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Ulcerative Colitis: HELP
Articles by Niels Vande Casteele
Based on 36 articles published since 2010
(Why 36 articles?)
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Between 2010 and 2020, N. Vande Casteele wrote the following 36 articles about Colitis, Ulcerative.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Efficient Early Drug Development for Ulcerative Colitis. 2016

Khanna, Reena / Jairath, Vipul / Vande Casteele, Niels / Mosli, Mahmoud H / Zou, Guangyong / Parker, Claire E / Levesque, Barrett G / Sandborn, William J / D'Haens, Geert / Feagan, Brian G. ·University of Western Ontario, London, Ontario, Canada. · University of Western Ontario, London, Ontario, Canada and University of Oxford, Oxford, UK. · University of Western Ontario, London, Ontario, Canada and Katholieke Universiteit Leuven, Leuven, Belgium. · University of Western Ontario, London, Ontario, Canada and King Abdulaziz University, Jeddah, Saudi Arabia. · University of Western Ontario, London, Ontario, Canada and University of California San Diego, La Jolla, California. · University of Western Ontario, London, Ontario, Canada and Academic Medical Centre, Amsterdam, The Netherlands. · University of Western Ontario, London, Ontario, Canada. Electronic address: bfeagan@robartsinc.com. ·Gastroenterology · Pubmed #27018491.

ABSTRACT: -- No abstract --

2 Editorial Fecal calprotectin-guided dosing of mesalamine in ulcerative colitis: concept proved but more data needed. 2014

Vande Casteele, Niels / Sandborn, William J. ·Division of Gastroenterology, University of California San Diego, La Jolla, California; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, Leuven, Belgium; Robarts Clinical Trials, Western University, London, Ontario, Canada. · Division of Gastroenterology, University of California San Diego, La Jolla, California; Robarts Clinical Trials, Western University, London, Ontario, Canada. ·Clin Gastroenterol Hepatol · Pubmed #24951843.

ABSTRACT: -- No abstract --

3 Review A product review of vedolizumab in inflammatory bowel disease. 2019

Battat, Robert / Dulai, Parambir S / Jairath, Vipul / Vande Casteele, Niels. ·Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla , CA , USA. · Robarts Clinical Trials Inc ., London , ON , Canada. · Department of Medicine, University of Western Ontario , London , ON , Canada. · Department of Epidemiology and Biostatistics, University of Western Ontario , London , ON , Canada. ·Hum Vaccin Immunother · Pubmed #30897022.

ABSTRACT: Vedolizumab is a monoclonal antibody to the α4β7 integrin that selectively reduces intestinal lymphocyte trafficking, thereby providing a safe and effective treatment option for patients with inflammatory bowel disease (IBD). This product review outlines the unique mechanism of vedolizumab in addition to efficacy, safety, pharmacokinetic and pharmacodynamic data from clinical trials, observational studies and meta-analyses. Vedolizumab has been shown to be effective as a first- or second-line induction and maintenance therapy in both ulcerative colitis (UC) and Crohn's disease (CD). Prolonged induction therapy may increase efficacy, particularly in tumor necrosis factor-alpha-exposed CD patients. To date, no drug-specific safety signals have been identified. In addition to the presence of an apparent exposure-response relationship, vedolizumab has demonstrated consistent pharmacodynamic effects on α4β7, mucosal vascular addressin cell adhesion molecule 1 and other cell adhesion molecules. Future efforts should focus on identifying predictive biomarkers capable of guiding personalized IBD treatment with vedolizumab.

4 Review Advances in Therapeutic Drug Monitoring for Small-Molecule and Biologic Therapies in Inflammatory Bowel Disease. 2019

Ma, Christopher / Battat, Robert / Jairath, Vipul / Vande Casteele, Niels. ·Division of Gastroenterology and Hepatology, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada. · Robarts Clinical Trials, Inc., #200, 100 Dundas Street, London, Ontario, N6A 5B6, Canada. · Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive, #0956, La Jolla, CA, 92093, USA. · Department of Medicine, Division of Gastroenterology, Western University, #200, 100 Dundas Street, London, Ontario, N6A 5B6, Canada. · Department of Epidemiology and Biostatistics, Western University, #200, 100 Dundas Street, London, Ontario, N6A 5B6, Canada. · Robarts Clinical Trials, Inc., #200, 100 Dundas Street, London, Ontario, N6A 5B6, Canada. nvandecasteele@ucsd.edu. · Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0956, La Jolla, CA, 92093, USA. nvandecasteele@ucsd.edu. ·Curr Treat Options Gastroenterol · Pubmed #30680599.

ABSTRACT: PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) is increasingly utilized as a strategy to optimize inflammatory bowel disease (IBD) therapeutics. As management paradigms have evolved towards treat-to-target strategies, there has been growing interest in expanding the role of TDM to guide drug optimization for achieving objective endpoints. This review summarizes the evidence for using TDM with biologic and oral small-molecule therapies, evaluates the role of reactive versus proactive TDM in treatment algorithms, and identifies potential future applications for TDM. RECENT FINDINGS: Achieving therapeutic drug concentrations has been associated with important clinical, endoscopic, and histologic outcomes in IBD. However, the optimal drug concentration varies by therapeutic agent, disease phenotype, inflammatory burden, phase of treatment, and target outcome. Traditionally, TDM has been used reactively to define pharmacokinetic versus mechanistic failures after loss of response to a tumor necrosis factor-α (TNF) antagonist and while observational data suggests a benefit to proactive TDM, this has not been definitively confirmed in prospective randomized controlled trials. The role of TDM in optimizing vedolizumab, ustekinumab, and tofacitinib remains unclear, given differences in pharmacokinetics and immunogenicity compared to TNF antagonists. Measuring drug action at the site of inflamed tissue may provide additional insights into treatment optimization. The use of TDM offers the possibility of a more personalized treatment approach for patients with IBD. High-quality studies are needed to delineate the role of proactive TDM for maintaining remission, for optimizing induction regimens, and for novel agents.

