Association of atopic dermatitis with being overweight and obese: A systematic review and metaanalysis April Zhang, MD,a and Jonathan I. Silverberg, MD, PhD, MPHa,b,c Chicago, Illinois Background: Previous studies found conflicting results about whether atopic dermatitis (AD) is associated with overweight/obesity. Objective: We sought to examine the relationship between AD and overweight/obesity by performing a systematic review and metaanalysis. Methods: Observational studies of the relationship between AD and overweight/obesity were selected from PubMed, Embase, and the Cochrane Library. The quality of evidence was assessed using the NewcastleeOttawa Scale. Fixed and random effects metaanalyses were performed to estimate pooled odds ratios (ORs). Sensitivity analyses were performed that compared results by location of study, study quality, and between studies in children and adults. Results: In total, 30 studies were included for review. Patients who were overweight (Cochrane-MantelHaenszel [CMH] OR, 1.27 [95% confidence interval {CI}: 1.19-1.36]; random effects OR, 1.23 [95% CI: 1.11-1.41]), obese (CMH OR, 1.68 [95% CI: 1.54-1.84]; random effects OR, 1.47 [95% CI: 1.21-1.79]), or overweight/obese (CMH OR, 1.42 [95% CI: 1.34-1.50]; random effects OR, 1.31 [95% CI: 1.16-1.48]) had higher odds of AD than normal weight patients. In sensitivity analyses, children who were overweight (random effects OR, 1.24 [95% CI: 1.08-1.43]), obese (random effects OR, 1.44 [95% CI: 1.12-1.86]), or overweight/obese (random effects OR, 1.32 [95% CI: 1.15-1.51]) and adults who were obese (random effects OR, 1.56 [95% CI: 1.24-1.95]) or overweight/obese (random effects OR, 1.29 [95% CI: 1.05-1.59]) had higher odds of AD. The association remained significant in North America and Asia but not Europe. Limitations: Most studies were cross-sectional. Conclusions: Overweight/obesity in North America and Asia is associated with an increased prevalence of AD. ( J Am Acad Dermatol 2015;72:606-16.) Key words: adiposity; atopic dermatitis; body mass index; eczema; metaanalysis; prevalence; obesity; overweight.

A

topic dermatitis (AD)/eczema is a chronic, recurrent inflammatory skin disease. Its etiology is multifactorial and includes genetic predisposition, immune dysfunction, and external environmental factors.1 The prevalence of AD has increased rapidly in the past 4 decades to as high as 20% in children and adolescents and 10% of adults in some countries.2-5 At the same time, there has been a

From the Departments of Dermatology,a Preventive Medicine,b and Medical Social Sciences,c Northwestern University Feinberg School of Medicine, Chicago. Funding sources: None. Conflicts of interest: None declared. Accepted for publication December 6, 2014. Correspondence to: Jonathan I. Silverberg, MD, PhD, MPH, Northwestern University, Department of Dermatology,

606

Abbreviations used: AD: BMI: CI: OR:

atopic dermatitis body mass index confidence interval odds ratio

significant increase in the prevalence of obesity worldwide,6-8 suggesting that the 2 conditions may be associated. 676 N St. Clair St Ste 1600, Chicago, IL 60611. E-mail: [email protected]. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.12.013

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Patients with AD have a defective skin barrier that was in press at the time of the literature search was also leads to dysregulated T-cell responses, manifesting included in the analysis.26 9-14 as TH2 inflammation. Previous studies found that All studies with primary epidemiologic data obesity is associated with impaired skin barrier reporting the relationship between AD and overfunction.15,16 In addition, obesity results in a chronic weight/obesity were included in the review (Table I). However, only studies that presented either low-grade inflammatory state that may directly affect the numbers or odds ratios (ORs) for AD cases inflammatory pathways in AD.17-20 Taken together, it among overweight/obesity may be that obesity triggers were included in the and/or worsens AD. metaanalysis. If data were Numerous studies have CAPSULE SUMMARY duplicated in [1 study, the examined the relationship most recent and complete between obesity and Previous studies found conflicting results study was included in the various atopic diseases, about whether atopic dermatitis is metaanalysis. including asthma, allergic associated with being overweight or rhinitis, allergic conobese. junctivitis, and AD.21 Data extraction This metaanalysis provides evidence that Epidemiologic studies Both reviewers (A.Z. patients with eczema have a higher have consistently found and J.S.) independently prevalence of overweight and obesity a strong link between performed data extraction than the general population. asthma and obesity.21-24 from 30 studies; any differPatients with eczema and overweight/ However, previous studies ences were resolved by obesity may benefit from weight loss found conflicting results discussion. Data items interventions. about whether AD is assocollected were as follows: ciated with overweight or study design; how AD/ obesity. This has imporeczema was diagnosed or tant clinical ramifications, because obesity may be accounted for; country of study; total number of a modifiable risk factor for and/or comorbidity of patients in study; number of AD/eczema, normal AD. Several narrative reviews of the association of weight, overweight, and/or obese patients; severity obesity and AD have been performed.21,25 To the of AD/eczema divided into mild, moderate, or best of our knowledge, no metaanalyses of the severe; mean age of patients; and percent of males association between AD and obesity have been in the study. Seven studies presented total group performed. We conducted a systematic review and sizes for BMI classifications and the ORs of AD/ metaanalysis to explore the relationship between eczema for each BMI classification. The frequencies AD and overweight/obesity. of AD/eczema within each BMI classification were reconstructed as previously described.27 METHODS The exposures were defined as overweight or obesity, and the dependent variable was AD/ Literature search eczema. The definitions for overweight and obesity We searched the following databases through July varied by region. For example, in the United States, 1, 2014: PubMed (1946-present), Embase (1947BMI $30 kg/m2 is considered obese, whereas a BMI present), and the Cochrane Library (1992-present). To search for the conditions of interest, we used the $28 kg/m2 was considered obese in a Chinese study. terms ‘‘atopic dermatitis’’ AND ‘‘obesity,’’ ‘‘eczema’’ AD/eczema was also defined differently; some used AND ‘‘obesity,’’ ‘‘atopic dermatitis’’ AND ‘‘overthe Hanifin and Rajka criteria,28 combinations of weight,’’ ‘‘eczema’’ AND ‘‘overweight,’’ ‘‘atopic dermavarious questions from the International Study of titis’’ AND ‘‘adiposity,’’ ‘‘eczema’’ AND ‘‘adiposity,’’ Allergy and Asthma in Children (ISAAC),29 or other ‘‘atopic dermatitis’’ AND ‘‘body mass index (BMI),’’ definitions. When data related to multiple apand ‘‘eczema’’ AND ‘‘BMI.’’ Studies published online proaches for the assessment of AD were presented, and in print and in press studies from all years were we selected the preferred definition of AD/eczema in considered. All search results with titles and abstracts the following order: diagnosis by Hanifin and Rajka written in any language were eligible for inclusion. criteria,28 other health care diagnosis of AD/eczema, Studies were then excluded based on the title and/or self-report of ever being diagnosed by a physician abstract if there was no clear indication that they were with eczema, presence of an itchy rash in the typical investigating characteristics of overweight/obesity or (flexural) distribution, history of eczema, and other AD patients. There were no relevant studies that had definitions. To address the varied definitions of the been published in foreign languages. One study that exposure and outcomes, we performed sensitivity d

