13 Diseases Rarely Associated with Atopic Eczema
A. Braae Olesen
Atopic eczema is a chronic inflammatory skin disease most prevalent in early childhood [23, 24]. The preva- lence of atopic eczema among children up to the age of 14 – 15 years is between 15 % and 20 % [21, 24, 31] and about two-thirds of affected children have a rise in total serum IgE associated with type I allergy [1, 13]. The increase in IgE is caused by a reduced production of interferon-* and an increased production of interleu- kin 4 in those who develop atopy later [12], which is called a Th2 immune reactivity pattern [10, 11]. It is often observed in early life [27]. In contrast, a Th1 immune reactivity pattern is associated with an increased production of interferon-* [11], which is associated with development of some autoimmune dis- orders such as insulin-dependent diabetes mellitus (IDMD), rheumatoid arthritis, thyroid disorders, and psoriasis [19].
A reciprocal relation between a Th1 and a Th2 reac- tivity pattern [10] suggests that diseases with a Th2 phenotype and diseases with a Th1 phenotype are mutually exclusive within individuals. The conse- quences of the Th1/Th2 concept would be that an indi- vidual with a Th2 phenotype disease such as atopic eczema or allergic asthma would be relatively protect- ed against development of a Th1 phenotype disease such as DDM, psoriasis, and rheumatoid arthritis.
However, several observations go against the Th1/
Th2 hypothesis. Firstly, a simultaneous rise in several Th1- and Th2-mediated diseases at the population level has been observed, which may suggest a common etiol- ogy or genetic background of some of the diseases [35].
Secondly, the evidence of an inverse relationship between Th2- and Th1-mediated diseases at the indi- vidual level is contradictory and will be discussed fur- ther in this chapter.
13.1
Atopic Eczema and Insulin-Dependent Diabetes Mellitus
Atopic eczema is a skin inflammation with activated T lymphocytes of yet unknown origin, with a peak inci- dence in the 1st years of life [23, 24]. Atopic disorders in general are strongly associated with type I allergen- specific reactions – a Th2 response [10, 26]. However, according to our present knowledge of the immunopa- thogenesis of atopic eczema, it seems more adequate to describe atopic eczema as a disease, which may present Th2-like reactions in some of the acute forms of the disease associated with allergen-specific reactions and Th1-like reactions in chronic eczema [14, 38]. IDDM involves a Th1-attack and damage to beta cells in pan- creas. It can be induced in mice by linking the interfer- on-* gene to the insulin promoter gene [29, 30]. Fur- ther, it can be prevented by administration of IL-4 to nonobese diabetic mice [8].
The reciprocal relationship between the Th1 and the Th2 type of immune responses suggests that atopic eczema with Th2 phenotype and IDDM with Th1 phe- notype are mutually exclusive, and it could be expected that IDDM is a rare disease among atopic eczema patients.
Only a few studies have investigated the association between atopic diseases including atopic eczema and IDDM. A recent Dutch case–control study among 7- to 12-year-old children found lower prevalence of atopic diseases, including atopic eczema symptoms, within the last year (odds ratio [OR], 0.693; 95 % Confidence Interval CI 0.43 – 1.12) among IDDM cases compared to age-matched nondiabetic controls [20]. Another study [2] reported a lower prevalence of atopic diseases, especially asthma, among IDDM patients. They did not find a lower rate of atopic eczema among IDDM cases, Chapter13
Age (years)
0 5 10 15
Cumulated incidence (per cent)
0.00 0.05 0.10 0.15 0.20 0.25
Diabeticpatients Non-diabetic controls
but when one center with deviant results out of eight centers studied was excluded, an insignificantly inverse association between atopic eczema and IDDM was observed (OR 0.78; 95 % CI 0.61 – 1.00). We performed a case–control study including all case children between 3 and 15 years of age with IDDM in Denmark and observed a significantly lower incidence of atopic eczema among IDDM cases compared to the nondia- betic controls before onset of IDDM (OR 0.49; 95 % CI 0.39 – 0.63), whereas the incidence of atopic eczema did not differ among IDDM cases compared with nondia- betic controls after the onset of IDDM (OR 1.36; 95 % CI 0.89 – 2.07; Fig. 13.1) [25]. A very strong inverse association of atopic eczema and IDDM in early life suggests that an early onset of atopic eczema may pro- tect against or postpone the onset of IDDM. However, the association between atopic eczema and IDDM after onset of IDDM underlines the fact that an atopic dis- ease such as atopic eczema and IDDM can coexist. This is confirmed in a small cross-sectional study from Swe- den that observed similar rates of atopy and atopic dis- eases among cases of IDDM and controls matched for age and gender [37].
