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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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Singh AK, Sachdeva S, Srivastava S, Sonika U, Kumar A, Sharma BC, Puri AS, Dalal A. Comparing Myelosuppression Frequency in Indian Inflammatory Bowel Disease Patients: A Randomized Trial of Full Dose Versus Gradual Escalation of Thiopurines. Cureus 2023; 15:e50969. [PMID: 38259414 PMCID: PMC10801346 DOI: 10.7759/cureus.50969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2023] [Indexed: 01/24/2024] Open
Abstract
INTRODUCTION We aimed to compare the frequency of myelosuppression in patients initiating azathioprine (AZA) at full dose versus those undergoing gradual dose escalation. METHODS Forty patients with inflammatory bowel disease were recruited over one year and randomized into two groups of 20. Group A initiated AZA at a full dose of 2 mg/kg, while group B started at 1 mg/kg with subsequent dose increases at regular intervals. RESULTS Seventeen patients from each group were included in the final analysis. During follow-up, two patients (11.8%) from group A and four patients (23.5%) from group B experienced relapses (p=0.65). Myelosuppression occurred in two patients (11.8%) from each group. Absolute neutrophil counts in group A tended to have lower median values than those in group B, particularly four weeks after AZA initiation. Univariate analysis identified serum proteins, albumin, and bilirubin as significantly associated with leukopenia, but these factors were not significant according to multivariate analysis. CONCLUSIONS The incidence of myelosuppression was similar between the groups. Patients with full-dose initiation of AZA had numerically fewer relapses during the follow-up period.
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Affiliation(s)
- Alok Kumar Singh
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, IND
| | - Sanjeev Sachdeva
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, IND
| | | | - Ujjwal Sonika
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, IND
| | - Ajay Kumar
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, IND
| | - Barjesh C Sharma
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, IND
| | - Amarender S Puri
- Department of Gastroenterology, Medanta - The Medicity Hospital, Gurugram, IND
| | - Ashok Dalal
- Department of Gastroenterology, G.B. Pant Hospital, New Delhi, IND
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Saha A, Dreyfuss I, Sarfraz H, Friedman M, Markowitz J. Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis. Cancers (Basel) 2022; 15:84. [PMID: 36612082 PMCID: PMC9817715 DOI: 10.3390/cancers15010084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.
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Affiliation(s)
- Aditi Saha
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Isabella Dreyfuss
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Humaira Sarfraz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Mark Friedman
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Joseph Markowitz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA
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Ferretti F, Cannatelli R, Monico MC, Maconi G, Ardizzone S. An Update on Current Pharmacotherapeutic Options for the Treatment of Ulcerative Colitis. J Clin Med 2022; 11:jcm11092302. [PMID: 35566428 PMCID: PMC9104748 DOI: 10.3390/jcm11092302] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/10/2022] [Accepted: 04/18/2022] [Indexed: 12/17/2022] Open
Abstract
The main goals of Ulcerative Colitis (UC) treatment are to both induce and maintain the clinical and endoscopic remission of disease, reduce the incidence of complications such as dysplasia and colorectal carcinoma and improve quality of life. Although a curative medical treatment for UC has not yet been found, new therapeutic strategies addressing specific pathogenetic mechanisms of disease are emerging. Notwithstanding these novel therapies, non-biological conventional drugs remain a mainstay of treatment. The aim of this review is to summarize current therapeutic strategies used as treatment for ulcerative colitis and to briefly focus on emerging therapeutic strategies, including novel biologic therapies and small molecules. To date, multiple therapeutic approaches can be adopted in UC and the range of available compounds is constantly increasing. In this era, the realization of well-designed comparative clinical trials, as well as the definition of specific therapeutic models, would be strongly suggested in order to achieve personalized management for UC patients.
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Nakase H, Uchino M, Shinzaki S, Matsuura M, Matsuoka K, Kobayashi T, Saruta M, Hirai F, Hata K, Hiraoka S, Esaki M, Sugimoto K, Fuji T, Watanabe K, Nakamura S, Inoue N, Itoh T, Naganuma M, Hisamatsu T, Watanabe M, Miwa H, Enomoto N, Shimosegawa T, Koike K. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020. J Gastroenterol 2021; 56:489-526. [PMID: 33885977 PMCID: PMC8137635 DOI: 10.1007/s00535-021-01784-1] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a general term for chronic or remitting/relapsing inflammatory diseases of the intestinal tract and generally refers to ulcerative colitis (UC) and Crohn's disease (CD). Since 1950, the number of patients with IBD in Japan has been increasing. The etiology of IBD remains unclear; however, recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development. UC and CD display heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management depends on the understanding and tailoring of evidence-based interventions by physicians. In 2020, seventeen IBD experts of the Japanese Society of Gastroenterology revised the previous guidelines for IBD management published in 2016. This English version was produced and modified based on the existing updated guidelines in Japanese. The Clinical Questions (CQs) of the previous guidelines were completely revised and categorized as follows: Background Questions (BQs), CQs, and Future Research Questions (FRQs). The guideline was composed of a total of 69 questions: 39 BQs, 15 CQs, and 15 FRQs. The overall quality of the evidence for each CQ was determined by assessing it with reference to the Grading of Recommendations Assessment, Development and Evaluation approach, and the strength of the recommendation was determined by the Delphi consensus process. Comprehensive up-to-date guidance for on-site physicians is provided regarding indications for proceeding with the diagnosis and treatment.
