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Atopic dermatitis disease control and age: A cohort study

2015; Elsevier BV; Volume: 136; Issue: 1 Linguagem: Inglês

10.1016/j.jaci.2015.03.028

1097-6825

Katrina Abuabara, Ole Hoffstad, Andrea B. Troxel, Joel M. Gelfand, David J. Margolis,

Asthma and respiratory diseases

We report the results of an observational cohort study examining atopic dermatitis (AD) disease control by age. AD is the most common chronic inflammatory skin disease and is characterized by an episodic course. Conventionally thought to remit by adolescence, increasing data suggest heterogeneity in disease courses, though detailed prospective studies are lacking.1Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine.Allergy. 2012; 67: 1475-1482Crossref PubMed Scopus (89) Google Scholar To examine AD disease control by age, we used longitudinal data from the Pediatric Eczema Elective Registry. It is a cohort study designed to test whether there is an increased risk of malignancy associated with the use of pimecrolimus, and includes a patient-reported measure of disease control every 6 months.2Kapoor R. Hoffstad O. Bilker W. Margolis D.J. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis.Pediatr Dermatol. 2009; 26: 682-687Crossref PubMed Scopus (5) Google Scholar, 3Margolis J.S. Abuabara K. Bilker W. Hoffstad O. Margolis D.J. Persistence of mild to moderate atopic dermatitis.JAMA Dermatol. 2014; 150: 593-600Crossref PubMed Scopus (198) Google Scholar To enroll, patients must have AD diagnosed by a physician and used 1% topical pimecrolimus cream for at least 42 of the last 180 days. Our primary outcome, disease control, is a repeating composite variable based on self-reported control (complete, good, limited, or poor) and treatment use (any prescription treatments for AD over the same 6-month period). Those who reported complete control were subcategorized into 2 groups: complete control without treatment (ie, apparent remission) and complete control with treatment. We examined the data graphically. Then, to account for the longitudinal nature of our data and repeated outcome, we created a separate binary generalized linear latent and mixed model for each level of disease control. This enabled us to calculate the subject-specific odds of better or worse control for each additional year of age while controlling for potential confounders specified a priori including age at onset, enrollment age, sex, race, family income, and history of atopic disease at enrollment. The number of subjects with at least 1 follow-up visit by October 2013 determined the sample size. For additional methodological details, see the Methods section in this article's Online Repository at www.jacionline.org. This study was approved by the institutional review board at the University of Pennsylvania. There were 5,798 participants aged 2 to 26 years who returned 49,840 surveys. A total of 47% were males, 44% were white, the mean age of enrolment was 7.2 years, and the mean duration of follow-up was 4.2 years (for additional cohort characteristics, see Table E1 in this article's Online Repository at www.jacionline.org). Complete control without treatment was reported on 8% of all surveys, whereas good or limited disease control was reported 80% of the time. The largest change with age occurred among the complete control with no treatment group (Fig 1). With multivariate models, we found an elevated subject-specific odds of complete control for each additional year of age and a reduced subject-specific odds of limited or poor control for each additional year of age (Table I). When we split those who reported complete control into treatment groups, we found that the subject-specific odds of complete control without treatment for each additional year of age compared with good, limited, or poor control were 1.78 (95% CI, 1.72-1.83; see Table I). This outcome was infrequent, however. Only 3967 (8% of all surveys), and 1205 (21% of all patients), ever reported a 6-month period of complete control without treatment. Of these patients, 546 (45%) subsequently reported medication use or less than complete control, suggesting that a minority of patients "outgrew" their disease while being followed in the Pediatric Eczema Elective Registry cohort.Table IResults of binomial logistic generalized linear latent and mixed model regression models for the subject-specific odds of each level of disease control for each additional year of ageDisease control levelNo. of surveys (% of total)Subject-specific odds of disease control level for each additional year of age∗Models adjusted for enrollment age, age of onset, sex, race, family income at enrollment, and history of atopic disease. In all models, age at onset, male sex, income more than US $50,000, and white race were positively associated