Several register-based studies have documented coexistence of Th1- and Th2-mediated diseases [17, 32, 33]. However, none of the mentioned register-based studies present any data concerning the association between atopic eczema and IDDM. These register- based studies have two serious limitations. Firstly, there are often serious problems with the misclassifica- tion of diseases, especially atopic diseases, which are
Fig. 13.1. Cumulative incidence of atopic eczema among dia- betic patients and nondiabetic controls [25]
often handled in general practice or without medical attention, compared to the typical Th1 disease such as IDDM and rheumatoid arthritis. Secondly, people with multiple diseases will be over-represented when there is a selection from a general population into adminis- trative data [6].
In conclusion, to date only few published papers have studied the association between atopic eczema and IDDM. There is no doubt that atopic eczema and IDDM can coexist. However, the significant inverse association between atopic eczema and IDDM that we have observed in a large population-based study indi- cates that an early onset of atopic eczema may protect against or postpone the onset of IDDM. The immune response in early life may be much more sensitive to disturbance of the Th1/Th2 balance than later in life.
Another plausible explanation may be that after the primary immune imbalance, which kills the beta cells of the pancreas and leads to IDDM, the immune response has been restored to normal or almost nor- mal. Later, a new imbalance may occur that leads to yet another disease. A third explanation may be that atopic eczema comes in at least two subtypes: A Th2-driven, extrinsic type and a Th1-driven, intrinsic type [41].
The etiology of diseases, which are dependent on age and develop over a longer period of time from initi- ation to break out of the disease, is only poorly studied in cross-sectional studies. This poor timing of events is the most serious limitation in the interpretation of study results.
13.2
Atopic Eczema and Psoriasis
Could atopic eczema and psoriasis be mutually exclu- sive? According to the concept of Th1 and Th2 pheno- types, it may be a plausible statement. Even though both atopic eczema and psoriasis are inflammatory skin diseases with several immunopathogenetic simi- larities, psoriasis is described as a Th1-mediated dis- ease, which should counteract the development of the Th2-mediated atopic eczema or vice-versa.
In a German hospital-based study among more than 42,000 patients, who had been admitted to the Depart- ment of Dermatology at the University of Kiel from 1955 to 1992, a strong inverse association between atopic eczema and psoriasis was observed [15]. Among 1,701 patients with a firm diagnosis of atopic eczema,
only five had concurrent psoriasis compared to an expected number of 125 patients. In contrast, a British study reporting from The National Child Development Survey of 1958 found an association between current atopic eczema and psoriasis at age 11 and 16 years [40].
These latter findings are consistent with the recent Scottish register-based study, which observed a strong association between current psoriasis and atopic ecze- ma (the prevalence ratio of psoriasis in eczema patients was 2.88; 95 % CI 2.38 – 3.45) [33].
To date, no studies on the association between atop- ic eczema and psoriasis have taken the sequence of events into consideration. The studies mentioned have several different limitations, including selection bias, which could be a serious and plausible limitation of the first study [15]; misclassification of diseases would be a plausible limitation of the two other studies [33, 40].
In conclusion, there are only very few published studies on the association between atopic eczema and psoriasis. The findings seem inconclusive. However, further studies on atopic eczema and psoriasis may indeed be very interesting. Theoretically, psoriasis may be only in part inversely associated with atopic eczema as a consequence of both opposing and shared immu- nopathological mechanisms of the two diseases.
