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Cwaliński J, Stawczyk-Eder K, Cwalinska A, Zasada W, Cholerzyńska H, Banasiewicz T, Paszkowski J. Insufficiency of ileocolic anastomosis in Crohn’s disease patients – prevention and treatment. World J Gastrointest Surg 2025; 17:102064. [DOI: 10.4240/wjgs.v17.i5.102064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 02/01/2025] [Accepted: 02/27/2025] [Indexed: 05/23/2025] Open
Abstract
Resection of the terminal ileum and ileocecal valve remains the most commonly performed procedure in patients with Crohn's disease. However, despite radical treatment, there is a risk of disease recurrence at the site of the intestinal anastomosis in some cases. Therefore, long-term postoperative management is crucial and requires systematic clinical assessment, endoscopic surveillance, and pharmacological support when indicated. A key challenge is identifying the risk factors associated with the recurrence of anastomotic failure and defining the principles of follow-up care to prevent secondary intestinal insufficiency. This paper focuses on both surgical and non-surgical factors that may play a role in preventing complications in patients undergoing ileocecal resection, providing a comprehensive approach to postoperative management.
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Affiliation(s)
- Jarosław Cwaliński
- Department of General, Endocrinological Surgery and Gastrointestinal Oncology, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Kamila Stawczyk-Eder
- Department of Gastroenterology, Dietetics, and Internal Medicine, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Agnieszka Cwalinska
- Department of Infectious Diseases and Child Neurology, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Wiktoria Zasada
- Department of General, Endocrinological Surgery and Gastrointestinal Oncology, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Hanna Cholerzyńska
- Department of General, Endocrinological Surgery and Gastrointestinal Oncology, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Tomasz Banasiewicz
- Department of General, Endocrinological Surgery and Gastrointestinal Oncology, Poznan University of Medical Sciences, Poznan 60-355, Poland
| | - Jacek Paszkowski
- Department of General, Endocrinological Surgery and Gastrointestinal Oncology, Poznan University of Medical Sciences, Poznan 60-355, Poland
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Dillman JR, Tkach JA, Fletcher JG, Bruining DH, Lu A, Kugathasan S, Alazraki AL, Knight-Scott J, Stidham RW, Adler J, Minar P, Trapnell BC, Bonkowski EL, Jurrell H, Lopez-Nunez O, Collins MH, Swanson SD, Fei L, Qian L, Towbin AJ, Kocaoglu M, Anton CG, Imbus RA, Dudley JA, Denson LA. Circulating and Magnetic Resonance Imaging Biomarkers of Intestinal Fibrosis in Small Bowel Crohn's Disease. Inflamm Bowel Dis 2025; 31:1380-1391. [PMID: 39853252 PMCID: PMC12069992 DOI: 10.1093/ibd/izae319] [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: 07/08/2024] [Indexed: 01/26/2025]
Abstract
BACKGROUND We previously identified circulating and MRI biomarkers associated with the surgical management of Crohn's disease (CD). Here we tested associations between these biomarkers and ileal resection inflammation and collagen content. METHODS Fifty CD patients undergoing ileal resection were prospectively enrolled at 4 centers. Circulating CD64, extracellular matrix protein 1 (ECM1), GM-CSF autoantibodies (GM-CSF Ab), and fecal calprotectin were measured by ELISA. Ileal 3-dimensional magnetization transfer ratio (3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, diffusion-weighted intravoxel incoherent motion (IVIM), and the simplified magnetic resonance index of activity (sMaRIA) were measured by MRI. Ileal resection specimen acute inflammation was graded, and collagen content was measured quantitatively using second harmonic imaging microscopy. Associations between biomarkers and ileal collagen content were tested. RESULTS Median (interquartile range [IQR]) age was 19.5 (16-33) years. We observed an inverse relationship between ileal acute inflammation and collagen content (r = -0.39 [95% confidence interval {CI}: -0.61, -0.10], P = .008). Most patients (33 [66%]) received biologics, with no variation in collagen content with treatment exposures. In the univariate analysis, CD64, GM-CSF Ab, fecal calprotectin, and sMaRIA were positively associated with acute inflammation and negatively associated with collagen content (P < .1). The multivariable model for ileal collagen content (R2 = 0.31 [95% CI: 0.11, 0.52]) included log CD64 (β = -.27; P = .19), log ECM1 (β = .47; P = .06), log GM-CSF Ab (β = -.15; P = .01), IVIM f (β = .29, P = .10), and IVIM D* (β = 1.69, P = .13). CONCLUSIONS Clinically available and exploratory circulating and MRI biomarkers are associated with the degree of inflammation versus fibrosis in CD ileal resections. With further validation, these biomarkers may be used to guide medical and surgical decision-making for refractory CD.
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Affiliation(s)
- Jonathan R Dillman
- Department of Radiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jean A Tkach
- Department of Radiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | - David H Bruining
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Aiming Lu
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Subra Kugathasan
- Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Adina L Alazraki
- Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
- Department of Radiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Jack Knight-Scott
- Department of Radiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Ryan W Stidham
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA
| | - Jeremy Adler
- Division of Pediatric Gastroenterology, Department of Pediatrics, C. S. Mott Children’s Hospital, Michigan Medicine, Ann Arbor, MI, USA
| | - Phillip Minar
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Bruce C Trapnell
- Departments of Medicine and Pediatrics, Translational Pulmonary Science Center, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Erin L Bonkowski
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Holden Jurrell
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Oscar Lopez-Nunez
- Division of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Margaret H Collins
- Division of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Scott D Swanson
- Department of Radiology, Michigan Medicine, Ann Arbor, MI, USA
| | - Lin Fei
- Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lucia Qian
- Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- University of Michigan, Ann Arbor, MI, USA
| | - Alexander J Towbin
- Department of Radiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Murat Kocaoglu
- Department of Radiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Christopher G Anton
- Department of Radiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rebecca A Imbus
- Department of Radiology, Imaging Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Jonathan A Dudley
- Department of Radiology, Imaging Research Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Lee A Denson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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de Carvalho MF, Carlos ADS, Kum AST, Bestetti AM, Gomes ILC, de Oliveira LB, Baroni LM, Bernardo WM, de Moura EGH. Invasive Therapeutic Strategies for Stricturing Crohn's Disease in Childhood: A Systematic Review and Meta-Analysis. Inflamm Bowel Dis 2025; 31:1032-1040. [PMID: 39049794 DOI: 10.1093/ibd/izae144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic inflammatory condition of the gastrointestinal tract. Current drugs are not effective for treating the primary fibrotic component of CD. Recommended invasive treatments include endoscopic balloon dilation, surgery with resection, or strictureplasty. This meta-analysis compared invasive treatment techniques for CD-related strictures in the pediatric population. METHODS The MEDLINE, EMBASE, and LILACS databases were searched from inception to December 2023. This meta-analysis was performed as per the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The outcome was measured by the rate of stenosis recurrence and the adverse events of the techniques. Eligibility criteria were studies that involved the analysis of the recurrence rate of stenosis in pediatric patients with CD requiring surgical intervention after undergoing any of the previously proposed therapies. Additionally, adverse events were analyzed. RESULTS Three studies comprising a total of 106 endoscopic balloon dilations demonstrated a combined rate of stricture recurrence in patients with CD requiring surgical intervention of 0.171 (95% confidence interval [CI], 0.110-0.255). Three studies comprising a total of 49 surgical resections demonstrated a pooled event rate of 0.100 (95% CI, 0.038-0.240). Finally, 2 studies comprising a total of 38 strictureplasties demonstrated a pooled event rate of 0.347 (95% CI, 0.070-0.789). Concerning adverse events, the most common occurrences were found after surgical resection. CONCLUSIONS Surgical resection is the best option for treating strictures in pediatric CD patients in terms of recurrence rate, compared with endoscopic balloon dilation and strictureplasty. Nevertheless, surgical resection is associated with more adverse events.
