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Ulcerative Colitis: HELP
Articles from University of Pennsylvania
Based on 97 articles published since 2008
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These are the 97 published articles about Colitis, Ulcerative that originated from University of Pennsylvania during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Infliximab vs Adalimumab for UC: Is There A Difference? 2017

Osterman, Mark T / Lichtenstein, Gary R. ·Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. ·Clin Gastroenterol Hepatol · Pubmed #28479503.

ABSTRACT: -- No abstract --

2 Editorial Dietary Recommendations for Ulcerative Colitis Remain a Mystery. 2017

Hou, Jason K / Lewis, James D. ·Houston VA HSR&D Center of Excellence and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas. · Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania; Departments of Medicine and Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania. ·Clin Gastroenterol Hepatol · Pubmed #28433782.

ABSTRACT: -- No abstract --

3 Editorial Challenges in detection and real-time diagnosis of dysplasia in Crohn's colitis: the search still continues. 2016

Buchner, Anna M. ·Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Gastrointest Endosc · Pubmed #27102530.

ABSTRACT: -- No abstract --

4 Editorial Editorial: Early corticosteroids in ulcerative colitis--authors' reply. 2014

Khan, N H / Almukhtar, R M. ·Department of Internal Medicine, Section of Gastroenterology, Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA; Section of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia VA Medical Center, Philadelphia, PA, USA. nabeel.khan@va.gov. ·Aliment Pharmacol Ther · Pubmed #25123385.

ABSTRACT: -- No abstract --

5 Review Evolving Considerations for Thiopurine Therapy for Inflammatory Bowel Diseases-A Clinical Practice Update: Commentary. 2019

Hanauer, Stephen B / Sandborn, William J / Lichtenstein, Gary R. ·Digestive Health Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois. · Division of Gastroenterology, University of California, San Diego, La Jolla, California. · Division of Gastroenterology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: grl@uphs.upenn.edu. ·Gastroenterology · Pubmed #30195449.

ABSTRACT: Thiopurines (azathioprine, mercaptopurine, thioguanine) and methotrexate are widely used in a variety of clinical management scenarios for ulcerative colitis and Crohn's disease. With the introduction of biologic therapies over the last 2 decades, controversies have emerged as to how these immunomodulators should be used in clinical practice, either alone as monotherapies or in combination with biologic therapies. Here, we provide a summary of evidence and our interpretations regarding how physicians can or should incorporate these agents into clinical practice. We have organized the review into sections regarding their utility as monotherapy or as combination therapy with biologics and safety considerations. Clinical pharmacologic considerations are important regarding both efficacy and safety.

6 Review Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. 2017

Saubermann, Lawrence J / Deneau, Mark / Falcone, Richard A / Murray, Karen F / Ali, Sabina / Kohli, Rohit / Ekong, Udeme D / Valentino, Pamela L / Grossman, Andrew B / Rand, Elizabeth B / Jonas, Maureen M / Saeed, Shehzad A / Kamath, Binita M. ·*Division of Pediatric Gastroenterology and Nutrition, Golisano Children's Hospital, University of Rochester, Rochester, NY †Division of Pediatric Gastroenterology, University of Utah, Salt Lake City ‡Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH §Division of Pediatric Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, WA ||Division of Pediatric Gastroenterology, Stanford Children's Health, Palo Alto, CA ¶Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH #Section of Pediatric Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, CT **Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Harvard Medical School, Boston, MA ††Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia ‡‡Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA §§Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Canada. ·J Pediatr Gastroenterol Nutr · Pubmed #27984347.

ABSTRACT: Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD.

7 Review Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches. 2017

Sartor, R Balfour / Wu, Gary D. ·Departments of Medicine, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Electronic address: rbs@med.unc.edu. · Division of Gastroenterology, Perelman School of Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: gdwu@mail.med.upenn.edu. ·Gastroenterology · Pubmed #27769810.

ABSTRACT: Intestinal microbiota are involved in the pathogenesis of Crohn's disease, ulcerative colitis, and pouchitis. We review the mechanisms by which these gut bacteria, fungi, and viruses mediate mucosal homeostasis via their composite genes (metagenome) and metabolic products (metabolome). We explain how alterations to their profiles and functions under conditions of dysbiosis contribute to inflammation and effector immune responses that mediate inflammatory bowel diseases (IBD) in humans and enterocolitis in mice. It could be possible to engineer the intestinal environment by modifying the microbiota community structure or function to treat patients with IBD-either with individual agents, via dietary management, or as adjuncts to immunosuppressive drugs. We summarize the latest information on therapeutic use of fecal microbial transplantation and propose improved strategies to selectively normalize the dysbiotic microbiome in personalized approaches to treatment.