5 Review The emerging role of histologic disease activity assessment in ulcerative colitis. 2018

Pai, Rish K / Jairath, Vipul / Vande Casteele, Niels / Rieder, Florian / Parker, Claire E / Lauwers, Gregory Y. ·Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA. · Robarts Clinical Trials Inc., London, Ontario, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada; Department of Medicine, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials Inc., London, Ontario, Canada; Department of Medicine, University of California, San Diego, La Jolla, California, USA. · Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA. · Robarts Clinical Trials Inc., London, Ontario, Canada. · Department of Anatomic Pathology, Moffitt Cancer Center, Tampa Bay, Florida, USA. ·Gastrointest Endosc · Pubmed #30142351.

ABSTRACT: BACKGROUND AND AIMS: Assessment of disease activity is essential for developing and determining appropriate therapy in patients with ulcerative colitis (UC). Validated clinical and endoscopic scoring systems have been established to accurately define disease activity. Clinical and endoscopic treatment targets have also been proposed, with gastroenterologists encouraged to optimize medical therapy to achieve these targets. Recently, histology has been recognized as an important prognostic factor and potential treatment target in patients with UC. METHODS: This review summarizes the recent literature regarding histologic scoring indices in UC and offers practical guidance to gastroenterologists on how to interpret histologic data. RESULTS: Substantial evidence indicates that histology accurately predicts clinical relapse, hospitalization, corticosteroid use, and development of dysplasia. Furthermore, compared with endoscopy, findings suggest that histology may be more predictive of these outcomes. Because microscopic disease activity can persist in the absence of clinical or endoscopic disease activity, histology may be the ideal marker of inflammation. Standardized definitions of histologic response and remission and a biopsy procurement protocol are needed to guide clinical decision making. It is recommended that overall assessment of disease severity be determined according to the worst affected biopsy fragment. Crypt architectural distortion, basal plasmacytosis, and neutrophilic activity should be reported. A 5-category classification system based on disease chronicity/activity and basal plasmacytosis is proposed. It is not yet necessary to report on the degree of mucosal eosinophilia or use a validated scoring system, although the latter may aid in determining therapeutic response. CONCLUSIONS: Although rarely used to measure inflammation and guide therapy, histologic disease activity is predictive of important clinical outcomes in UC. Randomized controlled trials are needed to determine whether histology should function as a treatment target.

6 Review Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease. 2018

Duijvestein, Marjolijn / Battat, Robert / Vande Casteele, Niels / D'Haens, Geert R / Sandborn, William J / Khanna, Reena / Jairath, Vipul / Feagan, Brian G. ·Robarts Clinical Trials, San Diego, CA, USA. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Academic Medical Center, Amsterdam, Netherlands. · Robarts Clinical Trials, Amsterdam, Netherlands. · Robarts Clinical Trials, London, Canada. · Department of Medicine, University of Western Ontario, London, ON, Canada. · Robarts Clinical Trials, London, Canada. vipul.jairath@robartsinc.com. · Department of Medicine, University of Western Ontario, London, ON, Canada. vipul.jairath@robartsinc.com. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, Canada. ·Curr Treat Options Gastroenterol · Pubmed #29411220.

ABSTRACT: PURPOSE OF REVIEW: This article reviews current treatment options and strategies and provides an update on the status of drug development programs of new therapeutic agents for inflammatory bowel diseases (IBD). RECENT FINDINGS: In the past two decades, tumor necrosis factor antagonist therapy has given clinicians better treatment options. However, not all patients respond to induction therapy with these agents, and of those initially responding, up to 40% ultimately lose response due to suboptimal drug exposure (e.g., caused by immunogenicity), side effects, or other poorly characterized mechanisms. Recently, additional therapies, such as vedolizumab, an integrin blocker that prevents T cell trafficking to the gut, and ustekinumab, an antibody blocking the common p40 subunit of interleukin (IL)-12 and 23, were introduced to the market. In addition, other agents including novel anti-trafficking therapies (e.g., anti-β7 and sphingosine-1-phosphate receptor modulators), antibodies against p19 (unique to IL-23), and small molecules including Janus kinase inhibitors are under investigation in phase II and III trials. Furthermore, the management of IBD has evolved from targeting control of symptoms to suppression of mucosal inflammation. This shift in thinking has been accompanied by the early use of highly effective therapy in poor prognosis patients, accelerated treatment escalation and utilization of a treat to target paradigm approach, and adoption of therapeutic drug monitoring. The treatment landscape for IBD is rapidly evolving with the recent approval of novel biologics as well as several other agents in late phase of clinical development. Moreover, we have started to use agents more intelligently with a focus on risk stratification and early use of highly effective therapy in high-risk patients, treat to target using patient-reported outcomes (PROs), biomarkers, endoscopy, and therapeutic drug monitoring.

7 Review Primary Non-Response to Tumor Necrosis Factor Antagonists is Associated with Inferior Response to Second-line Biologics in Patients with Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis. 2018

Singh, Siddharth / George, John / Boland, Brigid S / Vande Casteele, Niels / Sandborn, William J. ·Division of Gastroenterology, University of California San Diego, La Jolla, California. · Division of Biomedical Informatics, University of California San Diego, La Jolla, California. · Department of Internal Medicine, Bridgeport Hospital-Yale New Haven Health, Bridgeport, Connecticut. ·J Crohns Colitis · Pubmed #29370397.