Recently, it has been shown that several candidate genes for psoriasis may overlap with loci for atopic eczema and it has been speculated that these regions contain polymorphic genes with general effects con- cerning skin inflammation [9, 18, 22, 34]. A shared genetic background in several loci concerning skin inflammation and immunity could explain the coexis- tence of both diseases in some individuals. Further studies designed to take the sequence of events into consideration may add new knowledge to the etiology of both diseases.
13.3
Atopic Eczema and Rheumatoid Arthritis
Rheumatoid arthritis is a systemic autoimmune dis- ease with known autoantigen targets in joints, lungs, and heart [19]. The disease can be considered a Th1- mediated disease, with Th1 cytokines predominating over Th2 cytokines in the joints. Few studies have been published concerning the association between atopic disorders and rheumatoid arthritis. Only one study has presented results concerning atopic eczema [28].
A French study reported a significantly lower cumu- lative incidence of atopic symptoms among rheuma- toid arthritis cases compared with healthy controls (OR 0.39; 95 % CI 0.19 – 0.81) [3, 16]. Another study reported that the prevalence of hay fever was signifi- cantly lower in rheumatoid arthritis patients compared with patients without rheumatoid arthritis [39]. This study showed that the rheumatoid arthritis patients with hay fever had lower activity of their rheumatoid arthritis, and these patients had a lower interferon-* / IL-4 ratio compared with rheumatoid arthritis patients without hay fever [39].
In a recent case–control study, all atopic disorders including atopic eczema were studied and reported separately. The prevalence of the atopic disorders was decreased in rheumatoid patients compared with both healthy controls and ankylosing spondylitis patients [28]. The prevalence of atopic eczema was 4.9 % among healthy controls and 2.9 % among rheumatoid arthritis cases. Furthermore, it was noted that the rheumatoid arthritis was less severe among patients who had an atopic disorder before the onset of rheumatoid arthri- tis compared with patients who developed an atopic disorder after the onset of rheumatoid arthritis. How- ever, in this study the rheumatoid cases with atopic dis- orders were significantly younger than nonatopic rheu- matoid cases. Unfortunately, no adjustments were made of the confounding effect of age. In particular, the latter conclusion concerning the severity of rheu- matoid arthritis could result from an unadjusted con- founding age effect among study subjects.
In contrast to the results supporting the view that atopic diseases are rarely associated with rheumatoid arthritis, two register-based studies provide results that contradict these findings. In a Finnish study, the cumulative incidence of asthma at age 7 was 10 % among children with rheumatoid arthritis compared with a cumulative incidence at age 7 of 3.4 % among children without rheumatoid arthritis [17]. In another register-based study, no association was found be- tween rheumatoid arthritis and any atopic disorder (standardized prevalence ratio 1.05; 95 % CI 0.80 – 1.36) [33]. However, both register studies have serious limi- tations [6].
In conclusion, few published studies document an inverse association between atopic disease and rheu- matoid arthritis. Furthermore, a current atopic disor- der may alter the clinical course of rheumatoid arthri- tis. One study concerning atopic eczema and rheuma- 146 13 Diseases Rarely Associated with Atopic Eczema
toid arthritis indicated a tendency toward an inverse association. However, these findings are so far unsup- ported in two large registry-based studies.
13.4
Atopic Eczema and Melanocytic Nevi
In a recent Swedish study, the number of melanocytic nevi was counted in 51 patients with severe atopic ecze- ma since childhood and compared with 379 randomly selected adult subjects [7]. The total body count of nevi was significantly reduced among atopic eczema cases compared to the nonatopic controls, and there was a significant negative correlation between total IgE and the number of melanocytic nevi among atopic eczema cases (rs= –0.50; 95 % CI (–0.69; –0.24). The results are quite surprising, because the majority of the atopic eczema patients had received UVA and/or UVB treat- ment in dermatological clinics and 15 patients reported climatic therapy, which was expected to increase the number of melanocytic nevi among the atopic eczema cases [4, 5]. The inverse association between atopic eczema and melanocytic nevi may be a random finding, and the authors have no plausible explanation. To my knowledge, no other studies have studied the association between nevi or melanoma and atopic eczema.
