptable as an accurate tool for studies (11).

Genetic definition

From a genetic point of view, AE is a multitrait disorder and susceptibility loci (ATOD1-6) as well as single nucleotide polymorphisms (SNPs) have been described. Within the past 2 years, it has become apparent that of these susceptibility loci, ATOD2 known to be localized in the ‘epidermal differentiation complex’ on chromosome 1q21 harbours the filaggrin gene for which null mutations have been found. Filaggrin has a role in keratin cytoskeleton aggregation during epidermal differentiation and corneocyte formation, when cells of the granular layer collapse into corneal layer scales.

Mutations resulting in loss of filaggrin production, both rare and prevalent forms, have been identified in approximately 25% of AE patients in Western, mainly white Europeans (12–20). There is as yet no explanation for the remaining 75% of AE patients where the filaggrin gene is unaffected, or what is happening in 8% of the population who have a filaggrin null mutation but who have no atopy or AE.

Epidemiological definition

For epidemiological studies clear and simple definitions of AE and applicable diagnostic criteria are needed to enable large population studies using questionnaires or interviews such as by internet or telephone.

Clinical definition

We have recently reviewed the diagnostic criteria available for AE and the most important of them will be described below in the section ‘Diagnostic criteria’ (21). Most of them are entirely clinical.

Patients having the clinical phenotype of AE, but without allergen-specific IgE, are the focus of an ongoing debate. A major step was made by introducing the terms intrinsic and extrinsic AE (22). ‘Intrinsic atopic eczema’ is the term probably first coined by Wüthrich for patients having the phenotype of AE but without detectable allergen-specific IgE (23). In extrinsic AE, external allergens are assumed to sensitize the patient by penetration of a disturbed epidermal barrier.

There are two major problems with using the terms ‘intrinsic’ and ‘extrinsic’ and not AFD and AE, respectively. The genetic and thus intrinsic predisposition to produce allergen-specific IgE is by definition the core of atopy and the atopic syndrome. Using ‘extrinsic’ for what is actually ‘intrinsic’ is confusing. Second, using the term ‘intrinsic AE’ indicates that the patient is atopic (the A in AE) but in fact that is not the case.

This clinical entity has also been called the ‘non-allergic form of AE’ (24), ‘non-atopic flexural eczema’ and ‘non-allergic atopic eczema/dermatitis syndrome’ (AEDS) (25,26), all using the word ‘atopic’ which is confusing and perhaps an oxymoron. The term non-atopic dermatitis has also been proposed (10) but from a clinical point of view, that term is non-informative, as many forms of eczema exist, other than atopic.

Diagnostic criteria

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

During the last decades various lists of diagnostic criteria for AE have been proposed and validated, but uniformity in the use of diagnostic criteria for AE is lacking. Agreement about the definition of AE and widely accepted diagnostic criteria are needed to conduct future valuable studies and to compare, if applicably pooled, results of studies.

The most frequently used set of clinical criteria for the diagnosis of AE is that of Hanifin and Rajka (H&R). H&R criteria published after a meeting in 1980 have been used in genetic, biological, immunological, epidemiological and clinical studies ever since (27). Only two efforts have been directed at validating these H&R criteria (21).

The UK Working Party has tried to further identify and validate sets of clinical criteria (28–30). They went through the various stages of developing criteria, starting with a hospital-based population and ending with community oriented studies (31,32).

Together with the Millennium Criteria described below, the three sets are summarized in Table 1. It is difficult to explain why the original H&R criteria are still used frequently, and the best validated system, that of the UK Working Party, has not replaced them (21).

Table 1.   Diagnostic criteria for AE
Atopic eczema diagnostic criteriaH&RUK WPMillennium
  1. H&R: Hanifin & Rajka’s criteria, UK WP, U.K. Working Party’s Diagnostic criteria, Millennium: Millennium Criteria.