ABSTRACT: Background and Aims: We sought to analyze whether response to a second-line biologic varies depending on the reason for discontinuation of the primary anti-TNF agent (primary non-response [PNR], secondary loss of response [LOR] after initial response, or intolerance), through a systematic review and meta-analysis. Methods: Through a systematic search through May 31, 2017, we identified eight randomized controlled trials [RCTs] of biologics in patients with IBD with prior exposure to anti-TNF agents, that stratified response to second-line therapy by reason for discontinuing primary anti-TNF therapy [PNR vs. LOR vs. intolerance]. We estimated relative risk [RR] (and 95% confidence interval [CI]) of achieving clinical remission in patients with PNR as compared with patients with LOR, and intolerance, through random effects meta-analysis. Results: As compared with patients who discontinued prior anti-TNF due to intolerance, patients with prior PNR were 24% less likely to achieve remission with second-line biologics (RR,0.76 [0.61-0.96]). As compared with patients who discontinued prior anti-TNF due to LOR, patients with prior PNR were 27% less likely to achieve remission with induction therapy with second-line biologics (RR,0.73 [0.56-0.97]), particularly to ustekinumab (RR,0.64 [0.52-0.80]). There was no difference in response to vedolizumab in patients with prior PNR or LOR to anti-TNF agents (RR,1.16 [0.85-1.58]). Conclusion: Patients with PNR to anti-TNF agents are less likely to respond to second-line non-TNF biologics, as compared with patients who discontinued therapy due to secondary LOR or intolerance. This may be attributed to underlying pharmacokinetics and pharmacodynamics of anti-TNF agents in patients with PNR.

8 Review The Expanding Therapeutic Armamentarium for Inflammatory Bowel Disease: How to Choose the Right Drug[s] for Our Patients? 2018

Hindryckx, Pieter / Vande Casteele, Niels / Novak, Gregor / Khanna, Reena / D'Haens, Geert / Sandborn, William J / Danese, Silvio / Jairath, Vipul / Feagan, Brian G. ·Robarts Clinical Trials, Inc., University of Western Ontario, London, ON, Canada. · Department of Gastroenterology, University of Ghent, Ghent, Belgium. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Department of Gastroenterology, Ljubljana University Medical Centre, Ljubljana, Slovenia. · Department of Medicine, University of Western Ontario, London, ON, Canada. · Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands. · Department of Biomedical Sciences, Humanitas University, Milan, Italy. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. ·J Crohns Colitis · Pubmed #28961959.

ABSTRACT: The therapeutic landscape for inflammatory bowel disease [IBD] is rapidly evolving. Two new biologic drugs, vedolizumab and ustekinumab, have recently entered the marketplace, the first biosimilars have been introduced, and several other agents are at an advanced stage of clinical development. In parallel, therapeutic goals have shifted from symptom control towards mucosal healing and prevention of bowel damage. In the coming years, gastroenterologists will be faced with unprecedented choices when selecting the best treatment for their patients with IBD. In this article, we review existing data on the mechanisms of action, efficacy, and safety of recently approved and late-stage pipeline therapies, and use this information to speculate on the positioning of these drugs, alone or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.

9 Review Therapeutic Drug Monitoring of Golimumab in the Treatment of Ulcerative Colitis. 2017

Vande Casteele, Niels / Khanna, Reena. ·Department of Medicine, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, California, 92093, USA. nvandecasteele@ucsd.edu. · Robarts Clinical Trials Inc., Robarts Research Institute, London, Ontario, Canada. nvandecasteele@ucsd.edu. · Robarts Clinical Trials Inc., Robarts Research Institute, London, Ontario, Canada. · Department of Medicine, University of Western Ontario, London, Ontario, Canada. ·Pharm Res · Pubmed #28374338.

ABSTRACT: Ulcerative colitis (UC) is a relapsing-remitting chronic inflammatory disorder affecting the mucosal surface in a continuous manner from the rectum through part of, or the entire, colon. Patients with severe disease and those who become refractory or intolerant to corticosteroids and/or immunosuppressants, require treatment with biologic agents that target tumor necrosis factor-α (TNF). Golimumab, a fully human monoclonal antibody, is the latest TNF antagonist to get approved for the treatment of moderate-to-severe UC. Subcutaneously administered golimumab induces and maintains clinical response, remission, and mucosal healing. Serum concentrations of golimumab are associated with response to therapy, as patients with higher drug exposure are more likely to achieve these outcomes. Since various patient and disease-related factors were shown to influence the pharmacokinetics of TNF antagonists, drug exposure may be variable over time and between patients, affecting success of therapy. A major contributing factor is immunogenicity, with development of anti-drug antibodies (ADAb) and an accelerated clearance of drug as a result. Although there is a growing body of evidence to support therapeutic drug monitoring (TDM) for infliximab and adalimumab, two other TNF antagonists, only limited data is available for golimumab. In addition, the clinically important drug exposure thresholds are not widely known, which has limited the use of TDM for golimumab in clinical practice. This review summarizes available data regarding the use of golimumab for UC, with emphasis on the pharmacokinetics, exposure-response relationship, and the role of TDM in optimizing therapy.

10 Review Review article: dose optimisation of infliximab for acute severe ulcerative colitis. 2017

Hindryckx, P / Novak, G / Vande Casteele, N / Laukens, D / Parker, C / Shackelton, L M / Narula, N / Khanna, R / Dulai, P / Levesque, B G / Sandborn, W J / D'Haens, G / Feagan, B G / Jairath, V. ·Robarts Clinical Trials Inc., University of Western Ontario, London, Ontario, Canada. · Department of Gastroenterology, University of Ghent, Ghent, Belgium. · Department of Gastroenterology, Ljubljana University Medical Centre, Ljubljana, Slovenia. · Department of Medicine and Farncombe Family Digestive Health Research Institute, Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada. · Department of Medicine, University of Western Ontario, London, Ontario, Canada. · Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. · Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. ·Aliment Pharmacol Ther · Pubmed #28074618.

ABSTRACT: BACKGROUND: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. AIM: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. METHODS: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. RESULTS: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. CONCLUSIONS: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

11 Review Review article: pharmacological aspects of anti-TNF biosimilars in inflammatory bowel diseases. 2015

Papamichael, K / Van Stappen, T / Jairath, V / Gecse, K / Khanna, R / D'Haens, G / Vermeire, S / Gils, A / Feagan, B G / Levesque, B G / Vande Casteele, N. ·KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. · KU Leuven Department of Clinical and Experimental Medicine, Leuven, Belgium. · Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. · 1st Department of Medicine, Semmelweis University, Budapest, Hungary. · Robarts Clinical Trials Inc., London, ON, Canada. · Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. ·Aliment Pharmacol Ther · Pubmed #26365281.