d

d

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Table I. Study characteristics

No.

First author, year published

Normal weight (BMI \25 kg/m2 or \85th percentile unless otherwise specified) Location

Total

No. (%) with AD

1

Silverberg, 201466

United States

31,774

2954 (9.3)

2 3 4 5

Silverberg, 201426 Silverberg, 201469 Silverberg, 201469

United States United States United States

6

Sybilski, 201468

Poland

206 8689 12,143 8789 8789 8789 2555

96 773 864 123 211 1028 132

(46.6) (9.5) (7.1) (1.4) (2.4) (11.7) (5.2)

2555 4099 4099 5546 5546 149 181 (BMI \24)

219 177 381 175 205 33 59

(8.6) (4.3) (9.3) (3.2) (3.7) (22.6) (32.6)

7 8

Gibeon, 201362 Luo, 201364

Great Britain Harbin, China

9

Sidoroff, 201259

Finland

10 11 12 13

Silverberg, 201260 Vicedo-Cabrera, 201261 Kajbaf, 201154 Silverberg, 201155

63

Overweight (BMI 25-30 kg/m2 or 85th-95th percentile unless otherwise specified) Total

No. (%) with AD

Total

No. (%) with AD

7212

852 (12.9)

5940

754 (10.9)

29 8283 11491 1041 1041 1041 395

12 765 745 23 36 143 27

(41.4) (9.7) (6.6) (2.2) (3.5) (13.7) (6.8)

39 6878 9596 508 508 508 312

23 797 783 6 12 52 14

(59.0) (11.8) (8.2) (1.2) (2.4) (10.2) (4.5)

395 226 226 2455 2455 195 63 (BMI 24-27.9)

40 12 4 62 80 45 17

(10.1) (4.5) (3.5) (2.5) (3.3) (23.1) (37.0)

312 113 113 782 782 322 26 (BMI $28)

16 11 14 24 18 100 14

(5.0) (4.1) (12.4) (3.1) (2.3) (31.1) (53.8)

33 (52.4)

12

54 1258 10,591 755 1001

Naha City, Japan Seoul, South Korea Canada

15903 (BMI \65%) 478 5862

1064 (6.7) 49 (10.5) 563 (9.6)

Hong Kong Kyoto, Japan

388 38,868

59 (15.2) 2343 (6.0)

98 (BMI [25) 6869

17 (17.3) 439 (6.4)

19 Mai, 200749

Stockholm, Sweden

2596 (BMI \90%)

563 (21.7)

273 (BMI [90%)

61 (22.3)

20 Eneli, 200646

Germany

521

134 (25.7)

130 (BMI [85%)

20 (15.4)

445

48 (10.8)

111 (BMI [85%)

12 (10.8)

51

17 Leung, 2009 18 Kusunoki, 200850

(33.3) (30.2) (5.6) (2.6) (33.0)

11 278 4172 86 165

6 (50.0)

New York Spain Ahvaz, Iran Brooklyn, New York

14 Tanaka, 201156 15 Yoo, 201158 16 Wang, 201053

18 380 595 20 330

Obese (BMI [30 kg/m2 or [95th percentile unless otherwise specified)

7 130 242 2 46

7

3 (42.9)

(63.6) (46.7) (5.8) (2.3) (27.9)

16 277 2974 62 50

7286 (BMI 65-95%) 517 (7.1) 239 (BMI [25) 31 (13.2) 1161 96 (8.3)

1210

93 (7.7)

330

34 (10.3)

2286

1 94 226 1 38

(6.3) (33.9) (7.6) (1.5) (76.0)

149 (6.5)

21 Kilpelainen, 200647 22 Mai, 200344

Finland Sweden

9496 272 (BMI \75%)

1782 (18.8) 103 (37.9)

680 (BMI 25-27.4) 136 (20.0) 185 (BMI [75%) 96 (51.9)

296 (BMI [27.5)

59 (19.9)

23 Von Kries, 200143

Germany

8318 (BMI \90%)

1274 (15.3)

668 (BMI 90-97%)

327 (BMI [97%)

49 (15.0)

24 James, 201363

Australia

25 Mitchell, 201365

26 Yao, 201157

27 Suarez-Varela, 201052 28 Vlaski, 200648

29 Irei, 200533 30 Violante, 200545

Worldwide (Europe, India, Latin America, Africa, Asia, Eastern Mediterranean)

8318 (BMI \90%) 14,274 53,676

173,428 3746 3746 3746 Spain 11,913 (BMI \95%) Republic of Macedonia 2484 2484 2484 2484 Vietnam 1114 (BMI \95%) Mexico City 1393 (BMI \95%) 2429 (BMI \95%) Taiwan

575 (6.9) 1.00

99 (14.8)