We have recently conducted a register study of can- cer risk among all adult atopic dermatitis patients (n = 2,030), who were admitted to the hospital in Denmark from 1977 to 1996 under the main diagnosis of atopic eczema. All citizens of Denmark, including the adult atopic eczema cases, were followed up in the Danish Cancer Register [36]. In this study, no cases of malig- nant melanoma were found among the atopic dermati- tis patients vs 2.4 expected (Olesen et al. in press).
In conclusion, one study has reported an inverse association between atopic eczema and melanocytic nevi. This may be a random finding. The observation is interesting and deserves follow-up.
Table 13.1. Evidence for and against an association between selected Th1-medi- ated diseases and atopic disease
Th1-mediated disease Atopic disease Atopic disease Atopic disease Association Inverse association No association Insulin-dependent diabetes mellitus [17, 32, 33] [2, 20, 25] [37]
Psoriasis [33, 40] [15]
Rheumatoid arthritis [17] [3, 16, 28, 39] [33]
13.5
Concluding Remarks
The studies reported here point in the direction of both an inverse association between atopic Th2-mediated diseases and several autoimmune Th1-mediated dis- eases, as well as to some extent also toward coexistence (Table 13.1).
The association between atopic eczema and diseases with a Th1-phenotype has been given much less atten- tion than the sum of all atopic diseases, and the con- flicting findings may partly be due to the small number of studies. However, it has been possible to present results concerning the specific association between atopic eczema and IDDM, psoriasis, rheumatoid arthritis, and melanocytic nevi.
A simultaneous rise in several Th1- and Th2-related diseases at a population level has been observed and several studies describing results concerning a total sum of all atopic diseases and results concerning atopic eczema alone document that Th1- and Th2-mediated diseases may coexist on the individual level.
Several studies point to the fact that an onset of an atopic Th2-mediated disease before the onset of an autoimmune Th1-mediated disease may protect against, postpone, or alter the clinical course of an autoimmune Th1-mediated disease, whereas the asso- ciation between a Th1- and Th2-mediated disease may be neutral or even positive after the onset of a Th1- mediated disease. This implies that the immune bal- ance may be more vulnerable to exposures in early life, and the vulnerability of Th1-Th2 immune balance may be inversely associated with age. A Th1-mediated dis- ease often appears later in life than the atopic disorders, especially atopic eczema and asthma. The immune sys- tem is dominated by Th2-mediated immune response in early life. This may change to a Th1-mediated immune response within the 1st year of life. The immune system may be more vulnerable to different exposures at that period of life; i.e., more prone to cause imbalance between Th1- and Th2-mediated immune responses. This explanation also implies that
the concept of Th1-Th2 balance may be too simple, and some findings indicate that the regulation of the immune system is more important.
Another even simpler explanation may be that an imbalance in the immune system in one period of life, counteracted by a tendency to develop a new balance in the immune system, may later lead to yet another new imbalance, which may cause the initiation of another disease.
A third explanation may be limitations in the study design, representativity of the study group, misclassifi- cation, and selection bias. However, going through the references described in this chapter, I find it hard to believe that these factors alone can explain the divert- ing results.
The association between atopic eczema and psoria- sis, which have opposing and shared immunopathoge- netic mechanisms, deserves special attention. There is a common understanding that research focusing on the differences of diseases leads to new knowledge. Howev- er, in this case studying the two inflammatory skin dis- eases from opposite points of view, namely that they have much more in common than previously expected in terms of their immunopathogenesis, may lead to new important discoveries concerning both diseases.
References
1. ETAC Study Group (1997) Determinants of total and specif- ic IgE in infants with atopic dermatitis. Early treatment of the atopic child. Pediatr Allergy Immunol 8:177 – 1184 2. The EURODIAB Substudy 2 Study Group (2002) Decreased
prevalence of atopic diseases in children with diabetes. J Pediatr 137:470 – 474
3. Allanore Y, Hilliquin P, Coste J, Renoux M, Menkes CJ (1998) Decreased prevalence of atopy in rheumatoid arthri- tis. Lancet 351:497
4. Armstrong BK, Kricker A (2001) The epidemiology of UV- induced skin cancer. J Photochem Photobiol B 63:8 – 18 5. Armstrong BK, Kricker A, English DR (1997) Sun exposure
and skin cancer. Australas J Dermatol 38 [Suppl 1]:S1 – S6 6. Benn CS, Bendixen M, Krause TG, Olesen AB (2002) Ques-
tionable coexistence of T(H)1- and T(H)2-related diseases.