ABSTRACT: BACKGROUND: Anti-tumour necrosis factor (anti-TNF) monoclonal antibodies have shown efficacy in inflammatory bowel diseases (IBD). As these therapies lose patent protection, biosimilar versions of the originator products are being developed, such as the infliximab biosimilar CT-P13; however, some uncertainty exists regarding their pharmacology in IBD. AIM: To review the literature on anti-TNF biosimilars focusing on pharmacokinetics, pharmacodynamic properties and comparative effectiveness, related to their use in IBD. METHODS: A PubMed literature search was performed using the following terms individually or in combination: 'biosimilars,' 'CT-P13,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'anti-TNFα therapy,' 'infliximab,' 'adalimumab,' 'pharmacokinetics,' 'immunogenicity.' RESULTS: Bioequivalence of CT-P13 and infliximab was shown in ankylosing spondylitis (AS) and therapeutic equivalence in rheumatoid arthritis (RA). Preliminary results of CT-P13 in IBD come from small post-marketing registries and case series with a relatively short-term follow-up period and suggest comparable efficacy and safety to infliximab. Inter- and intra-individual differences in exposure and response are well known for the original molecules but dosing regimens and concomitant medications are different for RA compared to IBD, limiting the ability to translate some of the pharmacology data in RA to IBD. Uncertainty exists about cross-reactivity of anti-drug antibodies and whether similar exposure-response relationships will be observed for biosimilars and efficacy thresholds for therapeutic drug monitoring can be used interchangeably. CONCLUSIONS: It is likely that biosimilars will be widely used for the treatment of IBD due to their cost savings and comparable efficacy. Nevertheless, robust post-marketing studies and pharmacovigilance are warranted in the coming years.

12 Review Pharmacokinetics of anti-TNF monoclonal antibodies in inflammatory bowel disease: Adding value to current practice. 2015

Vande Casteele, Niels / Gils, Ann. ·Department of Pharmaceutical and Pharmacological Sciences, Therapeutic and Diagnostic Antibodies, KU Leuven - University of Leuven, Herestraat, Leuven, Belgium. ·J Clin Pharmacol · Pubmed #25707962.

ABSTRACT: Since anti-tumor necrosis factor (TNF) antibodies were introduced to treat patients with inflammatory bowel diseases, short- and long-term clinical and endoscopic endpoints can be achieved that were unreachable with conventional anti-inflammatory agents. Although a large proportion of patients (70-90%) initially respond to the treatment, remission rates after induction are still low (20-50%) and patients are at risk to lose response to the drug over time. This inter-individual variability in response is likely to be influenced by the observed inter-individual variability in pharmacokinetics. By extensively reviewing the literature, we evaluated the potential role of therapeutic drug monitoring to optimize dosing of anti-TNF drugs. Thereby we emphasize some of the pharmacokinetic cornerstones that can help to understand the observed concentration-effect relationship. After discussing some of the most commonly used assays to measure anti-TNF drug and anti-drug antibody concentrations, we reviewed the application of those tests and their potential clinical value in retrospective and prospective studies.

13 Review An update on anti-TNF agents in ulcerative colitis. 2014

Samaan, Mark A / Bagi, Preet / Vande Casteele, Niels / D'Haens, Geert R / Levesque, Barrett G. ·Department of Gastroenterology, Academic Medical Centre, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. · Division of Gastroenterology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0956, 92103, USA. · Division of Gastroenterology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0956, 92103, USA. Electronic address: bglevesque@ucsd.edu. ·Gastroenterol Clin North Am · Pubmed #25110254.

ABSTRACT: Anti-tumor necrosis factor-α agents are key therapeutic options for the treatment of ulcerative colitis. Their efficacy and safety have been shown in large randomized controlled trials. The key evidence gained from these trials of infliximab, adalimumab, and golimumab is reviewed along with their effect on mucosal healing and long-term outcomes. Also reviewed are methods for optimizing their effectiveness, including therapeutic drug monitoring and treat-to-target strategies. Finally, remaining unresolved questions regarding their role and effectiveness are considered including how these may be addressed in future clinical trials.

14 Clinical Trial Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial. 2019

Jairath, Vipul / Peyrin-Biroulet, Laurent / Zou, Guangyong / Mosli, Mahmoud / Vande Casteele, Niels / Pai, Reetesh K / Valasek, Mark A / Marchal-Bressenot, Aude / Stitt, Larry W / Shackelton, Lisa M / Khanna, Reena / D'Haens, Geert R / Sandborn, William J / Olson, Allan / Feagan, Brian G / Pai, Rish K. ·Robarts Clinical Trials Inc., London, Ontario, Canada. · Department of Gastroenterology, Lorraine University, Vandoeuvre-lès-Nancy, France. · Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. · Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. · Department of Pathology, University of California, San Diego, La Jolla, California, USA. · Department of Pathology, University of Reims et Champagne-Ardenne, Reims, France. · Celgene, San Diego, California, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA. ·Gut · Pubmed #30076171.

ABSTRACT: OBJECTIVE: We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment. DESIGN: Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo. RESULTS: Inter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608-0.649). CONCLUSION: All four existing histological indices were similarly reliable and responsive based on this dataset.

15 Clinical Trial The effects of pregnancy on the pharmacokinetics of infliximab and adalimumab in inflammatory bowel disease. 2017

Seow, C H / Leung, Y / Vande Casteele, N / Ehteshami Afshar, E / Tanyingoh, D / Bindra, G / Stewart, M J / Beck, P L / Kaplan, G G / Ghosh, S / Panaccione, R. ·Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Canada. · Department of Community Health Sciences, University of Calgary, Calgary, Canada. · Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA. ·Aliment Pharmacol Ther · Pubmed #28318043.