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Affiliation(s)
- Matheus Ferreira de Carvalho
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Alexandre de Sousa Carlos
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Angelo So Taa Kum
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Alexandre Moraes Bestetti
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Igor Logetto Caetité Gomes
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiza Bicudo de Oliveira
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiza Martins Baroni
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Wanderley Marques Bernardo
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
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Klemm NK, Feuerstein JD. A practical guide to dilating inflammatory bowel disease strictures. Expert Rev Gastroenterol Hepatol 2025; 19:377-387. [PMID: 39987913 DOI: 10.1080/17474124.2025.2471873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/13/2025] [Accepted: 02/21/2025] [Indexed: 02/25/2025]
Abstract
INTRODUCTION Stricturing Crohn's disease is a common phenotype and treatment aims to improve symptoms, prevent complications, assess for proximal bowel disease activity, and screen for upstream neoplasm. Management is challenging due to diagnostic limitations, stricture composition, and recurrence rate. AREAS COVERED Categorizing a stricture as inflammatory or fibrotic is necessary to determine appropriate management. Inflammatory strictures are treated with medical therapy, and fibrostenotic strictures require endoscopic or surgical management. While EBD is increasingly utilized, stricture recurrence rates remain high, necessitating repeat endoscopic procedures or surgery. We performed a PubMed (MEDLINE database) search for the latest research on IBD-related stricture management, including detection, diagnosis, and medical and procedural therapies. We highlight the current literature on endoscopic techniques for the treatment of intestinal strictures and future areas of research. EXPERT OPINION The field of intestinal stricture management is expected to evolve in the coming years and will include enhanced imaging modalities, medication optimization, and increasing use of advanced endoscopic techniques.
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Affiliation(s)
- Natasha K Klemm
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Joseph D Feuerstein
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Cui L, Su M, Ding YB, Wang M, Sun KW. Preliminary study on the clinical value of endoscopic stricturotomy in the treatment of stricturing Crohn's disease. World J Gastrointest Surg 2025; 17:100631. [DOI: 10.4240/wjgs.v17.i2.100631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 11/22/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Crohn's disease (CD) frequently leads to intestinal strictures, which pose significant challenges due to their complexity and limited treatment options. While medications can address inflammatory strictures, they are largely ineffective for fibrotic and mixed strictures, often necessitating surgical intervention. However, surgery carries considerable risks, including bleeding, infection, anastomotic leaks, and postoperative restricture formation. Endoscopic treatment, particularly endoscopic stricturotomy, offers a minimally invasive alternative that bridges the gap between medication and surgery.
AIM To investigate the safety and efficacy of stricturotomy under single-balloon enteroscopy in stricturing CD.
METHODS Patients diagnosed with stricturing CD at The First People's Hospital of Changzhou from June 2020 to April 2024 were enrolled and underwent endoscopic stricturotomy (ES). Relevant clinical data of patients were collected retrospectively. Outcomes included success rate, remission time, complications, and follow-up interventions. This observational study was followed up postoperatively to observe patient remission and recurrence rates.
RESULTS Seventeen endoscopic strictures were created in 11 patients, achieving a 100% immediate success rate without any serious complications. During the follow-up period, stricture recurrence was observed in two patients, resulting in an endoscopic reintervention rate of 18.2%. Additionally, two patients required subsequent surgical intervention, with a surgical treatment rate of 18.2%. One patient experienced bowel obstruction 18 months post-ES and was successfully managed with conservative treatment without surgical intervention. The remission duration after the initial ES treatment was 10.1 ± 8.2 months, with a median remission time of 10 months.
CONCLUSION ES is a safe and effective treatment for CD-related strictures and warrants further clinical promotion and application.
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Affiliation(s)
- Lu Cui
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu Province, China
| | - Min Su
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu Province, China
| | - Yan-Bo Ding
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu Province, China
| | - Mei Wang
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu Province, China
| | - Ke-Wen Sun
- Department of Gastroenterology, The Third Affiliated Hospital of Soochow University, Changzhou 213000, Jiangsu Province, China
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Nofal MN, Yousef AJ, Samarah SH, Al-Qudah BM. Surgery time for stenosed Crohn's disease: Case report. Int J Surg Case Rep 2025; 127:110903. [PMID: 39874808 PMCID: PMC11808665 DOI: 10.1016/j.ijscr.2025.110903] [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: 12/05/2024] [Revised: 01/15/2025] [Accepted: 01/18/2025] [Indexed: 01/30/2025] Open
Abstract
INTRODUCTION AND IMPORTANCE Stricture formation is a well-known Crohn's disease consequence that usually results from recurrent cycles of inflammation and healing and primarily affects the small intestine. CASE PRESENTATION In this report, we describe the case of a 35-year-old male with an 18-year history of Crohn's disease complicated by long-kinked ileal stricture who presented with a 3-month history of subacute small intestinal obstruction diagnosed with MR enterography and underwent failed medical treatment. CLINICAL DISCUSSION The patient, a male showing signs of wasting due to a prolonged subacute small intestinal obstruction, underwent an MR enterography which revealed a 6-cm kinked ileal stricture. Intraoperative observations included a significantly dilated small intestine proximal to the stricture and a collapsed distal small bowel. Following resection, the patient experienced a smooth recovery with marked improvement. CONCLUSION When there are clear indications for the surgical resection of a stenosed bowel segment caused by Crohn's disease, it is advisable to proceed with the surgery promptly, with a preference for side-to-side stapled anastomosis.
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Affiliation(s)
- Mohammad N Nofal
- General Surgery and Anesthesia Department, Faculty of Medicine, Mutah University, Karak 61710, Jordan
| | - Ali J Yousef
- General Surgery and Anesthesia Department, Faculty of Medicine, Mutah University, Karak 61710, Jordan.
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Garcia M, Debebe A, Mahmood F, Nirenberg S, Rendon A, Yang E, Xiang J, Colombel JF, Kahan T, Ghiasian G, Faye AS, Levine I, Farber M, Ramada M, Omoakhe T, Sultan K, Sachar DB. Intravenous Steroids Do Not Improve Short-Term Outcomes of Patients With Crohn's Disease Presenting With an Acute Small Bowel Obstruction. CROHN'S & COLITIS 360 2025; 7:otae064. [PMID: 39834354 PMCID: PMC11744190 DOI: 10.1093/crocol/otae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND Intravenous (IV) steroids are commonly used to treat acute flares of Crohn's disease (CD). However, it is unclear if they are beneficial in the setting of uncomplicated small bowel obstruction (SBO). We sought to examine if IV steroid administration improved short-term outcomes in patients with CD hospitalized for acute, uncomplicated SBO across three New York City hospital systems. METHODS This retrospective study included patients ≥ 18 years old admitted between January 1, 2011, and December 31, 2019, with Crohn's disease and an admission diagnosis of uncomplicated acute SBO, defined as cases without adhesions, fistula, phlegmon, and sepsis. Primary endpoints (length of stay and frequency of surgery) were compared between patients who received IV steroids upon admission and those who did not. RESULTS Our analysis included 674 unique patients. Ninety-two (14%) received IV steroids, and 582 (86%) did not. IV steroid use did not result in shorter hospital stays (median days [IQR]: 3.0 (2.0-5.5) days vs 3.0 (2.0-6.0) days in the no-steroid group, P = .65) or reduce the need for surgery (4 patients (4.4%) vs 28 patients (4.8%) in the no-steroid group, P = .85). Sex, age, disease duration, concomitant biologic therapy, and NG tube placement did not independently contribute to either outcome. CONCLUSIONS These findings suggest that IV steroid administration for uncomplicated SBO in CD patients does not decrease hospital length of stay or need for surgery. Further research may help identify specific obstruction patterns or other therapies associated with different outcomes.
