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Hisamatsu T, Kobayashi T, Motoya S, Fujii T, Kunisaki R, Shibuya T, Matsuura M, Hiraoka S, Takeuchi K, Yasuda H, Yokoyama K, Takatsu N, Maemoto A, Tahara T, Tominaga K, Shimada M, Kuno N, Fernandez JL, Hirose L, Ishiguro K, Cavaliere M, Hibi T. Real-World Effectiveness and Safety of Vedolizumab in Patients ≥ 70 Versus < 70 Years With Ulcerative Colitis: Multicenter Retrospective Study. J Gastroenterol Hepatol 2025. [PMID: 40370285 DOI: 10.1111/jgh.16936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 01/31/2025] [Accepted: 03/01/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND AND AIM Vedolizumab (VDZ) is often used in older patients with ulcerative colitis (UC) in clinical practice; however, real-world evidence is still limited, including in those with late-onset UC. METHODS This post hoc analysis of a multicenter, retrospective, observational chart review, enrolling 370 patients with UC receiving VDZ between December 2018 and February 2020, compared effectiveness and safety of VDZ among patients ≥ 70 (n = 40) versus < 70 years (n = 330), and among patients ≥ 70 years with and without late-onset UC (age at disease onset: ≥ 70 [n = 13] versus < 70 years [n = 26]). RESULTS There were no differences between patients ≥ 70 and < 70 years in clinical remission rates (week 6: 57.5% vs. 47.6%, p = 0.9174; week 14: 62.5% vs. 54.8%, p = 0.1317; week 54: 47.5% vs. 46.4%, p = 0.8149), primary nonresponse (10.0% vs. 15.5%, p = 0.6248), loss of response (12.5% vs. 9.4%, p = 0.5675), or overall safety. Among patients ≥ 70 years, the incidence of adverse drug reactions was numerically greater in those with concomitant corticosteroids than in those without. For older patients with and without late-onset UC, week 54 remission rates were 23.1% versus 57.7% (p = 0.0544); surgery was reported in 3/13 versus 2/26 patients and hospitalization in 5/13 versus 6/26 patients. One death was reported in patients with late-onset UC. CONCLUSIONS VDZ effectiveness and safety were similar in patients ≥ 70 and < 70 years; VDZ may be a suitable treatment option for patients ≥ 70 years with UC. Patients with late-onset UC tended to have more frequent surgery/hospitalization and lower effectiveness than those without, possibly necessitating greater caution when using VDZ. TRIAL REGISTRATION Japanese Registry of Clinical Trials registration number: jRCT-1080225363.
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Affiliation(s)
- Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Satoshi Motoya
- Inflammatory Bowel Disease Center, Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Institute of Science Tokyo, Tokyo, Japan
| | - Reiko Kunisaki
- Inflammatory Bowel Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Okayama, Japan
| | - Ken Takeuchi
- Department of Gastroenterology and Hepatology, IBD Center, Tsujinaka Hospital Kashiwanoha, Kashiwa, Chiba, Japan
| | - Hiroshi Yasuda
- Department of Gastroenterology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kaoru Yokoyama
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Noritaka Takatsu
- Inflammatory Bowel Disease Center, Fukuoka University Chikushi Hospital, Chikushino, Fukuoka, Japan
| | - Atsuo Maemoto
- Inflammatory Bowel Disease Center, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
| | - Toshiyuki Tahara
- Department of Gastroenterology, Saiseikai Utsunomiya Hospital, Utsunomiya, Tochigi, Japan
| | - Keiichi Tominaga
- Department of Gastroenterology, Dokkyo Medical University, Mibu, Tochigi, Japan
| | - Masaaki Shimada
- Department of Gastroenterology, NHO Nagoya Medical Center, Nagoya, Japan
| | - Nobuaki Kuno
- Department of Gastroenterology and Medicine, Fukuoka University Hospital, Fukuoka, Japan
| | | | - Lisa Hirose
- Japan Medical Office, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Kaori Ishiguro
- Japan Medical Office, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Mary Cavaliere
- Japan Medical Office, Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
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Armuzzi A, Vermeire S, Chaparro M, Biedermann P, Brown R, McStravick M, Meyer M, Schreiber S. Effectiveness and Treatment Persistence of Vedolizumab Compared to Anti-Tumour Necrosis Factor-α in Patients With Crohn's Disease: A Systematic Literature Review and Meta-Analysis. United European Gastroenterol J 2025; 13:552-565. [PMID: 39707930 PMCID: PMC12090838 DOI: 10.1002/ueg2.12705] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 05/14/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Vedolizumab is approved for the treatment of moderately to severely active Crohn's disease (CD). Real-world evidence is essential for understanding the effectiveness and benefit-risk profile of vedolizumab outside clinical trial settings. OBJECTIVE To identify, systematically review and assess the real-world effectiveness and treatment persistence of vedolizumab in patients with CD, particularly over long-term follow-up periods and among populations with differing treatment experience, and to compare with the treatment persistence of anti-tumour necrosis factor (TNF)-α treatment. METHODS Literature searches were conducted to identify studies published from 2014 to 2022. Relevant congress searches were conducted (2015-2022) using Embase or by hand. Data on adults with CD treated with vedolizumab or anti-TNFα treatment in a real-world setting were extracted for meta-analysis. RESULTS Data from 73 studies, including 29,894 patients with CD, reported ≥ 1 outcome of interest for this analysis. Vedolizumab treatment persistence rate was 65.3% (95% confidence interval [CI] 60.2-70.1) at 1 year and 54.8% (95% CI 43.9-65.3) at 2 years. The treatment persistence rate with vedolizumab versus anti-TNFα treatment was 84.6% (95% CI 70.2-92.8) versus 75.3% (95% CI 69.7-80.2) at 1 year and 70.6% (95% CI 60.7-78.8) versus 64.6% (95% CI 56.7-71.8) at 2 years. The mucosal healing rate at 1 year was 40.6% (95% CI 34.2-47.3). Clinical remission rates were 39.4% (95% CI 33.9-45.1) at 1 year and 34.3% (95% CI 18.1-55.2) at 2 years. Corticosteroid-free clinical remission rates were 33.2% (95% CI 28.5-38.3) at 1 year and 20.4% (95% CI 12.5-31.5) at 2 years. All clinical outcome rates were higher in biologic-naive than in biologic-experienced patients. CONCLUSION Real-world use of vedolizumab was associated with favourable long-term effectiveness and treatment persistence. Vedolizumab is a suitable first-line biological option for biologic-naive patients with CD.
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Affiliation(s)
- Alessandro Armuzzi
- IBD CenterIRCCS Humanitas Research HospitalRozzano, MilanItaly
- Department of Biomedical SciencesHumanitas UniversityPieve Emanuele, MilanItaly
| | - Séverine Vermeire
- Department of Gastroenterology and HepatologyUniversity Hospital LeuvenLeuvenBelgium
| | - María Chaparro
- Department of GastroenterologyHospital Universitario de La PrincesaInstituto de Investigación Sanitaria Princesa (IIS‐Princesa)Universidad Autónoma de MadridMadridSpain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)MadridSpain
| | - Patricia Biedermann
- Global Medical EvidenceTakeda Pharmaceuticals International AGZurichSwitzerland
| | - Rebecca Brown
- Market Access DepartmentPutnam AssociatesNewcastle upon TyneUK
| | - Megan McStravick
- Real‐World Evidence & Biostatistics DepartmentPutnam AssociatesNewcastle upon TyneUK
| | | | - Stefan Schreiber
- Institute of Clinical Molecular Biology and Clinic for Internal MedicineKiel UniversityKielGermany
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Chen M, Gao X, Cao Q, Rossiter G, Kitagawa T, Sun Y, Yang L. Efficacy and safety of intravenous vedolizumab treatment in Chinese patients with moderate-to-severe Crohn's disease. Clin Res Hepatol Gastroenterol 2025; 49:102591. [PMID: 40228712 DOI: 10.1016/j.clinre.2025.102591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 03/24/2025] [Accepted: 03/31/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND & AIMS Vedolizumab is a gut-selective monoclonal anti-α4β7 integrin antibody treatment for Crohn's disease (CD). A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (NCT03234907) assessed vedolizumab efficacy and safety in Chinese patients with moderate-to-severe CD and inadequate/loss of response/intolerance to previous conventional or anti-tumor necrosis factor-α therapy. METHODS Eligible patients aged ≥18 to ≤80 years with moderate-to-severe CD (CD Activity Index [CDAI] total score 220-400) were randomized 2:1 to vedolizumab 300 mg intravenous infusion or placebo at Weeks 0, 2, 6 of induction, and every 4/8 weeks during Week 14-58 maintenance treatment. Primary and secondary endpoints at Week 10 were enhanced clinical response (≥100-point decrease from baseline CDAI score), and clinical remission (CDAI score ≤150), respectively. Additional Week 10 and/or Week 60 assessments included endoscopic and biomarker (C-reactive protein and fecal calprotectin) measurements. RESULTS The study was conducted at 30 centers (August 2017 through August 2020). Enrolled patients (n = 215) were randomized to vedolizumab (n = 144) or placebo (n = 71). By Week 10, 19.4 % vedolizumab-treated versus 24.3 % placebo-treated patients achieved an enhanced clinical response. The Cui-Hung-Wang-adjusted p-value for the primary endpoint was 0.347. After maintenance treatment at Week 60, rates of enhanced clinical response, clinical remission, endoscopic response, mucosal healing, and biomarker improvements appeared greater for vedolizumab-treated than placebo-treated patients. CONCLUSIONS There were no new safety findings for vedolizumab treatment of Chinese patients with CD. Although the primary endpoint was not met, vedolizumab-treated patients showed improvements in other disease activity measures at Weeks 10 and 60.
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Affiliation(s)
- Minhu Chen
- The First Affiliated Hospital, Sun Yat-sen University, Guangdong, PR China
| | - Xiang Gao
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, PR China
| | - Qian Cao
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, PR China
| | | | | | - Yue Sun
- Takeda APAC Biopharmaceutical Research and Development Company Limited, Beijing, PR China
| | - Lili Yang
- Takeda Development Center Americas Inc., Cambridge, MA, USA
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Zhang Y, Li L, Kong J, Long Y, Lu X, Erb CJ, Miao Y, Kammula SV, Popov J, Tinana AJ, Selaru FM, Mao HQ. Long-acting injectable nanoparticle formulation for sustained release of anti-TNF-α antibody therapeutic in ulcerative colitis treatment. J Control Release 2025; 380:1005-1016. [PMID: 39978474 DOI: 10.1016/j.jconrel.2025.02.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 12/16/2024] [Accepted: 02/18/2025] [Indexed: 02/22/2025]
Abstract
Inflammatory bowel diseases (IBD) are chronic, remitting, and relapsing conditions of the gastrointestinal tract with incompletely elucidated etiology. The anti-TNF-α mAbs represent one of aflash nanocomplexation and flash nanoprecipitation process, resulting in particles with a narrow size distribution and tunable release profile, with the longest in vitro release lasting over four months. These mAb-releasing NPs are then incorporated into hyaluronic acid hydrogel microparticles (MPs) to enhance tissue retention, thus extending the duration of mAb release in vivo. A single i.m. injection of the LAI can maintain the serum mAb level above the therapeutically effective concentration for over 100 days in healthy mice. In a 9-week study using a dextran sulfate-induced chronic colitis model, the anti-TNF-α LAI formulation demonstrates substantial therapeutic efficacy and a better safety profile than free mAb injections. This work demonstrates the effectiveness of this LAI system in maintaining a persistent serum mAb level and its potential as a versatile, safer, and effective delivery system for antibody therapeutics.
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Affiliation(s)
- Yicheng Zhang
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Ling Li
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Jiayuan Kong
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Yuanmuhuang Long
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Xiaoya Lu
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Christopher J Erb
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Yurun Miao
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA
| | - Sachin V Kammula
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Jordan Popov
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Alexander J Tinana
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA
| | - Florin M Selaru
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
| | - Hai-Quan Mao
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Whiting School of Engineering and School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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5
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Chauhan G, Rieder F. The Pathogenesis of Inflammatory Bowel Diseases. Surg Clin North Am 2025; 105:201-215. [PMID: 40015812 PMCID: PMC11868724 DOI: 10.1016/j.suc.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2025]
Abstract
Inflammatory bowel diseases (IBDs) are relapsing, remitting inflammatory diseases of the intestinal tract. Familial aggregation and genome-wide association studies revealed susceptibility variants that point toward a combination of innate immune and adaptive immune dysregulation that in concert with environmental factors, such as our microbiome, can initiate and perpetuate inflammation. Innate immune perturbations include functional abnormalities in the intestinal barrier, endoplasmic reticulum stress, and abnormal recognition of microbes. Adaptive immune changes include dysregulation of cytokines, regulatory T cells, and leukocyte migration. IBD is linked with an abnormal wound-healing response leading to fibrosis. This article summarizes key pathogenic mechanisms in the pathogenesis of IBDs.
