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Huang CW, Wei SC, Shieh MJ, Chou JW, Chuang CH, Wang HY, Chang CW, Wu DC, Huang TY, Liu YH, Tsai TJ, Tai WC, Tai CM, Chung CS, Tsai WS, Chang CH, Lin CP, Lee HC, Chang CC, Feng IC, Lin CC, Cheng ML, Yen HH. Epidemiology and temporal trends of adult inflammatory bowel disease in Taiwan: Multicenter study from the TSIBD registration. J Formos Med Assoc 2025:S0929-6646(25)00034-8. [PMID: 39893095 DOI: 10.1016/j.jfma.2025.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 09/29/2024] [Accepted: 01/21/2025] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Despite industrialization and advances in healthcare, the prevalence of inflammatory bowel disease (IBD), which encompasses Crohn's disease (CD) and ulcerative colitis (UC), is increasing in Taiwan. Population-based studies can estimate the incidence or prevalence of IBD; however, there is a lack of information regarding the disease phenotype. Therefore, this study was designed to investigate the epidemiologic trends of IBD in Taiwan to gain a more comprehensive understanding. METHODS Patient data were reviewed from a prospectively registered study by the Taiwan Society of IBD (TSIBD). RESULTS We collected data from 2752 patients with IBD, of whom 881 had CD and 1871 had UC. Their average age was 41.99 ± 15.19 years. The CD group had more male patients than the UC group (67.88% vs. 60.72%; p < .001). The rates of appendectomy, bowel resection, and surgery for perianal disease before IBD diagnosis, along with the increased use of steroids, immunomodulators, and biologics, were higher in the CD group. From 2005 to 2023, the ratio of UC to CD cases in Taiwan decreased, the proportions of patients with colonic and penetrating CD also declined, and the proportion of patients with UC exhibiting ulcerative proctitis increased. CONCLUSION In Taiwan, similar to high-income countries, the ratio of UC to CD cases has declined. The reduced of colonic and penetrating CD indicates that diagnostic awareness has improved and colonoscopic examination has become more comprehensive in Taiwan.
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Affiliation(s)
- Chih-Wen Huang
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan
| | - Shu-Chen Wei
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Ming-Jium Shieh
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jen-Wei Chou
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Chiao-Hsiung Chuang
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Horng-Yuan Wang
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan; MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
| | - Chen-Wang Chang
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan; MacKay Junior College of Medicine, Nursing and Management, Taipei, Taiwan
| | - Deng-Chyang Wu
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Gangshan Hospital, Kaohsiung, Taiwan; Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Tien-Yu Huang
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yu-Hwa Liu
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shin Kong Wu Ho Su Memorial Hospital, Taipei, Taiwan
| | - Tzung-Jiun Tsai
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Chen Tai
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chi-Ming Tai
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Chen-Shuan Chung
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Far Eastern Memorial Hospital, New Taipei, Taiwan; Ultrasonography and Endoscopy Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Wen-Sy Tsai
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Colon and Rectal Surgery, Colorectal Section, Department of Surgery Chang, Gung Memorial Hospital, Taoyuan City, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chung-Hsin Chang
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ching-Pin Lin
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Hsi-Chang Lee
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Renai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Chao Chang
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; TMU Research Center for Digestive Medicine, Taipei Medical University, Taipei, 110301, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - I-Che Feng
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Gastroenterology and Hepatology, Chi Mei Medical Center, Tainan, Taiwan
| | - Chun-Chi Lin
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Division of Colon & Rectal Surgery, Department of Surgery Taipei Veterans General Hospital Taipei Taiwan, Taiwan; Department of Surgery, Faculty of Medicine, School of Medicine National Yang Ming Chiao Tung University Taipei Taiwan, Taiwan
| | - Mu-Liang Cheng
- Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Department of Gastroenterology, Mennonite Christian Hospital, Hualien, Taiwan
| | - Hsu-Heng Yen
- Division of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan; Taiwan Society of Inflammatory Bowel Disease (TSIBD), Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.
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Assadsangabi A, Evans CA, Corfe BM, Lobo AJ. Exploring Predictive Biomarkers of Relapse in Ulcerative Colitis: A Proteomics Approach. Inflamm Bowel Dis 2024; 30:808-819. [PMID: 37889841 DOI: 10.1093/ibd/izad241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Indexed: 10/29/2023]
Abstract
INTRODUCTION AND AIMS Risk stratification of subjects with a history of inflammatory bowel disease (IBD) into those likely to relapse and those who will remain quiescent continues to be a significant challenge. The aim of this study was to investigate whether certain proteomic signature profiles or biomarkers during remission are associated with future disease relapse in patients with ulcerative colitis (UC). METHODS Endoscopic rectal samples from patients with UC in clinical, endoscopic, and histological remission at index endoscopy were collected, as well as samplers from normal control individuals. The patients were stratified to early relapsers (ERs) if they developed clinical signs of UC flare within 6 months of index endoscopy or nonrelapsers (NRs) if there was no relapse after 36 months of follow-up. The pooled rectal samples from ERs, NRs, and control individuals were subjected to nano-liquid chromatography and tandem mass spectrometry as per standard iTRAQ (isobaric tags for relative and absolute quantitation) workflow methodology. Selected proteomics-yielded candidates were subjected to orthogonal validation via immunoblotting, in a biomarker discovery exercise. RESULTS Sixty-one patients were included, of whom 8 had clinical relapse within 6 months from the index endoscopy, and 43 patients had no clinical symptoms of relapse within the 36-month follow-up period. Ten patients who had clinical signs of relapse between 6 and 36 months were excluded. Seventeen control individuals were also included. Soluble proteomics analyses between ERs, NRs, and control individuals revealed a series of upregulated and downregulated proteins. Following orthogonal validation, upregulated TRX (P = .001) and IGHA1 (P = .001) were observed in ERs relative to NRs. CONCLUSIONS Several novel candidate tissue biomarkers have been identified in this study, which could discriminate patients with UC at risk of early relapse from those in long-term sustained remission. Our findings may pave the way for pre-emptive UC disease monitoring and therapeutic decision making.
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Affiliation(s)
- Arash Assadsangabi
- Molecular Gastroenterology Research Group, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom
- Gastroenterology Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom
- Gastroenterology Department, Salford Royal NHS Foundation Trust, Salford, United Kingdom
- Faculty of Biology, Medicine and Health, School of Medical Sciences, University of Manchester, Manchester, United Kingdom
| | - Caroline A Evans
- Molecular Gastroenterology Research Group, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom
- Biological and Systems Engineering Group, ChELSI Institute, Department of Chemical and Biological Engineering, University of Sheffield, Sheffield, United Kingdom
| | - Bernard M Corfe
- Molecular Gastroenterology Research Group, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom
| | - Alan J Lobo
- Molecular Gastroenterology Research Group, Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom
- Gastroenterology Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom
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Humphreys DT, Lewis A, Pan‐Castillo B, Berti G, Mein C, Wozniak E, Gordon H, Gadhok R, Minicozzi A, ChinAleong J, Feakins R, Giannoulatou E, James LK, Stagg AJ, Lindsay JO, Silver A. Single cell sequencing data identify distinct B cell and fibroblast populations in stricturing Crohn's disease. J Cell Mol Med 2024; 28:e18344. [PMID: 38685679 PMCID: PMC11058334 DOI: 10.1111/jcmm.18344] [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] [Received: 09/27/2023] [Revised: 02/20/2024] [Accepted: 04/05/2024] [Indexed: 05/02/2024] Open
Abstract
Single cell RNA sequencing of human full thickness Crohn's disease (CD) small bowel resection specimens was used to identify potential therapeutic targets for stricturing (S) CD. Using an unbiased approach, 16 cell lineages were assigned within 14,539 sequenced cells from patient-matched SCD and non-stricturing (NSCD) preparations. SCD and NSCD contained identical cell types. Amongst immune cells, B cells and plasma cells were selectively increased in SCD samples. B cell subsets suggested formation of tertiary lymphoid tissue in SCD and compared with NSCD there was an increase in IgG, and a decrease in IgA plasma cells, consistent with their potential role in CD fibrosis. Two Lumican-positive fibroblast subtypes were identified and subclassified based on expression of selectively enriched genes as fibroblast clusters (C) 12 and C9. Cells within these clusters expressed the profibrotic genes Decorin (C12) and JUN (C9). C9 cells expressed ACTA2; ECM genes COL4A1, COL4A2, COL15A1, COL6A3, COL18A1 and ADAMDEC1; LAMB1 and GREM1. GO and KEGG Biological terms showed extracellular matrix and stricture organization associated with C12 and C9, and regulation of WNT pathway genes with C9. Trajectory and differential gene analysis of C12 and C9 identified four sub-clusters. Intra sub-cluster gene analysis detected 13 co-regulated gene modules that aligned along predicted pseudotime trajectories. CXCL14 and ADAMDEC1 were key markers in module 1. Our findings support further investigation of fibroblast heterogeneity and interactions with local and circulating immune cells at earlier time points in fibrosis progression. Breaking these interactions by targeting one or other population may improve therapeutic management for SCD.
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Affiliation(s)
- David T. Humphreys
- Victor Chang Cardiac Research InstituteSydneyNew South WalesAustralia
- St Vincent's Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - Amy Lewis
- Centre for Genomics and Child Health, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Belen Pan‐Castillo
- Centre for Genomics and Child Health, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Giulio Berti
- Centre for Genomics and Child Health, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Charles Mein
- Genome Centre, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Eva Wozniak
- Genome Centre, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Hannah Gordon
- Centre for Immunobiology, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Radha Gadhok
- Centre for Immunobiology, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Annamaria Minicozzi
- Department of Colorectal Surgery, Division of Surgery and Perioperative CareThe Royal London HospitalLondonUK
| | | | - Roger Feakins
- Department of Cellular PathologyRoyal Free London NHS Foundation TrustLondonUK
| | - Eleni Giannoulatou
- Victor Chang Cardiac Research InstituteSydneyNew South WalesAustralia
- St Vincent's Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - Louisa K. James
- Centre for Immunobiology, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Andrew J. Stagg
- Centre for Immunobiology, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - James Oliver Lindsay
- Centre for Immunobiology, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
| | - Andrew Silver
- Centre for Genomics and Child Health, Blizard InstituteBarts and The London School of Medicine and DentistryLondonUK
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Santiago P, Coelho-Prabhu N, Lennon R, Rui S, Rajauria P, Friton J, Raffals LE, Deepali F, Daoud N, Farraye FA, Tuck J, Malik T, Leleiko NS, Shapiro J, Shah SA, Sands BE, Ungaro RC. Baseline Clinical Factors Are Associated With Risk of Complications in Crohn's Disease: Appraisal of the American Gastroenterological Association Clinical Care Pathway. Am J Gastroenterol 2024; 119:147-154. [PMID: 37713528 DOI: 10.14309/ajg.0000000000002498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 08/18/2023] [Indexed: 09/17/2023]
Abstract
INTRODUCTION The American Gastroenterological Association (AGA) has compiled risk factors that may be predictive of disease complications in Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate the performance of the AGA risk factors for risk stratification in UC and CD. METHODS We included participants of 2 cohorts: the Ocean State Crohn's and Colitis Area Registry cohort and the Mayo Clinic cohort. Baseline clinical risk factors were extracted according to the AGA pathway. Our primary end point was defined as follows: (i) any inflammatory bowel disease related-hospitalization, (ii) any inflammatory bowel disease-related bowel surgery, or (iii) any progression of disease. We analyzed the association of the number of AGA risk factors with our end point. Statistical multivariable modeling was performed with Cox proportional hazards model. RESULTS A total of 412 patients with CD were included. Comparing ≥3 risk factors with 0-1 risk factor, we found a significantly increased risk of complications in both the Ocean State Crohn's and Colitis Area Registry cohort (hazard ratio [HR] 2.75, 95% confidence interval 1.71-4.41) and Mayo Clinic cohort (HR 2.07, 95% confidence interval 1.11-3.84). Diagnosis at younger age (HR 2.07), perianal disease (HR 1.99), and B2/B3 behavior (HR 1.92) were significantly associated with disease complications. We did not observe a consistent association between number of risk factors nor any specific individual risk factors and risk of disease complications in the 265 patients with UC included. DISCUSSION We found a significant association between the number of AGA risk factors and the risk of disease complication in CD; this association was not significant in UC. The presence of ≥ 3 risk factors in CD leads to the highest risk of complications. The AGA care pathway is a useful tool to stratify patients who are at higher risk of disease complications in patients with CD.