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Affiliation(s)
- Mariely Garcia
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Anketse Debebe
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Farhan Mahmood
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sharon Nirenberg
- Department of Scientific Computing, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alexa Rendon
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eunyoung Yang
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jiani Xiang
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frédéric Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine, New York, NY, USA
| | - Tamara Kahan
- NYU Langone Health, NYU Grossman School of Medicine, New York, NY, USA
| | - Ghoncheh Ghiasian
- NYU Langone Health, NYU Grossman School of Medicine, New York, NY, USA
| | - Adam S Faye
- NYU Langone Health, NYU Grossman School of Medicine, New York, NY, USA
| | - Irving Levine
- Department of Medicine, Northwell Health, Manhasset, NY, USA
| | - Michael Farber
- Department of Medicine, Northwell Health, Manhasset, NY, USA
- College of Osteopathic Medicine, New York Institute of Technology, Old Westbury, NY, USA
| | - Michael Ramada
- Department of Medicine, Northwell Health, Manhasset, NY, USA
| | - Tisor Omoakhe
- Department of Medicine, Northwell Health, Manhasset, NY, USA
| | - Keith Sultan
- Department of Medicine, Division of Gastroenterology, Northwell Health, Manhasset, NY, USA
| | - David B Sachar
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine, New York, NY, USA
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Poulsen A, Ovesen PD, Lu C, Bettenworth D, Jairath V, Feagan BG, Seidelin JB, Rieder F. Serum Extracellular Matrix Molecules and Their Fragments as Biomarkers of Inflammation and Fibrosis in Inflammatory Bowel Diseases: A Systematic Review. J Crohns Colitis 2024; 18:1894-1934. [PMID: 38758527 DOI: 10.1093/ecco-jcc/jjae077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 05/04/2024] [Accepted: 05/16/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND AND AIM Contemporary techniques to assess disease activity or bowel damage in patients with inflammatory bowel disease [IBD], such as endoscopy and imaging, are either invasive or lack accuracy. Non-invasive biomarkers for this purpose remain an unmet medical need. Herein, we provide a comprehensive systematic review of studies evaluating blood extracellular matrix [ECM] biomarkers and their relevance in IBD. METHODS We conducted a systematic review of PubMed, EMBASE, Web of Science, and Scopus to identify citations pertaining to ECM biomarkers of IBD up to March 1, 2024. Studies were categorized based on marker subtype and clinical use. RESULTS Thirty-one ECM markers were identified, 28 of which demonstrated the ability to differentiate IBD disease activity. Collagen III emerged as the most extensively investigated [1212 IBD patients], with the degradation marker C3M and deposition marker PRO-C3 being associated with IBD and subtypes. Collagen V markers C5M and PRO-C5 emerged as the most accurate single markers for diagnosis of IBD, with an area under the curve of 0.91 and 0.93, respectively. Overall, studies were characterized by variable endpoints. None of the studies included histological grading of intestinal damage, repair, or fibrosis formation as the primary outcome in relation to the ECM blood markers. CONCLUSIONS Multiple ECM markers are linked with IBD and its phenotypes. However, more rigorous study designs and clearly defined endpoints are needed to ensure reproducibility and develop reliable and accurate biomarkers. ECM markers hold promise as they provide a 'window' into transmural tissue remodelling and fibrosis burden, warranting further investigation.
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Affiliation(s)
- Anja Poulsen
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen NV, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Pernille Dige Ovesen
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Cathy Lu
- Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Dominik Bettenworth
- Medical Faculty, University of Münster, Münster, Germany
- CED Schwerpunktpraxis, Münster, Germany
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, ON N6A 3K7, Canada
- Department of Epidemiology and Biostatistics, Western University, London, ON N6A, Canada
| | - Brian G Feagan
- Division of Gastroenterology, Department of Medicine, Western University, London, ON N6A 3K7, Canada
- Department of Epidemiology and Biostatistics, Western University, London, ON N6A, Canada
- Alimentiv Inc, London, ON N6A 5B6, Canada
| | - Jakob Benedict Seidelin
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
- Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
- Program for Global Translational Inflammatory Bowel Diseases, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
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He X, Wang Y, Sun J, Li Y, Ruan G, Li Y, Zheng W, Zhang X, Zhan R, Ding X, Liu A, Chen Y, Hu Y, Yang H, Qian J. Effectiveness comparison between ustekinumab and infliximab for Crohn's disease complicated with intestinal stenosis: a multicenter real-world study. Therap Adv Gastroenterol 2024; 17:17562848241290663. [PMID: 39493260 PMCID: PMC11528754 DOI: 10.1177/17562848241290663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 09/25/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND The efficacy of ustekinumab (UST) and infliximab (IFX) in Crohn's disease (CD) patients with intestinal stenosis remains uncertain. OBJECTIVE This study aims to compare the efficacy of UST and IFX in the treatment of CD patients with intestinal stenosis. DESIGN This was a retrospective and multicenter cohort study. METHODS In this retrospective study, we included CD patients treated with IFX or UST at five centers. We assessed the clinical response rate at weeks 12 and 24, steroid-free clinical remission rate at weeks 24 and 52 for overall patients and those with stenosis, and objective examination (intestinal ultrasound and/or endoscopy) response rate at week 52 for stenosis patients. RESULTS A total of 211 CD patients (106 IFX and 105 UST) were included, with 119 (56 IFX and 63 UST) having intestinal stenosis. In the overall patient population, there were no significant differences in clinical response rate and steroid-free clinical remission rate at weeks 12, 24, and 52 between the IFX and UST groups. In patients with stenosis, the steroid-free clinical remission rate at week 52 was significantly lower in the IFX group compared to the UST group (51.79% IFX vs 69.84% UST, p = 0.044). The objective examination response rate did not significantly differ between the IFX and UST groups at week 52 (66.67% IFX vs 76.19% UST, p = 0.690). In the UST group, steroid-free clinical remission rate was higher in bio-naïve patients than bio-experienced patients at week 24 (75.00% bio-naïve vs 55.38% bio-experienced, p = 0.043). CONCLUSION UST may be considered a more advantageous treatment option for those CD patients with intestinal stenosis, as it has better steroid-free clinical remission rates compared to IFX.
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Affiliation(s)
- Xidong He
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yufang Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Jingyao Sun
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yueqin Li
- The First Department of Gastroenterology, Jingmen People’s Hospital, Jingmen, China
| | - Gechong Ruan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weiyang Zheng
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaolan Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Rongrong Zhan
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xueli Ding
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ailing Liu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yijia Chen
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yiqun Hu
- Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, 201 Hubin South Road, Xiamen 361004, China
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing 100730, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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10
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Chirra P, Sleiman J, Gandhi NS, Gordon IO, Hariri M, Baker M, Ottichilo R, Bruining DH, Kurowski JA, Viswanath SE, Rieder F. Radiomics to Detect Inflammation and Fibrosis on Magnetic Resonance Enterography in Stricturing Crohn's Disease. J Crohns Colitis 2024; 18:1660-1671. [PMID: 38761165 PMCID: PMC11812255 DOI: 10.1093/ecco-jcc/jjae073] [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: 12/30/2023] [Revised: 04/07/2024] [Accepted: 05/13/2024] [Indexed: 05/20/2024]
Abstract
BACKGROUND AND AIMS Non-invasive cross-sectional imaging via magnetic resonance enterography [MRE] offers excellent accuracy for the diagnosis of stricturing complications in Crohn's disease [CD] but is limited in determining the degrees of fibrosis and inflammation within a stricture. We developed and validated a radiomics-based machine-learning model for separately characterizing the degree of histopathological inflammation and fibrosis in CD strictures and compared it to centrally read visual radiologist scoring of MRE. METHODS This single-centre, cross-sectional study included 51 CD patients [n = 34 for discovery; n = 17 for validation] with terminal ileal strictures confirmed on diagnostic MRE within 15 weeks of resection. Histopathological specimens were scored for inflammation and fibrosis and spatially linked with corresponding pre-surgical MRE sequences. Annotated stricture regions on MRE were scored visually by radiologists as well as underwent 3D radiomics-based machine learning analysis; both were evaluated against histopathology. RESULTS Two distinct sets of radiomic features capturing textural heterogeneity within strictures were linked with each of severe inflammation or severe fibrosis across both the discovery (area under the curve [AUC = 0.69, 0.83] and validation [AUC = 0.67, 0.78] cohorts. Radiologist visual scoring had an AUC = 0.67 for identifying severe inflammation and AUC = 0.35 for severe fibrosis. Use of combined radiomics and radiologist scoring robustly augmented identification of severe inflammation [AUC = 0.79] and modestly improved assessment of severe fibrosis [AUC = 0.79 for severe fibrosis] over individual approaches. CONCLUSIONS Radiomic features of CD strictures on MRE can accurately identify severe histopathological inflammation and severe histopathological fibrosis, as well as augment performance of the radiologist visual scoring in stricture characterization.