Mandatory+++ 1+++1+++
Major++3/4++ 2/3++
Minor+3/25+3/5+ 
Pruritus+++++++
Typical morphology and distribution of skin lesions+++++
Chronic or relapsing course++ ++
Personal or family history of atopy+++ 
Presence of allergen specific IgE  +++
Xerosis++ 
History of flexural involvement + 
Rash under age of 2 years + 
29 other minor criteria+ +

In the Millennium Criteria (MC), there is one mandatory criterium which is biological and immunological in nature (33). Presence of allergen-specific IgE in a given patient is a prerequisite for using the word atopy. A diagnosis of AE thus can only be made when there is allergen-specific IgE. Next, patients have to fulfil two of three major criteria which overlap with those of H&R and with those of the UK Working Party. Minor criteria were rearranged but are not necessary for the diagnosis. The MC have been recently validated and refined, and compared to the other sets mentioned (Brenninkmeijer et al. 2009, Diagnostic criteria for AE: validation and simplification of the millennium criteria; submitted). The MC performed well in our hospital-based setting (100% sensitivity, 88.6% specificity). Overall accuracy of the MC was 88.6%. Out of the MC, we identified the best discriminatory principal and additional criteria of the Millennium Criteria by using tree analysis. Tree analysis is an algorithmic model that splits up the data-set by detecting the best predictor of AD among the candidate criteria, creating associated subgroups of suspected AD and suspected non-AD patients until no more statistically significant predictors can be found.

Epidemiology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

Considerable efforts have been made to advance our understanding of the epidemiology of the disease. However, it must be noted that there are problems associated with performing accurate prevalence studies in AE. A major caveat in comparing epidemiological studies in AE is that the definition of AE and the methodological quality vary considerably from study to study.

A wide range of diagnostic criteria are used in prevalence studies of AE in epidemiological studies. As diagnostic criteria such as the Hanifin and Rajka and U.K. Working party criteria tend to be more time consuming (though more accurate), questionnaires are often used in large epidemiological studies (27,29). These questionnaires vary from asking parents whether their child has a rash, to addressing parents whether their child has been diagnosed with AE (34,35). As shown by validation studies of diagnostic and epidemiologic criteria that estimate prevalences using different criteria, substantial variation in prevalence outcome within the same population has been shown (36–38).

The International Study of Asthma and Allergies in Childhood (ISAAC) provided a standardized method for estimation of prevalences of all atopic diseases within and between countries over the world (39). In 1998, the prevalence of AE in 56 countries was measured using the ISAAC questionnaire; prevalences ranged from 0.3% to 20.5%. Using ISAAC on large scale contributes to comparable prevalence outcomes worldwide. In the past, validation studies showed lack of validity in diagnosing AE compared to clinical diagnosis and diagnostic criteria (36,40). This was overthrown by a recent study of Flohr et al. in which the ISAAC questionnaire showed a high correlation with clinical examination in 30 000 children (41).

Table S2 shows a summary of 1-year period prevalences from different epidemiological studies in different age groups and countries worldwide (Schram et al. 2009: Overview of prevalence studies on atopic dermatitis; submitted). From these data, though heterogeneous, it may be concluded that AE is a very common disease in the infantile and juvenile age periods and that probably at least one of every 30 adults has one or more periods of AE.

Although the definition of AE in these studies varies widely, there is hardly any doubt that during the second half of the 20th century, there has been an increase of the prevalence of AE in wealthy countries (35,42), for which various explanations have been put forward. At first sight the rise is difficult to understand given that AE is a multitrait genetic disorder. Environmental factors clearly have a major role in the expression of the disease and thus, in the genotype-phenotype switch. The idea that the increase in prevalence might be due to secular changes in diagnosing instead of real changes in disease prevalence, is easily overthrown by the increase in the presence of allergen-specific IgE in the general population (43,44). The increasing prevalence of atopy has come to a standstill now, at least in some wealthy countries (45), while it increases in developing nations (46).

