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BY AN EDUCATIONAL GRANT FROM NOVARTIS PHARMA AND NOVARTIS PHARMACEUTICALS CORPORATION
AG
Role of aeroallergens in atopic eczema: Proof of concept with the atopy patch test Johannes Ring, MD, PhD,a,b Ulf Darsow, MD,a,b and Heidrun Behrendt, MDb Munich, Germany
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e define atopy as familial tendency to develop certain diseases (bronchial asthma, allergic rhinoconjunctivitis, and/or atopic eczema) on the basis of hypersensitivity of skin and mucous membranes to environmental substances together with increased IgE production and/or altered nonspecific reactivity.1,2 This definition includes the two dimensions of atopy, namely, IgE production on the one hand and nonspecific altered reactivity on the other. Contrary to respiratory atopic diseases, the role of allergy in the pathophysiology of atopic eczema (AE) is still controversial. The most common theories on the pathophysiology of AE are shown in Table I, focusing from dry skin, superinfection, psychosomatic influence to different types of allergic inflammation. The dilemma starts with morphology. The disease has the appearance of eczema, and eczema is defined as a spongiotic epidermodermal inflammation with lymphocytic infiltrate, characteristically induced by type IV reactions (according to Coombs and Gell).1,3 The morphology of an immediate type I reaction (IgE-mediated allergy) in the skin is a wheal-and-flare reaction, such as that seen in urticaria. Further arguments against the role of allergy, brought forward mainly by Marchionini,4 regarded the commonly seen positive prick test reac-
From the Department of Dermatology and Allergy, Technical University of Municha and the Division of Environmental Dermatology and Allergy GSFITUM, Munich.b This article is part of a supplement sponsored by Novartis Pharma AG and Novartis Pharmaceuticals Corporation. Presented at the International Consensus Conference on Atopic Dermatitis, November 5-6, 1999, Rome, Italy. Disclosures: Dr Ring is a participant of a multicenter ascomycin derivative trial for Novartis Pharmaceutical Corporation and a participant in a multicenter tacrolimus trial for Fujisawa Healthcare Inc. Drs Darsow and Behrendt have no conflicts of interest to disclose. Reprint requests: Johannes Ring, MD, PhD, Technical University of Munich, Director, Department of Dermatology and Allergy, Biedersteiner Str 29, Munchen, 80802 Germany. E-mail: www.derma_allergie.med.tu-muenchen.de. J Am Acad Dermatol 2001;45:S49-52. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/0/117015 doi:10.1067/mjd.2001.117015
tions as mere epiphenomena on the basis of concomitant respiratory atopy. On the other hand, none of the atopic diseases shows so highly elevated serum IgE concentrations as AE; many “atopic sensitizations” are directed against allergens not relevant for asthma or rhinitis. Some patients experience exacerbation after contact with aeroallergens.
THE CONCEPT OF IgE AND LANGERHANS’ CELLS IN AE The conflict started to be solved by the demonstration of IgE on the surface of epidermal Langerhans’ cells (LCs) by Bruijnzeel-Koomen et al5 and the subsequent detection of all types of known IgE receptors on the same cells by Bieber et al.6,7 Later, Maurer et al8 showed the role of IgE in antigen presentation and Tanaka, Anan, and Yoshida9 demonstrated the major allergen of house dust mite in close proximity to IgE on the LC surface. Expression of the high-affinity receptor for IgE, previously only described for mast cells and basophils, opened our eyes to a new concept, particularly after it had been shown that this expression of FcεRI is significantly pronounced in lesional atopic skin compared with normal skin, nonlesional skin or in other inflammatory diseases such as contact dermatitis, psoriasis, or mycosis fungoides.10 Therefore theoretically it does appear that allergy contributes to the pathophysiology of AE; all the major components of an IgE-mediated reaction are present in the epidermis. But does allergy play a role in practice?
