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Outtier A, Janssens R, Barbier L, Sabino J, Verstockt B, Vermeire S, Huys I, Ferrante M. Evolution of Eligibility Criteria in Inflammatory Bowel Disease Clinical Trials: A Clinical Trial Databank Analysis. United European Gastroenterol J 2025; 13:542-551. [PMID: 39698868 PMCID: PMC12090829 DOI: 10.1002/ueg2.12731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Eligibility criteria in clinical trials have been criticised for being overly restrictive without clinical justification. OBJECTIVE We aimed to investigate the types, evolution, and current status of eligibility criteria in clinical trials for inflammatory bowel diseases (IBD). METHODS We performed a clinical trial databank search on clinicaltrials.gov, and included all Phase 3 placebo-controlled randomised-controlled trials (RCTs) investigating biologics or small molecules as induction therapy for moderate-to-severe Crohn's disease (CD) and ulcerative colitis (UC). Eligibility criteria were analysed both quantitatively and qualitatively. RESULTS Fifty-nine RCTs were identified between the year 2000 and 2022 (30 for CD and 29 for UC). The median (interquartile range) number of eligibility criteria was 44 (38-49), and did not significantly change over the studied time period (p = 0.26). Qualitative analysis showed that common patient populations, such as older patients, therapy refractory patients, patients with comorbidities, prior malignancies, unclassified IBD type, ulcerative proctitis, stricturing and fistulizing CD, as well as patients with an ostomy, were often excluded. Heterogeneity in eligibility criteria across the different IBD clinical trials was found, such as for disease activity measurement, dosage of concomitant medication, wash-out period of advanced therapies, and laboratory tests. CONCLUSION The median number of eligibility criteria for IBD RCTs did not significantly change over time. The eligibility criteria are however restrictive and complex, limiting the generalisability of efficacy and safety outcomes in daily practice when drugs are approved. Future research is needed to investigate the impact of broadening eligibility criteria to better encompass real-world practice.
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Affiliation(s)
- An Outtier
- Department of Gastroenterology and HepatologyUniversity Hospitals LeuvenLeuvenBelgium
- Translational Research in Gastrointestinal DisordersDepartment of Chronic Diseases and MetabolismKU LeuvenLeuvenBelgium
| | - Rosanne Janssens
- Department of Pharmaceutical and Pharmacological SciencesKU LeuvenLeuvenBelgium
| | - Liese Barbier
- Department of Pharmaceutical and Pharmacological SciencesKU LeuvenLeuvenBelgium
| | - João Sabino
- Department of Gastroenterology and HepatologyUniversity Hospitals LeuvenLeuvenBelgium
- Translational Research in Gastrointestinal DisordersDepartment of Chronic Diseases and MetabolismKU LeuvenLeuvenBelgium
| | - Bram Verstockt
- Department of Gastroenterology and HepatologyUniversity Hospitals LeuvenLeuvenBelgium
- Translational Research in Gastrointestinal DisordersDepartment of Chronic Diseases and MetabolismKU LeuvenLeuvenBelgium
| | - Séverine Vermeire
- Department of Gastroenterology and HepatologyUniversity Hospitals LeuvenLeuvenBelgium
- Translational Research in Gastrointestinal DisordersDepartment of Chronic Diseases and MetabolismKU LeuvenLeuvenBelgium
| | - Isabelle Huys
- Department of Pharmaceutical and Pharmacological SciencesKU LeuvenLeuvenBelgium
| | - Marc Ferrante
- Department of Gastroenterology and HepatologyUniversity Hospitals LeuvenLeuvenBelgium
- Translational Research in Gastrointestinal DisordersDepartment of Chronic Diseases and MetabolismKU LeuvenLeuvenBelgium
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Chauhan G, Rieder F. The Pathogenesis of Inflammatory Bowel Diseases. Surg Clin North Am 2025; 105:201-215. [PMID: 40015812 PMCID: PMC11868724 DOI: 10.1016/j.suc.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Inflammatory bowel diseases (IBDs) are relapsing, remitting inflammatory diseases of the intestinal tract. Familial aggregation and genome-wide association studies revealed susceptibility variants that point toward a combination of innate immune and adaptive immune dysregulation that in concert with environmental factors, such as our microbiome, can initiate and perpetuate inflammation. Innate immune perturbations include functional abnormalities in the intestinal barrier, endoplasmic reticulum stress, and abnormal recognition of microbes. Adaptive immune changes include dysregulation of cytokines, regulatory T cells, and leukocyte migration. IBD is linked with an abnormal wound-healing response leading to fibrosis. This article summarizes key pathogenic mechanisms in the pathogenesis of IBDs.
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Affiliation(s)
- Gaurav Chauhan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases Institute; Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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Zhang L, Liu Q, Yang X, Su C, Ding H, Hu J, Han W, Wu J, Zhang M, Zuo L, Mei Q. Mechanosensitive Ion Channel PIEZO1 as a Key Regulator of Intestinal Fibrosis in Crohn's Disease. Inflamm Bowel Dis 2025:izaf041. [PMID: 40053528 DOI: 10.1093/ibd/izaf041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Indexed: 03/09/2025]
Abstract
BACKGROUND We aimed to elucidate the function of the mechanosensitive ion channel PIEZO1 in intestinal fibrosis, which is invariably associated with Crohn's disease (CD) and often results in strictures and obstructions, requiring surgical intervention. Notably, PIEZO1 is strongly expressed in fibrotic tissues and linked with fibrotic progression. METHODS Intestinal tissues were procured from 28 patients diagnosed with CD and 8 healthy control subjects. Histological and immunofluorescence assays verified that PIEZO1 is substantially overexpressed in fibrotic intestinal tissues and is involved in epithelial‒mesenchymal transition (EMT). Further gene knockout experiments and transcriptome sequencing elucidated the specific role of PIEZO1 in the pathogenesis of intestinal fibrosis in CD. We generated mice with Piezo1 deletion specifically in intestinal epithelial cells (Piezo1f/f Vilcre) to validate in vivo that inhibiting Piezo1 function attenuates or reverses intestinal fibrosis associated with CD. RESULTS PIEZO1 expression was strongly increased in the fibrotic small intestine of CD patients, thereby promoting EMT and exacerbating intestinal fibrosis. In vivo investigations revealed that the conditional suppression of Piezo1 in intestinal epithelial cells significantly mitigated intestinal fibrosis in dextran sulphate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis model mice. In vitro examinations revealed that Piezo1 expression in intestinal epithelial cells preserved the stability of HIF-1α, induced EMT to stimulate the expression of fibrosis-associated molecules, and promoted fibrosis. CONCLUSION PIEZO1 plays a pivotal role in the regulation of intestinal fibrosis by maintaining the levels of HIF-1α, thereby promoting EMT. Therapeutic strategies targeting PIEZO1 could be used to prevent intestinal fibrosis in CD patients.
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Affiliation(s)
- Luyao Zhang
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiuyuan Liu
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiaodong Yang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Chang Su
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hao Ding
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jing Hu
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Han
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Juan Wu
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Manli Zhang
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Zuo
- College of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Qiao Mei
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Hefei, China
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Cosín-Roger J. Inflammatory Bowel Disease: Immune Function, Tissue Fibrosis and Current Therapies. Int J Mol Sci 2024; 25:6416. [PMID: 38928122 PMCID: PMC11203598 DOI: 10.3390/ijms25126416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/06/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
Inflammatory Bowel Disease (IBD) is a complex and challenging health problem that exerts a significant impact on the quality of life of millions of individuals worldwide [...].
