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Temido MJ, Honap S, Jairath V, Vermeire S, Danese S, Portela F, Peyrin-Biroulet L. Overcoming the challenges of overtreating and undertreating inflammatory bowel disease. Lancet Gastroenterol Hepatol 2025; 10:462-474. [PMID: 39919770 DOI: 10.1016/s2468-1253(24)00355-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 10/20/2024] [Accepted: 10/22/2024] [Indexed: 02/09/2025]
Abstract
Several therapeutic advances have been achieved over the past two decades for inflammatory bowel disease (IBD). The expanding therapeutic armamentarium and the increasingly ambitious treatment targets have led to an increased use of advanced therapies and better outcomes. Nevertheless, many patients remain suboptimally treated and are at risk of disease progression, hospital admission, and surgery, even when advanced therapies are cycled, escalated, or combined. Conversely, IBD can also be characterised by an indolent disease course. Top-down and treat-to-target strategies, although beneficial in a substantial proportion of patients, might not be advantageous in patients with mild disease and might risk overtreatment. Identifying patients with mild activity and a benign disease trajectory in the long-term is important; unnecessary exposure to advanced therapies increases the risk of adverse events and increases financial costs and health-care resource utilisation. This Review details the importance of adopting clinical strategies to avoid the pitfalls of undertreating and overtreating IBD.
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Affiliation(s)
- Maria José Temido
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France; Gastroenterology Department, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
| | - Sailish Honap
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France; 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
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine; Lawson Health Research Institute; and Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
| | - Severine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Francisco Portela
- Gastroenterology Department, Unidade Local de Saúde de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, CHRU Nancy, INSERM NGERE, Université de Lorraine, Vandœuvre-lès-Nancy, France.
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Vieujean S, Jairath V, Peyrin-Biroulet L, Dubinsky M, Iacucci M, Magro F, Danese S. Understanding the therapeutic toolkit for inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-024-01035-7. [PMID: 39891014 DOI: 10.1038/s41575-024-01035-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 02/03/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
| | - Vipul Jairath
- Division of Gastroenterology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marla Dubinsky
- Department of Paediatrics, Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy.
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3
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Purnak T, Ertan A. Optimal Management of Patients with Moderate-to-Severe Inflammatory Bowel Disease. J Clin Med 2024; 13:7026. [PMID: 39685485 PMCID: PMC11642585 DOI: 10.3390/jcm13237026] [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: 10/08/2024] [Revised: 11/07/2024] [Accepted: 11/11/2024] [Indexed: 12/18/2024] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and often debilitating condition requiring complex and individualized management. Over the past few decades, advancements in understanding IBD pathophysiology have led to a transformative shift in therapeutic approaches. This article provides a comprehensive overview of the evolution of IBD treatments, from early symptom-focused therapies to modern biologics, small molecule agents, and emerging treatment strategies. We discuss therapeutic goals centered on achieving clinical remission, endoscopic/mucosal healing, and enhancing patient quality of life. Additionally, we explore the rationale for the early and personalized use of biologic therapies in moderate-to-severe cases, review the current FDA-approved agents as of 2024, and highlight the advantages and limitations of these treatments. Special attention is given to the evolving role of novel oral therapies, including Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators, and future new directions. This paper aims to guide clinicians in navigating the expanding therapeutic landscape of IBD, emphasizing patient-centered decision-making and addressing ongoing challenges in achieving optimal disease control.
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Affiliation(s)
- Tugrul Purnak
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University Texas McGovern Medical School, Houston, TX 77030, USA;
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Ali GF, Hassanein EHM, Mohamed WR. Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8165-8188. [PMID: 38822868 PMCID: PMC11522073 DOI: 10.1007/s00210-024-03164-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 05/13/2024] [Indexed: 06/03/2024]
Abstract
Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX's severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury.
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Affiliation(s)
- Gaber F Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, 62514, Egypt
| | - Emad H M Hassanein
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Assiut Branch, Al-Azhar University, Assiut, 71524, Egypt
| | - Wafaa R Mohamed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni Suef, 62514, Egypt.
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Gordon H, Minozzi S, Kopylov U, Verstockt B, Chaparro M, Buskens C, Warusavitarne J, Agrawal M, Allocca M, Atreya R, Battat R, Bettenworth D, Bislenghi G, Brown SR, Burisch J, Casanova MJ, Czuber-Dochan W, de Groof J, El-Hussuna A, Ellul P, Fidalgo C, Fiorino G, Gisbert JP, Sabino JG, Hanzel J, Holubar S, Iacucci M, Iqbal N, Kapizioni C, Karmiris K, Kobayashi T, Kotze PG, Luglio G, Maaser C, Moran G, Noor N, Papamichael K, Peros G, Reenaers C, Sica G, Sigall-Boneh R, Vavricka SR, Yanai H, Myrelid P, Adamina M, Raine T. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis 2024; 18:1531-1555. [PMID: 38877997 DOI: 10.1093/ecco-jcc/jjae091] [Citation(s) in RCA: 56] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Indexed: 07/28/2024]
Affiliation(s)
- Hannah Gordon
- Translational Gastroenterology and Liver Unit, University of Oxford, Oxford, UK
| | - Silvia Minozzi
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Ramat Gan, Israel
| | - Bram Verstockt
- Department Gastroenterology & Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
- Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - María Chaparro
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - Christianne Buskens
- Department of Surgery, Amsterdam UMC, Location VUMC, Amsterdam, The Netherlands
| | | | - Manasi Agrawal
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Molecular Prediction of Inflammatory Bowel Disease [PREDICT], Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Mariangela Allocca
- IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Gastroenterology and Endoscopy, Milan, Italy
| | - Raja Atreya
- First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Robert Battat
- Division of Gastroenterology, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada
| | - Dominik Bettenworth
- CED Schwerpunktpraxis, Münster and Medical Faculty of the University of Münster, Münster, Germany
| | - Gabriele Bislenghi
- Department of Abdominal Surgery, University Hospitals Leuven, Leuven, Belgium
| | | | - Johan Burisch
- Gastrounit, Medical Division, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark; Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults; Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - María José Casanova
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - Wladyslawa Czuber-Dochan
- Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King's College London, London, UK
| | - Joline de Groof
- Colorectal Surgery, Royal Surrey NHS Foundation Trust, Guildford, UK
| | - Alaa El-Hussuna
- Department of Surgery, OpenSourceResearch Organization [OSRC.Network], Aalborg, Denmark
| | - Pierre Ellul
- Division of Gastroenterology, Mater Dei Hospital, L-Imsida, Malta
| | - Catarina Fidalgo
- Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
- Division of Gastroenterology, Hospital da Luz, Lisboa, Portugal
| | | | - Javier P Gisbert
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-Princesa], Universidad Autónoma de Madrid [UAM], Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - João Guedelha Sabino
- Department Gastroenterology & Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Jurij Hanzel
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Stefan Holubar
- Department of Colon & Rectal Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Nusrat Iqbal
- Department of Surgery, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | | | | | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Paulo Gustavo Kotze
- Health Sciences Postgraduate Program, Pontificia Universidade Católica do Paraná [PUCPR], Curitiba, Brazil
| | - Gaetano Luglio
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Christian Maaser
- Outpatients Department of Gastroenterology, University Teaching Hospital Lueneburg, Lueneberg, Germany
| | - Gordon Moran
- National Institute of Health Research Nottingham Biomedical Research Centre, University of Nottingham and Nottingham University Hospitals, Nottingham, UK
- Translational Medical Sciences, School of Medicine, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Nurulamin Noor
- Department of Medicine, University of Cambridge, School of Clinical Medicine, Cambridge, UK
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Georgios Peros
- Department of Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland
| | | | - Giuseppe Sica
- Department of Surgery, Università Tor Vergata, Roma, Italy
| | - Rotem Sigall-Boneh
- Pediatric Gastroenterology and Nutrition Unit, E. Wolfson Medical Center, Holon, Israel
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Henit Yanai
- IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva; Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Pär Myrelid
- Department of Surgery and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Michel Adamina
- Department of Surgery, Cantonal Hospital of Fribourg & Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Boustani P, Sadeghi A, Khayatian S, Alatab S, Anushiravani A, Sima AR, Vahedi H. Efficacy of Methotrexate and Anti-TNF Combination Therapy in Adults with Refractory Crohn's Disease. Middle East J Dig Dis 2024; 16:221-224. [PMID: 39807419 PMCID: PMC11725026 DOI: 10.34172/mejdd.2024.395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 09/11/2024] [Indexed: 01/16/2025] Open
Abstract
Background Biological medications have played a significant role in maintenance therapy for Crohn's disease (CD), but some cases become refractory to these agents. Methotrexate (MTX) appears to be a cost-effective and readily available drug for enhancing the effectiveness of maintenance therapy when used in combination with anti-tumor necrosis factor (anti-TNF) therapy in such cases. However, its effectiveness is still to be established. We aimed to assess the efficacy of MTX and anti-TNF combination therapy in patients with refractory CD. Methods A retrospective cohort study was conducted on adult patients with CD who were refractory to anti-TNF therapy and were initiated on weekly intravenous MTX in addition to the anti-TNF therapy. These patients were then followed up for over a year. The primary outcome measured was the clinical response to treatment, based on the Harvey-Bradshaw Index. The secondary outcomes included assessing the adverse events and complications of MTX therapy. Results Of 70 patients, 44 were included in the final analysis. Among them, 30 patients (68.2%) achieved complete remission, four patients (9.1%) had a partial clinical response, and 10 patients (22.7%) required surgery. The adverse events and complications of MTX therapy were mild and infrequent (9.1%). None of the demographic or clinical factors were significantly associated with response to treatment (P>0.05). Conclusion Combining MTX with anti-TNF therapy appears to be an effective and safe treatment for patients with Crohn's disease, particularly those with severe disease who are less responsive to monotherapy. However, further studies are needed to confirm these findings.
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Affiliation(s)
- Paria Boustani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Anahita Sadeghi
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sina Khayatian
- Department of Internal Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Sudabeh Alatab
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Anushiravani
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Reza Sima
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Homayoon Vahedi
- Digestive Disease Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Louis E, Schreiber S, Panaccione R, Bossuyt P, Biedermann L, Colombel JF, Parkes G, Peyrin-Biroulet L, D’Haens G, Hisamatsu T, Siegmund B, Wu K, Boland BS, Melmed GY, Armuzzi A, Levine P, Kalabic J, Chen S, Cheng L, Shu L, Duan WR, Pivorunas V, Sanchez Gonzalez Y, D’Cunha R, Neimark E, Wallace K, Atreya R, Ferrante M, Loftus EV. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials. JAMA 2024; 332:881-897. [PMID: 39037800 PMCID: PMC11264075 DOI: 10.1001/jama.2024.12414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 06/06/2024] [Indexed: 07/24/2024]
Abstract
IMPORTANCE The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. OBJECTIVE To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. DESIGN, SETTING, AND PARTICIPANTS Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. INTERVENTIONS For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. RESULTS Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. CONCLUSION AND RELEVANCE Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.