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Affiliation(s)
- Prathyush Chirra
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Joseph Sleiman
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Namita S Gandhi
- Section, Abdominal Imaging, Imaging Institute, and Digestive Diseases and Surgery Institute and Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ilyssa O Gordon
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Mohsen Hariri
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Mark Baker
- Section, Abdominal Imaging, Imaging Institute, and Digestive Diseases and Surgery Institute and Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ronald Ottichilo
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - David H Bruining
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Jacob A Kurowski
- Department of Pediatric Gastroenterology, Hepatology & Nutrition, Cleveland Clinic, Cleveland, OH, USA
| | - Satish E Viswanath
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA
| | - Florian Rieder
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Center for Global Translational Inflammatory Bowel Disease Research, Cleveland Clinic, Cleveland, OH, USA
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11
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Debnath P, Epstein KN, Kocaoglu M, Towbin AJ, Denson LA, Dillman JR. Imaging and clinical predictors of surgery in stricturing ileal Crohn's disease: a retrospective study from a large pediatric hospital. Abdom Radiol (NY) 2024; 49:3354-3363. [PMID: 38656368 DOI: 10.1007/s00261-024-04314-8] [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: 02/12/2024] [Revised: 03/23/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
PURPOSE (1) To determine the frequency of surgical management in children with Crohn's Disease (CD) and a new radiologic ileal stricture, and (2) to identify imaging and clinical features that predict the need for surgery. METHODS This retrospective study included pediatric patients (< 21 years old) with CD and a new ileal stricture diagnosed by MRE, CTE, or CT between July 2018 and June 2023. Three board-certified radiologists recorded stricture length, maximum mural thickness, minimum lumen diameter, maximum upstream diameter, and simplified magnetic resonance index of activity (sMaRIA) score. Anthropometrics, laboratory data, and surgical interventions performed after stricture diagnosis were also recorded. Multivariable logistic regression was used to identify imaging and clinical variables associated with the need for surgery. RESULTS 44 pediatric CD patients (median age 16.5 years) presented with a new ileal stricture during the study period. 30 (68.2%) patients required surgery, with a median time of 87.5 days between stricture diagnosis and surgery. Median stricture measurements were length: 7.0 cm, maximum mural thickness: 7.3 mm, minimum lumen diameter: 0.2 cm, and maximum upstream diameter: 3.3 cm. Median sMaRIA score was 3.0, and 14 (31.8%) strictures had associated internal penetrating disease. Stricture ratio (ratio of maximum upstream lumen diameter to minimum lumen diameter) (OR = 1.15 [95% CI 1.02-1.30]; p = 0.02) and sMaRIA (OR = 2.12 [95% CI 0.87-5.17; p = 0.10) were associated with need for surgery. CONCLUSION Surgery remains common in stricturing pediatric CD, with increasing stricture ratio and sMaRIA score associated with need for surgical management.
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Affiliation(s)
- Pradipta Debnath
- Department of Radiology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Kasota Building MLC 5031, Cincinnati, OH, 45229, USA.
| | - Katherine N Epstein
- Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Murat Kocaoglu
- Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Alexander J Towbin
- Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lee A Denson
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Jonathan R Dillman
- Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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12
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Veisman I, Massey WJ, Goren I, Liu W, Chauhan G, Rieder F. Muscular hyperplasia in Crohn's disease strictures: through thick and thin. Am J Physiol Cell Physiol 2024; 327:C671-C683. [PMID: 38912732 PMCID: PMC11427014 DOI: 10.1152/ajpcell.00307.2024] [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: 05/06/2024] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Fibrostenosing Crohn's disease (CD) represents a challenging clinical condition characterized by the development of symptomatic strictures within the gastrointestinal tract. Despite therapeutic advancements in managing inflammation, the progression of fibrostenotic complications remains a significant concern, often necessitating surgical intervention. Recent investigations have unveiled the pivotal role of smooth muscle cell hyperplasia in driving luminal narrowing and clinical symptomatology. Drawing parallels to analogous inflammatory conditions affecting other organs, such as the airways and blood vessels, sheds light on common underlying mechanisms of muscular hyperplasia. This review synthesizes current evidence to elucidate the mechanisms underlying smooth muscle cell proliferation in CD-associated strictures, offering insights into potential therapeutic targets. By highlighting the emerging significance of muscle thickening as a novel therapeutic target, this review aims to inform future research endeavors and clinical strategies with the goal to mitigate the burden of fibrostenotic complications in CD and other conditions.
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Affiliation(s)
- Ido Veisman
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - William J Massey
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Idan Goren
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Weiwei Liu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Gaurav Chauhan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States
- Cleveland Clinic Program for Global Translational Inflammatory Bowel Diseases (GRID), Cleveland, Ohio, United States
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13
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Carroll D, Kavalukas S. Management of Complications in Crohn's Disease. Adv Surg 2024; 58:19-34. [PMID: 39089776 DOI: 10.1016/j.yasu.2024.04.002] [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] [Indexed: 08/04/2024]
Abstract
Complications of Crohn's disease reach far beyond postsurgical leak, infection, and enterocutaneous fistula. Malnutrition, intestinal failure, and recurrent disease all will require ongoing attentions. The management of these patients may further be complicated by the need for chronic immunosuppression. The underlying principles continue to include optimization of nutritional status, and preservation of bowel length when possible. However, there have been several recent advances in both the medical and surgical management of the disease. Understanding the contribution of the mesentery to inflammation, new surgical techniques such as the Kono-S anastomosis and extended mesenteric resection is decreasing the need for repeated resections.
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Affiliation(s)
- Dylan Carroll
- Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40292, USA
| | - Sandy Kavalukas
- Colorectal Surgery, Department of Surgery, University of Louisville, 550 South Jackson Street, Louisville, KY 40292, USA.
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14
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Lu C, Feagan BG, Fletcher JG, Baker M, Holubar S, Rieder F. Management of Small Bowel Crohn's Disease Strictures: To Cut, to Stretch, or to Treat Inflammation? Gastroenterology 2024:S0016-5085(24)05413-1. [PMID: 39222715 DOI: 10.1053/j.gastro.2024.08.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Affiliation(s)
- Cathy Lu
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Brian G Feagan
- Alimentiv Inc., London, Ontario, Canada; Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | | | - Mark Baker
- Imaging Department, Enterprise Diagnostic Institute, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Stefan Holubar
- Department of Colon and Rectal Surgery, Digestive Diseases Institute, Cleveland Clinic, Cleveland, Ohio
| | - Florian Rieder
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Program for Global Translational Inflammatory Bowel Diseases, Cleveland Clinic, Cleveland, Ohio.
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15
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Clement B, Reyes Genere J. Interventional inflammatory bowel disease: current and future practice. Curr Opin Gastroenterol 2024; 40:276-284. [PMID: 38662195 DOI: 10.1097/mog.0000000000001028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
PURPOSE OF REVIEW Inflammatory bowel diseases (IBD) are associated with several well described neoplastic and structural complications. Increasing disease prevalence, healthcare barriers, and medication refractory phenotypes contribute to ongoing complications despite significant strides in medical management. Enhancements in endoscopic technology and techniques have allowed a minimally invasive approach for what has historically required surgery. In this article, we review the current and future landscape of endoscopic IBD intervention. RECENT FINDINGS Endoscopic resection is the first line for managing conventional and complex colitis-associated dysplasia. Evidence supporting endoscopic submucosal dissection is mounting, yet there is a paucity of studies evaluating modified endoscopic mucosal resection techniques or hybrid endoscopic submucosal dissection. We also have more clarity in how best to approach fibrostenotic disease, as we learn how to position endoscopic stricturotomy and stenting, relative to balloon dilation. Finally, applications in managing penetrating and postsurgical complications have been described, but still require further study. SUMMARY While important knowledge gaps still exist, the application of endoscopic therapies in IBD is more refined, especially within the management of colitis-associated dysplasia and strictures. The indications for endoscopy in perianal disease and other penetrating manifestations of Crohn's disease presents exciting opportunities for growth.
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Affiliation(s)
- Benjamin Clement
- Department of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio
| | - Juan Reyes Genere
- Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA
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16
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Jarmakiewicz-Czaja S, Gruszecka J, Filip R. The Diagnosis of Intestinal Fibrosis in Crohn's Disease-Present and Future. Int J Mol Sci 2024; 25:6935. [PMID: 39000043 PMCID: PMC11241173 DOI: 10.3390/ijms25136935] [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: 05/15/2024] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 07/14/2024] Open
Abstract
Crohn's disease (CD) progresses with periods of remission and exacerbations. During exacerbations, chronic inflammation leads to tissue destruction. As a result, intestinal fibrosis may develop in response to the ongoing inflammatory process. Fibrosis in CD should be considered the result of the response of the intestinal wall (over) to the presence of inflammation in the deep structures of the intestinal wall. In the absence of ideal noninvasive methods, endoscopic evaluation in combination with biopsy, histopathological analysis, stool analysis, and blood analysis remains the gold standard for assessing both inflammation and fibrosis in CD. On the contrary, the ability to identify markers of intestinal fibrosis would help to develop new diagnostic and therapeutic methods to detect early stages of fibrosis. It is speculated that miRNAs may, in the future, become biomarkers for early noninvasive diagnosis in the treatment of intestinal fibrosis. The purpose of this review is to summarise existing diagnostic methods for Crohn's disease and present recent scientific reports on molecular testing.
