Patterns of anti-TNF use and associated treatment outcomes in inflammatory bowel disease patients: results from an analysis of Dutch health insurance claims data.

INTRODUCTION: Real-life patterns of anti-tumour necrosis factor (anti-TNF) use remain largely unknown. We aimed to investigate survival rates, clinical outcomes and costs of anti-TNF agents in a large population of patients with inflammatory bowel disease (IBD). METHODS: Health insurance data from 22,082 IBD patients were provided by Achmea Healthcare. Time to anti-TNF discontinuation, treatment intensification, corticosteroid initiation and hospitalisation were analysed in patients starting on anti-TNF treatment from January 2008 until December 2014. Treatment regimens were analysed at different time points. RESULTS: In this cohort, 855 and 1199 subjects started infliximab and adalimumab treatment, respectively. The median time to anti-TNF discontinuation was 600 days (IQR 156-1693). The proportion of subjects receiving intensified treatment increased over time (infliximab at 3 vs. 24 months: 22.2% vs. 33.6%, p = 0.01; adalimumab at 3 vs. 24 months: 10.5% vs. 19.3%, p < 0.001). Cessation of anti-TNF treatment was less common in Crohn's disease patients (HR 0.79, p = 0.001) and in patients receiving intensified treatment (HR 0.62, p = 0.001). Immunomodulator use was associated with a longer time to corticosteroid initiation (HR 0.80, p = 0.048), but not with longer drug survival (HR 0.99, p = 0.617). Hospitalisation was more common in Crohn's patients (HR 1.49, p = 0.011). Corticosteroid initiation was lower in Crohn's patients (HR 0.57, p < 0.001) and in patients using infliximab (HR 0.55, p < 0.001). CONCLUSIONS: Discontinuation of anti-TNF therapy occurred earlier than previously reported and was associated with a diagnosis of ulcerative colitis and non-intensified anti-TNF treatment. Immunomodulator use at the start of anti-TNF treatment was associated with a longer time to corticosteroid initiation, but not with longer drug survival.

Raised faecal calprotectin is associated with subsequent symptomatic relapse, in children and adolescents with inflammatory bowel disease in clinical remission.

BACKGROUND: Reliable data on inflammatory biomarkers for predicting relapse of paediatric inflammatory bowel disease (IBD) are lacking. AIM: To investigate the predictive value of faecal calprotectin (FC) and CRP for symptomatic relapse in pediatric IBD in clinical remission. METHODS: In this cross-sectional cohort study, patients <18 years with Crohn's disease or ulcerative colitis in clinical remission ≥3 months were included. At baseline, clinical and biochemical disease activity were assessed using the abbreviated-Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index, and FC and CRP respectively. Disease course over the subsequent 12 months was retrospectively assessed. RESULTS: In total, 114 patients (56% males; median age 14.9 years) were included. Baseline FC was higher in patients that developed symptomatic relapse [median (IQR), relapse 370 µg/g (86-1100) vs. remission 122 µg/g (40-344), P = 0.003]. Baseline FC was predictive of symptomatic relapse within 6 months [HR per 250 µg/g (95% CI): 1.46 (1.21-1.77), P < 0.001], with good predictive accuracy (AUC: 0.82). Optimal FC cut-off was 350 µg/g, with positive and negative predictive value of 41% and 96%. Baseline CRP was higher in patients that developed symptomatic relapse [median (IQR), relapse 1.0 µg/g (0.6-5.0) vs. remission 1.0 µg/g (0.4-2.0), P = 0.033]. Baseline CRP was predictive of symptomatic relapse within 6 months from baseline [HR per 1 mg/L (95% CI): 1.10 (1.02-1.19), P = 0.011], with fair predictive accuracy (AUC: 0.72). Optimal CRP cut-off was 1.0 mg/L, with positive and negative predictive value of 21% and 94%. CONCLUSIONS: Faecal calprotectin and CRP are predictive of symptomatic relapse and may be valuable in management of paediatric IBD in clinical remission.

Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease.

BACKGROUND: Minimising placebo response is essential for drug development. AIM: To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. METHODS: MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. RESULTS: In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. CONCLUSIONS: Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.

The prevalence of irritable bowel syndrome-type symptoms in paediatric inflammatory bowel disease, and the relationship with biochemical markers of disease activity.