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Affiliation(s)
- Edouard Louis
- Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Stefan Schreiber
- Department of Internal Medicine, University Hospital Schleswig-Holstein, Christian-Albrecht University of Kiel, Kiel, Germany
| | - Remo Panaccione
- Inflammatory Bowel Disease Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Peter Bossuyt
- Imelda GI Clinical Research Center, Imelda General Hospital, Bonheiden, Belgium
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jean-Frederic Colombel
- Henry D. Janowitz Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gareth Parkes
- Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, England
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and INSERM U1256, University Hospital of Nancy, Lorraine University, Vandoeuvre, France
| | - Geert D’Haens
- Department of Gastroenterology, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Japan
| | - Britta Siegmund
- Department of Gastroenterology, Infectiology and Rheumatology, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Brigid S. Boland
- Division of Gastroenterology, University of California–San Diego, La Jolla
| | - Gil Y. Melmed
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars Sinai Medical Center, Los Angeles, California
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | | | | | - Su Chen
- AbbVie Inc, North Chicago, Illinois
| | | | - Lei Shu
- AbbVie Inc, North Chicago, Illinois
| | | | | | | | | | | | | | - Raja Atreya
- First Department of Medicine, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Edward V. Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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Sequier L, Caron B, Loeuille D, Honap S, Jairath V, Netter P, Danese S, Sibilia J, Peyrin-Biroulet L. Systematic review: Methotrexate-A poorly understood and underused medication in inflammatory bowel disease. Aliment Pharmacol Ther 2024; 60:686-700. [PMID: 39076140 DOI: 10.1111/apt.18194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/14/2024] [Accepted: 07/21/2024] [Indexed: 07/31/2024]
Abstract
BACKGROUND Methotrexate, an immunosuppressant used for the treatment of inflammatory bowel disease (IBD) for over 30 years, remains underused compared to thiopurines. AIMS To review the efficacy, safety, optimal dosing and delivery regimens of methotrexate in adults with IBD. METHODS We conducted a systematic review of studies involving patients with IBD treated with methotrexate from inception to August 2023. All studies were included from the MEDLINE database via PubMed. RESULTS For Crohn's disease, we included eight randomised controlled trials (RCTs) and 17 observational studies. Parenteral methotrexate effectively increased remission rates in steroid-dependent patients at 25 mg/week for 16 weeks and at 15 mg/week for maintenance. Methotrexate can be used in combination with anti-tumour necrosis factor (TNF) agents to reduce immunogenicity. Data comparing thiopurines and methotrexate remain scarce. For ulcerative colitis (UC), we included five RCTs and 10 observational studies were included; there was no evidence to support the use of methotrexate in (UC). We extracted safety data from 17 studies; mild-to-moderate adverse effects were common. The incidence of liver fibrosis or cirrhosis was low. CONCLUSION Methotrexate is effective at inducing and maintaining remission in steroid-refractory Crohn's disease and can reduce anti-TNF-induced immunogenicity when used in combination therapy. Data regarding tolerance and safety are reassuring. These findings challenge preconceived ideas on methotrexate and suggest that it is a valid first-line conventional option for the treatment of mild-to-moderate Crohn's disease.
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Affiliation(s)
- Léa Sequier
- Department of Gastroenterology and Hepatology, Nîmes University Hospital, Carémeau Hospital, Nîmes, France
- Department of Gastroenterology and Hepatology A, Saint-Éloi Hospital, Montpellier, France
| | - Bénédicte Caron
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- INSERM, NGERE, University of Lorraine, Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France
| | - Damien Loeuille
- Department of Rheumatology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA) UMR 7365 CNRS, University of Lorraine, Nancy, France
| | - Sailish Honap
- School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Vipul Jairath
- Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada
| | - Patrick Netter
- Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA) UMR 7365 CNRS, University of Lorraine, Nancy, France
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Department of Immunology, Transplantation and Infectious Disease, Università Vita-Salute San Raffaele, Milan, Italy
| | - Jean Sibilia
- Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- UMR INSERM 1109, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- INSERM, NGERE, University of Lorraine, Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France
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9
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Sturm A, Atreya R, Bettenworth D, Bokemeyer B, Dignass A, Ehehalt R, Germer CT, Grunert PC, Helwig U, Horisberger K, Herrlinger K, Kienle P, Kucharzik T, Langhorst J, Maaser C, Ockenga J, Ott C, Siegmund B, Zeißig S, Stallmach A. Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) (Version 4.1) – living guideline. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1229-1318. [PMID: 39111333 DOI: 10.1055/a-2309-6123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/02/2024]
Affiliation(s)
- Andreas Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - Raja Atreya
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Erlangen, Deutschland
| | | | - Bernd Bokemeyer
- Gastroenterologische Gemeinschaftspraxis Minden, Minden, Deutschland
| | - Axel Dignass
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt am Main, Deutschland
| | | | | | - P C Grunert
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
| | - Ulf Helwig
- Internistische Praxengemeinschaft, Oldenburg, Deutschland
| | - Karoline Horisberger
- Universitätsmedizin Johannes Gutenberg, Universität Klinik f. Allgemein-,Visceral- und Transplantationschirurgie, Mainz, Deutschland
| | | | - Peter Kienle
- Allgemein- und Viszeralchirurgie, Theresienkrankenhaus und Sankt Hedwig-Klinik GmbH, Mannheim, Deutschland
| | - Torsten Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Lüneburg, Deutschland
| | - Jost Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Klinikum am Bruderwald, Bamberg, Deutschland
| | - Christian Maaser
- Gastroenterologie, Ambulanzzentrum Lüneburg, Lüneburg, Deutschland
| | - Johann Ockenga
- Medizinische Klinik II, Klinikum Bremen Mitte - Gesundheit Nord, Bremen, Deutschland
| | - Claudia Ott
- Gastroenterologie Facharztzentrum, Regensburg, Deutschland
| | - Britta Siegmund
- Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Deutschland
| | - Sebastian Zeißig
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Deutschland
| | - Andreas Stallmach
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
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10
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Li L, Cheng R, Wu Y, Lin H, Gan H, Zhang H. Diagnosis and management of inflammatory bowel disease. J Evid Based Med 2024; 17:409-433. [PMID: 38934234 DOI: 10.1111/jebm.12626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 06/10/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disease of the gastrointestinal tract with a gradually increasing global incidence and prevalence. A prolonged course of IBD leads to a decline in patient quality of life and the creation of a substantial economic burden on society. Owing to the lack of specific diagnostic markers, the diagnosis of IBD still needs a gold standard based on a combination of clinical manifestations, imaging, laboratory, and endoscopic results. Accordingly, the current goals of IBD treatment are to alleviate clinical symptoms and reduce recurrence rates. Therefore, it is imperative to develop a standard set of procedures to diagnose and treat IBD. In this review, we summarize prominent and emerging studies, outline classical and contemporary approaches to diagnosing and managing IBD, and integrate multiple guidelines. Furthermore, we propose the possibility of establishing an early and comprehensive diagnostic workflow and personalized management strategy in the future. We aim to enhance the quality and standardization of diagnostic and treatment procedures for IBD.
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Affiliation(s)
- Lili Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Cheng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yushan Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Hao Lin
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Huatian Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- The Center of Gerontology and Geriatrics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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11
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Salazar J, Garcia-Planella E, Fernández-Clotet A, Esteve M, Gisbert JP, Busquets D, Lucendo A, Márquez L, Guardiola J, Martín-Arranz MD, Iglesias E, Monfort D, Villoria A, Cañete F, Bell O, Ricart E, Zabana Y, Chaparro M, Domènech E, Gordillo J. Genetic biomarkers of methotrexate response and safety in Crohn's disease: Data from the Spanish ENEIDA registry. Br J Clin Pharmacol 2024; 90:1301-1311. [PMID: 38369687 DOI: 10.1111/bcp.16017] [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: 10/20/2023] [Revised: 01/04/2024] [Accepted: 01/18/2024] [Indexed: 02/20/2024] Open
Abstract
AIMS Methotrexate (MTX) is used to induce and maintain remission in patients with steroid-dependent Crohn's disease (CD). Despite its proven efficacy, its use is limited due to associated adverse events. Polymorphisms involving folate pathway genes might influence MTX efficacy and toxicity. We aimed to assess the impact of certain polymorphisms on the therapeutic outcomes of MTX in CD. METHODS Patients with CD who exclusively followed MTX monotherapy and fulfilled inclusion criteria were identified from the GETECCU ENEIDA registry. Variants of ATIC, DHFR, MTHFR, SLC19A1, ABCB1 and ABCC3 genes were analysed and their association with efficacy and toxicity was assessed. RESULTS A total of 129 patients were included in the analysis. MTX was used at a median weekly dose of 25 mg (interquartile range, 15-25 mg) and a median time of 14 months (interquartile range, 4-52 months). Thirty-seven percent of the patients achieved disease remission with MTX monotherapy, while 34% were nonresponders (MTX failure). MTX-related toxicity occurred in 40 patients (30%), leading to MTX discontinuation in 19%. DHFR rs408626 (odds ratio [OR] 3.12, 95% confidence interval [CI] 1.22-7.69; P = .017) and MTHFR rs1801133 (OR 2.86, 95% CI 1.23-6.68; P = .015) variants, and smoking (OR 2.61, 95% CI 1.12-6.05; P = .026) were associated with a higher risk of MTX failure. Additionally, the MTHFR rs1801131 variant was associated with a higher risk of MTX-related adverse effects (OR 2.78, 95% CI 1.26-6.13, P = .011). CONCLUSION Our study shows that variants of MTHFR and DHFR genes may be associated with MTX efficacy and adverse events in patients with CD.
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Affiliation(s)
- Juliana Salazar
- Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Institut de Recerca Sant Pau - CERCA Center, Barcelona, Spain
| | | | - Agnès Fernández-Clotet
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Maria Esteve
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital Mútua de Terrassa, Terrassa, Spain
| | - Javier P Gisbert
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital Universitario de La Princesa. Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - David Busquets
- Gastroenterology Department, Hospital Universitari Dr. Josep Trueta, Girona, Spain
| | - Alfredo Lucendo
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital General de Tomelloso, Ciudad Real, Spain
| | - Lucía Márquez
- Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Jordi Guardiola
- Gastroenterology Department, Hospital Universitari Bellvitge, IDIBELL, Barcelona, Spain
- Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain
| | - María Dolores Martín-Arranz
- Department of Gastroenterology of La Paz University Hospital. School of Medicine, Universidad Autónoma de Madrid. Hospital La Paz Institute for Health Research, La Paz Hospital, Madrid, Spain
| | - Eva Iglesias
- Digestive System Service, Universidad de Córdoba/Instituto Maimónides de Investigación Biomédica de Córdoba/Hospital Universitario Reina Sofía, Córdoba, Spain
| | - David Monfort
- Gastroenterology Department, Consorci Sanitari de Terrassa, Terrassa, Spain
| | - Albert Villoria
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital Universitari Parc Taulí Sabadell i Departament de Medicina, Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Fiorella Cañete
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Olga Bell
- Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Institut de Recerca Sant Pau - CERCA Center, Barcelona, Spain
| | - Elena Ricart
- Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Yamile Zabana
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital Mútua de Terrassa, Terrassa, Spain
| | - María Chaparro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital Universitario de La Princesa. Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Universidad Autónoma de Madrid (UAM), Madrid, Spain
| | - Eugeni Domènech
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Jordi Gordillo
- Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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12
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Macaluso FS, Caprioli F, Benedan L, Bezzio C, Caporali R, Cauli A, Chimenti MS, Ciccia F, D'Angelo S, Fantini MC, Festa S, Iannone F, Lubrano E, Mariani P, Papi C, Provenzano G, Pugliese D, Rispo A, Saibeni S, Salvarani C, Variola A, Zenga M, Armuzzi A, Orlando A, Gerli R. The management of patients with inflammatory bowel disease-associated spondyloarthritis: Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and Italian Society of Rheumatology (SIR) recommendations based on a pseudo-Delphi consensus. Autoimmun Rev 2024; 23:103533. [PMID: 38521214 DOI: 10.1016/j.autrev.2024.103533] [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: 12/31/2023] [Revised: 03/20/2024] [Accepted: 03/20/2024] [Indexed: 03/25/2024]
Abstract
Spondyloarthritis (SpA) is the most frequent extraintestinal manifestation in patients with inflammatory bowel diseases (IBD). When IBD and spondyloarthritis coexist, musculoskeletal and intestinal disease features should be considered when planning a therapeutic strategy. Treatment options for IBD and SpA have expanded enormously over the last few years, but randomized controlled trials with specific endpoints focused on SpA are not available in the IBD setting. To address this important clinical topic, the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) and the Italian Society of Rheumatology (SIR) jointly planned to draw updated therapeutic recommendations for IBD-associated SpA using a pseudo-Delphi method. This document presents the official recommendations of IG-IBD and SIR on the management of IBD-associated SpA in the form of 34 statements and 4 therapeutic algorithms. It is intended to be a reference guide for gastroenterologists and rheumatologists dealing with IBD-associated SpA.
