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Patency capsule: A novel independent predictor for long-term outcomes among patients with quiescent Crohn's disease. Am J Gastroenterol 2022:00000434-990000000-00595. [PMID: 36563317 DOI: 10.14309/ajg.0000000000002118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 10/06/2022] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Patency capsule (PC) is a recommended procedure to rule-out small-bowel stenosis before video capsule endoscopy (VCE). We examined future clinical outcomes among patients with failed-PC versus patients in whom PC had passed (passed-PC). METHODS A Post-hoc analysis of two prospective cohort studies of adult patients with quiescent small-bowel CD that underwent PC between 2013-2020. The primary composite-outcome was the need for intestinal-surgery or endoscopic-dilation during follow-up in patients with or without failed-PC. RESULTS A total of 190 patients were included (47-failed PC, 143-passed PC, median follow-up 34.12 months). Patients with a failed-PC had higher rates of the primary composite-outcome (21.3% vs. 1.4%, Hazard ratio [HR] 20.3, 95% confidence interval [CI] 4.4-93.7, p<0.001) and also secondary outcomes including intestinal-surgery (14.9% vs. 0.70%, p<0.001), endoscopic-dilation (14.9% vs. 0.70%, p<0.001), admissions (23.3% vs. 5.7%, p<0.001) and clinical-flares (43.9% vs. 27.7%, p=0.005) during follow-up compared with controls. Failed-PC was the only statistically significant factor for surgery and/or endoscopic-dilation, regardless of a B2/B3 phenotype at baseline. In sensitivity-analyses restricted only to patients with stricturing phenotype (n=73), failed-PC still predicted worse long-term composite-outcome (HR 8.68 95% CI 1.72-43.68, p=0.002). Of the 190 patients ingesting a PC, only one patient with a failed-PC had 48 hours of self-limiting mild symptoms. DISCUSSION Clinically-stable CD patients with failed-PC have worse long-term clinical outcomes than those without, independently of CD phenotype. Standalone PC may serve as a novel, safe and affordable prognostic examination, to identify patients with quiescent CD who have a higher risk for future worse clinical outcomes.
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Halligan S, Boone D, Archer L, Ahmad T, Bloom S, Rodriguez-Justo M, Taylor SA, Mallett S. Prognostic biomarkers to identify patients likely to develop severe Crohn's disease: a systematic review. Health Technol Assess 2021; 25:1-66. [PMID: 34225839 DOI: 10.3310/hta25450] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Identification of biomarkers that predict severe Crohn's disease is an urgent unmet research need, but existing research is piecemeal and haphazard. OBJECTIVE To identify biomarkers that are potentially able to predict the development of subsequent severe Crohn's disease. DESIGN This was a prognostic systematic review with meta-analysis reserved for those potential predictors with sufficient existing research (defined as five or more primary studies). DATA SOURCES PubMed and EMBASE searched from inception to 1 January 2016, updated to 1 January 2018. REVIEW METHODS Eligible studies were studies that compared biomarkers in patients who did or did not subsequently develop severe Crohn's disease. We excluded biomarkers that had insufficient research evidence. A clinician and two statisticians independently extracted data relating to predictors, severe disease definitions, event numbers and outcomes, including odds/hazard ratios. We assessed risk of bias. We searched for associations with subsequent severe disease rather than precise estimates of strength. A random-effects meta-analysis was performed separately for odds ratios. RESULTS In total, 29,950 abstracts yielded just 71 individual studies, reporting 56 non-overlapping cohorts. Five clinical biomarkers (Montreal behaviour, age, disease duration, disease location and smoking), two serological biomarkers (anti-Saccharomyces cerevisiae antibodies and anti-flagellin antibodies) and one genetic biomarker (nucleotide-binding oligomerisation domain-containing protein 2) displayed statistically significant prognostic potential. Overall, the strongest association with subsequent severe disease was identified for Montreal B2 and B3 categories (odds ratio 4.09 and 6.25, respectively). LIMITATIONS Definitions of severe disease varied widely, and some studies confounded diagnosis and prognosis. Risk of bias was rated as 'high' in 92% of studies overall. Some biomarkers that are used regularly in daily practice, for example C-reactive protein, were studied too infrequently for meta-analysis. CONCLUSIONS Research for individual biomarkers to predict severe Crohn's disease is scant, heterogeneous and at a high risk of bias. Despite a large amount of potential research, we encountered relatively few biomarkers with data sufficient for meta-analysis, identifying only eight biomarkers with potential predictive capability. FUTURE WORK We will use existing data sets to develop and then validate a predictive model based on the potential predictors identified by this systematic review. Contingent on the outcome of that research, a prospective external validation may prove clinically desirable. STUDY REGISTRATION This study is registered as PROSPERO CRD42016029363. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 45. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Steve Halligan
- Centre for Medical Imaging, University College London, London, UK
| | - Darren Boone
- Centre for Medical Imaging, University College London, London, UK
| | - Lucinda Archer