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Affiliation(s)
- Priscila Santiago
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Ryan Lennon
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Shumin Rui
- The Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Palak Rajauria
- The Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Jessica Friton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Laura E Raffals
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Fnu Deepali
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nader Daoud
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Francis A Farraye
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Jaclyn Tuck
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Talha Malik
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Neal S Leleiko
- Division of Pediatric Gastroenterology, Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
| | - Jason Shapiro
- Department of Pediatric Gastroenterology, Warren Alpert Medical School of Brown University, Providence
| | - Samir A Shah
- Division of Gastroenterology, Warren Alpert Medical School of Brown University, Providence
| | - Bruce E Sands
- The Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ryan C Ungaro
- The Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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Jans D, Cleynen I. The genetics of non-monogenic IBD. Hum Genet 2023; 142:669-682. [PMID: 36720734 DOI: 10.1007/s00439-023-02521-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 01/10/2023] [Indexed: 02/02/2023]
Abstract
Inflammatory bowel disease (IBD), with Crohn's disease and ulcerative colitis as main subtypes, is a prototypical multifactorial disease with both genetic and environmental factors involved. Genetically, IBD covers a wide spectrum from monogenic to polygenic forms. In polygenic disease, many genetic variants each contribute a small amount to disease risk. With the advent of genome-wide association studies (GWAS), it became possible to find these variants and corresponding genes, leading so far to the discovery of ca 240 loci associated with IBD. Together, these however explain only 20-25% of the heritability of IBD, leaving a large portion unaccounted for. This missing heritability might be hidden in common variants with even lower effect than the ones currently found through GWAS, but also in rare variants which can be found through large-scale sequencing studies or potentially in multiplex families. In this review, we will give an overview of the current knowledge about the genetics of non-monogenic IBD and how it differs from the monogenic form(s), and future perspectives. The history of IBD genetic studies from twin studies over linkage studies to GWAS, and finally large-scale sequencing studies and the revisiting of multiplex families will be discussed.
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Affiliation(s)
- Deborah Jans
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49, box610, 3000, Louvain, Belgium
| | - Isabelle Cleynen
- Laboratory for Complex Genetics, Department of Human Genetics, KU Leuven, Herestraat 49, box610, 3000, Louvain, Belgium.
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Chen Y, Zhang G, Yang Y, Zhang S, Jiang H, Tian K, Arenbaoligao, Chen D. The treatment of inflammatory bowel disease with monoclonal antibodies in Asia. Biomed Pharmacother 2023; 157:114081. [PMID: 36481399 DOI: 10.1016/j.biopha.2022.114081] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/27/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), are chronic, systemic autoimmune diseases. As the incidence of IBD rapidly increases in Asia, increasing attention has been paid to developing additional treatment strategies. Presently, the end point of therapy is achieving clinical and endoscopic remission through the blockade of inflammatory cascades. Recent studies have shown that monoclonal antibodies (mAbs) use for precise molecular targeting of inflammatory pathways has a promising effect on IBD, especially moderate-to-severe CD and UC. Since the 1997 report on the use of infliximab (a monoclonal antibody against tumor necrosis factor alpha [TNF-α]) in patients with CD, mAbs have expanded therapeutic options and have also complicated initial management options and subsequent treatment. This review comprehensively summarizes the clinical reports and studies related to the use of mAbs for the treatment of IBD in Asian countries and regions in recent years thus demonstrating the current status of mAbs use in Asia. In addition, the differences in the use of mAbs for the treatment of IBD between the Asia and the West are expounded. Ultimately, it is hoped that this review will provide new insights and a scientific basis for the clinical application of mAbs.
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Affiliation(s)
- Yu Chen
- Dalian Medical University, Dalian, China
| | | | | | | | - Haozheng Jiang
- Department of Joint and Sports Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Kang Tian
- Department of Joint and Sports Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, China
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Lopes EW, Lochhead P, Burke KE, Richter JM, Ananthakrishnan AN, Chan AT, Khalili H. Risk Factors for Incident Inflammatory Bowel Disease According to Disease Phenotype. Clin Gastroenterol Hepatol 2022; 20:2347-2357.e14. [PMID: 35031525 PMCID: PMC9850926 DOI: 10.1016/j.cgh.2022.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/22/2021] [Accepted: 01/02/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We examined whether relationships between known risk factors for Crohn's disease (CD) and ulcerative colitis (UC) differ according to disease phenotype, defined by Montreal classification, at the time of diagnosis. METHODS We performed a prospective cohort study of 208,070 adults from the Nurses' Health Study (NHS), NHSII, and Health Professionals Follow-Up Study (HPFS). Dietary, lifestyle, and medical data were obtained at baseline and every 2-4 years. We confirmed cases of inflammatory bowel disease (IBD) and their phenotypes via medical record review. We tested for heterogeneity across CD subtypes using the likelihood ratio test and for linear heterogeneity across UC subtypes using the meta-regression method. RESULTS We ascertained 346 cases of CD and 456 cases of UC over 5,117,021 person-years of follow-up (1986-2016 for NHS and HPFS; 1991-2017 for NHSII). Fiber intake was associated with decreased risk for ileocolonic but not ileal or colonic CD (Pheterogeneity = .04). Physical activity was associated with decreased risk of nonstricturing and nonpenetrating CD but not of penetrating CD (Pheterogeneity = .02). Higher body mass index and current smoking were associated with decreased risk of proctitis and left-sided UC but not of pan-UC (Plinear heterogeneity= .004 and .02, respectively). The associations between other risk factors examined and risk of CD and UC did not differ by disease phenotype (all Pheterogeneity > .06). CONCLUSIONS In 3 large prospective cohorts, we observed that dietary and lifestyle risk factors for IBD may differ according to disease phenotype. These findings highlight the need for disease stratification in future epidemiologic studies.
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Affiliation(s)
- Emily W Lopes
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translation Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Paul Lochhead
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Kristin E Burke
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - James M Richter
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translation Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translation Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts; Clinical and Translation Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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9
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Steiner CA, Berinstein JA, Louissaint J, Higgins PDR, Spence JR, Shannon C, Lu C, Stidham RW, Fletcher JG, Bruining DH, Feagan BG, Jairath V, Baker ME, Bettenworth D, Rieder F. Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review. Clin Gastroenterol Hepatol 2022; 20:817-846.e10. [PMID: 34089850 PMCID: PMC8636551 DOI: 10.1016/j.cgh.2021.05.054] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Intestinal strictures are a common complication of Crohn's disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures. METHODS We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal). RESULTS Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties. CONCLUSIONS There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.
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Affiliation(s)
- Calen A Steiner
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
| | - Jeffrey A Berinstein
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jeremy Louissaint
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Peter D R Higgins
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jason R Spence
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Carol Shannon
- Taubman Health Sciences Library, University of Michigan, Ann Arbor, Michigan
| | - Cathy Lu
- Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Ryan W Stidham
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | | | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Brian G Feagan
- Alimentiv Inc, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Biostatistics and Epidemiology, Western University, London, Ontario, Canada
| | - Vipul Jairath
- Alimentiv Inc, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Biostatistics and Epidemiology, Western University, London, Ontario, Canada
| | - Mark E Baker
- Section of Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University of Münster, Münster, Germany
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio
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10
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Atreya R, Bojarski C, Kühl AA, Trajanoski Z, Neurath MF, Siegmund B. Ileal and colonic Crohn'´s disease: Ddoes location makes a difference in therapy efficacy? CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100097. [PMID: 35345820 PMCID: PMC8956925 DOI: 10.1016/j.crphar.2022.100097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/07/2022] [Accepted: 03/16/2022] [Indexed: 12/05/2022] Open
Abstract
Within the IBD entity of Crohn's disease, there is currently no differentiation between ileal and colonic manifestation for recruitment of patients in clinical trials, well-powered analysis of study results or therapeutic decisions in daily clinical practice. However, there is accumulating evidence from epidemiological, genetic, microbial, immunological, and clinical characteristics that clearly indicate that ileal Crohn's disease represents a distinct disease entity, which differentiates itself from colonic Crohn's disease. This is also reflected by lower efficacy of targeted therapies in isolated ileal compared to colonic Crohn's disease. The distinct site-specific mechanisms that drive heightened non-response in ileal disease need to be analysed in-depth in the future, to enable optimized therapy in the individual Crohn's disease patient.
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11
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Raine T, Verstockt B, Kopylov U, Karmiris K, Goldberg R, Atreya R, Burisch J, Burke J, Ellul P, Hedin C, Holubar SD, Katsanos K, Lobaton T, Schmidt C, Cullen G. ECCO Topical Review: Refractory Inflammatory Bowel Disease. J Crohns Colitis 2021; 15:1605-1620. [PMID: 34160593 DOI: 10.1093/ecco-jcc/jjab112] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic disease with variable degrees of extent, severity, and activity. A proportion of patients will have disease that is refractory to licensed therapies, resulting in significant impairment in quality of life. The treatment of these patients involves a systematic approach by the entire multidisciplinary team, with particular consideration given to medical options including unlicensed therapies, surgical interventions, and dietetic and psychological support. The purpose of this review is to guide clinicians through this process and provide an accurate summary of the available evidence for different strategies.