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Affiliation(s)
| | - Flavio Caprioli
- Department of Pathophysiology and Transplantation, University of Milan, Italy; Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico di Milano, Milan, Italy.
| | - Laura Benedan
- Bicocca-Applied Statistics Center, Department of Economics, Management and Statistics, University of Milano-Bicocca, Milano, Italy
| | - Cristina Bezzio
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Roberto Caporali
- Rheumatology Unit, Department of Clinical and Community Sciences, University of Milan, ASST Gaetano Pini-CTO, Milan, Italy
| | - Alberto Cauli
- Rheumatology Unit, Department of Medicine and Public Health, AOU and University of Cagliari, Cagliari, Italy
| | - Maria Sole Chimenti
- Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Italy
| | - Francesco Ciccia
- Department of Precision Medicine, Division of Rheumatology, Università della Campania L. Vanvitelli, Naples, Italy
| | - Salvatore D'Angelo
- Rheumatology Department of Lucania, San Carlo Hospital of Potenza, Potenza, Italy
| | - Massimo Claudio Fantini
- Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy; Azienda Ospedaliero-Universitaria di Cagliari, Cagliari, Italy
| | | | | | - Ennio Lubrano
- Dipartimento di Medicina e Scienze della Salute, Università degli Studi del Molise, Campobasso, Italy
| | - Paolo Mariani
- Bicocca-Applied Statistics Center, Department of Economics, Management and Statistics, University of Milano-Bicocca, Milano, Italy
| | | | | | - Daniela Pugliese
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy; IBD Unit, CEMAD, Digestive Diseases Center, Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
| | - Antonio Rispo
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples, Italy
| | - Simone Saibeni
- IBD Center, Gastroenterology Unit, Rho Hospital ASST Rhodense, Italy
| | - Carlo Salvarani
- Azienda USL-IRCCS di Reggio Emilia e Università di Modena e Reggio Emilia, Italy
| | | | - Mariangela Zenga
- Bicocca-Applied Statistics Center, Department of Economics, Management and Statistics, University of Milano-Bicocca, Milano, Italy
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | | | - Roberto Gerli
- Rheumatology Unit, Department of Medicine & Surgery, University of Perugia, Italy
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13
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Sokic-Milutinovic A, Milosavljevic T. Inflammatory Bowel Disease: From Conventional Immunosuppression to Biologic Therapy. Dig Dis 2023; 42:325-335. [PMID: 38096793 DOI: 10.1159/000535647] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 12/04/2023] [Indexed: 07/17/2024]
Abstract
BACKGROUND Inflammatory bowel diseases (IBDs) are chronic, recurrent inflammatory diseases with partly understood etiology and pathogenesis. The course of IBD, both ulcerative colitis and Crohn's disease, is characterized by periods of relapse and remission with the possible occurrence of extraintestinal manifestations. SUMMARY During the last decades, therapeutic goals in IBD evolved toward endoscopic remission and mucosal healing creating the need for early administration of disease-modifying agents (DMAs). DMAs include conventional immunosuppressants (thiopurines, methotrexate), biologic drugs (anti-TNF, anti-integrin, and anti-IL-12/23 monoclonal antibodies), and small molecules (JAK inhibitors, S1P receptor modulators). Patients with aggressive course of disease and risk factors for poor prognosis should be treated with biologic therapy early, while conventional immunomodulators should be used in those with milder course of disease in the absence of risk factors. KEY MESSAGES Challenges in the treatment of IBD patients include the choice of effective yet safe drug and prevention or overcoming loss of response.
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Affiliation(s)
- Aleksandra Sokic-Milutinovic
- Clinic for Gastroenterology and Hepatology, University Clinical Center of Serbia, Belgrade, Serbia
- School of Medicine, University of Belgrade, Belgrade, Serbia
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14
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Vermeer E, Hebing RCF, van de Meeberg MM, Lin M, de Meij TGJ, Struys EA, Jansen G, Nurmohamed MT, Ćalasan MB, de Jonge R. Oral Versus Subcutaneous Methotrexate in Immune-Mediated Inflammatory Disorders: an Update of the Current Literature. Curr Rheumatol Rep 2023; 25:276-284. [PMID: 37768405 PMCID: PMC10754736 DOI: 10.1007/s11926-023-01116-7] [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] [Accepted: 09/01/2023] [Indexed: 09/29/2023]
Abstract
PURPOSE This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory disorders (IMIDs) through analysis of efficacy, toxicity, pharmacokinetics and pharmacodynamics of both administration routes. RECENT FINDINGS Recent studies comparing the efficacy of oral versus subcutaneous MTX administration in IMIDs have revealed contradicting results. Some reported higher efficacy with subcutaneous administration, while others found no significant difference. Regarding toxicity, some studies have challenged the notion that subcutaneous administration is better tolerated than oral administration, while others have supported this. Pharmacokinetic studies suggest higher plasma bioavailability and increased accumulation of MTX-polyglutamates (MTX-PGs) in red blood cells (RBCs) with subcutaneous administration during the initial treatment phase. However, after several months, similar intracellular drug levels are observed with both administration routes. There is no conclusive evidence supporting the superiority of either oral or subcutaneous MTX administration in terms of efficacy and adverse events in IMIDs. Subcutaneous administration leads to higher plasma bioavailability and initial accumulation of MTX-PGs in RBCs, but the difference seems to disappear over time. Given the variable findings, the choice of administration route may be based on shared decision-making, offering patients the option of either oral or subcutaneous administration of MTX based on individual preferences and tolerability. Further research is needed to better understand the impact of MTX-PGs in various blood cells and TDM on treatment response and adherence to MTX therapy.
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Affiliation(s)
- Eva Vermeer
- Department of Paediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, Meibergdreef 9, 1105, AZ, Amsterdam, the Netherlands.
- Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam UMC, Amsterdam, the Netherlands.
- Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, Amsterdam, the Netherlands.
| | - Renske C F Hebing
- Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam, the Netherlands
- Reade, Amsterdam Rheumatology and Immunology Centre, Amsterdam, the Netherlands
| | | | - Marry Lin
- Department of Laboratory Medicine, Amsterdam UMC, Amsterdam, the Netherlands
| | - Tim G J de Meij
- Department of Paediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam UMC, Meibergdreef 9, 1105, AZ, Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
- Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, Amsterdam, the Netherlands
| | - Eduard A Struys
- Department of Laboratory Medicine, Amsterdam UMC, Amsterdam, the Netherlands
| | - Gerrit Jansen
- Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam, the Netherlands
| | - Michael T Nurmohamed
- Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam, the Netherlands
- Reade, Amsterdam Rheumatology and Immunology Centre, Amsterdam, the Netherlands
| | - Maja Bulatović Ćalasan
- Department of Laboratory Medicine, Amsterdam UMC, Amsterdam, the Netherlands
- Department of Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, the Netherlands
| | - Robert de Jonge
- Department of Laboratory Medicine, Amsterdam UMC, Amsterdam, the Netherlands
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15
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Atia O, Friss C, Ledderman N, Greenfeld S, Kariv R, Daher S, Yanai H, Loewenberg Weisband Y, Matz E, Dotan I, Turner D. Thiopurines Have Longer Treatment Durability than Methotrexate in Adults and Children with Crohn's Disease: A Nationwide Analysis from the epi-IIRN Cohort. J Crohns Colitis 2023; 17:1614-1623. [PMID: 37099729 DOI: 10.1093/ecco-jcc/jjad076] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Indexed: 04/28/2023]
Abstract
BACKGROUND Thiopurines and methotrexate have long been used to maintain remission in Crohn's disease [CD]. In this nationwide study, we aimed to compare the effectiveness and safety of these drugs in CD. METHODS We used data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel. Outcomes were compared by propensity-score matching and included therapeutic failure, hospitalisations, surgeries, steroid dependency, and adverse events. RESULTS Of the 19264 patients diagnosed with CD since 2005, 3885 [20%] ever received thiopurines as monotherapy and 553 [2.9%] received methotrexate. Whereas the use of thiopurines declined from 22% in 2012-2015 to 12% in 2017-2020, the use of methotrexate remained stable. The probability of sustaining therapy at 1, 3, and 5 years was 64%, 51%, and 44% for thiopurines and 56%, 30%, and 23% for methotrexate, respectively [p <0.001]. Propensity-score matching, including 303 patients [202 with thiopurines, 101 with methotrexate], demonstrated a higher rate of 5-year durability for thiopurines [40%] than methotrexate [18%; p <0.001]. Time to steroid dependency [p = 0.9], hospitalisation [p = 0.8], and surgery [p = 0.1] were comparable between groups. These outcomes reflect also shorter median time to biologics with methotrexate (2.2 [IQR 1.6-3.1 years) versus thiopurines (6.6 [2.4-8.5]; p = 0.02). The overall adverse events rate was higher with thiopurines [20%] than methotrexate [12%; p <0.001], including three lymphoma cases in males, although the difference was not significant [4.8 vs 0 cases/10 000 treatment-years, respectively; p = 0.6]. CONCLUSION Thiopurines demonstrated higher treatment durability than methotrexate but more frequent adverse events. However, disease outcomes were similar, partly due to more frequent escalation to biologics with methotrexate.
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Affiliation(s)
- Ohad Atia
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
| | - Chagit Friss
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
| | | | - Shira Greenfeld
- Maccabi Health Services, Tel-Aviv, Israel and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Revital Kariv
- Maccabi Health Services, Tel-Aviv, Israel and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Saleh Daher
- Israel Defense Forces Medical Corps, Department of Medical Services, Jerusalem, Israel and Hadadsah-Hebrew University Medical Center, Institute of Gastrointestinal and Liver Diseases, Jerusalem, Israel
| | - Henit Yanai
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | | | - Eran Matz
- Leumit Health Services, Tel-Aviv, Israel
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, and the Sackler Faculty of Medicine, Tel Aviv University, Israel
| | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Israel
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Salm S, Rutz J, van den Akker M, Blaheta RA, Bachmeier BE. Current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments. Front Pharmacol 2023; 14:1234701. [PMID: 37841934 PMCID: PMC10569491 DOI: 10.3389/fphar.2023.1234701] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/08/2023] [Indexed: 10/17/2023] Open
Abstract
Herbal medicines are becoming increasingly popular among patients because they are well tolerated and do not exert severe side effects. Nevertheless, they receive little consideration in therapeutic settings. The present article reviews the current state of research on the clinical benefits of herbal medicines on five indication groups, psychosomatic disorders, gynecological complaints, gastrointestinal disorders, urinary and upper respiratory tract infections. The study search was based on the database PubMed and concentrated on herbal medicines legally approved in Europe. After applying defined inclusion and exclusion criteria, 141 articles were selected: 59 for psychosomatic disorders (100% randomized controlled trials; RCTs), 20 for gynecological complaints (56% RCTs), 19 for gastrointestinal disorders (68% RCTs), 16 for urinary tract infections (UTI, 63% RCTs) and 24 for upper respiratory tract infections (URTI) (79% RCTs). For the majority of the studies, therapeutic benefits were evaluated by patient reported outcome measures (PROs). For psychosomatic disorders, gynecological complaints and URTI more than 80% of the study outcomes were positive, whereas the clinical benefit of herbal medicines for the treatment of UTI and gastrointestinal disorders was lower with 55%. The critical appraisal of the articles shows that there is a lack of high-quality studies and, with regard to gastrointestinal disorders, the clinical benefits of herbal medicines as a stand-alone form of therapy are unclear. According to the current state of knowledge, scientific evidence has still to be improved to allow integration of herbal medicines into guidelines and standard treatment regimens for the indications reviewed here. In addition to clinical data, real world data and outcome measures can add significant value to pave the way for herbal medicines into future therapeutic applications.
