Therapeutic Drug Monitoring Guides the Management of Crohn's Patients with Secondary Loss of Response to Adalimumab

Background: Managing loss of response (LOR) in Crohn's disase (CD) patients remains challenging. Compelling evidence supports therapeutic drug monitoring (TDM) to guide management in patients on infliximab, but data for other biologics are less robust. We aimed to asses if empiric dose escalation led to improved clinical outcome in addition to TDM-guided optimization in CD patients with LOR to adalimumab (ADA). Methods: Retrospective chart review of patients followed between 2014 and 2016 at McGill IBD Center with index TDM for LOR to ADA was performed. Primary outcomes were composite remission at 3, 6, and 12 months in those with empiric adjustments versus TDM-guided optimization. Results: There were 104 patients (54.8% men) who were included in the study. Of this group, 81 patients (77.9%) had serum level (SL) >= 5 mu g/ml at index TDM with a median value of 12 mu g/ml (IQR 6.1-16.5). There were 10 patients (9.6%) who had undetectable SL with high anti-ADA antibodies and 48 (46.2%) received empiric escalation. TDM led to change in treatment in 58 patients (55.8%). Among them, 28 (48.3%) had discontinued ADA, 12 (21.7%) had addition of immunomodulator or steroid, and 18 (31%) had ADA dose escalation. Empiric dose escalation before TDM-based optimization was not associated with improved outcomes at 3, 6, and 12 months, irrespective of SL levels. Clear SL cutoff associated with composite remission was not identified. Conclusions: Our data do not support empiric dose adjustment beyond that based on the result of the TDM in patients with LOR to ADA. TDM limits unnecessary dose escalation and provides appropriate treatment strategy without compromising clinical outcomes

Alcohol and cannabis consumption in patients with inflammatory bowel disease: prevalence, pattern of consumption and impact on the disease.

OBJECTIVES OF THE STUDY There is little guidance regarding the impact of alcohol and cannabis on the clinical course of inflammatory bowel disease. The aim of this study was to assess the prevalence, sociodemographic characteristics and impact of alcohol and cannabis use on the clinical course of the disease. METHODS We performed an analysis of prospectively collected data within the Swiss Inflammatory Bowel Disease Cohort Study with yearly follow-ups and substance-specific questionnaires. We analyzed the prevalence of use, the profile of users at risk for addiction and the impact of alcohol and cannabis on the course of the disease. RESULTS We collected data of 2828 patients included between 2006 and 2018 and analyzed it according to their completion of specific surveys on alcohol and cannabis use. The prevalence of patient-reported active use was 41.3% for alcohol and 6% for cannabis. Heavy drinkers were over-represented among retired, married smokers receiving mostly aminosalicylates and less immunosuppression. In ulcerative colitis patients, low-to-moderate drinking was associated with less extensive disease. Cannabis users were often students with ileal Crohn's disease. CONCLUSION A significant proportion of patients with inflammatory bowel disease consume alcohol or cannabis. Heavy alcohol consumption is most likely in male smokers >50 years, whereas young men with ileal disease rather use cannabis

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants with Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10501) and individuals with non-TRS (n = 20325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85490 participants (48635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P =.001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P =.04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance

Precision Medicine in Inflammatory Bowel Disease

Inflammatory bowel diseases (IBD) are immune-mediated diseases with complex pathogenesis. IBD's course is heterogeneous, as is the response of patients to drugs, but physicians often take a “one size-fits-all” approach. Many patients do not respond to their first treatment, lose response, or suffer adverse events caused by medications. The need to manage patients individually, through precision medicine, is clear. Personalizing IBD treatment depends on determining which patients are at high risk of adverse complications, choosing the best therapy for each patient and optimizing treatment efficacy through tight and tailored monitoring. To change the natural course of disease, an individual's prognosis rather than their symptoms should guide therapy. This thesis outlines current knowledge of IBD pathogenesis and discusses the use of precision medicine to manage IBD patients, with the goal of improving the quality of clinical practice through targeted care

Analyse computérisée de la fibrose hépatique assistée par un ordinateur chez les patients atteints de maladie alcoolique du foie: relation avec les paramètres cliniques et hémodynamiques

Nous avons comparé, sur des biopsies hépatiques transjugulaires, la quantité de fibrose mesurée par morphométrie entre un groupe de patients atteints de maladie chronique avancée du foie d'origine alcoolique et un groupe contrôle sain composé de candidats au don vivant de foie aux Hôpitaux Universitaires de Genève. Nous avons étudié, dans le groupe de patients atteints de maladie chronique avancée du foie d'origine alcoolique, l'association entre la quantité de fibrose mesurée par morphométrie, et (i)le gradient de pression hépatique, et (ii) des complications cliniques liées à l'hypertension portale. Dans le sous-groupe des consommateurs d'alcool actifs, la quantification de la fibrose par morphométrie était corrélée au gradient de pression hépatique. Le gradient de pression hépatique, mais pas la quantité de fibrose mesurée par morphométrie, était associé à la survenue de complications cliniques liées à l'hypertension portale. Ces résultats suggèrent que la consommation d'alcool est un facteur aggravant de l'hypertension portale

Update on TDM (Therapeutic Drug Monitoring) with Ustekinumab, Vedolizumab and Tofacitinib in Inflammatory Bowel Disease

The goal of therapeutic drug monitoring (TDM) is to optimize anti-TNF (tumor necrosis factor) biologic treatment in patients with inflammatory bowel disease (IBD). Although commercial assays are readily available for both ustekinumab and vedolizumab, the use of TDM with these newer biologic medications is at its infancy. The clinical utility of TDM with non-anti-TNF mechanisms of action is not clear. This review summarizes the latest available data on the pharmacokinetics of newer biologic and oral small molecules and highlights the threshold concentrations that have been associated with improved outcomes in IBD patients

Antibioprophylaxie de la péritonite bactérienne spontanée

Bacterial infections are frequent and severe complications in patients with cirrhosis. Spontaneous bacterial peritonitis (SBP) is the most common infection in such patients. The risk of recurrence at one year after a first episode of SBP is higher than 70% and hospital mortality is estimated between 30-50%. Therefore, there is growing interest in antibiotic prophylaxis (ATP) in these patients. Risk factors for the occurrence of SBP include low protein level in ascitis, a history of previous SBP and an episode of gastrointestinal bleeding. In all three situations, the indication of ATP, reviewed in this paper, is recognized and improves survival

Update on the management of inflammatory bowel disease during pregnancy and breastfeeding

Inflammatory bowel disease (IBD) affects patients during their peak reproductive years. This raises important questions, in both patients and healthcare providers, regarding conception, pregnancy, and breastfeeding. Lack of information and insufficient communication among healthcare providers can leave patients with limited information and even contradictory advice. Given the fact that pregnant and/or breastfeeding IBD patients are excluded from clinical studies the evidence on many questions related to pregnancy and postpartum period is limited. However, there exists increasing data from case series and cohort studies that allows to provide clinical guidance. The overarching concept is that optimizing the mother's health is critical for optimizing the health of the unborn child and benefit of continuing medical therapy in IBD during pregnancy outweighs possible risks in most instances. This paper provides an up-to-date systematic review of the literature on IBD in pregnancy and proposes guidance to questions frequently encountered by healthcare professionals

Polyethylene Glycol versus sodium picosulfalte Bowel Preparation in the Setting of a Colorectal Cancer Screening Program

BACKGROUND: Adequate bowel preparation for colonoscopy is an important predictor of colonoscopy quality