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Affiliation(s)
- Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bram Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, TARGID - IBD, KU Leuven, Leuven, Belgium
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
- Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Rimma Goldberg
- Department of Gastroenterology, Monash Health and School of Clinical Sciences, Monash University, Melbourne, VIC, Australia
| | - Raja Atreya
- Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark
| | - John Burke
- Colorectal and General Surgery, Beaumont Hospital, Dublin, Ireland
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | - Charlotte Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden
- Karolinska University Hospital, Gastroenterology Unit, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Stefan D Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Triana Lobaton
- Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Carsten Schmidt
- Medical Faculty of the Friedrich Schiller University, Jena, Germany
| | - Garret Cullen
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Gastroenterology, Dublin, Ireland
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12
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Mantzaris GJ, Zeglinas C, Theodoropoulou A, Koutroubakis I, Orfanoudaki E, Katsanos K, Christodoulou D, Michalopoulos G, Tzouvala M, Moschovis D, Michopoulos S, Zampeli E, Soufleris K, Ilias A, Chatzievangelinou C, Kyriakakis A, Antachopoulou K, Karmiris K. The Effect of Early vs Delayed Initiation of Adalimumab on Remission Rates in Patients With Crohn's Disease With Poor Prognostic Factors: The MODIFY Study. CROHN'S & COLITIS 360 2021; 3:otab064. [PMID: 36777275 PMCID: PMC9802300 DOI: 10.1093/crocol/otab064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Indexed: 12/07/2022] Open
Abstract
Background Data on the effectiveness of anti-tumor necrosis factor medications in patients with Crohn's disease (CD) with poor prognostic factors (PPFs) are scarce. This study aimed to generate real-world evidence on the effect of early (≤24 months after diagnosis) vs delayed (>24 months) initiation of adalimumab (ADL) on the 26-week remission rate (Harvey-Bradshaw Index ≤4) in these patients. Methods This multicentre, retrospective, chart review study performed in 10 Greek hospitals enrolled adult patients with moderate to severe CD (Harvey-Bradshaw Index ≥8) with ≥3 PPFs who were initiated on ADL ≥12 months before enrollment. A sample size of 164 patients (early:delayed cohort allocation ratio, 30:70) was required to address the primary endpoint. Results Eligible patients (n = 171) were consecutively enrolled. In the early vs delayed cohorts, the 26-week remission rates (off-steroids) using the last-observation-carried-forward imputation method were 60.7% (37/61) vs 47.2% (50/106), respectively (Δ = 13.5%, P = .044). The respective remission rates were 61.2% vs 42.4% among anti-tumor necrosis factor-naive patients (P = .023) and 58.3% vs 53.2% among anti-tumor necrosis factor-experienced patients (P = .374). The 52-week remission rates using as-observed data were 78.8% and 60.3%, and the intestinal resection rates were 6.5% and 11.9% in the early vs delayed ADL cohorts, respectively. Conclusions Patients with CD with PPFs who received early vs delayed treatment with ADL achieved higher clinical response and remission rates. This effect was more pronounced in those patients who were bio-naive and steroid-dependent/refractory with concurrent extraintestinal manifestations than those who were not.
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Affiliation(s)
- Gerassimos J Mantzaris
- Department of Gastroenterology, General Hospital of Athens “Evaggelismos”, Athens, Greece,Address correspondence to: Gerassimos J. Mantzaris, MD, PhD, Department of Gastroenterology, General Hospital of Athens “Evaggelismos”, 45-47 Ipsilantou St., 10676, Athens, Attiki, Greece ()
| | | | - Angeliki Theodoropoulou
- Department of Gastroenterology, General Hospital of Heraklion “Venizeleio-Pananeio”, Heraklion, Crete, Greece
| | | | - Eleni Orfanoudaki
- Department of Gastroenterology, University Hospital of Heraklion, Crete, Greece
| | - Konstantinos Katsanos
- Department of Gastroenterology, Pathology Unit, University General Hospital of Ioannina, Ioannina, Greece
| | - Dimitrios Christodoulou
- Department of Gastroenterology, Pathology Unit, University General Hospital of Ioannina, Ioannina, Greece
| | | | - Maria Tzouvala
- Department of Gastroenterology, General Hospital of Nikaia & Piraeus “Agios Panteleimon”-General Hospital Dytikis Attikis “Agia Varvara”, Nikaia, Greece
| | - Dimitrios Moschovis
- Department of Gastroenterology, General Hospital of Nikaia & Piraeus “Agios Panteleimon”-General Hospital Dytikis Attikis “Agia Varvara”, Nikaia, Greece
| | - Spyridon Michopoulos
- Department of Gastroenterology, Pathology Unit, General Hospital of Athens “Alexandra”, Athens, Greece
| | - Evanthia Zampeli
- Department of Gastroenterology, Pathology Unit, General Hospital of Athens “Alexandra”, Athens, Greece
| | - Konstantinos Soufleris
- Department of Gastroenterology-Oncology, Pathology Unit, Anticancer Hospital of Thessaloniki “Theageneio”, Thessaloniki, Greece
| | - Anastasios Ilias
- Department of Gastroenterology, Pathology Unit, General Hospital of Thessaloniki “G. Papanikolaou”, Thessaloniki, Greece
| | | | | | | | - Konstantinos Karmiris
- Department of Gastroenterology, General Hospital of Heraklion “Venizeleio-Pananeio”, Heraklion, Crete, Greece
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13
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Witte M, Reiner J, Bannert K, Jaster R, Maschmeier C, Schafmayer C, Lamprecht G, Berlin P. Ileocolonic Healing After Extended Small Bowel Resection in Mice: NOD2 Deficiency Impairs Anastomotic Healing and Postoperative Outcome. Inflamm Bowel Dis 2021; 27:1503-1512. [PMID: 33555306 PMCID: PMC8376130 DOI: 10.1093/ibd/izab022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations are a genetic risk factor for Crohn disease. Ileocecal resection is the most often performed surgery in Crohn disease. We investigated the effect of Nod2 knockout (KO) status on anastomotic healing after extended ileocecal resection (ICR) in mice. METHODS Male C57BL6/J wild-type and Nod2 KO mice underwent an 11 cm resection of the terminal ileum including the cecum. An end-to-end jejuno-colostomy was performed. Animals were killed after 5 days investigating bursting pressure, hydroxyproline content, and expression of matrix metabolism genes, key cytokines, and histology of the anastomosis. RESULTS Mortality was higher in the Nod2 KO group but not because of local or septic complications. Bursting pressure was significantly reduced in the Nod2 KO mice (32.5 vs 78.0 mmHg, P < 0.0024), whereas hydroxyprolin content was equal. The amount of granulation tissue at the anastomosis was similar but more unstructured in the Nod2 KO mice. Gene expression measured by real-time polymerase chain reaction showed significantly increased expression for Collagen 1alpha and for collagen degradation as measured by matrix metalloproteinase-2, -9, and -13 in the Nod2 KO mice. Gelatinase activity from anastomotic tissue was enhanced by Nod2 status. Gene expression of arginase I, tumor necrosis factor-α, and transforming growth factor-ß but not inducible nitric oxide synthase were also increased at the anastomosis in the Nod2 KO mice compared with the control mice. CONCLUSIONS We found that Nod2 deficiency results in significantly reduced bursting pressure after ileocecal resection. This effect is mediated via an increased matrix turnover. Patients with genetic NOD2 variations may be prone to anastomotic failure after bowel resection.
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Affiliation(s)
- Maria Witte
- Department of General, Visceral, Vascular and Transplant Surgery, Rostock University Medical Center, Rostock, Germany
| | - Johannes Reiner
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Karen Bannert
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Robert Jaster
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Christian Maschmeier
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Clemens Schafmayer
- Department of General, Visceral, Vascular and Transplant Surgery, Rostock University Medical Center, Rostock, Germany
| | - Georg Lamprecht
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
| | - Peggy Berlin
- Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Rostock, Germany
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14
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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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15
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Glapa-Nowak A, Szczepanik M, Iwańczak B, Kwiecień J, Szaflarska-Popławska AB, Grzybowska-Chlebowczyk U, Osiecki M, Dziekiewicz M, Stawarski A, Kierkuś J, Banasiewicz T, Banaszkiewicz A, Walkowiak J. Apolipoprotein E variants correlate with the clinical presentation of paediatric inflammatory bowel disease: A cross-sectional study. World J Gastroenterol 2021; 27:1483-1496. [PMID: 33911469 PMCID: PMC8047531 DOI: 10.3748/wjg.v27.i14.1483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/17/2020] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It has been suggested that apolipoprotein E (APOE) polymorphisms are associated with the risk of developing inflammatory bowel disease (IBD) and the early age of disease onset. However, there are no reports regarding the relationship with clinical characteristics and disease severity.
AIM To summarise that APOE polymorphisms are associated with the risk of developing IBD and the early age of disease onset.
METHODS In total, 406 patients aged 3-18 with IBD (192 had ulcerative colitis and 214 had Crohn’s disease) were genotyped using the TaqMan hydrolysis probe assay. Clinical expression was described at diagnosis and the worst flare by disease activity scales, albumin and C-reactive protein levels, localisation and behaviour (Paris classification). Systemic steroid intake with the total number of courses, immunosuppressive, biological, and surgical treatment with the time and age of the first intervention were determined. The total number of exacerbation-caused hospitalisations, the number of days spent in hospital due to exacerbation, the number of relapses, and severe relapses were also estimated.
RESULTS Ulcerative colitis patients with the APOEε4 allele had lower C-reactive protein values at diagnosis (P = 0.0435) and the worst flare (P = 0.0013) compared to patients with the APOEε2 allele and genotype APOEε3/ε3. Crohn’s disease patients with the APOEε2 allele scored lower on the Pediatric Crohn’s Disease Activity Index at diagnosis (P = 0.0204). IBD patients with APOEε2 allele spent fewer days in the hospital due to relapse (P = 0.0440).
CONCLUSION APOE polymorphisms are associated with the risk of developing IBD and the clinical expression of IBD. However, the clinical relevance of the differences identified is rather modest.
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Affiliation(s)
- Aleksandra Glapa-Nowak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznań University of Medical Sciences, Poznań 60-572, Poland
| | - Mariusz Szczepanik
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznań University of Medical Sciences, Poznań 60-572, Poland
| | - Barbara Iwańczak
- Department of Pediatrics, Medical University of Wroclaw, Wroclaw 50-369, Poland
| | - Jarosław Kwiecień
- Department of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Zabrze 41-800, Poland
| | | | - Urszula Grzybowska-Chlebowczyk
- Department of Pediatrics, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Katowice 40-752, Poland
| | - Marcin Osiecki
- Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children’s Memorial Health Institute, Warsaw 04-730, Poland
| | - Marcin Dziekiewicz
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw 02-091, Poland
| | - Andrzej Stawarski
- Department and Clinic of Pediatrics, Gastroenterology and Nutrition, Wroclaw Medical University, Wroclaw 50-369, Poland
| | - Jarosław Kierkuś
- Department of Gastroenterology, Hepatology, Feeding Disorders and Paediatrics, The Children’s Memorial Health Institute, Warsaw 04-730, Poland
| | - Tomasz Banasiewicz
- Chair and Department of General Surgery, Gastroenterological Surgical Oncology and Plastic Surgery, Poznań University of Medical Sciences, Poznań 60-355, Poland
| | - Aleksandra Banaszkiewicz
- Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw, Warsaw 02-091, Poland
| | - Jarosław Walkowiak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznań University of Medical Sciences, Poznań 60-572, Poland
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16
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A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease. Nature 2021; 593:275-281. [PMID: 33789339 DOI: 10.1038/s41586-021-03484-5] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 03/23/2021] [Indexed: 12/13/2022]
Abstract
Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment3. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD24,5, which increase the risk of stricturing6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease-potentially as a complement to anti-TNF therapy.
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17
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Scharrer S, Lissner D, Primas C, Reinisch W, Novacek G, Reinisch S, Papay P, Dejaco C, Vogelsang H, Miehsler W. Passive Smoking Increases the Risk for Intestinal Surgeries in Patients With Crohn's Disease. Inflamm Bowel Dis 2021; 27:379-385. [PMID: 32529214 DOI: 10.1093/ibd/izaa117] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Despite substantial evidence on the negative effect of active smoking, the impact of passive smoking on the course of Crohn's disease (CD) remains largely unclear. Our aim was to assess passive smoking as a risk factor for intestinal surgeries in CD. METHODS The study was conducted in a university-based, monocentric cohort of 563 patients with CD. Patients underwent a structured interview on exposure to passive and active smoking. For clinical data, chart review was performed. Response rate was 84%, leaving 471 cases available for analysis. For evaluation of the primary objective, which was the impact of exposure to passive smoking on the risk for intestinal surgery, only never actively smoking patients were included. RESULTS Of 169 patients who never smoked actively, 91 patients (54%) were exposed to passive smoking. Exposed patients were more likely to undergo intestinal surgery than nonexposed patients (67% vs 30%; P < 0.001). Multivariate Cox regression analysis revealed that passive smoking was an independent risk factor for intestinal surgeries (hazard ratio, 1.7; 95% CI, 1.04-2.9; P = 0.034) after adjustment for ileal disease at diagnosis (hazard ratio, 2.9; 95% CI, 1.9-4.5; P < 0.001) and stricturing or penetrating behavior at diagnosis (hazard ratio, 1.9; 95% CI, 1.2-3.1; P = 0.01). Passive smoking during childhood was a risk factor for becoming an active smoker in later life (odds ratio, 2.2; 95% CI, 1.5-3.2; P < 0.001). CONCLUSION Passive smoking increases the risk for intestinal surgeries in patients with CD.
