The alluvial diagram visualizes each child’s individual AD course according to diagnosis at different cross-sectional time points. The blue areas represent the children who did not develop AD.
Increasing genetic risk score is associated with increased atopic dermatitis duration. Data markers represent median duration; error bars, 95% CIs.
eTable 1. Gene Variants Comprising the AD Gene Risk Score and Their Respective Beta Coefficient and Effect Allele
eTable 2. Baseline Characteristics of the AD Study Group at 13 Years Compared to the Remaining Cohort (AD Controls)
eFigure 1. Flowchart of the Atopic Dermatitis Study Population
eFigure 2. Loading Plot: PCA Comparison of Minor HR Criteria at Diagnosis of Children With Atopic Dermatitis
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Thorsteinsdottir S, Stokholm J, Thyssen JP, et al. Genetic, Clinical, and Environmental Factors Associated With Persistent Atopic Dermatitis in Childhood. JAMA Dermatol. 2019;155(1):50–57. doi:10.1001/jamadermatol.2018.4061
Are there determinants of importance for the persistence of atopic dermatitis at age 13 years?
In the Copenhagen Prospective Study on Asthma in Childhood 2000 birth cohort study, known genetic atopic dermatitis risk variants, paternal asthma and atopic dermatitis, high social circumstances, diagnostic minor criteria of Hanifin and Rajka, and disease severity at onset were significantly associated with persistent atopic dermatitis.
The findings of this study suggest that genetic profile is one of the factors most often associated with persistent atopic dermatitis at age 13 years, and that the likelihood of persistence can be evaluated at the onset of atopic dermatitis using existing clinical tools.
Knowledge about factors associated with persistence of atopic dermatitis (AD) during childhood is sparse.
To explore heritable, environmental, and clinical factors associated with persistent AD based on 13 years’ follow-up of an at-risk birth cohort.
Design, Setting, and Participants
In the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) clinical birth cohort study, 411 children born to mothers with asthma were followed up until the age of 13 years at a clinical research unit in Copenhagen, Denmark, from August 1998 to June 2015. Atopic dermatitis was diagnosed prospectively during close clinical follow-up according to the criteria of Hanifin and Rajka. Data were gathered on parental history, social circumstances, and environmental factors through parent interviews. The cohort was followed up with biannual visits to the clinic until the age of 7 years and were seen again at age 13 years. Data were analyzed from August 2015 to January 2018.
Main Outcomes and Measures
Atopic dermatitis was diagnosed using Hanifin and Rajka major and minor criteria, and severity was determined by Scoring Atopic Dermatitis (SCORAD) index, with possible scores from 0 to 83, with higher scores indicating more severe AD.
Of the 411 children in the cohort, 203 (49.4%) were male and 186 (45.3%) were diagnosed with AD before the age of 13 years; 40 of 166 children (24.1%) had persistent AD at the age of 13 years, and 126 (76.0%) experienced remission. Factors associated with persistent AD to age 13 years included heritability, environmental exposures, asthma and allergic sensitization, clinical presentation at the time of diagnosis, the composition of Hanifin and Rajka diagnostic minor criteria, and AD severity according to SCORAD. A higher AD genetic risk score was associated with an increased the risk for persistent AD (multivariable odds ratio [OR], 1.8; 95% CI, 1.1-2.9; P = .02), together with paternal asthma (multivariable OR, 3.7; 95% CI, 1.2-11.5; P = .02); paternal AD (multivariable OR, 6.2; 95% CI, 1.17-23.2; P = .007), and higher social circumstances (multivariable OR, 1.6; 95% CI, 1.0-2.5; P = .05). Particular clinical presentations at time of diagnosis were also associated with specific minor criteria of Hanifin and Rajka (Dennie-Morgan and anterior neck folds, white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance, and food allergy) (OR, 2.6; 95% CI, 1.1-6.2; P = .03) as well as increased severity at diagnosis (OR, 1.1; 95% CI, 1.0-1.1; P = .007).