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Affiliation(s)
- Sandra Salm
- Institute of Pharmaceutical Biology, Goethe University, Frankfurt, Germany
- Institute of General Practice, Goethe University, Frankfurt, Germany
| | - Jochen Rutz
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
| | - Marjan van den Akker
- Institute of General Practice, Goethe University, Frankfurt, Germany
- Department of Family Medicine, Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands
- Department of Public Health and Primary Care, Academic Centre of General Practice, KU Leuven, Leuven, Belgium
| | - Roman A. Blaheta
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
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Park J, Chun J, Park SJ, Park JJ, Kim TI, Yoon H, Cheon JH. Effectiveness and tolerability of methotrexate monotherapy in Crohn's disease patients: a multicenter observational study. Therap Adv Gastroenterol 2023; 16:17562848231191664. [PMID: 37655055 PMCID: PMC10467270 DOI: 10.1177/17562848231191664] [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: 03/29/2023] [Accepted: 07/17/2023] [Indexed: 09/02/2023] Open
Abstract
Background Methotrexate monotherapy is recommended as a maintenance therapy for Crohn's disease (CD). However, long-term follow-up data are scarce. Objectives We aimed to examine the effectiveness and tolerability of methotrexate monotherapy in 94 CD patients from three inflammatory bowel disease Clinics in Korea. Design This was a multicenter retrospective observational study. Methods Patients with active CD treated with methotrexate monotherapy were included. Clinical characteristics, laboratory indicators, endoscopy indices were evaluated at baseline, 6, 12, and 24 months. Independent factors associated with long-term clinical and endoscopic outcomes were determined. Results Methotrexate was administered orally (70.2%) or parenterally (29.8%). The mean methotrexate induction dose was 15.3 ± 0.4 mg/week, and the mean duration of therapy was 26.2 months. Of 76 patients who were treated for >6 months, the clinical remission rates were 76.3%, 74.6%, and 80.0% at 6, 12, and 24 months, respectively, by per-protocol analysis. The mean CRP levels were 7.5 ± 1.3, 5.3 ± 1.2, 3.8 ± 0.7, and 2.6 ± 0.5 mg/L at 0, 6, 12, and 24 months, respectively. Of 31 patients who underwent follow-up endoscopy after 27.5 months, the endoscopic remission rate was 38.7%. Baseline hemoglobin level <10 g/dL was a significant independent factor negatively associated with clinical remission at 6 [odds ratio (OR): 0.023, 95% confidence interval (CI): 0.003-0.206, p = 0.001] and 12 (OR: 0.079, 95% CI: 0.009-0.699, p = 0.023) months. Parenteral administration was a significant independent factor positively associated with clinical remission (OR: 11.231, 95% CI: 1.027-122.811, p = 0.047) and endoscopic remission (hazard ratio: 4.711, 95% CI: 1.398-15.874, p = 0.012) at 12 months. Conclusions Methotrexate monotherapy was effective and tolerable as a maintenance therapy in CD patients.
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Affiliation(s)
- Jihye Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Jaeyoung Chun
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Soo Jung Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Jun Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Tae Il Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumin-ro, Bundang-gu, Seongnam-si, Gyunggi-do 463-707, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, South Korea
- Institute of Gastroenterology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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18
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Privitera G, Rana N, Armuzzi A, Pizarro TT. The gasdermin protein family: emerging roles in gastrointestinal health and disease. Nat Rev Gastroenterol Hepatol 2023; 20:366-387. [PMID: 36781958 PMCID: PMC10238632 DOI: 10.1038/s41575-023-00743-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/19/2023] [Indexed: 02/15/2023]
Abstract
Since the identification and characterization of gasdermin (GSDM) D as the main effector of inflammatory regulated cell death (or pyroptosis), literature on the GSDM family of pore-forming proteins is rapidly expanding, revealing novel mechanisms regulating their expression and functions that go beyond pyroptosis. Indeed, a growing body of evidence corroborates the importance of GSDMs within the gastrointestinal system, underscoring their critical contributions to the pathophysiology of gastrointestinal cancers, enteric infections and gut mucosal inflammation, such as inflammatory bowel disease. However, with this increase in knowledge, several important and controversial issues have arisen regarding basic GSDM biology and its role(s) during health and disease states. These include critical questions centred around GSDM-dependent lytic versus non-lytic functions, the biological activities of cleaved versus full-length proteins, the differential roles of GSDM-expressing mucosal immune versus epithelial cells, and whether GSDMs promote pathogenic or protective effects during specific disease settings. This Review provides a comprehensive summary and interpretation of the current literature on GSDM biology, specifically focusing on the gastrointestinal tract, highlighting the main controversial issues and their clinical implications, and addressing future areas of research to unravel the specific role(s) of this intriguing, yet enigmatic, family of proteins.
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Affiliation(s)
- Giuseppe Privitera
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Nitish Rana
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Department of Physiology & Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Theresa T Pizarro
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
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Claytor J, Kumar P, Ananthakrishnan AN, Colombel JF, Agrawal M, Ungaro RC. Mild Crohn's Disease: Definition and Management. Curr Gastroenterol Rep 2023; 25:45-51. [PMID: 36753033 DOI: 10.1007/s11894-023-00863-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2022] [Indexed: 02/09/2023]
Abstract
PURPOSE OF REVIEW Crohn's Disease (CD) is a chronic inflammatory disease that can lead to progressive damage to the gastrointestinal tract and significant disability. Early, "top-down" biologic therapy is recommended in moderate-to-severe CD to induce remission and to prevent hospitalization and complications. However, an estimated 20-30% of patients with CD have a mild disease course and may not garner sufficient benefit from expensive, immunosuppressing agents to justify their risks. Herein, we review characteristics of patients with mild CD, the available options for disease treatment and monitoring, and future directions of research. RECENT FINDINGS For ambulatory outpatients with low-risk, mild, ileal or ileocolonic CD, induction of remission with budesonide is recommended. For colonic CD, sulfasalazine is a reasonable choice, although other aminosalicylates have no role in the treatment of CD. No large, randomized trial has supported the use of antibiotics or antimycobacterials in the treatment of CD. Partial Enteral Nutrition and Crohn's Disease Exclusion Diets may be appropriate for inducing remission in some adult patients, with trials ongoing. Select patients with mild-to-moderate CD may benefit from maintenance therapy with azathioprines or gut specific biologics, such as vedolizumab. The role of complementary and alternative medicine is not well defined. The identification, risk stratification, and monitoring of patients with mild CD can be a challenging clinical scenario. Some patients with low risk of disease progression may be appropriate for initial induction of remission with budesonide or sulfasalazine, followed by close clinical monitoring. Future research should focus on pre-clinical biomarkers to stratify disease, novel therapies with minimal systemic immune suppression, and validation of rigorous clinical monitoring algorithms.
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Affiliation(s)
- Jennifer Claytor
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.
| | - Pushkar Kumar
- Center for Translational Medicine and Pharmacology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Metropolitan Hospital Center, New York, NY, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jean-Frederic Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA
| | - Manasi Agrawal
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.,Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Ryan C Ungaro
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA
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20
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Irwin J, Lord A, Ferguson E, Simms LA, Hanigan K, Montoya CA, Radford-Smith G. A Method Using Longitudinal Laboratory Data to Predict Future Intestinal Complication in Patients with Crohn's Disease. Dig Dis Sci 2023; 68:596-607. [PMID: 36125595 PMCID: PMC9905172 DOI: 10.1007/s10620-022-07639-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/20/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Stenosis, fistulization, and perforation of the bowel are severe outcomes which can occur in patients with Crohn's disease. Accurate prediction of these events may enable clinicians to alter treatment strategies and avoid these outcomes. AIMS To study the correlation between longitudinal laboratory testing and subsequent intestinal complications in patients with Crohn's disease. METHODS An observational cohort of patients with Crohn's disease at a single center were analyzed between 01/01/1994 and 06/30/2016. A complication was defined as the development of an intestinal fistula, stenosis, or perforation. Exploratory analysis using Cox regression was performed to select the best statistical method to represent longitudinal laboratory data. Cox regression was used to identify laboratory variables independently associated with the development of a subsequent complication. A clinical scoring tool was designed. RESULTS In 246 patients observed over a median of 5.72 years, 134 complications occurred. Minimum or maximum value in a preceding window period of one year was most strongly associated with subsequent complication. A Longitudinal Laboratory score of ≥ 2 (maximum albumin level < 39 g/L = 1, maximum mean cell volume < 88 fL = 1, minimum platelet count > 355 × 109/L = 1, minimum C reactive protein > 5 mg/L = 1) was 62% sensitive and 91% specific in identifying patients who develop a subsequent complication. CONCLUSION A consistent reduction in serum albumin and mean cell volume, and a consistent increase in platelet count and C reactive protein were associated with a subsequent complication in patients with Crohn's disease. Longitudinal laboratory tests may be used as described in this paper to provide a rational for earlier escalation of therapy.
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Affiliation(s)
- James Irwin
- QIMR Berghofer Medical Research Institute, Brisbane, Australia.
- Faculty of Medicine, The University of Queensland, Brisbane, Australia.
- Department of Gastroenterology, Palmerston North Hospital, 50 Ruahine Street, Palmerston North, 4442, New Zealand.
| | - Anton Lord
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Emma Ferguson
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Lisa A Simms
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | | | - Carlos A Montoya
- Smart Foods Innovation Centre of Excellence, AgResearch Limited, Te Ohu Rangahau Kai Facility, Palmerston North, 4474, New Zealand
- Riddet Institute, Massey University, Te Ohu Rangahau Kai Facility, Palmerston North, 4474, New Zealand
| | - Graham Radford-Smith
- QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, Australia
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Australia
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21
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Rosh JR. Methotrexate. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:401-406. [DOI: 10.1007/978-3-031-14744-9_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Otley A, Day AS, Zachos M. Nutritional Management of Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:355-383. [DOI: 10.1007/978-3-031-14744-9_27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Wang M, Zhao J, Wang H, Zheng C, Chang B, Sang L. Methotrexate showed efficacy both in Crohn’s disease and ulcerative colitis, predictors of surgery were identified in patients initially treated with methotrexate monotherapy. Front Pharmacol 2022; 13:996065. [PMID: 36225564 PMCID: PMC9548616 DOI: 10.3389/fphar.2022.996065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/12/2022] [Indexed: 11/30/2022] Open
Abstract
Objective: This study aimed to evaluate methotrexate efficacy in patients with Crohn’s disease (CD) and ulcerative colitis (UC), and identify predictors of surgery for patients who were initially treated with methotrexate monotherapy. Design: We performed a retrospective analysis of 34,860 patients with inflammatory bowel disease (IBD) in the IBD Bioresource (United Kingdom) prior to 9 November 2021. Logistic regression was used to identify factors associated with methotrexate efficacy. The data were randomly stratified into training and testing sets (7:3). Nomograms were developed based on Cox regression analysis outcomes. The predictive accuracy and discriminative ability were determined using the concordance index (C-index) and calibration curves. Results: Overall, 1,042 patients (CD: 791, UC: 251) were included. Independent factors associated with effective methotrexate monotherapy were younger age at diagnosis, latest therapy period, exclusive upper gastrointestinal tract disease (for CD), and longer duration between diagnosis and methotrexate initiation (for UC). For CD, predictors in the nomogram were gender, treatment era, tolerance, lesion site, perianal involvement, disease behaviour, and biologics requirements (C-index: 0.711 and 0.732 for training and validation cohorts, respectively). For UC, the factors were age at diagnosis and sex (C-index: 0.784 and 0.690 for training and validation cohorts, respectively). Calibration curves demonstrated good agreement between predictions and actual observations.