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Affiliation(s)
- Susanna Scharrer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Department of Gastroenterology and Endoscopy, University Hospital "Dr. José E. González," Monterrey, Mexico
| | - Donata Lissner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine with Endoscopy, St. Joseph Hospital Berlin-Tempelhof, Berlin, Germany
| | - Christian Primas
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Walter Reinisch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Gottfried Novacek
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Sieglinde Reinisch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Pavol Papay
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine, Hospital Baden, Baden, Austria
| | - Clemens Dejaco
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Harald Vogelsang
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Miehsler
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
- Department of Internal Medicine, Hospital Brothers of St. John of God Salzburg, Salzburg, Austria
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Jiang Y, Rim DS, Rodgers B, Ahlawat S. Sarcoidosis is associated with lower risks of penetrating disease and colectomy in hospitalized patients with inflammatory bowel disease. JGH OPEN 2020; 4:1199-1206. [PMID: 33319056 PMCID: PMC7731821 DOI: 10.1002/jgh3.12423] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 09/20/2020] [Indexed: 11/16/2022]
Abstract
Background and Aim Inflammatory bowel disease (IBD) and sarcoidosis, primarily considered distinct entities, share commonalties in pathophysiology and clinical manifestations. This study aimed to examine the in‐hospital outcomes of patients with concurrent IBD and sarcoidosis. Methods The National Inpatient Sample was used to identify hospitalized adult patients with IBD and sarcoidosis from 2010 to 2014. Primary outcomes were in‐hospital mortality, rates of septic shock, acute renal failure, respiratory failure, length of stay, and total hospitalization charges. Secondary outcomes were IBD‐specific complications and surgery interventions. Results A total of 3995 patients with IBD and coexisting sarcoidosis (IBD/sarcoidosis), of which 2500 patients had Crohn's disease with coexisting sarcoidosis (Crohn's disease [CD]/sarcoidosis) and 1495 patients had ulcerative colitis with coexisting sarcoidosis (ulcerative colitis [UC]/sarcoidosis), were included. Patients with IBD/sarcoidosis had a lower risk of penetrating disease (adjusted odds ratio [aOR] 0.3, 95% confidence interval [CI] 0.16–0.55, P < 0.0001) and colectomy (aOR 0.48, 95% CI 0.27–0.84, P < 0.05). Subgroup analysis demonstrated lower rates of colectomy when comparing CD/sarcoidosis (P < 0.05) and UC/sarcoidosis (P = 0.0003) versus CD or UC alone. There was no difference in mortality. Conclusion IBD/sarcoidosis is associated with lower risks of penetrating disease and colectomy when compared to patients with IBD alone.
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Affiliation(s)
- Yi Jiang
- Department of Medicine Rutgers New Jersey Medical School Newark New Jersey USA
| | - Daniel S Rim
- Department of Medicine Rutgers New Jersey Medical School Newark New Jersey USA
| | - Brandon Rodgers
- Department of Medicine Rutgers New Jersey Medical School Newark New Jersey USA
| | - Sushil Ahlawat
- Division of Gastroenterology and Hepatology Rutgers New Jersey Medical School Newark New Jersey USA
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19
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Papoutsopoulou S, Satsangi J, Campbell BJ, Probert CS. Review article: impact of cigarette smoking on intestinal inflammation-direct and indirect mechanisms. Aliment Pharmacol Ther 2020; 51:1268-1285. [PMID: 32372449 DOI: 10.1111/apt.15774] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 04/13/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The inflammatory bowel diseases, Crohn's disease and ulcerative colitis are related multifactorial diseases. Their pathogenesis is influenced by each individual's immune system, the environmental factors within exposome and genetic predisposition. Smoking habit is the single best-established environmental factor that influences disease phenotype, behaviour and response to therapy. AIM To assess current epidemiological, experimental and clinical evidence that may explain how smoking impacts on the pathogenesis of inflammatory bowel disease. METHODS A Medline search for 'cigarette smoking', in combination with terms including 'passive', 'second-hand', 'intestinal inflammation', 'Crohn's disease', 'ulcerative colitis', 'colitis'; 'intestinal epithelium', 'immune system', 'intestinal microbiota', 'tight junctions', 'mucus', 'goblet cells', 'Paneth cells', 'autophagy'; 'epigenetics', 'genes', 'DNA methylation', 'histones', 'short noncoding/long noncoding RNAs'; 'carbon monoxide/CO' and 'nitric oxide/NO' was performed. RESULTS Studies found evidence of direct and indirect effects of smoking on various parameters, including oxidative damage, impairment of intestinal barrier and immune cell function, epigenetic and microbiota composition changes, that contribute to the pathogenesis of inflammatory bowel disease. CONCLUSIONS Cigarette smoking promotes intestinal inflammation by affecting the function and interactions among intestinal epithelium, immune system and microbiota/microbiome.
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Affiliation(s)
- Stamatia Papoutsopoulou
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Jack Satsangi
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Experimental Medicine Division, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Barry J Campbell
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Chris S Probert
- Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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20
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Abstract
Fibrostenosis occurs in both Crohn's disease (CD) and ulcerative colitis (UC). Up to 21% of patients with CD present with strictures at diagnosis, while the rate of stenosis varies from 1% to 11% in UC. Despite the increasing use of immunomodulators and biologics in treatment, there has been no decrease in the rate of progression from inflammatory to complicated disease phenotypes (either stricturing or penetrating). The presence of stenosis is an independent risk factor for surgery in patients with CD, who are at a risk of postoperative recurrence at a rate of up to 55% at 10 years after surgery. Patients with inflammatory bowel disease (IBD) strictures are at risk of malignant transformation. Thus, surveillance colonoscopy should be offered to this group of patients. Several risk factors for the development of stricture have been identified. In CD, patients aged less than 40-years old, with perianal disease at diagnosis, who need steroids at the first flare up or have ileal disease are at the risk of developing strictures; while in UC, patients with extensive colitis and long-standing disease are at risk. Recently, microbiota signatures have also been identified as markers for stricture development. The presence of Ruminococcus spp. is associated with the development of stricture in pediatric patients with CD. In this review, we highlight the epidemiology, risk factors and natural history of fibrostenosing IBD.
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Affiliation(s)
- Joyce Wing Yan Mak
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Siew Chien Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Science, Chinese University of Hong Kong, Hong Kong SAR, China
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21
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Yoo JH, Holubar S, Rieder F. Fibrostenotic strictures in Crohn's disease. Intest Res 2020; 18:379-401. [PMID: 32259917 PMCID: PMC7609387 DOI: 10.5217/ir.2019.09148] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 01/26/2020] [Indexed: 12/15/2022] Open
Abstract
The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn’s disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD.
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Affiliation(s)
- Jun Hwan Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Stefan Holubar
- Department of Colorectal Surgery, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
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22
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Mak WY, Zhao M, Ng SC, Burisch J. The epidemiology of inflammatory bowel disease: East meets west. J Gastroenterol Hepatol 2020; 35:380-389. [PMID: 31596960 DOI: 10.1111/jgh.14872] [Citation(s) in RCA: 381] [Impact Index Per Article: 76.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/09/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022]
Abstract
The incidence of inflammatory bowel diseases (IBD) in East has risen over the past decade to become a global disease. The increasing number of studies on the incidence and course of IBD in East has enabled us to explore East versus West differences in the epidemiology of IBD which could enhance our understanding of the heterogeneity of the disease and eventually assist in the discovery of novel therapeutic targets and design of preventive strategies. Comparison of population-based data in East and West reveals that the incidence of IBD has risen rapidly in East while plateauing in West. Furthermore, the clinical presentation and course of IBD differs between East and West with more patients in East presenting with complicated disease. Considering the scarcity of population-based data from East and the lack of studies with long durations of follow-up, it remains to be clarified whether these differences reflect true differences in disease presentation. The effects of genetic and environmental risk factors contributing to IBD also differ between Eastern and Western populations. Considering the differential effects of genetic and environmental risk factors in East and West, future studies should seek to discover novel genetic and environmental risk factors which might specifically apply to eastern populations. In this narrative review, we compare the epidemiology of IBD between eastern and western countries by summarizing evidence from population-based cohort studies in the last ten years. Furthermore, we look at differences in genetic susceptibility and environmental triggers of IBD between East and West.
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Affiliation(s)
- Wing Yan Mak
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong
| | - Mirabella Zhao
- Gastrounit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark
| | - Siew Chien Ng
- Gastrounit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark
| | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark
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23
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Shen EX, Lord A, Doecke JD, Hanigan K, Irwin J, Cheng RKY, Radford-Smith G. A validated risk stratification tool for detecting high-risk small bowel Crohn's disease. Aliment Pharmacol Ther 2020; 51:281-290. [PMID: 31769537 DOI: 10.1111/apt.15550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 02/16/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Delays in Crohn's disease (CD) diagnosis are positively associated with ileal location and an increased risk of complications. AIM To develop a simple risk assessment tool to enable primary care physicians to recognise potential ileal CD earlier, shortening the delay to specialist investigation METHODS: Three cohorts were acquired for this study. Cohort 1 included 61 patients retrospectively identified with ileal CD between 2000 and 2010 and 78 matched controls drawn from a cohort referred for investigation of abdominal symptoms. Cohort 2 included 42 individuals diagnosed with ileal CD and 57 controls identified prospectively. Cohort 3 included an additional 84 individuals with ileal CD and 495 without CD referred for colonoscopy. Clinical symptoms and serological biomarkers were acquired and used to develop a risk prediction algorithm. The algorithm was trained independently on each of the three cohorts and tested on the latter two cohorts. RESULTS Altered bowel habit with abdominal pain combined with derangements in white cell count (WCC), albumin and platelet counts were important features in predicting ileal CD (AUC = 0.92, 95% CI = 0.89-0.92). This was validated in cohorts 2 (AUC = 0.96, 95% CI = 0.95-0.98) and 3 (AUC = 0.94, 95% CI = 0.92-0.96). C-reactive protein was independently associated with ileal CD but non-signficant in a multivariate model. CONCLUSION A web-based risk stratification tool for ileal CD has been developed from objective and symptom-based criteria. This tool enables primary care physicians to more confidently request urgent specialist assessment for patients identified as at high risk for ileal CD.