BACKGROUND: A large proportion (25-46%) of adults with inflammatory bowel disease in remission has symptoms of irritable bowel syndrome (IBS), which are thought to reflect ongoing inflammation. Data on paediatric inflammatory bowel disease patients are lacking. AIM: To investigate (i) the prevalence of IBS-type symptoms in paediatric inflammatory bowel disease patients in remission and (ii) the relationship of IBS-type symptoms with biochemical markers of disease activity. METHODS: This cross-sectional study included all patients (<18 years) with Crohn's disease or ulcerative colitis attending the out-patient clinic of one of three Dutch hospitals between March 2014 and June 2015. Clinical disease activity was determined using the abbreviated-PCDAI or PUCAI. Biochemical disease activity was assessed using faecal calprotectin and serum CRP. IBS-symptoms were assessed using physician-administered Rome III-questionnaires. RESULTS: We included 184 patients (92 female; mean age: 14.5 years) (Crohn's disease: 123, ulcerative colitis: 61). The prevalence of IBS-type symptoms in children with inflammatory bowel disease in clinical remission was 6.4% (95% CI: 2.5-11.1%; Crohn's disease: 4.5%; ulcerative colitis: 10.8%). Prevalence of IBS-type symptoms in children with faecal calprotectin <250 µg/g was 16.1% (95% CI: 7.6-25.8%; Crohn's disease: 16.7%; ulcerative colitis: 10.8%). No difference in faecal calprotectin or CRP was found between patients in clinical remission with or without IBS-type symptoms (faecal calprotectin: IBS+ median 58 µg/g, IBS- 221 µg/g, P = 0.12; CRP: IBS+ median 1.4 mg/L, IBS- 1.1 mg/L, P = 0.63). CONCLUSIONS: The prevalence of IBS-type symptoms in children with inflammatory bowel disease is highly dependent on the definition of remission. Nonetheless, the prevalence is much lower than that previously reported in studies in adult inflammatory bowel disease patients. IBS-type symptoms appear to be unrelated to gastrointestinal inflammation.

Inter- and intrarater reliability of the Chicago Classification in pediatric high-resolution esophageal manometry recordings.

BACKGROUND: The Chicago Classification (CC) facilitates interpretation of high-resolution manometry (HRM) recordings. Application of this adult based algorithm to the pediatric population is unknown. We therefore assessed intra and interrater reliability of software-based CC diagnosis in a pediatric cohort. METHODS: Thirty pediatric solid state HRM recordings (13M; mean age 12.1 ± 5.1 years) assessing 10 liquid swallows per patient were analyzed twice by 11 raters (six experts, five non-experts). Software-placed anatomical landmarks required manual adjustment or removal. Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL) and break size (BS), and an overall CC diagnosis were software-generated. In addition, raters provided their subjective CC diagnosis. Reliability was calculated with Cohen's and Fleiss' kappa (κ) and intraclass correlation coefficient (ICC). KEY RESULTS: Intra- and interrater reliability of software-generated CC diagnosis after manual adjustment of landmarks was substantial (mean κ = 0.69 and 0.77 respectively) and moderate-substantial for subjective CC diagnosis (mean κ = 0.70 and 0.58 respectively). Reliability of both software-generated and subjective diagnosis of normal motility was high (κ = 0.81 and κ = 0.79). Intra- and interrater reliability were excellent for IRP4s, DCI, and BS. Experts had higher interrater reliability than non-experts for DL (ICC = 0.65 vs ICC = 0.36 respectively) and the software-generated diagnosis diffuse esophageal spasm (DES, κ = 0.64 vs κ = 0.30). Among experts, the reliability for the subjective diagnosis of achalasia and esophageal gastric junction outflow obstruction was moderate-substantial (κ = 0.45-0.82). CONCLUSIONS & INFERENCES: Inter- and intrarater reliability of software-based CC diagnosis of pediatric HRM recordings was high overall. However, experience was a factor influencing the diagnosis of some motility disorders, particularly DES and achalasia.

The expanding role of quantitative structure-activity relationships (QSAR) in toxicology.

Quantitative structure-activity relationships (QSAR) have found wide use in correlating the bioactivity of all kinds of organic compounds with all kinds of biological entities. So many QSAR have been published that it is time for a new phase of study, that of comparative QSAR. From our current database of about 6000 QSAR illustrative examples are discussed.