Conclusions and Relevance
In a birth cohort of children at risk for asthma who received close clinical follow-up to age 13 years, known genetic AD risk variants, paternal asthma and AD, high social circumstances, diagnostic minor criteria, and disease severity at onset were associated with persistent AD at age 13 years. These findings may be applied in clinical practice to evaluate the likely disease course for individual patients.
Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease that most often begins in infancy1; between 1990 and 2010, it affected approximately 1 in 5 children in developed countries.2,3 Children with AD comprise a heterogeneous group with different disease courses, age at onset, clinical manifestations, severity, duration, and risk of comorbidity.4,5 Although most children with AD outgrow their disease, it is unclear how many experience persistence of symptoms into adulthood, and little is known about determinants of persistent AD.6
Known heritable AD risk factors include parental asthma, allergy, and AD (which almost doubles the child’s AD risk if present in both parents7) as well as concurrent asthma, wheezing, and allergic sensitization in the child.8-11 Furthermore, filaggrin gene (FLG) mutations are nonfunctional mutations that increase the risk of AD 2- to 3-fold.12-15 Other genetic risk loci have been identified but are of less importance.16 Suspected environmental risk factors for AD development include birth during winter,17,18 exposure to hard domestic water,19 air pollution, low ambient humidity,20,21 longer duration of breastfeeding,22 and maternal alcohol intake during pregnancy.23 However, exposure to a dog in the household near the time of birth has been found to protect against development of AD.24
There is an unmet need for an improved understanding of factors associated with a persistent disease course throughout childhood. This would be of clinical importance to patients, parents, and clinicians and could guide treatment.
In the present study, we examined the fluctuations in AD diagnosis throughout childhood and aimed to identify risk factors of persistent AD in a cohort of children followed up prospectively from birth to age 13 years.
The Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) is a single-center clinical cohort study of 411 children born to mothers with physician-diagnosed asthma. The cohort was followed up from August 1998 to June 2015, and data were analyzed from August 2015 to January 2018. Details on recruitment and characteristics of the cohort have been described previously.25-27 In brief, mothers were recruited during pregnancy and their children at 1 month of age. The children were seen in the research unit every 6 months for scheduled visits as well as on acute onset of airway or skin symptoms until the age of 7 years. The most recent follow-up visit was performed at age 13 years. Between the ages of 7 and 13 years, children were seen if they experienced any skin symptoms. Data validation and quality control followed the guidelines for good clinical practice, including the Danish Code of Conduct for Research Integrity, the European Union’s Directive on Good Clinical Practice, the International Conference on Harmonisation’s good clinical practice guidelines, the Danish Act on Processing of Personal Data, and the practice of the Danish Data Inspectorate. The study was performed in accordance with the Declaration of Helsinki28 and approved by the Copenhagen Ethics Committee and the Danish Data Protection Agency.25 Oral and written informed consent were obtained from parents or guardians before enrollment.
