Journal of Dermatology 2014; 41: 200–204
doi: 10.1111/1346-8138.12331
REVIEW ARTICLE
Epidemiology of atopic dermatitis in Japan Satoshi TAKEUCHI,1,2 Hitokazu ESAKI,2 Masutaka FURUE2 1
Department of Dermatology, Federation of National Public Service Personnel Mutual Aid Associations, Hamanomachi Hospital, and Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2
ABSTRACT Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic and eczematous skin disease. AD is the second most frequently observed skin disease in dermatology clinics in Japan. Prevalence of childhood AD is 12–13% in mainland Japan; however, it is only half that (~6%) in children from Ishigaki Island, Okinawa. Here, we summarize the prevalence, incidence and spontaneous regression of AD and the relation of AD to other allergic diseases from previous reports. We also refer to our recent findings from a population cohort study on Ishigaki Island, Okinawa.
Key words: prevalence.
allergic rhinitis, atopic dermatitis, bronchial asthma, CCL17/TARC, cohort, egg allergy,
INTRODUCTION Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic, eczematous skin disease. The incidence of AD is generally considered to be increasing worldwide,1,2 and that of adolescent- and adult-type AD has also been increasing.3,4 The etiology and pathogenesis of AD are not fully understood. Recent studies demonstrated that it involves a complex interaction of skin barrier dysfunction, exposure to external allergens or microbes, T-helper 2-prone response and psychosomatic reaction. Intense itching, sleep disturbance, appearance of skin inflammation and other atopic symptoms impose a remarkable burden on the individual, the affected individual’s family, and society. Genetic and environmental factors are apparently involved in the onset and exacerbation of AD in a mutually interactive manner. In 1993, Schultz Larsen reported that the pairwise concordance rate of AD in monozygotic twins was 72%, while it was only 23% in their dizygotic counterparts, clearly implying the presence of genetic effects in the development of AD. The author also noted that the prevalence of AD increased sharply from 3.2% in 1960–1964 to 10.2% in 1970–1974.5 The latter findings implied rather the non-genetic (more likely environmental) effects in the development of AD, because the genetic background of a population hardly changes in such a short time period. Interestingly, the results of a similar study published in 1971 indicated that the concordance rate seemed to be affected by the prevalence rate even in genetically identical twins.6 In the 6996 pairs of twins with a 4.3% AD prevalence rate, the pairwise concordance rate of AD was only 15.4% and 4.5% in the monozygotic and dizygotic twins, respectively. AD-causing environmental factors, as yet unknown, had
increased their power in industrialized and developing countries and seemed to trigger the onset of AD in almost all individuals who were genetically predisposed to the disease.
INCIDENCE OF AD IN DERMATOLOGY CLINICS IN JAPAN The incidence of AD in outpatient clinics was 4.1% in 36 233 patients who visited the Dermatology Clinic of the University of Tokyo from 1959 to 1961. In the Branch Hospital of the University of Tokyo, the incidence of AD in the first-visit patients was 5.6% (195/3491) in 1967, 8.7% in 1976 (277/3188), 7.7% (224/ 2913) in 1986 and 10.1% (261/2586) in 1996.7 Considering the results of previous reports on the incidence of AD in dermatological outpatient clinics (2.3% [Drake, 1928, London], 0.6% [Nexmand, 1926–1935, Copenhagen], 1.4% [Nexmand, 1936–1945, Copenhagen], 0.32–1.53% [Iijima and Saito, 1938–1955, Sen€ m and Rajka, dai], 1.4% [Ofuji, 1954–1956, Kyoto], 7% [Hellerstro 1953–1959, Karolinska] and 8.3% [Uehara and Ofuji, 1977, Kyoto]), AD had become a very common skin disease during the 1950s through the 1970s in Japan.7 The dramatic change in age distribution of patients with AD was another interesting point. In 1967, 73.9% of patients with AD were children aged 0–9 years at the Branch Hospital of the University of Tokyo, but this figure gradually dropped to 23.4% by 1996. On the contrary, the percentage of adult patients aged 20–29 years with AD was 3.1% in 1967 and markedly increased to 38.7% by 1996 (Fig 1). The number of patients with adult-type AD at dermatological clinics has clearly increased recently as pointed out by Sugiura et al.4 To clarify the current prevalence of skin disorders among dermatology patients in Japan, the Japanese Dermatological Association conducted a nationwide, cross-sectional, seasonal,
Correspondence: Satoshi Takeuchi, M.D., Ph.D., Department of Dermatology, Federation of National Public Service Personnel Mutual Aid Associations, Hamanomachi Hospital, 3-1-1 Nagahama, Chuo-ku, Fukuoka 810-8539, Japan. Email: [email protected] Received 27 September 2013; accepted 3 October 2013.
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Epidemiology of atopic dermatitis
Table 1. Top 20 diseases in dermatology clinics in Japan
%
80
73.9 68.1
0–9 years old 10–19 years old 20–29 years old More than 30 years old
60
39.3
40
38.7 33.1 21.8 23.2
20
16.9 3.1 6.1
0
1967
18.7
23.4 16.1
7.5 5.7
1976
4.4
1986
1996
Figure 1. Age distribution of outpatients with atopic dermatitis in Branch Hospital of University of Tokyo. Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. (http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3206256/figure/F1/) with permission. multicenter study in 2007–2008. Among the 67 448 cases, the top 20 skin disorders were, in descending order of incidence, miscellaneous eczema, AD, tinea pedis, urticaria/angioedema, tinea unguium, viral warts, psoriasis, contact dermatitis, acne, seborrheic dermatitis, hand eczema, miscellaneous benign skin tumors, alopecia areata, herpes zoster/postherpetic neuralgia, skin ulcers (non-diabetic), prurigo, epidermal cysts, vitiligo vulgaris, seborrheic keratosis and drug eruption/toxicoderma (Table 1). The incidence of AD was 9.8% without any sex difference. It is of note that the age distribution of AD was biphasic, peaking at the ages of 0–5 and 21–35 years (Fig. 2).8 Patients aged 46 years and older comprised 9.6% (649/6733) of all patients with AD.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
© 2014 Japanese Dermatological Association
%
12 590 6733 4379 3369 3231 3028 2985 2643 2430 2213 2024 1666 1653 1609 1334 1229 1194 1134 1095 1018 57 557
18.67 9.98 6.49 4.99 4.79 4.49 4.43 3.92 3.60 3.28 3.00 2.47 2.45 2.39 1.98 1.82 1.77 1.68 1.62 1.51 85.34
1,200
1078
n = 6733
1,000 843 826 824
800 624
600
505
582
396
Patients more than 46 y.o. = 649/6733 (9.64%) 374 215
200 0
108
98 88 51
44 26 15 4
0
0
32
0– 6 5 11–10 – 16 15 – 21 20 – 26 25 – 31 30 36–35 41 –40 – 46 45 – 51 50 56–55 – 61 60 – 66 65 – 71 70 76–75 – 81 80 – 86 85 91 –9 – 0 1 1 U 01 00 nk < no w n
The incidence of AD in Japanese elementary school students was approximately 3% in 1981–1983 but increased to approximately 6–7% in the 1990s.3 Yura and Shimizu conducted a questionnaire survey of health symptoms in 4 million school children (aged 7–12 years) in Osaka and reported that the lifetime prevalence of AD increased from 15.0% in 1985 to 24.1% in 1993 but leveled off thereafter (22.9% in both 1995 and 1997).9 Their subsequent study also confirmed the consecutive decrease in AD prevalence from 1993 to 2006 (16.5%).10 Meanwhile, the prevalence of wheezing was constant at 3.0 0.1% between 1975 and 1983 and then increased to 4.7% in 1993. It re-stabilized at 4.4 0.3% between 1993 and 2006. The prevalence of rhinitis increased from 12.3% in 1983 to 16.7% in 1991, increased further to 25.4% in 2003, and then leveled off at 24.7% in 2006. The reported prevalence of AD in Japanese children is summarized in Table 2.
