Pediatric Eczema Elective Registry Research Articles

KIR Allelic Variation and the Remission of Atopic Dermatitis Over Time.

Atopic dermatitis (AD) is a common chronic skin disease. Although generally thought to be a disease of T-cell dysregulation, recent studies have suggested that immune dysregulation of NK cells is also important. Killer cell Ig-like receptors (KIRs) are involved with NK cell regulation. The Pediatric Eczema Elective Registry is a U.S. nationwide longitudinal cohort with up to 10 y of follow-up in which 655 children had DNA available for full allelic KIR sequencing. Every 6 mo, AD activity was reported by Pediatric Eczema Elective Registry children. Using generalized estimating equations, we evaluated the association of KIR allelic variation in concert with known HLA binding ligands and whether the child reported AD in "remission" (no skin lesions and not using AD medication). KIR2DS4*001:01 (odds ratio 0.53, 95% CI [0.32, 0.88]) and KIR2DL4*001:02 (0.54, [0.33, 0.89]) in the presence of C*04:01 had the largest effect on decreasing the likelihood of AD remission. The haplotype KIR 2DL4*001:02 ∼ 2DS4*001:01 ∼ 3DL2*002:01 (0.77, [0.60, 0.99]) was also associated with a decreased likelihood of AD remission. Our findings add to the general body of evidence of a growing literature on the importance of NK cells with respect to the immunopathogenesis and natural history of AD.

Attrition of topical calcineurin inhibitor use over time in patients with atopic dermatitis

Attrition of topical calcineurin inhibitor use over time in patients with atopic dermatitis

Association of Atopic Dermatitis Severity With Learning Disability in Children

Recent population-based data indicate that atopic dermatitis (AD) is associated with learning disability (LD) in children, but the association between AD severity and LD is unknown. To evaluate the association of AD severity with learning problems in children with AD. This cross-sectional study analyzed data of US participants enrolled in the Pediatric Eczema Elective Registry (PEER) between November 1, 2004, and November 30, 2019. Participants were children aged 2 to 17 years at registry enrollment with physician-confirmed diagnosis of AD and had completed 10 years of follow-up in PEER. Atopic dermatitis severity measured by both the Patient-Oriented Eczema Measure (POEM) score and self-report. The POEM scores ranged from 0 to 28, with strata of clear or almost clear skin (0-2), mild (3-7), moderate (8-16), severe (17-24), and very severe (25-28). Self-reported AD severity was categorized as clear skin or no symptoms, mild, moderate, or severe. Learning disability diagnosed by a health care practitioner, as reported by the participants or their caregivers. Among the 2074 participants with AD (1116 girls [53.8%]; median [interquartile range (IQR)] age, 16.1 [13.9-19.5] years at 10-year follow-up), 169 (8.2%) reported a diagnosis of an LD. Children with an LD vs those without an LD were more likely to have worse AD severity, as measured by the median (IQR) total POEM score (5 [1-10] vs 2 [0-6]; P < .001), POEM severity category (moderate AD: 50 of 168 [29.8%] vs 321 of 1891 [17.0%]; severe to very severe AD: 15 of 168 [8.9%] vs 85 of 1891 [4.5%]; P < .001); and self-report (moderate AD: 49 of 168 [29.2%] vs 391 of 1891 [20.7%]; severe AD: 11 of 168 [6.5%] vs 64 of 1891 [3.4%]; P < .001). In multivariable logistic regression models adjusted for sex, age, race/ethnicity, annual household income, age of AD onset, family history of AD, and comorbid conditions, participants with mild AD (odds ratio [OR], 1.72; 95% CI, 1.11-2.67), moderate AD (OR, 2.09; 95% CI, 1.32-3.30), and severe to very severe AD (OR, 3.10; 95% CI, 1.55-6.19) on the POEM were all significantly more likely to have reported an LD than those with clear or almost clear skin. This cross-sectional study found that worse AD severity was associated with greater odds of reported LD, independent of socioeconomic characteristics, AD onset age, and other related disorders. Although additional prospective and mechanistic studies are needed to clarify the association of AD with learning, the findings suggest that children with more severe AD should be screened for learning difficulties to initiate appropriate interventions that can mitigate the consequences of an LD.