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Affiliation(s)
- Gaurav Chauhan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases Institute; Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
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6
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Hegazy AN. Reply. Gastroenterology 2025:S0016-5085(25)00544-X. [PMID: 40158740 DOI: 10.1053/j.gastro.2025.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025]
Affiliation(s)
- Ahmed N Hegazy
- Department of Gastroenterology, Infectious Diseases, and Rheumatology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, Institut der Leibniz-Gemeinschaft, Berlin, Germany
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7
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Horn V, Cancino CA, Steinheuer LM, Obermayer B, Fritz K, Nguyen AL, Juhran KS, Plattner C, Bösel D, Oldenburg L, Burns M, Schulz AR, Saliutina M, Mantzivi E, Lissner D, Conrad T, Mashreghi MF, Zundler S, Sonnenberg E, Schumann M, Haag LM, Beule D, Flatz L, Trajanoski Z, D'Haens G, Weidinger C, Mei HE, Siegmund B, Thurley K, Hegazy AN. Multimodal Profiling of Peripheral Blood Identifies Proliferating Circulating Effector CD4 + T Cells as Predictors for Response to Integrin α4β7-Blocking Therapy in Inflammatory Bowel Disease. Gastroenterology 2025; 168:327-343. [PMID: 39343250 DOI: 10.1053/j.gastro.2024.09.021] [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: 12/19/2023] [Revised: 09/06/2024] [Accepted: 09/18/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND & AIMS Despite the success of biological therapies in treating inflammatory bowel disease, managing patients remains challenging due to the absence of reliable predictors of therapy response. METHODS In this study, we prospectively sampled 2 cohorts of patients with inflammatory bowel disease receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry; single-cell RNA sequencing; single-cell B and T cell receptor sequencing (BCR/TCR-seq); serum proteomics; and multiparametric flow cytometry to comprehensively assess vedolizumab-induced immunologic changes in the peripheral blood and their potential associations with treatment response. RESULTS Vedolizumab treatment led to substantial alterations in the abundance of circulating immune cell lineages and modified the T-cell receptor diversity of gut-homing CD4+ memory T cells. Through integration of multimodal parameters and machine learning, we identified a significant increase in proliferating CD4+ memory T cells among nonresponders before treatment compared with responders. This predictive T-cell signature demonstrated an activated T-helper 1/T-helper 17 cell phenotype and exhibited elevated levels of integrin α4β1, potentially making these cells less susceptible to direct targeting by vedolizumab. CONCLUSIONS These findings provide a reliable predictive classifier with significant implications for personalized inflammatory bowel disease management.
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Affiliation(s)
- Veronika Horn
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Camila A Cancino
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lisa M Steinheuer
- Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany
| | - Benedikt Obermayer
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Konstantin Fritz
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Anke L Nguyen
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Department of Gastroenterology, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia
| | - Kim Susan Juhran
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Christina Plattner
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Diana Bösel
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Lotte Oldenburg
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marie Burns
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Axel Ronald Schulz
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Mariia Saliutina
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Eleni Mantzivi
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Donata Lissner
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Thomas Conrad
- Genomics Technology Platform, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany; Core Unit Genomics, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Mir-Farzin Mashreghi
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, Berlin, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Elena Sonnenberg
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Michael Schumann
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Lea-Maxie Haag
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Dieter Beule
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Dermatology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany
| | - Zlatko Trajanoski
- Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
| | - Geert D'Haens
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Carl Weidinger
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Henrik E Mei
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany
| | - Britta Siegmund
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany
| | - Kevin Thurley
- Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Institute of Experimental Oncology, Biomathematics Division, University Hospital Bonn, Bonn, Germany.
| | - Ahmed N Hegazy
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Berlin, Germany; Deutsches Rheuma-Forschungszentrum, ein Institut der Leibniz-Gemeinschaft, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin Institute of Health Academy, Clinician Scientist Program, Berlin, Germany.
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Silva R, de Azevedo JN, Machado JP, Rodrigues JM. Placebo-Controlled Trials in the Management of Crohn's Disease: An Umbrella Review of Meta-Analyses. Med Sci (Basel) 2025; 13:12. [PMID: 39982236 PMCID: PMC11843887 DOI: 10.3390/medsci13010012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/22/2025] [Accepted: 01/27/2025] [Indexed: 02/22/2025] Open
Abstract
INTRODUCTION Crohn's disease is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, and other symptoms. It can lead to significant complications and impact patients' quality of life. Therefore, effective management strategies are essential for improving outcomes. METHODS To assess the efficacy of the treatments for Crohn's disease, this umbrella review systematically addresses systematic reviews and meta-analyses on Crohn's disease management published between 2013 and 2023. The quality of the included studies was assessed using the National Institutes of Health's quality assessment tool. RESULTS Sixteen studies were included, evaluating various interventions for the induction and maintenance of remission. These included biologic agents (anti-TNF agents, anti-IL-12/23p40 antibodies, and integrin receptor antagonists), antimetabolites, and corticosteroids. CONCLUSIONS The findings suggest that biologic agents may be promising options for both the induction and maintenance of remission in Crohn's disease. Antimetabolites and corticosteroids may be effective in certain cases, but their efficacy and safety profiles require further investigation. The included studies varied in quality and sample size. More research is needed to confirm the findings and establish optimal treatment strategies. Moreover, while biologic agents show promise, the optimal management of Crohn's disease requires further research. A personalized approach considering patient factors and disease characteristics is crucial for optimizing outcomes.
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Affiliation(s)
- Richard Silva
- Clínica Médica Dr. Richard, 3700-317 São João da Madeira, Portugal
| | | | - Jorge Pereira Machado
- ICBAS, School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
- CBSin—Center of BioSciences in Integrative Health, 4000-105 Porto, Portugal
| | - Jorge Magalhães Rodrigues
- ICBAS, School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
- CBSin—Center of BioSciences in Integrative Health, 4000-105 Porto, Portugal
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9
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Su H, Xiao S, Liang Z, Xun T, Zhang J, Yang X. Systematic review and bayesian network meta-analysis: comparative efficacy and safety of six commonly used biologic therapies for moderate-to-severe Crohn's disease. Front Pharmacol 2025; 15:1475222. [PMID: 39911832 PMCID: PMC11794990 DOI: 10.3389/fphar.2024.1475222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/10/2024] [Indexed: 02/07/2025] Open
Abstract
Background In contrast to previous network meta-analysis using classical frequentist methods, we evaluated the efficacy and safety of six frequently-used biologics through a Bayesian method. Methods Web of Science, Scopus, CENTRAL, ClinicalTrials.gov and ICTRP were searched to collect randomized controlled trials (RCTs) in adults with moderate-to-severe Crohn's disease, comparing Infliximab, Adalimumab, Certolizumab pegol, Ustekinumab, Risankizumab, or Vedolizumab, relative to placebo or an active comparator for induction of clinical response (two different definitions) and maintenance of clinical remission. A random-effects model was performed with rankings according to the surface under cumulative ranking curve (SUCRA) probability. Finally, we completed sensitivity and consistency analyses, and evaluated the certainty of evidence through GRADE working group guidance. Results We identified 22 and 20 RCTs for induction and maintenance therapy, respectively. Infliximab combined with azathioprine was most effective for inducing clinical response in TNF (tumor necrosis factor) antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab (SUCRA 86.19) and Risankizumab (SUCRA 62.56) have the largest SUCRA in induction of clinical response. Risankizumab has the lowest risk of adverse events (SUCRA 84.81), serious adverse events (SUCRA 94.23), and serious infections (SUCRA 79.73) in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab rank highest for maintaining clinical remission. Conclusion This analysis suggests that Infliximab in combination with azathioprine may be preferred biologic agents for induction therapy in TNF antagonist-naïve patients. For TNF antagonist-experienced patients, Ustekinumab and Risankizumab may be preferred biologic agents for induction therapy. Risankizumab potentially has the lowest safety risk worth exploring in induction therapy. Adalimumab and the 10 mg/kg regimen of Infliximab have maintenance efficacy benefits for responders to induction therapy. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=458609, Identifier CRD42023458609.
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Affiliation(s)
- Haohang Su
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Shengwei Xiao
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Zhiqing Liang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China
| | - Tianrong Xun
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Jinfang Zhang
- Cancer Center, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, China
- Shenzhen Traditional Chinese Medicine Oncology Medical Center, Shenzhen, China
| | - Xixiao Yang
- Department of Pharmacy, Shenzhen Hospital, Southern Medical University, Shenzhen, China
- Shenzhen Clinical Research Center for Digestive Disease, Shenzhen, China
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10
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Chen J, Takanami Y, Jansson J, Rossiter G. Practical considerations of promising zone design for interim sample size Re-estimation: An application to GRAPHITE for graft vs host disease. Contemp Clin Trials 2025; 148:107765. [PMID: 39603384 DOI: 10.1016/j.cct.2024.107765] [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: 09/06/2024] [Revised: 11/07/2024] [Accepted: 11/23/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Sample size calculation and power estimate are an integral part of clinical trials. With accelerated development to address the unmet medical needs, the fast-paced development may lead to uncertainties in initial planning and assumptions of clinical trials. Promising zone design presents sponsors an opportunity to re-estimate the sample size based on the interim data to mitigate risks, reduce uncertainties, and increase probability of trial success. METHODS This paper aims to use the GRAPHITE trial (NCT03657160) as a real data application to showcase the practical considerations in implementation of promising zone design for interim sample size re-estimation (SSR), in light of sample size adaptation rules, maximum sample size allowed, multiplicity adjustment, and sponsor access to interim results. GRAPHITE is a phase 3 trial with vedolizumab for prophylaxis of acute graft vs host disease (aGvHD) after allogeneic hematopoietic stem cell transplant (allo-HSCT). The primary efficacy endpoint is lower intestinal aGVHD-free survival by Day +180 after allo-HSCT. A simulation study was conducted to demonstrate the evaluation of operating characteristics by various true underlying treatment effects at the design stage. CONCLUSION The application of promising zone design for interim SSR is novel and has successfully helped the sponsor achieve the balance between minimizing the risks and maintaining scientific integrity. This work aims to highlight the necessity of empirical guidance to gain better insights for clinical researchers in practice and is expected to facilitate the understanding and implementation of promising zone design for interim SSR in phase 3 trials.
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Affiliation(s)
- Jingjing Chen
- Takeda Development Center Americas, Inc., Cambridge, MA, USA.
| | | | - Johan Jansson
- Takeda Development Center Americas, Inc., Cambridge, MA, USA
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11
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Trentadue G, Kats-Ugurlu G, Blokzijl T, Haveman JW, Faber KN, Dijkstra G. Chronic Allograft Enteropathy Treated with Vedolizumab: A Case Report. Transplant Proc 2025; 57:148-155. [PMID: 39638713 DOI: 10.1016/j.transproceed.2024.11.021] [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: 04/17/2024] [Revised: 05/10/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION The most common cause of late graft loss in intestinal transplantation is chronic allograft enteropathy (CAE). The diagnosis is often delayed because of late symptoms and signs, and the only available treatment is graft enterectomy. We present the first case of CAE successfully treated with a gut-specific integrin blocker. CASE REPORT We present a patient who developed CAE 15 years after transplantation and was treated with vedolizumab, a gut-specific integrin blocker that is used for inflammatory bowel disease, thereby avoiding complete graft resection. We show the clinical, endoscopic, radiological, serological, and histopathological course of CAE beginning with discovery of the first signs of disease until 15 months after the start of vedolizumab treatment. CONCLUSION To our knowledge, this case represents the first use of vedolizumab in such a circumstance and provides evidence of its usefulness as a rescue therapy for chronic intestinal rejection to, at least, extend graft survival.
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Affiliation(s)
- Guido Trentadue
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Gursah Kats-Ugurlu
- Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Tjasso Blokzijl
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jan Willem Haveman
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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Liebert A, Kłopocka M, Michalak A, Cichoz-Lach H, Talar-Wojnarowska R, Domz.ał-Magrowska D, Konecki Ł, Filipiuk A, Krogulecki M, Kopertowska-Majchrzak M, Stawczyk-Eder K, Waszak K, Eder P, Zagórowicz E, Smoła I, Wojciechowski K, Drygała S. Effectiveness and safety outcomes after long-term (54 weeks) vedolizumab therapy for Crohn's disease: a prospective, real-world observational study including patient-reported outcomes (POLONEZ II). Therap Adv Gastroenterol 2024; 17:17562848241293938. [PMID: 39575158 PMCID: PMC11580093 DOI: 10.1177/17562848241293938] [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: 01/31/2024] [Accepted: 09/30/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND The Crohn's Disease (CD) Activity Index (CDAI), Inflammatory Bowel Disease (IBD) Questionnaire (IBDQ), and IBD-Fatigue (IBD-F) scale are useful patient-reported outcome (PRO) tools for assessing the treatment benefits of vedolizumab (VDZ) beyond clinical trial endpoints in patients with CD. OBJECTIVES To assess clinical response, clinical remission, steroid-free remission, changes from baseline for PROs, and safety in a real-world cohort of patients with moderate-to-severe active CD treated with VDZ. DESIGN POLONEZ II was a multicenter, observational, prospective study across 10 Polish centers from April 2020 to October 2023 for 54 weeks in patients with CD eligible for reimbursed VDZ. METHODS Primary endpoints at week 54 (W54) were clinical response (⩾70-point reduction in CDAI and >25% reduction vs baseline), remission (CDAI score ⩽150), and steroid-free remission. Other outcomes were changes in PROs (CDAI score and health-related quality of life) and safety. Kaplan-Meier survival analyses were performed. RESULTS Of 98 patients with CD, the mean age was 35.2 years, 57.1% were male, and 72.4% had an ileocolonic disease. At W54 (n = 98), 63.3% of patients achieved clinical response, 48.0% remission, and 36.0% steroid-free remission. The durability of clinical response, remission, and steroid-free remission (W14-W54) were 68.9%, 62.9%, and 57.1%, respectively. By W54, a significant reduction in the PROs, such as the total CDAI score (p < 0.001), stool frequency (p < 0.001), abdominal pain score (p < 0.001), IBDQ (p < 0.001), IBD-F (p < 0.05), and fatigue impact on daily activities (p < 0.001), was observed. During VDZ treatment, arthralgia (23.7%-8.7%) and anemia (22.6%-15.9%) decreased between baseline and W54. Non-serious adverse events (SAEs; 12.2%), SAEs (7.1%), and VDZ-related rash (1.0%) were reported. Mean CD-related hospitalization duration decreased from baseline (10.2 days) to the end of the study (5.3 days). CONCLUSION POLONEZ II demonstrated long-term real-world benefits of VDZ toward effectiveness, safety, and improved PROs and patients' quality of life. TRIAL REGISTRATION ENCePP (EUPAS32716).