668 (BMI 90-97%) 64 (9.6) 327 (BMI [97%) 21 (6.4) 1987 1.03 (0.93-1.14) 747 0.95 (0.81-1.12)

1.00

10046

1.08 (0.98-1.19)

4438

1.20 (1.05-1.37)

1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00

26317 1094 1094 1094

1.16 1.24 1.26 1.34

(1.07-1.24) (1.01-1.54) (1.01-1.59) (1.14-1.58)

5442 435 435 435 1240

1.42 1.45 1.39 1.45 1.38

(BMI [25) (BMI [25) (BMI [25) (BMI [25)

0.97 1.21 0.99 0.65

(0.64-1.48) (0.74-1.98) (0.47-2.69) (0.35-1.24)

442 442 442 442

71 215 158

(1.23-1.64) (1.08-1.94) (1.01-1.92) (1.15-1.83) (1.10-1.74)

1.02 (0.70-1.04) 0.44 (0.23-0.91) 0.29 (0.12-0.71)

BMI, Body mass index; ISAAC, International Study of Asthma and Allergies in Childhood; NR, not reported; SD, standard deviation.

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Table I. Cont’d

Age (y)

Sex (%)

Study design

Assessment of AD

10-17

M (52)

Cross-sectional

4-17 18-85 18-85 6-18

M M M M

(47) (48) (48) (49)

Cross-sectional Cross-sectional Cross-sectional Cross-sectional

6-7

M (51)

Cross-sectional

13-14

M (52)

20-44

M (41)

Adults (mean, 45; SD, 8.5): $18 (mean, 38.5; SD, 12.1)

M (35) M (30)

7.2

NR

12.3 181 6-7 7-11 1-21

M (31) NR M (34) M (52)

6-15 15-17 13-14

M (49) M (77) M (47)

Retrospective case control Cross-sectional Cross-sectional Retrospective case control (case:control 1:2; cases were patients with AD) Cross-sectional Cross-sectional Cross-sectional

Adolescents (median, 15) 7-15

M (50) M (50)

Cross-sectional Cross-sectional

4

NR

Prospective cohort

7-10 (median, 8.2)

M (55)

Cross-sectional (first study, 1994-5; follow-up study, 1997)

18-25 12

M (39) M (52)

5-6

M (52)

Cross-sectional Case control (case:control 161:296; cases were patients with current wheeze) Cross-sectional

4-6 6-7

M (51) NR

Cross-sectional Cross-sectional

13-14

NR

4-18

M (49)

Cross-sectional

6-7 13-14

M (50) M (52)

Cross-sectional Cross-sectional

ISAAC ISAAC ISAAC ISAAC ISAAC ISAAC ISAAC ISAAC

12-17 6-7 13-14

M (49) F M

Cross-sectional Cross-sectional

ISAAC (physician diagnosis) ISAAC (ever eczema)

Cross-sectional (of patients with severe asthma) Case control (case:control 1:2; cases were patients with any atopic disease) Prospective follow-up of children hospitalized for wheezing at \24 mos

National Survey of Children’s Health (eczema in past 12 mos) Hanifin and Rajka guidelines National Health Interview Survey 2010 National Health Interview Survey 2012 ISAAC (chronic rash in past 12 mos) ISAAC (chronic rash ever) ISAAC (ever eczema) ISAAC (recurrent itchy rash for $6 mos, present in past 12 mos, usual areas) Clinically diagnosed AD (Hanifin and Rajka criteria) ISAAC Clinically diagnosed AD ISAAC Clinically diagnosed AD Self-report of history Previously diagnosed, $1 allergen-specific immunoglobulin E Physician diagnosis in preceding 12 mos

Self-reported personal history ISAAC (itchy rash in past 12 mos, specific body parts) ISAAC (recurrent itchy rash for $6 mos, ever diagnosis) Hanifin and Rajka guidelines ISAAC (eczema in past 12 mos) ISAAC (AD in past 12 mos) ISAAC (recurrent itchy rash for $6 mos, present in past 12 mos, usual areas) ISAAC (recurrent itchy rash for $6 mos) ISAAC (ever itchy rash that comes/goes repeatedly, [3 typical symptoms or locations) Questionnaire (itchy rash for $2 wks with typical distribution 1 dry skin, or physician diagnosis between 2-4 yrs) ISAAC (physician diagnosis)

Follow-up in 3 y (median, 10.3) Self-reported (lifetime physician diagnosis) ISAAC (ever eczema) ISAAC (lifetime physician diagnosis) ISAAC (itchy rash in past 12 mos) ISAAC (ever eczema) ISAAC (current eczema: recurrent itchy rash for $6 mos, present in past 12 mos, usual areas)

(ever eczema) (eczema in past 12 mos) (physician diagnosis) (itchy rash in past 12 mos, usual locations) (itchy rash ever) (current itchy rash) (current sleep disturbing itchy rash) (ever eczema)

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considered statistically significant. Significant heterogeneity of results was detected across studies as judged by a Cochrane Q statistic P \ .05 and/or I2 statistic [50%. Therefore, random effects models were also performed that account for the variability between studies. Funnel plot visualization, Egger regression, Begg rank correlation, and funnel plot regression were used to assess for potential publication bias.

RESULTS

Fig 1. Preferred reporting items for systematic reviews and metaanalyses (PRISMA) flow diagram of literature search and study selection for metaanalysis of atopic dermatitis/eczema and overweight/obesity. AD, Atopic dermatitis.

analyses by location of study and by children compared to adults. Study quality assessment The NewcastleeOttawa Scale (NOS) for Assessing the Quality of Nonrandomized Studies in Metaanalysis was used to assess study quality.30 The scoring system summarized 9 aspects of each study: is the case definition adequate, representativeness of the cases, selection of controls, definition of controls, comparability of cases and controls on the basis of the design or analysis, ascertainment of exposure, same method of ascertainment for cases and controls, and comparison of nonresponse rate between cases and controls. The full score was 9 stars, and high-quality studies were those with $6 stars. Sensitivity analyses were performed that compared studies with NOS scores of \6 stars compared to those with $6 stars. Statistical analysis Given the relative dearth of well-constructed studies regarding this topic, we decided a priori to include all studies in the metaanalysis regardless of study quality. Our statistical analyses were performed using SAS software (v 9.4; SAS Institute Inc, Cary, NC). Comparable outcomes of all studies of AD and overweight/obesity were combined, and measures of consistency were obtained. Pooled ORs of AD in overweight and/or obesity with 95% confidence intervals (CIs) were estimated using the Cochrane-Mantel-Haenszel method. Forest plots were constructed for all studies included in the metaanalysis. Two-sided P values of .05 were

