Atopic eczema has, in many countries, a lifetime prevalence of at least 10%. Would anyone believe that the definition of this common disease is a matter of debate today? Surprisingly, it is and the international scientific community is highly divided over it.
Diagnostic criteria for the definition of atopic eczema
In 1979, experts attended a meeting and defined atopic eczema as a pruritic skin disease with four major and 23 minor clinical criteria. Patients had to have three of the four major and three of the 23 minor criteria before being given the diagnosis. The 1980 article (authored by Hanifin and Rajka Citation[1]) that resulted from this consensus conference is now a citation classic. It is an epidemiological definition, in which patients have to comply with a number of clinical signs and symptoms, as well as with some findings revealed by the patient’s history.
Immunological criteria for the definition of atopy & atopic syndrome
Immunologists agree that atopy is defined by an immunological imbalance in the central immune organs, where B cells are instructed by type 2 T cells to start producing antibodies, in particular allergen-specific immunoglobulin (Ig) E. The reason for this is unknown but may be related to delayed maturation of the immune system in atopic newborns Citation[2]. Our immune system is type 2 T-cell oriented when we are born. The reason is obvious: within a year, we will lose the transplacentally obtained acquired immune protection, represented by the passive acquisition of antibodies from our mother. Normally, the immune system restores later to a more balanced and less type 2 T-cell-oriented situation. In patients genetically predisposed to atopy, such maturation is thought to be delayed.
If the type 2 switch remains on for too long, IgE enters the circulation and reaches the Fcε receptors on cells of the organs involved primarily in clinical manifestations of atopy. In the respiratory tract, allergic rhinitis and asthma may ensue. In the gastrointestinal tract, food allergy is sometimes the result. In the skin, urticaria and eczema are the organ-specific end results of mast and dendritic cell-binding of these antibodies, respectively.
Strangely enough, many dermatologists appear to be the only specialists resisting this immunological and laboratory based definition of atopy. They see patients with the flexural phenotype of atopic eczema, with or without a family history of atopy, but without detectable allergen-specific IgE, and they still call it atopic. At a more basic investigative point of view, some hold the vision that atopic eczema is primarily a cutaneous, epidermal abnormality. The skin barrier is impeded in the first place and allergic and immunological phenomena are secondary to that. The recent finding that atopic dermatitis patients have common loss-of-function variants in the epidermal barrier protein filaggrin gives further support to this view Citation[3].
Immunological criteria for the definition of atopic eczema
Our research group proposed that the presence of allergen-specific IgE is a prerequisite for a diagnosis of atopic eczema (atopic dermatitis), similar to it being a prerequisite for diagnosing atopy or atopic syndrome in a given patient. The ‘millennium criteria’ were introduced to improve the Hanifin and Rajka criteria with the addition of allergen-specific IgE as a mandatory criterion Citation[4]. When a patient presents with a disease resembling atopic eczema but atopy cannot be detected (allergen-specific IgE is undetectable in blood and/or skin tests), a diagnosis of ‘atopiform dermatitis’ should be made Citation[5]. Our group believe that is a better term than ‘intrinsic atopic dermatitis’ because that still implicates that patients are ‘atopic’ Citation[6].
What then is going on in atopiform dermatitis?
It is probable that systematic consideration of a differential diagnosis, including atopiform dermatitis, will lead to more alertness in diagnostic processes. Patients that present, at first sight with an obvious diagnosis of atopic dermatitis might, when considering a differential diagnosis, be given a more appropriate diagnosis, such as nummular dermatitis or irritant contact dermatitis. It is highly possible that a proportion of patients that present with atopic dermatitis who have no allergen-specific IgE, in fact, have another disease.
There will, however, still be a small number of patients who really have the phenotype of atopic eczema, who fulfill the Hanifin and Rajka criteria and who have no detectable allergen-specific IgE. There are several explanations and hypotheses to explain this:
| • | The allergen-directed inflammatory response has slowly evolved into an autoantigen-directed chronic immune reaction Citation[7,8]; | ||||
| • | Methods to detect allergen-specific IgE are not sensitive enough; | ||||
| • | There are IgE antibodies, but only on dendritic cells, not on mast cells and not in the circulation (‘entopic atopic dermatitis’), therefore, no detection by skin or blood tests; | ||||
| • | Patients are not sensitized for inhalant and food allergens but for microbial agents Citation[9]. They are not detected by routine allergen panel tests for atopy; | ||||
| • | A subset of type 2 T cells not capable of producing interleukin-4 may be active, thus not stimulating IgE production Citation[10,11]; | ||||
| • | Unidentified allergens may play a role, also not detected by routine allergen panels. For example, sensitization may exist for the ubiquitous airborne fungal antigens derived from Coprinus comatusCitation[12]. | ||||
Pitfalls when denying the immunological origin of atopy & atopic eczema
As a result of the incomplete but widely accepted Hanifin and Rajka criteria, progress in our understanding of this often debilitating disease is, perhaps, impeded. Studies into its genetics, pathogenesis, epidemiology and treatment are biased by this lack of consensus. Patients who are not atopic, that is, lack allergen-specific IgE, are included in gene-chasing studies, immunological exercises, epidemiological surveys and therapy investigations, all leading to possibly improper and inconsistent outcomes. Some investigators try to do better and add minimum IgE-levels as an inclusion criterion for their investigations. However, IgE-levels may be ‘normal’ (below an arbitrary cut-off point, often 100 IU/ml) while allergen-specific IgE is readily detectable.