A major theory explaining the increased prevalence and incidence of AE and atopy in general is the ‘hygiene hypothesis’ (47–50). In summary, that view indicates that lack of microbial stimulation in the newborns’ immune system due to hygienic environments in modern societies has resulted in lack of signals diverting type two responses to regulatory and type 1 T cell responses.

Finally, the percentage of AFD (intrinsic AE) patients primarily diagnosed as AE varies from 6.9% to 55.6%, and in our own study was found to be 8% (Table S3) (51). A systematic review on this subject showed that the proportion of IgE sensitisation among phenotypic AE was more frequent in hospital than in population-based studies (52). In other words, the percentage of AFD patients primarily diagnosed as AE is higher in a population-based setting. In Table S3, an overview of these prevalence studies of AFD among AE patients is given. This illustrates the imprecision of diagnostic systems in daily use and is an argument for systematic testing of patients for presence of allergen-specific IgE. Informing patients that they have AE without demonstrating that they have atopy may result in disinformation in up to an appalling 55.6% of these patients, a percentage depending on country and clinic.

Distribution patterns and clinical phenotypes

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

Variations in localisations of eczema occur with age. Infantile, juvenile and adult types are usually, but not always discerned (53–55). In 45–60% of children, onset of AE occurs during the first 6 months of life and this ‘infantile AE’ runs until 2–3 years of age (56). In this phase, the typical distribution pattern is that of a balaclava (57), with eczematous and highly pruritic lesions on the head and neck, sparing the periorbital and perioral regions. In many cases, weeping and crusting occur. In ‘juvenile AE’, the flexural phenotype ensues. This childhood phase normally lasts from the age of 2–3 until puberty (13–15 years old). Typically, lesions are localized in the neck, and in the elbow and knee folds (Fig. S1a,b). In ‘adult AE’, in addition to this juvenile flexural distribution, there is pronounced involvement of wrists and ankles, and facial and neck eczema become common It must be emphasized that these are clinical observations, which still need confirmation in well designed studies. An example of AFD, showing how similar it is to AE, can be seen in Fig. 1.

image

Figure 1.  Atopiform dermatitis. In this 22-year-old woman, atopic eczema-like lesions have been present for many years. The elbow folds show a typical erythematous eczema with some papulation, excoriations, lichenification and ill-defined borders. IgE-levels were normal and allergen-specific IgE could not be detected at different points in time. The family history for atopy was negative, and the patient had never had symptoms of asthma or rhinitis.

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Some clinical eczema variations are called AE but without justification. Dyshidrotic eczema is associated with atopy in about 50% of cases, but should not be called AE. Nummular eczema is also common in atopy patients and it should be diagnosed as such: nummular eczema in an atopy patient. Next, there is a predisposition to develop irritant contact eczema of the dorsal side of the hands (and feet) in AE patients, but this, again, should not be called AE, but irritant contact eczema in a patient also having AE. Finally, erythroderma may occur during the course of AE. That should be called erythroderma in a case of AE, not AE as such.

Aetiology: the inside – outside paradigm

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

There is no consensus among dermatologists whether or not the terms ‘atopy’ and ‘atopic’ can only be used when presence of allergen-specific IgE is detectable, but we believe it is essential. A number of investigators including dermatologists and allergologists, taking part in a WAO consensus meeting, agreed that atopy is primarily characterized by the presence of allergen-specific IgE (25). Remarkably, studies that were directed at identifying the prevalence of atopy and that were published in high-ranking journals such as The Lancet and the New England Journal of Medicine used this mandatory criterium as well (43,45).