TSLP and IL-7R Variants Are Associated with Persistent Atopic Dermatitis

TSLP and IL-7R Variants Are Associated with Persistent Atopic Dermatitis

Association of Filaggrin Loss-of-Function Variants With Race in Children With Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated. To comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD. This prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019. Associations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD. A total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80). The FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.

Genetic ancestry does not explain increased atopic dermatitis susceptibility or worse disease control among African American subjects in 2 large US cohorts

Atopic dermatitis (AD) is more common among African American children. Whether there are racial/ethnic difference among adults with AD and the causes for those disparities are unclear. We sought to examine the relationship between self-reported race/ethnicity and AD and determine whether African genetic ancestry is predictive of these outcomes among African American subjects. We analyzed data from 2 independent multiethnic longitudinal studies: 86,893 subjects aged 18 to 100years from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and 5467 subjects aged 2 to 26years from the national Pediatric Eczema Elective Registry (PEER) cohort. The primary outcomes were physician-diagnosed AD in GERA and repeated measures of self-reported disease control among patients with physician-diagnosed AD at 6-month intervals in PEER. We examined whether self-identified African American race/ethnicity was predictive of these outcomes and then tested whether a continuous measure of African genetic ancestry was associated with outcomes within the African American group. AD was more common among self-identified African American subjects than non-Hispanic white subjects in GERA (4.4% vs 2.1%; odds ratio, 2.06; 95% CI, 1.70-2.48) and less well-controlled in PEER subjects (odds of 1-level worse control, 1.91; 95% CI, 1.64-2.22). However, African genetic ancestry was not associated with AD risk or control among self-identified African American subjects in either cohort, nor did an AD polygenic risk score or genetic skin pigment score explain the AD disparities in patients with AD. Ancestry-related genetic effects do not explain increased AD prevalence or poorer disease control among African American subjects.

Racial and Ethnic Differences in Atopic Dermatitis–Related School Absences Among US Children

This cross-sectional study examines data from the Pediatric Eczema Elective Registry to assess associations of race/ethnicity with school absences attributed to atopic dermatitis in US school-aged children (6 to 17 years).

Longitudinal atopic dermatitis control and persistence vary with timing of disease onset in children: A cohort study

Wide variation exists in the timing of atopic dermatitis (AD) disease onset among children. Distinct trajectories of early-onset, mid-onset, and late-onset AD have been previously described. To evaluate longitudinal disease control and persistence with respect to age at onset of AD. A cohort study was performed using the Pediatric Eczema Elective Registry, a prospective observational cohort of subjects with childhood-onset AD. AD control and persistence were assessed biannually for up to 10years. A total of 8015 subjects with 41,934 person-years of follow-up were included. In longitudinal analyses using generalized linear latent and mixed modeling, older age at onset of AD was associated with better disease control and less-persistent AD. For each additional year of age at onset of AD, the adjusted odds ratios for poorer AD control and for persistent AD were 0.93 (95% confidence interval, 0.91-0.94) and 0.84 (95% confidence interval, 0.80-0.88), respectively. Differences in AD control and persistence among subjects with early-, mid-, and late-onset AD were most pronounced from early adolescence onward. Misclassification bias may arise from using self-reported data on age at onset. Attrition and missing data in longitudinal studies may introduce bias. Early-, mid-, and late-onset pediatric AD appear to be clinically distinct subtypes of the disease.

306 Racial disparities in medical visits among children with atopic dermatitis in the Pediatric Eczema Elective Registry

306 Racial disparities in medical visits among children with atopic dermatitis in the Pediatric Eczema Elective Registry

Variations in risk of asthma and seasonal allergies between early- and late-onset pediatric atopic dermatitis: A cohort study

Atopic dermatitis is associated with other allergic conditions, but variations in this "atopic march" are poorly understood. To determine the impact of the age of atopic dermatitis onset on the risk for asthma and seasonal allergies. A cohort study was performed using the Pediatric Eczema Elective Registry, which is an observational cohort of subjects with pediatric onset atopic dermatitis. In total, 3966 children were included, and 73% reported atopic dermatitis onset before age 2years. At baseline, subjects with atopic dermatitis onset at ages 3 to 7 or 8 to 17years had significantly lower rates of seasonal allergies and asthma than those with onset before age 2. During follow-up, the adjusted relative risks for incident seasonal allergies were 0.82 (95% confidence interval, 0.72-0.91) and 0.64 (95% CI confidence interval, 0.47-0.83) in the 3- to 7- and 8- to 17-years-old at onset groups compared with the age 2years or younger at onset group. The adjusted risk for incident asthma was not significantly different between the older onset groups and the earliest onset group. Misclassification bias may arise from using self-reported onset age data. The timing of atopic dermatitis onset may explain part of the variation in the atopic march. These findings may improve future risk stratification of patients for treatment.