8 Review Application of computational methods in genetic study of inflammatory bowel disease. 2016

Li, Jin / Wei, Zhi / Hakonarson, Hakon. ·Jin Li, Hakon Hakonarson, Center for Applied Genomics, Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States. ·World J Gastroenterol · Pubmed #26811639.

ABSTRACT: Genetic factors play an important role in the etiology of inflammatory bowel disease (IBD). The launch of genome-wide association study (GWAS) represents a landmark in the genetic study of human complex disease. Concurrently, computational methods have undergone rapid development during the past a few years, which led to the identification of numerous disease susceptibility loci. IBD is one of the successful examples of GWAS and related analyses. A total of 163 genetic loci and multiple signaling pathways have been identified to be associated with IBD. Pleiotropic effects were found for many of these loci; and risk prediction models were built based on a broad spectrum of genetic variants. Important gene-gene, gene-environment interactions and key contributions of gut microbiome are being discovered. Here we will review the different types of analyses that have been applied to IBD genetic study, discuss the computational methods for each type of analysis, and summarize the discoveries made in IBD research with the application of these methods.

9 Review Budesonide Multi-matrix for the Treatment of Patients with Ulcerative Colitis. 2016

Lichtenstein, Gary R. ·Division of Gastroenterology, Department of Medicine, University of Pennsylvania Health System, GI Administration Offices, 7th Floor Perelman Center, Room 753, 3400 Civic Center Boulevard, Philadelphia, PA, 19104-4283, USA. grl@uphs.upenn.edu. ·Dig Dis Sci · Pubmed #26541989.

ABSTRACT: Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder in which patients cycle between active disease and remission. Budesonide multi-matrix (MMX) is an oral second-generation corticosteroid designed to deliver active drug throughout the colon. In pharmacokinetic studies, the mean relative absorption of budesonide in the region between the ascending colon and the descending/sigmoid colon was 95.9 %. In 2 identically designed, phase 3 studies (CORE I and II), budesonide MMX 9 mg once daily was efficacious and well tolerated for induction of remission of mild to moderate UC. Clinical and endoscopic remission rates were 17.9 % (CORE I) and 17.4 % (CORE II) for budesonide MMX 9 mg compared with 7.4 and 4.5 %, respectively, with placebo (p < 0.05, budesonide MMX 9 mg vs. placebo in both studies), 12.1 % with mesalamine 2.4 g, and 12.6 % with budesonide controlled ileal release capsules 9 mg. A 12-month maintenance therapy study suggested that budesonide MMX 6 mg may prolong time to clinical relapse: Median time was >1 year with budesonide MMX 6 mg versus 181 days (p = 0.02) with placebo; however, further studies are needed. In the CORE studies, budesonide MMX exhibited a favorable safety profile; the majority of adverse events were mild or moderate in intensity, and serious adverse events were uncommon. Furthermore, rates of potential glucocorticoid-related adverse events were comparable across treatment groups. The long-term (12-month) safety of budesonide MMX appears to be comparable with placebo. Data support budesonide MMX in the management algorithm of UC.

10 Review Therapy of inflammatory bowel disease: what to expect in the next decade. 2014

Leiman, David A / Lichtenstein, Gary R. ·Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. ·Curr Opin Gastroenterol · Pubmed #24902037.

ABSTRACT: PURPOSE OF REVIEW: The increased understanding of the molecular mechanisms that are responsible for inflammatory bowel disease (IBD) has led to a wide range of potential therapeutic targets for this condition. Physicians treating individuals with Crohn's disease and ulcerative colitis have a growing armamentarium of options to choose from in managing these patients. This article aims to summarize the relevant literature in the area of emerging therapy in IBD. RECENT FINDINGS: The widespread use of antitumor necrosis factor medications brought a landmark change in the treatment of IBD. More recently, several drugs have been shown to provide benefit in IBD in phase III studies by blocking other antiinflammatory pathways. The most likely new medications that will be available include vedolizumab for ulcerative colitis and ustekinumab for Crohn's disease, which target cellular adhesion and inflammatory cell signaling, respectively. Other promising drugs focus on blockade of Janus kinase, inhibition of various chemokines, and biologic therapy such as hematopoietic stem cell transplants and mesenchymal cell infusions. SUMMARY: The growing understanding of the pathogenesis of IBD has led to new molecular targets for therapy. Over the next decade, the number of treatments available will grow, targeting cellular adhesion, protein regulation, inflammatory signal pathways, and immune tolerance.

