- Email: [email protected]
The natural history of atopic dermatitis
SUPPORTED
BY AN EDUCATIONAL GRANT FROM NOVARTIS PHARMA AND NOVARTIS PHARMACEUTICALS CORPORATION
AG
The natural history of atopic dermatitis Alain Taieb, MD Bordeaux, France
I
deally, the approach to natural history of atopic dermatitis (AD) should be founded on studies with population-based representative samples, long-term follow-up, clear disease definition, short inclusion time, few losses to follow-up, no therapeutic intervention, and objective outcome measures.1 None of the existing major studies1-6 satisfies all these postulates.
PROBLEMS AND PITFALLS A source of variation is the geographic origin of the studies. Disease prevalence reaches from 2% in China to more than 20% in the United Kingdom and Nigeria.7 Up to now, all studies on natural history have been conducted in Europe, and none addresses the problem of migrant populations. In most Western countries, the prevalence of AD has increased, as documented in twin studies in Denmark.8 Figures derived from cohorts of patients enrolled in the late 1950s or 1960s are probably less relevant today because of rapid environmental changes. With regard to the potential influence of therapeutic intervention, it is frustrating that we have no long-term data. Overall, it is implicit that such intervention does not affect outcomes. In Vickers’ study,2 there is a rather vague feeling that early skin treatment with topical steroids is beneficial. Diet is a more carefully investigated intervention in prevention studies.9 The different perspective on the disease by physicians based on their specialty leads to a bias in organ assessment. Eczema is considered a minor disorder
From the Dermatology Service, Hôpital Saint André. 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. Disclosure: The author attests that he has no conflicts of interest to disclose. Reprint requests: Alain Taieb, MD, Hôpital Saint André, Science de Dermatologie, 1 Rue Jean Burguet, Bordeaux, 33076, France. Email: [email protected]. J Am Acad Dermatol 2001;45:S4-6. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/0/117027 doi:10.1067/mjd.2001.117027
S4
by pediatricians, pulmonologists, and allergy specialists who delegate its care. Thus there are few good studies addressing eczema, even when the end point is asthma, a disease that has received a higher priority in public health. Mild AD in babies is frequently overlooked, although it can be detected quite commonly when infants are examined for other conditions, such as hemangiomas. Early visits by a welltrained pediatric dermatologist are required to detect the disease, but there is no consensus on an operative definition. This is of considerable importance for denominators in longitudinal studies, as evidenced by the comparison of two UK cohorts,1,2 which show a difference in clearance around 25% at 10 to 11 years of age. This can be understood based on the higher prevalence of mild AD in infants than in children. A related problem is the status of the so-called infantile seborrheic dermatitis (ISD), some cases of which were included in Vickers’ cohort.2 Data on the number of cases admitted to our hospital since the 1940s show that this disorder was a real problem in pediatric dermatology until the early 1980s, with a declining incidence since then (Fig 1). This decline may correlate with improved hygiene and diaper care, but it is not known whether the inverse trend between AD and ISD in babies is significant in the context of the epidemics of atopy. Another important bias in natural history studies is the absence of operative definitions. We still do not know, for example, how to confidently make a diagnosis of ichthyosis vulgaris associated with AD. We do not know what can be called a remission or a clearance (is the use of emollients synonymous with disease activity when there is no more clinical inflammation?). We also need to address the problem of severity assessment in longitudinal studies, using validated tools such as the Severity Scoring of Atopic Dermatitis (SCORAD) or quality of life scales.10,11 Finally, the importance of our specialty for people who establish public health policies is felt to be low (ie, Cinderella syndrome). We should emphasize the economic impact of AD as well as its effect on quality of life. Few data address those points according to age groups. The European Task Force on AD
Taieb S5
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
(ETFAD) is currently looking at the use of hospital facilities for AD, and preliminary data demonstrate major differences within European countries.