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Affiliation(s)
- Ariel Liebert
- Department of Gastroenterology and Nutritional Disorders, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Maria Kłopocka
- Department of Gastroenterology and Nutritional Disorders, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland
| | - Agata Michalak
- Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
| | - Halina Cichoz-Lach
- Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
| | | | | | - Łukasz Konecki
- Department of Gastroenterology, Military Institute of Medicine, Warsaw, Poland
| | - Aleksandra Filipiuk
- Department of Gastroenterology, Military Institute of Medicine, Warsaw, Poland
| | - Michał Krogulecki
- Department of Gastroenterology, Military Institute of Medicine, Warsaw, Poland
| | | | - Kamila Stawczyk-Eder
- Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University Clinical Hospital, Poznań University of Medical Sciences, Poznań, Poland
| | - Katarzyna Waszak
- Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University Clinical Hospital, Poznań University of Medical Sciences, Poznań, Poland
| | - Piotr Eder
- Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University Clinical Hospital, Poznań University of Medical Sciences, Poznań, Poland
| | - Edyta Zagórowicz
- Department of Gastroenterology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center of Postgraduate Education, Warsaw, Poland
| | - Izabela Smoła
- Department and Clinic of Gastroenterology, Hepatology and Internal Medicine, Faculty of Medicine, Wrocław Medical University, Wrocław, Poland
| | | | - Szymon Drygała
- Szymon Drygała Takeda Pharma Sp. z.o.o., St. Prosta 68, Warsaw, Mazovia Province 00-838, Poland
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13
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Alghamdi M, Alyousfi D, Mukhtar MS, Mosli M. Association between vedolizumab and risk of clostridium difficile infection in patients with ulcerative colitis: A systematic review and meta-analysis. Saudi J Gastroenterol 2024; 30:346-352. [PMID: 38847060 PMCID: PMC11630484 DOI: 10.4103/sjg.sjg_118_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 04/16/2024] [Accepted: 05/04/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND The medical treatment of ulcerative colitis (UC) includes the use of biological agents such as vedolizumab, a gut-selective alpha4beta7 (ɑ4β7) antagonist. The mechanism of action of vedolizumab involves interfering with leukocyte trafficking into the gut vasculature, which halts inflammation. Due to this mechanism of action, concerns have arisen regarding an increased risk of gut infections, specifically, clostridium difficile infection (CDI). The aim is to provide clarity regarding the association between the use of vedolizumab as a therapy for ulcerative colitis and the risk of developing CDI. METHODS A systematic literature review was conducted, starting with the scoping search, followed by backward snowballing parallel with keyword-based search to identify related articles. A quality assessment was conducted on the initially selected articles and excluded low-quality papers. RESULTS Pooled analyses indicated that there was no significant association between the use of vedolizumab and the risk of developing CDI (effect size = 0.03 [-0.02, 0.07]). CONCLUSIONS Vedolizumab does not increase the risk of CDI in patients with UC. Further studies are needed to confirm these findings.
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Affiliation(s)
- Maha Alghamdi
- Department of Internal Medicine, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | - Dareen Alyousfi
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mariam S. Mukhtar
- Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mahmoud Mosli
- Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
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Matsumoto S, Mashima H. Clinical Profiles of Leucine-Rich Alpha-2 Glycoprotein for Indicating Mucosal Healing in Ulcerative Colitis Patients under Administration of Molecular-Targeted Drug. Dig Dis 2024; 43:11-18. [PMID: 39462503 DOI: 10.1159/000542062] [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: 08/03/2024] [Accepted: 10/12/2024] [Indexed: 10/29/2024]
Abstract
INTRODUCTION Leucine-rich alpha-2 glycoprotein (LRG) is a useful serum biomarker for monitoring disease activity during remission in ulcerative colitis (UC). Because LRG levels differ among patients, it is necessary to assess them after profiling patients, especially in patients with refractory UC undergoing treatment with molecular-targeted drugs. This study aimed to analyze LRG levels that indicate mucosal healing according to clinical characteristics and molecular-targeted drugs. METHODS Among 214 patients with UC treated with biologics or Janus kinase (JAK) inhibitors, this study evaluated 111 patients (174 measurements) who achieved mucosal healing based on colonoscopy performed within 2 months before and after LRG measurement and experienced no changes in disease status or treatment during the same period. We analyzed the relationship of LRG with clinical characteristics (including sex, age, body mass index, and disease type and duration) and molecular-targeted drugs. RESULTS Compared with men, women had significantly higher LRG levels (9.5 μg/mL vs. 11.3 μg/mL, p < 0.001). In addition, LRG levels were significantly higher in older patients (12.0 μg/mL vs. 9.8 μg/mL, p < 0.01). LRG levels were the highest in patients treated with vedolizumab and lower in patients treated with JAK inhibitors (vedolizumab: 12.7 μg/mL; tofacitinib: 8.9 μg/mL; upadacitinib: 8.5 μg/mL; and filgotinib: 9.1 μg/mL; p < 0.0001). CONCLUSION Among the patients who achieved mucosal healing, LRG levels were significantly higher in women and older patients. LRG levels differed according to the molecular-targeted drug used and were higher with vedolizumab and lower with JAK inhibitors.
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Affiliation(s)
- Satohiro Matsumoto
- Department of Gastroenterology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Hirosato Mashima
- Department of Gastroenterology, Jichi Medical University Saitama Medical Center, Saitama, Japan
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Huang Z, Tang J, Wu R, Long S, Chen W, Lu T, Xia Q, Wu Y, Yang H, Yang Q, Huang Z, Guo Q, Li M, Gao X, Chao K. Comparison of clinical and endoscopic efficacy between vedolizumab and infliximab in bio-naïve patients with ulcerative colitis: a multicenter, real-world study. Therap Adv Gastroenterol 2024; 17:17562848241281218. [PMID: 39420999 PMCID: PMC11483708 DOI: 10.1177/17562848241281218] [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: 03/21/2024] [Accepted: 08/18/2024] [Indexed: 10/19/2024] Open
Abstract
Background No head-to-head trial directly compares the effectiveness of vedolizumab (VDZ) and infliximab (IFX) in patients with ulcerative colitis (UC) who were naïve to biologic therapy. Objectives We aimed to compare the clinical and endoscopic effectiveness of VDZ and IFX in biologic-naïve patients with UC in real-world settings. Design It was a multicenter, observational, real-world cohort study conducted at five centers. Methods Patients diagnosed with UC and treated with either IFX or VDZ as their first-line biologic therapy were retrospectively enrolled. Steroid-free remission, clinical response, clinical remission, and endoscopic healing at week 14 and week 52 were compared between the two groups after propensity score weighting. Results A total of 199 patients (117 VDZ and 82 IFX) were included in the study. There were no significant differences in steroid-free remission (64.6% vs 56.1%, p = 0.224), clinical response (83.4% vs 73.4%, p = 0.086), or clinical remission (69.4% vs 60.1%, p = 0.174) at week 14. However, VDZ showed better results in steroid-free remission (67.5% vs 44.4%, p = 0.004), clinical response (69.7% vs 47.1%, p = 0.005), and clinical remission (67.5% vs 44.4%, p = 0.004) at week 52. In terms of endoscopic healing, VDZ was similar to IFX at week 14 (25.7% vs 17.4%, p = 0.185), but VDZ had a significantly higher rate at week 52 (29.5% vs 11.8%, p = 0.027). VDZ was found to be superior to IFX in therapeutic continuation (hazard ratio = 0.339, 95% CI: 0.187-0.614, p < 0.001). The rate of adverse events was similar between the two groups (6.8% vs 8.5%, p = 0.655). Conclusion VDZ demonstrated similar clinical and endoscopic effectiveness to IFX at week 14 in biologic-naïve patients with UC, but appeared to be superior at week 52. The safety outcomes were comparable between the groups.
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Affiliation(s)
- Zhaopeng Huang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jian Tang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ruibin Wu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Shunhua Long
- The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Wenke Chen
- Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Tingna Lu
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Qiuyue Xia
- The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Yanhui Wu
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hongsheng Yang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qingfan Yang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zicheng Huang
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Qin Guo
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Miao Li
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Road II, Tianhe District, Guangzhou 510000, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kang Chao
- Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, No. 26 Yuancun Road II, Tianhe District, Guangzhou 510000, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Liang Y, Li Y, Lee C, Yu Z, Chen C, Liang C. Ulcerative colitis: molecular insights and intervention therapy. MOLECULAR BIOMEDICINE 2024; 5:42. [PMID: 39384730 PMCID: PMC11464740 DOI: 10.1186/s43556-024-00207-w] [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: 07/08/2024] [Accepted: 09/13/2024] [Indexed: 10/11/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.
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Affiliation(s)
- Yuqing Liang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Yang Li
- Department of Respiratory, Sichuan Integrative Medicine Hospital, Chengdu, 610042, China
| | - Chehao Lee
- Department of Traditional Chinese Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Ziwei Yu
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Chongli Chen
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Chao Liang
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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Waterhouse T, Baron K, Eure W, Chen C, Dirks NL, Jansson J, Akbari M, Mehrotra S. Population pharmacokinetic modeling of vedolizumab for graft-versus-host disease prophylaxis in adults with allogeneic hematopoietic stem cell transplant. Pharmacol Res Perspect 2024; 12:e1257. [PMID: 39233318 PMCID: PMC11374527 DOI: 10.1002/prp2.1257] [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: 02/06/2024] [Revised: 06/27/2024] [Accepted: 07/13/2024] [Indexed: 09/06/2024] Open
Abstract
We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.
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MESH Headings
- Adolescent
- Adult
- Aged
- Female
- Humans
- Male
- Middle Aged
- Young Adult
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Dose-Response Relationship, Drug
- Gastrointestinal Agents/pharmacokinetics
- Gastrointestinal Agents/therapeutic use
- Gastrointestinal Agents/administration & dosage
- Graft vs Host Disease/prevention & control
- Hematopoietic Stem Cell Transplantation
- Models, Biological
- Transplantation, Homologous
- Clinical Trials, Phase I as Topic
- Clinical Trials, Phase III as Topic
- Randomized Controlled Trials as Topic
- Multicenter Studies as Topic
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Affiliation(s)
| | - Kyle Baron
- Metrum Research GroupTariffvilleConnecticutUSA
| | - Westley Eure
- Takeda Pharmaceuticals Inc.CambridgeMassachusettsUSA
| | - Chunlin Chen
- Takeda Pharmaceuticals Inc.CambridgeMassachusettsUSA
- Present address:
Bayer PharmaceuticalsWhippanyNew JerseyUSA
| | | | - Johan Jansson
- Takeda Pharmaceuticals Inc.CambridgeMassachusettsUSA
| | - Mona Akbari
- Takeda Pharmaceuticals Inc.CambridgeMassachusettsUSA
- Present address:
AbbVieCambridgeMassachusettsUSA
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18
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Zu Y, Gui R, Li Z, Wang J, Li P, Liu Y, Dong X, Zhou J. Vedolizumab for second-line treatment of steroid-refractory gastrointestinal late acute graft-versus-host disease. Ther Adv Hematol 2024; 15:20406207241276982. [PMID: 39247427 PMCID: PMC11380122 DOI: 10.1177/20406207241276982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 08/02/2024] [Indexed: 09/10/2024] Open
Abstract
Background Late acute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with little data regarding treatment and outcomes. There is no standard treatment for gastrointestinal (GI) late aGVHD, especially for steroid-refractory (SR) GI late aGVHD. Vedolizumab, a monoclonal antibody inhibiting the migration of both naive and activated lymphocytes into the GI endothelium, has been verified to be effective for SR GI aGVHD. Methods We retrospectively analyzed the clinical efficacy and safety of vedolizumab as the second line for SR GI late aGVHD in seven patients after allo-HSCT. Results Four patients received two doses of vedolizumab infusion, while three patients received only one dose of vedolizumab infusion. The complete response and partial response rates were 57.1% (4/7) and 42.9% (3/7), respectively. No patient progressed to chronic GVHD during the period of follow-up. There was no severe adverse event related to vedolizumab. Conclusion Our data suggest that vedolizumab is expected to ameliorate SR GI late aGVHD. Further data on the treatment timing, efficacy, and safety of vedolizumab are warranted in prospective clinical trials.
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Affiliation(s)
- Yingling Zu
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Ruirui Gui
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Zhen Li
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Juan Wang
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Pei Li
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Ying Liu
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Xiaofeng Dong
- Department of Blood Transfusion, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Jian Zhou
- Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, No. 127 Dongming Road, Jinshui District, Zhengzhou 450008, China
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19
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Zheng DY, Wang YN, Huang YH, Jiang M, Ma YN, Dai C. The impact of vedolizumab therapy on extraintestinal manifestations in patients with inflammatory bowel disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2024; 39:1745-1759. [PMID: 38740543 DOI: 10.1111/jgh.16612] [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: 11/25/2023] [Revised: 03/25/2024] [Accepted: 05/01/2024] [Indexed: 05/16/2024]
Abstract
BACKGROUND AND AIM Extraintestinal manifestations (EIMs) pose a significant threat in inflammatory bowel disease (IBD) patients. Vedolizumab (VDZ) primarily affects the gastrointestinal tract. However, its impact on EIMs remains uncertain. Therefore, we conducted this meta-analysis to examine the effects of VDZ on EIMs during treatment. METHODS Relevant studies were identified by conducting thorough searches across electronic databases, including PubMed, Ovid Embase, Medline, and Cochrane CENTRAL. Primary outcomes focused on the proportion of patients with resolution for pre-existing EIMs in IBD patients receiving VDZ. Secondary outcomes included the proportion of patients with EIM exacerbations and new onset EIMs during VDZ treatment. RESULTS Our meta-analysis encompassed 21 studies. The proportion of patients with resolution of pre-existing EIMs in VDZ-treated IBD patients was 39% (150/386; 95% confidence interval [CI] 0.31-0.48). The proportion of patients with EIM exacerbations occurred at a rate of 28% (113/376; 95% CI 0.05-0.50), while new onset EIMs had a rate of 15% (397/2541; 95% CI 0.10-0.20). Subgroup analysis revealed a 40% (136/337) proportion of patients with resolution for articular-related EIMs and a 50% (9/18) rate for erythema nodosum. Exacerbation rates for arthritis/arthralgia, erythema nodosum/pyoderma gangrenosum, and aphthous stomatitis during VDZ use were 28% (102/328), 18% (7/38), and 11% (3/28), respectively. The incidence rate of newly developed EIMs during treatment was 11% (564/4839) for articular-related EIMs, with other EIMs below 2%. CONCLUSION VDZ demonstrates efficacy in skin-related EIMs like erythema nodosum and joint-related EIMs including arthritis, arthralgia, spondyloarthritis, and peripheral joint diseases. Some joint and skin-related EIMs may experience exacerbation during VDZ therapy.