11 Review Treatment of ulcerative colitis. 2014

Blonski, Wojciech / Buchner, Anna M / Lichtenstein, Gary R. ·aDepartment of Internal Medicine, United Health Services, Johnson City, New York bDivision of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Curr Opin Gastroenterol · Pubmed #24285003.

ABSTRACT: PURPOSE OF REVIEW: Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause that is characterized by alternating intervals of active and inactive disease in 80-90% of patients. The primary goal of treatment is to induce and maintain remission using therapy tailored to the individual patient. The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti-tumor necrosis factor (TNF) agents. RECENT FINDINGS: Recent research has shown that new anti-TNF agents, adalimumab (ADA) and golimumab, are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis. In a recent study, infliximab was found to have comparable efficacy to cyclosporine in treatment of acute severe refractory to corticosteroids ulcerative colitis. SUMMARY: Anti-TNF therapy should be initiated in patients with acute severe refractory to corticosteroids ulcerative colitis and in patients with moderate-to-severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates, corticosteroids and immune modulators. Alternatives to infliximab are ADA and golimumab. Future research is needed to further assess the long-term efficacy and safety of ADA and golimumab in ulcerative colitis.

12 Review Mucosal healing in inflammatory bowel disease. 2013

Osterman, Mark T. ·Pennsylvania Presbyterian Medical Center, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. mark.osterman@uphs.upenn.edu ·J Clin Gastroenterol · Pubmed #23340060.

ABSTRACT: It is becoming increasingly recognized that purely clinical endpoints may not be sufficient in the treatment of patients with inflammatory bowel disease. As such, mucosal disease assessment has become a prominent component of the majority of recent clinical trials in Crohn's disease and ulcerative colitis. There is mounting evidence that the attainment of mucosal healing leads to improved clinical outcomes in both Crohn's disease and ulcerative colitis. However, the use of mucosal healing as a therapeutic endpoint in inflammatory bowel disease is in its early stages, as a number of issues limit its application to routine clinical practice.

13 Review Clinical predictors of aggressive/disabling disease: ulcerative colitis and crohn disease. 2012

Blonski, Wojciech / Buchner, Anna M / Lichtenstein, Gary R. ·Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA 19104-4283, USA. ·Gastroenterol Clin North Am · Pubmed #22500528.

ABSTRACT: Many clinical factors predict the aggressive course of CD. Younger age at initial diagnosis, the presence of perianal lesions, ileal involvement, smoking, and the need for therapy with corticosteroids are the major predictors of disabling disease or change of behavior to a more aggressive disease. On the other hand, treatment with azathioprine and biologic agents and colonic localization of disease are the major factors that are predictive of less aggressive CD course. The problem we face with determining the factors that increase the risk of disabling disease is that there is no standardized and consistent definition of disabling or aggressive disease. Only two studies analyzed predictors using the same definition of aggressive disease. Only Beaugerie and colleagues developed the score predictive of disabling disease based on three independent factors associated with disabling course that were present at the time of initial diagnosis of CD (requirement of corticosteroids, age less than 40 years, and presence of perianal disease). This score ranged from 0 to 3 points based on the presence of given parameters. The positive predictive value was 0.91 and 0.93 in patients having two or three risk factors, 0.61 for no factors present, and 0.67 for one factor present. In order to determine factors predictive of disabling CD there is a need to establish consistent definition of disabling disease with subsequent future studies on large group of patients to validate such definition and determine factors that may predict the aggressive course.

14 Review The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease. 2011

Lewis, James D. ·Center for Clinical Epidemiology and Biostatistics, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. lewisjd@mail.med.upenn.edu ·Gastroenterology · Pubmed #21530748.

