Persistence of mild to moderate Atopic Dermatitis

Abstract

Importance

Atopic dermatitis (AD) is a common illness of childhood

Objective

The goal of this study was to evaluate the natural history of AD and determine the persistence of symptoms over time.

Design

A cross-sectional and cohort study.

Setting

A nation-wide long-term registry of children with AD.

Participants

Children enrolled in the Pediatric Eczema Elective Registry (PEER).

Main outcome

Self-reported outcome of whether or not a child’s skin was AD symptom-free for 6 months at 6 month intervals.

Results

7,157 subjects were enrolled in the PEER study for a total of 22, 550 person-years. At least 2 years of follow-up was observed for 4,248 and at least 5 years of follow-up was observed for 2,416 children. Multiple demographic and exposure variables were associated with more persistent AD. At every age (i.e. 2 to 26 years), more than 80% of PEER subjects had symptoms of AD and/or were using medication to treat their AD. It was not until age 20 years that 50% of subjects had at least one lifetime six-month symptom and treatment free period.

Conclusions and Relevance

Based on this large longitudinal cohort study, symptoms associated with AD appear to persist well into the second decade of a child’s life and likely longer. AD is likely a life-long illness.

Atopic dermatitis (AD) or eczema is a common skin disease that often begins in early childhood^1–7. AD begins before the second year of life, has a waxing and waning clinical course, and is often reported to resolve soon after the first decade of life². The etiology of AD is likely multifactorial resulting from a complex interaction between genetic and environmental factors^2–5. Little has been reported about the natural history of AD and how genetic and environmental factors are associated with the waxing and waning nature of AD^7–11.

About a decade ago, the Food and Drug Administration (FDA) approved topical calcineurin inhibitors like pimecrolimus and tacrolimus for the treatment of AD. Because of potential safety concerns of the novel topical use of these products, the FDA and the European Medicines Agency (EMA) required the manufacturers of these drugs to each conduct long-term post-marketing safety studies^12;13. The pimecrolimus post-marketing study is called Pediatric Eczema Elective Registry (PEER). The PEER study is an ideal resource to examine the natural history of children with mild to moderate AD. The goal of our current study was to evaluate the natural history of AD in a group of children who were enrolled in the PEER study. Specifically, we evaluated the prevalence of symptoms of AD overtime and several risk factors that are associated with the persistence of AD.

Methods

Population

PEER is an ongoing prospective observational registry/cohort that began enrollment in 2004 and will follow participants for 10 years. The enrollment criteria and goals of the PEER study have been described in detail elsewhere^10;14;15. Briefly, eligible subjects were ≥ 2 and ≤ 17 years of age at the date of enrollment. Additional inclusion criteria included: a diagnosis of AD by a treating physician; the application of pimecrolimus cream for at least 42 days out of the preceding 180 days prior to enrollment; and informed consent by the subject or caregiver. The diagnosis of AD for each child was made by the enrolling physicians, the majority of whom were pediatricians, allergists, or dermatologists^10;14;15. Enrolling physicians had no other role in this study. The physician’s diagnosis was confirmed based on the subject’s self-report and the UK working party criteria¹⁴. Once enrolled subjects completed an enrollment survey as well as 6-month follow-up surveys via the mail. Missing information was obtained via telephone queries. Children were not required to continue to use pimecrolimus once they were enrolled in PEER and many did not¹⁵. Informed consent was obtained for each of the study participants and our research protocol was approved by the IRB at the University of Pennsylvania.

Outcome

We investigated the self-reported outcome of whether or not a child’s skin, without requiring the use of topical medication (e.g., steroids or calcineurin inhibitors to treat their AD), was AD symptom-free during the previous 6-months¹⁰. This was determined by their response to: “Has the rash cleared completely at any time during the past 6 months? ”. The patient self-described outcome of disease control is a well-validated measure of eczema severity that correlates with Eczema Area and Severity Index (EASI) scores^8;14–18. Since individuals in this study were followed longitudinally and surveyed every six months, this outcome was reported on more than one occasion⁵. A child’s AD was thought to be intermittent (i.e., not persistent) if in addition to having complete disease control they answered no to the treatment use questions. Information about this outcome was collected longitudinally every six months by survey thereby capturing the waxing and waning nature of AD.

