Letter to the Editor Atopic dermatitis disease control and age: A cohort study To the Editor: 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.1 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.2,3 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 subjectspecific 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),
FIG 1. Proportion of surveys with each level of disease control by year of age. The x-axis represents the proportion of surveys reporting the specified level of disease control at each age; the y-axis represents age in years. Proportion of surveys with each level of disease control by year of age displayed as Epanechnikov kernel-weighted local polynomial smoothed plots with 95% CIs.
1
2 LETTER TO THE EDITOR
J ALLERGY CLIN IMMUNOL nnn 2015
TABLE I. Results 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 age Disease control level
Complete No treatment/apparent remission With treatment Good Limited Poor Not reported
No. of surveys (% of total)
7,022 3,967 3,055 25,521 14,588 2,709 104
Subject-specific odds of disease control level for each additional year of age*
(14%) (8%) (6%) (51%) (29%) (5%) (0%)
1.37 1.78 1.07 1.13 0.87 0.85
(1.34-1.39) (1.72-1.83) (1.05-1.10) (1.11-1.14)à (0.6-0.88)§ (0.83-0.88)jj NA
NA, 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. àCompared with those with limited or poor control. §Compared with those with complete or good control. jjCompared 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).
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. In a secondary analysis, we also tested whether the subjectspecific 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,4 and data suggest that it is not typically used as a second-line treatment.5 After enrollment, subjects were not required to continue to use pimecrolimus, and in fact most stopped.2 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,6,7 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. Katrina Abuabara, MD, MAa Ole Hoffstad, MSb Andrea Troxel, ScDb Joel M. Gelfand, MD, MSCEa,b David J. Margolis, MD, PhDa,b From the Departments of aDermatology and bBiostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pa. E-mail: [email protected]. This work was supported by the Dermatology Foundation (grant no. T32-AR-0007465-3 to K.A., grant no. K24-AR064310 to J.M.G., and grant no. AR056755 to D.J.M.). The Pediatric Eczema Elective Registry study was funded by Valeant Pharmaceuticals International through a grant to the Trustees of the University of Pennsylvania and D.J.M. Disclosure of potential conflict of interest: K. Abuabara has been supported by a Dermatology Foundation Investigator Fellowship. J. M. Gelfand has received research support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24 AR064310) and Regeneron and has received payment for the development of educational presentations from Bracket. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012;67:1475-82. 2. Kapoor R, Hoffstad O, Bilker W, Margolis DJ. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis. Pediatr Dermatol 2009;26:682-7. 3. Margolis JS, Abuabara K, Bilker W, Hoffstad O, Margolis DJ. Persistence of mild to moderate atopic dermatitis. JAMA Dermatol 2014;150:593-600. 4. Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, 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;50:391-404. 5. Manthripragada AD, Pinheiro SP, MaCurdy TE, Saneinejad S, Worrall CM, Kelman JA, et al. Off-label topical calcineurin inhibitor use in children. Pediatrics 2013;132: e1327-32. 6. Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol 2014;134:769-79. 7. Abuabara K, Margolis DJ. Do children really outgrow their eczema, or is there more than one eczema? J Allergy Clin Immunol 2013;132:1139-40. http://dx.doi.org/10.1016/j.jaci.2015.03.028
J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn
METHODS 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,E1 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).E2-E6 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.E7 Baseline characteristics of the cohort were summarized descriptively. The proportion of all responses with each level of disease control are presented in
LETTER TO THE EDITOR 2.e1
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.E8 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.E9 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.
REFERENCES E1. Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ, Hunter JJ, 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: 383-96. E2. Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, 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;46:495-504. E3. Kapoor R, Hoffstad O, Bilker W, Margolis DJ. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis. Pediatr Dermatol 2009;26:682-7. E4. Schmitt 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;132:1337-47. E5. Vissing NH, Jensen SM, 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;12:160. E6. Kapp A, Papp K, Bingham A, Folster-Holst R, Ortonne JP, Potter PC, et al. Longterm management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002;110:277-84. E7. Williams HC. Clinical practice: atopic dermatitis. N Engl J Med 2005;352: 2314-24. E8. Fan J. Design-adaptive nonparametric regression. J Am Stat Assoc 1992;87: 998-1004. E9. Rabe-Hesketh S, Skrondal A. Multilevel and longitudinal modeling using Stata. College Station (TX): STATA Press; 2012.