ABSTRACT: Fecal and serologic biomarkers can be used in the diagnosis and management of inflammatory bowel disease (IBD). Fecal markers such as calprotectin and lactoferrin have been studied for their ability to identify patients with IBD, assess disease activity, and predict relapse. Antibodies against Saccharomyces cerevisiae and perinuclear antineutrophil cytoplasmic proteins have been used in diagnosis of IBD, to distinguish Crohn's disease (CD) from ulcerative colitis, and to predict the risk of complications of CD. Tests for C-reactive protein and erythrocyte sedimentation rate have been used to assess inflammatory processes and predict the course of IBD progression. Levels of drug metabolites and antibodies against therapeutic agents might be measured to determine why patients do not respond to therapy and to select alternative treatments. This review addresses the potential for biomarker assays to improve treatment strategies and challenges to their use and development.

15 Review Clinical pharmacology of 5-ASA compounds in inflammatory bowel disease. 2010

Sonu, Irene / Lin, Ming Valerie / Blonski, Wojciech / Lichtenstein, Gary R. ·University of Pennsylvania School of Medicine, Suite 100, Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104, USA. ·Gastroenterol Clin North Am · Pubmed #20951918.

ABSTRACT: Mesalamine has been the first-line of therapy in patients with inflammatory bowel disease (IBD) since the 1960s. This article serves as a review of the different 5-aminosalicylic acid compounds, release formulations, use and dosing in the treatment of IBD, in particular ulcerative colitis.

16 Review An approach to the management of refractory ulcerative colitis. 2010

Sonu, I / Blonski, W / Lin, M V / Lichtenstein, G R. ·University of Pennsylvania, School of Medicine, Philadelphia, PA, USA. ·Minerva Gastroenterol Dietol · Pubmed #20485258.

ABSTRACT: Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology associated with dysregulation of the gastrointestinal mucosal immune system. It is characterized by a waxing and waning course and approximately 15% of UC patients will experience a severe episode. The first line treatment for severe colitis includes IV corticosteroids, however, 40% of patients are non-responsive to corticosteroid therapy and may require either colectomy, intravenous infliximab or intravenous cyclosporine within 3-5 days of presentation. This review focuses on the management and treatment approaches to refractory UC.

17 Review Importance of mucosal healing in ulcerative colitis. 2010

Lichtenstein, Gary R / Rutgeerts, Paul. ·Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA 19104-4283, USA. gary.lichtenstein@uphs.upenn.edu ·Inflamm Bowel Dis · Pubmed #19637362.

ABSTRACT: Treatment of patients with ulcerative colitis (UC) has traditionally focused on improving symptoms, with the main objective of inducing and maintaining symptomatic remission. However, new evidence suggests that concentrating exclusively on clinical outcome measures may not be adequate to achieve long-term treatment success. Indeed, physicians should also be assessing the reduction of endoscopic activity, with the intention of achieving complete mucosal healing (defined as the absence of all mucosal ulceration, both microscopic and macroscopic, providing a sigmoidoscopy score of 0, as assessed on the Ulcerative Colitis Disease Activity Index). As a consequence of the customary reliance on symptomatic outcome measures, relatively few clinical trials have used mucosal healing or a composite including mucosal healing as a primary endpoint. This situation may soon change as new guidelines recommend the incorporation of mucosal healing into the primary endpoint of all new clinical trials in patients with UC. These recommendations are derived, in part, from data that have illustrated a correlation between mucosal healing and several important factors including long-term remission rates, disease-related complications (e.g., risk of colorectal cancer), healthcare utilization (e.g., need for colectomy), and patient quality of life. We already have drugs available to us that can effectively induce and maintain complete mucosal healing over long periods of time. This review evaluates the effect of medical therapy on mucosal healing in patients with UC and explores the importance of this outcome measure, both from the patient's perspective and clinical trial experience. Inflamm Bowel Dis 2009.

18 Review Reformulation of an aminosalicylate: an example of the importance of pill burden on medical compliance rates. 2009

Osterman, Mark T / Lichtenstein, Gary R. ·Division of Gastroenterology, Department of Medicine, Penn Presbyterian Medical Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA. ·Methods Find Exp Clin Pharmacol · Pubmed #19357797.

