Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease.

BACKGROUND: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). AIM: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. RESULTS: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection. CONCLUSION: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted.

Effectiveness of dupilumab treatment in 95 patients with atopic dermatitis: daily practice data.

BACKGROUND: Dupilumab is the first biologic registered for the treatment of moderate-to-severe atopic dermatitis (AD), and efficacy was shown in phase III clinical trials (primary outcome at week 16 was reached in 38% of patients). Currently, there are limited daily practice data available for dupilumab, especially when it is combined with systemic immunosuppressants. OBJECTIVES: To evaluate dupilumab treatment in daily practice in patients with AD. METHODS: In this observational cohort study, we prospectively included all adult patients with AD who had been treated with dupilumab in two university hospitals in the Netherlands. Concomitant systemic immunosuppressive treatment was monitored. Physician-reported outcome measures and patient-reported outcome measures (PROMs) after ≥ 12 weeks of follow-up were analysed. We used a linear mixed-effects model to determine changes in scores during follow-up. RESULTS: Ninety-five patients were included. Of these, 62 patients were using systemic immunosuppressants at baseline; the use of systemic immunosuppressants was continued during dupilumab treatment in 43 patients. From baseline to 16 weeks of treatment, the estimated mean Eczema Area and Severity Index score (0-72) decreased from 18·6 [95% confidence interval (CI) 16·0-21·4)] to 7·3 (95% CI 5·4-10·0), and the estimated mean PROMs showed a decrease of 41-66%. Investigator's Global Assessment 0 or 1 (clear/almost clear) was reached in 38% of the patients. Five patients discontinued dupilumab treatment due to side-effects or ineffectiveness. Eye symptoms and orofacial (nonocular) herpes simplex virus (HSV) reactivation were reported in 62% and 8% of the patients, respectively. CONCLUSIONS: Dupilumab treatment in daily practice shows a clinically relevant improvement of physician-reported outcome measures and PROMs, which is in line with efficacy data from clinical trials. Besides frequently reported eye symptoms and orofacial (nonocular) HSV reactivation, there were no apparent safety concerns. What's already known about this topic? Dupilumab has been shown to be an efficacious treatment for atopic dermatitis in several clinical trials. However, it is known that there may be considerable differences in patient characteristics and treatment responses between clinical trials and daily practice. What does this study add? This study presents the first experience with dupilumab treatment in 95 patients with atopic dermatitis in daily practice in two Dutch university hospitals. Less stringent inclusion and exclusion criteria and follow-up schedules, in contrast to those used in clinical trials, might better represent daily practice. Dupilumab treatment shows a clinically relevant improvement of physician- and patient-reported outcome measures; besides patient-reported eye symptoms (in 59 of 95 patients; 62%) and an apparent increase in orofacial (nonocular) herpes simplex virus reactivation (eight of 95 patients; 8%), there were no other safety concerns during follow-up up to 16 weeks of dupilumab treatment.

Most associations of early-life environmental exposures and genetic risk factors poorly differentiate between eczema phenotypes: the Generation R Study.

BACKGROUND: Childhood eczema is variable in onset and persistence. OBJECTIVES: To identify eczema phenotypes during childhood, and their associations with early-life environmental and genetic factors. METHODS: In this study of 5297 children from a multiethnic population-based prospective cohort study, phenotypes based on parent-reported physician-diagnosed eczema from age 6 months to 10 years were identified using latent class growth analysis. Information on environmental factors was obtained using postal questionnaires. Four filaggrin mutations were genotyped and a risk score was calculated based on 30 genetic variants. Weighted adjusted multinomial models were used for association analyses. RESULTS: We identified the following five eczema phenotypes: never (76%), early transient (8%), mid-transient (6%) and late transient (8%) and persistent eczema (2%). Early transient and persistent eczema were most common in first-born children, those with a parental history of eczema, allergy or asthma and those with persistent wheezing [range of odds ratio (OR): 1.37, 95% confidence interval (CI) 1.07-1.74 and OR 3.38, 95%CI 1.95-5.85]. Early transient eczema was most common in male children only (OR 1·49, 95% CI 1·18-1·89). Children with late transient or persistent eczema were more often of Asian ethnicity (OR 2·04, 95% CI 1·14-3·65 and OR 3·08, 95% CI 1·34-7·10, respectively). Children with early, late transient and persistent eczema more often had a filaggrin mutation or additional risk alleles (range OR: 1.07, 95%CI 1.02-1.12 and OR 2.21, 95%CI 1.39-3.50). Eczema phenotypes were not associated with maternal education, breastfeeding, day care attendance and pet exposure. CONCLUSIONS: Five eczema phenotypes were identified in a multiethnic paediatric population with limited differences in risk profiles, except for sex and ethnicity. What's already known about this topic? Two previous studies in longitudinal birth cohorts identified four and six different eczema phenotypes, predominantly in children of European ethnicity. What does this study add? Five eczema phenotypes were identified in a multiethnic paediatric population using latent class growth analysis. Children with early transient and persistent eczema were most often first-born children and had persistent wheezing, filaggrin mutation or additional risk alleles. Previously known eczema risk factors had limited differentiating capabilities for eczema phenotypes, except for the association of early transient eczema with male children, and late transient and persistent eczema with Asian ethnicity.

Sugar-containing beverage intake in toddlers and body composition up to age 6 years: the Generation R study.

BACKGROUND/OBJECTIVE: Intake of sugar-containing beverages (SCBs) has been associated with higher body mass index (BMI) in childhood. The potential effect of SCB intake during infancy is unclear. We examined the association of SCB intake at 13 months with BMI development until 6 years and body composition at age 6 years. SUBJECTS/METHODS: This study included 2371 Dutch children from a population-based prospective cohort study. SCB intake at 13 months was assessed using a Food Frequency Questionnaire with validation against 24-h recalls and was standardized for total energy. BMI was calculated from repeated weight and height measurements, and age- and sex-specific s.d. scores were calculated. Adiposity was measured using Dual-energy X-ray absorptiometry. RESULTS: In girls, higher SCB intake at 13 months was significantly associated with higher BMI at ages 2, 3, 4 and 6 years (at age 6 years BMI (s.d. score) increase 0.11 (95% confidence interval (CI) +0.00; 0.23), high versus low intake). We observed a tendency towards higher android/gynoid fat ratio in girls with high intake (s.d. increase 0.14 (95% CI -0.02; 0.29), versus low intake) but not with body fat percentage. In boys, there was no association with BMI or body composition, but boys with high SCB intake at 13 months were taller at age 6 years (s.d. increase 0.14 (95% CI +0.00; 0.27), versus low intake). CONCLUSIONS: Higher SCB intake at 13 months was associated with higher BMI up to age 6 years in girls but not in boys. Our results imply that the unfavorable effects of SCB intake start early in life and that dietary advice regarding limiting SCB intake should already be given early in life.