PROOF OF CONCEPT BY THE ATOPY PATCH TEST The proof of our concept came through a procedure we called the “atopy patch test” (APT).11-17 We performed investigations in several hundred patients with the aim to standardize the APT with regard to vehicle, dose, clinical covariates, and mode of application to bring it to clinical routine.18-22 First, we found that petrolatum was the best vehicle.19 Second, we showed that there is a clear-cut dose response with the amount of allergen in the preparaS49
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Table I. Atopic eczema: Pathophysiologic concepts • • • • • •
Genetic background (atopy, skin function) Barrier disturbance (“dry skin”) Microbial colonization Autonomic nervous system dysregulation Psychosomatic interaction Inflammation Nonimmune Allergic, classic delayed-type hypersensitivity (TH1) Allergic, atopic (TH2)
tion.20,21 Third, we demonstrated that the percentage of positive APT reactions was significantly elevated in patients with an air-exposed eczema distribution pattern.20 It was also possible to elicit a positive APT reaction with native pollen grains.22 Interestingly, when we patch-tested the same person with aeroallergens in the APT or classic contact allergens (lanolin or nickel), the morphology of the positive patch test reaction was similar. However, the barrier disruption measured as transepidermal water loss was significantly more pronounced in the APT compared with the positive contact allergy patch test.23 We speculated that this might be due to the more pronounced eosinophil infiltrate observed in APT reactions.24 In a large multicenter trial in Germany in more than 280 patients we found house dust mite to be the most common positive reaction, followed by grass pollen, cat epithelium, birch pollen, and mugwort pollen (Table II). Most of the patients were positive only to one allergen, rarely to 2 or 3. The reaction peaked at 48 hours and then decreased slightly in the following 24 hours. The concomitant use of negative control patches with petrolatum proved that APT reactions were no irritant phenomenon.21 Positive reactions occurred only in patients with AE and not in normal persons or in patients with pure respiratory atopy.19 When we closely followed the history of the patients, it was obvious that positive APT reactions were much more frequent in patients with a specific history of eczema flare after allergen contact (eg, cat, grass, pollen). The history for house dust mite exposure was much more difficult to obtain; however, there was still a significant difference.21 Now we understand the previously unexplained or UV-attributed flares of some AE patients in spring and summer to be an allergic skin reaction to pollen and manifesting as AE.22
COMPARISON OF APT WITH SKIN PRICK TEST AND RADIOALLERGOSORBENT TEST There was no complete concordance between APT and skin prick test or radioallergosorbent test
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Table II. Results of the APT multicenter study in Germany* Clear-cut positive results
Skin prick (%)
RAST (%)
APT 48-h (%)
Dust mite (N = 253) Cat dander (N = 253) Grass pollen (N = 253) Birch pollen (N = 88) Mugwort pollen (N = 88)
59 54 65 65 36
56 49 75 65 53
34 12 18 11 3
One allergen, 22%; 2 allergens, 8%, 3 allergens, 5% (APT 48 h). *Reactivity to different allergens in different test systems; percentages calculated referring to N. Reprinted from Darsow U, Ring J. In: Leung DYM, Greaves MW, editors. Allergic skin disease. New York: Marcel Dekker; 2000. p. 435-47, by courtesy of Marcel Dekker, Inc.