with periods of complete control without treatment, and age at enrollment and atopic history were negatively associated with periods of complete control without treatment.Complete7,022 (14%)1.37 (1.34-1.39)†Compared with those with good, limited, or poor control. No treatment/apparent remission3,967 (8%)1.78 (1.72-1.83)†Compared with those with good, limited, or poor control. With treatment3,055 (6%)1.07 (1.05-1.10)†Compared with those with good, limited, or poor control.Good25,521 (51%)1.13 (1.11-1.14)‡Compared with those with limited or poor control.Limited14,588 (29%)0.87 (0.6-0.88)§Compared with those with complete or good control.Poor2,709 (5%)0.85 (0.83-0.88)Compared with those with complete, good, or limited control. Results were robust to sensitivity analyses examining the impact of duration of follow-up, loss to follow-up, enrollment before the Food and Drug Administration's Black Box Warning in January 2006 regarding the potential cancer risk with pimecrolimus, and identity of the individual filling out the survey (ie, patient or parent).Not reported104 (0%)NANA, Not applicable.∗ Models adjusted for enrollment age, age of onset, sex, race, family income at enrollment, and history of atopic disease. In all models, age at onset, male sex, income more than US $50,000, and white race were positively associated with periods of complete control without treatment, and age at enrollment and atopic history were negatively associated with periods of complete control without treatment.† Compared with those with good, limited, or poor control.‡ Compared with those with limited or poor control.§ Compared with those with complete or good control.|| Compared with those with complete, good, or limited control. Results were robust to sensitivity analyses examining the impact of duration of follow-up, loss to follow-up, enrollment before the Food and Drug Administration's Black Box Warning in January 2006 regarding the potential cancer risk with pimecrolimus, and identity of the individual filling out the survey (ie, patient or parent). Open table in a new tab NA, Not applicable. In a secondary analysis, we also tested whether the subject-specific odds of a dermatologist visit during each 6-month period of follow-up changed with age. Regardless of the level of disease control, the odds of seeing a dermatologist declined for all patients as they aged (see Table E2 in this article's Online Repository at www.jacionline.org). Our findings add to the sparse literature on AD disease control over time and imply that most patients in this cohort had active disease at all ages. In addition, we found that the decline in the odds of a dermatologist visit was similar whether a subject reported complete control or poor control, suggesting that all patients tend to see their providers less as they get older possibly because they learn to manage their disease on their own or are simply less likely to visit a physician. This finding could help explain why some dermatologists may perceive that AD tends to resolve as children age. This is one of the largest longitudinal studies of AD with good representation of minority groups, data on treatment use, and repeated measures of disease control every 6 months. Because of the enrollment criteria, the results are most generalizable to patients who have used pimecrolimus for at least 6 weeks. The criteria may have selected patients with more severe or persistent disease, though the American Academy of Dermatology recommends topical pimecrolimus on the basis of the highest level of evidence,4Hanifin J.M. Cooper K.D. Ho V.C. Kang S. Krafchik B.R. Margolis D.J. et al.Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association "Administrative Regulations for Evidence-Based Clinical Practice Guidelines".J Am Acad Dermatol. 2004; 50: 391-404Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar and data suggest that it is not typically used as a second-line treatment.5Manthripragada A.D. Pinheiro S.P. MaCurdy T.E. Saneinejad S. Worrall C.M. Kelman J.A. et al.Off-label topical calcineurin inhibitor use in children.Pediatrics. 2013; 132: e1327-e1332Crossref PubMed Scopus (11) Google Scholar After enrollment, subjects were not required to continue to use pimecrolimus, and in fact most stopped.2Kapoor R. Hoffstad O. Bilker W. Margolis D.J. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis.Pediatr Dermatol. 2009; 26: 682-687Crossref PubMed Scopus (5) Google Scholar It is possible that the use of pimecrolimus reflects more about the prescribing tendencies of providers than the patient's disease characteristics. Our findings suggest heterogeneity in AD disease trajectories. We found that age is predictive of disease control, independent of sex, race, income, history of atopic disease, age at onset, and age at enrollment. Examination of the interaction between age and each of these factors is the focus of ongoing work. Along with increasing data about the role of immune and epidermal barrier dysfunction in patients with AD,6Leung D.Y. Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches.J Allergy Clin Immunol. 2014; 134: 769-779Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, 7Abuabara K. Margolis D.J. Do children really outgrow their eczema, or is there more than one eczema?.J Allergy Clin Immunol. 2013; 132: 1139-1140Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar our results argue for a shift in the general characterization from predominantly a childhood disease to a heterogeneous chronic disease with intermittent periods of disease activity. We performed an observational cohort study with data from the Pediatric Eczema Elective Registry, which is an ongoing prospective registry that began enrollment in 2004 and aims to follow 7000 subjects over 10 years. Inclusion criteria include AD diagnosis by a physician on the basis of the UK Working Party Criteria,E1Williams H.C. Burney P.G. Hay R.J. Archer C.B. Shipley M.J. Hunter J.J. et al.The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis, I: derivation of a minimum set of discriminators for atopic dermatitis.Br J Dermatol. 1994; 131: 383-396Crossref PubMed Scopus (848) Google Scholar ages 2 to 17 years at the time of enrollment, and use of 1% topical pimecrolimus cream for at least 42 of the 180 days before enrollment. There was no objective disease severity requirement, but the study was advertised for patients with mild-to-moderate disease because pimecrolimus was originally approved by the Food and Drug Administration for this indication. Subjects were excluded from enrollment into the cohort if they had a history of lymphoproliferative disease, systemic malignancy, or skin malignancy, or had used oral immunosuppressive medications such as cyclosporine, tacrolimus, or methotrexate. Subjects filled out an initial enrollment questionnaire and were followed longitudinally with repeat questionnaires every 6 months. Importantly, data collection was completely independent of physician visits and medication decisions after enrollment; subjects were not expected to continue to see the enrolling provider or to continue treatment with pimecrolimus if other medications were determined to be more appropriate for their condition. Written informed consent was obtained for each of the study participants, and the research protocol was approved by the institutional review board at the University of Pennsylvania. The primary outcome measure, disease control, was based on treatment use and the following question: "During the last 6 months, would you say you or your child's skin has shown complete disease control, good disease control, limited disease control, or uncontrolled disease?" This question was chosen because it is easily interpretable, patient-centered, and comprehensive. It has been used in randomized controlled trials and has been shown to correlate with a well-validated objective eczema severity measure, the Eczema Area and Severity Index (Spearman correlation coefficient at 6 months, 0.794).E2Eichenfield L.F. Lucky A.W. Boguniewicz M. Langley R.G. Cherill R. Marshall K. et al.Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents.J Am Acad Dermatol. 2002; 46: 495-504Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, E3Kapoor R. Hoffstad O. Bilker W. Margolis D.J. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis.Pediatr Dermatol. 2009; 26: 682-687Crossref PubMed Scopus (20) Google Scholar, E4Schmitt J. Langan S. Deckert S. Svensson A. von Kobyletzki L. Thomas K. et al.Assessment of clinical signs of atopic dermatitis: a systematic review and recommendation.J Allergy Clin Immunol. 2013; 132: 1337-1347Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, E5Vissing N.H. Jensen S.M. Bisgaard H. Validity of information on atopic disease and other illness in young children reported by parents in a prospective birth cohort study.BMC Med Res Methodol. 2012; 12: 160Crossref PubMed Scopus (34) Google Scholar, E6Kapp A. Papp K. Bingham A. Folster-Holst R. Ortonne J.P. Potter P.C. et al.Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug.J Allergy Clin Immunol. 