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Affiliation(s)
- Eddie X Shen
- QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia
| | - Anton Lord
- QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia
| | - James D Doecke
- CSIRO Health and Biosecurity/Australian e-Health Research Centre, Brisbane, Qld, Australia
| | | | - James Irwin
- QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
| | - Richard K Y Cheng
- QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
| | - Graham Radford-Smith
- QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Qld, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Qld, Australia
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24
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Berkowitz L, Pardo-Roa C, Salazar GA, Salazar-Echegarai F, Miranda JP, Ramírez G, Chávez JL, Kalergis AM, Bueno SM, Álvarez-Lobos M. Mucosal Exposure to Cigarette Components Induces Intestinal Inflammation and Alters Antimicrobial Response in Mice. Front Immunol 2019; 10:2289. [PMID: 31608070 PMCID: PMC6773925 DOI: 10.3389/fimmu.2019.02289] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 09/10/2019] [Indexed: 12/15/2022] Open
Abstract
The main environmental risk factor associated with the development of Crohn's disease (CD) is cigarette smoking. Although the mechanism is still unknown, some studies have shown that cigarette exposure affects the intestinal barrier of the small bowel. Among the factors that may be involved in this process are Paneth cells. These specialized epithelial cells are located into the small intestine, and they are able to secrete antimicrobial peptides, having an essential role in the control of the growth of microorganisms. Alterations in its function are associated with inflammatory processes, such as CD. To study how cigarette components impact ileum homeostasis and Paneth cells integrity, we used intragastric administration of cigarette smoke condensate (CSC) in mice. Our results showed that inflammation was triggered after mucosal exposure of CSC, which induced particular alterations in Paneth cells granules, antimicrobial peptide production, and a reduction of bactericidal capacity. In fact, exposure to CSC generated an imbalance in the fecal bacterial population and increased the susceptibility of mice to develop ileal damage in response to bacterial infection. Moreover, our results obtained in mice unable to produce interleukin 10 (IL-10−/− mice) suggest that CSC treatment can induce a symptomatic enterocolitis with a pathological inflammation in genetically susceptible individuals.
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Affiliation(s)
- Loni Berkowitz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina Pardo-Roa
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Geraldyne A Salazar
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco Salazar-Echegarai
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - José P Miranda
- Departamento de Nutrición, Diabetes y Metabolismo, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gigliola Ramírez
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - José L Chávez
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel Álvarez-Lobos
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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25
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Zakrzewski M, Simms LA, Brown A, Appleyard M, Irwin J, Waddell N, Radford-Smith GL. IL23R-Protective Coding Variant Promotes Beneficial Bacteria and Diversity in the Ileal Microbiome in Healthy Individuals Without Inflammatory Bowel Disease. J Crohns Colitis 2019; 13:451-461. [PMID: 30445599 DOI: 10.1093/ecco-jcc/jjy188] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS This study aimed to characterize the mucosa-associated microbiota in ileal Crohn's disease [CD] patients and in healthy controls in terms of host genotype and inflammation status. METHODS The mucosa-associated microbiotas of intestinal pinch biopsies from 15 ileal CD patients with mild and moderate disease and from 58 healthy controls were analysed based on 16S ribosomal sequencing to determine microbial profile differences between [1] IL23R, NOD2 and ATG16L1 genotypes in healthy subjects, [2] ileal CD patients and control subjects, and [3] inflamed and non-inflamed mucosal tissue in CD patients. RESULTS The protective variant of the IL23R gene [rs11209026] significantly impacted the microbial composition in the ileum of healthy subjects and was associated with an increased abundance of phylotypes within the family Christensenellaceae as well as increases in diversity and richness. Comparative analysis of healthy and non-inflamed CD microbiome samples indicated a notable decrease in the abundance of Faecalibacterium prausnitzii as well as Shannon diversity and richness. Inflamed and non-inflamed ileal samples of CD subjects had high intra-individual stability and inter-individual variability, but no significant alterations in diversity, richness or taxa were identified. Calprotectin correlated positively with the abundance of Proteobacteria and negatively with diversity in the samples from healthy subjects. CONCLUSIONS The observation of low diversity and low abundance of beneficial bacteria in healthy control subjects carrying the IL23R [rs11209026] wild-type GG genotype indicates that the gut microbiome is influenced by host genetics and is altered prior to disease diagnosis. Faecal calprotectin may be a potential non-invasive screening tool for dysbiosis in subjects without disorders of intestinal inflammation.
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Affiliation(s)
- Martha Zakrzewski
- Medical Genomics, QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, Australia
| | - Lisa A Simms
- Gut Health, QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, Australia
| | - Allison Brown
- Gut Health, QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Herston, Brisbane 4029, Australia
| | - Mark Appleyard
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Herston, Brisbane 4029, Australia
| | - James Irwin
- Gut Health, QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, Australia.,Department of Gastroenterology, Palmerston North Hospital, Palmerston North, New Zealand
| | - Nicola Waddell
- Medical Genomics, QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, Australia
| | - Graham L Radford-Smith
- Gut Health, QIMR Berghofer Medical Research Institute, Herston, Brisbane 4006, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Herston, Brisbane 4029, Australia.,University of Queensland School of Medicine, Herston, Brisbane 4029, Australia
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26
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Falloon K, Lazarev M. A Primer on IBD: Phenotypes, Diagnosis, Treatment, and Clinical Challenges. MOLECULAR GENETICS OF INFLAMMATORY BOWEL DISEASE 2019:3-24. [DOI: 10.1007/978-3-030-28703-0_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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27
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Pelzer N, Louter MA, van Zwet EW, Nyholt DR, Ferrari MD, van den Maagdenberg AM, Haan J, Terwindt GM. Linking migraine frequency with family history of migraine. Cephalalgia 2018; 39:229-236. [PMID: 29911421 PMCID: PMC6376592 DOI: 10.1177/0333102418783295] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Background Migraine is a complex genetic disorder that is brought about by multiple genetic and environmental factors. We aimed to assess whether migraine frequency is associated with genetic susceptibility. Methods We investigated in 2829 migraine patients (14% males) whether ‘migraine frequency’ (measured as the number of migraine days per month) was related to ‘genetic load’ (measured as the number of parents affected with migraine) using a validated web-based questionnaire. In addition, we investigated associations with age-at-onset, migraine subtype, use of acute headache medication, and comorbid depression. Results We found an association between the number of migraine days per month and family history of migraine for males (p = 0.03), but not for females (p = 0.97). This association was confirmed in a linear regression analysis. Also, a lower age-at-onset (p < 0.001), having migraine with aura (p = 0.03), and a high number of medication days (p = 0.006) were associated with a stronger family history of migraine, whereas lifetime depression (p = 0.13) was not. Discussion Migraine frequency, as measured by the number of migraine days per month, seems associated with a genetic predisposition only in males. A stronger family history of migraine was also associated with a lower age-at-onset, a higher number of medication days, and migraine with aura. Our findings suggest that specific clinical features of migraine seem more determined by genetic factors.
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Affiliation(s)
- Nadine Pelzer
- 1 Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Mark A Louter
- 1 Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.,2 Department of Psychiatry, Leiden University Medical Centre, Leiden, the Netherlands.,3 Viersprong Institute for Studies on Personality Disorders, De Viersprong, Halsteren, the Netherlands
| | - Erik W van Zwet
- 4 Department of Biostatistics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Dale R Nyholt
- 5 Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Michel D Ferrari
- 1 Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Arn Mjm van den Maagdenberg
- 1 Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.,6 Department of Human Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Joost Haan
- 1 Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands.,7 Department of Neurology, Alrijne Hospital, Leiderdorp, the Netherlands
| | - Gisela M Terwindt
- 1 Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
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28
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Berkowitz L, Schultz BM, Salazar GA, Pardo-Roa C, Sebastián VP, Álvarez-Lobos MM, Bueno SM. Impact of Cigarette Smoking on the Gastrointestinal Tract Inflammation: Opposing Effects in Crohn's Disease and Ulcerative Colitis. Front Immunol 2018; 9:74. [PMID: 29441064 PMCID: PMC5797634 DOI: 10.3389/fimmu.2018.00074] [Citation(s) in RCA: 120] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Accepted: 01/11/2018] [Indexed: 01/06/2023] Open
Abstract
Cigarette smoking is a major risk factor for gastrointestinal disorders, such as peptic ulcer, Crohn’s disease (CD), and several cancers. The mechanisms proposed to explain the role of smoking in these disorders include mucosal damage, changes in gut irrigation, and impaired mucosal immune response. Paradoxically, cigarette smoking is a protective factor for the development and progression of ulcerative colitis (UC). UC and CD represent the two most important conditions of inflammatory bowel diseases, and share several clinical features. The opposite effects of smoking on these two conditions have been a topic of great interest in the last 30 years, and has not yet been clarified. In this review, we summarize the most important and well-understood effects of smoking in the gastrointestinal tract; and particularly, in intestinal inflammation, discussing available studies that have addressed the causes that would explain the opposite effects of smoking in CD and UC.
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Affiliation(s)
- Loni Berkowitz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.,Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Bárbara M Schultz
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Geraldyne A Salazar
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina Pardo-Roa
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Valentina P Sebastián
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel M Álvarez-Lobos
- Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Susan M Bueno
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
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Abstract
Since the discovery of the first Crohn's disease (CD) gene NOD2 in 2001, 140 genetic loci have been found in whites using high-throughput genome-wide association studies. Several genes influence the CD subphenotypes and treatment response. With the observations of increasing prevalence in Asia and developing countries and the incomplete explanation of CD variance, other underexplored areas need to be integrated through novel methodologies. Algorithms that incorporate specific genetic risk alleles with other biomarkers will be developed and used to predict CD disease course, complications, and response to specific therapies, allowing precision medicine to become real in CD.
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Affiliation(s)
- Ming-Hsi Wang
- Department of Gastroenterology and Hepatology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
| | - Michael F Picco
- Department of Gastroenterology and Hepatology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA
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30
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The Characteristics and Long-term Outcomes of Pediatric Crohn's Disease Patients with Perianal Disease. Inflamm Bowel Dis 2017; 23:1659-1665. [PMID: 28590344 DOI: 10.1097/mib.0000000000001171] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Data on the outcomes of children with perianal Crohn's disease are limited. We aimed to assess phenotypic features at diagnosis and long-term disease-specific outcomes of this phenotype. METHODS The medical records of 296 pediatric onset patients with Crohn's disease, diagnosed from 2001 to 2015, were reviewed retrospectively. Baseline characteristics included age, sex, severity indices, laboratory data, endoscopic findings, and anthropometric measurements. Main outcome measures included time to first flare, hospitalization, surgery, and biological therapy. RESULTS Of the 296 included patients (median age 14.2 years), 70 (24%) had nonfistulizing perianal findings, whereas only 40 (13%) had fistulizing perianal disease at diagnosis. Perianal involvement was associated with female sex (P = 0.01), whereas fistulizing perianal disease resulted in a greater use of immunomodulators (P = 0.01). Time to hospitalization was shorter for both nonfistulizing and fistulizing perianal disease (hazard ratio [HR] 1.66 and 1.34, respectively, P = 0.027) and time to biological therapy (HR 2.1 and 1.7, respectively, P = 0.002). There were no differences in time to first flare or surgery. During a median follow-up of 8.5 years, additional 26 patients (10%) developed fistulizing perianal disease after a median time of 3.5 years. The presence of nonfistulizing disease at diagnosis was a significant risk factor for the development of fistulizing perianal disease (HR 3.4, P = 0.002). At the end of follow-up, complicated disease was more common in patients with any perianal involvement (P = 0.01). CONCLUSIONS Pediatric patients with Crohn's disease with both nonfistulizing and fistulizing disease have worse clinical outcomes. Nonfistulizing disease is a risk factor for the development of fistulizing disease over time.