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Affiliation(s)
- Hiroshi Nakase
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan ,grid.263171.00000 0001 0691 0855Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido 060-8543 Japan
| | - Motoi Uchino
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Shinichiro Shinzaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Minoru Matsuura
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Katsuyoshi Matsuoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Taku Kobayashi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Masayuki Saruta
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Fumihito Hirai
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Keisuke Hata
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Sakiko Hiraoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Motohiro Esaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Ken Sugimoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Toshimitsu Fuji
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Kenji Watanabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Shiro Nakamura
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Nagamu Inoue
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Toshiyuki Itoh
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Makoto Naganuma
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Tadakazu Hisamatsu
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Mamoru Watanabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
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Harmand PO, Solassol J. Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT. Genes (Basel) 2020; 11:genes11101212. [PMID: 33081236 PMCID: PMC7602704 DOI: 10.3390/genes11101212] [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] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient.
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Affiliation(s)
- Pierre-Olivier Harmand
- Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France;
| | - Jérôme Solassol
- Laboratoire de Biologie des Tumeurs Solides, Département de Pathologie et Oncobiologie, Centre Hospitalier Universitaire de Montpellier, 34295 Montpellier, France;
- Institut de Recherche en Cancérologie de Montpellier, INSERM, Université de Montpellier, Institut Régional du Cancer de Montpellier, 34298 Montpellier, France
- Correspondence: ; Tel.: + 33-4673-358-71
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Lamb CA, Kennedy NA, Raine T, Hendy PA, Smith PJ, Limdi JK, Hayee B, Lomer MCE, Parkes GC, Selinger C, Barrett KJ, Davies RJ, Bennett C, Gittens S, Dunlop MG, Faiz O, Fraser A, Garrick V, Johnston PD, Parkes M, Sanderson J, Terry H, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen R, Hawthorne AB. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019; 68:s1-s106. [PMID: 31562236 PMCID: PMC6872448 DOI: 10.1136/gutjnl-2019-318484] [Citation(s) in RCA: 1461] [Impact Index Per Article: 243.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/10/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
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Affiliation(s)
- Christopher Andrew Lamb
- Newcastle University, Newcastle upon Tyne, UK
- Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Nicholas A Kennedy
- Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
- University of Exeter, Exeter, UK
| | - Tim Raine
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
| | - Philip Anthony Hendy
- Chelsea and Westminster Hospital NHS Foundation Trust, London, UK
- Imperial College London, London, UK
| | - Philip J Smith
- Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
| | - Jimmy K Limdi
- The Pennine Acute Hospitals NHS Trust, Manchester, UK
- University of Manchester, Manchester, UK
| | - Bu'Hussain Hayee
- King's College Hospital NHS Foundation Trust, London, UK
- King's College London, London, UK
| | - Miranda C E Lomer
- King's College London, London, UK
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Gareth C Parkes
- Barts Health NHS Trust, London, UK
- Barts and the London School of Medicine and Dentistry, London, UK
| | - Christian Selinger
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
- University of Leeds, Leeds, UK
| | | | - R Justin Davies
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
- University of Cambridge, Cambridge, UK
| | - Cathy Bennett
- Systematic Research Ltd, Quorn, UK
- Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
| | | | - Malcolm G Dunlop
- University of Edinburgh, Edinburgh, UK
- Western General Hospital, Edinburgh, UK
| | - Omar Faiz
- Imperial College London, London, UK
- St Mark's Hospital, Harrow, UK
| | - Aileen Fraser
- University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | | | | | - Miles Parkes
- Cambridge University Hospitals NHS FoundationTrust, Cambridge, UK
| | - Jeremy Sanderson
- King's College London, London, UK
- Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - Daniel R Gaya
- Glasgow Royal Infirmary, Glasgow, UK
- University of Glasgow, Glasgow, UK
| | - Tariq H Iqbal
- Queen Elizabeth Hospital Birmingham NHSFoundation Trust, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - Stuart A Taylor
- University College London, London, UK
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Melissa Smith
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
- Brighton and Sussex Medical School, Brighton, UK
| | - Matthew Brookes
- Royal Wolverhampton NHS Trust, Wolverhampton, UK
- University of Wolverhampton, Wolverhampton, UK
| | - Richard Hansen
- Royal Hospital for Children Glasgow, Glasgow, UK
- University of Glasgow, Glasgow, UK
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8
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Abstract
Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.