67 448
Eczema (miscellaneous) Atopic dermatitis Tinea pedis Urticaria/angioedema Tinea unguium Viral warts Psoriasis Contact dermatitis Acne vulgaris Seborrheic dermatitis Hand eczema Benign skin tumors (miscellaneous) Alopecia areata Herpes zoster/postherpetic neuralgia Skin ulcer (non-diabetic) Prurigo Epidermoid cysts Vitiligo vulgaris Seborrheic keratosis Drug eruption/toxicoderma Total
Japanese Dermatological Association (2007). Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206256/table/T1/) with permission.
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INCIDENCE OF AD IN THE GENERAL POPULATION IN JAPAN
Disease
Figure 2. Age distribution of atopic dermatitis in dermatology clinics. Report from the Japanese Dermatological Association (n = 6733). Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3206256/figure/F2/) with permission.
From 2000 to 2002, a research team of the Japanese Ministry of Health, Labor and Welfare examined 48 072 children living in Asahikawa, Iwate, Tokyo, Gifu, Osaka, Hiroshima, Kochi and Fukuoka.11 They reported that the national average prevalence of AD was 12.8% in individuals aged 4 months, 9.8% in those aged 18 months, 13.2% in those aged 3 years, 11.8% in those aged 6–7 years, 10.6% in those aged 12–13 years and
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Table 2. Prevalence of atopic dermatitis in Japan 6–10 years 25 1990
Aichi Osaka, questionnaire 1992 West Japan (11 prefectures, questionnaire) 1993 Hirosaki 1993 Hamamatsu 1995 Nagasaki 1996 Ibaragi 1992-97 Hiroshima, Asa area 2001 Hiroshima 2001 Maebashi 2002 Isahaya 2002 West Japan (11 prefectures, questionnaire) 2000–2002 All Japan, eight cities
3.85% 19%
12–13 years
14–15 years
9.2%
1.96% 9.0%
17.3% 9% 24.3% 8.5% 7.6% 13.7%
9.2% 16.0%
10.9% 9.9% 10.1% 13.8%
10.9% 6.5%
11.8%
10.6%
5.9%
Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206256/table/T2/) with permission.
8.2% in those aged 18 years. In 2001, we started a population-based survey of children aged 6 years and younger on Ishigaki Island, Okinawa, Japan (Kyushu University Ishigaki Atopic Dermatitis Study; KIDS). The prevalence of childhood AD in this southern subtropical island was as low as 6%12 and did not increase continuously during the period from 2001 to 2011 (Takeuchi S et al. manuscript in preparation).
AD AS A SPONTANEOUSLY REMITTING DISEASE It is well documented that AD remits spontaneously, especially in infants and children. In a study of 102 4-month-old children, Kawaguchi et al.13 reported that AD remitted spontaneously in 83 children (81.4%) by the age of 18 months. Illi et al. reported that the cumulative prevalence of AD in the first 2 years of life was 21.5%. Among these children with early AD, 43.2% were in complete remission by the age of 3 years, 38.3% had an intermittent pattern of disease and 18.7% had symptoms of AD every year. Severity (adjusted cumulative odds ratio [OR], 5.86; 95% confidence interval [CI], 3.04–11.29] and atopic sensitization (adjusted cumulative OR, 2.76; 95% CI, 1.29–5.91) were major determinants of AD prognosis.14 In our KIDS cohort, AD remitted spontaneously in 71.6% of children (53/74) aged 5 years and younger, whereas 5.5% of individuals without AD (44/795) newly developed AD during the 3-year follow up. Increases in total immunoglobulin (Ig)E levels were greater and more rapid in children with long-term AD compared to those who had spontaneously remitted, had newly developed AD or did not have AD.15 Anan and Yamamoto reported that 287 of 1072 children aged 6 years in Nagasaki had a present (n = 91) or past history (n = 196) of AD in 1995; that is, 68.3% of children with AD (196/287) experienced spontaneous regression by
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the age of 6 years.16 They also followed 50 children aged 6 years with AD and found that AD had remitted spontaneously in 30 children within the subsequent 6 years. In Hiroshima, the mean prevalence of children aged 6 years with AD from 1992 to 1997 was 13.6% (male, 13.6%; female, 13.7%; total number, 1327).17 Among 121 children aged 6 years with AD, 61 remitted and 22 had improved 5 years later. Among 464 pupils aged 6 years without AD, six (1.3%) had developed AD 5 years later. Williams and Strachan analyzed the age of onset and clearance rates for examined and/or reported eczema in 6877 children born during the period of 3–9 March 1958 for whom linked data was available at birth and at the ages of 7, 11, 16 and 23 years. Of the 870 cases with examined or reported eczema by the age of 16 years, 66% had experienced onset by the age of 7 years. Of the 571 children with reported or examined eczema by the age of 7 years, the proportion of children who were clear in terms of examined or reported eczema in the last year at the ages of 11 and 16 years was 65% and 74%, respectively. These short-term clearance rates fell to 53% and 65%, respectively, after allowing for subsequent recurrences in adolescence and early adulthood.18 Uehara et al. examined the remission rate of 266 children aged 2 years or older with AD (at the first visit in 1953–1961) in 1966 (5–13 years later) by questionnaire and reported that 76 had experienced remission (29%).19 In the 190 children who did not experience remission, 40 experienced a short regression of more than a year. Of these 40 children, 36 (90%) reported that their transient regression appeared within 15 years after the onset of AD, and 29 children (79%) reported that their transient remission did not last more than 5 years. Another questionnaire study revealed that either transient or complete remission occurred in 33.3% of 794 patients aged 10–20 years with AD.20 In a mail-in questionnaire study, 220 patients with AD (mean age, 21.3 11.8 years) were monitored every 3 months for 3 years from 2006 to 2009, and 36 (16.4%) reported having remission of more than a year. Four developed atopic cataracts (aged 12, 13, 54 and 59 years) during this period and none of them experienced any remission. Patients aged 30 years and older had a significantly lower remission rate compared to those younger than 30 years.21 The remission of adult-type AD tends to occur more slowly. Our 95 cases of adult AD (mean age, 23.9 11.5 years in 1991–1992; 45 males and 50 females) reported the following in 1996: AD remitted (10.5%), much improved (32.6%), slightly improved (34.7%) and was unchanged or worse (22.1%). Eleven reported that the onset of AD was as late as 18 years or older. Association with other allergic diseases significantly lowered the remission/improvement rate compared to the pure AD group.22 The severity of AD also increased according to age. Yamamoto demonstrated that the percentage of mild cases decreased gradually with age (84.3% at the age of 1.5 years, 85% at the age of 3 years, 75.9% at the age of 6 years, 71.6% at the age of 12 years and 72.7% at the age of 18 years), while the percentage of moderate cases increased inversely (12.4% at the age of 1.5 years, 11.8% at the age of 3 years, 22.4% at the age of 6 years, 26.3% at the age of 12 years and 21.9% at the age of 18 years).11 This phenomenon can be caused by numerous aggravating factors, including
© 2014 Japanese Dermatological Association
Epidemiology of atopic dermatitis
hormonal imbalance in adolescence, increased physical and schoolwork stress, and emotional stress related to social and family issues. Decreased compliance with treatment regimens may also contribute to the deterioration of AD.