Literature search The literature search yielded 585 articles. After review of the titles and abstracts, 536 articles did not meet our inclusion criteria, and 12 were excluded31-42 for a lack of data for the frequency of AD/eczema or BMI classification. In total, 30 studies26,33,43-69 were included in the review, of which 20 had valid data that could be pooled to assess for the effects of overweight,26,43,47,50,53-57,59-69 23 for obesity,26,33,43,45,47,50,52-57,59-69 and 26 for overweight/obesity.26,43,44,46-51,53-69 The preferred reporting items for systematic reviews and metaanalyses (PRISMA) flow diagram is shown in Fig 1. Study characteristics The studies were cross-sectional with respect to prevalence of AD, either retrospective or prospective data collection, included both men and women, and encompassed subjects of all ages. Published years of studies ranged from 2001 to 2014. The 30 studies included 900,358 patients from 13 countries, including 878,354 children and 22,004 adults, of which 46,168 had AD. Study locations are mapped in Supplemental Fig 1 (available online at www.jaad. org). Quality assessment using the NOS scale revealed that 25 of 30 studies of overweight/obesity had scores $6 (Supplemental Table I, available at http://www.jaad.org). Only 4 studies addressed race/ethnicity,60,62,66,69 and no studies addressed vitamin D status. AD in overweight and obesity Overall, 28,498 (6.8% [range, 2.7-52.0%]) of normal weight patients, 6,648 (7.2% [range, 1.863.6]) of overweight patients, and 5,173 (8.8% [range, 1.6-76.0%]) of obese patients had a previous and/or current history of AD/eczema. AD/eczema prevalence was higher in studies with health care diagnosis compared to self-reported AD (11.2% vs. 7.2%, respectively). In the fixed effects pooled analysis, patients who were overweight (Cochrane-Mantel-Haenszel [CMH] OR, 1.27 [95% CI: 1.19-1.36]; P \.0001), obese

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Fig 2. Association between atopic dermatitis/eczema and overweight/obesity. Forest plot is presented for the log/odds ratios and 95% confidence interval of atopic dermatitis in overweight, obesity, and overweight/obesity compared with patients of normal weight. Cochrane-Mantel-Haenszel pooled odds ratios and 95% confidence intervals are presented at the bottom of each panel.

Table II. Random effect models and sensitivity analyses for the association between obesity and atopic dermatitis Odds ratio (95% confidence interval) Study subsets

Overall Age (y) Children (\18) Adults ($18) Region North America Asia Europe NOS score \6 $6

Overweight (n = 18)

Obesity (n = 23)

Overweight/obesity (n = 22)

1.25 (1.11-1.41)

1.47 (1.21-1.79)

1.31 (1.16-1.48)

1.24 (1.08-1.43) 1.15 (0.85-1.54)

1.44 (1.12-1.86) 1.56 (1.24-1.95)

1.32 (1.15-1.51) 1.29 (1.05-1.59)

1.21 (0.88-1.67) 1.28 (1.13-1.46) 0.98 (0.84-1.14)

1.74 (1.27-2.38) 1.36 (1.03-1.79) 1.21 (0.83-1.79)

1.53 (1.24-1.89) 1.30 (1.14-1.48) 1.01 (0.80-1.28)

1.23 (1.05-1.45) 1.17 (1.01-1.36)

1.51 (1.18-1.93) 1.55 (1.26-1.89)

1.31 (1.13-1.51) 1.30 (1.14-1.48)

Random effect models were performed with history of atopic dermatitis as the dependent variable and either overweight, obesity, or overweight/obesity as the independent variables. Pooled odds ratios and 95% confidence intervals were calculated. Sensitivity analyses were performed for children compared to adults, North America versus Asia versus Europe, and a NOS score of \6 or $6. NOS, NewcastleeOttawa Scale.

(CMH OR, 1.68 [95% CI: 1.54-1.84]; P \ .0001), or overweight/obese (CMH OR, 1.42 [95% CI: 1.341.50]; P \.0001) had significantly higher odds of AD than normal weight patients (Fig 2). However, significant heterogeneity was identified between those studies (Cochrane Q: P \ .0001 and I2 $75.8% for all 3 outcomes). In random effects models, overweight (CMH OR, 1.25 [95% CI: 1.111.41]), obesity (CMH OR, 1.47 [95% CI: 1.21-1.79]), and overweight/obesity (CMH OR, 1.31 [95% CI: 1.16-1.48]) status all had highly significant associations with increased odds of AD/eczema (Table II).

Only a single study examined measures of central adiposity and found that AD was associated with increased waist circumference and waist:height ratio.26 We also performed sensitivity analyses that compared results between children and adults, different regions, and higher- versus lower-quality studies. Children who were overweight (OR, 1.24 [95% CI: 1.08-1.43]), obese (OR, 1.44 [95% CI: 1.12-1.86]), or overweight/obese (OR, 1.32 [95% CI: 1.15-1.51]) had higher odds of AD. Adults who were obese (OR, 1.56 [95% CI: 1.24-1.95]) and

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In contrast, a recent case control study of 275 children 4 to 17 years of age found an association between obesity and AD prevalence but not AD severity.26 Publication bias Publication bias was not detected as judged by symmetric funnel plots (Fig 3) and nonsignificant Egger regression, Begg rank correlation, or funnel plot regression for any of the aforementioned outcomes (P $ .11). There were 12 additional related studies that did not provide sufficient data for inclusion in the metaanalysis (Supplemental Table III; available at http://www.jaad.org). Repeated attempts to obtain the data for all 12 studies were unsuccessful.