ABSTRACT: BACKGROUND: Transplacental transfer of infliximab and adalimumab results in detectable drug levels in the cord blood and infant. AIM: To determine if pregnancy influenced the pharmacokinetics of anti-TNF agents in women with inflammatory bowel disease. METHODS: Twenty-five women from the University of Calgary inflammatory bowel disease(IBD) pregnancy clinic on maintenance infliximab or adalimumab were recruited prospectively with serum bio-banking performed each trimester. Infliximab trough and adalimumab steady-state levels were the outcomes of interest and were analysed using the ANSER infliximab and adalimumab assays. Multivariate linear mixed-effects models were constructed to assess infliximab and adalimumab drug levels during pregnancy adjusting for the clinical covariates of albumin, BMI and CRP. RESULTS: Fifteen women (eight Crohn's disease, seven ulcerative colitis) received infliximab and 10 women with 11 pregnancies were treated with adalimumab. Median age was 29.6 years (IQR: 27.6-31.2 years). Median disease duration was 9.2 years (IQR: 3.16-15.0 years). Median trough infliximab concentrations were 8.50 μg/mL (IQR: 7.23-10.07 μg/mL), 10.31 μg/mL (IQR: 7.66-15.63 μg/mL) and 21.02 μg/mL (IQR: 16.01-26.70 μg/mL) at trimesters 1, 2 and 3 respectively. Significant changes in albumin and BMI (P < 0.05) but not CRP (P > 0.05) were documented throughout pregnancy. After adjusting for albumin, BMI and CRP, infliximab trough levels increased during pregnancy, by 4.2 μg/mL per trimester (P = 0.02), while adalimumab drug levels remained stable (P > 0.05). CONCLUSIONS: Infliximab levels rise during pregnancy, whereas adalimumab levels remain stable after accounting for changes in albumin, BMI and CRP. Therapeutic drug monitoring in the second trimester may be useful in guiding dosing in the third trimester.

16 Article Adverse Events and Nocebo Effects in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. 2019

Ma, Christopher / Panaccione, Nicola R / Nguyen, Tran M / Guizzetti, Leonardo / Parker, Claire E / Hussein, Isra M / Vande Casteele, Niels / Khanna, Reena / Dulai, Parambir S / Singh, Siddharth / Feagan, Brian G / Jairath, Vipul. ·Division of Gastroenterology & Hepatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. · Robarts Clinical Trials, Inc., London, Ontario, Canada. · Faculty of Health Science, Western University, London, Ontario, Canada. · Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Department of Medicine, University of California San Diego, La Jolla, California, USA. · Division of Gastroenterology, Western University, London, Ontario, Canada. · Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. · Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. ·J Crohns Colitis · Pubmed #31111881.

ABSTRACT: BACKGROUND AND AIMS: Nocebo effects, adverse outcomes occurring in patients receiving inert therapy, contribute to adverse event [AE] reporting in randomized controlled trials [RCTs]. High placebo AE rates may result in inaccurate estimation of treatment-related AEs. We estimate the pooled rate of AEs in patients randomized to placebo compared to active therapy in inflammatory bowel disease [IBD] RCTs. METHODS: MEDLINE, EMBASE and CENTRAL were searched to March 1, 2017 for RCTs of conventional medical therapies for Crohn's disease [CD] or ulcerative colitis [UC]. Rates of AEs, serious AEs [SAEs], AE-related trial withdrawal, infections and worsening IBD were pooled using a random-effects model. RESULTS: We included 124 CD [n = 26 042] and 71 UC RCTs [n = 16 798]. The pooled placebo AE rate was 70.6% (95% confidence interval [CI]: 65.3%, 75.4%) and 54.5% [47.8%, 61.1%] in CD and UC RCTs, respectively. There was no significant risk difference [RD] in AE, SAE or AE-related withdrawal rates between CD patients receiving placebo or active drug. A 1.6% [95% CI: 0.1%, 3.1%] increase in AE rates was observed among UC patients randomized to active therapy. Patients receiving active therapy had a higher risk of infection (RD 1.0% [95% CI: 0.4%, 1.7%] for CD, 2.9% [95% CI: 1.4%, 4.4%] for UC) although a lower risk of worsening CD (RD -3.2% [95% CI: -4.8%, -1.5%]) or UC (RD -3.7% [95% CI: -5.7%, -1.8%]). CONCLUSIONS: AEs are commonly reported by patients randomized to either placebo or active treatment in IBD RCTs. Clinically relevant differences in AE, SAE and AE-related withdrawal were not observed.

17 Article Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases. 2019

Papamichael, Konstantinos / Cheifetz, Adam S / Melmed, Gil Y / Irving, Peter M / Vande Casteele, Niels / Kozuch, Patricia L / Raffals, Laura E / Baidoo, Leonard / Bressler, Brian / Devlin, Shane M / Jones, Jennifer / Kaplan, Gilaad G / Sparrow, Miles P / Velayos, Fernando S / Ullman, Thomas / Siegel, Corey A. ·Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. Electronic address: acheifet@bidmc.harvard.edu. · Cedars-Sinai Medical Center, Los Angeles, California. · Guy's and St. Thomas' Hospitals, London, United Kingdom. · University of California San Diego, La Jolla, California. · Thomas Jefferson University, Philadelphia, Pennsylvania. · Mayo Clinic, Rochester, Minnesota. · Northwestern University Feinberg School of Medicine, Chicago, Illinois. · University of British Columbia, Vancouver, Canada. · University of Calgary, Calgary, Alberta, Canada. · Dalhousie University, Halifax, Canada. · Alfred Hospital, Melbourne, Australia. · University of California San Francisco, San Francisco, California. · Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York. · Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. ·Clin Gastroenterol Hepatol · Pubmed #30928454.

ABSTRACT: BACKGROUND & AIMS: Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. METHODS: We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. RESULTS: The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. CONCLUSION: Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

18 Article Histologic Healing Rates of Medical Therapies for Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. 2019

Battat, Robert / Duijvestein, Marjolijn / Guizzetti, Leonardo / Choudhary, Daksh / Boland, Brigid S / Dulai, Parambir S / Parker, Claire E / Nguyen, Tran M / Singh, Siddharth / Vande Casteele, Niels / Pai, Rish K / Feagan, Brian G / Sandborn, William J / Jairath, Vipul. ·Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA. · Robarts Clinical Trials Inc., London, Ontario, Canada. · Academic Medical Center, Amsterdam, Netherlands. · Department of Medicine, University of Western Ontario, London, Ontario, Canada. · Department of Pathology, Mayo Clinic Arizona, Scottsdale, Arizona, USA. · Department of Epidemiology and Biostatistics, University of Western Ontario, London Ontario, Canada. ·Am J Gastroenterol · Pubmed #30694863.