J Allergy Clin Immunol 110:328 – 329
7. Broberg A, Augustsson A (2000) Atopic dermatitis and melanocytic naevi. Br J Dermatol 142:306 – 309
8. Cameron MJ, Arreaza GA, Zucker P, Chensue SW, Strieter RM, Chakrabarti S, Delovitch TL (1997) IL-4 prevents insu- litis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 159:4686 – 4692
9. Cookson WO, Moffatt MF (2002) The genetics of atopic der- matitis. Curr Opin Allergy Clin Immunol 2:383 – 387
10. Del Prete G (1992) Human Th1 and Th2 lymphocytes:
their role in the pathophysiology of atopy. Allergy 47:450 – 455
11. Del Prete G (1998) The concept of type-1 and type-2 helper T cells and their cytokines in humans. Int Rev Immunol 16:427 – 455
12. Del Prete G, Maggi E, Parronchi P, Chretien I, Tiri A, Mac- chia D, Ricci M, Banchereau J, De Vries J, Romagnani S (1988) IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their superna- tants. J Immunol 140:4193 – 4198
13. Dotterud LK, Kvammen B, Lund E, Falk ES (1995) Preva- lence and some clinical aspects of atopic dermatitis in the community of Sor-Varanger. Acta Derm Venereol 75:50 – 53 14. Grewe M, Gyufko K, Schopf E, Krutmann J (1994) Lesional expression of interferon-gamma in atopic eczema. Lancet 343:25 – 26
15. Henseler T, Christophers E (1995) Disease concomitance in psoriasis. J Am Acad Dermatol 32:982 – 986
16. Hilliquin P, Allanore Y, Coste J, Renoux M, Kahan A, Men- kes CJ (2000) Reduced incidence and prevalence of atopy in rheumatoid arthritis. Results of a case-control study.
Rheumatology (Oxford) 39:1020 – 1026
17. Kero J, Gissler M, Hemminki E, Isolauri E (2001) Could TH1 and TH2 diseases coexist? Evaluation of asthma inci- dence in children with coeliac disease, type 1 diabetes, or rheumatoid arthritis: a register study. J Allergy Clin Immunol 108:781 – 783
18. Kluken H, Wienker T, Bieber T (2003) Atopic eczema/der- matitis syndrome – a genetically complex disease. New advances in discovering the genetic contribution. Allergy 58:5 – 12
19. Marrack P, Kappler J, Kotzin BL (2001) Autoimmune dis- ease: why and where it occurs. Nat Med 7:899 – 905 20. Meerwaldt R, Odink RJ, Landaeta R, Aarts F, Brunekr f B,
Gerritsen J, van Aalderen WM, Hoekstra MO (2002) A low- er prevalence of atopy symptoms in children with type 1 diabetes mellitus. Clin Exp Allergy 32:254 – 255
21. Mortz CG, Lauritsen JM, Bindslev-Jensen C, Andersen KE (2001) Prevalence of atopic dermatitis, asthma, allergic rhinitis, and hand and contact dermatitis in adolescents.