2.e2 LETTER TO THE EDITOR
J ALLERGY CLIN IMMUNOL nnn 2015
TABLE E1. Characteristics of the study population (N 5 5798) Characteristic
Age of onset (y), mean 6 SD Age at enrollment (y), mean 6 SD Median number of surveys (IQR) Sex: male, n (%) History of atopic disease, n (%)* Race, n (%) White Hispanic or Latino African American American Indian or Alaskan Native Asian Hawaiian or other Pacific Islander Income (in thousands of US $), n (%) 100 Prefer not to answer Duration of follow-up (y), mean 6 SD Lost to follow-up, n (%)à
Value
2.2 6 3.0 7.2 6 4.1 8 (2-16) 2709 (47) 4365 (75) 2523 541 2919 73 231 21
(44) (9) (50) (1) (4) (0)
2240 (39) 900 (16) 501 (9) 294 (5) 361 (6) 1498 (26) 4.2 6 2.6 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. àDrop out, or loss to follow-up, was defined as no surveys returned in the preceding 18 months.
LETTER TO THE EDITOR 2.e3
J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn
TABLE E2. Results of binomial logistic generalized linear latent and mixed model regression model for subject-specific odds of a dermatologist visit over a 6-month period Variable in model
Age at visit Complete control with treatment Good control Limited control Poor control Interaction term for age and level of disease control
Dermatologist visit, Odds ratio (95% CI)*
0.84 6.84 12.33 23.55 42.15 1.00
(0.81-0.87) (4.45-10.5) (7.83-19.43) (13.70-40.48) (22.13-80.27) (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.
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 subjectspecific 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),
FIG 1. Proportion of surveys with each level of disease control by year of age. The x-axis represents the proportion of surveys reporting the specified level of disease control at each age; the y-axis represents age in years. Proportion of surveys with each level of disease control by year of age displayed as Epanechnikov kernel-weighted local polynomial smoothed plots with 95% CIs.
1
2 LETTER TO THE EDITOR
J ALLERGY CLIN IMMUNOL nnn 2015
TABLE I. Results 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 age Disease control level
Complete No treatment/apparent remission With treatment Good Limited Poor Not reported
No. of surveys (% of total)
7,022 3,967 3,055 25,521 14,588 2,709 104
Subject-specific odds of disease control level for each additional year of age*
(14%) (8%) (6%) (51%) (29%) (5%) (0%)
1.37 1.78 1.07 1.13 0.87 0.85
(1.34-1.39) (1.72-1.83) (1.05-1.10) (1.11-1.14)à (0.6-0.88)§ (0.83-0.88)jj NA
NA, 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. àCompared with those with limited or poor control. §Compared with those with complete or good control. jjCompared 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).