PREDICTORS OF OUTCOME There is some overlap between outcome prediction studies (see R. Graham-Brown’s article in this supplement, pages S61-3) and natural history studies. Clinical markers of worse outcome have never been truly validated in well-designed studies, such as age at onset (which was clearly a bad prognosis factor in Vickers’ study2) and pattern (reversed in children2 or flexural in infants3). Family history is clearly an important marker for the risk of asthma. Prevention studies are interesting for natural history purposes when the follow-up is long, such as in the San Diego study of Zeiger and Heller9 in highrisk families. Results showed a stability of AD prevalence at 4 and 7 years of age, but without assessment of severity. We are eagerly waiting for the AD data in the ETAC (Early Treatment of the Atopic Child) study. This study was primarily aimed at preventing asthma, but has many methodologic strengths for appreciating the outcome of AD in a very young population. It also shows the heterogeneity of allergen sensitization in baseline tests according to the country of origin. In a pediatric study, we found a positive response in patch testing for major allergens such as house dust mite and pollens in about 90% of children younger than 1 year.12 The patients were usually still negative for prick tests and specific IgE. This pattern began to be reversed in the second year of life, suggesting that there is first a barrier problem. The conflicting views between intrinsic and extrinsic aspects of AD may correspond to evolutionary aspects of the disease, that is, the presence or absence of predisposing factors for IgE responsiveness, which are secondary to barrier impairment.
CONCLUSIONS Important questions for AD are still pending (eg, age at onset and outcome, severity, and outcome). Outcome measures should include public health– dependent parameters and objective/subjective severity assessment. REFERENCES 1. Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol 1998;139:834-9. 2. Vickers CFH. The natural history of atopic eczema. Acta Derm Venereol Suppl (Stockh) 1980;92:113-5. 3. Queille-Roussel C, Raynaud F, Saurat JH. A prospective computerized study of 500 cases of atopic dermatitis in childhood. Acta Derm Venereol Suppl (Stockh) 1986;114:87-92.
Fig 1. Infantile seborrheic dermatitis (ISD) cases admitted to Bordeaux Children’s Hospital since the 1940s. Since the 1980s, there has been a decline in incidence.
4. Rystedt I. Long term follow-up in atopic eczema. Acta Derm Venereol Suppl (Stockh) 1986;114:117-20. 5. Lammintausta K, Kalimo K, Raitala R, Forsten Y. Prognosis of atopic dermatitis. Int J Dermatol 1991;30:563-8. 6. Wüthrich B. Epidemiology and natural history of atopic dermatitis. Allergy Clin Immunol Int 1996;8:77-82. 7. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225-32. 8. Schultz-Larsen F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1993;28:719-23. 9. Zeiger RS, Heller S.The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance. J Allergy Clin Immunol 1995;95:1179-90. 10. Consensus Report of the European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Dermatology 1993;186:23-31. 11. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19:210-6. 12. Taieb A. Hypothesis: from epidermal barrier dysfunction to atopic disorders. Contact Dermatitis 1999;41:177-80.
DISCUSSION Dr Leung: I thought that was a fascinating piece of data you showed, that from 0 to 11 months you have a positive patch test and negative prick. It would be important, though, to follow the same cohort into the next group because you do not know if it was just a different group of people. What is your interpretation? Are the patients not making any IgE to dust mite? In this case, I think it would be very dangerous to say that atopic dermatitis and nonatopic dermatitis are identical. Because, to me, it suggests that it is like the mouse IgE knockouts,
S6 Taieb
where you can get respiratory allergy despite having no IgE. Dr Taieb: We would like to start prospective studies, looking at the same patients, to see if we can confirm this trend. I think the first step is a mechanism that may lead either to the production of IgE or to some kind of tolerance which allows AD to vanish
J AM ACAD DERMATOL JULY 2001
in some of the patients. It is an undifferentiated, but still specific, immunologic process that corresponds with the early phase and may be one of the major sensitization processes in atopy in general. In terms of primary sensitization, the skin is probably overlooked, beside the gut or the respiratory system.