FINDINGS FROM THE KIDS COHORT We have been conducting a cohort study named KIDS on AD in nursery school children on Ishigaki Island, Okinawa, Japan, every summer since 2001. Ishigaki Island is located approximately 410 km southwest from the main island of Okinawa and has a subtropical oceanic climate. The average annual temperature and humidity are 24.4°C and 73.1%, respectively, which are considerably high compared to those in Tokyo, Japan (16.5°C and 60%, respectively). The city of Ishigaki has a population of 46 922 and the number of children aged 6 years and younger is 4222, according to the national census in 2010. The KIDS cohort consists of a dermatologist-based physical examination, a questionnaire survey of the children’s parents (or guardians), and analysis of collected blood samples (e.g. total IgE, thymus and activation-regulated chemokine [TARC]). In total, 7856 nursery school children aged 6 years and younger were examined from 2001 to 2011 in the KIDS cohort. The annual numbers of examinees were approximately 600–850. The prevalence of AD was approximately 5–7% with some exception, and the average prevalence of AD through the period was 6.3% (Takeuchi S et al. manuscript in preparation). The average prevalence of AD in male children was 5.7% and that of female children was 7.0% without significant sex difference. In questionnaire surveys through 2006–2008, 1195 answers were obtained from 658 male and 537 female children after excluding duplication of an individual. The results of the questionnaire regarding incidental AD and related diseases such as allergic rhinitis (AR), bronchial asthma (BA) and food allergy (mostly egg allergy, EA) were separated by sex (Takeuchi S et al. manuscript in preparation). The incidences of AD in male and female children were 13.2% and 14.4%, respectively, with no sex difference. These values were considerably higher than those assessed by physical examination because the incidental AD contains populations who have had AD but remitted naturally at the time of physical examination. It has been known that most infantile AD cures or remits naturally. In the follow-up study of KIDS, it has been shown that 71.6% of children with AD who have been diagnosed by dermatologists are naturally cured within 3 years,15 explaining the gap between AD incidence in the questionnaire survey and the annual AD prevalence. The incidences of AR in male and female children were 3.1% and 2.5%, respectively, with no sex differences. Meanwhile, the incidences of BA in male and female patients were 17.4% and 11.9%, respectively, with a statistically significant difference (P = 0.008). There is currently no explanation for this sex difference in BA. Among food allergies, EA is the most frequent and has sufficient numbers for subsequent analysis; therefore, incidence of EA was used on behalf of food allergy. The incidences of EA in male and female children were 5.3% and 3.8%, respectively. When nursery school children were divided into incidental AD and non-AD groups regardless of
© 2014 Japanese Dermatological Association
sex, the incidences of AR in incidental AD and non-AD groups were 5.5% and 2.4%, respectively. The incidences of BA were 28.1% and 12.9%, and the incidences of EA were 18.4% and 2.3%, respectively. All allergic diseases, which are known as AD-related diseases, examined in the questionnaire survey showed significantly higher disease incidence rates in the incidental AD group than in the non-AD group (unpubl. Takeuchi S et al. manuscript in preparation). The difference in EA incidence between the incidental AD and non-AD groups was particularly remarkable. Univariate analysis of familial history of allergic diseases revealed that incidence of paternal AD, AR and BA, maternal AD and food allergy, and sibling AD and AR were significantly associated with incidental AD of the subject. Further, multivariate logistic regression analysis including other allergic diseases of the subject revealed that incidences of BA and EA of the subject, paternal AD and sibling AD were statistically significant risk factors for incidental AD of the subject as determined by an OR of more than 2 (Takeuchi S et al. manuscript in preparation). In the blood sample examination, an increase in the serum total IgE level was evident from the age of 2 years and the level in male children was significantly higher than that of female children from the age of 2–4 years (Takeuchi S et al. manuscript in preparation). As known, the serum total IgE level was higher in patients with AD coincident with BA than in those without BA. Therefore, the high incidence of BA in male children may have affected the sex difference of total IgE at the age of 2–4 years. When children were divided simply by having or not having each allergic disease, mean total IgE levels in incidental AD and nonAD were 425.3 678.3 and 141.9 315.4 IU/mL, respectively; those in incidental AR and non-AR were 454.8 592.4 and 172.7 385.0 IU/mL, respectively; those in incidental BA and non-BA were 328.3 505.6 and 157.3 376.6 IU/mL, respectively; and those in incidental EA and non-EA were 496.7 784.6 and 164.1 358.0 IU/mL, respectively. These mean total IgE levels in incidental disease groups were statistically higher than those in non-incidental groups of each allergic disease (P < 0.01). In the incidental AD children, coincidence of BA, but neither AR nor EA, significantly increased serum total IgE levels, as compared to incidental AD children without BA (Takeuchi S et al. manuscript in preparation). This result also supports the hypothesis that previous sex difference of total IgE may come from the higher incidence of BA in male children.
SEVERITY OF AD AND EA FROM THE KIDS COHORT CCL17 or TARC was found by Kakinuma et al.23 to be a disease marker that reflects disease severity of AD and has been admitted for national insurance coverage since 2008 in Japan. It is known that the upper limits of the normal range are higher in younger children as announced by the manufacturer. In our KIDS cohort, the mean CCL17 level of non-allergic nursery school children was highest (nearly 800 pg/mL) at the age of 1 year and decreased gradually as the age of the children increased to approximately half those values at the age of 5–6 years (Takeuchi S et al. manuscript in preparation).