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. In a secondary analysis, we also tested whether the subjectspecific 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,4 and data suggest that it is not typically used as a second-line treatment.5 After enrollment, subjects were not required to continue to use pimecrolimus, and in fact most stopped.2 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,6,7 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. Katrina Abuabara, MD, MAa Ole Hoffstad, MSb Andrea Troxel, ScDb Joel M. Gelfand, MD, MSCEa,b David J. Margolis, MD, PhDa,b From the Departments of aDermatology and bBiostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pa. E-mail: [email protected]. This work was supported by the Dermatology Foundation (grant no. T32-AR-0007465-3 to K.A., grant no. K24-AR064310 to J.M.G., and grant no. AR056755 to D.J.M.). The Pediatric Eczema Elective Registry study was funded by Valeant Pharmaceuticals International through a grant to the Trustees of the University of Pennsylvania and D.J.M. Disclosure of potential conflict of interest: K. Abuabara has been supported by a Dermatology Foundation Investigator Fellowship. J. M. Gelfand has received research support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24 AR064310) and Regeneron and has received payment for the development of educational presentations from Bracket. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Bieber T. Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. Allergy 2012;67:1475-82. 2. Kapoor R, Hoffstad O, Bilker W, Margolis DJ. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis. Pediatr Dermatol 2009;26:682-7. 3. Margolis JS, Abuabara K, Bilker W, Hoffstad O, Margolis DJ. Persistence of mild to moderate atopic dermatitis. JAMA Dermatol 2014;150:593-600. 4. Hanifin JM, Cooper KD, Ho VC, Kang S, Krafchik BR, Margolis DJ, 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;50:391-404. 5. Manthripragada AD, Pinheiro SP, MaCurdy TE, Saneinejad S, Worrall CM, Kelman JA, et al. Off-label topical calcineurin inhibitor use in children. Pediatrics 2013;132: e1327-32. 6. Leung DY, Guttman-Yassky E. Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches. J Allergy Clin Immunol 2014;134:769-79. 7. Abuabara K, Margolis DJ. Do children really outgrow their eczema, or is there more than one eczema? J Allergy Clin Immunol 2013;132:1139-40. http://dx.doi.org/10.1016/j.jaci.2015.03.028
J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn
METHODS 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,E1 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).E2-E6 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.E7 Baseline characteristics of the cohort were summarized descriptively. The proportion of all responses with each level of disease control are presented in
LETTER TO THE EDITOR 2.e1
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.E8 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.E9 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.
REFERENCES E1. Williams HC, Burney PG, Hay RJ, Archer CB, Shipley MJ, Hunter JJ, 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: 383-96. E2. Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, 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;46:495-504. E3. Kapoor R, Hoffstad O, Bilker W, Margolis DJ. The frequency and intensity of topical pimecrolimus treatment in children with physician-confirmed mild to moderate atopic dermatitis. Pediatr Dermatol 2009;26:682-7. E4. Schmitt 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;132:1337-47. E5. Vissing NH, Jensen SM, 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;12:160. E6. Kapp A, Papp K, Bingham A, Folster-Holst R, Ortonne JP, Potter PC, et al. Longterm management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002;110:277-84. E7. Williams HC. Clinical practice: atopic dermatitis. N Engl J Med 2005;352: 2314-24. E8. Fan J. Design-adaptive nonparametric regression. J Am Stat Assoc 1992;87: 998-1004. E9. Rabe-Hesketh S, Skrondal A. Multilevel and longitudinal modeling using Stata. College Station (TX): STATA Press; 2012.
2.e2 LETTER TO THE EDITOR
J ALLERGY CLIN IMMUNOL nnn 2015
TABLE E1. Characteristics of the study population (N 5 5798) Characteristic
Age of onset (y), mean 6 SD Age at enrollment (y), mean 6 SD Median number of surveys (IQR) Sex: male, n (%) History of atopic disease, n (%)* Race, n (%) White Hispanic or Latino African American American Indian or Alaskan Native Asian Hawaiian or other Pacific Islander Income (in thousands of US $), n (%) 100 Prefer not to answer Duration of follow-up (y), mean 6 SD Lost to follow-up, n (%)à
Value
2.2 6 3.0 7.2 6 4.1 8 (2-16) 2709 (47) 4365 (75) 2523 541 2919 73 231 21
(44) (9) (50) (1) (4) (0)
2240 (39) 900 (16) 501 (9) 294 (5) 361 (6) 1498 (26) 4.2 6 2.6 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. àDrop out, or loss to follow-up, was defined as no surveys returned in the preceding 18 months.
LETTER TO THE EDITOR 2.e3
J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn
TABLE E2. Results of binomial logistic generalized linear latent and mixed model regression model for subject-specific odds of a dermatologist visit over a 6-month period Variable in model
Age at visit Complete control with treatment Good control Limited control Poor control Interaction term for age and level of disease control
Dermatologist visit, Odds ratio (95% CI)*
0.84 6.84 12.33 23.55 42.15 1.00
(0.81-0.87) (4.45-10.5) (7.83-19.43) (13.70-40.48) (22.13-80.27) (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.