206 Racial/ethnic differences in healthcare utilization and school attendance among children with atopic dermatitis in the Pediatric Eczema Elective Registry

Little is known about healthcare utilization for atopic dermatitis (AD) and the impact of AD on school attendance especially among racial/ethnic minorities. We aimed to examine healthcare utilization and school missed due to AD by race/ethnicity among a cohort of U.S. children with AD. We performed a cross-sectional study of baseline data for children (ages 2-17) with physician-confirmed AD enrolled in the Pediatric Eczema Elective Registry (PEER; N=7,901). All subjects had to have used pimecrolimus cream for at least 6 weeks at the time of enrollment. Study outcomes were: 1) healthcare utilization by visit type, and 2) any school missed in the 6 months prior to enrollment. We performed multivariable logistic regression to assess the association between the outcomes and race/ethnicity, adjusting for age, gender, annual household income, history of asthma and allergic rhinitis, and AD severity (AD severity variable for outcome 2 only). For outcome 1, an interaction term of AD severity by race/ethnicity was included. The reference group was non-Hispanic whites. Non-Hispanic blacks (odds ratio [OR]=2.3; 95% CI=1.6-3.2) and Hispanics (3.1; 2.0-4.7) were more likely than whites to have visited the emergency room for their AD. Blacks were also less likely to have seen a dermatologist (0.6; 0.5-0.7). Interaction between race/ethnicity and AD severity was statistically significant but had small effects on the main ORs. Blacks (1.3; 1.1-1.6), Hispanics (1.8; 1.5-2.3), and Asians (3.6; 2.6-5.0) were more likely to have missed school due to their AD. Our results suggest disparities in healthcare utilization and poorer school attendance among racial/ethnic minority children with AD, after adjustment for AD severity. Further studies are needed to better understand these disparities and improve healthcare for and school attendance among racial/ethnic minority children with AD.

164 Changes in the geographic distribution of atopic dermatitis on the body with age

Atopic dermatitis (AD) is described as having a characteristic distribution that changes with age: peri-orifical among infants, flexural in early childhood, and other locations, such as on the hands or trunk, in adulthood. However, little data is available regarding changes in the geographic distribution of disease among individuals as they age. The objective of this study was to describe the geographic location of AD on the body among individuals over time in a cohort of US children and young adults followed for up to 10 years. 6,270 participants, ages 2-28 years, who returned 65,237 surveys as part of the Pediatric Eczema Elective Registry (PEER), a national post-marketing study of pimecrolimus, were analyzed. The mean age at enrollment was 7.2 years old, and 47% of the sample was male, 35% white, 49% black, and 75% had a history of atopic disease. 88% of individuals had flexural rashes ever, 83% had facial, and 94% had other rashes ever. Among 6-month periods during which a rash was reported, individuals reported flexural rashes 62% of the time (Standard Deviation 35%), facial rashes 50% of the time (SD 36%), and rashes in other areas 70% of the time (SD 31%). Using multilevel mixed effects logistic regression and controlling for age, sex, race, history of atopy, age at enrollment, and age at AD onset, we found that the odds of flexural rash decreased by 7% for each additional year of age (OR 0.93, 95%CI 0.92-0.94), the odds of facial rashes decreased by 8% for each additional year of age (OR 0.92, 95%CI 0.91-0.92), and the odds of rashes in other areas decreased by 8% for each additional year of age (OR 0.92, 95%CI 0.91-0.93). Individuals report rashes in fewer locations at one time as they age. In summary, there is heterogeneity in the geographic location of AD rashes among individuals; while 88% had flexural rashes ever, they were only present 62% of the time, and rashes in all measured areas became less frequent with age.