The major alternative for the inside (immunocentric – IgE-based) aetiology of AE is what can be named the outside (corneocentric) view. In that hypothesis, AE is primarily seen as a disorder of the skin barrier, characterized by malfunction of the corneal layer. Observations supporting this view are increased activity of endogenous (58) and of exogenous proteases such as house dust mite derived Der p 1 and Der f 1, perhaps combined with a deficiency in protease inhibition (59), leading to degradation of corneodesmosomes and a disturbed skin barrier, and filaggrin gene null mutations (see below), also leading to decreased skin barrier function. As a result, (parts of) allergens are suggested to be able to penetrate the epidermal barrier and lead to immunological sensitization. An important weakness of this extrinsic or corneocentric view is that there is no corneal layer in the epithelia of the pulmonary and gastrointestinal tracts, implying that everyone should be sensitized following allergen penetration as these mucosal interfaces with the environment have no corneal layer.

Perhaps there is a (speculative) way to bring the immunocentric and corneocentric views together. Filaggrin is not only expressed and functional in the skin but Hassall’s corpuscles in the thymus also express filaggrin (60). A possible effect of diminished filaggrin expression in the thymus on lymphocyte maturation and selection has as yet not been studied, but Hassall’s corpuscles have a role in the induction of regulatory T cells (61). The thymus is enlarged in children with AE (62) and abnormal levels of circulating immature T cells have been detected in AE (63).

Although much is known about cellular and humoral abnormalities in the skin immune system of AE patients [recently summarized by Homey et al. 2006 and Bieber 2008 (10,64)], we are still in the hypothetical stage as to explaining what is going wrong and in what order this occurs in the skin lesions of AE. The role of allergens and of IgE on mast cells (clearly involved in allergic contact urticaria) and on dendritic cells is insecure.

A major development was the recognition of functional subsets of T cells which by their cytokine production profile, may be divided into Th1 cells (mainly producing IFN-γ) and Th2 cells (mainly producing IL-4, IL-5 and IL-13). Langerhans’ cells of the skin are believed to contribute to Th2 polarization (65,66). Th2 cells have been implicated in stimulating B cells to become IgE producing plasma cells. Atopy thus may be seen as a syndrome in which for as yet unexplained reasons there is central immune dysregulation. Recent work indeed shows that myeloid and plasmacytoid DC isolated from peripheral blood of AE patients have an aberrant function compared to healthy controls, as they have a significantly decreased capacity to produce cytokines (IL-12) that may favour a Th2 cell response (67,68).

The concept of Th1 and Th2 cells was subsequently applied to AE lesions. It has been suggested that early in the development of AE lesions, Th2 cells dominate, while later Th1 cells become leading, the so called Th2-Th1 switch (69–71). There is one study that found that the majority of housedust mite-specific T cell clones generated from AE skin produced IFN-γ. These T cells were extracted and cloned out of ‘chronic’ AE lesions (72). The authors interpreted this as a confirmation of the hypothesis that a Th2-Th1 switch occurs in AE, and this is a study that is frequently referred to by other authors. However, in the remainder of the studies early AE lesions were represented by atopy patch tests and it may be questioned whether or not these are representative of early, new lesions of true AE.

Many chemokines, including CC chemokine ligand 18 (CCL18), thymus and activation-regulated chemokine (TARC) are known to be expressed in AE patients. Park et al. recently found that the chemokine micromilieu, and especially levels of CCL18, differed substantially between AE and AFD and that levels of CCL18 significantly decreased after immunotherapy (73). TARC, a chemokine that attracts CC chemokine receptor 4 or 8 -positive cells, was found to be associated with AE (74). Also, proliferating-inducing ligand (APRIL), a member of the tumor necrosis factor (TNF) family was identified as being associated with AE severity and activity (75).

Besides their role in understanding the pathogenesis of AE and AFD, the last two substances are emerging as markers for disease severity and could potentially be an objective outcome measurement for therapeutic interventions.

There are many other cytokines, chemokines and other mediators of inflammation possibly involved, for which readers are referred to excellent recent reviews (10,64,76). A new development has been the detection of IL-31 in AE (77–81). IL-31 is highly pruritic and it may be a major mediator of itch in T-cell mediated chronic inflammation in AE, in addition to the usual suspects histamine, neuropeptides, proteases and kinins. Large scale studies are currently being done to reveal its role in AE.