- Centre for Prognosis Research, School of Primary, Community and Social Care, Keele University, Keele, UK
| | - Tariq Ahmad
- Department of Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Stuart Bloom
- Department of Gastroenterology, University College Hospital, London, UK
| | | | - Stuart A Taylor
- Centre for Medical Imaging, University College London, London, UK
| | - Sue Mallett
- Centre for Medical Imaging, University College London, London, UK
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Kupka T, Simova J, Dvorackova J, Martinek L, Motyka O, Uvirova M, Dite P. Crohn's disease - genetic factors and progress of the disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 162:139-143. [PMID: 29358789 DOI: 10.5507/bp.2017.058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Crohn's disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC). The aim of this study was to determine the relationship between the presence of these variants and disease phenotype. MATERIAL AND METHODS 70 patients with Crohn's disease were examined for the presence of the above-mentioned mutations. The researchers used the medical records to retrospectively obtain clinical data and together with the information obtained prospectively according to the protocol they analysed the connection between gene mutations and disease phenotype. RESULTS At least one mutation was found in 22 patients with Crohn's disease (32%), four patients were found to have two different mutations (composed heterozygotes - 6%) and six patients (9%) were homozygotes for the 3020insC gene. No significant differences were found between the groups with wild-type form and the mutated form of the NOD2 / CARD15 gene with respect to age at the time of diagnosis, form of the disease or localization according to the Montreal classification. CONCLUSION Mutations of the NOD2 / CARD15 gene did not significantly affect the frequency of reoperations, homozygotes with 3020insC gene mutations, however, represented a high risk group. The phenotype was not related significantly to the presence of the examined mutations.
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Affiliation(s)
- Tomas Kupka
- Department of Internal Medicine, University Hospital Ostrava, Czech Republic.,Faculty of Medicine, University of Ostrava, Czech Republic
| | - Jarmila Simova
- Faculty of Medicine, University of Ostrava, Czech Republic.,CGB laborator, a.s., Laboratory of Molecular Genetics and Pathology, Ostrava, Czech Republic
| | - Jana Dvorackova
- Faculty of Medicine, University of Ostrava, Czech Republic.,Institute of Clinical Pathology, University Hospital Ostrava, Czech Republic
| | - Lubomir Martinek
- Faculty of Medicine, University of Ostrava, Czech Republic.,Clinic of Surgery, University Hospital Ostrava, Czech Republic
| | - Oldrich Motyka
- Department of Inorganic Analysis, Centre of Nanotechnology, VSB - Technical University of Ostrava, Czech Republic
| | - Magdalena Uvirova
- Faculty of Medicine, University of Ostrava, Czech Republic.,CGB laborator, a.s., Laboratory of Molecular Genetics and Pathology, Ostrava, Czech Republic
| | - Petr Dite
- Department of Internal Medicine, University Hospital Ostrava, Czech Republic.,Faculty of Medicine, University of Ostrava, Czech Republic
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Guizzetti L, Zou G, Khanna R, Dulai PS, Sandborn WJ, Jairath V, Feagan BG. Development of Clinical Prediction Models for Surgery and Complications in Crohn's Disease. J Crohns Colitis 2018; 12:167-177. [PMID: 29028958 PMCID: PMC5881746 DOI: 10.1093/ecco-jcc/jjx130] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 09/15/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Crohn's disease-related complications account for a substantial proportion of inflammatory bowel disease-associated health care expenditure. Identifying patients at risk for complications may allow for targeted use of early therapeutic interventions to offset this natural course. We aimed to develop risk prediction models for Crohn's disease-related surgery and complications. METHODS Using data from the Randomised Evaluation of an Algorithm for Crohn's Disease cluster-randomised clinical Trial [REACT], which involved 1898 patients from 40 community practices, separate prediction models were derived and internally validated for predicting Crohn's disease-related surgery and disease-related complications [defined as the first disease-related surgery, hospitalisation, or complication within 24 months]. Model performance was assessed in terms of discrimination and calibration, decision curves, and net benefit analyses. RESULTS There were 130 [6.8%] disease-related surgeries and 504 [26.6%] complications during the 24-month follow-up period. Selected baseline predictors of surgery included age, gender, disease location, Harvey-Bradshaw Index [HBI] score, stool frequency, antimetabolite or 5-aminosalicylate use, and the presence of a fistula, abscess, or abdominal mass. Selected predictors of complications included those same factors for surgery, plus corticosteroid or anti-tumour necrosis factor use, but excluded 5-aminosalicylate use. Discrimination ability, as measured by validated c-statistics, was 0.70 and 0.62 for the surgery and complication models, respectively. Score charts and nomograms were developed to facilitate future risk score calculation. CONCLUSIONS Separate risk prediction models for Crohn's disease-related surgery and complications were developed using clinical trial data involving community gastroenterology practices. These models could be used to guide Crohn's disease management. External validation is warranted.