At every clinical visit, a full physical examination was performed by a physician with training in dermatology, and the families were interviewed using structured questions with closed response categories focusing on airway and skin symptoms, use of medication and health care, lifestyle factors, and domestic environmental exposures. The physicians at the COPSAC clinic were solely responsible for diagnosis and treatment of all respiratory, allergy, and skin-related symptoms according to standard operating procedures.1
Atopic dermatitis was diagnosed prospectively until age 13 years according to the criteria of Hanifin and Rajka and with a clinical assessment.29 A diagnosis of AD required the presence of 3 of 4 major criteria (pruritus, typical morphologic features and distribution, chronic dermatitis, and personal or family history of atopy) and at least 3 of 23 minor criteria (early age at onset, xerosis, ichthyosis, keratosis pilaris, palmar hyperlinearity, hand or foot dermatitis, nipple eczema, cheilitis, perifollicular accentuation, pityriasis alba, anterior neck folds, itching when sweating, intolerance to wool, positive result on type 1 skin test, elevated serum IgE level, food intolerance, tendency to skin infection, facial pallor, white dermographism, conjunctivitis, Dennie-Morgan fold, orbital darkening, and course influenced by environmental factors, excluding keratoconus and anterior subcapsular cataracts. The severity of AD was scored at disease onset using the SCORAD (Scoring Atopic Dermatitis) index30; scores can range from 0 to 83 points (excluding the subjective components pruritus and sleeplessness from the modified SCORAD index, from which the subjective components of pruritus and sleeplessness have been excluded), with a higher score indicating more severe AD. Duration of AD was defined as days with ongoing AD diagnosis from 0 to 13 years of age. Exclusion criteria were incomplete follow-up from birth to 13 years of age and being older than 10 years at AD onset. Remission of AD was defined as a 1-year period without clinical symptoms and without use of topical anti-inflammatory treatment. A child with an AD diagnosis was classified as having persistent AD if the disease was ongoing at 13 years of age. Transient AD was defined as remission at 13 years of age. A child’s individual course from 0 to 13 years according to possible AD diagnosis at cross-sectional time points (2, 5, 7, and 13 years) was illustrated by an alluvial diagram that included only children with full follow-up.
Genotyping for common loss-of-function mutations in FLG (OMIM 135940), R501X, 2282del4, R2447X, and S3247X was performed as previously described.12 An FLG mutation carrier was defined as an individual having at least 1 gene mutation. An AD genetic risk score was constructed based on genetic variants that were associated with AD in a large meta–genome-wide association study31 as well as common FLG mutations (eTable 1 in the Supplement). The number of risk alleles for each child was calculated and weighted according to the child’s odds ratios (OR) and was z-score transformed. Information about parental physician-diagnosed asthma, allergy, and AD was obtained in the clinic by personal interviews.
Midwives collected cord blood by needle puncture from the umbilical cord vein, and plasma 25-hydroxyvitamin D levels were analyzed as previously detailed.32,33 The vitamin D level in cord blood was categorized as deficient (<20 ng/mL), insufficient (20-30 ng/mL), or sufficient (>30 ng/mL).34 (To convert vitamin D levels to nanomoles per liter, multiply by 2.496.)
Information about maternal smoking and antibiotic use during pregnancy, parity, duration of exclusive breastfeeding, child sex, gestational age, season of birth, mode of delivery, birth weight, head circumference at birth, as well as presence of a dog and cat in the home at birth was collected prospectively at scheduled visits.
“Social circumstances” included household income, maternal age, and maternal level of education when the child was aged 2 years and was analyzed in a principal components analysis (PCA). The first component explained 52% of the variance in the data and was used as a composite indicator of social circumstances.
Asthma or recurrent wheeze before age 3 years was diagnosed prospectively in the COPSAC research unit according to a strict predefined and previously validated quantitative algorithm based on daily symptoms captured prospectively in a diary.26
Allergic sensitization was measured at 6 and 18 months of age and defined as any skin prick test wheal larger than 2 mm (ALK-Abello) or specific serum IgE level of 0.35 kU/mL or greater using the ImmunoCAP Phadiatop Infant test (Pharmaca Diagnostics AB).6,35 (To convert the IgE level to milligrams per liter, multiply by 0.001.) Serum IgE levels were measured against 8 inhalant allergens (dog, cat, horse, birch, timothy grass, mugwort, Dermatophagoides pteronyssinus, and molds) and 9 food allergens (milk, egg, wheat flour, rye flour, oatmeal, cod, soybean, potato, and peanut).