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Affiliation(s)
- Dian-Yu Zheng
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, China
| | - Yi-Nuo Wang
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, China
| | - Yu-Hong Huang
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, China
| | - Min Jiang
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, China
| | - Yi-Nan Ma
- Department of Pathology, First Hospital and College of Basic Medical Sciences, China Medical University, Shenyang City, China
| | - Cong Dai
- Department of Gastroenterology, First Hospital of China Medical University, Shenyang City, China
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20
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Gabriëls RY, van der Waaij AM, Linssen MD, Dobosz M, Volkmer P, Jalal S, Robinson D, Hermoso MA, Lub-de Hooge MN, Festen EAM, Kats-Ugurlu G, Dijkstra G, Nagengast WB. Fluorescently labelled vedolizumab to visualise drug distribution and mucosal target cells in inflammatory bowel disease. Gut 2024; 73:1454-1463. [PMID: 38580386 PMCID: PMC11347245 DOI: 10.1136/gutjnl-2023-331696] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 03/22/2024] [Indexed: 04/07/2024]
Abstract
OBJECTIVE Improving patient selection and development of biological therapies such as vedolizumab in IBD requires a thorough understanding of the mechanism of action and target binding, thereby providing individualised treatment strategies. We aimed to visualise the macroscopic and microscopic distribution of intravenous injected fluorescently labelled vedolizumab, vedo-800CW, and identify its target cells using fluorescence molecular imaging (FMI). DESIGN Forty three FMI procedures were performed, which consisted of macroscopic in vivo assessment during endoscopy, followed by macroscopic and microscopic ex vivo imaging. In phase A, patients received an intravenous dose of 4.5 mg, 15 mg vedo-800CW or no tracer prior to endoscopy. In phase B, patients received 15 mg vedo-800CW preceded by an unlabelled (sub)therapeutic dose of vedolizumab. RESULTS FMI quantification showed a dose-dependent increase in vedo-800CW fluorescence intensity in inflamed tissues, with 15 mg (153.7 au (132.3-163.7)) as the most suitable tracer dose compared with 4.5 mg (55.3 au (33.6-78.2)) (p=0.0002). Moreover, the fluorescence signal decreased by 61% when vedo-800CW was administered after a therapeutic dose of unlabelled vedolizumab, suggesting target saturation in the inflamed tissue. Fluorescence microscopy and immunostaining showed that vedolizumab penetrated the inflamed mucosa and was associated with several immune cell types, most prominently with plasma cells. CONCLUSION These results indicate the potential of FMI to determine the local distribution of drugs in the inflamed target tissue and identify drug target cells, providing new insights into targeted agents for their use in IBD. TRIAL REGISTRATION NUMBER NCT04112212.
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Affiliation(s)
- Ruben Y Gabriëls
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Anne M van der Waaij
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Matthijs D Linssen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Michael Dobosz
- Department of Oncology and Immuno-Oncology, Regeneron Pharmaceuticals inc, Tarrytown, New York, USA
| | - Pia Volkmer
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Sumreen Jalal
- Department of Oncology and Immuno-Oncology, Regeneron Pharmaceuticals inc, Tarrytown, New York, USA
| | - Dominic Robinson
- Centre for Optical Diagnostics and Therapy, Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Marcela A Hermoso
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
- Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Marjolijn N Lub-de Hooge
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Gursah Kats-Ugurlu
- Department of Pathology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Wouter B Nagengast
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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21
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Chen YB, Mohty M, Zeiser R, Teshima T, Jamy O, Maertens J, Purtill D, Chen J, Cao H, Rossiter G, Jansson J, Fløisand Y. Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial. Nat Med 2024; 30:2277-2287. [PMID: 38844797 PMCID: PMC11333288 DOI: 10.1038/s41591-024-03016-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/23/2024] [Indexed: 08/21/2024]
Abstract
Acute graft-versus-host disease (aGVHD) of the lower gastrointestinal (GI) tract is a major cause of morbidity and mortality in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab is a gut-selective anti-α4β7 integrin monoclonal antibody that reduces gut inflammation by inhibiting migration of GI-homing T lymphocytes. The efficacy and safety of vedolizumab added to standard GVHD prophylaxis (calcineurin inhibitor plus methotrexate/mycophenolate mofetil) was evaluated for prevention of lower-GI aGVHD after unrelated donor allo-HSCT in a randomized, double-blind, placebo-controlled phase 3 trial. Enrollment closed early during the COVID-19 pandemic with 343 patients randomized (n = 174 vedolizumab, n = 169 placebo), and 333 received ≥1 intravenous dose of 300 mg vedolizumab (n = 168) or placebo (n = 165) and underwent allo-HSCT. The primary end point was met; Kaplan-Meier (95% confidence interval) estimated rates of lower-GI aGVHD-free survival by day +180 after allo-HSCT were 85.5% (79.2-90.1) with vedolizumab versus 70.9% (63.2-77.2) with placebo (hazard ratio, 0.45; 95% confidence interval, 0.27-0.73; P < 0.001). For the 5 key secondary efficacy end points analyzed by day +180 after allo-HSCT, rates of lower-GI aGVHD-free and relapse-free survival and grade C-D aGVHD-free survival were significantly higher with vedolizumab versus placebo. No significant treatment differences were found for the other key secondary end points of non-relapse mortality, overall survival and grade B-D aGVHD-free survival, respectively. Incidence of treatment-related serious adverse events analyzed in patients receiving ≥1 dose of study treatment (n = 334) was 6.5% (n = 11 of 169) vedolizumab versus 8.5% (n = 14 of 165) placebo. When added to standard calcineurin inhibitor-based GVHD prevention, lower-GI aGVHD-free survival was significantly higher with vedolizumab versus placebo. ClinicalTrials.gov identifier: NCT03657160 .
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Affiliation(s)
- Yi-Bin Chen
- Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA, USA.
| | - Mohamad Mohty
- Hematology Department, AP-HP, Hôpital Saint-Antoine, Sorbonne Université and INSERM UMRs 938, Paris, France
| | - Robert Zeiser
- Department of Medicine I - Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Omer Jamy
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Johan Maertens
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
- Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
| | - Duncan Purtill
- Department of Haematology, Fiona Stanley Hospital, Perth, Western Australia, Australia
- PathWest Laboratory Medicine, Perth, Western Australia, Australia
| | | | | | | | | | - Yngvar Fløisand
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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22
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Vootukuru N, Vasudevan A. Approach to loss of response to advanced therapies in inflammatory bowel disease. World J Gastroenterol 2024; 30:2902-2919. [PMID: 38947290 PMCID: PMC11212715 DOI: 10.3748/wjg.v30.i22.2902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/06/2024] [Accepted: 05/28/2024] [Indexed: 06/05/2024] Open
Abstract
BACKGROUND Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients. However, issues of primary non-response (PNR) and secondary loss of response (SLOR) to non-tumour necrosis factor inhibitor (TNFi) therapies remains a common problem. Specific issues include the choice of optimization of therapy, identifying when dose optimization will recapture response, establishing optimal dose for escalation and when to switch therapy. AIM To explores the issues of PNR and SLOR to non-TNFi therapies. METHODS This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR. It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring (TDM). RESULTS In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin (IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response. For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response. CONCLUSION The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.
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Affiliation(s)
- Nikil Vootukuru
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Box Hill 3128, Australia
- Eastern Health Clinical School, Monash University, Victoria, Box Hill 3128, Australia
| | - Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Box Hill 3128, Australia
- Eastern Health Clinical School, Monash University, Victoria, Box Hill 3128, Australia
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23
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Zhang R, Jia Z, Piao Y. Meta-analysis of etrolizumab versus placebo in ulcerative colitis: safety and efficacy outcomes. Therap Adv Gastroenterol 2024; 17:17562848241253685. [PMID: 38855341 PMCID: PMC11162133 DOI: 10.1177/17562848241253685] [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: 11/27/2023] [Accepted: 04/23/2024] [Indexed: 06/11/2024] Open
Abstract
Background The existing body of scientific literature offers inconclusive findings on the safety and therapeutic effectiveness of etrolizumab (ETR) for the treatment of ulcerative colitis (UC). Objectives The goal of this meta-analysis is to furnish a comprehensive synthesis of evidence that evaluates the safety and therapeutic effects of ETR in the management of UC. Design Meta-analysis. Data sources and methods PubMed, Embase, and Web of science were searched to collect relevant English studies, and the reference lists of eligible studies were manually searched to avoid missing any eligible studies. Outcome measures encompassed clinical response, incidence of adverse events, histological remission, endoscopic remission, endoscopic improvement, and antidrug antibodies. Relevant data were extracted by two independent investigators. Results The meta-analysis incorporated five eligible studies, involving a total of 1528 patients, with 1015 treated with ETR and 513 with placebo. The pooled analysis indicates that ETR is both effective and safe. The adverse event rates, endoscopic and histological response, as well as overall remission were comparable between the two groups. The monoclonal antibody group had a lower incidence rate of adverse reactions than the placebo group [odds ratio (OR): 0.81; 95% confidence interval (CI): 0.63-1.03; p = 0.09)]. Clinical response was higher in the ETR group than in the placebo group (OR: 1.56; 95% CI: 1.20-2.02; p = 0.0009), and endoscopic improvement was more favorable in the ETR group (OR: 1.88; 95% CI: 1.45-2,45; p < 0.00001). A higher rate of endoscopic remission was found in the ETR group than in the placebo group (OR: 2.48; 95% CI: 1.75-3.50; p < 0.00001); histological remission was significantly higher in the ETR group than in the placebo group (OR: 2.11; 95% CI: 1.55-2.86; p < 0.00001). The placebo group had a lower rate of positive antidrug antibodies (OR: 1.31; 95% CI: 0.79-2.17; p < 0.29), and the incidence of complications was significantly higher in the ETR group compared with the placebo group (OR: 2.05; 95% CI: 1.48-2.83; p < 0.0001). Conclusion Given the heterogeneity and potential biases in the included studies, gastroenterologists should cautiously tailor drug delivery strategies based on their clinical experience and the unique needs of individual patients. PROSPERO registration CRD42023396100.
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Affiliation(s)
- Rui Zhang
- Yanbian University Medical College, Yanji, Jilin, China
| | - Ziran Jia
- Yanbian University Medical College, Yanji, Jilin, China
| | - Yingshi Piao
- Yanbian University Medical College, No. 977 Gongyuan Road, Yanji, Jilin 133002, China
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24
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Lamichhane N, Melas N, Bergqvist V, Ekholm NP, Olén O, Ludvigsson JF, Hjortswang H, Marsal J, Eriksson C, Halfvarson J. Real-World Outcomes of Patients Starting Intravenous and Transitioning to Subcutaneous Vedolizumab in Inflammatory Bowel Disease. Dig Dis Sci 2024; 69:2175-2183. [PMID: 38637457 PMCID: PMC11162360 DOI: 10.1007/s10620-024-08422-9] [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: 08/11/2023] [Accepted: 03/28/2024] [Indexed: 04/20/2024]
Abstract
BACKGROUND Real-world data on starting intravenous (IV) vedolizumab (VDZ) and transitioning to subcutaneous (SC) treatment in inflammatory bowel disease (IBD) are scarce. AIMS To assess treatment outcomes of patients with IBD starting IV VDZ and switching to SC VDZ in routine clinical care. METHODS Adult patients with IBD switching from IV to SC VDZ treatment between 1 March 2020 and 31 December 2021 were identified from the Swedish IBD quality register. The primary outcome was SC VDZ persistence. Secondary outcomes included clinical remission, changes in quality of life (QoL) according to EuroQual 5-Dimensions 5-Levels (EQ-5D-5L) and the Short-Health Scale (SHS) and inflammatory markers, including faecal Calprotectin (FCP). RESULTS Altogether, 406 patients with IBD (Crohn's disease, n = 181; ulcerative colitis, n = 225) were identified. After a median follow-up of 30 months from starting IV VDZ treatment, the persistence rates were 98%(178/181) in Crohn's disease and 94% (211/225) in ulcerative colitis. Most patients (84%) transitioned during maintenance therapy, and the median follow-up from switch to SC VDZ was 10 months. Compared to baseline, statistically significant improvements were observed in all domains of the SHS, EQ-5D index value and visual analogue scale. Median (interquartile range) FCP concentrations (μg/g) decreased from 459 (185-1001) to 65 (26-227) in Crohn's disease (n = 45; p < 0.001) and from 646 (152-1450) to 49 (20-275) in ulcerative colitis (n = 58; p < 0.001). CONCLUSION Initiating IV VDZ and switching to SC treatment was associated with high persistence rates and improvements in measures of QoL and FCP. These findings are reassuring for patients who start IV VDZ and switch to SC VDZ.
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Affiliation(s)
- N Lamichhane
- School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - N Melas
- School of Health and Medical Sciences, Örebro University, Örebro, Sweden
- Central Hospital in Karlstad, Karlstad, Sweden
| | - V Bergqvist
- Department of Gastroenterology, Skåne University Hospital, Lund, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - N-P Ekholm
- Takeda Pharma, Medical Affairs, Stockholm, Sweden
| | - O Olén
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Stockholm South General Hospital, Sachs' Children and Youth Hospital, Stockholm, Sweden
- Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - J F Ludvigsson
- Department of Paediatrics, Örebro University Hospital, Örebro, Sweden
- Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - H Hjortswang
- Department of Gastroenterology and Hepatology in Linköping, Linköping University, Linköping, Sweden
- Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - J Marsal
- Department of Gastroenterology, Skåne University Hospital, Lund, Sweden
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - C Eriksson
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden
| | - J Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, 701 82, Örebro, Sweden.