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Affiliation(s)
- Mengyao Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Jingwen Zhao
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Heran Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Changqing Zheng
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Bing Chang
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Bing Chang, ; Lixuan Sang,
| | - Lixuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
- *Correspondence: Bing Chang, ; Lixuan Sang,
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24
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Methotrexate for Primary Maintenance Therapy in Mild-to-Moderate Crohn Disease in Children. J Pediatr Gastroenterol Nutr 2022; 75:320-324. [PMID: 35758420 DOI: 10.1097/mpg.0000000000003543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Despite limited data, methotrexate (MTX) is often used as primary maintenance therapy in pediatric Crohn disease (CD). We sought to assess the effectiveness of MTX as "initial" primary maintenance therapy in newly diagnosed mild/moderate pediatric CD and ascertain baseline predictive factors. METHODS Single-center 10-year retrospective review of newly diagnosed CD patients treated with MTX as primary maintenance therapy. We compared baseline characteristics of those patients with sustained response/clinical remission to those patients who escalated to anti-TNF therapy within 1 year. Pediatric Crohn Disease Activity Index (PCDAI) ≤ 10 defined remission. RESULTS We identified 65 patients (mean age, 11.8 years; 72 % male; mean ± SD PCDAI, 17.8 ± 10.5) who started MTX ≤4 months of diagnosis as their primary maintenance therapy. Initial therapy prior to MTX was corticosteroids (CS) (54/65), defined diet (4/65), and combination CS/diet (6/65). Oral dosing was used in 55%; mean dose was 11.4 mg/m 2 orally and 12.5 mg/m 2 subcutaneously. At 1 year, 36 of 65 (55%) were on MTX monotherapy, and of those, 32 of 36 were in clinical remission; 81% were in steroid-free remission for the year following induction. For the 36 patients on MTX at 1 year, 14 (39%) had gross mucosal healing (22% of the original cohort). Ten additional patients had mucosal improvement (37% of total healed/improved). Fifteen patients (23%) were early failures, transitioning to anti-TNF ≤4 months. Baseline PCDAI, hemoglobin, ESR, albumin, and route of administration were not predictive of outcome. MTX was well tolerated in our cohort, with only 1 patient stopping due to elevated aminotransferases. No patient required CD surgery in the 1-year follow-up. CONCLUSIONS MTX may have a primary maintenance role in mild/moderate CD.
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25
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van de Meeberg MM, Seinen ML, Fidder HH, Lin M, Oldenburg B, de Boer NK, Bouma G, de Jonge R, Bulatović Ćalasan M. Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn's disease: a cross-sectional study. BMC Gastroenterol 2022; 22:365. [PMID: 35907797 PMCID: PMC9338675 DOI: 10.1186/s12876-022-02439-y] [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: 03/08/2022] [Accepted: 07/20/2022] [Indexed: 11/25/2022] Open
Abstract
Background Methotrexate is an immunomodulatory drug for patients with Crohn’s disease. Erythrocyte MTX-polyglutamates (MTX-PG1-5) may be used for therapeutic drug monitoring (TDM) as MTX-PG is thought to mediate MTX’s efficacy. Information on determinants of the concentration of MTX-PG in patients with Crohn’s disease is lacking. We aim to identify clinical and biochemical determinants of the erythrocyte MTX-PG1-5 and MTX-PGtotal concentration in patients with Crohn’s disease. Methods Adults with Crohn’s disease on methotrexate treatment who visited the outpatient clinic of Amsterdam UMC were included. Erythrocyte MTX-PGs were measured by tandem mass spectrometry. Results Nineteen patients were included, with a median duration of MTX use of 77 months (range 7–202). Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant TNF-α inhibitors. The mean dose of MTX was 15.5 mg (SD ± 2.8) and 12 (63%) patients used subcutaneous MTX. MTX-PG1-5 were successfully measured in 18 patients, showing substantial variability in concentrations of MTX-PGtotal and individual species. The median MTX-PGtotal was 117.1 nmol/L (range 46.4–258.7) with preferential accumulation of MTX-PG3 (43.1 nmol/L, range 15.3–96.1). Patients on subcutaneous compared to oral MTX had higher median MTX-PG(4,5) levels (55 versus 9 nmol/L, p = 0.01). Higher age (β = 0.71) and lower estimated glomerular filtration rate (β = − 0.52) were associated with a significantly higher MTX-PGtotal concentration (R2 = 0.60, p = 0.001). Conclusion MTX-PG concentrations display a considerable inter-individual variability. Higher MTX-PG accumulation is associated with subcutaneous administration, higher age, and lower renal function in Crohn’s disease patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02439-y.
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Affiliation(s)
- M M van de Meeberg
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands. .,Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AGEM Research Institute, Amsterdam, The Netherlands.
| | - M L Seinen
- Department of Gastroenterology, OLVG, Amsterdam, The Netherlands
| | - H H Fidder
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - M Lin
- Department of Clinical Chemistry, Amsterdam UMC, Amsterdam, The Netherlands
| | - B Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - N K de Boer
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AGEM Research Institute, Amsterdam, The Netherlands
| | - G Bouma
- Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, AGEM Research Institute, Amsterdam, The Netherlands
| | - R de Jonge
- Department of Clinical Chemistry, Amsterdam UMC, Amsterdam, The Netherlands
| | - M Bulatović Ćalasan
- Department of Clinical Chemistry, Amsterdam UMC, Amsterdam, The Netherlands.,Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
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Spondyloarthropathy in Inflammatory Bowel Disease: From Pathophysiology to Pharmacological Targets. Drugs 2022; 82:1151-1163. [PMID: 35900700 DOI: 10.1007/s40265-022-01750-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2022] [Indexed: 11/03/2022]
Abstract
Spondyloarthritis (SpA) represents one of the most frequent extraintestinal manifestations of inflammatory bowel disease (IBD). Evidence of shared genetic and molecular pathways underlying both diseases is emerging, which has led to rational approaches when treating patients with concomitant diseases. Clinical efficacy of tumor necrosis factor (TNF) antagonists has been ascertained over the years, and they currently represent the cornerstone of treatment in patients with IBD and SpA, but the therapeutic armamentarium in these cases has been recently expanded. Evidence for vedolizumab is controversial, as it was associated both with improvement and development of arthralgias, while ustekinumab, the first anti-interleukin 12/23 (IL-12/23) approved for IBD, has demonstrated good efficacy, especially in peripheral arthritis, and more IL-23 inhibitors are being developed in IBD. Tofacitinib was the first Janus kinase (JAK) inhibitor to be approved in IBD, and as it demonstrated efficacy in treating ankylosing spondylitis, it may represent a good choice in axial arthritis, while more selective JAK inhibitors are yet to be approved. Unexpectedly, the first anti-IL17 that was studied in IBD (secukinumab) has shown not to be effective in treating IBD, and the role of anti-IL17 drugs in these diseases needs further investigation. Therefore, as availability of biologics and small molecules is increasing, their positioning in clinical practice is becoming more and more challenging, and multidisciplinary management needs to be implemented in both research and clinical settings in order to enhance early recognition of SpA in IBD patients, optimize treatment and ultimately improve the patients' quality of life.
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AlAmeel T, Al Sulais E, Raine T. Methotrexate in inflammatory bowel disease: A primer for gastroenterologists. Saudi J Gastroenterol 2022; 28:250-260. [PMID: 35042318 PMCID: PMC9408741 DOI: 10.4103/sjg.sjg_496_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/24/2021] [Accepted: 11/22/2021] [Indexed: 11/06/2022] Open
Abstract
Methotrexate is an antineoplastic agent that is also used at lower doses for anti-inflammatory properties. Along with thiopurines (azathioprine and 6-mercaptopurine), it has historically been an important part of pharmacological treatment for patients with inflammatory bowel disease. Despite an increase in therapeutic options, these immunomodulators continue to play important roles in the management of inflammatory bowel disease, used either as a monotherapy in mild to moderate cases or in combination with monoclonal antibodies to prevent immunogenicity and maintain efficacy. In light of data linking the use of thiopurines with the risk of malignancies, methotrexate has regained attention as a potential alternative. In this article, we review data on the pharmacology, safety, and efficacy of methotrexate and discuss options for the positioning of methotrexate alone, or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis.
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Affiliation(s)
- Turki AlAmeel
- Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Eman Al Sulais
- Division of Gastroenterology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
| | - Tim Raine
- Division of Gastroenterology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
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Privitera G, Pizarro TT. Live or let die: Translational insights and clinical perspectives of gasdermin B-dependent intestinal epithelial cell fate. Clin Transl Med 2022; 12:e787. [PMID: 35485236 PMCID: PMC9052010 DOI: 10.1002/ctm2.787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/31/2022] Open
Affiliation(s)
- Giuseppe Privitera
- Department of PathologyCase Western Reserve University School of MedicineClevelandOhioUSA
| | - Theresa T. Pizarro
- Department of PathologyCase Western Reserve University School of MedicineClevelandOhioUSA
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29
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Cassinotti A, Batticciotto A, Parravicini M, Lombardo M, Radice P, Cortelezzi CC, Segato S, Zanzi F, Cappelli A, Segato S. Evidence-based efficacy of methotrexate in adult Crohn's disease in different intestinal and extraintestinal indications. Therap Adv Gastroenterol 2022; 15:17562848221085889. [PMID: 35340755 PMCID: PMC8949794 DOI: 10.1177/17562848221085889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 02/18/2022] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Methotrexate (MTX) is included in the therapeutic armamentarium of Crohn's disease (CD), although its positioning is currently uncertain in an era in which many effective biological drugs are available. No systematic reviews or meta-analysis have stratified the clinical outcomes of MTX according to the specific clinical scenarios of its use. METHODS Medline, PubMed and Scopus were used to extract eligible studies, from database inception to May 2021. A total of 163 studies were included. A systematic review was performed by stratifying the outcomes of MTX according to formulation, clinical indication and criteria of efficacy. RESULTS The use of MTX is supported by randomized clinical trials only in steroid-dependent CD, with similar outcomes to thiopurines. The use of MTX in patients with steroid-refractoriness, failure of thiopurines or in combination with biologics is not supported by high levels of evidence. Combination therapy with biologics can optimize the immunogenic profile of the biological drug, but the impact on long-term clinical outcomes is described only in small series with anti-TNFα. Other off-label uses, such as fistulizing disease, mucosal healing, postoperative prevention and extraintestinal manifestations, are described in small uncontrolled series. The best performance in most indications was shown by parenteral MTX, favouring higher doses (25 mg/week) in the induction phase. DISCUSSION Evidence from high-quality studies in favour of MTX is scarce and limited to the steroid-dependent disease, in which other drugs are the leading players today. Many limitations on study design have been found, such as the prevalence of retrospective underpowered studies and the lack of stratification of outcomes according to specific types of patients and formulations of MTX. CONCLUSION MTX is a valid option as steroid-sparing agent in steroid-dependent CD. Numerous other clinical scenarios require well-designed clinical studies in terms of patient profile, drug formulation and dosage, and criteria of efficacy.
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Affiliation(s)
| | | | | | | | - Paolo Radice
- Ophtalmology Unit, ASST Sette Laghi, Varese, Italy
| | | | - Simone Segato
- Gastroenterology Unit, ASST Sette Laghi, Varese, Italy
| | | | | | - Sergio Segato
- Gastroenterology Unit, ASST Sette Laghi, Varese, Italy
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30
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Sturm A, Atreya R, Bettenworth D, Bokemeyer B, Dignaß A, Ehehalt R, Germer C, Grunert PC, Helwig U, Herrlinger K, Kienle P, Kreis ME, Kucharzik T, Langhorst J, Maaser C, Ockenga J, Ott C, Siegmund B, Zeißig S, Stallmach A. Aktualisierte S3-Leitlinie „Diagnostik und Therapie des Morbus Crohn“ der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) – August 2021 – AWMF-Registernummer: 021-004. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:332-418. [PMID: 35263784 DOI: 10.1055/a-1713-3941] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Andreas Sturm
- Klinik für Innere Medizin mit Schwerpunkt Gastroenterologie, DRK Kliniken Berlin Westend, Berlin, Deutschland
| | - Raja Atreya
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Deutschland
| | | | - Bernd Bokemeyer
- Gastroenterologische Gemeinschaftspraxis Minden, Deutschland
| | - Axel Dignaß
- Medizinische Klinik I, Agaplesion Markus Krankenhaus, Frankfurt am Main, Deutschland
| | | | - Christoph Germer
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Deutschland
| | - Philip C Grunert
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
| | - Ulf Helwig
- Internistische Praxengemeinschaft, Oldenburg, Deutschland
| | | | - Peter Kienle
- Allgemein- und Viszeralchirurgie, Theresienkrankenhaus und Sankt Hedwig-Klinik GmbH, Mannheim, Deutschland
| | - Martin E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité Campus Benjamin Franklin - Universitätsmedizin Berlin, Deutschland
| | - Torsten Kucharzik
- Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Deutschland
| | - Jost Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Klinikum am Bruderwald, Bamberg, Deutschland
| | | | - Johann Ockenga
- Medizinische Klinik II, Klinikum Bremen Mitte - Gesundheit Nord, Bremen, Deutschland
| | - Claudia Ott
- Gastroenterologie Facharztzentrum, Regensburg, Deutschland
| | - Britta Siegmund
- Medizinische Klinik I, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Deutschland
| | - Sebastian Zeißig
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Deutschland
| | - Andreas Stallmach
- Klinik für Innere Medizin IV (Gastroenterologie, Hepatologie und Infektiologie), Universitätsklinikum Jena, Deutschland
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Kumar A, Cole A, Segal J, Smith P, Limdi JK. A review of the therapeutic management of Crohn's disease. Therap Adv Gastroenterol 2022; 15:17562848221078456. [PMID: 35198041 PMCID: PMC8859667 DOI: 10.1177/17562848221078456] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 01/19/2022] [Indexed: 02/04/2023] Open
Abstract
Crohn's disease is a chronic inflammatory, relapsing-remitting, and progressive gastrointestinal disorder with an often-negative impact on the physical, emotional, and psychological well-being. Over the past two decades, the medical compendium for the treatment of Crohn's disease has increased significantly, enabling treatment beyond symptoms. Indeed, early and timely use of effective medical therapy has been reflected by improved outcomes with reduction in surgery and ability to achieve clinical and endoscopic remission, reduce corticosteroid dependance, and prevent long-term complications in more patients. In this review, we discuss the key milestones in the medical management of Crohn's disease.