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Affiliation(s)
| | - Jolanta Gruszecka
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
- Department of Clinical Microbiology, Clinical Hospital No. 2, 35-301 Rzeszow, Poland
| | - Rafał Filip
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
- Department of Gastroenterology with IBD Unit, Clinical Hospital No. 2, 35-301 Rzeszow, Poland
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17
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Gonçalves A, Barbeiro S, Leal C, Santos A, Vasconcelos H. Infective Endocarditis After Endoscopic Stricture Dilation in Crohn's Disease. ACG Case Rep J 2024; 11:e01377. [PMID: 38903449 PMCID: PMC11188858 DOI: 10.14309/crj.0000000000001377] [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: 01/20/2024] [Accepted: 05/01/2024] [Indexed: 06/22/2024] Open
Abstract
Stricture formation is common in Crohn's disease, and endoscopic intervention plays an increasingly important role in managing these strictures. A 61-year-old man with biological aortic prosthesis and a 30-year history of ileocolonic stricturing Crohn's disease, managed with azathioprine and infliximab, presented with marked occlusive symptoms. Colonoscopy revealed a descending colon stricture, prompting endoscopic balloon dilation. At the time of the procedure, no prophylactic antibiotic was given. Subsequently, he developed Streptococcus gallolyticus endocarditis, necessitating aortic valve replacement. The authors present a case of late Streptococcus gallolyticus endocarditis associated with endoscopic balloon dilation of a Crohn-related colonic stricture.
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Affiliation(s)
- André Gonçalves
- Department of Gastroenterology, Centro Hospitalar de Leiria, Leiria, Portugal
| | - Sandra Barbeiro
- Department of Gastroenterology, Centro Hospitalar de Leiria, Leiria, Portugal
| | - Carina Leal
- Department of Gastroenterology, Centro Hospitalar de Leiria, Leiria, Portugal
| | - Antonieta Santos
- Department of Gastroenterology, Centro Hospitalar de Leiria, Leiria, Portugal
| | - Helena Vasconcelos
- Department of Gastroenterology, Centro Hospitalar de Leiria, Leiria, Portugal
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18
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Wang X, Li X, Ma X, Zhang L, Han T, Zhang D. Dihydromyricetin alleviates inflammatory bowel disease associated intestinal fibrosis by inducing autophagy through the PI3K/AKT/mTOR signaling pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:4183-4194. [PMID: 38041777 DOI: 10.1007/s00210-023-02856-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/13/2023] [Indexed: 12/03/2023]
Abstract
Intestinal fibrosis is a common complication of inflammatory bowel disease and is characterized by tissue stiffening and luminal narrowing. Dihydromyricetin (DHM) can alleviate liver fibrosis and renal interstitial fibrosis by inducing autophagy. However, whether DHM can alleviate intestinal fibrosis remains unclear. This study is aimed at evaluating the role and mechanism of action of DHM in inflammatory bowel disease-associated intestinal fibrosis. Mice were administered dextran sulfate sodium (DSS) in drinking water to induce inflammatory bowel disease-associated intestinal fibrosis. HE staining, qPCR, and Western blotting were used to analyze colon inflammation. Masson's trichrome staining, qPCR, Western blotting, and immunofluorescence staining were used to evaluate the severity of fibrosis. Transmission electron microscopy and Western blotting were used to assess the activation of autophagosomes. The human colonic fibroblast line CCD-18Co was cultured in the presence of TGF-β1 to develop a fibrotic phenotype. Immunofluorescence staining, Western blotting, and qPCR were used to assess the alteration of fibrosis markers and used to investigate whether DHM-induced autophagy was involved in the inactivation of CCD-18Co cells. Additionally, the role of the PI3K/AKT/mTOR pathway was investigated. DHM alleviated intestinal inflammation and inhibited the progression of intestinal fibrosis. Additionally, DHM induced the activation of autophagy, thereby alleviating intestinal fibrosis, and downregulated the PI3K/AKT/mTOR signaling pathway in vitro. Overall, this study demonstrated that DHM can inhibit the progression of intestinal fibrosis and activation of colonic fibroblasts by inducing autophagy through the PI3K/AKT/mTOR signaling pathway, thereby playing a preventive and therapeutic role in intestinal fibrosis.
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Affiliation(s)
- XiaoChun Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
- Department of Gastroenterology, Gansu Provincial Hospital, Lanzhou, 730000, China
| | - XiaoLi Li
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - XueNi Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - LuDan Zhang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, China
| | - TiYun Han
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, 730000, China
| | - DeKui Zhang
- Key Laboratory of Digestive Diseases, Lanzhou University Second Hospital, Lanzhou, 730000, China.
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, 730000, China.
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19
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Talafha MM, Qasem A, Naser SA. Mycobacterium avium paratuberculosis Infection Suppresses Vitamin D Activation and Cathelicidin Production in Macrophages through Modulation of the TLR2-Dependent p38/MAPK-CYP27B1-VDR-CAMP Axis. Nutrients 2024; 16:1358. [PMID: 38732603 PMCID: PMC11085596 DOI: 10.3390/nu16091358] [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: 03/22/2024] [Revised: 04/27/2024] [Accepted: 04/28/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Vitamin D plays a vital role in modulating both innate and adaptive immune systems. Therefore, vitamin D deficiency has been associated with higher levels of autoimmune response and increased susceptibility to infections. CYP27B1 encodes a member of the cytochrome P450 superfamily of enzymes. It is instrumental in the conversion of circulating vitamin D (calcifediol) to active vitamin D (calcitriol). This is a crucial step for macrophages to express Cathelicidin Anti-microbial Peptide (CAMP), an anti-bacterial factor released during the immune response. Our recent study indicated that a Crohn's disease (CD)-associated pathogen known as Mycobacterium avium paratuberculosis (MAP) decreases vitamin D activation in macrophages, thereby impeding cathelicidin production and MAP infection clearance. The mechanism by which MAP infection exerts these effects on the vitamin D metabolic axis remains elusive. METHODS We used two cell culture models of THP-1 macrophages and Caco-2 monolayers to establish the effects of MAP infection on the vitamin D metabolic axis. We also tested the effects of Calcifediol, Calcitriol, and SB203580 treatments on the relative expression of the vitamin D metabolic genes, oxidative stress biomarkers, and inflammatory cytokines profile. RESULTS In this study, we found that MAP infection interferes with vitamin D activation inside THP-1 macrophages by reducing levels of CYP27B1 and vitamin D receptor (VDR) gene expression via interaction with the TLR2-dependent p38/MAPK pathway. MAP infection exerts its effects in a time-dependent manner, with the maximal inhibition observed at 24 h post-infection. We also demonstrated the necessity to have toll-like receptor 2 (TLR2) for MAP infection to influence CYP27B1 and CAMP expression, as TLR2 gene knockdown resulted in an average increase of 7.78 ± 0.88 and 13.90 ± 3.5 folds in their expression, respectively. MAP infection also clearly decreased the levels of p38 phosphorylation and showed dependency on the p38/MAPK pathway to influence the expression of CYP27B1, VDR, and CAMP which was evident by the average fold increase of 1.93 ± 0.28, 1.86 ± 0.27, and 6.34 ± 0.51 in their expression, respectively, following p38 antagonism. Finally, we showed that calcitriol treatment and p38/MAPK blockade reduce cellular oxidative stress and inflammatory markers in Caco-2 monolayers following macrophage-mediated MAP infection. CONCLUSIONS This study characterized the primary mechanism by which MAP infection leads to diminished levels of active vitamin D and cathelicidin in CD patients, which may explain the exacerbated vitamin D deficiency state in these cases.
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Affiliation(s)
| | | | - Saleh A. Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA; (M.M.T.); (A.Q.)
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20
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Seco-Cervera M, Ortiz-Masiá D, Macias-Ceja DC, Coll S, Gisbert-Ferrándiz L, Cosín-Roger J, Bauset C, Ortega M, Heras-Morán B, Navarro-Vicente F, Millán M, Esplugues JV, Calatayud S, Barrachina MD. Resistance to apoptosis in complicated Crohn's disease: Relevance in ileal fibrosis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166966. [PMID: 37995775 DOI: 10.1016/j.bbadis.2023.166966] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 11/02/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND AND AIMS The stiffening of the extracellular matrix, and changes in its cellular and molecular composition, have been reported in the pathogenesis of fibrosis. We analyze the mechanisms that perpetuate ileal fibrosis in surgical resections of complicated Crohn's disease patients. METHODS Ileal resections were obtained from affected and non-affected tissue of stenotic or penetrating Crohn's disease behavior. Ilea from non-IBD patients were used as control tissue. All samples underwent RNA sequencing. Human small intestinal fibroblasts were treated for 48 h with IL-1β, TFGβ1, PDGFB or TNF-α. Resistance to apoptosis was analysed by RT-PCR, western blot and immunohistochemistry in ileal tissue and by RT-PCR and FACS in cultured cells. RESULTS Growth factor-driven signaling pathways and increased RAS GTPase activity were up-regulated in affected ilea in which we found expression of both the antiapoptotic molecule MCL1 and the transcription factor ETS1 in submucosal fibroblasts, and a senescence-associated secretory phenotype. In cultured intestinal fibroblasts, PDGFB induced an ETS1-mediated resistance to apoptosis that was associated with the induction of both of TGFB1 and IL1B, a cytokine that replicated the expression of SASP detected in ileal tissue. ETS1 drove fibroblast polarization between inflammatory and fibrogenic phenotypes in IL1β-treated cells. CONCLUSIONS Our data show resistance to apoptosis in complicated ileal CD, and demonstrate that PDGFB induce an ETS1-mediated resistance to apoptosis associated with an inflammatory and fibrogenic pattern of expression in intestinal fibroblasts. Results point to PDGFRB, IL1R1 or MCL1 as potential targets against ileal fibrosis.