ABSTRACT: Ulcerative colitis is an idiopathic chronic inflammatory disease of the colon characterized by symptoms of bloody diarrhea and abdominal pain. Although conventional aminosalicylates have been the foundation of treatment of mild to moderate ulcerative colitis for both the induction and maintenance of remission, they are limited in a number of ways, such as which formulation and what dose are optimal, as well as the high pill burden, which often leads to low compliance with these medications. Multi-Matrix System (MMX) mesalamine (SPD476) is a promising new aminosalicylate formulation; it seems to have solved some of the problems of conventional aminosalicylates, as it is effective as a once-daily treatment in high doses and induces both clinical remission and endoscopic mucosal healing. This review article summarizes the data on the use of both conventional aminosalicylates and MMX mesalamine in the treatment of ulcerative colitis.

19 Review Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis--methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosa. 2008

Lichtenstein, G R / Kamm, M A. ·Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. gary.lichtenstein@uphs.upenn.edu ·Aliment Pharmacol Ther · Pubmed #18532992.

ABSTRACT: BACKGROUND: Many oral 5-aminosalicylic acid (5-ASA) formulations are designed to maximize 5-ASA release in the colon where it acts topically on the colonic mucosa. Delayed-release formulations and azo-prodrugs minimize 5-ASA absorption in the upper gastrointestinal (GI) tract. AIMS: To review methods for assessing 5-ASA release and colonic distribution from oral formulations, and the potential use of this information for guiding clinical decisions. METHODS: PubMed and recent conference abstracts were searched for articles describing techniques used to assess 5-ASA release from ulcerative colitis (UC) therapies. RESULTS: In-vitro GI models, although unable to simulate more complex aspects of GI physiology, can provide useful data on 5-ASA release kinetics and bioaccessibility. Gamma-scintigraphy is useful for investigating GI disintegration of different formulations, but may not accurately reflect 5-ASA distribution. Plasma pharmacokinetic studies provide data on systemic exposure, but not on colonic distribution or mucosal uptake. Mucosal biopsies provide direct evidence of colonic distribution and may predict clinical efficacy, but must be interpreted cautiously because of considerable inter-subject variability and other confounding factors. CONCLUSION: While assessment of 5-ASA release is important, limitations of individual measurement techniques mean that randomized clinical studies in UC patients remain the best guide for dosing and treatment regimen decisions.

20 Review Maximizing patient adherence and clinical outcomes with mesalamine in mildly-to-moderately active ulcerative colitis. 2008

Lichtenstein, Gary R / Rubin, David T / Sabesin, Seymour M / Velayos, Fernando S / Vitat, Philippe. ·Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Rev Gastroenterol Disord · Pubmed #18477967.

ABSTRACT: Recent evidence suggests that there is a link between increased colonic inflammation and risk of colorectal cancer, stressing the importance of preventing relapse. The risk of relapse is associated with several factors, of which the foremost is patient nonadherence to prescribed medical therapy. Nonadherence may be affected by such factors as complicated dosing regimens, forgetfulness, male sex, and treatment delivery methods. Mesalamine is the standard, first-line therapy and the treatment of choice for inducing and maintaining clinical and endoscopic remission of inflammation in patients with mild-to-moderate ulcerative colitis. Novel formulations of mesalamine and newly devised, high-dose regimens offer additional therapeutic options and may lead to improved treatment adherence, longer-lasting periods of remission, and enhanced patient well-being.

21 Review Classification of genetic profiles of Crohn's disease: a focus on the ATG16L1 gene. 2008

Grant, Struan F A / Baldassano, Robert N / Hakonarson, Hakon. ·The Center for Applied Genomics and Division of Human Genetics, The Abramson Research Center of the Joseph Stokes Jr Research Institute, Department of Pediatrics, The Children's Hospital of Philadelphia, PA 19104-4318, USA. grants@chop.edu ·Expert Rev Mol Diagn · Pubmed #18366306.