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However, mean CCL17 levels in children with AD did not show such a decrease with age. Children with AD were divided according to having or not having incidental AR, BA or EA. The mean CCL17 level in children with AD and incidental EA was significantly higher than in those without incidental EA (Takeuchi S et al. manuscript in preparation). Such differences were not observed when children with AD were divided by having or not having AR or BA (data not shown). It is of interest that the coincidence of EA increased TARC levels in children with AD, because the chemokine is a disease severity marker of AD. In addition to using questionnaire-based incidental EA analysis, children with prevalent AD were divided into groups of highly specific IgE to ovomucoid, a major egg whites antigen whites (as determined by the score of ≥2 by IMMULITE 3gAllergy [Siemens Healthcare Diagnostics, Tokyo, Japan]) and lower as having tentative EA (EA-IgE) and not, respectively. The TARC level in prevalent AD with EA-IgE was significantly higher than in those without EA-IgE (Esaki H et al. manuscript in preparation). For this association between AD and EA, there are two possible explanations: coexistence (or coincidence) of EA somehow increased disease severity, for example, through IgE-mediated (wheal or transient erythema) and/or nonIgE-mediated (papules and lichenification) mechanisms. Alternatively, children with higher disease severity tended to develop or have exacerbated EA. The latter interpretation may be more interesting from the standpoint of impaired skin barrier functions by filaggrin gene mutation, the major predisposing factor for AD,24 and the relation of food allergy with the gene mutation.25 These results, including ours, may suggest that more severe or inadequate control of AD may lead to food allergy presumably by repetitive percutaneous sensitization to allergenic foods through the impaired skin barrier. For further verification of this hypothesis, long-term interventional studies in the field of pediatric AD are of interest. We have summarized the epidemiology of AD in Japan in terms of prevalence/incidence and spontaneous remission from previous reports. We also referred to our recent findings from our KIDS cohort. More findings from any case–control or cohort studies or even from basic studies are awaited to understand the complex but interesting disease, AD.
ACKNOWLEDGMENT:
This work was partially supported by
a research grant from the Ministry of Health, Labor and Welfare, Japan. We thank Mr Masaki Takemura for his wonderful technical assistance.
CONFLICT OF INTEREST:
None.
REFERENCES 1 Williams HC. Is the prevalence of atopic dermatitis increasing? Clin Exp Dermatol 1992; 17: 385–391. 2 Williams H, Robertson C, Stewart A et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999; 103: 125–138.
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3 Takeuchi M, Ueda H. Increase of atopic dermatitis (AD) in recent Japan. Environ Dermatol 2000; 7: 133–136. 4 Sugiura H, Umemoto N, Deguchi H et al. Prevalence of childhood and adolescent atopic dermatitis in a Japanese population: comparison with the disease frequency examined 20 years ago. Acta Derm Venereol 1998; 78: 293–294. 5 Schultz Larsen F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1993; 28: 719–723. 6 Edfors-Lubs ML. Allergy in 7000 twin pairs. Acta Allergol 1971; 26: 249–285. 7 Furue M. History of atopic dermatitis. In: Kunihiko Tamaki, Masutaka Furue, Hidemi Nakagawa, eds. Atopic Dermatitis and Topical Steroid Therapy. Tokyo, Japan: Chugai-igakusha, 19981–19. Chugai-igakusha (in Japanese). 8 Furue M, Yamazaki S, Jimbow K et al. Prevalence of dermatological disorders in Japan: a nationwide, cross-sectional, seasonal, multicenter, hospital-based study. J Dermatol 2011; 38: 310–320. 9 Yura A, Shimizu T. Trends in the prevalence of atopic dermatitis in school children: longitudinal study in Osaka Prefecture, Japan, from 1985 to 1997. Br J Dermatol 2001; 145: 966–973. 10 Yura A, Kouda K, Iki M, Shimizu T. Trends of allergic symptoms in school children: large-scale long-term consecutive cross-sectional studies in Osaka Prefecture Japan. Pediatr Allergy Immunol 2011; 22: 631–637. 11 Yamamoto S. Prevalence and exacerbation factors of atopic dermatitis. Skin Allergy Frontier 2003; 1: 85–90. (in Japanese) 12 Hamada M, Furusyo N, Urabe K et al. Prevalence of atopic dermatitis and serum IgE values in nursery school children in Ishigaki Island, Okinawa, Japan. J Dermatol 2005; 32: 248–255. 13 Kawaguchi H, Takeuchi M, Tanaka Y, Ishii N, Ikezawa Z. Atopic dermatitis at 18-months physical examination. Arerugi 2000; 49: 653–657. €ber C, Niggemann B, Wahn 14 Illi S, von Mutius E, Lau S, Nickel R, Gru U, Multicenter Allergy Study Group. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004; 113: 925–931. 15 Fukiwake N, Furusyo N, Kubo N et al. Incidence of atopic dermatitis in nursery school children - a follow-up study from 2001 to 2004, Kyushu University Ishigaki Atopic Dermatitis Study (KIDS). Eur J Dermatol 2006; 16: 416–419. 16 Anan S, Yamamoto N. Spontaneous regression of atopic dermatitis. Hifu 1996; 38(Suppl 18): 13–15. (in Japanese) 17 Okano S, Takahashi H, Yano T et al. Prevalence of childhood atopic dermatitis in first-year pupils of elementary school and its follow-up: Asa district in Hiroshima. Nihon Ishikai Zasshi 2006; 135: 97–103. (in Japanese) 18 Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol 1998; 139: 834–839. 19 Uehara M, Otaka T, Ogawa Y, Ofuji K. Clinical course of atopic dermatitis. Hifuka-Kiyo 1970; 65: 1–6. (in Japanese) 20 Furue M, Kawashima M, Furukawa F et al. Questionnaire study for chronological change in atopic dermatitis. Rinshohifuka 2007; 61: 286–295. (in Japanese) 21 Furue M, Kawashima M, Furukawa F et al. A prospective questionnaire study for atopic dermatitis. Rinshohifuka 2011; 65: 83–92. (in Japanese) 22 Furue M, Hayashida S, Uchi H. Natural history of atopic dermatitis. Rinshomeneki-Arerugika 2009; 52: 320–325. 23 Kakinuma T, Nakamura K, Wakugawa M et al. Serum macrophagederived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clin Exp Immunol 2002; 127: 270–273. 24 Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Common loss-offunction variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38: 441–446. 25 Brown SJ, Asai Y, Cordell HJ et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 2011; 127: 661–667.