The differences between children with persistent and transient AD at age 13 years were analyzed by χ2 test, unpaired, 2-tailed t test, and logistic and linear regression. Thereafter, all significant determinants were included in a multivariable model. A PCA was used to identify common systematic variation in the Hanifin and Rajka minor criteria at diagnosis. Variables with no variance were omitted. Differences in the Hanifin and Rajka minor criteria patterns between transient and persistent AD were tested using a nonparametric Adonis PERMANOVA model from the R package “vegan,” version 2.3-5 (R Foundation for Statistical Computing) with euclidean distances. Analysis of severity by modified SCORAD at AD onset was analyzed with linear regression models adjusted for age at AD onset. A linear regression model was used to analyze the association between the AD genetic risk score, PC1 (first principal component) from the Hanifin and Rajka PCA, modified SCORAD score, and the duration of AD.
Results were reported with 95% CIs, and a significance level of P < .05 was used. Missing observations were treated as missing data. Data processing was conducted using SAS, version 9.3 for Windows (SAS Institute Inc) and R, version 3.3.0 (R Foundation for Statistical Computing).
Age and race/ethnicity were homogeneous for the COPSAC2000 cohort; of the 411 children, 203 (49.4%) were male. Of the children in the cohort, 186 (45.3%) experienced AD from birth to age 13 years (Figure 1). Sixteen children were excluded owing to incomplete follow-up, and 4 owing to onset of AD after age 10 years, leaving 166 children with AD in the final study group of children (eFigure 1 in the Supplement). The 166 children with AD were characterized by having more mothers with AD and fathers with asthma and allergic rhinitis. Furthermore, fewer mothers used antibiotic medications during pregnancy in the AD group (eTable 2 in the Supplement). By age 13 years, 40 of the 166 children with AD (24.1%) had an ongoing diagnosis and were classified as having persistent AD, whereas 126 (76.0%) were in remission (transient).
Figure 2 illustrates the prevalence of AD across the first 13 years of life for children with AD in the cohort. The prevalence peaked at age 2 years, when 159 (40.7%) of the children had AD, and declined gradually to age 13 years, when 40 (11.2%) still had a diagnosis of AD. The individual child’s AD course over this period was illustrated in an alluvial diagram showing the fluctuation in diagnosis between time points (Figure 3). Descriptive statistics for all determinants analyzed for association with persistent AD are shown in the Table and detailed below.
Paternal asthma was present in 15 of 40 children (37.5%) with persistent AD compared with 16 of 125 (12.8%) with transient AD (OR, 4.1; 95% CI, 1.8-9.4; P < .001). Eleven of the children (30.6%) with persistent AD had fathers with an AD diagnosis compared with 7 (7.0%) with transient AD (OR, 5.8; 95% CI, 2.0-17.0; P < .001). Maternal asthma, AD, and allergic rhinitis and paternal allergic rhinitis were not significantly associated with persistent AD.
Eleven of the 38 children (28.9%) with persistent AD had FLG mutations compared with 17 of 126 children (13.5%) with transient AD (OR, 2.6; 95% CI, 1.1-6.2; P = .03). Furthermore, a higher AD genetic risk score was associated with increased risk of persistent AD (OR, 1.6; 95% CI, 1.1-2.4; P = .03). Children with persistent AD had a mean (SD) AD genetic risk score of 0.47 (1.07) compared with 0.02 (0.94) for children with transient AD.
A positive dose-dependent linear association was found between the AD genetic risk score and duration of AD (Figure 4), with an increase of 270 days for each additional step in the AD genetic risk standard score (95% CI, 105-436; P = .002).
A higher level of social circumstances score (household income, maternal age, and maternal level of education) at age 2 years was associated with persistent AD (OR, 1.6; 95% CI, 1.1-2.2; P = .02). Sex, parity, and maternal smoking as well as antibiotic use during pregnancy, cord blood vitamin D levels, season of birth, gestational age, head circumference, weight at birth, mode of delivery, domestic exposure to a dog or cat around birth, having older children in the home, and days of exclusive breastfeeding were not significantly associated with persistent AD (Table).
No associations were found between asthma or persistent wheeze and persistent AD until 3 years of age (OR, 1.6; 95% CI, 0.6-4.0; P = .30) or allergic sensitization at 6 and 18 months (OR, 1.1; 95% CI, 0.5-2.6; P = .80) and persistent AD.