ABSTRACT: Inflammatory bowel disease constitutes two related clinical entities, Crohn's disease (CD) and ulcerative colitis (UC), both of which have increased in prevalence over the last decade. Family and twin studies have strongly indicated that genetic factors play a large role in an individual's risk of developing inflammatory bowel disease. Despite this, it has proven difficult to isolate disease genes that confer susceptibility to this disease using classical candidate gene and linkage approaches, with the notable exception of the isolation of the caspase recruitment domain family, member 15 (CARD15) gene. However, over the last 2 years, genome-wide association (GWA) studies have become feasible, where modern high-throughput single nucleotide polymorphism (SNP) genotyping technologies can be applied to large and comprehensively phenotyped patient cohorts. Such approaches have enabled scientists to robustly associate specific variants with many complex diseases, including age-related macular degeneration, Type 2 diabetes, breast cancer and asthma. In the inflammatory bowel disease field, positive associations with CD and UC coming from GWA studies have been reported for an ever increasing number of genes. The most consistently and strongly associated variants have been in the CARD15, the interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes. With respect to ATG16L1, the G allele of SNP rs2241880 has been shown in multiple association studies to confer strong risk for CD, although its association with UC remains more debatable. This SNP is in fact a common coding variant, specifically a threonine-to-alanine substitution at amino acid position 300 of the ATG16L1 protein (T300A), and appears to account for all of the disease risk conferred by this locus. This review addresses recent advances in GWA studies of inflammatory bowel disease, with specific focus on the growing evidence of the ATG16L1 gene's role in CD and how its protein product operating within the autophagic pathway makes autophagy an attractive therapeutic target for this debilitating disorder.

22 Clinical Trial Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study. 2019

Hyams, Jeffrey S / Davis Thomas, Sonia / Gotman, Nathan / Haberman, Yael / Karns, Rebekah / Schirmer, Melanie / Mo, Angela / Mack, David R / Boyle, Brendan / Griffiths, Anne M / LeLeiko, Neal S / Sauer, Cary G / Keljo, David J / Markowitz, James / Baker, Susan S / Rosh, Joel / Baldassano, Robert N / Patel, Ashish / Pfefferkorn, Marian / Otley, Anthony / Heyman, Melvin / Noe, Joshua / Oliva-Hemker, Maria / Rufo, Paul A / Strople, Jennifer / Ziring, David / Guthery, Stephen L / Sudel, Boris / Benkov, Keith / Wali, Prateek / Moulton, Dedrick / Evans, Jonathan / Kappelman, Michael D / Marquis, M Alison / Sylvester, Francisco A / Collins, Margaret H / Venkateswaran, Suresh / Dubinsky, Marla / Tangpricha, Vin / Spada, Krista L / Saul, Bradley / Wang, Jessie / Serrano, Jose / Hommel, Kevin / Marigorta, Urko M / Gibson, Greg / Xavier, Ramnik J / Kugathasan, Subra / Walters, Thomas / Denson, Lee A. ·Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA. Electronic address: jhyams@connecticutchildrens.org. · Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC, USA; Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA; RTI International, Research Triangle Park, NC, USA. · Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA; Sheba Medical Center, affiliated with the Tel Aviv University, Tel Hashomer, Israel. · Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA. · The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Biostatistics, Harvard T H Chan School of Public Health, Boston, MA, USA. · Georgia Institute of Technology, Atlanta, GA, USA. · School of Biological Sciences, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA. · Divisioin of Pediatric Gastroenterology, Hospital For Sick Children, Toronto, ON, Canada. · IBD Centre, Department of Paediatrics, Hasbro Children's Hospital, Providence, RI, USA. · Divisioin of Pediatric Gastroenterology, Nutritiion, and Liver Disease, Emory University, Atlanta, GA, USA. · Division of Gastroenterology, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Cohen Children's Medical Center Of New York, New Hyde Park, NY, USA. · Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Women & Children's Hospital of Buffalo WCHOB, Buffalo, NY, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Goryeb Children's Hospital, Atlantic Health, Morristown, NJ, USA. · Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. · Division of Gastroenterology, Hepatology, and Nutrition, UT Southwestern, Dallas, TX, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Riley Children's Hospital Indiana, Indianapolis, IN, USA. · Division of Gastroenterology, Hepatology, and Nutrition, IWK Health Centre, Halifax, NS, Canada. · Division of Gastroenterology, Hepatology, and Nutrition, University of California at San Francisco, San Francisco, CA, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Johns Hopkins Children's Center, Baltimore, MD, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital Boston, Harvard Medical School Boston, MA, USA. · Division of Gastroenterology, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA. · Division of Gastroenterology, Hepatology, and Nutrition, UCLA Medical Center, Los Angeles, CA, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Primary Children's Hospital and the University of Utah, Salt Lake City, UT, USA. · Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota Medical Center, Minneapolis, MN, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Mt Sinai Hospital, New York City, NY, USA. · Division of Gastroenterology, Hepatology, and Nutrition, State University of New York Upstate Medical University, Syracuse, NY, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Monroe Carell Jr Children's Hospital of Vanderbilt, Nashville, TN, USA. · Division of Gastroenterology, Hepatology, and Nutrition, Nemours Children's Clinic, Jacksonville, FL, USA. · Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA. · Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA. · National Institutes of Diabetes, Digestive and Kidney Diseases, Bethesda, MD, USA. · The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Computational and Integrative Biology, Gastrointestinal Unit, and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA. ·Lancet · Pubmed #30935734.