(RAST) results.19 Cross-table analysis and logistic regression in a large group of patients revealed significant concordances of APT results with history, skin prick test, and specific corresponding IgE for house dust mite, cat epithelium, and grass pollen (P < .001).21 However, the results also showed that high allergen-specific IgE in serum is not mandatory for a positive APT; the same holds true for the correlation with skin prick tests. At the first Georg Rajka symposium on atopic eczema in 1998, Taieb showed exciting data with APTs in infants who were prick test and RAST negative, but were APT positive to foods. These were not irritant reactions. On the other hand, it has to be kept in mind that IgE plays a role in APT because most APT-positive patients also showed elevated specific IgE compared with those patients with negative APT.21,25 To evaluate the relevance of APT as a diagnostic test, we analyzed the results on the background of disease history. In 79 patients, significantly higher frequencies of positive APTs were seen in patients with a history of eczema exacerbation in summer months than in patients without a summer eruption of AE. We were able to calculate precision data of APT. With regard to a predictive history of grass pollen–induced eczema exacerbation, the APT specificity exceeded the specificity of the skin prick test and RAST whereas sensitivity was lower. Similar results were obtained in the German multicenter study.21
MECHANISM OF THE APT REACTION Regarding the correlation of APT with skin prick test and specific IgE results, no complete concordance was observed. This means that with APT a different dimension of atopic skin inflammation is registered than in the skin prick test or RAST. The allergen-specific nature of APT reactions has been shown by several groups. Langeland, Braathen, and Borch26 transferred APT reactivity to egg, performing a
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Prausnitz-Küstner test. van Reijsen et al27 characterized allergen-specific T-cell clones derived from skin specimens taken from APT sites. Mite allergen has been demonstrated in the epidermis under natural conditions28 and in APT sites9,16 in proximity to LCs. Because LCs carry all 3 human IgE binding structures, namely, the high- and low-affinity IgE receptors (FcεRI and II) and the ε-binding protein,5-7 they are capable of binding allergens via specific IgE on their surface. According to their known function as antigen-presenting cells, they may also internalize, process, and present these allergens to T cells.8 We and others described a significant association of positive APT reactions and specific serum IgE. This might explain how IgE-associated activation of allergen-specific T cells can lead to eczematous skin eruptions in the APT. A similar situation is found in natural lesions of AE and APT sites characterized by a predominance of CD4+ T cells.29,30 APT reactions were significantly more frequent in patients with elevated CD54+ or CD30+ T cells after in vitro stimulation with the corresponding allergen. Positive APTs were associated with an allergen-specific lymphocyte proliferation (P < .001).31 These data sustain the clinical results on allergen specificity of APT reactions. When serial biopsies of APT were performed to analyze the cytokine pattern, marked time-dependent differences were seen: interleukin 4 messenger (m)RNA as marker of the TH2 response was noted after 24 hours, followed by a switch to a TH1-like cytokine response with increased levels of interferon gamma mRNA after 48 hours.32 Other cell populations may also be involved in the initiation and perpetuation of APT reactions. Among these are basophils, present in the infiltrate after 48 hours,13 and activated eosinophils.24 Eosinophil-derived basic proteins (MBP, ECP, EPX) can be detected in AE lesions by immunohistochemical staining, even with low eosinophil counts in normal hematoxylin-eosin staining. These eosinophil products may have a role in barrier impairment, thus perpetuating allergen penetration. In addition, the role of mast cells remains to be elucidated. With regard to neutrophil density, marked differences of APT (low numbers) versus experimental late-phase reactions (high numbers) were described.33
CONCLUSIONS By the APT we have shown that AE can be elicited by external contact with an aeroallergen, suggesting something like atopic contact eczema. In contrast to classic contact dermatitis in which a TH1 reaction is elicited by a hapten, atopic (contact) eczema is characterized by a TH2 type pathophysiology triggered by
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Table III. Classification of eczema/dermatitis Classic (contact) eczema/dermatitis Irritative, toxic Allergic Atopic eczema/dermatitis Extrinsic Intrinsic Others Seborrheic eczema/dermatitis Nummular eczema/dermatitis