Covariates

The initial enrollment questionnaire contained 39 questions. These included information on the age of onset of AD, the age of enrollment into the PEER study, gender, U.S. census categories for race/ethnicity, annual household income, baseline eczema symptoms such as the question noted above, age of disease onset, and pruritic regions of the body, visits to health professionals, questions on history of asthma and wheezing, seasonal allergies, food allergies, other environmental allergies such as to pets, questions on family history of AD and other atopic illnesses. Many of the atopic disease based questions were modeled after the ISAAC (International Study of Asthma and Allergies in Childhood) questionnaire[http://isaac.auckland.ac.nz/]⁶. Follow up questionnaires were sent to enrollees every six months.

Analysis Plan

Data was evaluated using two different epidemiologic designs. First, using a cross-sectional design we evaluated the demographic information and covariates described above from the full PEER population at baseline. For these analyses, means with 95% confidence intervals or standard deviations and medians (as appropriate) were estimated. Statistical comparisons were made using t-test, ANOVA, or chi-square tests as appropriate.

Next we analyzed our dataset as a longitudinal cohort study in order to examine “risk factors” for any given 6-month symptom and treatment-free period. For this analysis statistical comparisons were assessed using random-intercept logistic regression (XTLOGIT) that allowed for repeated measures of our outcome within each child. For these analyses we present unadjusted and adjusted odds ratios with 95% confidence intervals. All analyses were repeated using a variant of a mixed logistic regression model called generalized linear latent and mixed models (gllamm) with nearly identical results (results not reported). The variables used in the adjusted models were selected based on a priori knowledge of their potential association with the persistence of AD and included age at onset, age at enrollment, gender, any family history of atopy, personal history of atopy, and self-report severity at enrollment. We also estimated a Kaplan-Meir plot to graphically depict the proportion of individuals at any given age who ever reported a 6-month symptom and treatment-free period for those who had been enrolled for at least 5 years. Finally, we used this cohort to create prognostic models. For this evaluation, we created an outcome based on whether a child had any symptom-free and medication-free period during their first 2-years or their first 5-years of observation. In this setting, we used logistic regression and assessed our prediction models using the area under the receiver operating curve. All statistical analyses were conducted using Stata software (version 12.1; Stata Corp, College Station, Texas).

Results

At the time of analysis, 7,157 subjects were enrolled in the PEER study. At least 2 years of follow-up was observed for 4,248 and at least 5 years of follow-up was observed for 2,416 children. The mean age at the onset of their AD was 1.73 (95% confidence interval (CI): 1.68, 1.78) years and the average age at enrollment into the PEER study was 7.43 (CI:7.33, 7.53) years. Since their enrollment into PEER a median of 5 (25%:3, 75%:9) surveys at 6-month intervals were completed per subject most often by a parent. With respect to those eligible to respond to a survey, approximately 70% responded to any given query, and 1.9% have withdrawn from the study. With slight variation during the study period of observation, between 85.3 % and 89.6% of children reported that they were seen by a healthcare provider for a well-visit at least once per year. Subjects were followed for 22,550 person-years of observation. As noted in Table 1, 46.9% of the children enrolled in PEER were male, 41.8% were white, and many had other findings of atopic illnesses. Slightly more than half of PEER participants lived in the South Atlantic or the East South Central census regions (Table 1). However, at least one PEER participant resided in 47 of the 48 contiguous states in the US (Figure 1). At the time of enrollment, 14.2%, 20.8%, and 37.5% of the children were directly seeking care for their AD from a Dermatologist, Allergist or Pediatrician, respectively. At enrollment self-reported disease activity in the previous 6-months was complete disease control in 5.2%, good disease control in 48.9%, limited disease control in 36.2%, or uncontrolled disease control in 9.8%. Self-reported disease activity at baseline was associated with more persistent disease (complete disease control: reference (i.e. 1.0), good disease control: 0.52 (0.37, 0.74); limited disease control: 0.29 (0.20, 0.40); or uncontrolled disease: 0.18 (0.12, 0.27)). At enrollment all had used topical medications in the last 6-months: 100% pimecrolimus, 12.5% tacrolimus, and 60.9% topical steroids. By the fifth year of follow-up topical medications used were: 46.3% pimecrolimus; 16.7% tacrolimus; and 52.9% topical steroids (medications could be used in combination during the 6-month period). During 5 years of follow-up 64.0% of subjects never reported a 6-month period when their skin was symptom free while they were not using topical medications and less than 1.5% of the population reported that they had achieved this outcome more than 60% of the time.