Heritable and environmental determinants significantly associated with the persistence of AD were analyzed in a multivariable model to examine covariance. In this combined analysis, we found that a higher AD genetic risk score was significantly associated with persistent AD (multivariable OR, 1.8; 95% CI, 1.1-2.9; P = .02). Paternal asthma and AD were also associated with persistent AD: paternal asthma (multivariable OR, 3.7; 95% CI, 1.2-11.5; P = .02) and paternal AD (multivariable OR, 6.2; 95% CI, 1.2-23.2; P = .007). Social circumstances were also associated with persistent AD (multivariable OR, 1.6; 95% CI, 1.0-2.5; P = .05).
A PCA analysis of Hanifin and Rajka’s minor criteria registered at AD onset showed that PC1 explained 18% and PC2 explained 15% of the variation in the original variables. There was a significant overall shift in PCA scores between the persistent and transient AD groups (F = 2.0; R2 = 0.0; P = .003). This shift was most prominent in PC1, where increased scores among persistent AD for several features, including Dennie-Morgan folds, anterior neck folds, white dermographism, intolerance to wool, itching when sweating, a tendency to skin infection, food intolerance, and food allergy, were contributing factors (eFigure 2 in the Supplement).
The mean (SD) severity score at AD onset as measured by modified SCORAD in the COPSAC clinic was 18 (9.4) among all children with AD. The modified SCORAD mean (SD) score was higher for children with persistent (22 [8.6]) vs transient (17 [9.3]) AD (OR, 1.1; 95% CI, 1.0-1.1; P = .007). Duration of AD was increased by 27 days per 1-U increase in modified SCORAD score at the first visit (95% CI, 7-46; P < .001).
Atopic dermatitis genetic risk score, including common FLG mutations, was the only significant nonclinical risk factor for AD persistence.9,36 Furthermore, paternal asthma and AD as well as high social circumstances were risk factors for AD persistence at age 13 years in this at-risk cohort followed up prospectively from birth until 13 years of age. The clinical presentation at diagnosis, including selected Hanifin and Rajka minor criteria, and increased AD severity were also associated with AD persistence, whereas early-life wheezing and allergic sensitization were not associated with AD persistence. These findings suggest that heritability combined with AD characteristics at diagnosis may be used for personalized disease courseestimation.
We found that 24.1% of children diagnosed with AD during childhood had persistent disease at age 13 years, which is in line with a recent meta-analysis that included 45 studies showing that 20% of children with AD had persistent disease after 8 years of age.6 Additional longitudinal studies have shown genetic variance associated with persistent AD through childhood.9 We showed that most children had disease onset in the first 2 years of life, with a smaller fraction diagnosed after this age. We described the prevalence of AD according to age: the highest prevalence occurred at 2 years of age and declined gradually throughout childhood. We further illustrated the fluctuations of AD over the first 13 years of life, documenting that the majority of children with persistent AD at age 13 years had already received a diagnosis at age 2 years. Genetics, summarized by an AD genetic risk score, was the strongest nonclinical risk factor for persistent AD at age 13 years in a dose-dependent manner with the duration of AD.36-39 Twin studies have suggested that heritability of AD is approximately 80% to 90%.40 However, the genetic risk score explained approximately 8% of the difference between a persistent vs transient AD course from age 0 to 13 years, in line with previous AD genome-wide association study analyses that were able to explain approximately 15% of variance in the risk of developing AD.31 This finding suggests that both onset and duration of AD are contributed to by a large number of genetic variants with small effect size.