For example, epidemiology is hindered by the lack of agreement about the definition of the disease entity. One dermatologist, involved in epidemiological studies using questionnaires, explained that the presence of ‘eczema’ or a ‘rash’ on the cheeks in childhood would be enough to make a diagnosis of atopic eczema. Telephone, mail or internet interviews then enable a quick and easy estimation of its prevalence. However, such a superficial approach underestimates the precision of dermatological diagnosis that is possible today. What people (parents) report as a cheek rash could easily be or have been something different (Box 1).
In addition, patients misdiagnosed with atopic eczema may be given advice as to the elimination of food and inhalant allergens while there is no sensitization to them. Also, as atopic eczema clearly predisposes to the development of irritant contact eczema, patients are advised to avoid certain professions, such as a nurse or hairdresser. Such lifestyle advice makes no sense in a patient having atopiform dermatitis and no atopy.
Semantical loop
Investigators and clinicians are imprisoned in a semantical loop. The number of patients having ‘atopic eczema’ but lacking allergen-specific IgE varies from 4% (our own observations) to as much as 80% (past or present cheek eczema as the only criterion). A common figure is that approximately 20% of patients fulfilling Hanifin and Rajka criteria have no detectable allergen-specific IgE. This is used as support for the idea that atopic eczema is not primarily the result of a primary immunological abnormality, closing the circle of argumentation.
Perhaps one may compare this with systemic lupus erythematosus (SLE). There are undisputed criteria for this disease. Patients need to fulfill at least four out of 13 diagnostic criteria. One of them is the presence of (antinuclear) autoantibodies. However, a very small minority of patients having SLE do not have detectable autoantibodies but nobody would argue that the presence of autoantibodies is not central to its pathogenesis. The fact that some patients have no detectable autoantibodies is not used by anyone as evidence that SLE is not primarily an autoimmune disease. Compare that with atopic eczema, where investigators argue that patients do not always have detectable IgE antibodies, thereby concluding that IgE plays no central role and even that the disease is not primarily immunological in nature.
Conclusions
It is about time that this lack of consensus is replaced by worldwide agreement and recognition that one may only make a diagnosis of atopic eczema when the immunological disturbance behind it can be proven in the individual patient. If not, a diagnosis of atopiform dermatitis appears appropriate, assuming that the other entities mentioned in the differential diagnosis (Box 1) have been excluded.
Having atopy implies a lifestyle, in which food and more importantly aeroallergens have to be eliminated from the living and working environments of the patient. If not for modifying the course of atopic diseases, such as rhinitis, asthma and eczema, then simply because these diseases may manifest at any age or occur later in the children of these same truly atopic individuals.
Summary
Two opposing views exist as to the origin of atopic dermatitis. In one, epidermal barrier dysfunction allows transcutaneous penetration of allergens with subsequent systemic sensitization and IgE production. That allows a diagnosis of atopic dermatitis, even if there is no allergen-specific IgE detectable. In the other view, atopy is a maturation disorder of the immune system, leading to persistent type 2 T-cell responses and production of allergen-specific IgE. According to that view, a diagnosis of atopic dermatitis can only be made when there is atopy and, thus, when there is allergen-specific IgE. Patients having the phenotype of atopic eczema but without allergen-specific IgE should be given a diagnosis of atopiform dermatitis. In these patients, elimination of allergens and advice as to lifestyle cannot be given.
Box 1. Differential diagnosis of juvenile atopic dermatitis phenotype ‘cheek eczema’.
| • | Atopiform dermatitis | ||||
| • | Nummular eczema | ||||
| • | Irritant contact dermatitis | ||||
| • | Seborrheic dermatitis | ||||
| • | Scabies | ||||
| • | Juvenile acne | ||||
| • | Erythema infectiosum | ||||
| • | Other viral exanthema | ||||
| • | Ulerythema ophryogenes | ||||
| • | Keratosis pilaris | ||||
| • | Neonatal lupus erythematosus | ||||
| • | Rosacea | ||||
| • | Couperose | ||||
| • | Essential telangiectasia | ||||
| • | Allergic contact dermatitis | ||||
| • | Dermatitis herpetiformis | ||||
References
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- Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet.38, 441–446 (2006).
- Bos JD, Van Leent EJM, Sillevis Smitt JH. The millennium criteria for the diagnosis of atopic dermatitis. Exp. Dermatol.7, 132–138 (1998).
- Bos JD. Atopiform dermatitis. Br. J. Dermatol.147, 415–417 (2002).
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- Akdis CA, Akdis M, Simon D et al. T cells and T cell-derived cytokines as pathogenic factors in the nonallergic form of atopic dermatitis. J. Invest. Dermatol.13, 628–634 (1999).
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