DISCUSSION

Fig 3. Funnel plot of published studies about an association between atopic dermatitis/eczema and overweight/ obesity.

overweight/obese (OR, 1.29 [95% CI: 1.05-1.59]) also had higher odds of AD. The association between AD/eczema and overweight/obesity remained significant in North America and Asia but not Europe (Table II). The associations between overweight and overweight/obesity remained significant with similar effect sizes in studies with NOS scores \6 and $6. Obesity was associated with AD only in studies with NOS scores \6, although there were only 4 studies of obesity with NOS scores $6.

AD severity in overweight/obesity There were 4 studies of the association between overweight/obesity and AD/eczema severity26,55,65,66; however, these were not amenable to metaanalysis because of heterogeneous methods and outcomes (Supplemental Table II, available at http://www.jaad.org). A US population study found an association between overweight/obesity with moderate to severe eczema.66 Another study found an association between obesity and severe eczema in children 13 to 14 years of age but not 6 to 7 years of age.65 In addition, a retrospective case control study of 1242 children and adolescents between 0 and 21 years of age found that obesity was associated with overall greater eczema severity.55

The results of this metaanalysis of observational studies suggest that overweight/obesity is associated with increased prevalence and severity of AD. The cross-sectional nature of most of the available studies precludes a determination of whether obesity causes AD or vice versa. The overall effect sizes were modest, suggesting that obesity is clinically relevant in AD but perhaps not as much of a problem as in other disorders, such as psoriasis. Sensitivity analyses also revealed association between overweight/obesity and AD in North America and Asia but not in Europe. This is likely because of the varied definitions of overweight, obesity, and AD used in European studies. However, there is significant worldwide variation of AD prevalence70 that is multifactorial, including industrialization, urban living, black race, higher education levels, higher household incomes, and smaller family sizes.71-74 These factors may confound the association of overweight/obesity and AD, and regional variation thereof may explain why the association is significant in some regions but not others. The mechanism behind the association of obesity and AD remains unknown. Obesity has been shown to alter the skin’s epidermal barrier, leading to increased transepidermal water loss and dry skin,15,16 which may aggravate underlying barrier defects in AD patients. In addition, obesity modifies cutaneous and systemic inflammation, with [50 bioactive molecules being secreted in adipose tissue, including cytokines such as tumor necrosis factorealpha and interleukin 6.75 The increased secretion of these proinflammatory molecules leads to a chronic low-grade inflammatory state and may predispose patients to hypersensitivity reactions.21,75-78 Adipokines, such as leptin and adiponectin, are also produced and released by

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adipocytes. Leptin has been found to enhance T cell survival and stimulate the production of proinflammatory cytokines, including tumor necrosis factorealpha, interferon-gamma, and interleukins 6, 12, and 2, thereby playing an important role in the modulation of the immune system.79,80 Adiponectin has antiinflammatory properties,75 and its secretion is decreased with obesity20,81,82 and also notably with AD.83 In addition, AD predisposes to a more sedentary lifestyle, which may increase risk for obesity and cardiovascular disease.69 Together, these studies suggest that the mechanism of association between obesity and AD is multifactorial. There are multiple strengths to this metaanalysis, including the use of random effects models and multiple sensitivity analyses. The majority of the included studies (25 of 30) was of high quality and adjusted for confounding factors, such as age and sex, with no publication bias detected. However, this study has limitations that should be considered. There were no randomized, controlled trials that investigated the effect of weight loss on obese persons with AD. The included studies were predominantly cross-sectional, which limits the ability to determine a temporal relationship between overweight/obesity and AD. Despite most studies adjusting for various confounders, such as age, sex, physical activity, diet, parents’ education level, and siblings, etc, residual confounding is still possible. The countries represented in this study were largely confined to North America, Asia, and Europe. The results may therefore not be generalizable to countries in South America, Africa, or the Middle East. The included studies used varying definitions of overweight and obesity, although the majority of studies defined overweight as BMI $25 kg/m2 or 85th percentile and obesity as BMI $30 kg/m2 or 95th percentile. While most studies divided BMI classifications into normal weight, overweight, and obese, other studies divided participants into normal weight versus overweight/obesity or normal weight/overweight versus obese. To address this, we evaluated overweight, obesity, and overweight/ obesity as 3 distinct outcomes. Most studies used BMI to determine obesity, whereas only 1 study also found higher odds of AD with increased waist circumference,26 which has been shown to better classify weight-related health risk.84,85 Few studies addressed the role of race/ethnicity, and no studies addressed vitamin D status in the link between obesity and AD—both of which may be important mediators.86 Future studies are needed to better elucidate the role of these factors in the association between obesity and AD. Finally, only 4 of 28 studies analyzed did not rely on self- or parent-reported AD/

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eczema; 3 used the Hanifin and Rajka criteria and 1 required at least 1 positive allergen-specific immunoglobulin E.26,55,64,68 The use of questionnaires introduces potential recall and misclassification bias, because AD may clinically mimic other eczematous processes, such as contact and nummular dermatitis. Nevertheless, the ISAAC questionnaire used in most of the self-reported studies has been validated and used widely in epidemiologic studies regarding allergy in children.87-89 In conclusion, overweight/obesity is associated with an increased prevalence of AD, particularly in children and adults in North America and Asia. Future studies are needed to address the knowledge gaps about the association of overweight/obesity and AD, including studies using more rigorous clinical criteria for AD, such as the Hanifin and Rajka criteria,28 longitudinal studies to determine the temporal relationship, and translational studies to explore the mechanisms of association. REFERENCES 1. Thomsen SF. Atopic dermatitis: natural history, diagnosis, and treatment. ISRN Allergy. 2014;2014:354250. 2. Asher MI, Montefort S, Bjorksten B, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006;368:733-743. 3. Wuthrich B. Clinical aspects, epidemiology, and prognosis of atopic dermatitis. Ann Allergy Asthma Immunol. 1999;83: 464-470. 4. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol. 2013;132:1132-1138. 5. Silverberg JI, Hanifin J, Simpson EL. Climatic factors are associated with childhood eczema prevalence in the United States. J Invest Dermatol. 2013;133:1752-1759. 6. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010. JAMA. 2012;307:483-490. 7. de Onis M, Blossner M, Borghi E. Global prevalence and trends of overweight and obesity among preschool children. Am J Clin Nutr. 2010;92:1257-1264. 8. Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766-781. 9. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Curr Allergy Asthma Rep. 2009;9: 265-272. 10. Oyoshi MK, He R, Kumar L, Yoon J, Geha RS. Cellular and molecular mechanisms in atopic dermatitis. Adv Immunol. 2009;102:135-226. 11. Terui T. Analysis of the mechanism for the development of allergic skin inflammation and the application for its treatment: overview of the pathophysiology of atopic dermatitis. J Pharmacol Sci. 2009;110:232-236. 12. Agrawal R, Wisniewski JA, Woodfolk JA. The role of regulatory T cells in atopic dermatitis. Curr Probl Dermatol. 2011;41: 112-124.