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Affiliation(s)
- Aditi Kumar
- Gastroenterology Department, The Royal Wolverhampton NHS Trust, Wolverhampton WV10 0QP, UK
| | | | - Jonathan Segal
- Department of Gastroenterology and Hepatology, St Mary’s Hospital, London, UK
| | - Philip Smith
- Department of Gastroenterology, The Royal Liverpool and Broadgreen University Hospitals, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
- Faculty of Medicine, University of Liverpool, Liverpool, UK
| | - Jimmy K. Limdi
- Department of Gastroenterology, Northern Care Alliance NHS Foundation NHS Trust, Manchester, UK
- Manchester Academic Health Sciences, University of Manchester, Manchester, UK
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32
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Venner JM, Bernstein CN. Immunomodulators: still having a role? Gastroenterol Rep (Oxf) 2022; 10:goac061. [PMID: 36381225 PMCID: PMC9642324 DOI: 10.1093/gastro/goac061] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/08/2022] [Accepted: 10/09/2022] [Indexed: 11/09/2022] Open
Abstract
Immunomodulators, particularly the thiopurines and to a lesser extent methotrexate, were standard of care for inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, for >40 years. While there has been a renaissance in available therapies with the advent of biologics and small molecules, an impetus remains for the ongoing use of thiopurines and methotrexate. This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies. This article summarizes the data behind immunomodulator use in Crohn’s disease, focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.
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Affiliation(s)
- Jeffery M Venner
- University of Manitoba IBD Clinical and Research Centre , Winnipeg, Manitoba, Canada
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, Manitoba, Canada
| | - Charles N Bernstein
- University of Manitoba IBD Clinical and Research Centre , Winnipeg, Manitoba, Canada
- Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba , Winnipeg, Manitoba, Canada
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Łodyga M, Eder P, Gawron-Kiszka M, Dobrowolska A, Gonciarz M, Hartleb M, Kłopocka M, Małecka-Wojciesko E, Radwan P, Reguła J, Zagórowicz E, Rydzewska G. Guidelines for the management of patients with Crohn's disease. Recommendations of the Polish Society of Gastroenterology and the Polish National Consultant in Gastroenterology. PRZEGLAD GASTROENTEROLOGICZNY 2021; 16:257-296. [PMID: 34976235 PMCID: PMC8690943 DOI: 10.5114/pg.2021.110914] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 10/25/2021] [Indexed: 12/13/2022]
Abstract
This paper is an update of the diagnostic and therapeutic recommendations of the National Consultant for Gastroenterology and the Polish Society of Gastroenterology from 2012. It contains 46 recommendations for the diagnosis and treatment, both pharmacological and surgical, of Crohn's disease in adults. The guidelines were developed by a group of experts appointed by the Polish Society of Gastroenterology and the National Consultant in the field of Gastroenterology. The methodology related to the GRADE methodology was used to assess the quality and strength of the available recommendations. The degree of expert support for the proposed statement, assessment of the quality of evidence and the strength of the recommendation was assessed on a 6-point Likert scale. Voting results, quality and strength ratings with comments are included with each statement.
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Affiliation(s)
- Michał Łodyga
- Department of Gastroenterology with the Inflammatory Bowel Disease Subdivision, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland
| | - Piotr Eder
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, Heliodor Święcicki University Hospital, Poznan, Poland
| | - Magdalena Gawron-Kiszka
- Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Medicine, Poznan University of Medical Sciences, Heliodor Święcicki University Hospital, Poznan, Poland
| | - Maciej Gonciarz
- Department of Gastroenterology and Internal Medicine, Military Institute of Medicine, Warsaw, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland
| | - Maria Kłopocka
- Department of Gastroenterology and Nutritional Disorders, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Poland
| | | | - Piotr Radwan
- Department of Gastroenterology, Medical University of Lublin, Lublin, Poland
| | - Jarosław Reguła
- Department of Gastroenterology, Hepatology and Clinical Oncology, Center of Postgraduate Medical Education, Warsaw, Poland
- Department of Oncological Gastroenterology, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Edyta Zagórowicz
- Department of Gastroenterology, Hepatology and Clinical Oncology, Center of Postgraduate Medical Education, Warsaw, Poland
- Department of Oncological Gastroenterology, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Grażyna Rydzewska
- Department of Gastroenterology with the Inflammatory Bowel Disease Subdivision, Central Clinical Hospital of the Ministry of the Interior and Administration, Warsaw, Poland
- Collegium Medicum, Jan Kochanowski University, Kielce, Poland
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Nayar S, Cho JH. From single-target to cellular niche targeting in Crohn's disease: intercepting bad communications. EBioMedicine 2021; 74:103690. [PMID: 34773892 PMCID: PMC8601974 DOI: 10.1016/j.ebiom.2021.103690] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/20/2021] [Accepted: 10/27/2021] [Indexed: 02/07/2023] Open
Abstract
The mainstay of moderate to severe Crohn's disease (CD), anti-TNF treatment, shows no clinical benefit in ∼40% of patients, likely due to incomplete cellular targeting and delayed treatment institution. While single-target therapeutics have been highly effective for some CD patients, substantial limitations with respect to safety, efficacy, and long-term, complete remission remain. Deconvolution of the cellular and molecular circuitry of tissue lesions underscores the importance of combinatorial strategies targeting cellular niches. This review aims to evaluate current therapeutic approaches used to manage CD, and highlight recent advances to our cellular, genetic, and molecular understanding of mechanisms driving pathogenic niche activation in CD. We propose new frameworks outlining that combinatorial therapies, along with serial tissue sampling and studies guided by genetics and genomics, can advance on current treatment approaches and will inform newer strategies upon which we can move towards precision therapeutics in IBD.
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Affiliation(s)
- Shikha Nayar
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, Hess CSM Building Room 8-201, New York, NY 10029, USA.
| | - Judy H Cho
- The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, 1470 Madison Ave, Hess CSM Building Room 8-201, New York, NY 10029, USA
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35
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Rui M, Fei Z, Wang Y, Shi F, Meng R, Shang Y, Ma A, Li H. Will the Inducing and Maintaining Remission of Non-biological Agents and Biological Agents Differ for Crohn's Disease? The Evidence From the Network Meta-Analysis. Front Med (Lausanne) 2021; 8:679258. [PMID: 34540859 PMCID: PMC8440847 DOI: 10.3389/fmed.2021.679258] [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: 03/11/2021] [Accepted: 08/09/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Several drugs currently are available for the treatment of Crohn's disease, including non-biological agents such as anti-inflammatory agents, steroids, immunosuppressive agents, and biologic agents such as anti-tumor necrosis factor (TNF), anti-α4β7 integrin, anti-alpha-4 integrin and anti-interleukin 12/23. However, the choice of treatments for induction and maintenance is still a challenge. The relevant comparison between non-biologic agents and biologic agents is few. In our research, we aimed to help making decisions, as well as providing clinicians and patients with medication references. Methods: We searched MEDLINE, Embase, and the Cochrane Central Register of controlled trials for relevant randomized controlled trials published through to July 2020 and systematic reviews published from January 2011 to December 2020. Search results were screened by 2 independent reviewers first by title and abstract and then by full text. Disagreements were resolved through discussion with a third reviewer. Results: 54 randomized controlled trials were included in our analysis. For induction of remission, azathioprine (OR, 3.5; 95% Crl, 1.4–8.9), infliximab (OR, 4.1; 95% Crl, 1.2–16.0), infliximab + azathioprine (OR, 7.0; 95% Crl, 1.2–41.0) and infliximab+ methotrexate (OR, 7.8; 95% Crl, 1.2–65.0) were more effective in first-line therapy than placebo. Adalimumab showed superiority to placebo in second-line therapy, but the range of SD was wide. For maintenance of remission, adalimumab (OR,2.24;95% Crl,1.17–4.76) and azathioprine (OR,2.05; 95% Crl,1.14–3.96) were more effective than placebo. Adalimumab (OR,0.56; 95%Crl,0.27–1.2), budesonide (OR,0.63; 95%Crl,0.26–1.6) and natalizumab (OR,0.65; 95%Crl,0.30–1.4) was associated with less risk of withdrawals when compared with placebo. Conclusion: For induction of remission, azathioprine, infliximab, and infliximab + azathioprine were more effective in first-line therapy. In second-line therapy, adalimumab was more effective but should be interpreted carefully. For maintenance of remission, adalimumab and azathioprine were more effective. Besides, adalimumab, budesonide, natalizumab had lower withdrawals. Therefore, biological agents were not always better than non-biological agents and they have their own advantages in different treatment methods of Crohn's disease.
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Affiliation(s)
- Mingjun Rui
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Zhengyang Fei
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Yingcheng Wang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Fenghao Shi
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Rui Meng
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Ye Shang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Aixia Ma
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Hongchao Li
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
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36
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Hong HS, Kim K, Oh K, Lee JY, Hong SW, Park JH, Hwang SW, Yang DH, Ye BD, Byeon JS, Myung SJ, Yang SK, Park SH. Short-term tolerability and effectiveness of methotrexate monotherapy in adult patients with Crohn's disease: a retrospective study. Therap Adv Gastroenterol 2021; 14:17562848211043017. [PMID: 34539814 PMCID: PMC8442506 DOI: 10.1177/17562848211043017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 08/03/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Immunomodulators remain fundamental for the medical treatment of Crohn's disease (CD). Methotrexate (MTX) is widely used as a second-line immunomodulator; however, there is a lack of recent data on MTX monotherapy among the Asian population with CD. Therefore, in this study, we aimed to investigate the tolerability and clinical outcomes of MTX in Korean patients with CD. METHODS A retrospective chart review was performed for CD patients treated with MTX monotherapy or in combination with 5-aminosalicylic acid (5-ASA), at the Asan Medical Center, Seoul, South Korea. The tolerability of MTX monotherapy within 6 months was assessed and the clinical effectiveness of MTX was evaluated based on the Crohn's disease activity index (CDAI). RESULTS In total, 85 patients were included, of which 29 (34.1%) discontinued MTX due to intolerability during the follow-up. Adverse events (AEs) were reported in 41 (48.2%) patients. The most common AE was gastrointestinal disorders (17/41) and only one patient experienced a serious AE, a systemic infection that required hospitalization. Among the 56 patients who tolerated MTX within 6 months, 44 (65.9%) showed a clinical response. Moreover, no factor was significantly associated with intolerability. The administration method was the only factor significantly associated with a response to MTX (p = 0.041). The adjusted odds ratio of parenteral injection compared to oral administration was 5.68 (95% confidence interval (CI), 1.07-30.08). CONCLUSION In this study, one-third of patients were intolerant to MTX; nonetheless, the response rate was as high as 65.9% among tolerant patients. In addition, no significant factors affected intolerability. In terms of the clinical response, parenteral injection could be better than oral administration.