Association of Filaggrin Loss of Function and Thymic Stromal Lymphopoietin Variation With Treatment Use in Pediatric Atopic Dermatitis

ImportanceAtopic dermatitis (AD) is a common illness of childhood.ObjectiveTo determine whether variations in FLG and TSLP genotype corresponded to differences in treatment use over time.Design, Setting, and ParticipantsThis prospective cohort study recruited and followed a volunteer sample of 842 children enrolled in the Pediatric Eczema Elective Registry who provided saliva samples for DNA extraction for 10 years. Eligibility criteria included age 2 to 17 years, AD diagnosis without cancer, and prior pimecrolimus use. Participants were followed for an average of 7.6 years (approximately 6396 person-years); 138 patients (16.4%) had no missing data over 10 years of follow-up.ExposuresEvaluation of FLG and TSLP genotypes.Main Outcomes and MeasuresSelf-reported outcomes of whether a child’s AD required the use of topical steroids, topical calcineurin inhibitors, or other medications within the past 6 months at 6-month intervals.ResultsOverall, 842 children (mean [SD] age, 1.9 [2.7] years; 438 girls) were included in this study. Treatment use among patients with 0, 1, or 2 FLG loss of function (LOF) alleles was compared as well as those that were wildtype, heterozygous, or homozygous for the TSLP rs1898671 single-nucleotide polymorphism. Patients with 2 FLG LOF alleles were less likely to report skin clearance (odds ratio [OR], 0.20; 95% CI, 0.07-0.55) and more likely to use steroids (OR, 5.04; 95% CI, 1.91-13.31). TSLP rs1898671 homozygotes were less likely to report topical calcineurin inhibitor use (OR, 0.16; 95% CI, 0.06-0.42), and among all patients that had discontinued topical calcineurin inhibitors, those with the rs1898671 single-nucleotide polymorphism were more likely to have stopped all other treatment as well (OR, 0.45; 95% CI, 0.26-0.76). In all but 1 of our comparisons, no significant difference between wildtype and heterozygous patients were found.Conclusions and RelevanceTreatment use and likely effectiveness was associated with genetic variation. Variation was limited to children with 2 FLG LOF alleles or TSLP rs1898671 homozygotes, with no significant difference observed between wildtype and heterozygous patients in the majority of the outcomes studied. Therefore, the key differentiating factor in our analyses was the number of FLG LOF alleles or TSLP SNPs rather than the absolute presence or absence of these variants. This may be an important consideration for future studies.

Association Between Malignancy and Topical Use of Pimecrolimus.

A black box warning describes a potential risk of malignancy associated with topical use of pimecrolimus to treat atopic dermatitis due to its similarity to oral calcineurin inhibitors used in solid-organ transplantation and spontaneous reporting of malignancies, including lymphomas and cutaneous malignancies. To evaluate the risk of malignancy in a postmarketing study of children exposed to pimecrolimus. A longitudinal cohort study among a nationwide ongoing long-term cohort of children enrolled in the Pediatric Eczema Elective Registry (PEER) who had a history of atopic dermatitis and pimecrolimus use with data available up through May 2014. Reports of malignancy among those in the PEER compared with expected rates from the Surveillance, Epidemiology, and End Results (SEER) program. Overall, 7457 children were enrolled in the PEER, for a total of 26,792 person-years. Children used a mean (SD) of 793 (1356) g of pimecrolimus when enrolled in the study. As of May 2014, five malignancies had been reported. These include 2 leukemias, 1 osteosarcoma, and 2 lymphomas. No skin cancers were reported. The standardized incidence ratio for all malignancies (primary outcome) based on the age-standardized SEER population was 1.2 (95% CI, 0.5-2.8). As secondary analyses, the standardized incidence ratios (based on 2 cases for each) were 2.9 (95% CI, 0.7-11.7) for lymphoma and 2.0 (95% CI, 0.5-8.2) for leukemia. None of these findings were statistically significant. Based on more than 25,000 person-years of follow-up, it seems unlikely that topical pimecrolimus as it was used in the PEER cohort to treat atopic dermatitis is associated with an increased risk of malignancy.

