Atopic dermatitis, cognitive function and psychiatric comorbidities across early childhood and adolescence in a population-based UK birth cohort.

BACKGROUND: Atopic dermatitis (AD) may affect cognitive function, but studies are limited and inconsistent. The effect of AD severity on cognition remains underexplored and few previous studies have examined clinically validated or repeated measures of cognition throughout childhood. OBJECTIVES: To evaluate the relationship of AD activity and severity with validated measures of general cognition in a longitudinal birth cohort. METHODS: We conducted cross-sectional analyses using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK cohort of 14 975 individuals followed prospectively since their birth in 1991-92. AD was assessed 11 times between the age of 6 and 166 months. Mothers were asked if their child had an 'itchy, dry skin rash in the joints and creases', and AD status was time-updated accordingly as 'never', 'maybe', 'inactive', 'active/mild' or 'active/moderate-severe'. General cognition [i.e. intelligence quotient (IQ)] was measured at 18, 49, 103 and 186 months of age using the Griffiths Mental Development Scales (GMDS), Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Wechsler Intelligence Scale for Children (WISC) and Wechsler Abbreviated Scale of Intelligence (WASI), respectively. Multivariable linear regression was used to compare IQ with respect to nearest time-updated AD status. Secondary analyses were stratified by the presence or absence of psychiatric or learning disorders. An exploratory longitudinal analysis of IQ across all four outcome assessments was conducted using generalized estimating equations. RESULTS: No significant associations between AD status and full-scale IQ scores on the GMDS, WPPSI, WISC and WASI were observed after adjustment for sociodemographic factors, atopic comorbidities and sleep characteristics. However, at 8 years of age, WISC Performance IQ was slightly, although statistically significantly, lower among children with active/moderate-severe AD [ß coefficient -2.16, 95% confidence interval (CI) -4.12 to -0.19] and Verbal IQ was slightly, but statistically significantly, higher among those with inactive AD (ß coefficient 1.31, 95% CI 0.28-2.34) compared with those without AD. Analyses stratified by psychiatric or learning disorders, and exploratory longitudinal analyses of cognition revealed similar findings. CONCLUSIONS: We did not find any clinically meaningful associations between AD activity and severity and general cognitive function during early childhood and adolescence. Future studies should incorporate objective measures of AD severity and investigate outcomes beyond IQ.

Neuropsychiatric disorders in adults with atopic dermatitis: A population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) may be associated with an increased burden of neuropsychiatric outcomes such as anxiety and depression, but longitudinal data on the impact of AD severity is lacking, and a comprehensive assessment of neuropsychiatric disease in adults with AD is needed. OBJECTIVES: Determine risk of incident neuropsychiatric disease among adults with AD by severity. METHODS: A cohort study using electronic health records data from UK general practices from 1994 to 2015. Adults (≥18 years) with AD were matched on age, practice and index date to patients without AD. AD severity was categorized using treatments and dermatology referrals. Outcomes were incident anxiety, depression, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), autism, obsessive-compulsive disorder (OCD), suicidality and completed suicide. RESULTS: Comparing 625,083 adults with AD to 2,678,888 adults without AD, AD was associated with higher risk of anxiety [HR 1.14 (1.13-1.15)], depression [1.14 (1.13-1.15)] and OCD [1.48 (1.38-1.58)] across all severities. Mild or moderate AD was also associated with higher risk of autism, ADHD, bipolar disorder and suicidality. CONCLUSIONS: Atopic dermatitis is associated with a higher risk of multiple neuropsychiatric conditions, but these risks differ by specific condition and AD severity. Clinicians should inquire about mental health in patients with AD.