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25
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Huang K, Yao L, Liu J, Cao Q. Take vedolizumab home: transition from intravenous to subcutaneous treatment. Ther Adv Chronic Dis 2024; 15:20406223241247648. [PMID: 38726235 PMCID: PMC11080802 DOI: 10.1177/20406223241247648] [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] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 04/01/2024] [Indexed: 05/12/2024] Open
Abstract
In 2020, the European Medicines Agency approved subcutaneous (SC) vedolizumab (VDZ) for the maintenance treatment of adult patients with moderate to severe inflammatory bowel disease (IBD). This article reviews the efficacy, safety, persistence, pharmacology, patient satisfaction, and economic implications of transitioning to SC VDZ treatment and explores whether SC formulations can be recommended by the same guidelines as intravenous (IV) formulations. Clinical trials and real-world evidence indicate that transitioning from IV to SC VDZ in patients with IBD maintains clinical, biochemical, and patient-reported clinical remission and is well-tolerated, with no new safety issues identified, except for injection site reactions. Moreover, SC VDZ has an exposure-response relationship and low immunogenicity, is economical, and provides a high level of patient satisfaction. Owing to these advantages, transitioning may be advisable. In the future, more studies are needed to clarify the exact role of SC VDZ in IBD treatment, including optimization and transitioning strategies and individualized treatments based on baseline characteristics.
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Affiliation(s)
- Kaituo Huang
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Inflammatory Bowel Disease Center of Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Lingya Yao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Inflammatory Bowel Disease Center of Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jing Liu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Inflammatory Bowel Disease Center of Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Qian Cao
- Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, 3 East Qingchun Road, Shangcheng District, Hangzhou 310016, China
- Inflammatory Bowel Disease Center of Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Gupta B, Rai RP, Pal PB, Rossmiller D, Chaudhary S, Chiaro A, Seaman S, Singhi AD, Liu S, Monga SP, Iyer SS, Raeman R. Selective Targeting of α 4β 7/MAdCAM-1 Axis Suppresses Fibrosis Progression by Reducing Proinflammatory T Cell Recruitment to the Liver. Cells 2024; 13:756. [PMID: 38727292 PMCID: PMC11083209 DOI: 10.3390/cells13090756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Integrin α4β7+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of α4β7+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl4-induced liver fibrosis was associated with enrichment of intrahepatic α4β7+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α4β7 or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl4-treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α4β7+ CD4 and CD8 T cells, suggesting that α4β7/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α4β7+ T cells promote hepatic fibrosis progression. Analysis of hepatic α4β7+ and α4β7- CD4 T cells revealed that α4β7+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α4β7+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α4β7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.
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Affiliation(s)
- Biki Gupta
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Ravi Prakash Rai
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Pabitra B. Pal
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Daniel Rossmiller
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Sudrishti Chaudhary
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Anna Chiaro
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Shannon Seaman
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Aatur D. Singhi
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Silvia Liu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Satdarshan P. Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Smita S. Iyer
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
| | - Reben Raeman
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; (B.G.); (R.P.R.)
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Kong L, Chen S, Huang S, Zheng A, Gao S, Ye J, Hua C. Challenges and opportunities in inflammatory bowel disease: from current therapeutic strategies to organoid-based models. Inflamm Res 2024; 73:541-562. [PMID: 38345635 DOI: 10.1007/s00011-024-01854-z] [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: 11/12/2023] [Revised: 01/20/2024] [Accepted: 01/24/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is an increasingly prevalent global health concern that has garnered substantial attention. However, the underlying mechanisms are still unclear and the current treatments have significant limitations. Intestinal organoids provide an in vitro model to explore the pathogenesis, test the therapeutic effects, and develop regenerative treatments as well as offer the potential to transform drug discovery of IBD. METHODS To advance our understanding of the whole story of IBD spanning from the pathogenesis to the current therapeutic strategies and latest advancements, a comprehensive search of major databases including PubMed, Scopus, and Web of Science was conducted to retrieve original articles and reviews related to IBD, organoids, pathogenesis and therapy. RESULTS This review deciphers the etiopathogenesis and the current therapeutic approaches in the treatment of IBD. Notably, critical aspects of intestinal organoids in IBD, such as their potential applications, viability, cell renewal ability, and barrier functionality are highlighted. We also discuss the advances, limitations, and prospects of intestinal organoids for precision medicine. CONCLUSION The latest strides made in research about intestinal organoids help elucidate intricate aspects of IBD pathogenesis, and pave the prospective avenues for novel therapeutic interventions.
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Affiliation(s)
- Lingjie Kong
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Siyan Chen
- School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Shenghao Huang
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Anzhe Zheng
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Jianzhong Ye
- Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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Chugh R, Long MD, Jiang Y, Weaver KN, Beaulieu DB, Scherl EJ, Mahadevan U. Maternal and Neonatal Outcomes in Vedolizumab- and Ustekinumab-Exposed Pregnancies: Results From the PIANO Registry. Am J Gastroenterol 2024; 119:468-476. [PMID: 37796648 DOI: 10.14309/ajg.0000000000002553] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 09/22/2023] [Indexed: 10/07/2023]
Abstract
BACKGROUND Pregnancy outcomes in patients with inflammatory bowel disease with quiescent disease are similar to those in the general population. Data from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes registry have demonstrated the safety of antitumor necrosis factor (TNF) α agents and thiopurines in pregnancy. The objective of this study was to provide information from the Pregnancy Inflammatory bowel disease And Neonatal Outcomes registry on maternal and fetal outcomes in patients exposed to the newer biologics ustekinumab (UST) and vedolizumab (VDZ). METHODS In this multicenter prospective observational study, we included pregnant women with singleton pregnancies and a diagnosis of inflammatory bowel disease. Questionnaires were administered to women at study intake, each subsequent trimester, delivery, and 4, 9, and 12 months after birth. Bivariate analyses were used to determine the independent effects of specific drug classes on outcomes. The exposure cohorts were VDZ, UST, anti-TNF, immunomodulators, and combination with anti-TNF and immunomodulators. All were compared with no exposure and with biologics/immunomodulators. RESULTS There were 1,669 completed pregnancies with 1,610 live births. The maternal mean age was 32.1 (SD 4.6) years at delivery with 66 VDZ exposed and 47 UST exposed. Women on UST were more likely to have Crohn's disease. There was no increased risk of spontaneous abortion, small for gestational age, low birth weight, neonatal intensive care unit stay, congenital malformations, or intrauterine growth restriction with in utero VDZ or UST exposure. The rate of preterm birth was lower (0.0%) for the UST-exposed cohort when compared with other cohorts including VDZ (13.8%), anti-TNF (8.2%), combination therapy (14.2%), immunomodulators (12.3%), and unexposed (9.7%) ( P = 0.03). Rates of serious infections at birth, 4 months, and within the first 12 months of life were comparable among all cohorts. Nonserious infections were lower at 12 months in UST-exposed pregnancies. There was no increased risk signal for placental complications in the VDZ cohort. UST infant concentrations at birth were increased whereas VDZ concentrations were overall decreased compared with maternal serum drug concentration. DISCUSSION This analysis of UST and VDZ exposure during pregnancy suggests no increase in complications compared with TNF, immunomodulators, and combination TNF/immunomodulators. No signal was found for increased placental events with either therapy. Continuation of UST and VDZ throughout pregnancy is recommended.
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Affiliation(s)
- Rishika Chugh
- Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, California, USA
| | - Millie D Long
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Yue Jiang
- Department of Statistical Science, Duke University, Durham, North Carolina, USA
| | - Kimberly N Weaver
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Dawn B Beaulieu
- Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ellen J Scherl
- Division of Gastroenterology, Weill Cornell Medicine, New York Presbyterian Hospital, New York, New York, USA
| | - Uma Mahadevan
- Division of Gastroenterology and Hepatology, University of California San Francisco, San Francisco, California, USA
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Tursi A, Mocci G, Del Gaudio A, Papa A. Clinical use of biologics for Crohn's disease in adults: lessons learned from real-world studies. Expert Opin Biol Ther 2024:1-19. [PMID: 38321868 DOI: 10.1080/14712598.2024.2316180] [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: 11/01/2023] [Accepted: 02/05/2024] [Indexed: 02/08/2024]
Abstract
INTRODUCTION The therapeutic armamentarium for managing Crohn's disease (CD) has expanded significantly in recent decades. Several biologics with three different mechanisms of action [anti-tumor necrosis factor (TNF)-α, anti-integrin α4β7, and anti-IL 12/23] are currently available to manage CD. AREA COVERED This narrative review aims to summarize the most significant efficacy and safety data on the use of infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ) and ustekinumab (UST) for the treatment of CD obtained from studies conducted in the real world (RW), compared to the results of randomized clinical trials (RCTs). EXPERT OPINION RW studies reported that biologic agents included in this analysis have higher remission rates and lower adverse event rates than findings from RCTs for treating patients with CD. All biological agents have proven effective and safe in RW studies, even when using biosimilars or switching to subcutaneous administration of the molecules for which they are available. Finally, anti-TNF-α agents, particularly IFX, have a higher rate of adverse events (AEs) than VDZ and UST. Therefore, patients at higher risk of AEs may benefit from other biologics than anti-TNF-α. However, further long-term RW studies are needed to confirm these findings.
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Affiliation(s)
- Antonio Tursi
- Territorial Gastroenterology Service, ASL BAT, Andria, Italy
- Department of Medical and Surgical Sciences, Catholic University, School of Medicine, Rome, Italy
| | - Giammarco Mocci
- Division of Gastroenterology, "Brotzu" Hospital, Cagliari, Italy
| | - Angelo Del Gaudio
- Division of Internal Medicine and Gastroenterology, Policlinico Universitario "A. Gemelli" IRCCS Foundation, Rome, Italy
| | - Alfredo Papa
- Department of Medical and Surgical Sciences, Catholic University, School of Medicine, Rome, Italy
- Division of Internal Medicine and Gastroenterology, Policlinico Universitario "A. Gemelli" IRCCS Foundation, Rome, Italy
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30
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Wen Y, Wang H, Tian D, Wang G. TH17 cell: a double-edged sword in the development of inflammatory bowel disease. Therap Adv Gastroenterol 2024; 17:17562848241230896. [PMID: 38390028 PMCID: PMC10883129 DOI: 10.1177/17562848241230896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 01/17/2024] [Indexed: 02/24/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic nonspecific inflammatory disease of the gastrointestinal tract, and its pathogenesis has not been fully understood. Extensive dysregulation of the intestinal mucosal immune system is critical in the development and progression of IBD. T helper (Th) 17 cells have the characteristics of plasticity. They can transdifferentiate into subpopulations with different functions in response to different factors in the surrounding environment, thus taking on different roles in regulating the intestinal immune responses. In this review, we will focus on the plasticity of Th17 cells as well as the function of Th17 cells and their related cytokines in IBD. We will summarize their pathogenic and protective roles in IBD under different conditions, respectively, hoping to further deepen the understanding of the pathological mechanisms underlying IBD and provide insights for future treatment.
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Affiliation(s)
- Yue Wen
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
| | - Ge Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China
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31
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Mennillo E, Kim YJ, Lee G, Rusu I, Patel RK, Dorman LC, Flynn E, Li S, Bain JL, Andersen C, Rao A, Tamaki S, Tsui J, Shen A, Lotstein ML, Rahim M, Naser M, Bernard-Vazquez F, Eckalbar W, Cho SJ, Beck K, El-Nachef N, Lewin S, Selvig DR, Terdiman JP, Mahadevan U, Oh DY, Fragiadakis GK, Pisco A, Combes AJ, Kattah MG. Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis. Nat Commun 2024; 15:1493. [PMID: 38374043 PMCID: PMC10876948 DOI: 10.1038/s41467-024-45665-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 01/30/2024] [Indexed: 02/21/2024] Open
Abstract
Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.
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Affiliation(s)
- Elvira Mennillo
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | | | - Gyehyun Lee
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Iulia Rusu
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Ravi K Patel
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | | | - Emily Flynn
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Stephanie Li
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jared L Bain
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Christopher Andersen
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Arjun Rao
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Stanley Tamaki
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Jessica Tsui
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Alan Shen
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Madison L Lotstein
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Maha Rahim
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Mohammad Naser
- Biological Imaging Development CoLab, University of California San Francisco, San Francisco, CA, USA
| | | | - Walter Eckalbar
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Soo-Jin Cho
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kendall Beck
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Najwa El-Nachef
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Sara Lewin
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Daniel R Selvig
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jonathan P Terdiman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Uma Mahadevan
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - David Y Oh
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Gabriela K Fragiadakis
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | | | - Alexis J Combes
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Michael G Kattah
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
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Mennillo E, Kim YJ, Lee G, Rusu I, Patel RK, Dorman LC, Flynn E, Li S, Bain JL, Andersen C, Rao A, Tamaki S, Tsui J, Shen A, Lotstein ML, Rahim M, Naser M, Bernard-Vazquez F, Eckalbar W, Cho SJ, Beck K, El-Nachef N, Lewin S, Selvig DR, Terdiman JP, Mahadevan U, Oh DY, Fragiadakis GK, Pisco A, Combes AJ, Kattah MG. Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.01.21.525036. [PMID: 36711576 PMCID: PMC9882264 DOI: 10.1101/2023.01.21.525036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.