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Affiliation(s)
- Jesús Cosín-Roger
- Departamento de Farmacología, Facultad de Medicina y Odontología, Universidad de Valencia, 46010 Valencia, Spain;
- CIBERehd (Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas), Instituto de Salud Carlos III, Monforte de Lemos, 3-5, 28029 Madrid, Spain
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Rieder F, Mukherjee PK, Massey WJ, Wang Y, Fiocchi C. Fibrosis in IBD: from pathogenesis to therapeutic targets. Gut 2024; 73:854-866. [PMID: 38233198 PMCID: PMC10997492 DOI: 10.1136/gutjnl-2023-329963] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 12/29/2023] [Indexed: 01/19/2024]
Abstract
BACKGROUND Intestinal fibrosis resulting in stricture formation and obstruction in Crohn's disease (CD) and increased wall stiffness leading to symptoms in ulcerative colitis (UC) is among the largest unmet needs in inflammatory bowel disease (IBD). Fibrosis is caused by a multifactorial and complex process involving immune and non-immune cells, their soluble mediators and exposure to luminal contents, such as microbiota and environmental factors. To date, no antifibrotic therapy is available. Some progress has been made in creating consensus definitions and measurements to quantify stricture morphology for clinical practice and trials, but approaches to determine the degree of fibrosis within a stricture are still lacking. OBJECTIVE We herein describe the current state of stricture pathogenesis, measuring tools and clinical trial endpoints development. DESIGN Data presented and discussed in this review derive from the past and recent literature and the authors' own research and experience. RESULTS AND CONCLUSIONS Significant progress has been made in better understanding the pathogenesis of fibrosis, but additional studies and preclinical developments are needed to define specific therapeutic targets.
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Affiliation(s)
- Florian Rieder
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Pranab K Mukherjee
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - William J Massey
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Yan Wang
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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Wang H, Yan G, Wu Y, Zhuoma D, Liu Z, Gao X, Wang X. Fecal microbiota related to postoperative endoscopic recurrence in patients with Crohn's disease. Gastroenterol Rep (Oxf) 2024; 12:goae017. [PMID: 38524186 PMCID: PMC10960934 DOI: 10.1093/gastro/goae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 11/05/2023] [Accepted: 02/26/2024] [Indexed: 03/26/2024] Open
Abstract
Background Postoperative recurrence (POR) remains a major challenge for patients with Crohn's disease (CD). Gut microbial dysbiosis has been reported to be involved in the pathogenesis of POR. This study aims to investigate the relationship between fecal microbiome and endoscopic recurrence in patients with CD after ileocolonic resection. Methods This is a cross-sectional study. Fecal samples were collected from 52 patients with CD after surgical intervention from 6 to 12 months before endoscopic examination. Endoscopic recurrence was defined as Rutgeerts score ≥ i2. The microbiome was analyzed by sequencing the V3-V4 hypervariable regions of the 16S rRNA gene. Results A total of 52 patients were included and classified into POR (n = 27) and non-POR (n = 25) groups. Compared with the non-POR group, the POR group had a significantly lower community richness (Chao1 index: 106.5 vs 124, P = 0.013) and separated microbial community (P = 0.007 for Adonis, P = 0.032 for Anosim), combined with different distribution of 16 gut microbiotas and decrease of 11 predicted metabolic pathways (P < 0.05). Lactobacillus and Streptococcus were identified to closely correlate to non-POR (P < 0.05) after controlling for confounding factors. Kaplan-Meier analysis indicated that the patients with higher abundance of Streptococcus experienced longer remission periods (P < 0.01), but this was not for Lactobacillus. The predicted ethylmalonyl-coA pathway related to increased amount of succinate was positively correlated with Streptococcus (r > 0.5, P < 0.05). Conclusions The characteristic alterations of fecal microbiota are associated with postoperative endoscopic recurrence in patients with CD; particularly, high abundance of Streptococcus may be closely related to endoscopic remission.
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Affiliation(s)
- Haichao Wang
- Department of Nephrology and Rheumatology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, P. R. China
| | - Guorong Yan
- Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, P. R. China
| | - Yaling Wu
- Department of Geriatrics, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Deji Zhuoma
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, P. R. China
| | - Zhanju Liu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, P. R. China
| | - Xuefeng Gao
- Integrative Microecology Center, Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, P. R. China
| | - Xiaolei Wang
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, P. R. China
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Amadu M, Soldera J. Duodenal Crohn's disease: Case report and systematic review. World J Methodol 2024; 14:88619. [PMID: 38577197 PMCID: PMC10989410 DOI: 10.5662/wjm.v14.i1.88619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 12/16/2023] [Accepted: 01/18/2024] [Indexed: 03/07/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease, including ulcerative colitis, microscopic colitis, and Crohn's disease (CD), has a global impact. This review focuses on duodenal CD (DCD), a rare subtype affecting the duodenum. DCD's rarity and asymptomatic nature create diagnostic challenges, impacting prognosis and patient well-being. Delayed diagnosis can worsen DCD outcomes. AIM To report a rare case of DCD and to discuss the diagnostic challenges and its implications on prognosis. METHODS A systematic literature search, following the PRISMA statement, was conducted. Relevant studies were identified and analysed using specific Medical Subject Terms (MeSH) from PubMed/MEDLINE, American Journal of Gastroenterology, and the University of South Wales database. Data collection included information from radiology scans, endoscopy procedures, biopsies, and histopathology results. RESULTS The review considered 8 case reports and 1 observational study, involving 44 participants diagnosed with DCD, some of whom developed complications due to delayed diagnosis. Various diagnostic methods were employed, as there is no gold standard workup for DCD. Radiology scans [magnetic resonance imaging (MRI), computed tomography (CT), and upper gastrointestinal X-ray], endoscopy procedures (colonoscopy and esophagogastroduodenoscopy), biopsies, and clinical suspicions were utilized. CONCLUSION This review discusses DCD diagnosis challenges and the roles of CT, MRI, and fluoroscopy. It notes their limitations and compares findings with endoscopy and histopathology studies. Further research is needed to improve diagnosis, emphasizing scan interpretation, endoscopy procedures, and biopsies, especially in high-risk patients during routine endoscopy.
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Affiliation(s)
- Muniratu Amadu
- Department of Gastroenterology, University of South Wales, Cardiff CF37 1DL, United Kingdom
| | - Jonathan Soldera
- Department of Gastroenterology, University of South Wales, Cardiff CF37 1DL, United Kingdom
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Xanthohumol Interferes with the Activation of TGF-β Signaling in the Process Leading to Intestinal Fibrosis. Nutrients 2022; 15:nu15010099. [PMID: 36615756 PMCID: PMC9824381 DOI: 10.3390/nu15010099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
Fibrosis has various biological processes and affects almost every organ, especially in patients with inflammatory bowel disease, including Crohn's disease, who experience discomfort caused by intestinal fibrosis, which is a problem that needs to be resolved. TGF-β signaling is known to act as a key regulator of intestinal fibrosis, and its modulation could be an excellent candidate for fibrosis therapy. Xanthohumol (XN) has various effects, including anti-inflammation and anti-cancer; however, the detailed mechanism of TGF-β signaling has not yet been studied. The purpose of this study was to investigate the mechanism underlying the anti-fibrotic effect of XN on TGF-β1-induced intestinal fibrosis using primary human intestinal fibroblasts (HIFs). In this study, to check the anti-fibrotic effects of XN on intestinal fibrosis, we assessed the expression of fibrosis-related genes in TGF-β1-stimulated HIFs by qPCR, immunoblotting, and immunofluorescence staining. As a result, XN showed the ability to reduce the expression of fibrosis-associated genes increased by TGF-β1 treatment in HIFs and restored the cell shape altered by TGF-β1. In particular, XN repressed both NF-κB- and Smad-binding regions in the α-SMA promoter, which is important in fibrosis. In addition, XN inhibited NF-κB signaling, including phosphorylated-IkBα and cyclooxygenase-2 expression, and TNF-α-stimulated transcriptional activity of NF-κB. XN attenuated TGF-β1-induced phosphorylation of Smad2 and Smad3, and the transcriptional activity of CAGA. Particularly, XN interfered with the binding of TGF-Receptor I (TβRI) and Smad3 by binding to the kinase domain of the L45 loop of TβRI, thereby confirming that the fibrosis mechanism did not proceed further. In conclusion, XN has an inhibitory effect on TGF-β1-induced intestinal fibrosis in HIFs, significantly affecting TGF-β/Smad signaling.