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Affiliation(s)
- M Seco-Cervera
- Hospital Universitario Dr. Peset, FISABIO, Valencia, Spain.
| | - D Ortiz-Masiá
- Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; Hospital La Fe, Valencia, Spain.
| | - D C Macias-Ceja
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | - S Coll
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | - L Gisbert-Ferrándiz
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | - J Cosín-Roger
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd, Valencia, Spain.
| | - C Bauset
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | - M Ortega
- Departamento de Anatomía Patológica, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | - B Heras-Morán
- Departamento de Anatomía Patológica, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
| | | | - M Millán
- Hospital La Fe, Valencia, Spain.
| | - J V Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd, Valencia, Spain.
| | - S Calatayud
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd, Valencia, Spain.
| | - M D Barrachina
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; CIBERehd, Valencia, Spain.
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21
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Steiner CA, Koch SD, Evanoff T, Welch N, Kostelecky R, Callahan R, Murphy EM, Nguyen TT, Hall CHT, Lu S, de Zoeten EF, Weiser-Evans MCM, Cartwright IM, Colgan SP. The TNF ΔARE Mouse as a Model of Intestinal Fibrosis. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1013-1028. [PMID: 37169343 PMCID: PMC10433691 DOI: 10.1016/j.ajpath.2023.04.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/03/2023] [Accepted: 04/27/2023] [Indexed: 05/13/2023]
Abstract
Crohn disease (CD) is a highly morbid chronic inflammatory disease. Although many patients with CD also develop fibrostenosing complications, there are no medical therapies for intestinal fibrosis. This is due, in part, to a lack of high-fidelity biomimetic models to enhance understanding and drug development, which highlights the need for developing in vivo models of inflammatory bowel disease-related intestinal fibrosis. This study investigates whether the TNFΔARE mouse, a model of ileal inflammation, also develops intestinal fibrosis. Several clinically relevant outcomes were studied, including features of structural fibrosis, histologic fibrosis, and gene expression. These include the use of a new luminal casting technique, traditional histologic outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNFΔARE mice as well as in cohorts of numerous ages. At >24 weeks of age, TNFΔARE mice developed structural, histologic, and transcriptional changes of ileal fibrosis. Protein and RNA expression profiles showed changes as early as 6 weeks, coinciding with histologic changes as early as 14 to 15 weeks. Overt structural fibrosis was delayed until at least 16 weeks and was most developed after 24 weeks. This study found that the TNFΔARE mouse is a viable and highly tractable model of ileal fibrosis. This model and the techniques used herein can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis.
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Affiliation(s)
- Calen A Steiner
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado.
| | - Samuel D Koch
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Tamara Evanoff
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Nichole Welch
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Rachael Kostelecky
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Rosemary Callahan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Emily M Murphy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program and Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado, Aurora, Colorado
| | - Tom T Nguyen
- Mucosal Inflammation Program and Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado, Aurora, Colorado
| | - Caroline H T Hall
- Mucosal Inflammation Program and Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado, Aurora, Colorado
| | - Sizhao Lu
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Edwin F de Zoeten
- Mucosal Inflammation Program and Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children's Hospital Colorado, University of Colorado, Aurora, Colorado
| | - Mary C M Weiser-Evans
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Consortium for Fibrosis Research and Translation, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado; Cardiovascular Pulmonary Research Program, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Ian M Cartwright
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Sean P Colgan
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Mucosal Inflammation Program, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado; Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
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22
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Tavares de Sousa H, Magro F. How to Evaluate Fibrosis in IBD? Diagnostics (Basel) 2023; 13:2188. [PMID: 37443582 DOI: 10.3390/diagnostics13132188] [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: 05/25/2023] [Revised: 06/21/2023] [Accepted: 06/25/2023] [Indexed: 07/15/2023] Open
Abstract
In this review, we will describe the importance of fibrosis in inflammatory bowel disease (IBD) by discussing its distinct impact on Crohn's disease (CD) and ulcerative colitis (UC) through their translation to histopathology. We will address the existing knowledge on the correlation between inflammation and fibrosis and the still not fully explained inflammation-independent fibrogenesis. Finally, we will compile and discuss the recent advances in the noninvasive assessment of intestinal fibrosis, including imaging and biomarkers. Based on the available data, none of the available cross-sectional imaging (CSI) techniques has proved to be capable of measuring CD fibrosis accurately, with MRE showing the most promising performance along with elastography. Very recent research with radiomics showed encouraging results, but further validation with reliable radiomic biomarkers is warranted. Despite the interesting results with micro-RNAs, further advances on the topic of fibrosis biomarkers depend on the development of robust clinical trials based on solid and validated endpoints. We conclude that it seems very likely that radiomics and AI will participate in the future non-invasive fibrosis assessment by CSI techniques in IBD. However, as of today, surgical pathology remains the gold standard for the diagnosis and quantification of intestinal fibrosis in IBD.
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Affiliation(s)
- Helena Tavares de Sousa
- Gastroenterology Department, Algarve University Hospital Center, 8500-338 Portimão, Portugal
- ABC-Algarve Biomedical Center, University of Algarve, 8005-139 Faro, Portugal
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal
- Department of Gastroenterology, São João University Hospital Center, 4200-319 Porto, Portugal
- CINTESIS@RISE, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal
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23
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Jarmakiewicz-Czaja S, Sokal A, Ferenc K, Motyka E, Helma K, Filip R. The Role of Genetic and Epigenetic Regulation in Intestinal Fibrosis in Inflammatory Bowel Disease: A Descending Process or a Programmed Consequence? Genes (Basel) 2023; 14:1167. [PMID: 37372347 DOI: 10.3390/genes14061167] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/24/2023] [Accepted: 05/26/2023] [Indexed: 06/29/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are a group of chronic diseases characterized by recurring periods of exacerbation and remission. Fibrosis of the intestine is one of the most common complications of IBD. Based on current analyses, it is evident that genetic factors and mechanisms, as well as epigenetic factors, play a role in the induction and progression of intestinal fibrosis in IBD. Key genetic factors and mechanisms that appear to be significant include NOD2, TGF-β, TLRs, Il23R, and ATG16L1. Deoxyribonucleic acid (DNA) methylation, histone modification, and ribonucleic acid (RNA) interference are the primary epigenetic mechanisms. Genetic and epigenetic mechanisms, which seem to be important in the pathophysiology and progression of IBD, may potentially be used in targeted therapy in the future. Therefore, the aim of this study was to gather and discuss selected mechanisms and genetic factors, as well as epigenetic factors.