Malignancy risk in patients with atopic dermatitis: a population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is associated with immunological dysfunction, which may influence cancer development. Previous studies of AD and cancer demonstrate inconsistent results and few of these studies examined children or AD severity and treatment. OBJECTIVES: To determine malignancy risk among children and adults with AD. METHODS: We conducted a cohort study using electronic health records data from UK general practices in The Health Improvement Network between 1994 and 2015. Children (< 18 years old) and adults (≥ 18 years old) with AD were matched on age, practice and index date to patients without AD. AD was categorized as mild, moderate or severe using treatments and dermatology referrals as proxies. The primary outcome was any incident malignancy, including in situ malignancy, identified using diagnosis codes and categorized into haematological, skin and solid organ malignancies. Secondary outcomes included specific malignancies: leukaemia, lymphoma, melanoma, nonmelanoma skin cancer (NMSC) and common solid-organ cancers. RESULTS: Among 409 431 children with AD (93.2% mild, 5.5% moderate, 1.3% severe) and 1 809 029 children without AD who had median follow-up of 5-7 years, the incidence rates of malignancy were 1.9-3.4 and 2.0 per 10 000 person-years (PY), respectively. The adjusted risk of malignancy overall did not differ with respect to AD [hazard ratio (HR) 1.02 (95% confidence interval 0.92-1.12)]. Severe AD was associated with increased lymphoma risk [HR 3.18 (1.41-7.16), excluding cutaneous T-cell lymphoma (CTCL)], and mild AD was associated with increased NMSC risk [1.55 (1.06-2.27)]. Among 625 083 adults with AD (65.7% mild, 31.4% moderate, 2.9% severe) and 2 678 888 adults without AD who had median follow-up of 5 years, incidence rates of malignancy were 97.4-125.3 per 10 000 PY and 103.7 per 10 000 PY, respectively. The adjusted risk of any malignancy did not differ with respect to AD [HR 1.00 (0.99-1.02)]. However, adults with severe AD had a twofold higher risk of non-CTCL lymphoma. AD was also associated with slightly higher skin cancer risk [HR 1.06 (1.04-1.08)] and slightly lower solid cancer risk [0.97 (0.96-0.98)] but results varied by specific cancers and AD severity. CONCLUSIONS: Epidemiological evidence does not support a strong overall malignancy risk in AD but lymphoma risk may be increased with severe AD.

Atopic dermatitis and risk of major neuropsychiatric disorders in children: A population-based cohort study.

BACKGROUND: Paediatric atopic dermatitis (AD) has been linked to neuropsychiatric comorbidities such as depression, anxiety and attention-deficit/hyperactivity disorder (ADHD). However, longitudinal data are limited, and the effect of AD severity on neuropsychiatric outcomes requires further characterization. OBJECTIVES: To determine the risk of several major neuropsychiatric conditions in children with AD. METHODS: We analysed UK health records data in a population-based cohort study. Each patient <18 years old with AD was matched to up to five unaffected patients on age, practice and index date. Treatments served as proxies for AD severity, which was analysed in a time-updated manner. Outcomes were incident anxiety, depression, bipolar disorder, schizophrenia, ADHD, autism, obsessive-compulsive disorder (OCD), suicidal ideation or attempt, and completed suicide. RESULTS: A total of 409,431 children with AD (93.2% mild, 5.5% moderate, 1.3% severe) were compared to 1,809,029 children without AD. In Cox regression models adjusted for age, sex, socioeconomic status and other atopic comorbidities, no statistically significant relationships were observed between AD and incident anxiety (HR 1.01, 95% CI 0.99-1.03), ADHD (1.02, 0.97-1.06), autism (1.02, 0.98-1.06), bipolar disorder (1.08, 0.85-1.36), suicidal ideation/attempt (0.98, 0.95-1.01) or completed suicide (0.85, 0.64-1.14). Children with AD were less likely to develop depression (0.93, 0.91-0.95) or schizophrenia (0.72, 0.54-0.95) but more likely to develop OCD (1.26, 1.16-1.37). However, there was substantial variation by AD severity and age in both the direction and magnitude of effect for many of the neuropsychiatric conditions examined. CONCLUSIONS: The was no substantial impact of AD on the overall risk of many neuropsychiatric conditions in children, but disease severity and age may be important modifying factors. Additional research is needed to further dissect the complex relationship between paediatric AD and neuropsychiatric comorbidities.

Differences in prescriptions for systemic medications and nonsteroidal topicals among children with atopic dermatitis.

Nonsteroidal topicals and systemic therapies are often utilized for atopic dermatitis (AD) in children with inadequate response to topical corticosteroids. We sought to characterize patient factors associated with prescriptions for nonsteroidal topical (tacrolimus, pimecrolimus, crisaborole), systemic immunosuppressant (methotrexate, mycophenolate, cyclosporine, azathioprine), and systemic corticosteroid therapy among children with AD. In a cross-sectional study of patients <18 years old with AD seen at a large children's hospital between 2009 and 2017, we found that nonsteroidal topical and systemic medication prescriptions were associated with older age of the patient, male sex, comorbid atopy, greater healthcare utilization, specialist care, and race/ethnicity. Compared to White patients, Black and Hispanic patients were less likely to be prescribed nonsteroidal topicals and non-White patients were less likely to be prescribed systemic medications, suggesting that further examination of potential disparities in pediatric AD treatment is needed.