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33
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Merza N, Nawras Y, Saab O, Dahiya DS, Ahmed Z, Ranabothu M, Boujemaa S, Hassan M, Kobeissy A, Lilley K. Comparing the Efficacy and Safety of Adalimumab and Vedolizumab in Treating Moderate to Severe Crohn's Disease and Ulcerative Colitis. Gastroenterology Res 2023; 16:289-306. [PMID: 38186583 PMCID: PMC10769610 DOI: 10.14740/gr1664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 10/14/2023] [Indexed: 01/09/2024] Open
Abstract
Background Numerous patients with inflammatory bowel disease (IBD) do not respond to conventional or biological therapy. Adalimumab (ADA) and vedolizumab (VDZ), according to certain research, may be a useful alternative treatment for these people. The purpose of this study was to assess the effectiveness and safety of using ADA and VDZ to treat moderate to severe IBD: Crohn's disease (CD) and ulcerative colitis (UC). Methods We searched PubMed, Medline, Web of Science, Scopus, the Cochrane Library, Embase, Google Scholar, CINAHL, Clinicaltrials.gov, and WHO trials registry (ICTRP). Randomized controlled trials (RCTs) comparing ADA or VDZ with placebo in participants with active CD or UC were included. The primary outcomes were the clinical response and remission at induction and maintenance phases and mucosal healing. The secondary outcome was the incidence of profound negative events. The research used Comprehensive Meta-Analysis version 3 (Biostat Inc., USA). Results Eighteen RCTs were incorporated, in which 11 studies described the usefulness and safeness of ADA or VDZ in CD patients, and seven studies investigated the efficacy and safety of ADA or VDZ in UC patients. The meta-analysis revealed that both ADA and VDZ treatments were superior to placebo for producing clinical remission and eliciting clinical response at induction and maintenance phases in individuals with moderately to severely active CD or UC. Interestingly, we found that ADA was superior to VDZ as first-line treatment for patients with CD, but not UC. Conclusion ADA and VDZ are effective and safe in CD and UC patients. However, RCTs of a larger number of patients are still required for better assessing the safety profile of ADA and VDZ.
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Affiliation(s)
- Nooraldin Merza
- Department of Internal Medicine, University of Toledo, Toledo, OH, USA
| | - Yusuf Nawras
- University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Omar Saab
- Department of Internal Medicine, Cleavland Clinic, Cleavland, OH, USA
| | - Dushyant Singh Dahiya
- Department of Gastroenterology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Zohaib Ahmed
- Department of Gastroenterology, University of Toledo, Toledo, OH, USA
| | - Meghana Ranabothu
- University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Safa Boujemaa
- Biotechnology Development, Institute Pasteur De Tunis, University De Tunis El Manar, Tunis, Tunisia
| | - Mona Hassan
- Department of Gastroenterology, University of Toledo, Toledo, OH, USA
| | - Abdallah Kobeissy
- Department of Gastroenterology, University of Toledo, Toledo, OH, USA
| | - Kirthi Lilley
- Department of Gastroenterology, Wayne State University, Detroit, MI, USA
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Mehandru S, Colombel JF, Juarez J, Bugni J, Lindsay JO. Understanding the molecular mechanisms of anti-trafficking therapies and their clinical relevance in inflammatory bowel disease. Mucosal Immunol 2023; 16:859-870. [PMID: 37574127 PMCID: PMC11141405 DOI: 10.1016/j.mucimm.2023.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 08/06/2023] [Indexed: 08/15/2023]
Abstract
In patients with inflammatory bowel disease (IBD), a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is driven by a complex interplay between the mucosal immune system and the environment and sustained by immune priming and ongoing cellular recruitment to the gut. The localization of immune cells is mediated by their expression of chemokine receptors and integrins, which bind to chemokines and adhesion molecules, respectively. In this article, we review the mechanisms of action of anti-trafficking therapies for IBD and consider clinical observations in the context of the different mechanisms of action. Furthermore, we discuss the evolution of molecular resistance to anti-cytokines, in which the composition of immune cells in the gut changes in response to treatment, and the potential implications of this for treatment sequencing. Lastly, we discuss the relevance of mechanism of action to combination therapy for IBD.
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Affiliation(s)
- Saurabh Mehandru
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Jean-Frederic Colombel
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Julius Juarez
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James Bugni
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James O Lindsay
- Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK; Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK
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Weisshof R, Vavricka SR, Pouillon L, Braegger F, Roset M, Bent-Ennakhil N, Ferrante M. Effectiveness and safety of vedolizumab induction with or without budesonide in patients with moderately to severely active Crohn's disease in Europe: a retrospective observational study. BMC Gastroenterol 2023; 23:417. [PMID: 38030966 PMCID: PMC10688148 DOI: 10.1186/s12876-023-03032-7] [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: 04/26/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Vedolizumab (VDZ), a gut-selective anti-lymphocyte trafficking integrin antibody, is effective in treating patients with moderately to severely active Crohn's disease (CD). In this study, we examined the real-world effectiveness and safety of induction therapy using VDZ alone or in combination with budesonide (VDZ + BUD) among patients with CD in Belgium, Israel, and Switzerland. METHODS This retrospective chart review analysis included adult patients with moderately to severely active CD who started induction treatment with VDZ or VDZ + BUD (January 2015 through January 2019). The primary objective of this study was to assess the effectiveness in terms of clinical remission of VDZ alone or VDZ + BUD using patient-reported outcomes (PRO) of abdominal pain (AP) and/or loose stool frequency (LSF) (PRO-2) at weeks 0, 2, 6, 10, and 14. Regression models were used to assess differences and associations between the treatment groups. RESULTS Overall, 123 patients were included (VDZ, n = 73; VDZ + BUD, n = 50). Clinical remission rates at week 14 were 71.4% (50/70) and 68.0% (34/50) with VDZ and VDZ + BUD, respectively. Mean percentage change in AP and LSF from baseline to week 14 was comparable between the groups. Median (95% confidence interval [CI]) time to clinical remission was 91 [70.0-98.0] and 95 [70.0-98.0] days, respectively. One patient in each group discontinued VDZ and 68.0% of patients in the VDZ + BUD group discontinued BUD before week 14. The rates of overall adverse events were similar between the groups (VDZ, 23.3%; VDZ + BUD, 26.0%). CONCLUSIONS In this retrospective study, VDZ alone and VDZ + BUD showed similar high remission rates in patients with moderately to severely active CD. Prospective randomized studies are needed to conclude on the role of combining VDZ with BUD. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Roni Weisshof
- Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
- Center for Gastroenterology and Hepatology AG, Zürich, Switzerland
| | - Lieven Pouillon
- Department of Gastroenterology and Hepatology, Imelda GI Clinical Research Center, Imeldaziekenhuis Bonheiden, Belgium
| | - Fiona Braegger
- EUCAN Evidence Generation, Takeda Pharmaceuticals International AG, Glattpark-Opfikon, Zürich, Switzerland
| | | | - Nawal Bent-Ennakhil
- EUCAN Evidence Generation, Takeda Pharmaceuticals International AG, Glattpark-Opfikon, Zürich, Switzerland
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
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Schulze LL, Becker E, Dedden M, Liu LJ, van Passen C, Mohamed-Abdou M, Müller TM, Wiendl M, Ullrich KAM, Atreya I, Leppkes M, Ekici AB, Kirchner P, Stürzl M, Sexton D, Palliser D, Atreya R, Siegmund B, Neurath MF, Zundler S. Differential Effects of Ontamalimab Versus Vedolizumab on Immune Cell Trafficking in Intestinal Inflammation and Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1817-1832. [PMID: 37208197 DOI: 10.1093/ecco-jcc/jjad088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/16/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND AND AIMS The anti-MAdCAM-1 antibody ontamalimab demonstrated efficacy in a phase II trial in ulcerative colitis and results of early terminated phase III trials are pending, but its precise mechanisms of action are still unclear. Thus, we explored the mechanisms of action of ontamalimab and compared it to the anti-α4β7 antibody vedolizumab. METHODS We studied MAdCAM-1 expression with RNA sequencing and immunohistochemistry. The mechanisms of action of ontamalimab were assessed with fluorescence microscopy, dynamic adhesion and rolling assays. We performed in vivo cell trafficking studies in mice and compared ontamalimab and vedolizumab surrogate [-s] antibodies in experimental models of colitis and wound healing. We analysed immune cell infiltration under anti-MAdCAM-1 and anti-α4β7 treatment by single-cell transcriptomics and studied compensatory trafficking pathways. RESULTS MAdCAM-1 expression was increased in active inflammatory bowel disease. Binding of ontamalimab to MAdCAM-1 induced the internalization of the complex. Functionally, ontamalimab blocked T cell adhesion similar to vedolizumab, but also inhibited L-selectin-dependent rolling of innate and adaptive immune cells. Despite conserved mechanisms in mice, the impact of ontamalimab-s and vedolizumab-s on experimental colitis and wound healing was similar. Single-cell RNA sequencing demonstrated enrichment of ontamalimab-s-treated lamina propria cells in specific clusters, and in vitro experiments indicated that redundant adhesion pathways are active in these cells. CONCLUSIONS Ontamalimab has unique and broader mechanisms of action compared to vedolizumab. However, this seems to be compensated for by redundant cell trafficking circuits and leads to similar preclinical efficacy of anti-α4β7 and anti-MAdCAM-1 treatment. These results will be important for the interpretation of pending phase III data.
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Affiliation(s)
- Lisa Lou Schulze
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Emily Becker
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Mark Dedden
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Li-Juan Liu
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Chiara van Passen
- Department of Surgery, Division of Molecular and Experimental Surgery, University Hospital Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Germany
| | - Mariam Mohamed-Abdou
- Department of Surgery, Division of Molecular and Experimental Surgery, University Hospital Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Germany
| | - Tanja M Müller
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Maximilian Wiendl
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Karen A M Ullrich
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Imke Atreya
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Moritz Leppkes
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Philipp Kirchner
- Institute of Human Genetics, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
| | - Michael Stürzl
- Department of Surgery, Division of Molecular and Experimental Surgery, University Hospital Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Germany
| | - Dan Sexton
- Shire HGT, a Takeda company, Cambridge, MA, USA
| | | | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany
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Miyazaki H, Hoshi N, Ishida T, Nishioka C, Ouchi S, Shirasaka D, Yoshie T, Munetomo Y, Sakamoto Y, Osuga T, Matsui S, Hyodo T, Denda T, Watanabe D, Ooi M, Kodama Y. Association of CD4-positive cell infiltration with response to vedolizumab in patients with ulcerative colitis. Sci Rep 2023; 13:20262. [PMID: 37985889 PMCID: PMC10662207 DOI: 10.1038/s41598-023-47618-3] [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: 03/26/2023] [Accepted: 11/16/2023] [Indexed: 11/22/2023] Open
Abstract
Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4β7) integrin, suppresses immune cell migration by blocking the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule 1. Reports about histological features that predict vedolizumab efficacy are scarce. So, we examined the association between histological features and vedolizumab efficacy. This was a multicenter, retrospective study of patients with UC treated with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified. We enrolled 42 patients. Patients with a high CD4+ infiltration showed a better response to vedolizumab [odds ratio (OR) = 1.44, P = 0.014]. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR = 0.11, P = 0.008 and OR = 0.50, P = 0.009, respectively). Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.
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Affiliation(s)
- Haruka Miyazaki
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Namiko Hoshi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Tsukasa Ishida
- Division of Gastroenterology, Akashi Medical Center, Akashi, Japan
| | | | - Sachiko Ouchi
- Division of General Internal Medicine, Hyogo Prefectural Harima-Himeji General Medical Center, Himeji, Japan
| | - Daisuke Shirasaka
- Division of Gastroenterology, Japanese Red Cross Kobe Hospital, Kobe, Japan
| | - Tomoo Yoshie
- Division of Gastroenterology, Kita-Harima Medical Center, Ono, Japan
| | | | - Yoshio Sakamoto
- Division of Gastroenterology, Hyogo Prefectural Kakogawa Medical Center, Kakogawa, Japan
| | - Tatsuya Osuga
- Division of Gastroenterology, Takatsuki General Hospital, Takatsuki, Japan
| | - Saori Matsui
- Division of Gastroenterology, Yodogawa Christian Hospital, Osaka, Japan
| | - Toshiki Hyodo
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tamami Denda
- Department of Pathology, The Institute of Medical Science Research Hospital, The University of Tokyo, Tokyo, Japan
| | - Daisuke Watanabe
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Makoto Ooi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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Chu X, Biao Y, Liu C, Zhang Y, Liu C, Ma JZ, Guo Y, Gu Y. Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis. BMC Gastroenterol 2023; 23:346. [PMID: 37803294 PMCID: PMC10557260 DOI: 10.1186/s12876-023-02938-6] [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: 05/07/2023] [Accepted: 08/29/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND Therapeutic options for ulcerative colitis (UC) have increased since the introduction of biologics a few decades ago. Due to the wide range of biologics available, physicians have difficulty in selecting biologics and do not know how to balance the best drug between clinical efficacy and safety. This study aimed to compare the efficacy and safety of biologics in treating ulcerative colitis. METHODS In this study, eight electronic databases (PubMed, Web of Science, Cochrane, Embase, Sinomed, China National Knowledge Infrastructure, Chongqing VIP Information, and WanFang Data) were searched to collect eligible studies without language restrictions. Retrieved 1 June 2023, from inception. All articles included in the mesh analysis are randomised controlled trials (RCTs). The inclusion of drugs for each outcome was ranked using a curved surface under cumulative ranking (SUCRA). Higher SUCRA scores were associated with better outcomes, whereas lower SUCRA scores were associated with better safety. This study has registered with PROSPERO, CRD42023389483. RESULTS Induction Therapy: Among the biologic therapies evaluated for induction therapy, vedolizumab demonstrated the highest efficacy in achieving clinical remission (OR vs daclizumab, 9.09; 95% CI, 1.01-81.61; SUCRA 94.1) and clinical response. Guselkumab showed the lowest risk of recurrence of UC (SUCRA 94.9%), adverse events resulting in treatment discontinuation (SUCRA 94.8%), and serious infections (SUCRA 78.0%). Maintenance Therapy: For maintenance therapy, vedolizumab ranked highest in maintaining clinical remission (OR vs mesalazine 4.36; 95% CI, 1.65-11.49; SUCRA 89.7) and endoscopic improvement (SUCRA 92.6). Infliximab demonstrated the highest efficacy in endoscopic improvement (SUCRA 92.6%). Ustekinumab had the lowest risk of infections (SUCRA 92.9%), serious adverse events (SUCRA 91.3%), and serious infections (SUCRA 67.6%). CONCLUSION Our network meta-analysis suggests that vedolizumab is the most effective biologic therapy for inducing and maintaining clinical remission in UC patients. Guselkumab shows promise in reducing the risk of recurrence and adverse events during induction therapy. Infliximab is effective in improving endoscopic outcomes during maintenance therapy. Ustekinumab appears to have a favorable safety profile. These findings provide valuable insights for clinicians in selecting the most appropriate biologic therapy for UC patients.