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Affiliation(s)
| | - Aneta Sokal
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Katarzyna Ferenc
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Elżbieta Motyka
- Centre for Innovative Research in Medical and Natural Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Kacper Helma
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
| | - Rafał Filip
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland
- Department of Gastroenterology with IBD, Clinical Hospital No. 2 im. Św. Jadwigi Królowej, 35-301 Rzeszow, Poland
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24
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Scharitzer M, Macher-Beer A, Mang T, Unger LW, Haug A, Reinisch W, Weber M, Nakuz T, Nics L, Hacker M, Bergmann M, Rasul S. Evaluation of Intestinal Fibrosis with 68Ga-FAPI PET/MR Enterography in Crohn Disease. Radiology 2023; 307:e222389. [PMID: 36853176 DOI: 10.1148/radiol.222389] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Background In Crohn disease, differentiation between active intestinal inflammation and fibrosis has implications for treatment, but current imaging modalities are not reliably accurate. Purpose To evaluate the predictive value of gallium 68 (68Ga)-labeled fibroblast activation protein inhibitor (FAPI) PET/MR enterography for the assessment of bowel wall fibrosis in Crohn disease. Materials and Methods In this prospective single-center study, consecutive participants with Crohn disease and obstructive symptoms underwent preoperative 68Ga-FAPI PET/MR enterography from May 2021 to January 2022. Histopathologic analysis of resected bowel segments was performed to grade active inflammation (A0-A2) and fibrosis (F0-F2), which served as the reference standard. The fibroblast activation protein (FAP) expression in bowel wall layers was analyzed immunohistochemically for each layer. 68Ga-FAPI-derived maximum standardized uptake value (SUVmax) was compared with histopathologic results by using mixed-model analysis of variance and Bonferroni-corrected post hoc tests. Results In 14 participants (mean age, 45 years ± 9 [SD]; 10 men), fibrosis was diagnosed histopathologically in 28 of 51 bowel segments (grade F1, n = 14; grade F2, n = 14). Mean SUVmax was higher in segments with fibrosis than without (7.6 vs 2.0; P < .001). In severe fibrosis, mean SUVmax was higher than in mild to moderate fibrosis (8.9 ± 0.9 vs 6.2 ± 0.9; P = .045). Bowel segments with isolated active inflammation had lower mean 68Ga-FAPI uptake than segments with combined active inflammation and fibrosis (SUVmax, 3.2 ± 0.4 vs 8.1 ± 0.1; P = .005). With an SUVmax cutoff value of 3.5, the area under the receiver operating characteristic curve for the prediction of fibrosis was 0.94 (95% CI: 0.9, 1.0), with sensitivity of 26 of 28 segments (93%) and specificity of five of six segments (83%). 68Ga-FAPI-derived SUVmax correlated with FAP expression across all bowel layers (R2 = 0.50, P < .001). Conclusion Higher gallium 68 fibroblast activation protein inhibitor uptake at PET/MR enterography was associated with histopathologically assessed bowel wall fibrosis in participants with Crohn disease, suggesting diagnostic potential for treatment decisions. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by O'Shea in this issue.
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Affiliation(s)
- Martina Scharitzer
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Andrea Macher-Beer
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Thomas Mang
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Lukas W Unger
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Alexander Haug
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Walter Reinisch
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Michael Weber
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Thomas Nakuz
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Lukas Nics
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Marcus Hacker
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Michael Bergmann
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Sazan Rasul
- From the Department of Biomedical Imaging and Image-Guided Therapy (M.S., T.M., A.H., M.W., T.N., L.N., M.H., S.R.), Department of Pathology (A.M.B.), Department of General Surgery, Division of Visceral Surgery and Comprehensive Cancer Center (L.W.U., M.B.), and Department of Medicine III, Division of Gastroenterology and Hepatology (W.R.), Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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25
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Steiner CA, Koch SD, Evanoff T, Welch N, Kostelecky R, Callahan R, Murphy EM, Hall CHT, Lu S, Weiser-Evans MC, Cartwright IM, Colgan SP. The TNF ΔARE mouse as a model of intestinal fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.13.523973. [PMID: 36712048 PMCID: PMC9882211 DOI: 10.1101/2023.01.13.523973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Background & Aims Crohn's disease (CD) is a highly morbid chronic inflammatory disease. The majority of CD patients also develop fibrostenosing complications. Despite this, there are no medical therapies for intestinal fibrosis. This is in part due to lack of high-fidelity biomimetic models to enhance understanding and drug development. There is a need to develop in vivo models of inflammatory bowel disease-related intestinal fibrosis. We sought to determine if the TNF ΔARE mouse, a model of ileal inflammation, may also develop intestinal fibrosis. Methods Several clinically relevant outcomes were studied including features of structural fibrosis, histological fibrosis, and gene expression. These include the use of a luminal casting technique we developed, traditional histological outcomes, use of second harmonic imaging, and quantitative PCR. These features were studied in aged TNF ΔARE mice as well as in cohorts of numerous ages. Results At ages of 24+ weeks, TNF ΔARE mice develop structural, histological, and genetic changes of ileal fibrosis. Genetic expression profiles have changes as early as six weeks, followed by histological changes occurring as early as 14-15 weeks, and overt structural fibrosis delayed until after 24 weeks. Discussion The TNF ΔARE mouse is a viable and highly tractable model of intestinal fibrosis. This model and the techniques employed can be leveraged for both mechanistic studies and therapeutic development for the treatment of intestinal fibrosis.
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26
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Zhang J, Qian X, Yan W, Diao Y, Da B, Shen J, Wang Z, Zhu W. Single-balloon Enteroscopy for Evaluation of Small Bowel Crohn Disease Strictures: Peripheral Blood Lymphocytes As a Risk Factor for Strictures. Surg Laparosc Endosc Percutan Tech 2022; 32:741-746. [PMID: 36468898 DOI: 10.1097/sle.0000000000001117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 10/11/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Few reports have focused on single-balloon enteroscopy (SBE) for evaluation of small bowel Crohn disease (CD) strictures. The aim of this study was to analyze the relationships between peripheral blood inflammatory markers and small bowel CD strictures observed by SBE. MATERIALS AND METHODS CD patients who underwent SBE between January 2016 and December 2020 were enrolled. The clinical characteristics and peripheral blood inflammatory markers were collected and analyzed to screen for predictive factors significantly associated with small bowel CD strictures. RESULTS A total of 221 CD patients underwent SBE. The lymphocyte (LC) counts in peripheral blood were significantly lower in the active group (n=178) than in the inactive group (n=43) according to the simple endoscopic score for CD (SES-CD), P =0.011, and was correlated with the SES-CD ( r =-0.134, P =0.047). The LC levels were significantly lower in the stricture group (n=116) than in the nonstricture group (n=105) based on whether small bowel strictures developed, P =0.000, and LC was a risk factor for strictures in the multivariate analysis [hazard ratio (HR), 2.332; 95% CI, 1.102-4.937; P =0.027]. In the subgroup analysis, LC levels notably decreased after stricture aggravation ( P =0.000). Forty-seven patients who underwent small bowel resection underwent SBE at 6 to 12 months after surgery. The LC level was significantly lower in the postoperative patients with strictures ( P =0.025), and LC (HR, 4.444; 95% CI, 1.265-15.617; P =0.020) was a risk of postoperative strictures by univariate analysis, but the age at diagnosis (HR, 6.462; 95% CI, 1.272-22.560; P =0.022) was an independent risk factor by multivariate analysis. CONCLUSION Peripheral blood LC levels were correlated with SES-CD and gradually decreased as the intestinal stricture increased in small bowel CD patients. The LC level was also significantly lower in the postoperative CD patients with strictures. The level of LC was a risk factor for small bowel strictures. These results suggest that peripheral blood LC could be a novel marker of small bowel CD strictures to guide CD diagnosis and therapy.
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Affiliation(s)
| | - Xiaoli Qian
- Research Institute of General Surgery, Jinling Hospital
| | - Wei Yan
- Research Institute of General Surgery, Jinling Hospital
| | - Yanqing Diao
- Research Institute of General Surgery, Jinling Hospital
| | - Binlin Da
- Research Institute of General Surgery, Jinling Hospital
| | | | - Zhiming Wang
- Research Institute of General Surgery, Jinling Hospital
| | - Weiming Zhu
- Research Institute of General Surgery, Jinling Hospital
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27
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El Ouali S, Baker ME, Lyu R, Fletcher JG, Bruining DH, Holubar SD, Click B, Qazi T, Cohen BL, Rieder F, Stenosis Therapy and Anti‐Fibrotic Research (STAR) Consortium. Validation of stricture length, duration and obstructive symptoms as predictors for intervention in ileal stricturing Crohn's disease. United European Gastroenterol J 2022; 10:958-972. [PMID: 36479841 PMCID: PMC9731662 DOI: 10.1002/ueg2.12314] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 09/10/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Risk factors for intervention in terminal ileal (TI) stricturing Crohn's disease (CD) are poorly defined. Novel and rigorous definitions for TI strictures recently became available. OBJECTIVE We aimed to describe the rates of symptoms or need for endoscopic balloon dilation (EBD) or surgery as well as risk factors of progression in a well-defined stricturing CD cohort. METHODS Consecutive adult patients with non-penetrating stricturing TI CD, as defined by centrally-read magnetic resonance enterography CONSTRICT criteria, were separated into a derivation and validation cohort. Clinical and imaging characteristics were collected following prespecified scoring conventions. Primary outcome was a composite endpoint of EBD or surgery ("intervention"). Multivariable analysis was performed. RESULTS Eighty-six patients (48.8% female, median age 36 years) met selection criteria, 17.4% had prior EBD, 59.3% previously received biologics and 58.1% of strictures were anastomotic. Median follow-up was 63.4 [95% CI: 57, 68.9] months. In the derivation cohort, at 12 and 48 months, 26% and 45% of patients had intervention, respectively. Multivariable analysis showed obstructive symptoms (Hazard ratio [HR] 1.444; 95% CI 1.126-1.852), stricture duration (HR 0.974; 95% CI, 0.954-0.995) and length (HR 1.039; 95% CI, 1.011-1.069) predicted intervention. The concordance index for split-sample validation was 0.74 and 0.67, respectively. Biologics were not associated with intervention. An online risk calculator was constructed. CONCLUSION In patients with TI stricturing CD, 26% and 45% required intervention at 1 and 4 years. Obstructive symptoms, stricture duration and length were independent and validated predictors of the need for intervention. These findings are important for clinical practice and aid in the design of future trials for CD strictures.