Mental health comorbidity in youth with atopic dermatitis: A narrative review of possible mechanisms.

The presence of atopic dermatitis (AD) in youth has been linked to a variety of mental health concerns including disruptive behavior, symptoms of anxiety and depression, and diagnoses of attention deficit/hyperactivity disorder and autism spectrum disorder. However, the factors accounting for these relationships are not well understood. The current review summarizes possible mechanisms identified in previous research and highlights areas for future investigation. Among the primary mechanisms studied to date, child sleep is the only factor that has been characterized in relative detail, with findings generally supporting the mediating role of sleep problems in the relationship between AD and psychological symptoms. There is substantial evidence suggesting a negative impact of child AD on parent mental health and the impact of parent mental health on child psychological functioning, although the latter has not been assessed specifically in populations of children with AD. There is also preliminary support for other mechanisms, including pruritus and pain, atopic comorbidities, social functioning, and systemic antihistamine use, in the development of mental health concerns in pediatric AD. Furthermore, research suggests the presence of bidirectional relationships between AD and psychological functioning via inflammatory responses to stress and impaired treatment adherence. Overall, significant additional research is needed to better characterize the nature and magnitude of the relationships among these multiple mechanisms and various psychosocial outcomes. Nevertheless, the findings to date support routine screening of psychological health in patients with AD as well as screening for potential risk factors, which may also serve as targets of therapeutic intervention.

Cognitive functioning in children with atopic dermatitis: Pilot observations.

Atopic dermatitis (AD) is a common and chronic inflammatory skin disease that can adversely affect quality of life and carry significant burdens on physical, emotional, and social health. Recent evidence suggests that AD may also impair cognition, including attention and memory. In a pilot study of six children with AD, we administered a comprehensive battery of assessments to evaluate cognition and behavior and found that this approach was feasible and practical, which will enable the conduct of future larger-scale studies to characterize the impact of AD on cognitive function.

Risk of liver disease in patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis receiving methotrexate: A population-based study.

BACKGROUND: Patients with psoriatic disease may be more susceptible to methotrexate hepatotoxicity than those with rheumatoid arthritis (RA); however, direct evidence supporting this notion is lacking. OBJECTIVE: To compare liver disease risk among patients with psoriasis (PsO), psoriatic arthritis (PsA), or RA receiving methotrexate. METHODS: In a population-based cohort study, Danish individuals with PsO, PsA, or RA receiving methotrexate between 1997 and 2015 were compared according to 4 disease outcomes: mild liver disease, moderate-to-severe liver disease, cirrhosis, and cirrhosis-related hospitalization. RESULTS: Among 5687, 6520, and 28,030 patients with PsO, PsA, and RA, respectively, the incidence rate of any liver disease was greatest for PsO, followed by PsA, and lowest for RA. Compared with patients with RA, patients with PsO were 1.6-3.4 times more likely to develop at least one of the liver disease outcomes, whereas those with PsA were 1.3-1.6 times more likely to develop mild liver disease and cirrhosis after adjusting for demographics, smoking, alcohol use, comorbidities, and methotrexate dose. LIMITATIONS: Confounding due to unmeasured variables, misclassification, and surveillance bias. CONCLUSION: PsO, PsA, and RA differentially influence liver disease risk in the setting of methotrexate use independent of other major risk factors. More conservative monitoring should be considered in patients receiving methotrexate for psoriatic disease, particularly in PsO patients.

Treatment utilization and drug survival of systemic medications among commercially insured children with psoriasis.