2002; 110: 277-284Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Subjects were also asked about the use of any prescription creams or ointments for AD, and about the number of visits made to a health professional (nurse, family doctor, pediatrician, dermatologist, hospital emergency department, and other health care provider) for AD over the last 6 months. The medication data were used to subcategorize those with self-described complete control into 2 groups: those with apparent remission (ie, complete control without using any medications for AD over the last 6 months) and those with complete control who were using medications. Duration of follow-up was calculated from the date of enrollment and the last available survey date. Lost to follow-up was defined as no surveys returned in the preceding 18 months. Personal history of atopy was defined as a personal history of asthma or seasonal allergies if aged 4 years or more, or a family history of asthma or seasonal allergies or eczema in a parent or sibling if younger than 4 years.E7Williams H.C. Clinical practice: atopic dermatitis.N Engl J Med. 2005; 352: 2314-2324Crossref PubMed Scopus (442) Google Scholar Baseline characteristics of the cohort were summarized descriptively. The proportion of all responses with each level of disease control are presented in table format. It is important to note that these analyses do not account for repeated measures within subject (ie, a subject may have returned more than 1 survey within each age group). The proportion of responses with each level of disease control by age is also presented graphically using kernel-weighted local polynomial smoothed graphs with 95% confidence bands.E8Fan J. Design-adaptive nonparametric regression.J Am Stat Assoc. 1992; 87: 998-1004Crossref Scopus (745) Google Scholar To account for repeated disease control measurements, we created a separate generalized linear latent and mixed model (GLLAMM) with binomial logistic links for each level of disease control. We included random slopes and intercepts to account for individual heterogeneity in disease trajectories, and time was modeled as a linear term for age.E9Rabe-Hesketh S. Skrondal A. Multilevel and longitudinal modeling using Stata. STATA Press, College Station (TX)2012Google Scholar Adjusted odds ratios were calculated using multivariable models controlling for potential confounders specified a priori including age at onset, enrollment age, sex, race, family income, and history of atopic disease at enrollment. Finally, in an exploratory secondary analysis, GLLAMM models were used to assess the subject-specific odds of dermatologist visits by age, and potential effect modification by level of disease control and age was addressed by including a multiplicative interaction term. We reported missing data where applicable, and checked the missing at random assumption in sensitivity analyses. Stata version 12.1 (StataCorp, College Station, Tex) was used for all data analyses.Table E1Characteristics of the study population (N = 5798)CharacteristicValueAge of onset (y), mean ± SD2.2 ± 3.0Age at enrollment (y), mean ± SD7.2 ± 4.1Median number of surveys (IQR)8 (2-16)Sex: male, n (%)2709 (47)History of atopic disease, n (%)∗Personal history of atopy was defined as a personal history of asthma or seasonal allergies if aged 4 years or more, or a family history of asthma or seasonal allergies or eczema in a parent or sibling if younger than 4 years.4365 (75)Race, n (%)†Numbers sum to >100% because respondents could select more than 1 racial category. White2523 (44) Hispanic or Latino541 (9) African American2919 (50) American Indian or Alaskan Native73 (1) Asian231 (4) Hawaiian or other Pacific Islander21 (0)Income (in thousands of US $), n (%) 100361 (6) Prefer not to answer1498 (26)Duration of follow-up (y), mean ± SD4.2 ± 2.6Lost to follow-up, n (%)‡Drop out, or loss to follow-up, was defined as no surveys returned in the preceding 18 months.1544 (27)IQR, Interquartile range.∗ Personal history of atopy was defined as a personal history of asthma or seasonal allergies if aged 4 years or more, or a family history of asthma or seasonal allergies or eczema in a parent or sibling if younger than 4 years.† Numbers sum to >100% because respondents could select more than 1 racial category.‡ Drop out, or loss to follow-up, was defined as no surveys returned in the preceding 18 months. Open table in a new tab Table E2Results of binomial logistic generalized linear latent and mixed model regression model for subject-specific odds of a dermatologist visit over a 6-month periodVariable in modelDermatologist visit, Odds ratio (95% CI)∗Model adjusted for age of onset, enrollment age, sex, race, family income, and history of atopic disease at enrollment.Age at visit0.84 (0.81-0.87)Complete control with treatment†Odds relative to complete control without treatment.6.84 (4.45-10.5)Good control†Odds relative to complete control without treatment.12.33 (7.83-19.43)Limited control†Odds relative to complete control without treatment.23.55 (13.70-40.48)Poor control†Odds relative to complete control without treatment.42.15 (22.13-80.27)Interaction term for age and level of disease control1.00 (0.99-1.02)∗ Model adjusted for age of onset, enrollment age, sex, race, family income, and history of atopic disease at enrollment.† Odds relative to complete control without treatment. Open table in a new tab IQR, Interquartile range.