ABSTRACT: BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.

23 Clinical Trial Peficitinib, an Oral Janus Kinase Inhibitor, in Moderate-to-severe Ulcerative Colitis: Results From a Randomised, Phase 2 Study. 2018

Sands, Bruce E / Sandborn, William J / Feagan, Brian G / Lichtenstein, Gary R / Zhang, Hongyan / Strauss, Richard / Szapary, Philippe / Johanns, Jewel / Panes, Julian / Vermeire, Severine / O'Brien, Christopher D / Yang, Zijiang / Bertelsen, Kirk / Marano, Colleen / Anonymous1851071. ·Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. · Department of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Robarts Clinical Trials Inc., Western University, London, ON, Canada. · Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA, USA. · Immunology, Janssen Research & Development, LLC, Spring House, PA, USA. · Department of Gastroenterology, Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. · Departments of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium. ·J Crohns Colitis · Pubmed #29917064.

ABSTRACT: Background and Aims: Janus kinase [JAK] inhibitors have shown efficacy in ulcerative colitis [UC]. We studied the dose-response, efficacy, and safety of peficitinib, an oral JAK inhibitor, in patients with moderate-to-severe UC. Methods: In this Phase 2b, dose-ranging trial, we evaluated peficitinib at 25 mg once daily [o.d.], 75 mg o.d., 150 mg o.d., and 75 mg twice daily versus placebo for efficacy and safety in 219 patients with moderate-to-severe UC. The primary outcome was peficitinib dose-response at Week 8, with response assessed using Mayo score change from baseline. Secondary endpoints were clinical response, clinical remission, mucosal healing, change from baseline in Inflammatory Bowel Disease Questionnaire [IBDQ], and normalisation of inflammatory biomarkers at Week 8; other secondary endpoints were treatment response through Week 16 and through Week 32 for patients in clinical response at Week 8. Safety was assessed through Week 36 or 4 weeks after the last dose. Results: A statistically significant peficitinib dose-response was not demonstrated at Week 8, although a numerically greater proportion of patients receiving peficitinib ≥75 mg o.d. achieved clinical response, remission, and mucosal healing at Week 8, supported by IBDQ improvement and inflammatory biomarker normalisation. Treatment-emergent adverse event [TEAE] rates reported through Week 8 and the final safety visit were higher in the combined peficitinib group than in the placebo group; patients receiving doses of ≥75 mg o.d. peficitinib reported TEAEs more frequently. Conclusions: No dose-response in patients with moderate-to-severe UC was demonstrated with peficitinib, but evidence of efficacy was suggested at doses ≥75 mg o.d. The safety profile of peficitinib was consistent with current information. ClinicalTrials.gov NCT01959282.

24 Clinical Trial Once-daily mesalamine granules for maintaining remission of ulcerative colitis: pooled analysis of efficacy, safety, and prognostic factors. 2016

Zakko, Salam F / Gordon, Glenn L / Murthy, Uma / Sedghi, Shahriar / Pruitt, Ronald / Barrett, Andrew C / Bortey, Enoch / Paterson, Craig / Forbes, William P / Lichtenstein, Gary R. ·a Connecticut Gastroenterology Institute , Bristol Hospital , Bristol , Connecticut , USA. · b Center for Digestive and Liver Diseases, Inc ., Mexico , Missouri , USA. · c Department of Medicine , Syracuse VA Medical Center , Syracuse , New York , USA. · d Gastroenterology Associates of Central Georgia, LLC , Macon , Georgia , USA. · e Nashville Medical Research Institute and The Maria Nathanson Center at Saint Thomas Hospital , Nashville , Tennessee , USA. · f Salix, a Division of Valeant Pharmaceuticals North America LLC , Bridgewater , NJ , USA. · g Department of Medicine , University of Pennsylvania School of Medicine , Philadelphia , Pennsylvania , USA. ·Postgrad Med · Pubmed #26861051.