BACKGROUND/OBJECTIVES: Systemic medications and phototherapy are used to treat pediatric psoriasis, but real-world data on treatment utilization and persistence are limited. The study objective was to determine systemic and phototherapy treatment utilization and compare drug survival among systemics in pediatric psoriasis. METHODS: Using United States commercial insurance claims data, a cross-sectional analysis was conducted to describe the prevalence of systemic treatment and phototherapy use among patients <18 years old with psoriasis. We compared drug survival among new users of methotrexate, adalimumab, etanercept, and ustekinumab using a retrospective cohort design. RESULTS: Among 13 759 patients, 14.6% used systemic or phototherapy treatment during 2001-2016, with rising utilization of systemics over this period. Among 579 new users of methotrexate, adalimumab, etanercept, and ustekinumab, the median durations of the initial treatment course were 141 (IQR 59-314), 179 (79-339), 175 (90-419), and 216 (64-435) days, respectively (P = .04). Drug discontinuation was less likely among ustekinumab (HR 0.47 [95% CI 0.27-0.83]), etanercept (0.74 [0.59-0.92]), and adalimumab (0.75 [0.55-1.02]) initiators than methotrexate initiators after adjustment for sociodemographic factors and psoriatic arthritis. Drug survival differences were limited to systemic-naïve patients. Potential limitations include short follow-up and residual confounding. CONCLUSIONS: Utilization of systemic therapies for pediatric psoriasis is increasing, but differences in drug survival exist.

Mental health impairment among children with atopic dermatitis: A United States population-based cross-sectional study of the 2013-2017 National Health Interview Survey.

BACKGROUND: Atopic dermatitis (AD) is associated with mental health disorders, but its impact on global mental health symptoms is less clear. OBJECTIVE: To determine the association between pediatric AD and mental health impairment. METHODS: In a cross-sectional study using 2013-2017 United States National Health Interview Survey data, children with and without AD were assessed for mental disorder with impairment (MDI) using a validated behavioral screening questionnaire. Mental health services utilization was also reported. RESULTS: The prevalence of any MDI was 26.7% (95% confidence interval [CI], 25.1-28.3) among children with AD and 17.7% (95% CI, 17.2-18.2) among those without AD, with severe MDI being present in 10.9% (95% CI 9.9-12.1) and 6.2% (95% CI 5.9-6.5), respectively. Adjusted for sociodemographic factors, AD was associated with higher odds of MDI (odds ratio, 1.52; 95% CI, 1.39-1.67), including impairments in conduct, emotions, peer relationships, and attention. Among children with AD, 19.9% (95% CI, 16.6-23.8) and 53.5% (95% CI, 48.5-58.5) of those with mild or severe MDI, respectively, had seen a mental health professional in the last year. LIMITATIONS: Misclassification bias may arise from self-reported data. CONCLUSION: AD is associated with clinically significant mental health symptoms, but many affected children may not seek or receive care for their symptoms.

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

BACKGROUND: 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. OBJECTIVE: To evaluate longitudinal disease control and persistence with respect to age at onset of AD. METHODS: 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 10 years. RESULTS: 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. LIMITATIONS: Misclassification bias may arise from using self-reported data on age at onset. Attrition and missing data in longitudinal studies may introduce bias. CONCLUSION: Early-, mid-, and late-onset pediatric AD appear to be clinically distinct subtypes of the disease.

Evaluation of a modified outpatient model for using propranolol to treat infantile hemangiomas.

BACKGROUND: For infantile hemangiomas requiring treatment, existing recommendations advise initiation of propranolol followed by a 2-hour period of blood pressure and heart rate monitoring, resulting in prolonged office visits for both families and clinicians. OBJECTIVES: In order to reduce visit times, we evaluate our current practice of at-home or in-office propranolol administration followed by in-office vital sign monitoring. METHODS: We retrospectively reviewed the medical records of 157 patients with infantile hemangiomas (IH) who initiated propranolol under this outpatient protocol. Blood pressure (BP) and heart rate (HR) were obtained at a baseline visit and 1-2 hours after initial dose administration. We identified potential risk factors for clinically significant decreases in systolic blood pressure (SBP) and HR (defined as decrease of > 20 mm Hg and > 15 bpm, respectively) using logistic regression analysis, and adverse events were recorded. RESULTS: Fifty-five individuals (35.4%) showed a decrease in HR of more than 15 bpm, and 23 individuals (14.7%) showed a decrease in SBP of more than 20 mm Hg. Multivariable logistic regression suggested that younger age, history of preterm birth, and Caucasian race may slightly increase the odds of clinically significant changes in vital signs upon propranolol initiation. However, no clinically symptomatic adverse events occurred upon initiation of propranolol. CONCLUSIONS: Vital sign monitoring may be important when starting propranolol treatment in younger or historically preterm patients. However, routine mandatory in-office vital sign monitoring may not be necessary in healthy infants more than 45 weeks postconceptional age.