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Perianal Pediatric Crohn Disease Is Associated With a Distinct Phenotype and Greater Inflammatory Burden. J Pediatr Gastroenterol Nutr 2017; 65:293-298. [PMID: 28362690 DOI: 10.1097/mpg.0000000000001484] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVES Data on the outcomes of children with perianal Crohn disease (pCD) are limited, although its presence is often used for justifying early use of biologics. We aimed to assess whether pCD in children is associated with more severe outcomes as found in adults. METHODS Data were extracted from the ImageKids database, a prospective, multicenter, longitudinal cohort study. The study enrolled 246 children at disease onset or thereafter. All patients underwent comprehensive clinical, endoscopic, and radiologic evaluation at enrollment; 98 children had repeat evaluation at 18 months. RESULTS Of the 234 included patients (mean age 14.2 ± 2.4 years; 131 [56%] boys), 57 (24%) had perianal findings, whereas only 21 (9%) had fistulizing perianal disease. Children with pCD had reduced weight and height z scores compared with non-pCD patients (-0.9 vs -0.35, P = 0.03 and -0.68 vs -0.23, respectively; P = 0.04), higher weighted pediatric CD activity index (32 [interquartile range 16-50] vs 20 [8-37]; P = 0.004), lower serum albumin (3.6 ± 0.7 vs 4.5 ± 0.8, P = 0.016), and higher magnetic resonance enterography global inflammatory score (P = 0.04). Children with pCD had more rectal (57% vs 38%, P = 0.04), and jejunal involvement (31% vs 11% P = 0.003) and a higher prevalence of granulomas (64% vs 23%, P = 0.0001). Magnetic resonance enterography-based damage scores did not differ between groups. Patients with skin tags/fissures only, had similar clinical, endoscopic, and radiologic characteristics as patients with no perianal findings. CONCLUSIONS Pediatric patients with pCD with fistulizing disease have distinct phenotypic features and a predisposition to a greater inflammatory burden.
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32
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Chen GB, Lee SH, Montgomery GW, Wray NR, Visscher PM, Gearry RB, Lawrance IC, Andrews JM, Bampton P, Mahy G, Bell S, Walsh A, Connor S, Sparrow M, Bowdler LM, Simms LA, Krishnaprasad K, Radford-Smith GL, Moser G. Performance of risk prediction for inflammatory bowel disease based on genotyping platform and genomic risk score method. BMC MEDICAL GENETICS 2017; 18:94. [PMID: 28851283 PMCID: PMC5576242 DOI: 10.1186/s12881-017-0451-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 08/14/2017] [Indexed: 12/11/2022]
Abstract
Background Predicting risk of disease from genotypes is being increasingly proposed for a variety of diagnostic and prognostic purposes. Genome-wide association studies (GWAS) have identified a large number of genome-wide significant susceptibility loci for Crohn’s disease (CD) and ulcerative colitis (UC), two subtypes of inflammatory bowel disease (IBD). Recent studies have demonstrated that including only loci that are significantly associated with disease in the prediction model has low predictive power and that power can substantially be improved using a polygenic approach. Methods We performed a comprehensive analysis of risk prediction models using large case-control cohorts genotyped for 909,763 GWAS SNPs or 123,437 SNPs on the custom designed Immunochip using four prediction methods (polygenic score, best linear genomic prediction, elastic-net regularization and a Bayesian mixture model). We used the area under the curve (AUC) to assess prediction performance for discovery populations with different sample sizes and number of SNPs within cross-validation. Results On average, the Bayesian mixture approach had the best prediction performance. Using cross-validation we found little differences in prediction performance between GWAS and Immunochip, despite the GWAS array providing a 10 times larger effective genome-wide coverage. The prediction performance using Immunochip is largely due to the power of the initial GWAS for its marker selection and its low cost that enabled larger sample sizes. The predictive ability of the genomic risk score based on Immunochip was replicated in external data, with AUC of 0.75 for CD and 0.70 for UC. CD patients with higher risk scores demonstrated clinical characteristics typically associated with a more severe disease course including ileal location and earlier age at diagnosis. Conclusions Our analyses demonstrate that the power of genomic risk prediction for IBD is mainly due to strongly associated SNPs with considerable effect sizes. Additional SNPs that are only tagged by high-density GWAS arrays and low or rare-variants over-represented in the high-density region on the Immunochip contribute little to prediction accuracy. Although a quantitative assessment of IBD risk for an individual is not currently possible, we show sufficient power of genomic risk scores to stratify IBD risk among individuals at diagnosis. Electronic supplementary material The online version of this article (doi:10.1186/s12881-017-0451-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guo-Bo Chen
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia
| | - Sang Hong Lee
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia.,School of Environmental and Rural Science, The University of New England, Armidale, Australia
| | - Grant W Montgomery
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Naomi R Wray
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia
| | - Peter M Visscher
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia.,University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Australia
| | - Richard B Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand.,Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Ian C Lawrance
- Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, Australia.,Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco, Australia
| | - Jane M Andrews
- Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, School of Medicine, University of Adelaide, Adelaide, Australia
| | - Peter Bampton
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Adelaide, Australia
| | - Gillian Mahy
- Department of Gastroenterology, Townsville Hospital, Townsville, Australia
| | - Sally Bell
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia
| | - Alissa Walsh
- Department of Gastroenterology and Hepatology, St Vincent's Hospital, Sydney, Australia
| | - Susan Connor
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, Australia.,University of NSW, Sydney, Australia
| | - Miles Sparrow
- Department of Gastroenterology, Alfred Health, Melbourne, Australia
| | - Lisa M Bowdler
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia
| | - Lisa A Simms
- Inflammatory Bowel Disease Research Group, Immunology Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Krupa Krishnaprasad
- Inflammatory Bowel Disease Research Group, Immunology Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | | | - Graham L Radford-Smith
- School of Medicine, The University of Queensland, Brisbane, Australia.,Inflammatory Bowel Disease Research Group, Immunology Division, QIMR Berghofer Medical Research Institute, Brisbane, Australia.,Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia
| | - Gerhard Moser
- Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
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Tamzaourte M, Errabih I, Krami H, Maha F, Maria L, Benzzoubeir N, Ouazzani L, Sefiani A, Ouazzani H. [NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease]. Pan Afr Med J 2017; 27:116. [PMID: 28819537 PMCID: PMC5554695 DOI: 10.11604/pamj.2017.27.116.9187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/29/2017] [Indexed: 12/16/2022] Open
Abstract
L'objectif était de déterminer la prévalence des mutations du gène NOD2/CARD15 dans un groupe de patients Marocains atteint de Maladie de Crohn et étudier sa corrélation génotype-expression phénotypique. Etude transversale cas témoin menée sur une durée de 16 mois. Ont été inclus 101 patients atteints de la maladie de Crohn, entre Janvier 2012 et Avril 2013 ainsi qu'un groupe contrôle de 107 patients. L'analyse génétique a consisté à rechercher 3 variants du gène NOD2: p.Arg702Trp, p.Gly908Arg et p.Leu1007fsins. Puis une étude de corrélation génotype-expression phénotypique a été menée. L'analyse génétique des patients atteint de maladie de crohn a mis en évidence la présence de la mutation NOD2 chez 14 patients (13,77%) contre 7 patients (6,53%) du groupe témoin. L'étude de la fréquence des différents allèles a retrouvé la mutation de p.Gly908Arg dans 6,43%, p.Leu1007fsins dans 0,99% et p.Arg702Trp dans 0,49% contre respectivement 2,80%, 0% et 0,46% dans le groupe témoin. L'étude de la corrélation génotype, expression phénotypique a démontré que la mutation CARD15 est corrélée à une localisation iléo-caecale de la maladie, à une présentation fistulisante et sténosante ainsi qu'à une évolution sévère avec recours fréquent à la chirurgie et aux immunosuppresseurs. La prévalence de la mutation NOD2/ CARD15 dans notre série est faible. Cette mutation est corrélée à une forme grave de la maladie.
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Affiliation(s)
- Mouna Tamzaourte
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Ikram Errabih
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Hayat Krami
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Fadlouallah Maha
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Lahmiri Maria
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Nadia Benzzoubeir
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Laaziza Ouazzani
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
| | - Ahmed Sefiani
- Service de Génétique Médicale, Centre Nationale d'Hygiène, Rabat, Maroc
| | - Houria Ouazzani
- Service d'Hépato-Gastroentérologie «B», Centre Hospitalier Universitaire Ibn Sina, Rabat, Maroc
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Corridoni D, Rodriguez-Palacios A, Di Stefano G, Di Martino L, Antonopoulos DA, Chang EB, Arseneau KO, Pizarro TT, Cominelli F. Genetic deletion of the bacterial sensor NOD2 improves murine Crohn's disease-like ileitis independent of functional dysbiosis. Mucosal Immunol 2017; 10:971-982. [PMID: 27848951 PMCID: PMC5433921 DOI: 10.1038/mi.2016.98] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 09/23/2016] [Indexed: 02/07/2023]
Abstract
Although genetic polymorphisms in NOD2 (nucleotide-binding oligomerization domain-containing 2) have been associated with the pathogenesis of Crohn's disease (CD), little is known regarding the role of wild-type (WT) NOD2 in the gut. To date, most murine studies addressing the role of WT Nod2 have been conducted using healthy (ileitis/colitis-free) mouse strains. Here, we evaluated the effects of Nod2 deletion in a murine model of spontaneous ileitis, i.e., the SAMP1Yit/Fc (SAMP) strain, which closely resembles CD. Remarkably, Nod2 deletion improved both chronic cobblestone ileitis (by 50% assessed, as the % of abnormal mucosa at 24 wks of age), as well as acute dextran sodium sulfate (DSS) colitis. Mechanistically, Th2 cytokine production and Th2-transcription factor activation (i.e., STAT6 phosphorylation) were reduced. Microbiologically, the effects of Nod2 deletion appeared independent of fecal microbiota composition and function, assessed by 16S rRNA and metatranscriptomics. Our findings indicate that pharmacological blockade of NOD2 signaling in humans could improve health in Th2-driven chronic intestinal inflammation.
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Affiliation(s)
- D Corridoni
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - A Rodriguez-Palacios
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - G Di Stefano
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - L Di Martino
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - D A Antonopoulos
- Biosciences Division, Argonne National Laboratory, Argonne, Illinois, USA
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - E B Chang
- Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | - K O Arseneau
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
| | - T T Pizarro
- Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
| | - F Cominelli
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
- Case Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio, USA
- Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA
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Colombel JF, Narula N, Peyrin-Biroulet L. Management Strategies to Improve Outcomes of Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152:351-361.e5. [PMID: 27720840 DOI: 10.1053/j.gastro.2016.09.046] [Citation(s) in RCA: 201] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 09/07/2016] [Accepted: 09/16/2016] [Indexed: 12/12/2022]
Abstract
Strategies for management of inflammatory bowel diseases are shifting from simple control of symptoms toward full control of these diseases (clinical and endoscopic remission), with the final aim of blocking their progression and preventing bowel damage and disability. New goals have been proposed for treatment, such as treat to target and tight control based on therapeutic monitoring and early intervention. For patients who achieve clinical remission, there is often interest in discontinuation of therapy due to safety or economic concerns. We review the evidence supporting these emerging paradigms, the reasons that early effective treatment can alter progression of inflammatory bowel diseases, the importance of examining objective signs of inflammation, and the safety of reducing treatment dosage. We also discuss recent findings regarding personalization of care, including factors that predict patient outcomes and response to therapies, as well as preventative strategies.