Persistence of Mild to Moderate Atopic Dermatitis

Atopic dermatitis (AD) is a common illness of childhood. To evaluate the natural history of AD and determine the persistence of symptoms over time. A cross-sectional and cohort study of a nation-wide long-term registry of children with AD enrolled in the Pediatric Eczema Elective Registry (PEER). Self-reported outcome of whether a child's skin was AD symptom-free for 6 months at 6-month intervals. A total of 7157 patients were enrolled in the PEER study for a total of 22,550 person-years. At least 2 years of follow-up were observed for 4248 children and at least 5 years of follow-up were observed for 2416 children. Multiple demographic and exposure variables were associated with more persistent AD. At every age (ie, 2-26 years), more than 80% of PEER participants had symptoms of AD and/or were using medication to treat their AD. It was not until age 20 years that 50% of patients had at least 1 lifetime 6-month symptom- and treatment-free period. Based on this large longitudinal cohort study, symptoms associated with AD seem to persist well into the second decade of a child's life and likely longer. Atopic dermatitis is probably a life-long illness.

Childhood Atopic Dermatitis Often Persists into Adulthood

Little has been reported about the natural history of atopic dermatitis (AD). When topical calcineurin inhibitors were approved for AD treatment, the FDA required manufacturers to conduct post-marketing safety studies. One such effort is the Pediatric Eczema Elective Registry (PEER), which enrolled patients aged 2 to 17 years with mild-to-moderate AD who had used pimecrolimus cream for >42 days in the prior 6 months; …

Thymic Stromal Lymphopoietin Variation, Filaggrin Loss of Function, and the Persistence of Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic illness of childhood. To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD. A prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation. Self-reported outcome of whether a child's skin had no symptoms of AD and required no medications for 6 months at 6-month intervals. We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86). The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.

Warm, Humid, and High Sun Exposure Climates Are Associated with Poorly Controlled Eczema: PEER (Pediatric Eczema Elective Registry) Cohort, 2004–2012

Anecdotal reports of children experiencing eczema flares during winter and summer months along with global variation in eczema prevalence has fueled speculation that climate may modulate disease activity. The aim of this study was to determine if long-term weather patterns affect the severity and persistence of eczema symptoms in children. We performed a prospective cohort study of U.S. children (N=5,595) enrolled in PEER (Pediatric Eczema Elective Registry) between 2004 and 2012 to evaluate the effect of climate (daily temperature, daily sun exposure, daily humidity) on the severity of eczema symptoms. Odds ratios were calculated for the patient evaluated outcome of disease control. Multivariate logistic regression modeling adjusting for gender, race, income, and topical medication use demonstrated that higher temperature (OR=0·90, 95% CI: 0·87–0·93, p<0·001) and increased sun exposure (OR=0·93, 95% CI: 0·89–0·98, p=0·009) were associated with poorly controlled eczema. Higher humidity (OR=0·90, 95% CI: 0·812–0.997, p=0·04) was also associated with poorly controlled disease, but the statistical significance of this association was lost in our multivariate analysis (p=0.44).

Asthma and frequency of wheeze: risk factors for the persistence of atopic dermatitis in children

BackgroundStudies have examined the development of asthma in children with atopic dermatitis (AD); however, none have looked at the association of asthma or the frequency of wheeze with respect to persistence or difficulty in achieving AD clinical improvement in children. ObjectiveTo determine whether children with AD who have asthma and increasing frequency of wheezing have more persistent AD. MethodsThis is a cohort study using the Pediatric Eczema Elective Registry (PEER) database, which includes data obtained at enrollment and 3 years later. The AD outcome was the persistence of skin symptoms. Our covariates of interest were asthma diagnosis and wheezing symptoms, which were measured at enrollment and again at year 3 of the study. Multivariate logistic regression models assessed the magnitude of associations among AD symptoms, asthma diagnosis, and the frequency of wheeze. All models were adjusted for sex, age, and ethnicity. ResultsA total of 2104 children were enrolled in the PEER study and had at least 3 years of follow-up at the time of this study. At enrollment, an asthma diagnosis decreased the likelihood of being rash free in the preceding 6 months by 30% (odds ratio, 0.70; 95% confidence interval, 0.59-0.84). At year 3, having asthma decreased the likelihood by 40% (odds ratio, 0.60; 95% confidence interval, 0.49-0.72). Increasing frequency of wheezing also decreased the likelihood that a child was rash free (P < .001). ConclusionFor children with AD, a history of asthma and an increasing frequency of wheezing correlate strongly with more persistent AD.