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9
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Wang Y, Huang B, Jin T, Ocansey DKW, Jiang J, Mao F. Intestinal Fibrosis in Inflammatory Bowel Disease and the Prospects of Mesenchymal Stem Cell Therapy. Front Immunol 2022; 13:835005. [PMID: 35370998 PMCID: PMC8971815 DOI: 10.3389/fimmu.2022.835005] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/26/2022] [Indexed: 12/12/2022] Open
Abstract
Intestinal fibrosis is an important complication of inflammatory bowel disease (IBD). In the course of the development of fibrosis, certain parts of the intestine become narrowed, significantly destroying the structure and function of the intestine and affecting the quality of life of patients. Chronic inflammation is an important initiating factor of fibrosis. Unfortunately, the existing anti-inflammatory drugs cannot effectively prevent and alleviate fibrosis, and there is no effective anti-fibrotic drug, which makes surgical treatment the mainstream treatment for intestinal fibrosis and stenosis. Mesenchymal stem cells (MSCs) are capable of tissue regeneration and repair through their self-differentiation, secretion of cytokines, and secretion of extracellular vesicles. MSCs have been shown to play an important therapeutic role in the fibrosis of many organs. However, the role of MSC in intestinal fibrosis largely remained unexplored. This review summarizes the mechanism of intestinal fibrosis, including the role of immune cells, TGF-β, and the gut microbiome and metabolites. Available treatment options for fibrosis, particularly, MSCs are also discussed.
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Affiliation(s)
- Yifei Wang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Bin Huang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- General Surgery Department, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
| | - Tao Jin
- Department of Gastrointestinal and Endoscopy, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
- Directorate of University Health Services, University of Cape Coast, Cape Coast, Ghana
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Jiajia Jiang, ; Fei Mao,
| | - Fei Mao
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Jiajia Jiang, ; Fei Mao,
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10
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Ismail MS, Charabaty A. Management of Crohn's stricture: medical, endoscopic and surgical therapies. Frontline Gastroenterol 2022; 13:524-530. [PMID: 36250181 PMCID: PMC9555137 DOI: 10.1136/flgastro-2021-101827] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/21/2022] [Indexed: 02/04/2023] Open
Abstract
Patients with Crohn's disease are at high risk of presenting with or developing a bowel stricture during the course of their disease. The available therapeutic options to manage a symptomatic Crohn's stricture include medical therapy (mainly biologics), surgical resection and endoscopic interventions. The choice of therapeutic modality depends on the clinical presentation of the stricture, the nature of the stricture (inflammatory vs fibrotic, primary vs anastomotic) and its anatomical characteristics on endoscopy and imaging (length, number, location of strictures and severity of obstruction). The aim herein is to provide an overview of the comprehensive assessment of a Crohn's stricture and to review the indications of the different therapeutic modalities, their success rates and their limitations to help clinicians properly evaluate and manage Crohn's strictures.
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Affiliation(s)
- Mohamed Saleh Ismail
- Gastroenterology and Hepatology, The University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Aline Charabaty
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Sibley Memorial Hospital, Washington, District of Columbia, USA
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Watanabe D, Kamada N. Contribution of the Gut Microbiota to Intestinal Fibrosis in Crohn's Disease. Front Med (Lausanne) 2022; 9:826240. [PMID: 35198577 PMCID: PMC8859331 DOI: 10.3389/fmed.2022.826240] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/13/2022] [Indexed: 12/16/2022] Open
Abstract
In Crohn's disease (CD), intestinal fibrosis is a critical determinant of a patient's prognosis. Although inflammation may be a prerequisite for the initiation of intestinal fibrosis, research shows that the progression or continuation of intestinal fibrosis can occur independently of inflammation. Thus, once initiated, intestinal fibrosis may persist even if medical treatment controls inflammation. Clearly, an understanding of the pathophysiological mechanisms of intestinal fibrosis is required to diminish its occurrence. Accumulating evidence suggests that the gut microbiota contributes to the pathogenesis of intestinal fibrosis. For example, the presence of antibodies against gut microbes can predict which CD patients will have intestinal complications. In addition, microbial ligands can activate intestinal fibroblasts, thereby inducing the production of extracellular matrix. Moreover, in various animal models, bacterial infection can lead to the development of intestinal fibrosis. In this review, we summarize the current knowledge of the link between intestinal fibrosis in CD and the gut microbiota. We highlight basic science and clinical evidence that the gut microbiota can be causative for intestinal fibrosis in CD and provide valuable information about the animal models used to investigate intestinal fibrosis.
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Affiliation(s)
- Daisuke Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Nobuhiko Kamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
- WPI Immunology Frontier Research Center, Osaka University, Suita, Japan
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Caparrós E, Wiest R, Scharl M, Rogler G, Gutiérrez Casbas A, Yilmaz B, Wawrzyniak M, Francés R. Dysbiotic microbiota interactions in Crohn's disease. Gut Microbes 2021; 13:1949096. [PMID: 34313550 PMCID: PMC8320851 DOI: 10.1080/19490976.2021.1949096] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Crohn's disease (CD) is a major form of inflammatory bowel disease characterized by transmural inflammation along the alimentary tract. Changes in the microbial composition and reduction in species diversity are recognized as pivotal hallmarks in disease dynamics, challenging the gut barrier function and shaping a pathological immune response in genetically influenced subjects. The purpose of this review is to delve into the modification of the gut microbiota cluster network during CD progression and to discuss how this shift compromises the gut barrier integrity, granting the translocation of microbes and their products. We then complete the scope of the review by retracing gut microbiota dysbiosis interactions with the main pathophysiologic factors of CD, starting from the host's genetic background to the immune inflammatory and fibrotic processes, providing a standpoint on the lifestyle/exogenous factors and the potential benefits of targeting a specific gut microbiota.
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Affiliation(s)
- Esther Caparrós
- Dpto Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain,Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain
| | - Reiner Wiest
- Department for Biomedical Research, Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Ana Gutiérrez Casbas
- Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain,CIBERehd, Instituto De Salud Carlos III, Madrid, Spain
| | - Bahtiyar Yilmaz
- Department for Biomedical Research, Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Rubén Francés
- Dpto Medicina Clínica, Universidad Miguel Hernández, San Juan De Alicante, Spain,Iis Isabial, Hospital General Universitario De Alicante, Alicante, Spain,CIBERehd, Instituto De Salud Carlos III, Madrid, Spain,CONTACT Rubén Francés Hepatic and Intestinal Immunobiology Group. Departamento De Medicina Clínica, Universidad Miguel Hernández De Elche. Carretera Alicante-Valencia, Km 8,703550San Juan De Alicante
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13
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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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Dmochowska N, Tieu W, Keller MD, Hollis CA, Campaniello MA, Mavrangelos C, Takhar P, Hughes PA. 89Zr-pro-MMP-9 F(ab') 2 detects colitis induced intestinal and kidney fibrosis. Sci Rep 2020; 10:20372. [PMID: 33230169 PMCID: PMC7683569 DOI: 10.1038/s41598-020-77390-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 11/04/2020] [Indexed: 12/26/2022] Open
Abstract
Intestinal fibrosis is a common complication of inflammatory bowel disease but remains difficult to detect. Matrix metalloproteases (MMPs) have key roles in fibrosis and are therefore potential targets for fibrosis detection. We determined whether immunoPET of F(ab′)2 antibody fragments targeting MMPs detects colitis induced colonic fibrosis. Mice were administered 2% dextran sulfate sodium treated water for 1 cycle (inflamed) or 3 cycles (fibrotic), or were untreated (control). Colonic and kidney collagen, innate cytokine, MMPs and fecal MPO concentrations were analyzed by multiplex/ELISA. α-pro-MMP-9 F(ab′)2 fragments were engineered and conjugated to 89Zr for PET imaging, ex-vivo Cherenkov analysis and bio-distribution. Colonic innate cytokine concentrations and fecal myeloperoxidase were increased in inflamed mice but not fibrotic mice, while collagen concentrations were increased in fibrotic mice. MMPs were increased in inflamed mice, but only pro-MMP-9 remained increased in fibrotic mice. 89Zr-pro-MMP-9 F(ab′)2 uptake was increased in the intestine but also in the kidney of fibrotic mice, where collagen and pro-MMP-9 concentrations were increased. 89Zr-pro-MMP-9 F(ab′)2 detects colitis induced intestinal fibrosis and associated kidney fibrosis.