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Affiliation(s)
- Xinqiao Chu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences - No.5, Beixian Pavilion, Xicheng District, Beijing, 100053, China
| | - Yaning Biao
- School of Pharmacy, Hebei University of Chinese Medicine, 326 New Shinan Road, Qiaoxi District, Shijiazhuang, Hebei, 050091, China
| | - Chengjiang Liu
- Department of General Medicine, Affiliated Anqing First People's Hospital of Anhui Medical University, Anqing, Anhui, China
| | - Yixin Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Chenxu Liu
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Ji-Zheng Ma
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences - No.5, Beixian Pavilion, Xicheng District, Beijing, 100053, China
| | - Yufeng Guo
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences - No.5, Beixian Pavilion, Xicheng District, Beijing, 100053, China.
| | - Yaru Gu
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China.
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Dotti AZ, Magro DO, Vilela EG, Chebli JMF, Chebli LA, Steinwurz F, Argollo M, Carvalho NS, Parente JML, Lima MM, Parra RS, Perin RL, Flores C, Morsoletto EM, da Costa Ferreira S, Ludvig JC, Kaiser Junior RL, Faria MAG, Nicollelli GM, Andrade AR, Queiroz NSF, Kotze PG. Vedolizumab in Mild-to-Moderate Crohn's Disease Patients Naïve to Biological Therapy: A Multicentric Observational Study. CROHN'S & COLITIS 360 2023; 5:otad053. [PMID: 37859629 PMCID: PMC10583759 DOI: 10.1093/crocol/otad053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Indexed: 10/21/2023] Open
Abstract
BACKGROUND In real-world experience, the number of patients using vedolizumab as first-line biological therapy was low. We aimed to evaluate the effectiveness and safety of vedolizumab in mild-to-moderate Crohn's disease (CD) biologic-naïve patients. METHODS We performed a retrospective multicentric cohort study with patients who had clinical activity scores (Harvey-Bradshaw Index [HBI]) measured at baseline and weeks 12, 26, 52, as well as at the last follow-up. Clinical response was defined as a reduction ≥3 in HBI, whereas clinical remission as HBI ≤4. Mucosal healing was defined as the complete absence of ulcers in control colonoscopies. Kaplan-Meier survival analysis was used to assess the persistence with vedolizumab. RESULTS From a total of 66 patients, 53% (35/66) reached clinical remission at week 12. This percentage increased to 69.7% (46/66) at week 26, and 78.8% (52/66) at week 52. Mucosal healing was achieved in 62.3% (33/53) of patients. Vedolizumab was well tolerated, and most adverse events were minor. During vedolizumab treatment, 3/66 patients underwent surgery. CONCLUSIONS This study demonstrates the effectiveness and safety of vedolizumab as a first-line biological agent in patients with mild-to-moderate CD.
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Affiliation(s)
| | | | - Eduardo Garcia Vilela
- Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | | | | | | | | | | | | | - Rogério Serafim Parra
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil
| | | | | | | | - Sandro da Costa Ferreira
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil
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Akbari P, Vuckovic D, Stefanucci L, Jiang T, Kundu K, Kreuzhuber R, Bao EL, Collins JH, Downes K, Grassi L, Guerrero JA, Kaptoge S, Knight JC, Meacham S, Sambrook J, Seyres D, Stegle O, Verboon JM, Walter K, Watkins NA, Danesh J, Roberts DJ, Di Angelantonio E, Sankaran VG, Frontini M, Burgess S, Kuijpers T, Peters JE, Butterworth AS, Ouwehand WH, Soranzo N, Astle WJ. A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology. Nat Commun 2023; 14:5023. [PMID: 37596262 PMCID: PMC10439125 DOI: 10.1038/s41467-023-40679-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 08/07/2023] [Indexed: 08/20/2023] Open
Abstract
Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes-including cell-type specific measures of granularity, nucleic acid content and reactivity-in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types-variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.
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Affiliation(s)
- Parsa Akbari
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK
- Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
| | - Dragana Vuckovic
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Luca Stefanucci
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Tao Jiang
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK
| | - Kousik Kundu
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
| | - Roman Kreuzhuber
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
| | - Erik L Bao
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA, 02115, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA
- Harvard-MIT Health Sciences and Technology, Harvard Medical School, 77 Massachusetts Ave, Cambridge, MA, 02139, USA
| | - Janine H Collins
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- Department of Haematology, Barts Health National Health Service Trust, London, E1 1BB, UK
| | - Kate Downes
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
| | - Luigi Grassi
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Jose A Guerrero
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
| | - Stephen Kaptoge
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK
| | - Julian C Knight
- Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Stuart Meacham
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
| | - Jennifer Sambrook
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Denis Seyres
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Institute for Health and Care Research Cambridge BioResource, Box 229, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
| | - Oliver Stegle
- European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK
- European Molecular Biology Laboratory, Genome Biology Unit, 69117, Heidelberg, Germany
- Division of Computational Genomics and Systems Genetics, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
| | - Jeffrey M Verboon
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA, 02115, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA
| | - Klaudia Walter
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK
| | - Nicholas A Watkins
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
| | - John Danesh
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK
| | - David J Roberts
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Headley Way, Headington, Oxford, OX3 9DU, UK
- National Institute for Health Research Oxford Biomedical Research Centre-Haematology Theme, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK
- National Health Service Blood and Transplant, Oxford Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK
| | - Emanuele Di Angelantonio
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK
- Health Data Science Research Centre, Fondazione Human Technopole, Viale Rita Levi Montalcini 1, Milan, 20157, Italy
| | - Vijay G Sankaran
- Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA, 02115, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA
| | - Mattia Frontini
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK
- Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Faculty of Health and Life Sciences, RILD Building, Barrack Road, Exeter, EX2 5DW, UK
| | - Stephen Burgess
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK
- Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK
| | - Taco Kuijpers
- Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, CB2 0PT, UK
- Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Sanquin, University of Amsterdam, Amsterdam, Netherlands
| | - James E Peters
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK
- Department of Immunology and Inflammation, Imperial College London, Commonwealth Building, The Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Adam S Butterworth
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
- Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, CB2 0BB, UK.
- Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.
| | - Willem H Ouwehand
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
- Department of Haematology, University College London Hospitals, WC1E 6AS, London, UK.
| | - Nicole Soranzo
- Department of Human Genetics, The Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
- Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
- British Heart Foundation Centre of Research Excellence, University of Cambridge, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
- Genomics Research Centre, Fondazione Human Technopole, Viale Rita Levi Montalcini 1, Milan, 20157, Italy.
| | - William J Astle
- Medical Research Council Biostatistics Unit, University of Cambridge, East Forvie Building, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge, CB2 0SR, UK.
- The National Institute for Health and Care Research Blood and Transplant Unit in Donor Health and Genomics, Strangeways Research Laboratory, Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge, CB1 8RN, UK.
- National Health Service Blood and Transplant, Cambridge Centre, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
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Honap S, Netter P, Danese S, Peyrin-Biroulet L. An update on the safety of long-term vedolizumab use in inflammatory bowel disease. Expert Opin Drug Saf 2023; 22:767-776. [PMID: 37610086 DOI: 10.1080/14740338.2023.2247976] [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: 05/11/2023] [Accepted: 08/10/2023] [Indexed: 08/24/2023]
Abstract
INTRODUCTION Vedolizumab (Entyvio) is a humanized monoclonal antibody that disrupts the interaction between α4β7 integrin on circulating T-lymphocytes and MAdCAM-1 on the vascular endothelium to prevent their egress to sites of gut inflammation. It has proven therapeutic efficacy for the treatment of moderate-to-severe Crohn's disease, ulcerative colitis, and pouchitis. AREAS COVERED This narrative review assesses the safety profile of vedolizumab from the registration trial programs, open-label extension studies, observational real-world data, and pooled safety analyses. This includes an evaluation of the long-term overall safety in special populations typically underrepresented in clinical trials. EXPERT OPINION Vedolizumab is an effective therapy for inflammatory bowel disease with a well-established safety profile. No unexpected long-term safety signals have been identified. Safety data in pregnancy, in pediatric and elderly populations, in patients undergoing surgery, and in patients with a prior history of cancer are reassuring. Due to its safety merits, we propose that vedolizumab is an excellent candidate for advanced combination treatment with an anti-cytokine approach using another biologic or novel small molecule inhibitor. This is important in patients with medically refractory IBD, in patients at high risk of developing disease-related complications, or in patients with concomitant uncontrolled immune-mediated inflammatory diseases.
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Affiliation(s)
- Sailish Honap
- Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Patrick Netter
- Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, Faculté de Médecine, University of Lorraine and University Hospital of Nancy, Nancy, France
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Groupe Hospitalier privé Ambroise Paré - Hartmann, Paris IBD center, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
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Sandborn WJ, Chen J, Kisfalvi K, Loftus EV, D’Haens G, Candela N, Lasch K, Wolf DC, Uddin SM, Danese S. Practical Primer Addressing Real-World Use Scenarios of Subcutaneous Vedolizumab in Ulcerative Colitis and Crohn's Disease: Post Hoc Analyses of VISIBLE Studies. CROHN'S & COLITIS 360 2023; 5:otad034. [PMID: 37636008 PMCID: PMC10449415 DOI: 10.1093/crocol/otad034] [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: 01/12/2023] [Indexed: 08/29/2023] Open
Abstract
Background Vedolizumab, an anti-α4β7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios. Methods Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1-46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening. Results No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W. Conclusions Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD.
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Affiliation(s)
- William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Jingjing Chen
- Department of Statistics and Quantitative Sciences, Takeda Development Center Americas Inc., Cambridge, MA, USA
| | - Krisztina Kisfalvi
- Department of Statistics and Quantitative Sciences, Takeda Development Center Americas Inc., Cambridge, MA, USA
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Geert D’Haens
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Ninfa Candela
- Department of Gastroenterology, Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - Karen Lasch
- Department of Gastroenterology, Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - Douglas C Wolf
- Department of US Medical, Atlanta Gastroenterology Associates, Atlanta, GA, USA
| | - Sharif M Uddin
- Department of Gastroenterology, Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - Silvio Danese
- Gastroenterology and Digestive Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
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Schreidah CM, Fahmy LM, Lapolla BA, Kwinta BD, Magro CM, Geskin LJ. Clinical Remission of Primary Cutaneous Marginal Zone B-Cell Lymphoma in a Patient With Crohn's Disease After Helicobacter pylori Quadruple Therapy and Vedolizumab. Am J Dermatopathol 2023; Publish Ahead of Print:00000372-990000000-00206. [PMID: 37377200 DOI: 10.1097/dad.0000000000002470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Affiliation(s)
- Celine M Schreidah
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY
| | - Lauren M Fahmy
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY
| | - Brigit A Lapolla
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY; and
| | - Bradley D Kwinta
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY
| | - Cynthia M Magro
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Larisa J Geskin
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY; and
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Lee SH, Moon SJ, Woo SH, Ahn G, Kim WK, Lee CH, Hwang JH. CrebH protects against liver injury associated with colonic inflammation via modulation of exosomal miRNA. Cell Biosci 2023; 13:116. [PMID: 37370191 DOI: 10.1186/s13578-023-01065-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Hepatic liver disease, including primary sclerosing cholangitis (PSC), is a serious extraintestinal manifestations of colonic inflammation. Cyclic adenosine monophosphate (cAMP)-responsive element-binding protein H (CrebH) is a transcription factor expressed mostly in the liver and small intestine. However, CrebH's roles in the gut-liver axis remain unknown. METHODS Inflammatory bowel disease (IBD) and PSC disease models were established in wild-type and CrebH-/- mice treated with dextran sulfate sodium, dinitrobenzene sulfonic acid, and diethoxycarbonyl dihydrocollidine diet, respectively. RNA sequencing were conducted to investigate differential gene expression. Exosomes were isolated from plasma and culture media. miRNA expression profiling was performed using the NanoString nCounter Mouse miRNA Panel. Effects of miR-29a-3p on adhesion molecule expression were investigated in bEnd.3 brain endothelial cells. RESULTS CrebH-/- mice exhibited accelerated liver injury without substantial differences in the gut after administration of dextran sulfate sodium (DSS), and had similar features to PSC, including enlarged bile ducts, enhanced inflammation, and aberrant MAdCAM-1 expression. Furthermore, RNA-sequencing analysis showed that differentially expressed genes in the liver of CrebH-/- mice after DSS overlapped significantly with genes changed in PSC-liver. Analysis of plasma exosome miRNA isolated from WT and CrebH-/- mice indicates that CrebH can contribute to the exosomal miRNA profile. We also identified miR-29a-3p as an effective mediator for MAdCAM-1 expression. Administration of plasma exosome from CrebH-/- mice led to prominent inflammatory signals in the liver of WT mice with inflammatory bowel disease (IBD). CONCLUSIONS CrebH deficiency led to increased susceptibility to IBD-induced liver diseases via enhanced expression of adhesion molecules and concomitant infiltration of T lymphocytes. Exosomes can contribute to the progression of IBD-induced liver injury in CrebH-/- mice. These study provide novel insights into the role of CrebH in IBD-induced liver injury.
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Affiliation(s)
- Sang-Hee Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- Department of Biology, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon, 34520, Korea
| | - Sung-Je Moon
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
| | - Seung Hee Woo
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
- Department of Biology and Microbiology, Changwon National University, 20 Chanwondaehak-ro, Uichan-gu, Chanwon-si, Gyeonsangnam-do, 51140, Korea
| | - Gwangsook Ahn
- Department of Biology, Daejeon University, 62 Daehak-ro, Dong-gu, Daejeon, 34520, Korea
| | - Won Kon Kim
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea
- Metabolic Regulation Research Center, KRIBB, 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea.