Table 1.

Demographic factors and exposures measured at enrollment and results of unadjusted and adjusted models for 6-month medication and symptom-free period

Variable	Total	Frequency	unadjusted	adjusted
Demographic
Gender (female)	7157	53.11 (3,801)	0.72 (0.61,0.84)*	0.72 (0.60, 0.87)ˆ
Race (white)	7157	41.8 (2988)	2.80 (2.39, 3.29)*	2.65 (2.20, 3.20)*
Age at onset (years)	6733	1.73 (1.68, 1.78)	1.12 (1.07,1.16)*	1.21 (1.16, 1.27)*
Income ($ /year) <24,999 25000–49,999 50,000–74,999 75,000–99,999 ≥100,000 Declined to answer	7152	40.9(2926) 14.8 (1061) 7.56 (541) 4.43 (317) 5.43 (388) 26.8 (1919)	Ref 1.52 (1.20, 1.94)ˆ 3.52 (2.66, 4.66)* 3.97 (2.83, 5.57)* 3.97 (2.89, 5.44)* 1.59 (1.28, 1.96)*	Ref 0.84 (0.63, 1.12) 1.57 (1.12, 2.21)ˆ 1.81 (1.22, 2.70)ˆ 1.72 (1.18,2.52)ˆ 1.27 (0.98, 1.65)
Age Enrollment	7,157	Mean=7.43	0.98 (0.96, 1.00)#	0.93 (0.91, 0.96)*
Location  New England  Middle Atlantic  East North Central  West North Central  South Atlantic  East South Central  West South Central  Mountain  Pacific	7,154	1.19 (83) 7.21 (516) 17.21 (1,231) 4.71 (337) 26.48 (1,894) 27.34 (1,955) 11.27 (806) 1.72 (123) 2.87 (205)	Ref 0.75 (0.38, 1.49) 1.03 (0.54, 1.98) 1.15 (0.57, 2.33) 0.51 (0.27,0.98)# 0.45 (0.23,0.85)# 0.43 (0.22,0.85)# 1.01 (0.45, 2.29) 1.27 (0.60, 2.68)	Ref 1.10 (0.49,2.50) 1.59 (0.73, 3.45) 1.28 0(.56, 2.96) 1.22 (0.56, 2.63) 1.21 (0.56, 2.62) 0.72 (0.32, 1.61) 1.19 (0.45, 3.11) 2.11 (0.88, 5.07)
Environmental Exposures
Weather Made Itch Worsen	7,157	61.98 (4,436)	0.98 (0.83, 1.16)	0.82 (0.67, 1.01)
Pollen Made Itch Worsen	7,157	7,157 (2,099)	0.48 (0.40, 0.58)*	0.59 (0.47,0.74)*
Emotion Made Rash Worsen	7,157	12.77 (6,123)	0.45 (0.35, 0.59)*	0.36 (0.27, 0.49)*
Fumes Made Itch Worsen	7,157	3.52 (252)	0.29 (0.17, 0.49)*	0.34 (0.19, 0.63)ˆ
Dust Made Itch Worsen	7,157	19.94 (1,427)	0.39 (0.31,0.49)*	0.45 (0.35, 0.58)*
Pets Made Itch Worsen	7,157	13.97 (1,000)	0.49 (0.38,0.62)*	0.46 (0.34, 0.61)*
Wool Clothing Made Itch Worsen	7,157	12.56 (899)	0.51 (0.39, 0.65)*	0.48 (0.35, 0.65)*
Cold or Flu Made Itch Worsen	7,157	15.38 (1,101)	0.65 (0.52, 0.81)*	0.72 (0.55, 0.93)#
Cigarettes Made Itch Worsen	7,157	2.77 (198)	0.34 (0.20, 0.60)*	0.33 (0.17, 0.61)*
Food Or Drink Made Itch Worsen	7,157	14.92 (1,068)	0.56 (0.44, 0.71)*	0.55 (0.42, 0.73)*