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53. Wang HY, Pizzichini MM, Becker AB, et al. Disparate geographic prevalences of asthma, allergic rhinoconjunctivitis and atopic eczema among adolescents in five Canadian cities. Pediatr Allergy Immunol. 2010;21:867-877. 54. Kajbaf TZ, Asar S, Alipoor MR. Relationship between obesity and asthma symptoms among children in Ahvaz, Iran: a cross sectional study. Ital J Pediatr. 2011;37:1. 55. Silverberg JI, Kleiman E, Lev-Tov H, et al. Association between obesity and atopic dermatitis in childhood: a case-control study. J Allergy Clin Immunol. 2011;127:1180-1186.e1. 56. Tanaka K, Miyake Y, Arakawa M, Sasaki S, Ohya Y. U-shaped association between body mass index and the prevalence of wheeze and asthma, but not eczema or rhinoconjunctivitis: the ryukyus child health study. J Asthma. 2011;48:804-810. 57. Yao TC, Ou LS, Yeh KW, et al. Associations of age, gender, and BMI with prevalence of allergic diseases in children: PATCH study. J Asthma. 2011;48:503-510. 58. Yoo S, Kim HB, Lee SY, et al. Association between obesity and the prevalence of allergic diseases, atopy, and bronchial hyperresponsiveness in Korean adolescents. Int Arch Allergy Immunol. 2011;154:42-48. 59. Sidoroff V, Hyvarinen MK, Piippo-Savolainen E, Korppi M. Overweight does not increase asthma risk but may decrease allergy risk at school age after infantile bronchiolitis. Acta Paediatr. 2012;101:43-47. 60. Silverberg JI, Silverberg NB, Lee-Wong M. Association between atopic dermatitis and obesity in adulthood. Br J Dermatol. 2012;166:498-504. 61. Vicedo-Cabrera AM, Garcia-Marcos L, Llopis-Gonzalez A, et al. Atopic dermatitis and indoor use of energy sources in cooking and heating appliances. BMC Public Health. 2012;12:890. 62. Gibeon D, Batuwita K, Osmond M, et al. Obesity-associated severe asthma represents a distinct clinical phenotype: analysis of the British Thoracic Society Difficult Asthma Registry Patient cohort according to BMI. Chest. 2013;143: 406-414. 63. James S, Pezic A, Ponsonby AL, et al. Obesity and asthma at school entry: co-morbidities and temporal trends. J Paediatr Child Health. 2013;49:E273-E280. 64. Luo X, Xiang J, Dong X, et al. Association between obesity and atopic disorders in Chinese adults: an individually matched case-control study. BMC Public Health. 2013; 13:12. 65. Mitchell EA, Beasley R, Bjorksten B, et al. The association between BMI, vigorous physical activity and television viewing and the risk of symptoms of asthma, rhinoconjunctivitis and eczema in children and adolescents: ISAAC Phase Three. Clin Exp Allergy. 2013;43:73-84. 66. Silverberg JI, Simpson EL. Association between obesity and eczema prevalence, severity and poorer health in US adolescents. Dermatitis. 2014;25:172-181. 67. Song N, Shamssain M, Zhang J, et al. Prevalence, severity and risk factors of asthma, rhinitis and eczema in a large group of Chinese schoolchildren. J Asthma. 2014;51:232-242. 68. Sybilski AJ, Raciborski F, Lipiec A, et al. Obesity - a risk factor for asthma, but not for atopic dermatitis, allergic rhinitis and sensitization. Public Health Nutr. 2014:1-7 [Epub ahead of print]. 69. Silverberg JI, Greenland P. Eczema and cardiovascular risk factors in two US adult population studies. J Allergy Clin Immunol. http://dx.doi.org/10.1016/j.jaci.2014.11.023. Published online January 8, 2015. 70. 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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71. Wegienka G, Havstad S, Joseph CL, et al. Racial disparities in allergic outcomes in African Americans emerge as early as age 2 years. Clin Exp Allergy. 2012;42:909-917. 72. Shaw TE, Currie GP, Koudelka CW, Simpson EL. Eczema prevalence in the United States: data from the 2003 National Survey of Children’s Health. J Invest Dermatol. 2011;131:67-73. 73. Mercer MJ, Joubert G, Ehrlich RI, et al. Socioeconomic status and prevalence of allergic rhinitis and atopic eczema symptoms in young adolescents. Pediatr Allergy Immunol. 2004;15:234-241. 74. Yemaneberhan H, Bekele Z, Venn A, Lewis S, Parry E, Britton J. Prevalence of wheeze and asthma and relation to atopy in urban and rural Ethiopia. Lancet. 1997;350:85-90. 75. Gorgievska-Sukarovska B, Lipozencic J, Susac A. Obesity and allergic diseases. Acta Dermatovenerol Croat. 2008;16: 231-235. 76. Shipman AR, Millington GW. Obesity and the skin. Br J Dermatol. 2011;165:743-750. 77. Eliakim A, Schwindt C, Zaldivar F, Casali P, Cooper DM. Reduced tetanus antibody titers in overweight children. Autoimmunity. 2006;39:137-141. 78. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796-1808. 79. Loffreda S, Yang SQ, Lin HZ, et al. Leptin regulates proinflammatory immune responses. FASEB J. 1998;12:57-65. 80. Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol. 2007;4:1-13. 81. Manigrasso MR, Ferroni P, Santilli F, et al. Association between circulating adiponectin and interleukin-10 levels in android obesity: effects of weight loss. J Clin Endocrinol Metab. 2005;90:5876-5879. 82. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79-83. 83. Nagel G, Koenig W, Rapp K, Wabitsch M, Zoellner I, Weiland SK. Associations of adipokines with asthma, rhinoconjunctivitis, and eczema in German schoolchildren. Pediatr Allergy Immunol. 2009;20:81-88. 84. Ardern CI, Katzmarzyk PT, Janssen I, Ross R. Discrimination of health risk by combined body mass index and waist circumference. Obes Res. 2003;11:135-142. 85. Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Arch Intern Med. 2002;162:2074-2079. 86. Lagunova Z, Porojnicu AC, Lindberg F, Hexeberg S, Moan J. The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Res. 2009;29:3713-3720. 87. Yamada E, Vanna AT, Naspitz CK, Sole D. International Study of Asthma and Allergies in Childhood (ISAAC): validation of the written questionnaire (eczema component) and prevalence of atopic eczema among Brazilian children. J Investig Allergol Clin Immunol. 2002;12:34-41. 88. Flohr C, Weinmayr G, Weiland SK, et al. How well do questionnaires perform compared with physical examination in detecting flexural eczema? Findings from the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Two. Br J Dermatol. 2009;161:846-853. 89. Chan HH, Pei A, Van Krevel C, Wong GW, Lai CK. Validation of the Chinese translated version of ISAAC core questions for atopic eczema. Clin Exp Allergy. 2001;31:903-907. 90. Kim JL, Brisman J, Aberg MA, et al. Trends in the prevalence of asthma, rhinitis, and eczema in 15 year old adolescents over an 8 year period. Respir Med. 2014;108:701-708.