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Affiliation(s)
- Nicole Dmochowska
- Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Level 7, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia
| | - William Tieu
- Molecular Imaging and Therapy Research Unit (MITRU), South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Marianne D Keller
- Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Level 7, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia.,Preclinical, Imaging and Research Laboratories (PIRL), South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Courtney A Hollis
- Molecular Imaging and Therapy Research Unit (MITRU), South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Melissa A Campaniello
- Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Level 7, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia
| | - Chris Mavrangelos
- Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Level 7, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia
| | - Prab Takhar
- Molecular Imaging and Therapy Research Unit (MITRU), South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Patrick A Hughes
- Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Level 7, University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, South Australia, 5000, Australia.
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Yang SB, Du SW, Wang JH. Correlation between age of onset and gastrointestinal stenosis in hospitalized patients with Crohn's disease. World J Clin Cases 2020; 8:2769-2777. [PMID: 32742987 PMCID: PMC7360709 DOI: 10.12998/wjcc.v8.i13.2769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/26/2020] [Accepted: 06/13/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Patients affected by Crohn's disease (CD) are more likely to develop gastrointestinal stenosis and often undergo surgery during the duration of disease.
AIM To identify the risk factors for gastrointestinal stenosis in hospitalized CD patients in China.
METHODS The clinical data of CD patients hospitalized at the Seventh Medical Center, Chinese People's Liberation Army General Hospital from January 2010 to December 2018 were included. Patients with gastrointestinal stenosis were compared to those without gastrointestinal stenosis for clinical variables. The risk factors for gastrointestinal stenosis were identified using univariate and multivariable logistic regression analyses. The treatments for patients with gastrointestinal stenosis were analyzed, and the characteristics of different treatment methods were discussed.
RESULTS The incidence of gastrointestinal stenosis was 59.02% in the 122 hospitalized CD patients. Age of onset of more than 40 years (odds ratio [OR] = 3.072, 95% confidence interval [CI]: 1.298-7.272, P = 0.009) and duration of disease of more than 5 years (OR = 2.101, 95%CI: 1.002-4.406, P = 0.048) were associated with the occurrence of gastrointestinal stenosis. Fifteen (20.83%) patients did not undergo surgery and received internal medicine and nutrition treatment. Surgical treatments were performed in 72.22% (52) of cases. The rate of postoperative complications was 15.38% (8 cases), and during a median follow-up period of 46 mo, 11.54% (6 cases) underwent reoperation. A total of 29.17% (21 cases) were treated with endoscopic therapy, and during a median follow-up period of 32 mo, 76.19% (16 cases) had no surgical event, 23.81% (5 cases) failed to avoid surgical treatments, and no serious postoperative complications occurred after endoscopic therapy.
CONCLUSION Age of onset of more than 40 years and duration of disease of more than 5 years may be strongly correlated with a higher risk of gastrointestinal stenosis in hospitalized CD patients. Endoscopic therapy for gastrointestinal stenosis is relatively safe and effective, and may help to prevent or delay surgery.
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Affiliation(s)
- Shan-Bing Yang
- Department of Gastroenterology, the Seventh Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100700, China
| | - Shu-Wen Du
- Department of Gastroenterology, the Seventh Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100700, China
| | - Ji-Heng Wang
- Department of Gastroenterology, the Seventh Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100700, China
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16
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Ballengee CR, Stidham RW, Liu C, Kim MO, Prince J, Mondal K, Baldassano R, Dubinsky M, Markowitz J, Leleiko N, Hyams J, Denson L, Kugathasan S. Association Between Plasma Level of Collagen Type III Alpha 1 Chain and Development of Strictures in Pediatric Patients With Crohn's Disease. Clin Gastroenterol Hepatol 2019; 17:1799-1806. [PMID: 30213581 PMCID: PMC6531351 DOI: 10.1016/j.cgh.2018.09.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 09/04/2018] [Accepted: 09/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There are few serum biomarkers to identify patients with Crohn's disease (CD) who are at risk for stricture development. The extracellular matrix components, collagen type III alpha 1 chain (COL3A1) and cartilage oligomeric matrix protein (COMP), could contribute to intestinal fibrosis. We investigated whether children with inflammatory CD (B1) who later develop strictures (B2) have increased plasma levels of COL3A1 or COMP at diagnosis, compared with children who remain B1. We compared results with previously studied biomarkers, including autoantibodies against colony-stimulating factor 2 (CSF2). METHODS We selected 161 subjects (mean age, 12.2 y; 62% male) from the Risk Stratification and Identification of Immunogenic and Microbial Markers of Rapid Disease Progression in Children with Crohn's cohort, completed at 28 sites in the United States and Canada from 2008 through 2012. The children underwent colonoscopy and upper endoscopy at diagnosis and were followed up every 6 months for 36 months; plasma samples were collected at baseline. Based on CD phenotype, children were separated to group 1 (B1 phenotype at diagnosis and follow-up evaluation), group 2 (B2 phenotype at diagnosis), or group 3 (B1 phenotype at diagnosis who developed strictures during follow-up evaluation). Plasma samples were collected from patients and 40 children without inflammatory bowel disease (controls) at baseline and analyzed by enzyme-linked immunosorbent assay to measure COL3A1 and COMP. These results were compared with those from a previous biomarker study. The Kruskal-Wallis test and the pairwise Dunn test with Bonferroni correction were used to compare differences among groups. RESULTS The median baseline concentration of COL3A1 was significantly higher in plasma from group 3 vs group 1 (P < .01) and controls (P = .01). Median baseline plasma concentrations of COMP did not differ significantly among groups. A model comprising baseline concentrations of COL3A1 and anti-CSF2 identified patients with B2 vs B1 CD with an area under the curve of 0.80 (95% CI, 0.71-0.89); the combined concentration identified patients with strictures with a sensitivity value of 0.70 (95% CI, 0.55-0.83) and a specificity value of 0.83 (95% CI, 0.67-0.93). CONCLUSIONS We found median plasma concentrations of COL3A1, measured by enzyme-linked immunosorbent assay at diagnosis, to be significantly higher in patients with CD who later developed strictures than in patients without strictures. The combination of concentrations of COL3A1 and anti-CSF2 might be used to identify pediatric patients at CD diagnosis who are at risk for future strictures. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00790543.
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Affiliation(s)
| | | | - Chunyan Liu
- Cincinnati Children’s Hospital Medical Center
| | - Mi-Ok Kim
- University of California San Francisco
| | | | | | | | | | | | | | | | - Lee Denson
- Cincinnati Children’s Hospital Medical Center
| | - Subra Kugathasan
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, Georgia.