BY AN EDUCATIONAL GRANT FROM NOVARTIS PHARMA AND NOVARTIS PHARMACEUTICALS CORPORATION
AG
The natural history of atopic dermatitis Alain Taieb, MD Bordeaux, France
I
deally, the approach to natural history of atopic dermatitis (AD) should be founded on studies with population-based representative samples, long-term follow-up, clear disease definition, short inclusion time, few losses to follow-up, no therapeutic intervention, and objective outcome measures.1 None of the existing major studies1-6 satisfies all these postulates.
PROBLEMS AND PITFALLS A source of variation is the geographic origin of the studies. Disease prevalence reaches from 2% in China to more than 20% in the United Kingdom and Nigeria.7 Up to now, all studies on natural history have been conducted in Europe, and none addresses the problem of migrant populations. In most Western countries, the prevalence of AD has increased, as documented in twin studies in Denmark.8 Figures derived from cohorts of patients enrolled in the late 1950s or 1960s are probably less relevant today because of rapid environmental changes. With regard to the potential influence of therapeutic intervention, it is frustrating that we have no long-term data. Overall, it is implicit that such intervention does not affect outcomes. In Vickers’ study,2 there is a rather vague feeling that early skin treatment with topical steroids is beneficial. Diet is a more carefully investigated intervention in prevention studies.9 The different perspective on the disease by physicians based on their specialty leads to a bias in organ assessment. Eczema is considered a minor disorder
From the Dermatology Service, Hôpital Saint André. 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. Disclosure: The author attests that he has no conflicts of interest to disclose. Reprint requests: Alain Taieb, MD, Hôpital Saint André, Science de Dermatologie, 1 Rue Jean Burguet, Bordeaux, 33076, France. Email: [email protected]. J Am Acad Dermatol 2001;45:S4-6. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/0/117027 doi:10.1067/mjd.2001.117027
S4
by pediatricians, pulmonologists, and allergy specialists who delegate its care. Thus there are few good studies addressing eczema, even when the end point is asthma, a disease that has received a higher priority in public health. Mild AD in babies is frequently overlooked, although it can be detected quite commonly when infants are examined for other conditions, such as hemangiomas. Early visits by a welltrained pediatric dermatologist are required to detect the disease, but there is no consensus on an operative definition. This is of considerable importance for denominators in longitudinal studies, as evidenced by the comparison of two UK cohorts,1,2 which show a difference in clearance around 25% at 10 to 11 years of age. This can be understood based on the higher prevalence of mild AD in infants than in children. A related problem is the status of the so-called infantile seborrheic dermatitis (ISD), some cases of which were included in Vickers’ cohort.2 Data on the number of cases admitted to our hospital since the 1940s show that this disorder was a real problem in pediatric dermatology until the early 1980s, with a declining incidence since then (Fig 1). This decline may correlate with improved hygiene and diaper care, but it is not known whether the inverse trend between AD and ISD in babies is significant in the context of the epidemics of atopy. Another important bias in natural history studies is the absence of operative definitions. We still do not know, for example, how to confidently make a diagnosis of ichthyosis vulgaris associated with AD. We do not know what can be called a remission or a clearance (is the use of emollients synonymous with disease activity when there is no more clinical inflammation?). We also need to address the problem of severity assessment in longitudinal studies, using validated tools such as the Severity Scoring of Atopic Dermatitis (SCORAD) or quality of life scales.10,11 Finally, the importance of our specialty for people who establish public health policies is felt to be low (ie, Cinderella syndrome). We should emphasize the economic impact of AD as well as its effect on quality of life. Few data address those points according to age groups. The European Task Force on AD
Taieb S5
J AM ACAD DERMATOL VOLUME 45, NUMBER 1
(ETFAD) is currently looking at the use of hospital facilities for AD, and preliminary data demonstrate major differences within European countries.