The Odense Adolescence Cohort Study on Atopic Diseases and Dermatitis. Br J Dermatol 144:523 – 532
22. Novelli G, Giardina E, Paradisi M, Pedicelli C, Girolomoni G, Nasorri F, Chimenti S, Marulli G, Rossi P, Moschese V, Chini L, Capon F (2003) Insight into genetics of atopic der- matitis: future approaches and directions. Abstract book of The Third Georg Rajka Symposium, Rome, Italy, p 35 23. Olesen AB, Ellingsen AR, Larsen FS, Larsen PO, Veien NK,
Thestrup PK (1996) Atopic dermatitis may be linked to whether a child is first- or second-born and/or the age of the mother. Acta Derm Venereol 76:457 – 460
24. Olesen AB, Ellingsen AR, Olesen H, Juul S, Thestrup PK (1997) Atopic dermatitis and birth factors: historical fol- low-up by record linkage. BMJ 314:1003 – 1008
25. Olesen AB, Juul S, Birkebaek N, Thestrup-Pedersen K (2001) Association between atopic dermatitis and insulin- dependent diabetes mellitus: a case–control study. Lancet 357:1749 – 1752
26. Prescott SL, MacAubas C, Smallacombe T, Holt BJ, Sly PD, 148 13 Diseases Rarely Associated with Atopic Eczema
Holt PG (1999) Development of allergen-specific T-cell memory in atopic and normal children. Lancet 353:
196 – 200
27. Prescott SL, Macaubes C, Yabuhara A, Venaille TJ, Holt BJ, Habre W, Loh R, Sly PD, Holt PG (1997) Developing pat- terns of T cell memory to environmental allergens in the first two years of life. Int Arch Allergy Immunol 113:75 – 79 28. Rudwaleit M, Andermann B, Alten R, Sorensen H, Listing J, Zink A, Sieper J, Braun J (2002) Atopic disorders in anky- losing spondylitis and rheumatoid arthritis. Ann Rheum Dis 61:968 – 974
29. Sarvetnick N, Liggitt D, Pitts SL, Hansen SE, Stewart TA (1988) Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 52:773 – 782
30. Sarvetnick N, Shizuru J, Liggitt D, Martin L, McIntyre B, Gregory A, Parslow T, Stewart T (1990) Loss of pancreatic islet tolerance induced by beta-cell expression of interfer- on-gamma. Nature 346:844 – 847
31. Schultz LF, Diepgen T, Svensson A (1996) The occurrence of atopic dermatitis in north Europe: an international questionnaire study. J Am Acad Dermatol 34:760 – 764 32. Sheikh A, Smeeth L, Hubbard R (2003) There is no evi-
dence of an inverse relationship between TH2-mediated atopy and TH1-mediated autoimmune disorders: lack of support for the hygiene hypothesis. J Allergy Clin Immu- nol 111:131 – 135
33. Simpson CR, Anderson WJ, Helms PJ, Taylor MW, Watson L, Prescott GJ, Godden DJ, Barker RN (2002) Coincidence of immune-mediated diseases driven by Th1 and Th2 sub- sets suggests a common aetiology. A population-based
study using computerized general practice data. Clin Exp Allergy 32:37 – 42
34. Speckman RA, Wright Daw JA, Helms C, Duan S, Cao L, Taillon-Miller P, Kwok PY, Menter A, Bowcock AM (2003) Novel immunoglobulin superfamily gene cluster, mapping to a region of human chromosome 17q25, linked to psoria- sis susceptibility. Hum Genet 112:34 – 41
35. Stene LC, Nafstad P (2001) Relation between occurrence of type 1 diabetes and asthma. Lancet 357:607 – 608 36. Storm HH, Michelsen EV, Clemmensen IH, Pihl J (1997)
The Danish Cancer Registry – history, content, quality and use. Dan Med Bull 44:535 – 539
37. Stromberg LG, Ludvigsson GJ, Bjorksten B (1995) Atopic allergy and delayed hypersensitivity in children with dia- betes. J Allergy Clin Immunol 96:188 – 192
38. Thepen T, Langeveld-Wildschut EG, Bihari IC, van Wichen DF, van Reijsen FC, Mudde GC, Bruijnzeel-Koomen CA (1996) Biphasic response against aeroallergen in atopic dermatitis showing a switc from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol 97:828 – 837
39. Verhoef CM, van Roon JA, Vianen ME, Bruijnz l-Koomen CA, Lafeber FP, Bijlsma JW (1998) Mutual antagonism of rheumatoid arthritis and hay fever; a role for type 1/type 2 T cell balance. Ann Rheum Dis 57:275 – 280
40. Williams HC, Strachan DP (1994) Psoriasis and eczema are not mutually exclusive diseases. Dermatology 189:238 – 240 41. Wuthrich B (1999) Clinical aspects, epidemiology, and prognosis of atopic dermatitis. Ann Allergy Asthma Immunol 83:464 – 470