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Affiliation(s)
- Hee Seung Hong
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Kyuwon Kim
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Kyunghwan Oh
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Jae Yong Lee
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Seung Wook Hong
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Jin Hwa Park
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Sung Wook Hwang
- Department of Gastroenterology and Inflammatory
Bowel Disease Center, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, Republic of Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Byong Duk Ye
- Department of Gastroenterology and Inflammatory
Bowel Disease Center, Asan Medical Center, University of Ulsan College of
Medicine, Seoul, Republic of Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, Asan Medical
Center, University of Ulsan College of Medicine, Seoul, Republic of
Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology and
Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan
College of Medicine, Seoul, Republic of Korea
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Mlcoch T, Decker B, Dolezal T. Cost-Effectiveness Analysis of Parenteral Methotrexate for the Treatment of Crohn's Disease. APPLIED HEALTH ECONOMICS AND HEALTH POLICY 2021; 19:593-604. [PMID: 33426625 DOI: 10.1007/s40258-020-00628-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/28/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Despite worldwide use of parenteral methotrexate (pMTX), health economic evidence for its use in Crohn's disease (CD) is limited. The low price of this generic drug has removed any commercial incentive to further invest in research. However, there is an unmet need for treatment of mild-to-moderate CD, since biological/targeted therapies are usually reserved for patients with more severe disease due to the higher costs of these treatments. OBJECTIVE To evaluate the cost-effectiveness of pMTX compared to the standard of care (SOC, i.e., high doses of oral corticosteroids (hdCS) followed by gradual tapering) for the treatment of mild-to-moderate CD in the Czech Republic. METHODS We developed a 3-year Markov model with a 1-week cycle length comprising five health states. The model projected quality-adjusted life-years (QALYs) and costs from the healthcare payers' perspective. Efficacy data were obtained from a systematic literature review of clinical trials and extrapolated using survival analysis. RESULTS Over a 3-year time-horizon, pMTX yields additional 0.111 QALYs (1.798 vs. 1.687) at an additional cost of €513 (€3087 vs. €2574), with an incremental deterministic (probabilistic) cost-effectiveness ratio of €4627 (€4742)/QALY, far below the willingness-to-pay (WTP) threshold (≈ €47,000/QALY). The probabilistic sensitivity analysis showed that the probability of pMTX being cost-effective was 100%. A one-way sensitivity and scenario analysis confirmed the robustness of the base-case result. CONCLUSION Parenteral MTX proved to be cost-effective in patients with mild-to-moderate CD. This is the first published cost-effectiveness analysis of pMTX for this indication. It also shows an example of a lack of valuation of generic therapy despite its cost-effectiveness and a clear benefit to the healthcare system.
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Affiliation(s)
- Tomas Mlcoch
- Value Outcomes, Vaclavska 316/12, 12000, Prague 2, Czech Republic
| | - Barbora Decker
- Value Outcomes, Vaclavska 316/12, 12000, Prague 2, Czech Republic.
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
| | - Tomas Dolezal
- Value Outcomes, Vaclavska 316/12, 12000, Prague 2, Czech Republic
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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Chinese consensus on diagnosis and treatment in inflammatory bowel disease (2018, Beijing). J Dig Dis 2021; 22:298-317. [PMID: 33905603 DOI: 10.1111/1751-2980.12994] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 04/22/2021] [Indexed: 12/11/2022]
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Noninvasive assessment of liver fibrosis in Crohn's disease patients exposed to methotrexate. Eur J Gastroenterol Hepatol 2021; 33:794-798. [PMID: 32804842 DOI: 10.1097/meg.0000000000001799] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Methotrexate is widely used to treat some inflammatory chronic disorders, though it is hampered by the risk of liver fibrosis. Many recommendations have been made to assess methotrexate-related hepatotoxicity, including liver biopsy. However, other noninvasive methods to assess liver fibrosis have been developed and could be implemented for patients treated with methotrexate. AIM The aim of the study was to compare the prevalence of liver fibrosis by means of noninvasive methods [aspartate transaminase-to-platelet ratio index (APRI) Forns index, and transient elastography] in patients with Crohn's disease exposed or not to methotrexate, and to identify risk factors for liver fibrosis. METHODS Prospective, cross-sectional study. All patients with Crohn's disease exposed to methotrexate were included and compared to an unselected cohort of outpatients with Crohn's disease never exposed to methotrexate. RESULTS A total of 84 patients with Crohn's disease, 56 exposed to methotrexate, and 28 controls, were included. Significant liver fibrosis was found in 7% of methotrexate-exposed patients with Crohn's disease and 10% of controls as measured by transient elastography, and in 7% of controls as measured by the Forns index. No cases of liver fibrosis were detected by APRI. Only alcohol consumption, diabetes mellitus, and age were associated with significant liver fibrosis. CONCLUSIONS Significant liver fibrosis is uncommon among patients with Crohn's disease, even among those exposed to methotrexate. The risk of liver fibrosis in Crohn's disease seems to depend on common risk factors for liver disease.
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Singh S, Proctor D, Scott FI, Falck-Ytter Y, Feuerstein JD. AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology 2021; 160:2512-2556.e9. [PMID: 34051985 PMCID: PMC8986997 DOI: 10.1053/j.gastro.2021.04.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The incidence and prevalence of Crohn's disease (CD) is rising globally. Patients with moderate to severe CD are at high risk for needing surgery and hospitalization and for developing disease-related complications, corticosteroid dependence, and serious infections. Optimal management of outpatients with moderate to severe luminal and/or fistulizing (including perianal) CD often requires the use of immunomodulator (thiopurines, methotrexate) and/or biologic therapies, including tumor necrosis factor-α antagonists, vedolizumab, or ustekinumab, either as monotherapy or in combination (with immunomodulators) to mitigate these risks. Decisions about optimal drug therapy in moderate to severe CD are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Since the last iteration of these guidelines published in 2013, significant advances have been made in the field, including the regulatory approval of 2 new biologic agents, vedolizumab and ustekinumab. Therefore, the American Gastroenterological Association prioritized updating clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The review addressed the following focused questions (in adult outpatients with moderate to severe luminal CD): overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to tumor necrosis factor-α antagonists, comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, comparative efficacy of a top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up treatment strategy (acceleration to biologic and/or immunomodulator therapy only after failure of mesalamine), and the role of corticosteroids and mesalamine for induction and/or maintenance of remission. Finally, in adult outpatients with moderate to severe fistulizing CD, this review addressed the efficacy of pharmacologic interventions for achieving fistula and the role of adjunctive antibiotics without clear evidence of active infection.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Deborah Proctor
- Division of Gastroenterology, Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Frank I. Scott
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Yngve Falck-Ytter
- Division of Gastroenterology and Liver Disease, Case Western Reserve University, Cleveland, Ohio CA
| | - Joseph D. Feuerstein
- Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, MA
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Mesonero F, Castro-Poceiro J, Benítez JM, Camps B, Iborra M, López-García A, Torres P, Esteve M, Tosca J, Bertoletti F, Almela P, Calvet X, Vera I, Bujanda L, Gomollón F, Rodríguez C, Antolín B, Busquets D, Hernández A, Rivero M, Monfort I Miquel D, Castaño-García A, Gisbert JP, Domènech E, López-Sanromán A. Effectiveness and safety of methotrexate monotherapy in patients with Crohn's disease refractory to anti-TNF-α: results from the ENEIDA registry. Aliment Pharmacol Ther 2021; 53:1021-1029. [PMID: 33715177 DOI: 10.1111/apt.16315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/27/2021] [Accepted: 02/16/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Methotrexate can be used to maintain remission in Crohn's disease patients who are intolerant to thiopurines. Data on its use as monotherapy in other scenarios are limited. AIM To assess the effectiveness of methotrexate monotherapy in Crohn's disease patients after previous failure to anti-tumour necrosis factor (anti-TNFα) drugs. METHODS A retrospective, observational multicentre study of data from the Spanish ENEIDA registry. Participants were patients with active Crohn's disease and previous failure to anti-TNFα started on methotrexate monotherapy. Short-term effectiveness was assessed at 12-16 weeks based on Harvey-Bradshaw index (HBI): clinical remission as HBI ≤ 3 points and clinical response as HBI drop of ≥ 3 points over baseline. Long-term effectiveness was defined as steroid-free methotrexate persistence from 12 to 16 weeks until maximum follow up. Adverse events were recorded. RESULTS Data were compiled for 110 patients treated with methotrexate after a failed response to one (39%) or two (55.6%) anti-TNFα agents. Short-term clinical response and remission rates were 60% and 30.9% respectively. Of 74 patients who continued after week 16, long-term effectiveness was achieved in 82% and 74% at 12 and 24 months respectively. In the multivariate analysis, non-remission at short term (vs remission) was associated with long-term failure (HR 2.58, 95%CI 1.95-3.68, P = 0.028). Adverse events (evaluated in 100 patients) were recorded in 44%, and in 30.4% of these patients, they led to methotrexate discontinuation. CONCLUSIONS The benefits observed suggest methotrexate monotherapy could be a valid option in Crohn's disease patients with previous failure to anti-TNFα.
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Bhatt AP, Sartor RB. 'Bugs on drugs': implications for gut health. Nat Rev Gastroenterol Hepatol 2021; 18:287-288. [PMID: 33692569 PMCID: PMC8610095 DOI: 10.1038/s41575-021-00437-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- Aadra P. Bhatt
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,
| | - R. Balfour Sartor
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Gastrointestinal Biology and Disease, and the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Sleiman J, Ouali SE, Qazi T, Cohen B, Steele SR, Baker ME, Rieder F. Prevention and Treatment of Stricturing Crohn's Disease - Perspectives and Challenges. Expert Rev Gastroenterol Hepatol 2021; 15:401-411. [PMID: 33225766 PMCID: PMC8026566 DOI: 10.1080/17474124.2021.1854732] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Fibrostenosis is a hallmark of Crohn's disease (CD), remains a challenge in today's clinical management of inflammatory bowel disease patients and represents a key event in the disease course necessitating improved preventative strategies and a multidisciplinary approach to diagnosis and management. With the advent of anti-fibrotic therapies and well-defined clinical endpoints for stricturing CD, there is promise to impact the natural history of disease.Areas covered: This review summarizes current evidence in the natural history of stricturing Crohn's disease, discusses management approaches as well as future perspectives on intestinal fibrosis.Expert opinion: Currently, there are no specific therapies to prevent progression to fibrosis or to treat it after it becomes clinically apparent. In addition to the international effort by the Stenosis Therapy and Anti-Fibrotic Research (STAR) consortium to standardize definitions and propose endpoints in the management of stricturing CD, further research to improve our understanding of mechanisms of intestinal fibrosis will help pave the way for the development of future anti-fibrotic therapies.