PREDICTORS OF OUTCOME There is some overlap between outcome prediction studies (see R. Graham-Brown’s article in this supplement, pages S61-3) and natural history studies. Clinical markers of worse outcome have never been truly validated in well-designed studies, such as age at onset (which was clearly a bad prognosis factor in Vickers’ study2) and pattern (reversed in children2 or flexural in infants3). Family history is clearly an important marker for the risk of asthma. Prevention studies are interesting for natural history purposes when the follow-up is long, such as in the San Diego study of Zeiger and Heller9 in highrisk families. Results showed a stability of AD prevalence at 4 and 7 years of age, but without assessment of severity. We are eagerly waiting for the AD data in the ETAC (Early Treatment of the Atopic Child) study. This study was primarily aimed at preventing asthma, but has many methodologic strengths for appreciating the outcome of AD in a very young population. It also shows the heterogeneity of allergen sensitization in baseline tests according to the country of origin. In a pediatric study, we found a positive response in patch testing for major allergens such as house dust mite and pollens in about 90% of children younger than 1 year.12 The patients were usually still negative for prick tests and specific IgE. This pattern began to be reversed in the second year of life, suggesting that there is first a barrier problem. The conflicting views between intrinsic and extrinsic aspects of AD may correspond to evolutionary aspects of the disease, that is, the presence or absence of predisposing factors for IgE responsiveness, which are secondary to barrier impairment.
CONCLUSIONS Important questions for AD are still pending (eg, age at onset and outcome, severity, and outcome). Outcome measures should include public health– dependent parameters and objective/subjective severity assessment. REFERENCES 1. Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol 1998;139:834-9. 2. Vickers CFH. The natural history of atopic eczema. Acta Derm Venereol Suppl (Stockh) 1980;92:113-5. 3. Queille-Roussel C, Raynaud F, Saurat JH. A prospective computerized study of 500 cases of atopic dermatitis in childhood. Acta Derm Venereol Suppl (Stockh) 1986;114:87-92.
Fig 1. Infantile seborrheic dermatitis (ISD) cases admitted to Bordeaux Children’s Hospital since the 1940s. Since the 1980s, there has been a decline in incidence.
4. Rystedt I. Long term follow-up in atopic eczema. Acta Derm Venereol Suppl (Stockh) 1986;114:117-20. 5. Lammintausta K, Kalimo K, Raitala R, Forsten Y. Prognosis of atopic dermatitis. Int J Dermatol 1991;30:563-8. 6. Wüthrich B. Epidemiology and natural history of atopic dermatitis. Allergy Clin Immunol Int 1996;8:77-82. 7. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998;351:1225-32. 8. Schultz-Larsen F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1993;28:719-23. 9. Zeiger RS, Heller S.The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance. J Allergy Clin Immunol 1995;95:1179-90. 10. Consensus Report of the European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Dermatology 1993;186:23-31. 11. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol 1994;19:210-6. 12. Taieb A. Hypothesis: from epidermal barrier dysfunction to atopic disorders. Contact Dermatitis 1999;41:177-80.
DISCUSSION Dr Leung: I thought that was a fascinating piece of data you showed, that from 0 to 11 months you have a positive patch test and negative prick. It would be important, though, to follow the same cohort into the next group because you do not know if it was just a different group of people. What is your interpretation? Are the patients not making any IgE to dust mite? In this case, I think it would be very dangerous to say that atopic dermatitis and nonatopic dermatitis are identical. Because, to me, it suggests that it is like the mouse IgE knockouts,
S6 Taieb
where you can get respiratory allergy despite having no IgE. Dr Taieb: We would like to start prospective studies, looking at the same patients, to see if we can confirm this trend. I think the first step is a mechanism that may lead either to the production of IgE or to some kind of tolerance which allows AD to vanish
J AM ACAD DERMATOL JULY 2001
in some of the patients. It is an undifferentiated, but still specific, immunologic process that corresponds with the early phase and may be one of the major sensitization processes in atopy in general. In terms of primary sensitization, the skin is probably overlooked, beside the gut or the respiratory system.