© 2014 Japanese Dermatological Association
doi: 10.1111/1346-8138.12331
REVIEW ARTICLE
Epidemiology of atopic dermatitis in Japan Satoshi TAKEUCHI,1,2 Hitokazu ESAKI,2 Masutaka FURUE2 1
Department of Dermatology, Federation of National Public Service Personnel Mutual Aid Associations, Hamanomachi Hospital, and Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2
ABSTRACT Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic and eczematous skin disease. AD is the second most frequently observed skin disease in dermatology clinics in Japan. Prevalence of childhood AD is 12–13% in mainland Japan; however, it is only half that (~6%) in children from Ishigaki Island, Okinawa. Here, we summarize the prevalence, incidence and spontaneous regression of AD and the relation of AD to other allergic diseases from previous reports. We also refer to our recent findings from a population cohort study on Ishigaki Island, Okinawa.
Key words: prevalence.
allergic rhinitis, atopic dermatitis, bronchial asthma, CCL17/TARC, cohort, egg allergy,
INTRODUCTION Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic, eczematous skin disease. The incidence of AD is generally considered to be increasing worldwide,1,2 and that of adolescent- and adult-type AD has also been increasing.3,4 The etiology and pathogenesis of AD are not fully understood. Recent studies demonstrated that it involves a complex interaction of skin barrier dysfunction, exposure to external allergens or microbes, T-helper 2-prone response and psychosomatic reaction. Intense itching, sleep disturbance, appearance of skin inflammation and other atopic symptoms impose a remarkable burden on the individual, the affected individual’s family, and society. Genetic and environmental factors are apparently involved in the onset and exacerbation of AD in a mutually interactive manner. In 1993, Schultz Larsen reported that the pairwise concordance rate of AD in monozygotic twins was 72%, while it was only 23% in their dizygotic counterparts, clearly implying the presence of genetic effects in the development of AD. The author also noted that the prevalence of AD increased sharply from 3.2% in 1960–1964 to 10.2% in 1970–1974.5 The latter findings implied rather the non-genetic (more likely environmental) effects in the development of AD, because the genetic background of a population hardly changes in such a short time period. Interestingly, the results of a similar study published in 1971 indicated that the concordance rate seemed to be affected by the prevalence rate even in genetically identical twins.6 In the 6996 pairs of twins with a 4.3% AD prevalence rate, the pairwise concordance rate of AD was only 15.4% and 4.5% in the monozygotic and dizygotic twins, respectively. AD-causing environmental factors, as yet unknown, had
increased their power in industrialized and developing countries and seemed to trigger the onset of AD in almost all individuals who were genetically predisposed to the disease.
INCIDENCE OF AD IN DERMATOLOGY CLINICS IN JAPAN The incidence of AD in outpatient clinics was 4.1% in 36 233 patients who visited the Dermatology Clinic of the University of Tokyo from 1959 to 1961. In the Branch Hospital of the University of Tokyo, the incidence of AD in the first-visit patients was 5.6% (195/3491) in 1967, 8.7% in 1976 (277/3188), 7.7% (224/ 2913) in 1986 and 10.1% (261/2586) in 1996.7 Considering the results of previous reports on the incidence of AD in dermatological outpatient clinics (2.3% [Drake, 1928, London], 0.6% [Nexmand, 1926–1935, Copenhagen], 1.4% [Nexmand, 1936–1945, Copenhagen], 0.32–1.53% [Iijima and Saito, 1938–1955, Sen€ m and Rajka, dai], 1.4% [Ofuji, 1954–1956, Kyoto], 7% [Hellerstro 1953–1959, Karolinska] and 8.3% [Uehara and Ofuji, 1977, Kyoto]), AD had become a very common skin disease during the 1950s through the 1970s in Japan.7 The dramatic change in age distribution of patients with AD was another interesting point. In 1967, 73.9% of patients with AD were children aged 0–9 years at the Branch Hospital of the University of Tokyo, but this figure gradually dropped to 23.4% by 1996. On the contrary, the percentage of adult patients aged 20–29 years with AD was 3.1% in 1967 and markedly increased to 38.7% by 1996 (Fig 1). The number of patients with adult-type AD at dermatological clinics has clearly increased recently as pointed out by Sugiura et al.4 To clarify the current prevalence of skin disorders among dermatology patients in Japan, the Japanese Dermatological Association conducted a nationwide, cross-sectional, seasonal,
Correspondence: Satoshi Takeuchi, M.D., Ph.D., Department of Dermatology, Federation of National Public Service Personnel Mutual Aid Associations, Hamanomachi Hospital, 3-1-1 Nagahama, Chuo-ku, Fukuoka 810-8539, Japan. Email: [email protected] Received 27 September 2013; accepted 3 October 2013.
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Table 1. Top 20 diseases in dermatology clinics in Japan
%
80
73.9 68.1
0–9 years old 10–19 years old 20–29 years old More than 30 years old
60
39.3
40
38.7 33.1 21.8 23.2
20
16.9 3.1 6.1
0
1967
18.7
23.4 16.1
7.5 5.7
1976
4.4
1986
1996
Figure 1. Age distribution of outpatients with atopic dermatitis in Branch Hospital of University of Tokyo. Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. (http:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3206256/figure/F1/) with permission. multicenter study in 2007–2008. Among the 67 448 cases, the top 20 skin disorders were, in descending order of incidence, miscellaneous eczema, AD, tinea pedis, urticaria/angioedema, tinea unguium, viral warts, psoriasis, contact dermatitis, acne, seborrheic dermatitis, hand eczema, miscellaneous benign skin tumors, alopecia areata, herpes zoster/postherpetic neuralgia, skin ulcers (non-diabetic), prurigo, epidermal cysts, vitiligo vulgaris, seborrheic keratosis and drug eruption/toxicoderma (Table 1). The incidence of AD was 9.8% without any sex difference. It is of note that the age distribution of AD was biphasic, peaking at the ages of 0–5 and 21–35 years (Fig. 2).8 Patients aged 46 years and older comprised 9.6% (649/6733) of all patients with AD.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
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%
12 590 6733 4379 3369 3231 3028 2985 2643 2430 2213 2024 1666 1653 1609 1334 1229 1194 1134 1095 1018 57 557
18.67 9.98 6.49 4.99 4.79 4.49 4.43 3.92 3.60 3.28 3.00 2.47 2.45 2.39 1.98 1.82 1.77 1.68 1.62 1.51 85.34
1,200
1078
n = 6733
1,000 843 826 824
800 624
600
505
582
396
Patients more than 46 y.o. = 649/6733 (9.64%) 374 215
200 0
108
98 88 51
44 26 15 4
0
0
32
0– 6 5 11–10 – 16 15 – 21 20 – 26 25 – 31 30 36–35 41 –40 – 46 45 – 51 50 56–55 – 61 60 – 66 65 – 71 70 76–75 – 81 80 – 86 85 91 –9 – 0 1 1 U 01 00 nk < no w n
The incidence of AD in Japanese elementary school students was approximately 3% in 1981–1983 but increased to approximately 6–7% in the 1990s.3 Yura and Shimizu conducted a questionnaire survey of health symptoms in 4 million school children (aged 7–12 years) in Osaka and reported that the lifetime prevalence of AD increased from 15.0% in 1985 to 24.1% in 1993 but leveled off thereafter (22.9% in both 1995 and 1997).9 Their subsequent study also confirmed the consecutive decrease in AD prevalence from 1993 to 2006 (16.5%).10 Meanwhile, the prevalence of wheezing was constant at 3.0 0.1% between 1975 and 1983 and then increased to 4.7% in 1993. It re-stabilized at 4.4 0.3% between 1993 and 2006. The prevalence of rhinitis increased from 12.3% in 1983 to 16.7% in 1991, increased further to 25.4% in 2003, and then leveled off at 24.7% in 2006. The reported prevalence of AD in Japanese children is summarized in Table 2.