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Affiliation(s)
- Joseph Sleiman
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Sara El Ouali
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA,Digestive Diseases Institute, Cleveland Clinic Abu Dhabi, United Arab Emirates
| | - Taha Qazi
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Benjamin Cohen
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Scott R. Steele
- Department of Colorectal Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Mark E. Baker
- Section Abdominal Imaging, Imaging Institute, Digestive Diseases and Surgery Institute, Cleveland, Ohio, USA
| | - Florian Rieder
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA,Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA,Corresponding author: Florian Rieder, Address: Department of Gastroenterology, Hepatology and Nutrition, Digestive Diseases and Surgery Institute, 9500 Euclid Avenue – NC22, Cleveland, OH, 44195,
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Calafat M, Mañosa M, Cañete F, Domènech E. Clinical Considerations Regarding the Use of Thiopurines in Older Patients with Inflammatory Bowel Disease. Drugs Aging 2021; 38:193-203. [PMID: 33438138 DOI: 10.1007/s40266-020-00832-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/27/2020] [Indexed: 12/19/2022]
Abstract
The number of older patients with inflammatory bowel disease (IBD) is increasing due to both improvements in the life expectancy of patients with long-lasting IBD and later onset of the disease. In spite of a less aggressive IBD phenotype, disease management in older patients is hampered by comorbidities and polypharmacy (which increase the risk of drug-related adverse events and errors in medication intake) and also by an increased risk of the infections and malignancies associated with the immunosuppressive drugs that are frequently used to treat IBD. Thiopurines are the most frequently used immunosuppressive drugs in IBD, though they are often discontinued due to adverse events. However, when tolerated, thiopurines are efficient in the maintenance of remission in ulcerative colitis and Crohn's disease. In fact, thiopurines still have a role to play in the treatment algorithm of older patients with IBD because anti-tumor necrosis factor agents do not provide clear advantages for this population in terms of their safety profile, while data on the new biological drugs are still scarce. In this article, we review the optimal use of thiopurines in older patients with IBD.
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Affiliation(s)
- Margalida Calafat
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain
| | - Míriam Mañosa
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain
| | - Fiorella Cañete
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain
| | - Eugeni Domènech
- Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916, Badalona, Catalonia, Spain.
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain.
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
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Abstract
IMPORTANCE Crohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance. OBSERVATIONS The optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti-tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4β7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy. CONCLUSIONS AND RELEVANCE The treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.
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Affiliation(s)
- Kelly Cushing
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor
| | - Peter D R Higgins
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor
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Alkhatry M, Al-Rifai A, Annese V, Georgopoulos F, Jazzar AN, Khassouan AM, Koutoubi Z, Nathwani R, Taha MS, Limdi JK. First United Arab Emirates consensus on diagnosis and management of inflammatory bowel diseases: A 2020 Delphi consensus. World J Gastroenterol 2020; 26:6710-6769. [PMID: 33268959 PMCID: PMC7684461 DOI: 10.3748/wjg.v26.i43.6710] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/15/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis and Crohn's disease are the main entities of inflammatory bowel disease characterized by chronic remittent inflammation of the gastrointestinal tract. The incidence and prevalence are on the rise worldwide, and the heterogeneity between patients and within individuals over time is striking. The progressive advance in our understanding of the etiopathogenesis coupled with an unprecedented increase in therapeutic options have changed the management towards evidence-based interventions by clinicians with patients. This guideline was stimulated and supported by the Emirates Gastroenterology and Hepatology Society following a systematic review and a Delphi consensus process that provided evidence- and expert opinion-based recommendations. Comprehensive up-to-date guidance is provided regarding diagnosis, evaluation of disease severity, appropriate and timely use of different investigations, choice of appropriate therapy for induction and remission phase according to disease severity, and management of main complications.
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Affiliation(s)
- Maryam Alkhatry
- Gastroenterology and Endoscopy Department, Ibrahim Bin Hamad Obaid Allah Hospital, Ministry of Health and Prevention, Ras Al Khaiman, United Arab Emirates
| | - Ahmad Al-Rifai
- Department of Gastroenterology, Sheikh Shakbout Medical City, Abu Dhabi, United Arab Emirates
| | - Vito Annese
- Department of Gastroenterology, Valiant Clinic, Dubai, United Arab Emirates
- Department of Gastroenterology and Endoscopy, American Hospital, Dubai, United Arab Emirates
| | | | - Ahmad N Jazzar
- Gastroenterology Division, Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates
| | - Ahmed M Khassouan
- Digestive Disease Unit, Rashid Hospital, Dubai, United Arab Emirates
| | - Zaher Koutoubi
- Digestive Disease Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates
| | - Rahul Nathwani
- Department of Gastroenterology, Mediclinic City Hospital, Dubai, United Arab Emirates
- Department of Gastroenterology, Mohammed Bin Rashid University, Dubai, United Arab Emirates
| | - Mazen S Taha
- Gastroenterology and Hepatology, Tawam Hospital, Al Ain, United Arab Emirates
| | - Jimmy K Limdi
- Department of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester Academic Health Sciences, University of Manchester, Manchester M8 5RB, United Kingdom
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Vasudevan A, Parthasarathy N, Con D, Nicolaides S, Apostolov R, Chauhan A, Bishara M, Luber RP, Joshi N, Wan A, Rickard JA, Long T, Connoley D, Sparrow MP, Gibson PR, van Langenberg DR. Thiopurines vs methotrexate: Comparing tolerability and discontinuation rates in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther 2020; 52:1174-1184. [PMID: 32794599 DOI: 10.1111/apt.16039] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/17/2020] [Accepted: 07/23/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD). AIM To compare the long-term tolerability, and persistence of thiopurine and methotrexate therapy in IBD. METHODS A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records. RESULTS There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow-up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6-TGN was 298 pmol/8 x 108 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08). CONCLUSION Discontinuation of methotrexate occurred at rates twice that of dose-optimised thiopurine therapy.
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Affiliation(s)
- Abhinav Vasudevan
- Department of Gastroenterology and Hepatology, Monash University, Eastern Health Clinical School, Victoria, Australia
| | - Nina Parthasarathy
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Danny Con
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Steven Nicolaides
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Ross Apostolov
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Ayushi Chauhan
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Maria Bishara
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Raphael P Luber
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Neetima Joshi
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Anna Wan
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - James A Rickard
- Department of Gastroenterology and Hepatology, Eastern Health, Victoria, Australia
| | - Tony Long
- Monash University, Eastern Health Clinical School, Victoria, Australia
| | - Declan Connoley
- Monash University, Eastern Health Clinical School, Victoria, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Victoria, Australia
| | - Daniel R van Langenberg
- Department of Gastroenterology and Hepatology, Monash University, Eastern Health Clinical School, Victoria, Australia
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Guo D, Shi C, Wang L, Ji X, Zhang S, Luo J. A Rationally Designed Micellar Nanocarrier for the Delivery of Hydrophilic Methotrexate in Psoriasis Treatment. ACS APPLIED BIO MATERIALS 2020; 3:4832-4846. [PMID: 34136761 DOI: 10.1021/acsabm.0c00342] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Methotrexate (MTX) is broadly applied in the clinic for the treatments of cancers and autoimmune diseases. Targeted delivery of MTX is attractive to improve its efficacy and reduce off-target toxicity. However, MTX encapsulation in nanoparticle is challenging due to its high water solubility. We rationally designed a well-defined telodendrimer (TD) nanocarrier based on MTX structure to sequester it in nanoparticles. Riboflavin (Rf) and positive charges groups were precisely conjugated on TD to form multivalent hydrogen bonds, π-π stacking and electrostatic interactions with MTX. A reverse micelle approach was developed to preset MTX and TD interactions in the core of micelles, which ensures the effective MTX loading upon dispersion into aqueous solution. As results, MTX loading capacity reaches over 20% (w/w) in the optimized nanocarrier with the particle size of 20-30 nm. The nanoformulations sustain the release of MTX in a controlled manner and exhibit excellent hemocompatibility. The in vitro cellular uptake of MTX was significantly improved by the nanoformulations. The potency of MTX nanoformulations is comparable to the free MTX in cytotoxicity. A psoriasis-like skin inflammation model was induced in mouse by imiquimod (IMQ) stimulation. MTX nanoformulations improved the psoriasis targeting and exhibited a superior long-lasting efficacy in reducing skin inflammation compared with the free MTX in psoriasis treatment.
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Affiliation(s)
- Dandan Guo
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA
| | - Changying Shi
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA
| | - Lili Wang
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA
| | - Xiaotian Ji
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA
| | - Shengle Zhang
- Department of Pathology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA
| | - Juntao Luo
- Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.,Department of Surgery, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.,Upstate Cancer Center, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.,Sepsis Interdisciplinary Research Center, State University of New York Upstate Medical University, Syracuse, New York 13210, USA
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Crouwel F, Buiter HJC, de Boer NK. Gut microbiota-driven drug metabolism in inflammatory bowel disease. J Crohns Colitis 2020; 15:jjaa143. [PMID: 32652007 PMCID: PMC7904070 DOI: 10.1093/ecco-jcc/jjaa143] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS The gut microbiota plays an important role in the metabolization and modulation of several types of drugs. With this study we aimed to review the literature about microbial drug metabolism of medication prescribed in inflammatory bowel disease practice. METHODS A systematic literature search was performed in Embase and PubMed from inception to October 2019. The search was conducted with predefined MeSH/Emtree and text terms. All studies about drug metabolism by microbiota of medication prescribed in inflammatory bowel disease practice were eligible. A total of 1018 records were encountered and 89 articles were selected for full text reading. RESULTS Intestinal bacterial metabolism or modulation is of influence in four specific drugs used in inflammatory bowel disease (mesalazines, methotrexate, glucocorticoids and thioguanine). The gut microbiota cleaves the azo-bond of sulfasalazine, balsalazide and olsalazine and releases the active moiety 5-aminosalicylic acid. It has an impact on the metabolization and potentially on the response of methotrexate therapy. Especially thioguanine can be converted by intestinal bacteria into the pharmacological active 6-thioguanine nucleotides without the requirement of host metabolism. Glucocorticoid compounds can be prone to bacterial degradation. CONCLUSION The human intestinal microbiota can have a major impact on drug metabolism and efficacy of medication prescribed in inflammatory bowel disease practice. A better understanding of these interactions between microbiota and drugs is needed and should be an integral part of the drug development pathway of new inflammatory bowel disease medication.
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Affiliation(s)
- Femke Crouwel
- Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Hans J C Buiter
- Department of Clinical Pharmacology and Pharmacy, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Nanne K de Boer
- Department of Gastroenterology and Hepatology, AG&M Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
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Harris RE, Aloi M, de Ridder L, Croft NM, Koletzko S, Levine A, Turner D, Veereman G, Neyt M, Bigot L, Ruemmele FM, Russell RK. Protocol for a multinational risk-stratified randomised controlled trial in paediatric Crohn's disease: methotrexate versus azathioprine or adalimumab for maintaining remission in patients at low or high risk for aggressive disease course. BMJ Open 2020; 10:e034892. [PMID: 32611737 PMCID: PMC7332179 DOI: 10.1136/bmjopen-2019-034892] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
INTRODUCTION Immunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn's disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups. AIMS To compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation. METHODS AND ANALYSIS REDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6-17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk). ETHICS AND DISSEMINATION ClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access. TRIAL REGISTRATION NUMBER NCT02852694; Pre-results.
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Affiliation(s)
- Rachel E Harris
- Department of Paediatric Gastroenterology, Royal Hospital for Children Glasgow, Glasgow, UK
| | - Marina Aloi
- Paediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Roma, Lazio, Italy
| | - Lissy de Ridder
- Paediatrics, Erasmus MC/Sophia Childrens Hospital, Rotterdam, The Netherlands
| | - Nicholas M Croft
- Department of Paediatric Gastroenterology, Barts and The London School of Medicine and Dentistry, London, UK
| | - Sibylle Koletzko
- Pediatric Gastroenterology and Hepatology, Dr. V. Hauner Children's Hospital, Munich, Germany
- Department of Pediatrics, Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Arie Levine
- Edith Wolfson Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Dan Turner
- Department of Paediatric Gastroenterology, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Gigi Veereman
- Pediatric GI, UZBrussels-VUB, Brussels, Belgium
- Free University Brussels, University Hospital, Brussels, Belgium
| | - Mattias Neyt
- ME-TA Medical Evaluation and Technology Assessment, Merendree, Belgium
| | - Laetitia Bigot
- PIBD-Net, Hôpital universitaire Necker-Enfants malades, Paris, Île-de-France, France
| | - Frank M Ruemmele
- Service de Gastroentérologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Paris, Île-de-France, France
- Department of Paediatric Gastroenterology, Université Paris Descartes, Paris, Île-de-France, France
| | - Richard K Russell
- Department of Paediatric Gastroenterology, Royal Hospital for Children Glasgow, Glasgow, UK
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