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Affiliation(s)
- Leonardo Guizzetti
- Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada
| | - Guangyong Zou
- Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada,Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada
| | - Reena Khanna
- Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, ON, Canada,Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada
| | - Parambir S Dulai
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - William J Sandborn
- Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Vipul Jairath
- Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada,Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, ON, Canada,Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada
| | - Brian G Feagan
- Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada,Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, ON, Canada,Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada,Corresponding author: Brian G. Feagan, MD, Robarts Clinical Trials Inc., 100 Dundas Street, Suite 200, London, ON, Canada N6A 5B6. Tel.: 226-270-7675; fax: 519-931-5278;
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Association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease risk in Caucasian: a meta-analysis. Inflamm Res 2015; 64:825-31. [PMID: 26289093 DOI: 10.1007/s00011-015-0866-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Revised: 07/15/2015] [Accepted: 08/04/2015] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVE Published studies on the association between NCF4 rs4821544T/C polymorphism and inflammatory bowel disease (IBD) risk in Caucasian have yielded conflicting results. The present study aimed to provide more reliable conclusions by conducting a meta-analysis. METHODS All eligible studies were extracted from Wiley Online Library, Chinese National Knowledge Infrastructure and PubMed databases. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations between rs4821544T/C polymorphism and IBD risk in Caucasian. RESULTS A total of 13 case-control studies comprising 7441 Crohn's disease (CD) patients, 2565 ulcerative colitis (UC) patients and 8315 controls were included in this meta-analysis. Significant associations were found between CD and the rs4821544T/C polymorphism in three genetic models (C vs T: OR = 1.11, 95 % CI: 1.06, 1.16, P = 0.000; CC vs TT: OR = 1.31, 95 % CI: 1.18, 1.45, P = 0.000; CC/TC vs TT: OR = 1.07, 95 % CI: 1.01, 1.13, P = 0.014; CC vs TC/TT OR = 1.28, 95 % CI: 1.16, 1.42, P = 0.000). However, significant associations were not found in UC under any genetic models (C vs T: OR = 1.04, 95 % CI: 0.97, 1.11, P = 0.264; CC vs TT: OR = 1.10, 95 % CI: 0.93, 1.30, P = 0.284; TC vs TT: OR = 1.04, 95 % CI: 0.95, 1.13, P = 0.429; CC/TC vs TT: OR = 1.04, 95 % CI: 0.95, 1.13, P = 0.390; CC vs TC/TT OR = 1.07, 95 % CI: 0.91, 1.26, P = 0.409). CONCLUSION This meta-analysis suggested that the rs4821544T/C polymorphism was associated with CD, but not UC in Caucasian.
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Bhullar M, Macrae F, Brown G, Smith M, Sharpe K. Prediction of Crohn’s disease aggression through NOD2/ CARD15 gene sequencing in an Australian cohort. World J Gastroenterol 2014; 20:5008-5016. [PMID: 24803813 PMCID: PMC4009534 DOI: 10.3748/wjg.v20.i17.5008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 08/04/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would benefit from early aggressive medical intervention.
METHODS: We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000; Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not. Full sequencing of the NOD2/CARD15 gene using dHPLC for exons 3, 5, 7, 10 and 12 and direct sequencing for exons 2, 4, 6, 8, 9 and 11 was conducted. CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2/CARD15 gene.
RESULTS: About 13.3% of the cohort (four patients) carried at least one mutant allele of 3020insC of the NOD2/CARD15 gene. There were 20 males and 10 females with a mean age of 43.3 years (range 25-69 years). The mean follow up was 199.6 mo and a median of 189.5 mo. Sixteen sequence variations within the NOD2/CARD15 gene were identified, with 9 of them occurring with an allele frequency of greater than 10 %. In this study, there was a trend to suggest that patients with the 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery. This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries.
CONCLUSION: These findings suggest that patients carrying NOD2/CARD15 mutations follow a rapid and more aggressive form of Crohn’s disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery.
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