ABSTRACT: OBJECTIVES: Histologic remission is a potentially valuable means of assessing disease activity and treatment response in ulcerative colitis (UC). However, the efficacy of existing therapies to achieve this outcome is unclear. We performed a systematic review and meta-analysis of histologic outcomes in UC randomized controlled trials and examined the relationship between histologic and endoscopic outcomes. METHODS: MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Register were searched for randomized controlled trials of aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. Histologic and endoscopic remission and response data were independently extracted and pooled using binomial-normal random-effect or fixed-effect models. Pooled efficacy estimates were calculated as risk ratios (RRs) using the Mantel-Haenszel method. Univariable and multivariable random-effect meta-regression models examined factors associated with histologic remission. RESULTS: Seventy-four studies (68 induction and 7 maintenance) were identified. Topical aminosalicylate enemas [37.2%, 95% confidence interval (CI), 29.0-46.3] and suppositories (44.9%, 95% CI, 28.9-62.3) had the highest induction of histologic remission rates. Aminosalicylate enemas (RR = 4.14, 95% CI, 2.35-7.31), aminosalicylate suppositories (RR = 3.94, 95% CI, 1.26-12.32), and budesonide multimatrix (RR = 1.47, 95% CI 1.08-1.99) had higher histologic remission rates than placebo. Data were lacking for biologics and immunosuppressives. The pooled histologic remission rate for placebo in induction studies was 10.4% (95% CI, 7.1-15.2). Histologic and endoscopic remission correlated strongly (r = 0.66; 95% CI, 0.50-0.78). In multivariate analysis of placebo-arm data, less severe clinical disease activity and corticosteroid use were associated with higher histologic remission rates. Similarly, mild clinical disease activity was associated with higher histologic remission rates when active-arm data were analyzed. CONCLUSIONS: Histologic remission rates for current UC treatments ranged from 15.0% to 44.9% according to drug class and patient population with the highest rates observed for topical aminosalicylates. Placebo remission rates were low with relatively narrow CIs. These data provide benchmarks to inform future trial design. Histologic remission is a potential treatment target in clinical practice.

19 Article Biomarkers Are Associated With Clinical and Endoscopic Outcomes With Vedolizumab Treatment in Ulcerative Colitis. 2019

Battat, Robert / Dulai, Parambir S / Vande Casteele, Niels / Evans, Elisabeth / Hester, Kelly D / Webster, Edvelyn / Jain, Anjali / Proudfoot, James A / Mairalles, Ara / Neill, Jennifer / Singh, Siddharth / Chang, John T / Rivera-Nieves, Jesus / Sandborn, William J / Boland, Brigid S. ·Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California. · Prometheus Laboratories Inc., San Diego, California. · Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California. ·Inflamm Bowel Dis · Pubmed #30295781.

ABSTRACT: Background: Vedolizumab inhibits α4β7-mediated lymphocyte trafficking and is effective in ulcerative colitis (UC). This study evaluated drug and biomarker concentrations and patient outcomes during vedolizumab treatment in UC. Methods: Prospectively scored maintenance clinical (26.5 weeks; interquartile range [IQR], 16.3-37.0 weeks) and endoscopic (23.5 weeks; IQR, 16.8-35.6 weeks) outcomes were compared with serum vedolizumab concentrations, antivedolizumab antibodies, and serum biomarkers at baseline and weeks 2, 6, 14, and 26. A linear mixed-effects model compared biomarker trajectories over time between clinical and endoscopic remitters and nonremitters. Results: Thirty-two patients were included. Soluble (s)-tumor necrosis factor (TNF)-α, s-α4β7, s-mucosal addressin cell adhesion molecule (s-MAdCAM-1), and s-amyloid A (s-AA) significantly changed with treatment. A linear mixed-effects model demonstrated that s-α4β7 (P = 0.044) increased and s-MAdCAM-1 (P = 0.006) and s-vascular cell adhesion molecule-1 (s-VCAM-1, P = 0.001) decreased more rapidly in patients achieving clinical remission in maintenance. S-MAdCAM-1 (P = 0.005), s-intracellular adhesion molecule-1 (ICAM-1; P = 0.014), s-VCAM-1 (P < 0.001), and s-TNF (P = 0.052) decreased more rapidly in endoscopic remitters. In clinical remitters, higher week 14 (20.3 ng/mL vs 6.0 ng/mL; P = 0.013) and week 26 (14.1 ng/mL vs 8.6 ng/mL; P = 0.05) s-α4β7 were observed. In endoscopic remitters, week 2 (6.7 pg/mL vs 17.8 pg/mL; P = 0.038) and week 6 (3.9 pg/mL vs 15.6 pg/mL; P = 0.005) s-TNF and week 14 s-VCAM (589.1 ng/mL vs 746.0 ng/mL; P = 0.05) were lower. Conclusion: Serum biomarkers were associated with outcomes in vedolizumab-treated UC patients. s-α4β7 increased, whereas s-MAdCAM-1, s-VCAM-1, s-ICAM-1, and s-TNF decreased more rapidly in remitters. At individual time points, induction s-TNF and maintenance s-VCAM-1 concentrations were lower, whereas maintenance s-α4β7 concentrations were higher in remitters.