67 448
Eczema (miscellaneous) Atopic dermatitis Tinea pedis Urticaria/angioedema Tinea unguium Viral warts Psoriasis Contact dermatitis Acne vulgaris Seborrheic dermatitis Hand eczema Benign skin tumors (miscellaneous) Alopecia areata Herpes zoster/postherpetic neuralgia Skin ulcer (non-diabetic) Prurigo Epidermoid cysts Vitiligo vulgaris Seborrheic keratosis Drug eruption/toxicoderma Total
Japanese Dermatological Association (2007). Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206256/table/T1/) with permission.
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INCIDENCE OF AD IN THE GENERAL POPULATION IN JAPAN
Disease
Figure 2. Age distribution of atopic dermatitis in dermatology clinics. Report from the Japanese Dermatological Association (n = 6733). Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. (http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3206256/figure/F2/) with permission.
From 2000 to 2002, a research team of the Japanese Ministry of Health, Labor and Welfare examined 48 072 children living in Asahikawa, Iwate, Tokyo, Gifu, Osaka, Hiroshima, Kochi and Fukuoka.11 They reported that the national average prevalence of AD was 12.8% in individuals aged 4 months, 9.8% in those aged 18 months, 13.2% in those aged 3 years, 11.8% in those aged 6–7 years, 10.6% in those aged 12–13 years and
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Table 2. Prevalence of atopic dermatitis in Japan 6–10 years 25 1990
Aichi Osaka, questionnaire 1992 West Japan (11 prefectures, questionnaire) 1993 Hirosaki 1993 Hamamatsu 1995 Nagasaki 1996 Ibaragi 1992-97 Hiroshima, Asa area 2001 Hiroshima 2001 Maebashi 2002 Isahaya 2002 West Japan (11 prefectures, questionnaire) 2000–2002 All Japan, eight cities
3.85% 19%
12–13 years
14–15 years
9.2%
1.96% 9.0%
17.3% 9% 24.3% 8.5% 7.6% 13.7%
9.2% 16.0%
10.9% 9.9% 10.1% 13.8%
10.9% 6.5%
11.8%
10.6%
5.9%
Reproduced from Furue et al: Asia Pac Allergy. 2011 July;1(2): 64–72. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206256/table/T2/) with permission.
8.2% in those aged 18 years. In 2001, we started a population-based survey of children aged 6 years and younger on Ishigaki Island, Okinawa, Japan (Kyushu University Ishigaki Atopic Dermatitis Study; KIDS). The prevalence of childhood AD in this southern subtropical island was as low as 6%12 and did not increase continuously during the period from 2001 to 2011 (Takeuchi S et al. manuscript in preparation).
AD AS A SPONTANEOUSLY REMITTING DISEASE It is well documented that AD remits spontaneously, especially in infants and children. In a study of 102 4-month-old children, Kawaguchi et al.13 reported that AD remitted spontaneously in 83 children (81.4%) by the age of 18 months. Illi et al. reported that the cumulative prevalence of AD in the first 2 years of life was 21.5%. Among these children with early AD, 43.2% were in complete remission by the age of 3 years, 38.3% had an intermittent pattern of disease and 18.7% had symptoms of AD every year. Severity (adjusted cumulative odds ratio [OR], 5.86; 95% confidence interval [CI], 3.04–11.29] and atopic sensitization (adjusted cumulative OR, 2.76; 95% CI, 1.29–5.91) were major determinants of AD prognosis.14 In our KIDS cohort, AD remitted spontaneously in 71.6% of children (53/74) aged 5 years and younger, whereas 5.5% of individuals without AD (44/795) newly developed AD during the 3-year follow up. Increases in total immunoglobulin (Ig)E levels were greater and more rapid in children with long-term AD compared to those who had spontaneously remitted, had newly developed AD or did not have AD.15 Anan and Yamamoto reported that 287 of 1072 children aged 6 years in Nagasaki had a present (n = 91) or past history (n = 196) of AD in 1995; that is, 68.3% of children with AD (196/287) experienced spontaneous regression by
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the age of 6 years.16 They also followed 50 children aged 6 years with AD and found that AD had remitted spontaneously in 30 children within the subsequent 6 years. In Hiroshima, the mean prevalence of children aged 6 years with AD from 1992 to 1997 was 13.6% (male, 13.6%; female, 13.7%; total number, 1327).17 Among 121 children aged 6 years with AD, 61 remitted and 22 had improved 5 years later. Among 464 pupils aged 6 years without AD, six (1.3%) had developed AD 5 years later. Williams and Strachan analyzed the age of onset and clearance rates for examined and/or reported eczema in 6877 children born during the period of 3–9 March 1958 for whom linked data was available at birth and at the ages of 7, 11, 16 and 23 years. Of the 870 cases with examined or reported eczema by the age of 16 years, 66% had experienced onset by the age of 7 years. Of the 571 children with reported or examined eczema by the age of 7 years, the proportion of children who were clear in terms of examined or reported eczema in the last year at the ages of 11 and 16 years was 65% and 74%, respectively. These short-term clearance rates fell to 53% and 65%, respectively, after allowing for subsequent recurrences in adolescence and early adulthood.18 Uehara et al. examined the remission rate of 266 children aged 2 years or older with AD (at the first visit in 1953–1961) in 1966 (5–13 years later) by questionnaire and reported that 76 had experienced remission (29%).19 In the 190 children who did not experience remission, 40 experienced a short regression of more than a year. Of these 40 children, 36 (90%) reported that their transient regression appeared within 15 years after the onset of AD, and 29 children (79%) reported that their transient remission did not last more than 5 years. Another questionnaire study revealed that either transient or complete remission occurred in 33.3% of 794 patients aged 10–20 years with AD.20 In a mail-in questionnaire study, 220 patients with AD (mean age, 21.3 11.8 years) were monitored every 3 months for 3 years from 2006 to 2009, and 36 (16.4%) reported having remission of more than a year. Four developed atopic cataracts (aged 12, 13, 54 and 59 years) during this period and none of them experienced any remission. Patients aged 30 years and older had a significantly lower remission rate compared to those younger than 30 years.21 The remission of adult-type AD tends to occur more slowly. Our 95 cases of adult AD (mean age, 23.9 11.5 years in 1991–1992; 45 males and 50 females) reported the following in 1996: AD remitted (10.5%), much improved (32.6%), slightly improved (34.7%) and was unchanged or worse (22.1%). Eleven reported that the onset of AD was as late as 18 years or older. Association with other allergic diseases significantly lowered the remission/improvement rate compared to the pure AD group.22 The severity of AD also increased according to age. Yamamoto demonstrated that the percentage of mild cases decreased gradually with age (84.3% at the age of 1.5 years, 85% at the age of 3 years, 75.9% at the age of 6 years, 71.6% at the age of 12 years and 72.7% at the age of 18 years), while the percentage of moderate cases increased inversely (12.4% at the age of 1.5 years, 11.8% at the age of 3 years, 22.4% at the age of 6 years, 26.3% at the age of 12 years and 21.9% at the age of 18 years).11 This phenomenon can be caused by numerous aggravating factors, including
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Epidemiology of atopic dermatitis
hormonal imbalance in adolescence, increased physical and schoolwork stress, and emotional stress related to social and family issues. Decreased compliance with treatment regimens may also contribute to the deterioration of AD.