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Pittet V, Michetti P, Mueller C, Braegger CP, von Känel R, Schoepfer A, Macpherson AJ, Rogler G, Anderegg C, Bauerfeind P, Beglinger C, Begré S, Belli D, Bengoa JM, Biedermann L, Bigler B, Binek J, Blattmann M, Boehm S, Borovicka J, Braegger CP, Brunner N, Bühr P, Burnand B, Burri E, Buyse S, Cremer M, Criblez DH, de Saussure P, Degen L, Delarive J, Doerig C, Dora B, Dorta G, Egger M, Ehmann T, El-Wafa A, Engelmann M, Ezri J, Felley C, Fliegner M, Fournier N, Fraga M, Frei P, Frei PR, Fried M, Froehlich F, Funk C, Furlano RI, Gallot-Lavallée S, Geyer M, Girardin M, Golay D, Grandinetti T, Gysi B, Haack H, Haarer J, Helbling B, Hengstler P, Herzog D, Hess C, Heyland K, Hinterleitner T, Hiroz P, Hirschi C, Hruz P, Iwata R, Jost R, Juillerat P, Keller C, Knellwolf C, Knoblauch C, Köhler H, Koller R, Krieger-Grübel C, Kullak-Ublick G, Künzler P, Landolt M, Lange R, Lehmann FS, Macpherson A, Maerten P, Maillard MH, Manser C, Manz M, Marbet U, Marx G, Matter C, Meier R, Mendanova M, Michetti P, Misselwitz B, Morell B, Mosler P, Mottet C, Müller C, Müller P, Müllhaupt B, Münger-Beyeler C, Musso L, et alPittet V, Michetti P, Mueller C, Braegger CP, von Känel R, Schoepfer A, Macpherson AJ, Rogler G, Anderegg C, Bauerfeind P, Beglinger C, Begré S, Belli D, Bengoa JM, Biedermann L, Bigler B, Binek J, Blattmann M, Boehm S, Borovicka J, Braegger CP, Brunner N, Bühr P, Burnand B, Burri E, Buyse S, Cremer M, Criblez DH, de Saussure P, Degen L, Delarive J, Doerig C, Dora B, Dorta G, Egger M, Ehmann T, El-Wafa A, Engelmann M, Ezri J, Felley C, Fliegner M, Fournier N, Fraga M, Frei P, Frei PR, Fried M, Froehlich F, Funk C, Furlano RI, Gallot-Lavallée S, Geyer M, Girardin M, Golay D, Grandinetti T, Gysi B, Haack H, Haarer J, Helbling B, Hengstler P, Herzog D, Hess C, Heyland K, Hinterleitner T, Hiroz P, Hirschi C, Hruz P, Iwata R, Jost R, Juillerat P, Keller C, Knellwolf C, Knoblauch C, Köhler H, Koller R, Krieger-Grübel C, Kullak-Ublick G, Künzler P, Landolt M, Lange R, Lehmann FS, Macpherson A, Maerten P, Maillard MH, Manser C, Manz M, Marbet U, Marx G, Matter C, Meier R, Mendanova M, Michetti P, Misselwitz B, Morell B, Mosler P, Mottet C, Müller C, Müller P, Müllhaupt B, Münger-Beyeler C, Musso L, Nagy A, Neagu M, Nichita C, Niess J, Nydegger A, Obialo N, Oneta C, Oropesa C, Peter U, Peternac D, Petit LM, Piccoli-Gfeller F, Pilz JB, Pittet V, Raschle N, Rentsch R, Restellini RS, Richterich JP, Rihs S, Ritz MA, Roduit J, Rogler D, Rogler G, Rossel JB, Rueger V, Saner G, Sauter B, Sawatzki M, Schäppi M, Scharl M, Scharl S, Schelling M, Schibli S, Schlauri H, Uebelhart SS, Schnegg JF, Schoepfer A, Seibold F, Seirafi M, Semadeni GM, Semela D, Senning A, Sidler M, Sokollik C, Spalinger J, Spangenberger H, Stadler P, Steuerwald M, Straumann A, Straumann-Funk B, Sulz M, Suter A, Thorens J, Tiedemann S, Tutuian R, Vavricka S, Viani F, Vögtlin J, Von Känel R, Vonlaufen A, Vouillamoz D, Vulliamy R, Wermuth J, Werner H, Wiesel P, Wiest R, Wylie T, Zeitz J, Zimmermann D. Cohort Profile Update: The Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS). Int J Epidemiol 2019; 48:385-386f. [DOI: 10.1093/ije/dyy298] [Show More Authors] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/08/2019] [Indexed: 02/06/2023] Open
Affiliation(s)
- Valérie Pittet
- Institute of Social & Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland
| | - Pierre Michetti
- Crohn and Colitis Center, Gastroentérologie Beaulieu SA, Lausanne, Switzerland
- Division of Gastroenterology & Hepatology, Lausanne University Hospital, Lausanne, Switzerland
| | | | - Christian P Braegger
- Division of Gastroenterology and Nutrition, University Children's Hospital Zurich, Zurich, Switzerland
| | - Roland von Känel
- Department of Consultation-Liaison-Psychiatry and Psychosomatic Medicine, University Hospital Zurich, Zurich, Switzerland
| | - Alain Schoepfer
- Division of Gastroenterology & Hepatology, Lausanne University Hospital, Lausanne, Switzerland
| | - Andrew J Macpherson
- University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland
- Maurice Muller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology & Hepatology, Zurich University Hospital, Zurich, Switzerland
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Zhang HJ, Zhang YN, Zhou H, Guan L, Li Y, Sun MJ. IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT. Dig Dis Sci 2018; 63:2898-2909. [PMID: 30097894 DOI: 10.1007/s10620-018-5234-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 07/31/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intestinal fibrosis is a common complication of Crohn's disease (CD). Its exact mechanism is still unclear, and effective treatments to control or reverse the fibrosis process are unavailable. Epithelial-mesenchymal transition (EMT) may promote intestinal fibrosis by increasing deposition of extracellular matrix protein. IL-17A is a pro-inflammatory cytokine, and it has been shown as a profibrotic factor as its association with fibrosis of multiple organs was reported. AIMS To assess the roles of IL-17A and EMT in the initiation and development of intestinal fibrosis and to verify the potential inductive effect of IL-17A on EMT. METHODS In this study, we evaluated the expression of IL-17A and EMT-related genes in colonic mucosal biopsy tissues of CD patients and control individuals. Then, we examined the changes of EMT-related genes and fibrosis-related genes of IEC-6 cells which cultured for 72 h under increasing concentrations of IL-17A or with TGF-β1, to verify the potential inductive effect of IL-17A on EMT in vitro. We blocked the IL-17A of the mouse model of TNBS-induced experimental intestinal colitis and fibrosis to further verify the potential inductive effect of IL-17A on EMT in vivo. RESULTS We found the occurrence of EMT and high-level expression of IL-17A in intestinal mucosa of CD patients. Using IEC-6 cells, we showed that IL-17A may induce EMT in intestinal epithelial cells that come with reduced E-cadherin expression and increased expression of vimentin, snail, and α-SMA. We further found that anti-IL-17A treatment alleviated intestinal fibrosis through reducing EMT in mouse intestine. CONCLUSIONS Our study confirmed the involvement of IL-17A in the development of intestinal fibrosis through inducing EMT.
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Affiliation(s)
- Hui-Jing Zhang
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yi-Ning Zhang
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Huan Zhou
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Lin Guan
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yue Li
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ming-Jun Sun
- Department of Endoscopy, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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Age at disease onset of inflammatory bowel disease is associated with later extraintestinal manifestations and complications. Eur J Gastroenterol Hepatol 2018; 30:598-607. [PMID: 29360691 DOI: 10.1097/meg.0000000000001072] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION A small but increasing number of patients with inflammatory bowel disease are diagnosed during childhood or adolescence, and disease distribution and severity at onset vary according to the age at diagnosis. Clinical factors present at the time of diagnosis can be predictive of the disease course. AIM The aim of this study was to characterize disease behavior and the cumulative complications and extraintestinal manifestations 10 years after the diagnosis and to assess their association with age at diagnosis. PATIENTS AND METHODS Data of patients participating with the Swiss IBD cohort study registry, a disease duration of 10 years and a complete data set were analyzed. The outcome was defined as the cumulative change of disease behavior, the occurrence of extra-intestinal manifestations or complications, and the necessity for medical or surgical interventions. RESULTS A total of 481 patients with Crohn's disease (CD) and 386 patients with ulcerative colitis (UC), grouped according to disease onset before 10, 17, 40, or after 40 years of age, were analyzed. Despite differences in sex, initial disease location, and smoking habits, at 10 years after the diagnosis, no difference was found regarding disease behavior in CD or regarding progression of disease extension in UC. Similarly, no age-of-onset-dependent cumulative need for medical or surgical therapies was found. However, higher rates of anemia and lower rates of arthralgia and osteopenia were found in both pediatric-onset CD and UC, and a tendency toward higher rates of stomatitis in pediatric-onset CD, and of primary sclerosing cholangitis and ankylosing spondylitis in pediatric-onset UC. CONCLUSION After 10 years of disease evolution, age at disease onset is not anymore associated with disease behavior but only with a small difference in the occurrence of specific extraintestinal manifestations and complications.