20 Article Predictors and Management of Loss of Response to Vedolizumab in Inflammatory Bowel Disease. 2018

Shmidt, Eugenia / Kochhar, Gursimran / Hartke, Justin / Chilukuri, Prianka / Meserve, Joseph / Chaudrey, Khadija / Koliani-Pace, Jenna L / Hirten, Robert / Faleck, David / Barocas, Morris / Luo, Michelle / Lasch, Karen / Boland, Brigid S / Singh, Siddharth / Vande Casteele, Niels / Sagi, Sashidhar Varma / Fischer, Monika / Chang, Shannon / Bohm, Matthew / Lukin, Dana / Sultan, Keith / Swaminath, Arun / Hudesman, David / Gupta, Nitin / Kane, Sunanda / Loftus, Edward V / Sandborn, William J / Siegel, Corey A / Sands, Bruce E / Colombel, Jean-Frederic / Shen, Bo / Dulai, Parambir S. ·Icahn School of Medicine at Mount Sinai, New York, NY, USA. · University of Minnesota, Minneapolis, MN, USA. · Cleveland Clinic Foundation, Cleveland, OH, USA. · Indiana University, Indianapolis, IN, USA. · University of California, San Diego, La Jolla, CA, USA. · Mayo Clinic, Rochester, MN, USA. · Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · Takeda Pharmaceuticals USA Inc., Deerfield, IL, USA. · New York University (NYU), New York, NY, USA. · Montefiore Medical Center, New York, NY, USA. · North Shore University Hospital, Manhasset, NY, USA. · Lenox Hill Hospital, New York, NY, USA. · University of Mississippi, Jackson, MS, USA. ·Inflamm Bowel Dis · Pubmed #29788240.

ABSTRACT: Background: We quantified loss of response (LOR) to vedolizumab (VDZ) in clinical practice and assessed the effectiveness of VDZ dose intensification for managing LOR. Methods: Retrospective review (May 2014-December 2016) of a prospectively maintained inflammatory bowel disease (IBD) registry. Kaplan-Meier estimates were used to determine rates of LOR to VDZ . Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Success of recapturing response (>50% reduction in symptoms from baseline) and remission (complete resolution of symptoms) after dose intensification was quantified. Results: Cumulative rates for VDZ LOR were 20% at 6 months and 35% at 12 months, with slightly lower rates in Crohn's disease than in ulcerative colitis (6 months 15% vs 18% and 12 months 30% vs 39%, P = 0.03). On multivariable analysis, LOR to a tumor necrosis factor (TNF) antagonist before VDZ use was associated with an increased risk for LOR to VDZ [hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.25-2.97] in all patients. For Crohn's disease patients specifically, higher baseline C-reactive protein concentration was associated with increased risk for LOR to VDZ (HR 1.01 per mg/dL increase, 95% CI 1.01-1.02). Shortening of VDZ infusion interval from 8 to every 4 or 6 weeks recaptured response in 49% and remission in 18% of patients. Conclusions: LOR to a TNF antagonist before VDZ use and higher baseline C-reactive protein are important predictors of VDZ LOR. Treatment response can be recaptured in almost half of these patients with VDZ infusion interval shortening.

21 Article Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis. 2018

Ma, C / Guizzetti, L / Panaccione, R / Fedorak, R N / Pai, R K / Parker, C E / Nguyen, T M / Khanna, R / Vande Casteele, N / D'Haens, G / Sandborn, W J / Feagan, B G / Jairath, V. ·Division of Gastroenterology and Hepatology, University of Calgary, Calgary, AB, Canada. · Robarts Clinical Trials, Western University, London, ON, Canada. · Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada. · Department of Pathology and Laboratory Medicine, Mayo Clinic Arizona, Scottsdale, AZ, USA. · Department of Medicine, Western University, London, ON, Canada. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands. · Department of Epidemiology and Biostatistics, Western University, London, ON, Canada. ·Aliment Pharmacol Ther · Pubmed #29696670.

ABSTRACT: BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

22 Article High body mass index is associated with increased risk of treatment failure and surgery in biologic-treated patients with ulcerative colitis. 2018

Kurnool, S / Nguyen, N H / Proudfoot, J / Dulai, P S / Boland, B S / Vande Casteele, N / Evans, E / Grunvald, E L / Zarrinpar, A / Sandborn, W J / Singh, S. ·School of Medicine, University of California San Diego, La Jolla, CA, USA. · Department of Internal Medicine, University of California San Diego, La Jolla, CA, USA. · Biostatistics Unit, Altman Clinical and Translational Research Institute, University of California San Diego, La Jolla, CA, USA. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Weight Management Program, Department of Medicine, University of California San Diego, La Jolla, CA, USA. · Institute for Diabetes and Metabolic Health, University of California San Diego, La Jolla, CA, USA. · VA San Diego Health Systems, La Jolla, CA, USA. · Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, USA. ·Aliment Pharmacol Ther · Pubmed #29665045.

ABSTRACT: BACKGROUND: Though pharmacokinetic studies suggest accelerated biologic drug clearance with increasing body weight, evidence of obesity's impact on clinical outcomes in biologic-treated patients with ulcerative colitis (UC) is inconsistent. AIM: To evaluate the impact of obesity on real world response to biological therapy in patients with UC. METHODS: In a single-centre retrospective cohort study between 2011-2016 of biologic-treated patients with UC, we evaluated treatment response by baseline body mass index (BMI). Primary outcome was treatment failure (composite outcome of IBD-related surgery/hospitalisation or treatment modification including dose escalation, treatment discontinuation or addition of corticosteroids); secondary outcomes were risk of IBD-related surgery/hospitalisation and endoscopic remission. We conducted multivariate Cox proportional hazard analyses to evaluate the independent impact of BMI on clinical outcomes. Stratified analysis by weight-based regimens (infliximab) or fixed-dose regimens (adalimumab, golimumab, vedolizumab, certolizumab pegol) was performed. RESULTS: We included 160 biologic-treated UC patients (50% males, 55% on infliximab) with median (IQR) age 36 y (26-52) and BMI 24.3 kg/m CONCLUSION: BMI is independently associated with increased risk of treatment failure in biologic-treated patients with UC, independent of dosing regimen.

23 Article Assays for measurement of TNF antagonists in practice. 2017

Vande Casteele, Niels. ·Division of Gastroenterology, IBD Center, University of California San Diego, La Jolla, California, USA. · Department of Pharmaceutical and Pharmacological Sciences, Therapeutic and Diagnostic Antibodies, KU Leuven-University of Leuven, Leuven, Belgium. ·Frontline Gastroenterol · Pubmed #29067148.