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Affiliation(s)
| | - Neeraj Narula
- Division of Gastroenterology, Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, France
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36
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Torres J, Caprioli F, Katsanos KH, Lobatón T, Micic D, Zerôncio M, Van Assche G, Lee JC, Lindsay JO, Rubin DT, Panaccione R, Colombel JF. Predicting Outcomes to Optimize Disease Management in Inflammatory Bowel Diseases. J Crohns Colitis 2016; 10:1385-1394. [PMID: 27282402 PMCID: PMC5174730 DOI: 10.1093/ecco-jcc/jjw116] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 04/29/2016] [Accepted: 05/26/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Efforts to slow or prevent the progressive course of inflammatory bowel diseases [IBD] include early and intensive monitoring and treatment of patients at higher risk for complications. It is therefore essential to identify high-risk patients - both at diagnosis and throughout disease course. METHODS As a part of an IBD Ahead initiative, we conducted a comprehensive literature review to identify predictors of long-term IBD prognosis and generate draft expert summary statements. Statements were refined at national meetings of IBD experts in 32 countries and were finalized at an international meeting in November 2014. RESULTS Patients with Crohn's disease presenting at a young age or with extensive anatomical involvement, deep ulcerations, ileal/ileocolonic involvement, perianal and/or severe rectal disease or penetrating/stenosing behaviour should be regarded as high risk for complications. Patients with ulcerative colitis presenting at young age, with extensive colitis and frequent flare-ups needing steroids or hospitalization present increased risk for colectomy or future hospitalization. Smoking status, concurrent primary sclerosing cholangitis and concurrent infections may impact the course of disease. Current genetic and serological markers lack accuracy for clinical use. CONCLUSIONS Simple demographic and clinical features can guide the clinician in identifying patients at higher risk for disease complications at diagnosis and throughout disease course. However, many of these risk factors have been identified retrospectively and lack validation. Appropriately powered prospective studies are required to inform algorithms that can truly predict the risk for disease progression in the individual patient.
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Affiliation(s)
- Joana Torres
- Surgical Department, Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Flavio Caprioli
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano and Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, Milan, Italy
| | - Konstantinos H Katsanos
- Division of Gastroenterology, Department of Internal Medicine, School of Medical Sciences, University of Ioannina, Ioannina, Greece
| | - Triana Lobatón
- Department of Gastroenterology, Germans Trias i Pujol University Hospital, Badalona, Barcelona, Spain
| | - Dejan Micic
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA
- Barts Health NHS Trust, Royal London Hospital, Whitechapel, London, UK
| | - Marco Zerôncio
- Inflammatory Bowel Disease Unit, Potiguar University School of Medicine, Natal, Brazil
| | - Gert Van Assche
- Division of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - James C Lee
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - James O Lindsay
- Barts Health NHS Trust, Royal London Hospital, Whitechapel, London, UK
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA
- Barts Health NHS Trust, Royal London Hospital, Whitechapel, London, UK
| | - Remo Panaccione
- Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Jean-Frédéric Colombel
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Ye BD, McGovern DP. Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility. Expert Rev Clin Immunol 2016; 12:1091-107. [PMID: 27156530 PMCID: PMC5083126 DOI: 10.1080/1744666x.2016.1184972] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD.
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Affiliation(s)
- Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dermot P.B. McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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Verstockt B, Cleynen I. Genetic Influences on the Development of Fibrosis in Crohn's Disease. Front Med (Lausanne) 2016; 3:24. [PMID: 27303667 PMCID: PMC4885006 DOI: 10.3389/fmed.2016.00024] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 05/13/2016] [Indexed: 12/11/2022] Open
Abstract
Fibrostenotic strictures are an important complication in patients with Crohn’s disease (CD), very often necessitating surgery. This fibrotic process develops in a genetically susceptible individual and is influenced by an interplay with environmental, immunological, and disease-related factors. A deeper understanding of the genetic factors driving this fibrostenotic process might help to unravel the pathogenesis, and ultimately lead to development of new, anti-fibrotic therapy. Here, we review the genetic factors that have been associated with the development of fibrosis in patients with CD, as well as their potential pathophysiological mechanism(s). We also hypothesize on clinical implications, if any, and future research directions.
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Affiliation(s)
- Bram Verstockt
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK; Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Isabelle Cleynen
- Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven , Leuven , Belgium
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Nunes T, Etchevers MJ, García-Sánchez V, Ginard D, Martí E, Barreiro-de Acosta M, Gomollón F, Arroyo M, Bastida G, Gonzalez B, Monfort D, García-Planella E, Figueroa C, Panés J, Sans M. Impact of Smoking Cessation on the Clinical Course of Crohn's Disease Under Current Therapeutic Algorithms: A Multicenter Prospective Study. Am J Gastroenterol 2016; 111:411-9. [PMID: 26856753 DOI: 10.1038/ajg.2015.401] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 10/03/2015] [Accepted: 11/01/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Given the importance of tobacco smoking (TS) as the only environmental factor repeatedly linked to the development of the Crohn's disease (CD), it is surprising that very few prospective studies have assessed whether TS is associated with an increased frequency of clinical relapse. Our aim was to evaluate the current impact of TS on disease relapse and the clinical benefit of quitting smoking in the present era of widespread use of anti-TNF drugs and immunosuppressants. METHODS This was a multicenter prospective cohort study, which included 573 CD patients in clinical remission with various smoking habits. All smokers were advised to quit. Patients not exposed to tobacco before inclusion (non- and former smokers), continuing smokers, and quitters were compared regarding differences in disease outcomes during a follow-up of 4 years. RESULTS A total of 148 continuing smokers, 190 nonsmokers, 160 former smokers, and 75 quitters were included. In comparison with nonsmokers, continuing smokers relapsed more frequently with an incidence rate ratio of 1.53 (95% confidence interval (CI): 1.10-2.17). Former smokers and quitters had similar relapse incidences compared with nonsmokers. Smoking was an independent predictor for disease relapse in the multivariate analysis (hazard ratio: 1.58 (95% CI 1.20-2.09). In the time-dependent analysis, continuing smokers had earlier relapse, regardless of anti-TNF or immunosuppressant use. CONCLUSIONS Continuing smokers have more disease relapses, and patients who quit smoking have a similar relapse incidence compared with nonsmokers.
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Affiliation(s)
- Tiago Nunes
- Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | | | | | - Daniel Ginard
- Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | - Eva Martí
- Hospital Universitario Son Espases, Palma de Mallorca, Spain
| | | | | | | | | | | | | | | | | | - Julián Panés
- Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Miquel Sans
- Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.,Centro Médico Teknon, Barcelona, Spain
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Sifuentes-Dominguez L, Patel AS. Genetics and Therapeutics in Pediatric Ulcerative Colitis: the Past, Present and Future. F1000Res 2016; 5. [PMID: 26973787 PMCID: PMC4776672 DOI: 10.12688/f1000research.7440.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2016] [Indexed: 12/19/2022] Open
Abstract
Ulcerative colitis (UC) is a relapsing and remitting disease with significant phenotypic and genotypic variability. Though more common in adults, UC is being increasingly diagnosed in childhood. The subsequent lifelong course of disease results in challenges for the patient and physician. Currently, there is no medical cure for UC. Even though surgical removal of the colon can be curative, complications including infertility in females make colectomy an option often considered only when the disease presents with life-threatening complications or when medical management fails. One of the greatest challenges the clinician faces in the care of patients with UC is the inability to predict at diagnosis which patient is going to respond to a specific therapy or will eventually require surgery. This therapeutic conundrum frames the discussion to follow, specifically the concept of individualized or personalized treatment strategies based on genetic risk factors. As we move to therapeutics, we will elucidate traditional approaches and discuss known and novel agents. As we look to the future, we can expect increasing integrated approaches using several scientific disciplines to inform how genetic interactions shape and mold the pathogenesis and therapeutics of UC.
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Affiliation(s)
| | - Ashish S Patel
- Children's Health, UT Southwestern Medical Center, Dallas, Texas, USA
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Cleynen I, Boucher G, Jostins L, Schumm LP, Zeissig S, Ahmad T, Andersen V, Andrews JM, Annese V, Brand S, Brant SR, Cho JH, Daly MJ, Dubinsky M, Duerr RH, Ferguson LR, Franke A, Gearry RB, Goyette P, Hakonarson H, Halfvarson J, Hov JR, Huang H, Kennedy NA, Kupcinskas L, Lawrance IC, Lee JC, Satsangi J, Schreiber S, Théâtre E, van der Meulen-de Jong AE, Weersma RK, Wilson DC, Parkes M, Vermeire S, Rioux JD, Mansfield J, Silverberg MS, Radford-Smith G, McGovern DPB, Barrett JC, Lees CW. Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet 2016; 387:156-67. [PMID: 26490195 PMCID: PMC4714968 DOI: 10.1016/s0140-6736(15)00465-1] [Citation(s) in RCA: 542] [Impact Index Per Article: 60.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. METHODS This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. FINDINGS After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). INTERPRETATION Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. FUNDING International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
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Affiliation(s)
- Isabelle Cleynen
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium
| | - Gabrielle Boucher
- Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
| | - Luke Jostins
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Christ Church, University of Oxford, St Aldates, UK
| | - L Philip Schumm
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Sebastian Zeissig
- Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Tariq Ahmad
- Peninsula College of Medicine and Dentistry, Exeter, UK
| | - Vibeke Andersen
- Medical Department, Viborg Regional Hospital, Viborg, Denmark; Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark
| | - Jane M Andrews
- Inflammatory Bowel Disease Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia
| | - Vito Annese
- Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy; Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy
| | - Stephan Brand
- Department of Medicine II, University Hospital Munich-Grosshadern, Ludwig-Maximilians-University, Munich, Germany
| | - Steven R Brant
- Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Judy H Cho
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
| | - Mark J Daly
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Marla Dubinsky
- Department of Pediatrics, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
| | - Lynnette R Ferguson
- School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Richard B Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand; Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | - Philippe Goyette
- Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
| | - Hakon Hakonarson
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Sweden; School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Johannes R Hov
- Norwegian PSC Research Center, Research Insitute of Internal Medicine and Department of Transplantation Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Hailang Huang
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nicholas A Kennedy
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Limas Kupcinskas
- Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Ian C Lawrance
- Centre for Inflammatory Bowel Diseases, Saint John of God Hospital, Subiaco WA and School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute for Medical Research, Murdoch, WA, Australia
| | - James C Lee
- Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Jack Satsangi
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Stephan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
| | - Emilie Théâtre
- Unit of Animal Genomics, Groupe Interdisciplinaire de Genoproteomique Appliquee (GIGA-R) and Faculty of Veterinary Medicine, University of Liege, Liege, Belgium; Division of Gastroenterology, Centre Hospitalier Universitaire, Universite de Liege, Liege, Belgium
| | | | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
| | - David C Wilson
- Child Life and Health, University of Edinburgh, Edinburgh, UK; Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK
| | - Miles Parkes
- Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Severine Vermeire
- Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium; Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
| | - John D Rioux
- Université de Montréal and the Montreal Heart Institute, Research Center, Montréal, Québec, Canada
| | - John Mansfield
- Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK
| | - Mark S Silverberg
- Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, ON, Canada
| | - Graham Radford-Smith
- Inflammatory Bowel Diseases, Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, and School of Medicine, University of Queensland, Brisbane, Australia
| | - Dermot P B McGovern
- F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jeffrey C Barrett
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
| | - Charlie W Lees
- Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
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Mahdi BM. Role of HLA typing on Crohn's disease pathogenesis. Ann Med Surg (Lond) 2015; 4:248-53. [PMID: 26288728 PMCID: PMC4537883 DOI: 10.1016/j.amsu.2015.07.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 07/10/2015] [Accepted: 07/15/2015] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) is the main type of chronic inflammatory bowel disease of unknown etiology. Evidence from family and twin studies suggests that genetics plays a significant role in predisposing an individual to develop Crohn's disease. A susceptibility locus for Crohn's disease has been mapped 3 to chromosome 16: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators which is expressed in hematopoietic compartment cells and intestinal epithelial cells as well as in paneth cells, where NOD2 may play an important role in the pathogenesis of Crohn disease in the gastrointestinal system. This leads to alteration the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has two functions, first an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. Thus, NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in intestinal epithelial cells as well as in paneth cells. Further confirmation of a genetic predisposition comes from studies of the association between the human leukocyte antigen (HLA) system and CD. The immunogenetic predisposition may be considered an important requirement for the development of CD, as several alleles of human major histocompatibility complex had an association with CD. Although it is difficult to estimate the importance of this region in determining overall genetic susceptibility in a population, studies of HLA allele sharing within families suggest that this region contributes between 10% and 33% of the total genetic risk of Crohn's disease.