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
| | - Jung Hwan Hwang
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseoung-gu, Daejeon, 34141, Korea.
- KRIBB School of Bioscience, University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Korea.
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Tang HJ, Bie CQ, Guo LL, Zhong LX, Tang SH. Efficacy and safety of vedolizumab in the treatment of patients with inflammatory bowel disease: A systematic review and meta‑analysis of randomized controlled trials. Exp Ther Med 2023; 25:298. [PMID: 37229320 PMCID: PMC10203751 DOI: 10.3892/etm.2023.11997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 04/05/2023] [Indexed: 05/27/2023] Open
Abstract
Few studies have thoroughly assessed the efficacy and safety of vedolizumab (VDZ) in the treatment of inflammatory bowel disease (IBD). Therefore, this systematic review and meta-analysis was performed to further evaluate this association. PubMed, Embase, and the Cochrane databases were searched until April 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of VDZ in the treatment of IBD were included. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome using a random effects model. A total of 12 RCTs, including 4,865 patients, met the inclusion criteria. In the induction phase, VDZ was more effective than placebo for patients with ulcerative colitis and Crohn's disease (CD) in clinical remission (RR=2.09; 95% CI=1.66-2.62) and clinical response (RR=1.54; 95% CI=1.34-1.78). In the maintenance therapy group, VDZ reached higher clinical remission (RR=1.98; 95% CI=1.58-2.49) and clinical response (RR=1.78; 95% CI=1.40-2.26) rates compared with the placebo group. VDZ particularly improved clinical remission (RR=2.07; 95% CI=1.48-2.89) and clinical response (RR=1.84; 95% CI=1.54-2.21) in patients with TNF antagonist failure. In terms of corticosteroid-free remission, VDZ was also more effective than placebo in patients with IBD (RR=1.98; 95% CI=1.51-2.59). In Crohn's patients, VDZ was more effective than placebo in terms of mucosal healing (RR=1.78; 95% CI=1.27-2.51). With respect to adverse events, VDZ significantly reduced the risk of IBD exacerbation compared with the placebo (RR=0.60; 95% CI=0.39-0.93; P=0.023). However, when compared with the placebo, VDZ increased the risk of nasopharyngitis in patients with CD (RR=1.77; 95% CI=1.01-3.10; P=0.045). No significant differences in other adverse events were observed. Although there might be underlying risk, such as selection bias, in the present study it can be safely concluded that VDZ is a safe and effective biological agent for IBD, particularly for patients with TNF antagonist failure.
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Affiliation(s)
- Hui-Jun Tang
- Department of Gastroenterology, Shenzhen Integrated Traditional Chinese and Western Medicine Hospital, Shenzhen, Guangdong 518104, P.R. China
| | - Cai-Qun Bie
- Department of Gastroenterology, Shenzhen Integrated Traditional Chinese and Western Medicine Hospital, Shenzhen, Guangdong 518104, P.R. China
| | - Li-Liangzi Guo
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Li-Xian Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Shao-Hui Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, P.R. China
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Oki Y, Nagano S, Ishikawa Y, Yamada T, Ichimori T, Uchida K. Ulcerative colitis successfully treated with vedolizumab in the presence of comorbid opportunistic infections: a case report. J Med Case Rep 2023; 17:227. [PMID: 37254193 DOI: 10.1186/s13256-023-03940-y] [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: 11/28/2022] [Accepted: 04/21/2023] [Indexed: 06/01/2023] Open
Abstract
BACKGROUND Opportunistic infections associated with immunosuppressive treatments for inflammatory bowel disease pose an important safety concern. Here we report the case of a patient with active ulcerative colitis and cryptococcal pneumonia who was treated with vedolizumab combined with fluconazole. CASE PRESENTATION A 56-year-old Japanese man with ulcerative colitis and a history of Sweet's syndrome who was taking prednisolone and azathioprine presented with a moderate exacerbation of ulcerative colitis, abdominal pain, diarrhea, and bloody stools along with cytomegalovirus infection. Increasing the prednisolone dose without using antiviral drugs improved cytomegalovirus infection; however, ulcerative colitis did not improve, and cryptococcal pneumonia occurred. Thus, treatment with fluconazole followed by vedolizumab was initiated for ulcerative colitis. The patient gradually recovered and achieved clinical remission without the exacerbation of pneumonia. CONCLUSIONS We reported the first case of a patient with ulcerative colitis who was treated with vedolizumab and concomitant fluconazole for active cryptococcal pneumonia. Vedolizumab constitutes a high-potential treatment regimen owing to its safety in inflammatory bowel disease associated with opportunistic infections.
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Affiliation(s)
- Yusuke Oki
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan.
| | - Sho Nagano
- Department of Gastroenterology, Kochi Health Sciences Center, Kochi, Japan
| | - Yoichi Ishikawa
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Takayoshi Yamada
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
| | - Toshiki Ichimori
- Department of Internal Medicine, Susakikuroshio Hospital, Susaki, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, Kochi, 783-8505, Japan
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Li R, Li X, Zhou H, Shi Y, Wang F, Wu T, Liang J. Successful treatment of a refractory intestinal Behcet's disease with an oncology history by Vedolizumab: a case report and literature review. Front Immunol 2023; 14:1205046. [PMID: 37287984 PMCID: PMC10242066 DOI: 10.3389/fimmu.2023.1205046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 05/10/2023] [Indexed: 06/09/2023] Open
Abstract
Objective Behçet's Disease (BD) is an intractable systemic vasculitis. When accompanied by intestinal symptoms, the prognosis is usually poor. 5-Aminosalicylic acid (5-ASA), corticosteroids, immunosuppressive drugs, and anti-tumor necrosis factor-α (anti-TNF-α) biologics are standard therapies to induce or maintain remission for intestinal BD. However, they might not be effective in refractory cases. Safety should also be considered when patients have an oncology history. Regarding the pathogenesis of intestinal BD and the specific targeting effect of vedolizumab (VDZ) on the inflammation of the ileum tract, previous case reports suggested that VDZ might be a potential treatment for refractory intestinal BD. Methods We report a 50-year-old woman patient with intestinal BD who had oral and genital ulcers, joint pain, and intestinal involvement for about 20 years. The patient responds well to anti-TNF-α biologics but not to conventional drugs. However, biologics treatment was discontinued due to the occurrence of colon cancer. Results VDZ was intravenously administered at a dose of 300 mg at 0, 2, and 6 weeks and then every eight weeks. At the 6-month follow-up, the patient reported significant improvement in abdominal pain and arthralgia. We observed complete healing of intestinal mucosal ulcers under endoscopy. However, her oral and vulvar ulcers remained unresolved, which disappeared after adding thalidomide. Conclusion VDZ may be a safe and effective option for refractory intestinal BD patients who do not respond well to conventional treatments, especially those with an oncology history.
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Affiliation(s)
| | | | | | | | | | - Tong Wu
- *Correspondence: Tong Wu, ; Jie Liang,
| | - Jie Liang
- *Correspondence: Tong Wu, ; Jie Liang,
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Imaichi-Kobayashi S, Kassab R, Piersigilli A, Robertson R, Leonard C, Long N, Dean B, Phaneuf M, Ling V. An electrospun macrodevice for durable encapsulation of human cells with consistent secretion of therapeutic antibodies. Biomaterials 2023; 298:122123. [PMID: 37172505 DOI: 10.1016/j.biomaterials.2023.122123] [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: 09/15/2022] [Revised: 03/31/2023] [Accepted: 04/08/2023] [Indexed: 05/15/2023]
Abstract
Frequent subcutaneous or intravenous administrations of therapeutic biomolecules can be costly and inconvenient for patients. Implantation of encapsulated recombinant cells represents a promising approach for the sustained delivery of biotherapeutics. However, foreign body and fibrotic response against encapsulation materials results in drastically reduced viability of encapsulated cells, presenting a major engineering challenge for biocompatibility. Here, we show that the multi-laminate electrospun retrievable macrodevice (Bio-Spun) protects genetically modified human cells after subcutaneous implant in mice. We describe here a biocompatible nanofiber device that limits fibrosis and extends implant survival. For more than 150 days, these devices supported human cells engineered to secrete the antibodies: vedolizumab, ustekinumab, and adalimumab, while eliciting minimal fibrotic response in mice. The porous electrospun cell chamber allowed secretion of the recombinant antibodies into the host bloodstream, and prevented infiltration of host cells into the chamber. High plasma levels (>50 μg/mL) of antibody were maintained in the optimized devices for more than 5 months. Our findings demonstrate that macrodevices constructed from electrospun materials are effective in protecting genetically engineered cells for the sustained administration of recombinant therapeutic antibodies.
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Affiliation(s)
| | | | - Alessandra Piersigilli
- Department of Drug Safety Research and Evaluation, Takeda Pharmaceuticals, Cambridge, MA, USA
| | | | - Christopher Leonard
- Department of Drug Safety Research and Evaluation, Takeda Pharmaceuticals, Cambridge, MA, USA
| | | | | | | | - Vincent Ling
- Department of Pharmaceutical Science, Takeda Pharmaceuticals, Cambridge, MA, USA.
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Khan N, Mahmud N, Patel M, Sundararajan R, Reinisch W. Risk of severe and opportunistic infections and the impact of SARS-COV-2 on this risk in a nationwide cohort of patients with inflammatory bowel disease. Aliment Pharmacol Ther 2023; 57:800-807. [PMID: 36645110 PMCID: PMC10023400 DOI: 10.1111/apt.17393] [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: 10/20/2022] [Revised: 11/27/2022] [Accepted: 01/04/2023] [Indexed: 01/17/2023]
Abstract
BACKGROUND The Inflammatory Bowel Disease (IBD) patients have adopted lifestyle modifications to prevent infection via SARS COV-2. AIMS This study aims to examine rate of serious infections and opportunistic infections in the pre-pandemic and pandemic period, and to analyse if the risk associated with medications used to treat IBD were potentially modified by associated change in lifestyle. METHODS We conducted a retrospective cohort study of patients from the US national Veteran Affairs Healthcare System (VAHS). Patients were stratified into two groups: pre-pandemic (prior to SARS COV-2 pandemic) and pandemic (during SARS COV-2 pandemic) and outcomes were measured in these groups. Primary outcome was occurrence of any serious infection. Secondary outcome was occurrence of any opportunistic infection. RESULTS There were 17,202 IBD patients in the pre-pandemic era and 15,903 patients in the pandemic era. The pre-pandemic era had a significantly higher proportion of serious infections relative to the pandemic era (5.1% vs. 4.4%, p = 0.002). The proportion of opportunistic infections were similar between pre-pandemic and pandemic eras (0.3% vs. 0.3%, p = 0.82). Relative to 5-ASA, patients taking anti-TNF (HR = 1.50 (1.31-1.72)), anti-TNF+TP (HR = 1.56 (1.24-1.95)) or vedolizumab (HR = 1.81 (1.49-2.20)) had an increased hazard of serious infection (p > 0.001). CONCLUSION In a nationwide cohort of IBD patients, we found that risk of serious infections could possibly be affected by behavioural modifications due to SARS-COV-2 pandemic.
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Affiliation(s)
- Nabeel Khan
- Department of Gastroenterology, Corporal Michael J Crescenz
VA Medical Center, Philadelphia, Pennsylvania, USA
- Division of Gastroenterology, University of Pennsylvania,
Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Nadim Mahmud
- Department of Gastroenterology, Corporal Michael J Crescenz
VA Medical Center, Philadelphia, Pennsylvania, USA
- Division of Gastroenterology, University of Pennsylvania,
Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Manthankumar Patel
- Department of Gastroenterology, Corporal Michael J Crescenz
VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Ramaswamy Sundararajan
- Department of Gastroenterology, Corporal Michael J Crescenz
VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Walter Reinisch
- Division of Gastroenterology and Hepatology, Medical
University of Vienna, Vienna, Austria
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Haglund S, Söderman J, Almer S. Differences in Whole-Blood Transcriptional Profiles in Inflammatory Bowel Disease Patients Responding to Vedolizumab Compared with Non-Responders. Int J Mol Sci 2023; 24:ijms24065820. [PMID: 36982892 PMCID: PMC10052064 DOI: 10.3390/ijms24065820] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Vedolizumab is efficacious in the treatment of Crohn's disease (CD) and ulcerative colitis (UC). However, a significant proportion of patients present with a non-response. To investigate whether differences in the clinical response to vedolizumab is reflected in changes in gene expression levels in whole blood, samples were collected at baseline before treatment, and at follow-up after 10-12 weeks. Whole genome transcriptional profiles were established by RNA sequencing. Before treatment, no differentially expressed genes were noted between responders (n = 9, UC 4, CD 5) and non-responders (n = 11, UC 3, CD 8). At follow-up, compared with baseline, responders displayed 201 differentially expressed genes, and 51 upregulated (e.g., translation initiation, mitochondrial translation, and peroxisomal membrane protein import) and 221 downregulated (e.g., Toll-like receptor activating cascades, and phagocytosis related) pathways. Twenty-two of the upregulated pathways in responders were instead downregulated in non-responders. The results correspond with a dampening of inflammatory activity in responders. Although considered a gut-specific drug, our study shows a considerable gene regulation in the blood of patients responding to vedolizumab. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes. However, treatment outcomes may depend on several interacting genes, and our results indicate a possible potential of pathway analysis in predicting response to treatment, which merits further investigation.
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Affiliation(s)
- Sofie Haglund
- Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden
- Laboratory Medicine, Region Jönköping County, 551 85 Jönköping, Sweden
| | - Jan Söderman
- Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden
- Laboratory Medicine, Region Jönköping County, 551 85 Jönköping, Sweden
| | - Sven Almer
- IBD-Unit, Division of Gastroenterology, Karolinska University Hospital, 171 76 Stockholm, Sweden
- Department of Medicine, Karolinska Institutet-Solna, 171 76 Stockholm, Sweden
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