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91. Rha Y, Lee K, Kim M, Choi S. Relationship between socioeconomic and sociodemographic risk factors and atopic dermatitis in Korean adolescents. Allergy. 2013;68(Suppl 97):446-447. 92. Weinmayr G, Forastiere F, Buchele G, et al. Overweight/ obesity and respiratory and allergic disease in children: international study of asthma and allergies in childhood (ISAAC) phase two. PloS one. 2014;9. e113996. 93. Lin L, Han J, Camargo C, Quershi A. Atopic dermatitis prevalence and co-morbidities in US women. J Invest Dermatol. 2012;132(Suppl 1):116. 94. Yoshida K, Ohya Y, Adachi Y, et al. The association between obesity and eczema in children: a cross-sectional study. Allergy. 2012;67(Suppl 96):203. 95. Apfelbacher C, Schmitt J, Loerbroks A. Overweight, obesity and atopic disease: evidence from a population based cross-sectional study in Germany (KiGGS). Exp Dermatol. 2011;20:173. 96. Lee SI, Shin MH, Lee HB, et al. Prevalences of symptoms of asthma and other allergic diseases in korean children: a

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98.

99.

100.

101.

nationwide questionnaire survey. J Korean Med Sci. 2001;16: 155-164. Murray CS, Canoy D, Buchan I, et al. Body mass index in young children and allergic disease: gender differences in a longitudinal study. Clin Exp Allergy. 2011;41:78-85. Chung S, Park S, Lee H, et al. Atopic dermatitis was not associated with overweight, but with parental control over feeding in 1-3 year old children. Obes Rev. 2011;11(Suppl 1), 318-319. Van Gysel D, Govaere E, Verhamme K, et al. Body mass index in Belgian schoolchildren and its relationship with sensitization and allergic symptoms. Pediatr Allergy Immunol. 2009;20: 246-253. Irei AV, Sato Y, Lin TL, et al. Overweight is associated with allergy in school children of Taiwan and Vietnam but not Japan. J Med Invest. 2005;52:33-40. Shaheen SO, Sterne JA, Montgomery SM, Azima H. Birth weight, body mass index and asthma in young adults. Thorax. 999;54:396-402.

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Supplemental Fig 1. Regional distribution of the included studies. Red dots indicate studies in children, blue dots indicate studies in adults, and green dots indicate all the centers included in the worldwide International Study of Asthma and Allergies in Childhood study performed by Mitchell et al.65

Selection

First author, year

Is case definition adequate?

Representativeness of the cases

Selection of controls

Definition of controls

B * * * * B B B B * B B * B B B B B B B B B B B B B B B

* B B B * B * * B * * * * * * * * * * * * * * * * * B *

* * * * * * * * * * * * * * * * * * * * * * * * * * * *

* * * * * * * * * * * * * * * * * * * * * * * * * * * *

** ** ** ** * 0 ** ** * ** ** * ** ** * ** ** ** ** ** ** * * ** ** ** * *

Comparison of nonresponse rate between cases and controls

Total quality scores

Power/sample size calculation

D * * * D * * D * * D * * D * * D D * D * * D D * D * *

* * * * * * * * * * * * * * * * * * * * * * * * * * * *

N/A * * * N/A N/A B B B B N/A N/A B B B B B N/A N/A * N/A N/A N/A B N/A N/A B N/A

6 8 8 8 6 4 7 6 5 8 6 6 8 6 6 7 6 6 7 7 7 6 5 6 7 6 5 6

No Yes No No No No No No No No No Yes Yes No No No No No No No No No No No No Yes No No

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Ascertainment of exposure

Same method of ascertainment for cases and controls

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Silverberg, 201466 Silverberg, 201426 Silverberg, 201469 Silverberg, 201469 Sybilski, 201468 Gibeon, 201362 James, 201363 Mitchell, 201365 Sidoroff, 201259 Silverberg, 201260 Vicedo-Cabrera, 201261 Kajbaf, 201154 Silverberg, 201155 Tanaka, 201156 Yao, 201157 Yoo, 201158 Suarez-Varela, 201052 Wang, 201053 Leung, 200951 Kusunoki, 200850 Mai, 200749 Eneli, 200646 Kilpelainen, 200647 Vlaski, 200648 Irei, 200533 Violante, 200545 Mai, 200344 Von Kries, 200143