ABSTRACT: OBJECTIVES: A capsule formulation of mesalamine granules (MG) was developed for once-daily dosing and better compliance. The study aim was to evaluate MG efficacy and tolerability in maintaining ulcerative colitis (UC) remission. METHODS: Pooled analysis of 2 identical phase 3, randomized, double-blind trials of once-daily MG 1.5 g or placebo for up to 6 months. The primary endpoint was percentage of patients remaining relapse-free at month 6 versus placebo. Relapse was defined as revised Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, UC flare, or UC-related adverse event (AE). RESULTS: Data were pooled for patients receiving MG (n = 373) and placebo (n = 189). Significantly more patients were relapse-free at 6 months with MG (79.4%) than placebo (62.4%; P < 0.001) and across subgroups based on select demographic and baseline characteristics (P < 0.05). Secondary outcome measures including rectal bleeding, physician rating of disease activity, stool frequency, total SDAI score, and relapse-free duration favored MG (P < 0.01). Common AEs with MG and placebo, respectively, were headache (10.9% and 7.6%), diarrhea (7.9% and 7.0%), and abdominal pain (6.3% and 6.5%). CONCLUSION: Once-daily MG was more efficacious than and as well tolerated as placebo in maintaining UC remission. ClinicalTrials.gov identifiers: NCT00744016 and NCT00767728.

25 Clinical Trial Once-daily Mesalamine Formulation for Maintenance of Remission in Ulcerative Colitis: A Randomized, Placebo-controlled Clinical Trial. 2016

Gordon, Glenn L / Zakko, Salam / Murthy, Uma / Sedghi, Shahriar / Pruitt, Ronald / Barrett, Andrew C / Bortey, Enoch / Paterson, Craig / Forbes, William P / Lichtenstein, Gary R. ·*Center for Digestive and Liver Diseases Inc., Mexico, MO†Connecticut Gastroenterology Institute, Bristol, CT‡Syracuse VA Medical Center, Syracuse, NY§Gastroenterology Associates of Central Georgia LLC, Macon, GA∥Nashville Medical Research Institute and The Maria Nathanson Center at Saint Thomas Hospital, Nashville, TN¶Salix, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ#Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA. ·J Clin Gastroenterol · Pubmed #26368296.

ABSTRACT: GOALS: To evaluate the efficacy and safety of mesalamine granules 1.5 g once daily for maintenance of ulcerative colitis (UC) remission. BACKGROUND: Mesalamine is a first-line treatment for induction and maintenance of UC remission. STUDY: A phase 3, randomized, double-blind, placebo-controlled trial of patients with a history of mild to moderate UC, currently in remission, who received mesalamine granules once daily for 6 months. The primary efficacy endpoint was percentage of patients maintaining UC remission at 6 months. RESULTS: A significantly greater percentage of patients receiving mesalamine granules versus placebo were in remission at 6 months (79.9% vs. 66.7%; P=0.03). A greater percentage of patients receiving mesalamine granules maintained a revised Sutherland Disease Activity Index (SDAI)≤2 with no individual component of revised SDAI>1 and rectal bleeding=0 at 6 months (72.0% vs. 58.1%; P=0.04). No significant differences between groups were observed for change from baseline to 6 months for total SDAI score or its components (ie, stool frequency, rectal bleeding, mucosal appearance, physician's rating of disease). Mesalamine granules treatment resulted in a significantly longer remission duration versus placebo (P=0.02) and decreased patients' risk of relapse by 43% (hazard ratio=0.57; 95% confidence interval, 0.35-0.93; P=0.02). Mesalamine granules were well tolerated, and adverse events related to hepatic, renal, and pancreatic function-potential concerns with long-term treatment-occurred at a rate similar to placebo. CONCLUSIONS: Once-daily mesalamine granules are efficacious and safe for the maintenance of UC remission.

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