Soaps or Detergents Made Itch Worsen	7,157	50.64 (3,624)	0.59 (0.51, 0.70)*	0.63 (0.52, 0.76)*
Atopic related and allergic illnesses
Child Has Had Wheezing, Asthma, or Whistling in the Chest	7,157	47.27 (3,380)	0.67 (0.57, 0.78)*	0.78 (0.62, 0.99)#
Sneezing and runny or blocked nose without having the flu	7,150	62.32 (4,456)	0.73 (0.62, 0.86)*	0.89 (0.70, 1.12)
Seasonal Allergies	7,137	62.84 (4,485)	0.65 (0.55, 0.77)*	0.81 (0.58, 1.12)
Animal Allergy	7,147	22.02 (1,574)	0.72 (0.60, 0.88)ˆ	0.62 (0.49,0.79)*
Dog Allergy	7,157	14.91 (1,067)	0.67 (0.53,0.84)ˆ	0.60 (0.46,0.79)*
Cat Allergy	7,157	18.00 (1,288)	0.67 (0.54, 0.82)*	0.55 (0.43, 0.71)*
Bird Allergy	7,157	1.63 (117)	0.50 (0.25, 1.02)	0.50 (0.22, 1.13)
Rabbit Allergy	7,157	2.57 (184)	0.76 (0.46, 1.28)	0.64 (0.35, 1.17)
Hamster Allergy	7,157	1.48 (106)	0.62 (0.32, 1.22)	0.60 (0.28, 1.29)
Guinea Pig Allergy	7,157	1.34 (96)	0.71 (0.36, 1.41)	0.72 (0.34, 1.56)*
Allergic to Other Animal	7,157	3.34 (239)	0.41 (0.24,0.70)ˆ	0.48 (0.26, 0.88)#
Food Allergy	7,157	23.52 (1,682)	0.69 (0.57, 0.83)*	0.63 (0.51, 0.79)*
Rice Allergy	7,157	0.82 (59)	0.48 (0.17, 1.38)	0.57 (0.17, 1.87)
Peanut Allergy	7,157	9.98 (714)	0.59 (0.45,0.78)*	0.52 (0.38, 0.71)*
Milk Allergy	7,157	6.02 (431)	0.50 (0.35,0.71)*	0.42 (0.28,0.63)*
Tree Nut Allergy	7,157	4.30 (308)	0.71 (0.48, 1.05)	0.58 (0.37, 0.91)#
Soy Allergy	7,157	3.26 (233)	0.96 (0.62, 1.49)	0.83 (0.51, 1.36)
Fish Allergy	7,157	3.88 (278)	0.47 (0.30, 0.73)ˆ	0.58, (0.35, 0.97)#
Egg Allergy	7,157	7.41 (530)	0.59 (0.43, 0.81)ˆ	0.42 (0.29, 0.61)*
Shellfish Allergy	7,157	4.39 (314)	0.63 (0.42,0.95)#	0.77 (0.49, 1.21)#
Corn Allergy	7,157	1.51 (108)	0.74 (0.38, 1.47)	0.63 (0.29, 1.36)
Wheat Allergy	7,157	2.82 (202)	0.62 (0.38, 1.02)	0.57 (0.32, 0.99)#
Allergic to a Different Food	7,157	9.82 (703)	0.69(0.52, 0.91)	0.71 (0.51, 0.98)#
Medication Allergy	7,152	11.91 (852)	1.27 (1.00, 1.61)#	1.18 (0.90, 1.56)
Family history of atopic illnesses
Child’s Mother has Asthma	7,157	19.58 (1,401)	0.64 (0.52, 0.79)*	0.71 (0.55, 0.90)#
Child’s Father Has Eczema	7,157	12.70 (909)	0.72 (0.57,0.92)#	0.68 (0.51, 0.90)#
Child’s Mother Has Eczema	7,157	22.13 (1,584)	0.72 (0.59,0.87)ˆ	0.77 (0.61, 0.96)#
Child’s Sister/ Brother Have Eczema	7,157	41.12 (2,943)	0.70 (0.59,0.82)*	0.92 (0.76, 1.11)