Our study suggests associations between paternal asthma and AD and persistence of childhood AD, whereas we observed no significant associations with maternal disease. This difference between maternal and paternal heritage might be explained by the at-risk nature of the cohort. It was an inclusion criterion that all mothers had asthma, and they were therefore also much more likely to have AD and allergic rhinitis, whereas there were no inclusion criteria involving paternal disease. Previously, AD has been reported to be a disease of children from high socioeconomic groups.41-43 Our results corroborate these findings and show that children with AD from families with higher social circumstances are at greater risk of experiencing persistent AD.
An increased prevalence of asthma and allergy among individuals with AD is often described as the “atopic march.”44,45 However asthma and persistent wheeze and allergic sensitization in early childhood were not significant risk factors for persistent AD at 13 years of age. This finding is supported by a study examining individual development of AD, asthma, and rhinitis in 9801 children.46 In that study, 3% of the examined children followed the “atopic march.” In fact, we proposed that the atopic march is restricted to a specific endotype of children with AD, but that it does not describe the natural development of AD, asthma, and sensitization in childhood.11
We examined the clinical presentation of children with AD at first diagnosis and found that the validated diagnostic minor criteria of Hanifin and Rajka29,30 were useful to estimate the likelihood of AD persistence at age 13 years. In particular, the minor criteria (Dennie-Morgan folds, anterior neck folds, white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance, and food allergy) contributed to this association. Furthermore, we found that high SCORAD at diagnosis was a risk factor for persistent AD. Both of these clinical AD factors were also associated with duration of AD. These, in combination with genetic assessments, might thus be useful tools for personalized disease course estimation.
A major advantage of the study is that all AD diagnoses were made longitudinally at the COPSAC clinic according to standard operating procedures.25 Furthermore, all children were seen in the COPSAC clinic at acute and scheduled visits for skin-related symptoms, which minimized the risk of parental recall bias. This meticulous prospective follow-up is a significant strength that enabled accurate assessment of AD onset and remission. Limitations of the study were that all mothers in the project had a history of asthma and that the findings require validation in an unselected population.
The findings of this study suggest that an AD genetic risk score, selected minor criteria of Hanifin and Rajka, and AD severity at diagnosis are risk factors for persistence of AD through childhood. These findings could be used in clinical practice for personalized disease course estimation.
Corresponding Author: Hans Bisgaard, MD, DMSc, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Gentofte, Copenhagen, Denmark (email@example.com).
Accepted for Publication: September 14, 2018.
Published Online: November 14, 2018. doi:10.1001/jamadermatol.2018.4061
Author Contributions: Dr Bisgaard had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Thorsteinsdottir, Stokholm, Thyssen, Chawes, Bisgaard.
Acquisition, analysis, or interpretation of data: Stokholm, Thyssen, Nørgaard, Thorsen, Chawes, Bønnelykke, Waage, Bisgaard.
Drafting of the manuscript: Thorsteinsdottir, Thyssen.
Critical revision of the manuscript for important intellectual content: Stokholm, Thyssen, Nørgaard, Thorsen, Chawes, Bønnelykke, Waage, Bisgaard.
Statistical analysis: Thorsteinsdottir, Thyssen, Nørgaard, Thorsen, Waage.
Obtained funding: Thorsteinsdottir, Chawes, Bønnelykke, Bisgaard.
Administrative, technical, or material support: Thorsteinsdottir.
Supervision: Stokholm, Thyssen, Chawes, Bønnelykke, Waage, Bisgaard.
Conflict of Interest Disclosures: None reported.
Funding/Support: The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) is funded by private and public research funds, all listed at http://www.copsac.com. Core support for COPSAC has been provided by grant R16-A1694 from the Lundbeck Foundation, grant 903516 from the Danish Ministry of Health, grant 0603-00280B from the Danish Council for Strategic Research, grants 10-082884 and 271-08-0815 from the Danish Council for Independent Research, and a grant from the Capital Region Research Foundation. This study was further supported by Gangstedfonden. Thermo Fisher Scientific Inc sponsored the IgE analyses. Dr Thyssen is funded by an unrestricted grant from the Lundbeck Foundation.
Role of the Funder/Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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