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The operative risk and natural history after the diagnosis of ileal penetrating Crohn's disease. Eur J Gastroenterol Hepatol 2018; 30:539-545. [PMID: 29462028 DOI: 10.1097/meg.0000000000001091] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND PURPOSE Crohn's disease (CD) is marked by transmural inflammation of the bowel wall leading to stricturing and/or penetrating complications in the majority of patients. The natural history and operative risk after the diagnosis of an ileal penetrating complication is understudied. The aim was to study the disease course and need for surgery in patients diagnosed with a penetrating ileal CD complication and to assess the risk factors associated with worse postoperative outcome. PATIENTS AND METHODS In this cohort study, all cross-sectional imaging exams (computed tomography and/or magnetic resonance imaging) performed between 2006 and 2014 in patients with CD in a tertiary referral centre were reviewed for the presence of ileal penetrating complications (defined as abscesses, phlegmones and/or fistula). Demographic, clinical, biochemical, radiological and endoscopic factors were assessed retrospectively in these patients as well as the need for surgery (intestinal resection and/or strictureplasties) and postoperative complications. RESULTS In total, 1803 cross-sectional imaging exams in 957 CD patients were performed during the study period. In 113 patients, penetrating ileal CD complications were identified. The majority of these patients were referred for surgery (86%) (median time to surgery 1 month, interquartile range: 1-4.9 months). In multivariate analysis, only the presence of abscesses was associated with subsequent surgery (P=0.034; hazard ratio=1.65; 95% confidence interval: 1.04-2.61). Severe postoperative complications (Dindo-Clavien>II) were present in 13% of the patients. Albumin less than 32 g/l was associated with a five-fold increase in severe complications (P=0.039; hazard ratio=4.9; 95% confidence interval: 1-22). Up to 35% of the patients needed no further medical treatment during the first 5 years postoperatively. CONCLUSION In this cohort, the majority of patients with penetrating ileal CD underwent surgery. The presence of an abscess showed a significant association with the need for surgery. There was an acceptable postoperative complication rate. Patients with low albumin had an unfavourable postoperative course. The long-term outcome after surgery was favourable.
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Bossuyt P, Debeuckelaere C, Ferrante M, de Buck van Overstraeten A, Vanbeckevoort D, Billiet T, Wolthuis A, Cleynen I, Van Assche G, D'Hoore A, Vermeire S. Risk Stratification for Surgery in Stricturing Ileal Crohn's Disease: The BACARDI Risk Model. J Crohns Colitis 2018; 12:32-38. [PMID: 28981768 DOI: 10.1093/ecco-jcc/jjx110] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 08/01/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Transmural inflammation in Crohn's disease [CD] leads to stricturing or penetrating complications. Factors impacting on the need and timing of surgery in ileal stricturing CD [IS-CD] are understudied. Our aim was to identify risk factors in IS-CD associated with the need for surgery over time. METHODS All cross-sectional imaging [XSI] performed for CD between 2006 and 2015 in a tertiary referral centre was analysed. The electronic charts of patients with IS-CD were reviewed for demographic, clinical, biochemical, imaging, genetic, and endoscopic factors. An independent cohort was used for validation. RESULTS A total of 1803 XSI were performed in 957 patients with CD. IS-CD was diagnosed in 235 patients, and 161 of these [69%] needed surgery. Prestenotic dilation (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.22-3.45, p = 0.007], C-reactive protein at diagnosis of IS-CD > 11 mg/L [HR 1.53, 95% CI 1.05-2.24, p = 0.026], Montreal B3 phenotype [HR 1.58, 95% CI 1.06-2.36, p = 0.023], previous/current anti-tumour necrosis factor [TNF] exposure [HR 1.44, 95% CI 1.00-2.06, p = 0.048], and presence of at least one NOD2 rs2066844 risk allele [HR 1.51, 95% CI 1.02-2.23, p = 0.038] significantly impacted on the need for surgery in multivariate analysis. The risk stratification model [BACARDI] yielded a surgery-free survival after 5 years of 77%, 38%,19%, and 0% for the low, medium, high, and all risk groups, respectively. Based on an independent cohort of 27 patients, the results were validated and demonstrated adequate performance. CONCLUSIONS This risk model can facilitate therapeutic decisions in IS-CD and suggest the correct time for surgery in daily clinical practice.
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Affiliation(s)
- Peter Bossuyt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.,Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium
| | - Celine Debeuckelaere
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | | | | | - Thomas Billiet
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Albert Wolthuis
- Department of Radiology, University Hospitals Leuven, Leuven, Belgium
| | | | - Gert Van Assche
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Andre D'Hoore
- Department of Radiology, University Hospitals Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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22
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Rogler G. Challenges of Translation of Anti-Fibrotic Therapies into Clinical Practice in IBD. FIBROSTENOTIC INFLAMMATORY BOWEL DISEASE 2018:295-305. [DOI: 10.1007/978-3-319-90578-5_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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23
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Lang BM, Biedermann L, van Haaften WT, de Vallière C, Schuurmans M, Begré S, Zeitz J, Scharl M, Turina M, Greuter T, Schreiner P, Heinrich H, Kuntzen T, Vavricka SR, Rogler G, Beerenwinkel N, Misselwitz B. Genetic polymorphisms associated with smoking behaviour predict the risk of surgery in patients with Crohn's disease. Aliment Pharmacol Ther 2018; 47:55-66. [PMID: 29052254 DOI: 10.1111/apt.14378] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 08/04/2017] [Accepted: 09/22/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Smoking is a strong environmental factor leading to adverse outcomes in Crohn's disease, but a more benign course in ulcerative colitis. Several single nucleotide polymorphisms (SNPs) are associated with smoking quantity and behaviour. AIM To assess whether smoking-associated SNPs interact with smoking to influence the clinical course of inflammatory bowel diseases. METHODS Genetic and prospectively obtained clinical data from 1434 Swiss inflammatory bowel disease cohort patients (821 Crohn's disease and 613 ulcerative colitis) were analysed. Six SNPs associated with smoking quantity and behaviour (rs588765, rs1051730, rs1329650, rs4105144, rs6474412 and rs3733829) were combined to form a risk score (range: 0-12) by adding the number of risk alleles. We calculated multivariate models for smoking, risk of surgery, fistula, Crohn's disease location and ulcerative colitis disease extent. RESULTS In Crohn's disease patients who smoke, the number of surgeries was associated with the genetic risk score. This translates to a predicted 3.5-fold (95% confidence interval: 2.4- to 5.7-fold, P<.0001) higher number of surgical procedures in smokers with 12 risk alleles than individuals with the lowest risk. Patients with a risk score >7 had a significantly shorter time to first intestinal surgery. The genetic risk score did not predict surgery in ulcerative colitis or occurrence of fistulae in Crohn's disease. SNP rs6265 was associated with ileal disease in Crohn's disease (P<.05) and proctitis in ulcerative colitis (P<.05). CONCLUSIONS SNPs associated with smoking quantity is associated with an increased risk for surgery in Crohn's disease patients who smoke. Our data provide an example of genetics interacting with the environment to influence the disease course of inflammatory bowel disease.