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Abstract
The disease spectrum and natural course of Crohn's disease and ulcerative colitis are highly variable. The majority of Crohn's disease patients will require surgery at a certain stage in their disease compared to only a fraction of the ulcerative colitis patients. Similarly, some patients are destined to experience an indolent disease course while others will require early intensive therapy. Ideally, these subtypes of patients should be identified as early as possible with the help of reliable prognostic factors in order to guide personalized therapeutic decisions. In this review, the authors focused on the most relevant reports on the use of different prognostic factors to predict disease course, postoperative recurrence and response to therapy in patients with inflammatory bowel disease. The last 15 years have seen a wealth of novel genetic and serological markers of disease severity. Nevertheless, none of these markers have proven to be superior to careful clinical phenotyping and endoscopic features early in the disease course. Future attempts should apply an integrated approach that unites clinical, serological and (epi)genetic information with environmental influences, with a clear focus on the microbiome to ultimately identify molecular-based and clinically relevant subgroups.
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Risk factors for initial surgery in patients with Crohn's disease in Central China. Surg Today 2014; 45:1002-8. [PMID: 25524561 DOI: 10.1007/s00595-014-1093-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 08/07/2014] [Indexed: 01/26/2023]
Abstract
PURPOSES To establish the risk factors for initial surgery in patients with Crohn's disease (CD) in Central China. METHODS The subjects of this study were patients with CD treated at Zhongnan Hospital of Wuhan University, an IBD center in Wuhan City, Central China, between January, 1992 and June, 2012. We conducted uni- and multivariate analyses of the risk factors for initial surgery for CD in these patients. RESULTS A total of 197 patients with CD were included in this study. The cumulative incidence of initial surgery was 21.8, 28.9, and 32.5%, at 1, 5, and 10 years, respectively, after the onset of symptoms. Analysis using multivariate Cox models showed that the relative risk for initial surgery was lower in patients who were younger than 16 years at diagnosis (HR = 0.57, 95% CI 0.34-0.96, P = 0.034). The risk increased in patients with stricturing (HR = 4.75, 95% CI 2.48-9.11), those with CD showing penetrating behavior at diagnosis (HR = 5.14, 95% CI 2.54-10.39), and those with a history of appendectomy (HR = 1.87, 95% CI 1.03-3.40). Azathioprine (AZA) treatment appeared to decrease the risk for initial surgery in patients with non-penetrating and non-stricturing CD (HR = 0.14, 95% CI 0.13-3.10). CONCLUSION Age at diagnosis, disease behavior, and a history of appendectomy appeared to have an impact on the risk for initial surgery. AZA treatment might be helpful for decreasing the risk of needing initial surgery for patients in whom stricturing or fistulizing disease has not yet developed.
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45
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Corridoni D, Arseneau KO, Cifone MG, Cominelli F. The dual role of nod-like receptors in mucosal innate immunity and chronic intestinal inflammation. Front Immunol 2014; 5:317. [PMID: 25071778 PMCID: PMC4090755 DOI: 10.3389/fimmu.2014.00317] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Accepted: 06/24/2014] [Indexed: 01/11/2023] Open
Abstract
Nucleotide-binding and oligomerization domain NOD-like receptors (NLRs) are highly conserved cytosolic pattern recognition receptors that play, in combination with toll-like receptors, a critical role in innate immunity and inflammation. These proteins are characterized by a central oligomerization domain termed nucleotide-binding domain, and a protein interaction domain containing leucine-rich repeats. Some NLRs, including NOD1 and NOD2, sense the cytosolic presence of conserved bacterial molecular signatures and drive the activation of mitogen-activated protein kinase and the transcription factor NF-κB. A different set of NLRs induces caspase-1 activation through the assembly of large protein complexes known as inflammasomes. Activation of NLR proteins results in secretion of pro-inflammatory cytokines and subsequent inflammatory responses. The critical role of NLRs in innate immunity is underscored by the fact that polymorphisms within their genes are implicated in the development of several immune-mediated diseases, including inflammatory bowel disease. Over the past few years, the role of NLRs in intestinal homeostasis has been highlighted, however the mechanism by which dysfunction in these proteins leads to aberrant inflammation is still the focus of much investigation. The purpose of this review is to systematically evaluate the function of NLRs in mucosal innate immunity and understand how genetic or functional alterations in these components can lead to the disruption of intestinal homeostasis, and the subsequent development of chronic inflammation.
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Affiliation(s)
- Daniele Corridoni
- Department of Medicine, Case Western Reserve University , Cleveland, OH , USA ; Digestive Health Research Center, Case Western Reserve University , Cleveland, OH , USA
| | - Kristen O Arseneau
- Department of Medicine, Case Western Reserve University , Cleveland, OH , USA ; Digestive Health Research Center, Case Western Reserve University , Cleveland, OH , USA
| | - Maria Grazia Cifone
- Department of Life, Health and Environmental Sciences, University of L'Aquila , L'Aquila , Italy
| | - Fabio Cominelli
- Department of Medicine, Case Western Reserve University , Cleveland, OH , USA ; Digestive Health Research Center, Case Western Reserve University , Cleveland, OH , USA
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Abstract
BACKGROUND While therapeutic strategies able to change the natural history of inflammatory bowel diseases (IBD) are being developed, factors predicting aggressive disease are needed to be able to choose the appropriate therapeutic strategy for the individual patient based on the risk/benefit ratio. The aim of this review is to focus on the tools assisting the clinician in routine practice regarding the prediction of disease evolution. METHODS A literature review was performed, which was mainly based on PubMed search, using the following terms: Crohn's disease, ulcerative colitis, inflammatory bowel disease, genetics, serology, biomarkers, endoscopy, C-reactive protein, faecal calprotectin, disease evolution and complications. RESULTS For the prediction of disease evolution, clinical characteristics, particularly disease location and behaviour, are probably currently the most useful. In addition, a series of biomarkers, including genetic, serological and inflammatory markers, as well as characteristics of endoscopic lesions may have an added value. CONCLUSIONS Simple clinical, biological and endoscopic tools may help the clinician in predicting disease evolution in IBD. However, these tools are still insufficient, and prospective evaluation of new genetic and biological markers are needed.
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Affiliation(s)
- Jose-Manuel Benitez
- Department of Gastroenterology, CHU Liège, and GIGA Research, Liège University, Liège, Belgium
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47
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Abstract
IBD is a spectrum of chronic disorders that constitute an important health problem worldwide. The hunt for genetic determinants of disease onset and course has culminated in the Immunochip project, which has identified >160 loci containing IBD susceptibility genes. In this Review, we highlight how genetic association studies have informed our understanding of the pathogenesis of IBD by focusing research efforts on key pathways involved in innate immunity, autophagy, lymphocyte differentiation and chemotaxis. Several of these novel genetic markers and cellular pathways are promising candidates for patient stratification and therapeutic targeting.
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48
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Abstract
The expanding knowledge of the role of genetic variants involved in the susceptibility to IBD heralds an era of disease categorization beyond Crohn's disease and ulcerative colitis. A more robust molecular definition of the spectrum of IBD subtypes is likely to be based on specific molecular pathways that determine not only disease susceptibility but also disease characteristics such as location, natural history and therapeutic response. Evolving diagnostic panels for IBD will include clinical variables and genetic markers as well as other indicators of gene function and interaction with environmental factors, such as the microbiome. Multimodal algorithms that combine clinical, serologic and genetic information are likely to be useful in predicting disease course. Variation in IBD-susceptibility and drug-related pathway genes seems to influence the response to anti-TNF therapy. Furthermore, gene expression signatures and composite models have both shown promise as predictors of therapeutic response. Ultimately, models based on combinations of genotype and gene expression data with clinical, biochemical, serological, and microbiome data for clinically meaningful subgroups of patients should permit the development of tools for individualized risk stratification and treatment selection.
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Ahmed FE. Role of genes, the environment and their interactions in the etiology of inflammatory bowel diseases. Expert Rev Mol Diagn 2014; 6:345-63. [PMID: 16706738 DOI: 10.1586/14737159.6.3.345] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Few of the studied genes demonstrate association with inflammatory bowel disease (IBD). Three mutations in the nucleotide-binding oligomerization domain 2 gene have consistently shown to be independent risk factors for Crohn's disease, but none of the alleles exhibited high sensitivity or specificity for IBD. Linkage analysis implicated several loci on various chromosomes, and epistasis has been demonstrated. The etiopathogenesis of IBD remains unknown, and environmental contribution to their pathogenesis is evident from genetic studies that demonstrated incomplete monozygotic twins concordandance rate for both Crohn's and ulcerative colitis. Smoking has shown an opposite effect on disease phenotype, with an adverse effect on disease course for Crohn's disease, but a slight beneficial effect in ulcerative colitis. The contribution of infectious agents to susceptibility to IBD appears to be strong. However, the role of nutrition on the etiology and therapy of IBD is not clear. Inconsistencies in environmental risk factors could be due to gene-environment interactions, making it essential to study the role of genetics and environmental contribution to the etiopathology of IBD. Transgenic or knockout mice, such as interleukin-10(-/-), T-cell receptor alpha(-/-), Galphai(2) (-/-) and N-cadherin(-/-), develop colitis-like inflammation similar to humans. Therefore, animal models must be further studied to explore mechanistic interactions.
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Affiliation(s)
- Farid E Ahmed
- The Brody School of Medicine at East Carolina University, Department of Radiation Oncology, Leo W Jenkins Cancer Center, Greenville, NC 27858, USA.
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50
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Cleynen I, González JR, Figueroa C, Franke A, McGovern D, Bortlík M, Crusius BJA, Vecchi M, Artieda M, Szczypiorska M, Bethge J, Arteta D, Ayala E, Danese S, van Hogezand RA, Panés J, Peña SA, Lukas M, Jewell DP, Schreiber S, Vermeire S, Sans M. Genetic factors conferring an increased susceptibility to develop Crohn's disease also influence disease phenotype: results from the IBDchip European Project. Gut 2013; 62:1556-65. [PMID: 23263249 DOI: 10.1136/gutjnl-2011-300777] [Citation(s) in RCA: 206] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course. DESIGN This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied. RESULTS Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02 × 10(-06), OR=1.90), stenosing (p=3.16 × 10(-06), OR=1.82) and penetrating (p=1.26 × 10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28 × e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86 × 10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48 × 10(-06), OR=0.35) and surgical rate (p=1.71 × 10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12 × 10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01 × 10(-02), HR=1.29) among patients with low and high score. CONCLUSIONS This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.
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Affiliation(s)
- Isabelle Cleynen
- Department of Clinical and Experimental Medicine, KU Leuven, , Leuven, Belgium
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