FINDINGS FROM THE KIDS COHORT We have been conducting a cohort study named KIDS on AD in nursery school children on Ishigaki Island, Okinawa, Japan, every summer since 2001. Ishigaki Island is located approximately 410 km southwest from the main island of Okinawa and has a subtropical oceanic climate. The average annual temperature and humidity are 24.4°C and 73.1%, respectively, which are considerably high compared to those in Tokyo, Japan (16.5°C and 60%, respectively). The city of Ishigaki has a population of 46 922 and the number of children aged 6 years and younger is 4222, according to the national census in 2010. The KIDS cohort consists of a dermatologist-based physical examination, a questionnaire survey of the children’s parents (or guardians), and analysis of collected blood samples (e.g. total IgE, thymus and activation-regulated chemokine [TARC]). In total, 7856 nursery school children aged 6 years and younger were examined from 2001 to 2011 in the KIDS cohort. The annual numbers of examinees were approximately 600–850. The prevalence of AD was approximately 5–7% with some exception, and the average prevalence of AD through the period was 6.3% (Takeuchi S et al. manuscript in preparation). The average prevalence of AD in male children was 5.7% and that of female children was 7.0% without significant sex difference. In questionnaire surveys through 2006–2008, 1195 answers were obtained from 658 male and 537 female children after excluding duplication of an individual. The results of the questionnaire regarding incidental AD and related diseases such as allergic rhinitis (AR), bronchial asthma (BA) and food allergy (mostly egg allergy, EA) were separated by sex (Takeuchi S et al. manuscript in preparation). The incidences of AD in male and female children were 13.2% and 14.4%, respectively, with no sex difference. These values were considerably higher than those assessed by physical examination because the incidental AD contains populations who have had AD but remitted naturally at the time of physical examination. It has been known that most infantile AD cures or remits naturally. In the follow-up study of KIDS, it has been shown that 71.6% of children with AD who have been diagnosed by dermatologists are naturally cured within 3 years,15 explaining the gap between AD incidence in the questionnaire survey and the annual AD prevalence. The incidences of AR in male and female children were 3.1% and 2.5%, respectively, with no sex differences. Meanwhile, the incidences of BA in male and female patients were 17.4% and 11.9%, respectively, with a statistically significant difference (P = 0.008). There is currently no explanation for this sex difference in BA. Among food allergies, EA is the most frequent and has sufficient numbers for subsequent analysis; therefore, incidence of EA was used on behalf of food allergy. The incidences of EA in male and female children were 5.3% and 3.8%, respectively. When nursery school children were divided into incidental AD and non-AD groups regardless of
© 2014 Japanese Dermatological Association
sex, the incidences of AR in incidental AD and non-AD groups were 5.5% and 2.4%, respectively. The incidences of BA were 28.1% and 12.9%, and the incidences of EA were 18.4% and 2.3%, respectively. All allergic diseases, which are known as AD-related diseases, examined in the questionnaire survey showed significantly higher disease incidence rates in the incidental AD group than in the non-AD group (unpubl. Takeuchi S et al. manuscript in preparation). The difference in EA incidence between the incidental AD and non-AD groups was particularly remarkable. Univariate analysis of familial history of allergic diseases revealed that incidence of paternal AD, AR and BA, maternal AD and food allergy, and sibling AD and AR were significantly associated with incidental AD of the subject. Further, multivariate logistic regression analysis including other allergic diseases of the subject revealed that incidences of BA and EA of the subject, paternal AD and sibling AD were statistically significant risk factors for incidental AD of the subject as determined by an OR of more than 2 (Takeuchi S et al. manuscript in preparation). In the blood sample examination, an increase in the serum total IgE level was evident from the age of 2 years and the level in male children was significantly higher than that of female children from the age of 2–4 years (Takeuchi S et al. manuscript in preparation). As known, the serum total IgE level was higher in patients with AD coincident with BA than in those without BA. Therefore, the high incidence of BA in male children may have affected the sex difference of total IgE at the age of 2–4 years. When children were divided simply by having or not having each allergic disease, mean total IgE levels in incidental AD and nonAD were 425.3 678.3 and 141.9 315.4 IU/mL, respectively; those in incidental AR and non-AR were 454.8 592.4 and 172.7 385.0 IU/mL, respectively; those in incidental BA and non-BA were 328.3 505.6 and 157.3 376.6 IU/mL, respectively; and those in incidental EA and non-EA were 496.7 784.6 and 164.1 358.0 IU/mL, respectively. These mean total IgE levels in incidental disease groups were statistically higher than those in non-incidental groups of each allergic disease (P < 0.01). In the incidental AD children, coincidence of BA, but neither AR nor EA, significantly increased serum total IgE levels, as compared to incidental AD children without BA (Takeuchi S et al. manuscript in preparation). This result also supports the hypothesis that previous sex difference of total IgE may come from the higher incidence of BA in male children.
SEVERITY OF AD AND EA FROM THE KIDS COHORT CCL17 or TARC was found by Kakinuma et al.23 to be a disease marker that reflects disease severity of AD and has been admitted for national insurance coverage since 2008 in Japan. It is known that the upper limits of the normal range are higher in younger children as announced by the manufacturer. In our KIDS cohort, the mean CCL17 level of non-allergic nursery school children was highest (nearly 800 pg/mL) at the age of 1 year and decreased gradually as the age of the children increased to approximately half those values at the age of 5–6 years (Takeuchi S et al. manuscript in preparation).