Exposure

Comparability Comparability of cases and controls on the basis of the design or analysis

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Supplemental Table I. NewcastleeOttawa assessment scale for studies included in the metaanalysis*

Overweight

Obese

AD severity Study

Definition of severity

Silverberg, 201466 NSCH question: ‘‘Would you describe child’s eczema as mild, moderate, or severe?’’ Mitchell, 201365 ‘‘Severe eczema,’’ not defined Silverberg, 201155 Classified by pediatrician as mild, moderate, or severe based on extent and intensity of eczematous lesions, pruritus, and sleep disturbance Silverberg, 201426 Classified by dermatologists as mild, moderate, severe, or very severe using Investigator Global Assessment

Age (y)

Mild

10-17

780 (77.7%)

6-7 13-14 1-21

4-17

Moderate

Severe

309 (22.2%)

aOR

N/A N/A N/A 1.00 N/A N/A N/A 1.00 51 (16.0%) 235 (73.7%) 33 (10.3%) 1.00

N/A

1 (25.0)

3 (75.0)

Mild

1.00 1383 (58.4%)

1.00

Moderate

Severe

725 (41.2%)

aOR

N/A N/A N/A 1.03 (0.80-1.32) N/A N/A N/A 1.13 (0.98-1.31) 8 (17.8%) 33 (73.3%) 33 (10.3%) 0.82 (0.41-1.61)

N/A

52 (56.5)

40 (43.5)

Mild

2.35 (1.66-3.31) 390 (54.2%)

1.82 (0.54-6.16)

Moderate

N/A N/A N/A N/A 4 (12.5%) 20 (62.5%)

N/A

Severe

274 (45.7%)

10 (43.5)

aOR

2.59 (1.64-4.10)

N/A 0.84 (0.58-1.22) N/A 1.94 (1.52-2.46) 8 (25.0%) 2.28 (1.03-5.05)

13 (56.5)

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Normal weight

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Supplemental Table II. Association between current severity of atopic dermatitis and overweight/obesity

1.69 (0.67-4.25)

AD, Atopic dermatitis; aOR, adjusted odds ratio; NSCH, National Survey of Children’s Health.

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Supplemental Table III. Additional studies that did not have adequate information for inclusion in the metaanalysis. Study

Kim, 2014

Conclusions 90

Rha, 201391 Weinmayr, 201392 Lin, 201293 Yoshida, 201294

Apfelbacher, 201195

Lee, 201196 Murray, 201197

Chung, 201098

Van Gysel, 200999 Irei, 2005100

Shaheen, 1999101

Sweden. Age 15 y (n = 10,837). Cross-sectional study. Over an 8-year period from 2000 to 2008, eczema decreased in those with normal BMI (OR = .87, CI .79-0.96) and increased in obese adolescents (OR = 2.01, CI .99-.07). Korea. Ages 12-18 y (n = 79,202). Cross-sectional study. In a multivariate analysis, obesity was correlated with atopic dermatitis. Europe. Ages 8-12 y (n = 10,652). Cross-sectional study. Overweight and obesity were related to increased eczema incidence. United States. Ages 47-50 y (n = 3843). Females. Cross-sectional study. BMI is not significantly associated with risk of AD (RR = .96, CI .88-1.04). Japan. Ages 6-8 y (n = 40,623), 13-15 y (n = 48,466), 16-18 y (n =5 3,958). Cross-sectional study. The adjusted odds ratios for overweight with the prevalence of current eczema were .97 (CI .90-1.05) for 6-8-year olds, 1.15 (CI 1.06-1.26) for 13-15 year-olds and 1.13 (CI 1.04-1.21) for 16-18 year-olds. The aORs for overweight with the prevalence of severe eczema were 1.19 (CI .99-1.44), 1.20 (CI .98-1.47) and 1.26 (CI 1.09-1.46), respectively. In boys, the ORs with the prevalence of current eczema were .99 (CI .89-1.10), 1.22 (CI 1.22-1.37) and 1.14 (CI 1.03- 1.26). In girls, the ORs with the prevalence of current eczema were 0.96 (CI .86-1.07), 1.06 (CI .92-1.21) and 1.06 (CI .94-1.18). Germany. Ages: children and adolescents. Cross-sectional study. Ever physician-diagnosed eczema was unrelated to both overweight in girls (OR = 1.08, CI .8-1.44, n=4063) and boys (OR = .97, CI .72-1.30, n = 4366) and obesity in girls (OR = 1.05, CI 0.67-1.65, n = 3736) and boys (OR = .87, CI 0.56-1.34, n = 4013). Korea. Ages 6-12 y (n = 25,361), 12-15 yr (n =1 5068). Cross sectional study. BMI increased the risk of eczema in both 6-12 year-olds (aOR=1.29, CI 1.15-1.44) and 12-15 year-olds (aOR=.26, CI 1.01-1.50). United Kingdom. Ages 3, 5, and 8 y (n = 731). Prospective birth cohort study. In all children, the multivariate model increasing BMI significantly increased the risk of physician-diagnosed eczema at age 5 (OR = 1.2, P = .02) and 8 (OR = 1.2, P = .02). Ages 1-3 y (n = 63 cases, 76 controls). Case control study. There was no statistically significant proportion difference of overweight in children with atopic dermatitis (19.1%) and children without atopic dermatitis (26.3%). Belgium. Ages 3-14 y (n = 1567). Cross sectional study. There were no correlations between BMI and eczema. Japan, Taiwan, Vietnam. Ages 9-13 y (n = 2027). Cross sectional study. BMI per age was positively associated with a risk of atopic dermatitis in Taiwanese and Vietnamese children but not Japanese children. Great Britain. Age 26 y (n = 8960). Prospective birth cohort study. BMI quintiles were not associated with self-reported eczema in the past 12 months.