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Affiliation(s)
- B M Lang
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.,Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - L Biedermann
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - W T van Haaften
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland.,Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - C de Vallière
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - M Schuurmans
- Division of Pneumology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - S Begré
- Hohenegg Hospital, Meilen, Switzerland
| | - J Zeitz
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - M Scharl
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - M Turina
- Division of Visceral Surgery, University Hospital Zurich (USZ), Zurich, Switzerland
| | - T Greuter
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - P Schreiner
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - H Heinrich
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - T Kuntzen
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - S R Vavricka
- Division of Gastroenterology, Triemli Hospital Zurich, Zürich, Switzerland
| | - G Rogler
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
| | - N Beerenwinkel
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.,Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - B Misselwitz
- Division of Gastroenterology, University Hospital Zurich (USZ) and Zurich University, Zurich, Switzerland
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24
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Zangenberg MS, Horesh N, Kopylov U, El-Hussuna A. Preoperative optimization of patients with inflammatory bowel disease undergoing gastrointestinal surgery: a systematic review. Int J Colorectal Dis 2017; 32:1663-1676. [PMID: 29051981 DOI: 10.1007/s00384-017-2915-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/09/2017] [Indexed: 02/04/2023]
Abstract
PURPOSE Surgical management of inflammatory bowel disease (IBD) is a challenging task. The aim of preoperative optimization (PO) is to decrease the risk of complications and reduce the length of postoperative stay. The aim of this study was to review and grade the available evidence, attain clear recommendations, and point out potential future research. METHODS Studies were identified from electronic databases (PubMed, Embase, and Cochrane Library) and scanning reference lists in relevant papers. English-written studies examining PO in adult patients with IBD were included. Eight PO factors were investigated. RESULTS Management of IBD is a multidisciplinary task. Steroid withdrawal is recommended while steroid stress dose is not recommended. Thiopurines appear to be safe, but it may be prudent to plan the procedure remotely from the last dose of an anti-TNF agent. Nutritional risk screening is recommended to unveil and correct any malnutrition. Thrombosis prophylaxis prior to surgery is well supported by evidence while extended 4-week prophylaxis needs further research. Percutaneous ultrasound or CT-guided drainage for intra-abdominal abscesses is recommended, but it is unclear for how long supplementary antibiotics (ABs) should be used. Oral AB 24 h prior to open surgery might improve outcome if given as complementary to IV perioperative AB. Mechanical bowel preparation is not supported by evidence. Comorbidities must be treated accordingly prior to surgical intervention. Smoking cessation can be beneficial for wound healing. CONCLUSION Multimodel PO intervention in IBD patients is recommended.
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Affiliation(s)
| | - Nir Horesh
- Department of Surgery, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alaa El-Hussuna
- Department of Surgery, Aalborg University Hospital, Hobrovej 18-22, 9000, Aalborg, Denmark.
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25
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Rieder F, Fiocchi C, Rogler G. Mechanisms, Management, and Treatment of Fibrosis in Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152:340-350.e6. [PMID: 27720839 PMCID: PMC5209279 DOI: 10.1053/j.gastro.2016.09.047] [Citation(s) in RCA: 354] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 09/07/2016] [Accepted: 09/12/2016] [Indexed: 02/08/2023]
Abstract
In the last 10 years, we have learned much about the pathogenesis, diagnosis, and management of intestinal fibrosis in patients with inflammatory bowel diseases. Just a decade ago, intestinal strictures were considered to be an inevitable consequence of long-term inflammation in patients who did not respond to anti-inflammatory therapies. Inflammatory bowel diseases-associated fibrosis was seen as an irreversible process that frequently led to intestinal obstructions requiring surgical intervention. This paradigm has changed rapidly, due to the antifibrotic approaches that may become available. We review the mechanisms and diagnosis of this serious complication of inflammatory bowel diseases, as well as factors that predict its progression and management strategies.
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Affiliation(s)
- Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute; Cleveland Clinic, Cleveland, Ohio; Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio.
| | - Claudio Fiocchi
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute; Cleveland Clinic, Cleveland, Ohio; Department of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital, University of Zurich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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26
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Experts Opinion on the Practical Use of Azathioprine and 6-Mercaptopurine in Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:2733-2747. [PMID: 27760078 DOI: 10.1097/mib.0000000000000923] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The relevance of azathioprine and 6-mercaptopurine therapy in inflammatory bowel disease, Crohn's disease, and ulcerative colitis, has been challenged in recent publications. In this article, a panel of experts gives advice, based on the relevant literature, on indications and practical use of azathioprine/6-mercaptopurine, prevention, and management of drug adverse reactions and special situations such as vaccination, pregnancy, and lactation.
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27
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Abstract
BACKGROUND Crohn's disease (CD) is increasing in incidence and prevalence in Asia, but there is a paucity of population-based studies on risk factors for surgery in Asian patients with CD. This will be useful to identify patients who may benefit from top-down treatment. This study describes the rates of abdominal surgery and identifies associated risk factors in Singaporean patients with CD. METHODS This was a retrospective observational study. The medical records of Singaporeans diagnosed with CD from 1970 to 2013 were reviewed from 8 different hospitals in Singapore. The cumulative probability of CD-related abdominal surgery was estimated using the Kaplan-Meier method. The logistic regression model was used to assess associations between independent risk factors and surgery. RESULTS The cohort of 430 Singaporean patients with CD included 63.5% Chinese, 11.9% Malay, and 24.7% Indians, with a male to female ratio of 1.6; median follow-up was 7.3 years (range, 2.9-13.0 yr) and median age at diagnosis 30.5 years (range, 19.5-43.7 yr). One hundred twelve patients (26.0%) required major abdominal surgery: the cumulative risk of surgery was 14.9% at 90 days, 21.2% at 5 years, 28.8% at 10 years, 38.3% at 20 years, and 50.6% at 30 years from diagnosis. Of the surgical patients, 75.0% were Chinese, 10.7% Malays, and 14.3% Indians; 21.4% underwent surgery for inflammatory disease, 40.2% for stricturing disease, and 38.4% for penetrating disease. Age at diagnosis (A2 17-40 yr, OR: 2.75, 95% confidence interval [CI], 1.14-7.76), ileal disease (L1 location, OR: 2.35, 95% CI, 1.14-5.0), stricturing (B2 OR: 6.09, 95% CI, 3.20-11.8), and penetrating behavior (B3 OR: 21.6, 95% CI, 9.0-58.8) were independent risk factors for CD-related abdominal surgery. Indian patients were less likely to require surgery (OR: 0.40, 95% CI, 0.19-0.78). CONCLUSIONS Age at diagnosis, L1 location, B2, and B3 disease behavior are independent risk factors for abdominal surgery. Interestingly, despite a higher prevalence of CD in Indians, a smaller proportion of Indian patients required surgery. These findings suggest that both environmental and genetic factors contribute to the risk of surgery in Asian patients with CD.
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28
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Biedermann L, Fournier N, Misselwitz B, Frei P, Zeitz J, Manser CN, Pittet V, Juillerat P, von Känel R, Fried M, Vavricka SR, Rogler G. High Rates of Smoking Especially in Female Crohn's Disease Patients and Low Use of Supportive Measures to Achieve Smoking Cessation--Data from the Swiss IBD Cohort Study. J Crohns Colitis 2015; 9:819-29. [PMID: 26116554 DOI: 10.1093/ecco-jcc/jjv113] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 06/08/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Smoking is a crucial environmental factor in inflammatory bowel disease [IBD]. However, knowledge on patient characteristics associated with smoking, time trends of smoking rates, gender differences and supportive measures to cease smoking provided by physicians is scarce. We aimed to address these questions in Swiss IBD patients. METHODS Prospectively obtained data from patients participating in the Swiss IBD Cohort Study was analysed and compared with the general Swiss population [GSP] matched by age, sex and year. RESULTS Among a total of 1770 IBD patients analysed [49.1% male], 29% are current smokers. More than twice as many patients with Crohn's disease [CD] are active smokers compared with ulcerative colitis [UC] [UC, 39.6% vs CD 15.3%, p < 0.001]. In striking contrast to the GSP, significantly more women than men with CD smoke [42.8% vs 35.8%, p = 0.025], with also an overall significantly increased smoking rate compared with the GSP in women but not men. The vast majority of smoking IBD patients [90.5%] claim to never have received any support to achieve smoking cessation, significantly more in UC compared with CD. We identify a significantly negative association of smoking and primary sclerosing cholangitis, indicative of a protective effect. Psychological distress in CD is significantly higher in smokers compared with non-smokers, but does not differ in UC. CONCLUSIONS Despite well-established detrimental effects, smoking rates in CD are alarmingly high with persistent and stagnating elevations compared with the GSP, especially in female patients. Importantly, there appears to be an unacceptable underuse of supportive measures to achieve smoking cessation.