^*p < 0.0001;

^ˆp ≤ 0.001;

^#p < 0.05

Figure 1.

PEER locations: Zip codes inhabited by at least one PEER enrollee.

We conducted both unadjusted and adjusted (age at onset, gender, race, age at enrollment, and any history of seasonal allergies or asthma) analyses for each question item on the enrollment survey with respect to whether the child achieved the 6-month symptom and medication free outcome longitudinally by survey completed. The questions listed in Table 1 were grouped in categories roughly related to basic demographics, atopic and allergic illnesses/responses, environmental exposures, family atopic illnesses, and disease specific. Many of the variables within a category likely have overlapping pathophysiologies and/or are on the causal pathway with respect to AD symptoms. However, most are associated with a decreased odds of reporting a symptom-free and medication-free state overtime (e.g. more persistence AD) (Table 1). Our adjusted and unadjusted effect estimates were often nearly identical with the exception of income which was primarily confounded by race (or vice versa). A random effects model using location as a marker of center-based effects did not change our estimates.

The large majority of children and young adults still reported symptoms of AD that required the use of medication. But, as a child got older they were more likely to have experienced at least one symptom-free and medication-free period. We depict this graphically in two ways (Figure 2). Based on Kaplan-Meir survival estimate of those with at least 5 years of follow-up, by age 20 about 50% reported at least one six-month symptom and medicine free period (Figure 2a). However at every age more than 80% of PEER subjects had symptoms of AD and/or were using medication to treat their AD (Figure 2b). The odds that a child reported no symptoms of AD while not using medication was increased 30% for every survey answered (1.30 (1.28, 1.31)).

Figure 2.

Persistence of AD by age: A Kaplan-Meir curve demonstrating the proportion of individuals with at least 5-years of follow at a given age who ever reported a 6-month symptom free and medication free period (A) and the proportion of enrollees at a given age who reported no symptoms of AD and medication use in the previous 6-months (B).

Models were created to predict the likelihood that a child would have persistent disease after up to two years and up to 5 years of follow up (Table 3). Table 2 contains complex multivariable prognostic models as well as simple models. For example, a prediction model containing information on age at onset, age at enrollment (e.g., age of the visit), race (white), any associated atopy (food, asthma, and/or seasonal allergy), AD at the time of examination reported to be of limited control or to be uncontrolled, and who lives in a household with an income of greater than $50,000 per year can differentiate between a child with or without persistent during their first 2 years of care (e,g, at least one 6-month period of symptom and topical medication free period) AD 67.3% (AROC=0.673) of the time. A simple count model created based on logistic regression coefficients and several dichotomized variables also had a similar AROC of 0.644. This model is a simple summation of 1 point for household with an income of greater than $50,000 per year, two points if the child reported complete or good disease control at the first meeting, their age at onset of eczema, and a reduction of one point if they had any other atopic illness and a reduction of one-half their age at the visit.

Table 2.

The area under the receiver operator curve (AROC) for prognostic models of the likelihood that an individual will have at least one AD symptom free and medication free 6-month period by the first 2 or 5-years of follow-up for the listed variables as noted at enrollment. The models are listed from the most complex (multiple variable logistic regression requiring an estimate from the regression model) to the simplest (count or additive model based on the actual variable).