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Affiliation(s)
- Sara El Ouali
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery InstituteCleveland Clinic FoundationClevelandOhioUSA
- Digestive Disease InstituteCleveland ClinicAbu DhabiUAE
| | | | - Ruishen Lyu
- Department of Quantitative Health SciencesCleveland ClinicClevelandOhioUSA
| | | | - David H. Bruining
- Department of Gastroenterology & HepatologyMayo ClinicRochesterMinnesotaUSA
| | - Stefan D. Holubar
- Department of Colorectal SurgeryDigestive Diseases and Surgery InstituteCleveland Clinic FoundationClevelandOhioUSA
| | - Benjamin Click
- Division of Gastroenterology and HepatologyUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Taha Qazi
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery InstituteCleveland Clinic FoundationClevelandOhioUSA
- Digestive Disease InstituteCleveland ClinicAbu DhabiUAE
| | - Benjamin L. Cohen
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery InstituteCleveland Clinic FoundationClevelandOhioUSA
- Digestive Disease InstituteCleveland ClinicAbu DhabiUAE
| | - Florian Rieder
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery InstituteCleveland Clinic FoundationClevelandOhioUSA
- Digestive Disease InstituteCleveland ClinicAbu DhabiUAE
- Department of Inflammation and ImmunityLerner Research InstituteCleveland Clinic FoundationClevelandOhioUSA
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28
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Lin X, Wang Y, Liu Z, Lin S, Tan J, He J, Hu F, Wu X, Ghosh S, Chen M, Liu F, Mao R. Intestinal strictures in Crohn's disease: a 2021 update. Therap Adv Gastroenterol 2022; 15:17562848221104951. [PMID: 35757383 PMCID: PMC9218441 DOI: 10.1177/17562848221104951] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 05/17/2022] [Indexed: 02/04/2023] Open
Abstract
Intestinal strictures remain one of the most intractable and common complications of Crohn's disease (CD). Approximately 70% of CD patients will develop fibrotic strictures after 10 years of CD diagnosis. Since specific antifibrotic therapies are unavailable, endoscopic balloon dilation and surgery remain the mainstay treatments despite a high recurrence rate. Besides, there are no reliable methods for accurately evaluating intestinal fibrosis. This is largely due to the fact that the mechanisms of initiation and propagation of intestinal fibrosis are poorly understood. There is growing evidence implying that the pathogenesis of stricturing CD involves the intricate interplay of factors including aberrant immune and nonimmune responses, host-microbiome dysbiosis, and genetic susceptibility. Currently, the progress on intestinal strictures has been fueled by the advent of novel techniques, such as single-cell sequencing, multi-omics, and artificial intelligence. Here, we perform a timely and comprehensive review of the substantial advances in intestinal strictures in 2021, aiming to provide prompt information regarding fibrosis and set the stage for the improvement of diagnosis, treatment, and prognosis of intestinal strictures.
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Affiliation(s)
- Xiaoxuan Lin
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yu Wang
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zishan Liu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Sinan Lin
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinyu Tan
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jinshen He
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fan Hu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaomin Wu
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Subrata Ghosh
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fen Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2nd, Guangzhou 510080, People’s Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2nd, Guangzhou 510080, People’s Republic of China
- Department of Gastroenterology, Huidong People’s Hospital, Huizhou 516399, China
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29
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Kataria J, Kerr J, Lourenssen SR, Blennerhassett MG. Nintedanib regulates intestinal smooth muscle hyperplasia and phenotype in vitro and in TNBS colitis in vivo. Sci Rep 2022; 12:10275. [PMID: 35715562 PMCID: PMC9206006 DOI: 10.1038/s41598-022-14491-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 06/08/2022] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammation of the human intestine in Crohn’s disease (CD) causes bowel wall thickening, which typically progresses to stricturing and a recurrent need for surgery. Current therapies have limited success and CD remains idiopathic and incurable. Recent evidence shows a key role of intestinal smooth muscle cell (ISMC) hyperplasia in stricturing, which is not targeted by current anti-inflammatory therapeutics. However, progression of idiopathic pulmonary fibrosis, resembling CD in pathophysiology, is controlled by the tyrosine kinase inhibitors nintedanib (NIN) or pirfenidone, and we investigated these drugs for their effect on ISMC. In a culture model of rat ISMC, NIN inhibited serum- and PDGF-BB-stimulated growth and cell migration, and promoted the differentiated phenotype, while increasing secreted collagen. NIN did not affect signaling through PDGF-Rβ or NFκB but did inhibit cytokine-induced expression of the pro-inflammatory cytokines IL-1β and TNFα, supporting a transcriptional level of control. In TNBS-induced colitis in mice, which resembles CD, NIN decreased ISMC hyperplasia as well as expression of TNFα and IL-1β, without effect in control animals. NIN also inhibited growth of human ISMC in response to human serum or PDGF-BB, which further establishes a broad range of actions of NIN that support further trial in human IBD.
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Affiliation(s)
- Jay Kataria
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada
| | - Jack Kerr
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada
| | - Sandra R Lourenssen
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada
| | - Michael G Blennerhassett
- Gastrointestinal Diseases Research Unit, Department of Medicine, GIDRU Wing, Kingston General Hospital, Queen's University, Kingston, ON, K7L 2V7, Canada.
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Fousekis FS, Mitselos IV, Tepelenis K, Pappas-Gogos G, Katsanos KH, Lianos GD, Frattini F, Vlachos K, Christodoulou DK. Medical, Endoscopic and Surgical Management of Stricturing Crohn's Disease: Current Clinical Practice. J Clin Med 2022; 11:2366. [PMID: 35566492 PMCID: PMC9104530 DOI: 10.3390/jcm11092366] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/12/2022] [Accepted: 04/20/2022] [Indexed: 12/10/2022] Open
Abstract
The development of fibrostenotic intestinal disease occurs in approximately one-third of patients with Crohn's disease and is associated with increased morbidity. Despite introducing new biologic agents, stricturing Crohn's disease remains a significant clinical challenge. Medical treatment is considered the first-line treatment for inflammatory strictures, and anti-TNF agents appear to provide the most considerable benefit among the available medical treatments. However, medical therapy is ineffective on strictures with a mainly fibrotic component, and a high proportion of patients under anti-TNF will require surgery. In fibrotic strictures or cases refractory to medical treatment, an endoscopic or surgical approach should be considered depending on the location, length, and severity of the stricture. Both endoscopic balloon dilatation and endoscopic stricturoplasty are minimally invasive and safe, associated with a small risk of complications. On the other hand, the surgical approach is indicated in patients not suitable for endoscopic therapy. This review aimed to present and analyze the currently available medical, endoscopic, and surgical management of stricturing Crohn's disease.
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Affiliation(s)
- Fotios S. Fousekis
- Department of Gastroenterology and Hepatology, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (F.S.F.); (I.V.M.); (K.H.K.)
| | - Ioannis V. Mitselos
- Department of Gastroenterology and Hepatology, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (F.S.F.); (I.V.M.); (K.H.K.)
| | - Kostas Tepelenis
- Department of Surgery, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (K.T.); (G.P.-G.); (G.D.L.); (K.V.)
| | - George Pappas-Gogos
- Department of Surgery, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (K.T.); (G.P.-G.); (G.D.L.); (K.V.)
| | - Konstantinos H. Katsanos
- Department of Gastroenterology and Hepatology, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (F.S.F.); (I.V.M.); (K.H.K.)
| | - Georgios D. Lianos
- Department of Surgery, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (K.T.); (G.P.-G.); (G.D.L.); (K.V.)
| | | | - Konstantinos Vlachos
- Department of Surgery, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (K.T.); (G.P.-G.); (G.D.L.); (K.V.)
| | - Dimitrios K. Christodoulou
- Department of Gastroenterology and Hepatology, University Hospital of Ioannina, University of Ioannina, 45110 Ioannina, Greece; (F.S.F.); (I.V.M.); (K.H.K.)
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31
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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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