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However, mean CCL17 levels in children with AD did not show such a decrease with age. Children with AD were divided according to having or not having incidental AR, BA or EA. The mean CCL17 level in children with AD and incidental EA was significantly higher than in those without incidental EA (Takeuchi S et al. manuscript in preparation). Such differences were not observed when children with AD were divided by having or not having AR or BA (data not shown). It is of interest that the coincidence of EA increased TARC levels in children with AD, because the chemokine is a disease severity marker of AD. In addition to using questionnaire-based incidental EA analysis, children with prevalent AD were divided into groups of highly specific IgE to ovomucoid, a major egg whites antigen whites (as determined by the score of ≥2 by IMMULITE 3gAllergy [Siemens Healthcare Diagnostics, Tokyo, Japan]) and lower as having tentative EA (EA-IgE) and not, respectively. The TARC level in prevalent AD with EA-IgE was significantly higher than in those without EA-IgE (Esaki H et al. manuscript in preparation). For this association between AD and EA, there are two possible explanations: coexistence (or coincidence) of EA somehow increased disease severity, for example, through IgE-mediated (wheal or transient erythema) and/or nonIgE-mediated (papules and lichenification) mechanisms. Alternatively, children with higher disease severity tended to develop or have exacerbated EA. The latter interpretation may be more interesting from the standpoint of impaired skin barrier functions by filaggrin gene mutation, the major predisposing factor for AD,24 and the relation of food allergy with the gene mutation.25 These results, including ours, may suggest that more severe or inadequate control of AD may lead to food allergy presumably by repetitive percutaneous sensitization to allergenic foods through the impaired skin barrier. For further verification of this hypothesis, long-term interventional studies in the field of pediatric AD are of interest. We have summarized the epidemiology of AD in Japan in terms of prevalence/incidence and spontaneous remission from previous reports. We also referred to our recent findings from our KIDS cohort. More findings from any case–control or cohort studies or even from basic studies are awaited to understand the complex but interesting disease, AD.
ACKNOWLEDGMENT:
This work was partially supported by
a research grant from the Ministry of Health, Labor and Welfare, Japan. We thank Mr Masaki Takemura for his wonderful technical assistance.
CONFLICT OF INTEREST:
None.
REFERENCES 1 Williams HC. Is the prevalence of atopic dermatitis increasing? Clin Exp Dermatol 1992; 17: 385–391. 2 Williams H, Robertson C, Stewart A et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999; 103: 125–138.
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3 Takeuchi M, Ueda H. Increase of atopic dermatitis (AD) in recent Japan. Environ Dermatol 2000; 7: 133–136. 4 Sugiura H, Umemoto N, Deguchi H et al. Prevalence of childhood and adolescent atopic dermatitis in a Japanese population: comparison with the disease frequency examined 20 years ago. Acta Derm Venereol 1998; 78: 293–294. 5 Schultz Larsen F. Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J Am Acad Dermatol 1993; 28: 719–723. 6 Edfors-Lubs ML. Allergy in 7000 twin pairs. Acta Allergol 1971; 26: 249–285. 7 Furue M. History of atopic dermatitis. In: Kunihiko Tamaki, Masutaka Furue, Hidemi Nakagawa, eds. Atopic Dermatitis and Topical Steroid Therapy. Tokyo, Japan: Chugai-igakusha, 19981–19. Chugai-igakusha (in Japanese). 8 Furue M, Yamazaki S, Jimbow K et al. Prevalence of dermatological disorders in Japan: a nationwide, cross-sectional, seasonal, multicenter, hospital-based study. J Dermatol 2011; 38: 310–320. 9 Yura A, Shimizu T. Trends in the prevalence of atopic dermatitis in school children: longitudinal study in Osaka Prefecture, Japan, from 1985 to 1997. Br J Dermatol 2001; 145: 966–973. 10 Yura A, Kouda K, Iki M, Shimizu T. Trends of allergic symptoms in school children: large-scale long-term consecutive cross-sectional studies in Osaka Prefecture Japan. Pediatr Allergy Immunol 2011; 22: 631–637. 11 Yamamoto S. Prevalence and exacerbation factors of atopic dermatitis. Skin Allergy Frontier 2003; 1: 85–90. (in Japanese) 12 Hamada M, Furusyo N, Urabe K et al. Prevalence of atopic dermatitis and serum IgE values in nursery school children in Ishigaki Island, Okinawa, Japan. J Dermatol 2005; 32: 248–255. 13 Kawaguchi H, Takeuchi M, Tanaka Y, Ishii N, Ikezawa Z. Atopic dermatitis at 18-months physical examination. Arerugi 2000; 49: 653–657. €ber C, Niggemann B, Wahn 14 Illi S, von Mutius E, Lau S, Nickel R, Gru U, Multicenter Allergy Study Group. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol 2004; 113: 925–931. 15 Fukiwake N, Furusyo N, Kubo N et al. Incidence of atopic dermatitis in nursery school children - a follow-up study from 2001 to 2004, Kyushu University Ishigaki Atopic Dermatitis Study (KIDS). Eur J Dermatol 2006; 16: 416–419. 16 Anan S, Yamamoto N. Spontaneous regression of atopic dermatitis. Hifu 1996; 38(Suppl 18): 13–15. (in Japanese) 17 Okano S, Takahashi H, Yano T et al. Prevalence of childhood atopic dermatitis in first-year pupils of elementary school and its follow-up: Asa district in Hiroshima. Nihon Ishikai Zasshi 2006; 135: 97–103. (in Japanese) 18 Williams HC, Strachan DP. The natural history of childhood eczema: observations from the British 1958 birth cohort study. Br J Dermatol 1998; 139: 834–839. 19 Uehara M, Otaka T, Ogawa Y, Ofuji K. Clinical course of atopic dermatitis. Hifuka-Kiyo 1970; 65: 1–6. (in Japanese) 20 Furue M, Kawashima M, Furukawa F et al. Questionnaire study for chronological change in atopic dermatitis. Rinshohifuka 2007; 61: 286–295. (in Japanese) 21 Furue M, Kawashima M, Furukawa F et al. A prospective questionnaire study for atopic dermatitis. Rinshohifuka 2011; 65: 83–92. (in Japanese) 22 Furue M, Hayashida S, Uchi H. Natural history of atopic dermatitis. Rinshomeneki-Arerugika 2009; 52: 320–325. 23 Kakinuma T, Nakamura K, Wakugawa M et al. Serum macrophagederived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clin Exp Immunol 2002; 127: 270–273. 24 Palmer CN, Irvine AD, Terron-Kwiatkowski A et al. Common loss-offunction variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006; 38: 441–446. 25 Brown SJ, Asai Y, Cordell HJ et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 2011; 127: 661–667.
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