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Affiliation(s)
- Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Nicolas Fournier
- Institute of Social and Preventive Medicine, University of Lausanne, Lausanne, Switzerland
| | - Benjamin Misselwitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Pascal Frei
- Division of Gastroenterology & Hepatology, Seespital Horgen, Horgen, Switzerland
| | - Jonas Zeitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Christine N Manser
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Valerie Pittet
- Institute of Social and Preventive Medicine, University of Lausanne, Lausanne, Switzerland
| | - Pascal Juillerat
- Division of Gastroenterology & Hepatology, Inselspital Bern, Bern, Switzerland
| | - Roland von Känel
- Department of Psychosomatic Medicine, Clinic Barmelweid, Barmelweid, Switzerland
| | - Michael Fried
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Stephan R Vavricka
- Division of Gastroenterology & Hepatology, Triemli Hospital, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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29
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Safroneeva E, Vavricka SR, Fournier N, Pittet V, Peyrin-Biroulet L, Straumann A, Rogler G, Schoepfer AM. Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease. Aliment Pharmacol Ther 2015; 42:977-89. [PMID: 26271358 DOI: 10.1111/apt.13363] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Revised: 12/09/2014] [Accepted: 07/23/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. AIM To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. METHODS Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. RESULTS The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). CONCLUSIONS Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.
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Affiliation(s)
- E Safroneeva
- Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
| | - S R Vavricka
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland
| | - N Fournier
- Institut Universitaire de Médecine Sociale et Préventive, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland
| | - V Pittet
- Institut Universitaire de Médecine Sociale et Préventive, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland
| | - L Peyrin-Biroulet
- Inserm U954, Department of Hepato-Gastroenterology, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - A Straumann
- Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - G Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - A M Schoepfer
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland
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30
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Abstract
Crohn's disease (CD) evolution is characterized by increasing proportions of patients developing complications such as strictures, abscesses and fistulas that require surgical management. After resection of a diseased intestinal segment, CD recurrence concerns up to 60% of patients within a year post surgery. The mucosa just above the site of the intestinal anastomosis is at particularly high risk of relapse. Prophylactic medical therapy to prevent recurrence has been shown to be effective with a variety of medications, but the recurrence rate remains high, demanding that a better risk stratification of patients be achieved. Recognized risk factors for postsurgical CD recurrence include young age at diagnosis and at surgery, smoking, need for repeated surgeries and penetrating disease. These patients require full dose immunosuppressive or anti-tumor necrosis factor (anti-TNF) therapy, which should be initiated in the immediate postoperative period, to prevent the onset of an inflammatory activity in the bowel. Systematic follow-up by endoscopy to monitor treatment benefit should also be part of the management, as endoscopic recurrence heralds clinical relapse in these patients. The role of noninvasive markers of mucosal inflammation, such as stool calprotectin levels, show promise to complete this monitoring. Although the efficacy of mesalazine and imidazole antibiotics has been long recognized, more aggressive approaches, such as thiopurines and anti-TNF antibodies, have shown higher efficacies in direct comparison trials. The potential place of anti-homing agents is not yet defined, but these agents should in principle be of interest for this prophylactic indication due to their mode of action and interesting side-effect profile. The current recommendations are based on a step-up approach that includes immunosuppressors and/or imidazole antibiotics, followed by an anti-TNF agent, such as infliximab and adalimumab, both already tested in randomized trials in this indication. When endoscopic recurrence is identified during follow-up, upscaling to anti-TNF or dose escalation is advocated.
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31
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Prostaglandin E₂ and polyenylphosphatidylcholine: stiff competition for the fibrotic complications of inflammatory bowel disease? Dig Dis Sci 2015; 60:1514-6. [PMID: 25902749 PMCID: PMC4830265 DOI: 10.1007/s10620-015-3668-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 04/10/2015] [Indexed: 12/09/2022]
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32
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Rogler G. New therapeutic avenues for treatment of fibrosis: can we learn from other diseases? Dig Dis 2014; 32 Suppl 1:39-49. [PMID: 25531352 DOI: 10.1159/000367825] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Crohn's disease (CD) is characterized by the frequent occurrence of complications, such as fibrotic strictures and subsequently the need for CD-related surgery. Chronic or recurrent inflammation is generally regarded to be a necessary precondition for the initiation of intestinal fibrosis. In this view, fibrosis is a pathologically augmented healing response to inflammation-induced mucosal tissue destruction and injury. At present, there are no approved or effective medical therapies aimed specifically at fibrosis or stricture in IBD. Indirect benefits may occur from anti-inflammatory therapies, although there is no consensus on this. Therapy for fibrosis is complicated by the fact that a wound-healing response is essential in CD and ulcerative colitis. Several pharmaceutical companies are now working on the therapy of fibrosis in other diseases. Strategies interfering with TGF-β expression and activation are promising. Pirfenidone has been studied in several clinical trials. Further therapeutic options are second-generation and wide-spectrum tyrosine kinase inhibitors. These inhibit growth factor receptor signaling, thus reducing fibrosis in animal models and some patients with tumor-associated fibrosis. At present, the development of antifibrotic therapies takes place in other diseases such as lung and liver fibrosis. This is partially due to a lack of experimental models for gut fibrosis and the fact that reliable readouts (MRI, serum markers) in patients are lacking. It will be important to test the above-mentioned newly available treatment strategies in IBD to profit from progress in other fibrotic diseases.
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Affiliation(s)
- Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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33
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Cumulative incidence of second intestinal resection in Crohn's disease: a systematic review and meta-analysis of population-based studies. Am J Gastroenterol 2014; 109:1739-48. [PMID: 25331349 DOI: 10.1038/ajg.2014.297] [Citation(s) in RCA: 177] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Accepted: 07/01/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Approximately 50% of Crohn's disease patients undergo an intestinal resection within 10 years of diagnosis. The risk of second surgery in Crohn's disease and the influence of time are not well characterized. We performed a systematic review and meta-analysis to establish the risk of second abdominal surgery in patients with Crohn's disease among patients who had a previous surgery. METHODS We searched Medline, EMBASE, PubMed (March 2014), and conference proceedings for terms related to Crohn's disease and intestinal surgery. We included population-based articles (n=11) and an abstract (n=1) reporting surgical risk for the overall study period and for 5 and 10 years after the first surgery for Crohn's disease. We stratified studies by year (start year before vs. after 1980) to explore the role of time. RESULTS For all population-based studies, the overall risk of second surgery was 28.7% (95% confidence interval (CI): 22.6-36.6%). The 5-year risk of second surgery was 24.2% (95% CI: 22.3-26.4%). The 10-year risk of second surgery was 35.0% (95% CI: 31.8-38.6%). A significant difference in the 10-year risk of second surgery was observed over time such that studies conducted after 1980 had a lower risk of second surgery (33.2%; 95% CI: 31.2-35.4%) compared with those that started before 1980 (44.6%; 95% CI: 37.7-52.7%). CONCLUSIONS Approximately one-quarter of Crohn's disease patients who have a first surgery also have a second, and the majority of these surgeries occur within 5 years of the first surgery. The 10-year risk of second surgery is significantly decreasing over time.
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Mosli MH, Sandborn WJ, Kim RB, Khanna R, Al-Judaibi B, Feagan BG. Toward a personalized medicine approach to the management of inflammatory bowel disease. Am J Gastroenterol 2014; 109:994-1004. [PMID: 24842338 DOI: 10.1038/ajg.2014.110] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Accepted: 03/30/2014] [Indexed: 12/11/2022]
Abstract
The medical management of inflammatory bowel disease (IBD) is evolving toward a personalized medicine-based model. Modern therapeutic algorithms that feature use of tumor necrosis factor (TNF) antagonists in combination with immunosuppressive are highly effective when initiated in high-risk patients early in the course of disease. Defined targets that guide intensification of therapy are critical interventions. In this model, therapy is optimized through appropriate pretreatment testing, therapeutic drug monitoring, and patient-based monitoring strategies. This review discusses the current application of personalized medicine to the management of IBD.
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Affiliation(s)
- Mahmoud H Mosli
- 1] Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada [2] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada [3] Department of Medicine, Division of Gastroenterology, King Abdulaziz University, Jeddah, Saudi Arabia
| | - William J Sandborn
- 1] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada [2] Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | - Richard B Kim
- Department of Medicine, Division of Clinical Pharmacology, Western University, London, Ontario, Canada
| | - Reena Khanna
- 1] Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada [2] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada
| | - Bandar Al-Judaibi
- 1] Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada [2] Department of Medicine, Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Brian G Feagan
- 1] Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada [2] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada
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