Model type	Variables	2 years	5 years
Logistic regression	Gender, White, Age at enrollment, Age at AD onset, Rash noted on ankles at enrollment, Rash worsens in response to emotional outburst, Rash worsens in response to fume, History of seasonal allergy, History of wheezing, Allergy to cats, Allergy to birds, Allergy to eggs, mother with a history of Asthma, Father with a history of eczema, and Family income less than 50,000 per year.	0.6583	0.6640
Logistic regression	Family income less than 50,000 per year, Age at enrollment, Age at AD onset, Child history of any other atopic illness, Child history of skin symptom free at enrollment.	0.6729	0.6442
Count model	Family income less than 50,000 per year +(−0.5* Age at enrollment) + Age at AD onset +(−1* Child history of any other atopic illness) + (2* Child history of skin symptom free at enrollment)	0.6440	N/A
Count model	Family income less than 50,000 per year +(−0.5* Age at enrollment) + (0.5* Age at AD onset) +(−1* Child history of any other atopic illness) + (2* Child history of skin symptom free at enrollment)	N/A	0.6507

Discussion

This study of more than 7000 children is one of the largest prospective longitudinal reports of children with mild to moderate AD. Most the children enrolled in this study developed AD before two years of age. An advantage of this study was regular 6-month measurements of disease activity. Unlike past teaching, the large majority of children enrolled in our study continued to report symptoms and used medications well into the second and even the third decade of life (Figure 2)^2;7;8. In our PEER cohort, during the second decade of life a majority of enrollees were very likely to have had at least one period when their skin was clear while not requiring medications (Figure 2a). However, this finding did not persist and should not be confused with a “permanent” remission in that at most ages the vast majority of enrollees had symptoms and were using medications (Figure 2b). Past teaching that nearly 50 to 70% of children with AD will achieve a resolution by age 12 of their AD was not achieved in our study^2;3;11;19. Interestingly, the persistence of AD symptoms noted in our study is consistent with recent studies that have shown that in the US the yearly prevalence of AD or eczema in childhood and adulthood does not differ dramatically as would be expected if few with childhood AD continue to have AD in adulthood²⁰. It is also important to realize that many previous studies evaluated the time to when a child was first symptom free and these studies were not designed to re-evaluate subjects longitudinally^4;5;9;21;22. In contrast we have many years of follow-up concerning both symptoms and the use of topical medications.

Further nearly every environmental exposure we queried at enrollment as well as history of other atopic illnesses, race, and income less than $50,000 were associated with more persistent AD. This was also noted with respect to household pet allergies and allergies to common foods. Many of these exposures were also described by Langan et al and by others as factors that were associated with flares of AD^9;23;24. The difference between the outcome used by Langan et al and the one used by us may be semantic or in the extreme the outcome measured by Langan et al was included within the outcome we measured⁹. Even if our outcomes were different the Langan et al study and ours both measured longitudinal outcomes related to disease activity. However, it is important to note that our study as well as Langan et al did not evaluate factors that cause incident AD⁹. Factors that cause the onset of a disease and either contribute to its persistence or exacerbation are not always the same. This is an important difference because many previous reports on factors that “cause” AD do not consistently attribute all of the factors that Langan et al or we report to causation^5;25.

A recent study by Ballardini et al evaluated a birth cohort in Sweden at ages 1, 2, 4, 8 and 12 for allergy-related disease¹⁹. As part of this study they determined the yearly prevalence of eczema at these 5 time points. Childhood eczema prevalence was between 15 and 20% with the maximum prevalence occurring at age 4 years and the minimum prevalence at age 12 years. They also measured “remissions” or periods where a previously active child noted no AD activity in the preceding year. Remissions occurred in 5 and 15% of the active population at a given time point¹⁹. The overall change in AD prevalence between age 4 and age 12 in the Ballardini et al study was a 25% decrease and in ours was decreased by approximately 15%. Another birth cohort study of close to 1200 initially healthy children from the Isle of Wright evaluated the presence of eczema as defined by an itchy rash in the previous year also showed little variation in the prevalence of eczema in those 1, 4, 10, and 18 years of age²⁶. Although very few from the subcohort of 160 children that had eczema at inception had persistence eczema as defined by the presence of disease at all time-points²⁶.