Furthermore, it is expected that molecular genetics and phenotyping as well as broader allergy testing with microarrays will solve many of the nosological problems we now have with the disease. Various gene localizations and polymorphisms have been associated with AD, the most notably the association with null mutations in the filaggrin gene. Recently, polymorphisms within the C3 gene were identified that were associated with less serum-specific IgE levels and milder disease expression (82). Thereby suggesting a role of these polymorphisms in the aetiology of AE. But is seems we are only at the beginning of full genetic testing.

In Fig. 2, a loop of possible pathogenetic events is presented, based on recent reviews on AE immunopathogenesis (10,64). A vicious circle of pathogenetic events represents the lack of insight into where the AE lesions actually begin.

image

Figure 2.  Pathogenesis of atopic eczema. AE may be seen as a vicious circle of pathogenetic events in which it is as yet uncertain where it starts. Central is the immunological background of atopy in which a systemic abnormality may be present, perhaps at the level of plasmacytoid dendritic cells (pDCs) which by their abnormal cytokine production profile preferentially induce type 2 T cells (Th2) in the secondary immune organs such as lymph nodes. Pruritus, to begin with, leads to stress and vice versa, and the resulting skin excoriations add to an already existing skin barrier defect. The damage to epithelial cells leads to the production of pro-inflammatory mediators that recruit leukocytes, such as monocytes, eosinophils and T cells, into the lesions. These T cells are activated by dendritic cells that are supposed to present allergens and superantigens to them. The route by which these antigens reach the skin is as yet undetermined but many assume they directly enter the skin through the damaged skin barrier. The activation of type 2 T cells, for which there may be a role for abnormal pDCs, is of particular importance as their production of IL-31 seems to be a major mediator of the pruritus.

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Prevention and management

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

In practice today, most physicians do not make a difference between AE and AFD (or intrinsic AE). From a scientific point of view, little is known about differences in efficacy of preventive and other management procedures, such as topical steroids, phototherapy, or immunomodulating agents. It may be anticipated that avoidance of (food) allergens makes no sense in AFD. It also is to be predicted that innovative therapies such as anti-IgE will not be effective in AFD.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

From the epidemiological data, though limited in precision, it may be concluded that AE is a very common disease in the infantile and juvenile age periods and that probably at least one of every 30 adults has one or more periods of AE. That makes it one of the most common skin disorders throughout all ages, underscoring the need for further consensus on its definition and its diagnostic criteria. In order to make further progress, we think it is essential to adopt a uniform definition, in which the term ‘atopy’ is, logically, only used in patients having demonstrable ‘atopy’, thus allergen-specific IgE. Patients having the phenotype of AE without atopy should be given a diagnosis of AFD. Accepting that has major implications for management and patient information on a worldwide basis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definitions
  5. Diagnostic criteria
  6. Epidemiology
  7. Distribution patterns and clinical phenotypes
  8. Aetiology: the inside – outside paradigm
  9. Prevention and management
  10. Conclusions
  11. References
  12. Supporting Information

Figure S1. (a,b) Atopic eczema. In this 12-year old girl, with typical lesions in the neck and arm, eczema is represented by some papulation, excoriations, lichenification and ill-defined borders.

Table S1. Flexural and/or cheek eczema: Differential diagnosis in patients with AE clinical phenotype [based in part on Leung et al. 2004 (83)].

Table S2. Age period prevalence of AE in five continents over the last 15 years, based on 1-year period prevalences.

Table S3. Frequency of AFD among AE in various studies.

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EXD_1024_sm_f1a.jpg1397KSupporting info item
EXD_1024_sm_f1b.jpg507KSupporting info item
EXD_1024_sm_tS1-S3.doc142KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.