a protein. To avoid confusion, we suggested adding the term classic to the traditional term contact eczema/contact dermatitis (Table III). However, we should not forget that there are some AE patients (maybe 10%-20%) without detectible IgE elevation in the serum or positive skin prick tests or RAST. Wüthrich’s concept of extrinsic (allergic) versus intrinsic (cryptogenic) AE seems valid to explain this heterogeneity. This is not the end of the story. AE starts in the acute phase with a TH2 reaction.32 Later, during the chronic stage, TH1 secretion patterns are found32; recently Valenta et al34 have described IgE autoantibodies against an epidermal allergen, Homo sapiens I, which we measured in particularly high concentrations in patients with very severe AE. In these patients, the eczema perpetuates in the direction of an autoimmune disease; these are the cases in which allergen avoidance does not help and the use of immunosuppressants will be the only chance of relief. The message from our studies is the new concept that AE is not only a disease of dry skin but possibly also an allergic disease. Only if we find the causal trigger factors and eliminate them will we be able to help patients for longer periods. Avoidance strategies play a role, and our concept means much more than writing a prescription. We35 proposed the term “patient management” for this combined approach. Today, we prefer “self-management” and tell our patients: “You will be your own dermatologist. I shall teach you and you will know what your skin needs.” REFERENCES 1. Ring J. Angewandte Allergologie. 2nd ed. Munich: MMV Medizin Verlag; 1991. 2. Ring J. Atopy: condition, disease or syndrome? In: Ruzicka T, Ring J, Przybilla B, editors. Handbook of atopic eczema. Berlin: Springer; 1993. p. 3-8. 3. Leung DYM, Rhodes AR, Geha RS, Schneider LC, Ring J. Atopic dermatitis (atopic eczema). In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. 4th ed. New York: McGraw-Hill; 1993. p. 1543-63. 4. Marchionini A. Neuere Untersuchungen über die Neurodermitis constitutionalis. In: Fortschritte der praktischen
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24. Bruijnzeel-Koomen C, van Wichen D, Spry C, Venge P, Bruijnzeel P. Active participation of eosinophils in patch test reactions to inhalant allergens in patients with atopic dermatitis. Br J Dermatol 1988;118:229-38. 25. Darsow U, Ring J. The atopy patch test: its role in the evaluation and management of atopic eczema. In: Leung DYM, Greaves MW, editors. Allergic skin disease. New York: Marcel Dekker; 2000. p. 435-47. 26. Langeland T, Braathen L, Borch M. Studies of atopic patch tests. Acta Derm Venereol Suppl (Stockh) 1989;144:105-9. 27. van Reijsen FC, Bruynzeel-Koomen CAFM, Kalthoff FS, Maggi E, Romagnani S, Westland JKT, et al. Skin-derived aeroallergenspecific T-cell clones of TH2 phenotype in patients with atopic dermatitis. J Allergy Clin Immunol 1992;90:184-92. 28. Maeda K, Yamamoto K, Tanaka Y, Anan S, Yoshida H. House dust mite (HDM) antigen in naturally occurring lesions of atopic dermatitis (AD): the relationship between HDM antigen in the skin and HDM antigen-specific IgE antibody. J Dermatol Sci 1992;3: 73-7. 29. Reitamo S,Visa K, Kähönen K, Stubb S, Salo OP. Eczematous reactions in atopic patients caused by epicutaneous testing with inhalant allergens. Br J Dermatol 1986:114:303-9. 30. Leung DYM, Bhan AK, Schneeberger EE, Geha RS. Characterization of the mononuclear cell infiltrate in atopic dermatitis using mononuclear antibodies. J Allergy Clin Immunol 1983:71:47-56. 31. Wistokat-Wülfing A, Schmidt P, Darsow U, Ring J, Kapp A, Werfel T. Atopy patch test reactions are associated with T-lymphocyte mediated allergen-specific immune responses in atopic dermatitis. J Allergy Clin Immunol 1998;101:196-7. 32. Grewe M, Walther S, Gyufko K, Czech W, Schöpf E, Krutmann J. Analysis of the cytokine pattern expressed in situ in inhalant allergen patch test reactions of atopic dermatitis patients. J Invest Dermatol 1995;105:407-10. 33. Langeveld-Wildschut EG, Thepen T, Bihari IC, van Reijsen FC, de Vries IJM, Bruijnzeel PLB, et al. Evaluation of the atopy patch test and the cutaneous late-phase reaction as relevant models for the study of allergic inflammation in patients with atopic eczema. J Allergy Clin Immunol 1996;98:1019-27. 34. Valenta R, Maurer D, Steiner R, et al. Immunglobulin E response to human proteins in atopic patients. J Invest Dermatol 1996; 107:203-8. 35. Ring J, Brockow K, Abeck D.The therapeutic concept of “patient management” in atopic eczema. Allergy 1996;51:206-15.
DISCUSSION Dr Leung: In your original model you showed that IgE-positive Langerhans’ cells are critical for the APT. One would expect that IgE would also bind on mast cells, and you might see a positive skin prick test. Why do these patients have a negative skin prick test? Dr Ring: I do not know why, but it is the fact. Dr Leung: Would you expect that those people would develop wheals and flares after an intradermal injection? Dr Ring: We did the intradermal injections and they were negative.