There are several potential explanations for our findings. It could be possible that PEER subjects have more severe disease and therefore have more persistent AD. It might also be possible that many previous studies lacked sufficiently long follow-up to measure disease persistence and ultimately followed too few with eczema to precisely estimate persistence. Perhaps, individuals with AD since childhood are not bothered sufficiently to continue to seek care by adolescence or young adulthood, thereby making it appear to healthcare providers and that a young patient’s AD had resolved. It is also possible that healthcare providers focus more on the other atopic illnesses like asthma and allergic rhinitis then the concomitant skin disease. However, our report of the lack of resolution of AD lends support to recent findings that demonstrate genetic associations with AD and filaggrin loss of function mutations²⁷. About 16.2% of a subset of PEER have these mutations and they do have more persistent AD¹⁰. These mutations result in the inability of an individual to make FLG protein resulting in skin barrier dysfunction²⁷. Since these are germline mutations, the ability to produce FLG does not improve with age. Finally a recent study by Silverberg and Hanifin on the prevalence of eczema in US adults revealed that the yearly prevalence is about 10% which when compared to the childhood prevalence rates of about 10 to 15% would seem to argue that childhood AD often persists into adulthood^19;20;28.

We also created prognostic models. Our models had AROC of about 60–65% indicating that the prognostic ability of these models was fair to good. The prognostic models could be very helpful in two settings. First, when planning clinical trials, if the goal is to treat children with more persistent AD the models can be used to define who is more likely to have more persistent disease and thereby will modestly improve the likelihood that more persistent subjects will be enrolled. The second setting is during the initial visit between the physician and child/family. Often parents inquire about how long their child will have symptoms of AD. Here the models can be helpful in informing the parents that their child will likely have more persistent symptoms of AD.

As with all epidemiologic studies, there are limitations to this report. It is possible that our results do not generalize to all children with AD. Individuals enrolled in the PEER cohort had mild to moderate AD at the time of enrollment that required the use of topical medications (specifically received pimecrolimus) and may have had more severe at baseline than those seen in general practice. We were not able to capture incident disease and have only self-reported data on the time of onset. We do not know about disease persistence prior to enrollment; although we do know that the children had “persistent” disease at the start of the study and if they had it during the study. We do not know why local providers decided to use pimecrolimus or stop using pimecrolimus or any other topical medication; although we know that medications were used thereby making the disease “persistent”. It is also possible that our definition of persistent disease is different from what is used clinically to clinical determination that AD is in remission. It may be possible that those who answered surveys had more persistent disease or were more likely to report their disease as being persistent. However, our definition is based on self-reported eczema severity and is likely a useful measure for following disease activity over time. It might be possible that children in our study were not adequately treated. However, this is highly unlikely in that many were initially enrolled from specialists’ offices (allergists and dermatologist), all on enrollment were receiving topical therapies, the vast majority had at least yearly follow-up with a pediatrician, and the definition of persistent disease included the use of a topical agent. We do not know if their treatment had an effect on AD persistence. Finally, our prognostic models are based on the PEER cohort and, like all prognostic models, need to be validated in other cohorts. However, it is important to remember that this is one of the largest longitudinal studies of children with diagnosed AD and children were enrolled from nearly every US state.

In conclusion, symptoms associated with AD appear to persist well into the second decade of a child’s life and likely longer. As previously reported, we reported that many factors are associated with more persistent disease. While some of these factors may not be associated with the onset of AD, there is at least a belief by PEER subjects that they make their symptoms worse. It is important to realize that these statements may not be mutually exclusive. Because of the broad geographic distribution of children enrolled in the PEER study and because they were enrolled from several different health care providers’ offices, it is likely that these results generalize to children with mild to moderate AD. Based on our findings it is likely that AD does not fully resolve in the majority of children with mild to moderate symptoms. Physicians who treat children with mild to moderate AD should tell children and their caregivers that AD is a life-long illness with periods of waxing and waning skin problems.