ABSTRACT: Tumour necrosis factor (TNF) antagonist drug exposure is correlated with clinical, endoscopic and pathophysiological outcomes during induction and maintenance therapy. Measuring drug concentrations is therefore a useful tool when treating to target and optimising therapy. One of the main factors leading to suboptimal drug exposure is the formation of antidrug antibodies (ADAs), due to an immunogenic reaction of the immune system towards the non-self protein. The development of ADA does pose important concerns for drug efficacy and for safety as ADAs have been associated with acute infusion reactions, hypersensitivity reactions and serum sickness. Various assays exist to measure serum drug and ADA concentrations, either offered as a service in a specialised laboratory or commercially available as a kit. It is unclear how the performance of these assays relates to each other, until recently various comparative studies were carried out. The majority of these studies show that indeed a good correlation exists between the assays that measure drug, but that absolute concentrations can differ across tests. This is particularly relevant in clinical practice when a specific threshold or drug concentration range is targeted. For ADA assays, drug sensitivity or the ability of the assay to measure ADA in the presence of drug remains an important issue, especially for drugs with a higher dosing frequency. In addition, standardisation across ADA assays is difficult, making it hard to compare quantitative or semiquantitative (low/medium/high) results across assays and across studies.

24 Article Appropriateness of Testing for Anti-Tumor Necrosis Factor Agent and Antibody Concentrations, and Interpretation of Results. 2016

Melmed, Gil Y / Irving, Peter M / Jones, Jennifer / Kaplan, Gilaad G / Kozuch, Patricia L / Velayos, Fernando S / Baidoo, Leonard / Sparrow, Miles P / Bressler, Brian / Cheifetz, Adam S / Devlin, Shane M / Raffals, Laura E / Vande Casteele, Niels / Mould, Diane R / Colombel, Jean-Fred / Dubinsky, Marla / Sandborn, William J / Siegel, Corey A. ·Cedars-Sinai Medical Center, Los Angeles, California. Electronic address: gil.melmed@cshs.org. · Guy's and St. Thomas' Hospitals, London, United Kingdom. · Dalhousie University, Halifax, Canada. · University of Calgary, Calgary, Canada. · Jefferson University, Philadelphia, Pennsylvania. · University of California San Francisco, San Francisco, California. · University of Pittsburgh, Pittsburgh, Pennsylvania. · Alfred Hospital, Melbourne, Australia. · University of British Columbia, Vancouver, Canada. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Mayo Clinic, Rochester, Minnesota. · University of California San Diego, San Diego, California; KU Leuven - University of Leuven, Leuven, Belgium. · Projections Research Inc, Phoenixville, Pennsylvania. · Icahn School of Medicine at Mount Sinai, New York, New York. · University of California San Diego, San Diego, California. · Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. ·Clin Gastroenterol Hepatol · Pubmed #27189916.

ABSTRACT: BACKGROUND & AIMS: The availability of tests for blood concentrations of anti-tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. METHODS: We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. RESULTS: Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. CONCLUSIONS: Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.

25 Article Long-Term Outcome of Patients with Ulcerative Colitis and Primary Non-response to Infliximab. 2016

Papamichael, Konstantinos / Rivals-Lerebours, Oliviane / Billiet, Thomas / Vande Casteele, Niels / Gils, Ann / Ferrante, Marc / Van Assche, Gert / Rutgeerts, Paul J / Mantzaris, Gerassimos J / Peyrin-Biroulet, Laurent / Vermeire, Severine. ·KU Leuven, Translational Research Center for Gastrointestinal Disorders, and University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium Evangelismos Hospital, Department of Gastroenterology, Athens, Greece. · Nancy University Hospital, Inserm U954 and Department of Gastroenterology, Nancy, France. · KU Leuven, Translational Research Center for Gastrointestinal Disorders, and University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium. · KU Leuven, Laboratory for Therapeutic and Diagnostic Antibodies, Leuven, Belgium. · Evangelismos Hospital, Department of Gastroenterology, Athens, Greece. · KU Leuven, Translational Research Center for Gastrointestinal Disorders, and University Hospitals Leuven, Department of Gastroenterology, Leuven, Belgium severine.vermeire@uzleuven.be. ·J Crohns Colitis · Pubmed #27022161.

ABSTRACT: BACKGROUND AND AIMS: We studied the long-term outcome of patients with ulcerative colitis [UC] and primary non response [PNR] to infliximab and searched for predictors of colectomy in these patients. METHODS: This retrospective, multi-centre study included UC patients from three European referral centres, with PNR to infliximab defined as a lack of clinical improvement after the induction therapy, leading to drug discontinuation. Relapse, for patients who continued on biologicals after PNR to infliximab, was defined as drug discontinuation for PNR, loss of response, or serious adverse event. Serum infliximab concentrations at Weeks 2 and 6 were evaluated using an enzyme-linked immunosorbent assay [ELISA] developed in house. RESULTS: The study population consisted of 99 anti-tumour necrosis factor [TNF]-naïve patients with UC and PNR to infliximab. At the end of follow-up (median: 3.2 [interquartile range 1-6.3] years), 55 [55.6%] of these patients underwent colectomy. Multiple Cox regression analysis identified acute severe UC (hazard ratio [HR]: 24; 95% confidence interval [CI]: 2.5-231; p = 0.006], baseline C-reactive protein [CRP] > 5mg/l [HR: 11; 95% CI: 2.1-58.8; p = 0.005], baseline albumin < 40g/l [HR: 9.5; 95% CI: 1.3-71.4; p = 0.026], and infliximab concentration at Week 2 < 16.5 μg/ml [HR: 5.6; 95% CI: 1.1-27.8; p = 0.034] as independent predictors of colectomy. Regarding patients who continued on biologicals after PNR to infliximab, there was a marginally higher cumulative probability for relapse in patients switching to another anti-TNF agent compared with those swapping to vedolizumab [p logrank = 0.08]. CONCLUSIONS: About half of UC patients with PNR to infliximab will undergo colectomy. Patients with severe inflammation and low serum infliximab concetrations during the induction phase are at greatest risk.

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