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9
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Özgenç F, Karakoyun M, Ecevit Ç, Hekimci H, Kıran Taşçı E, Erdemir G. Efficacy and safety of long-term thiopurine maintenance treatment for ulcerative colitis in Turkey: A single-center experience. TURKISH JOURNAL OF GASTROENTEROLOGY 2019; 29:650-654. [PMID: 30381272 DOI: 10.5152/tjg.2018.17151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND/AIMS Thiopurines are widely used in the treatment of inflammatory bowel disease, but data are limited. Or aim was to determine the outcome of thiopurine application in children diagnosed with ulcerative colitis (UC). MATERIALS AND METHODS Forty-eight patients with UC, diagnosed at our center between 2005 and 2016 and applied azathiopurine (AZA), were included in the study. Data were collected retrospectively. The diagnosis of UC was based on the conventional clinical, radiological, histological, and endoscopic assessment. All patients with UC at this intercept were analyzed at the 4- and 6-week and 3-month intervals after remission to determine patient characteristics, thiopurine properties, and its efficacy and toxicity. Determination of remission, relapse, and steroid refractoriness/dependency were guided according to the European Crohn's and Colitis Organisation consensus. RESULTS Azathiopurine was started at the median 1 month (0-12 months), and it was applied thereafter for maintenance (n=43). Response to remission induction was obtained in 40 (93.7%) patients. The median duration of the AZA treatment was 24 months (5-63). In 34 (85%) of the 40 children, it was well tolerated until the last visit. During the follow-up, adverse events occurred in 6 patients. These are leucopenia, neutropenia, vomiting, diarrhea, and skin rush. CONCLUSION Thiopurine is an appropriate treatment option for remission in patients with UC. For a long-term follow-up, it is very important to identify patients with UC who have clinical remission with side effects and with thiopurine application.
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Affiliation(s)
- Funda Özgenç
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine, İzmir, Turkey
| | - Miray Karakoyun
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Tepecik Training and Research Hospital, İzmir, Turkey
| | - Çiğdem Ecevit
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Dr. Behçet Uz Children Hospital, İzmir, Turkey
| | - Hamiyet Hekimci
- Department of Pediatric Hematology, Ege University School of Medicine, İzmir, Turkey
| | - Ezgi Kıran Taşçı
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ege University School of Medicine, İzmir, Turkey
| | - Gülin Erdemir
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Dr. Behçet Uz Children Hospital, İzmir, Turkey
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Falloon K, Lazarev M. A Primer on IBD: Phenotypes, Diagnosis, Treatment, and Clinical Challenges. MOLECULAR GENETICS OF INFLAMMATORY BOWEL DISEASE 2019:3-24. [DOI: 10.1007/978-3-030-28703-0_1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Matsuoka K, Kobayashi T, Ueno F, Matsui T, Hirai F, Inoue N, Kato J, Kobayashi K, Kobayashi K, Koganei K, Kunisaki R, Motoya S, Nagahori M, Nakase H, Omata F, Saruta M, Watanabe T, Tanaka T, Kanai T, Noguchi Y, Takahashi KI, Watanabe K, Hibi T, Suzuki Y, Watanabe M, Sugano K, Shimosegawa T. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol 2018; 53:305-353. [PMID: 29429045 PMCID: PMC5847182 DOI: 10.1007/s00535-018-1439-1] [Citation(s) in RCA: 365] [Impact Index Per Article: 52.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 01/23/2018] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a chronic disorder involving mainly the intestinal tract, but possibly other gastrointestinal and extraintestinal organs. Although etiology is still uncertain, recent knowledge in pathogenesis has accumulated, and novel diagnostic and therapeutic modalities have become available for clinical use. Therefore, the previous guidelines were urged to be updated. In 2016, the Japanese Society of Gastroenterology revised the previous versions of evidence-based clinical practice guidelines for ulcerative colitis (UC) and Crohn's disease (CD) in Japanese. A total of 59 clinical questions for 9 categories (1. clinical features of IBD; 2. diagnosis; 3. general consideration in treatment; 4. therapeutic interventions for IBD; 5. treatment of UC; 6. treatment of CD; 7. extraintestinal complications; 8. cancer surveillance; 9. IBD in special situation) were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases. The guidelines were developed with the basic concept of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Recommendations were made using Delphi rounds. This English version was produced and edited based on the existing updated guidelines in Japanese.
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Affiliation(s)
- Katsuyoshi Matsuoka
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Taku Kobayashi
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Fumiaki Ueno
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Ofuna Central Hospital, 6-2-24 Ofuna, Kamakura-shi, Kanagawa, 247-0056, Japan.
| | - Toshiyuki Matsui
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Fumihito Hirai
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Nagamu Inoue
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Jun Kato
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kenji Kobayashi
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kiyonori Kobayashi
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazutaka Koganei
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Reiko Kunisaki
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Satoshi Motoya
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masakazu Nagahori
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroshi Nakase
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Fumio Omata
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masayuki Saruta
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Toshiaki Watanabe
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Toshiaki Tanaka
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takanori Kanai
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshinori Noguchi
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ken-Ichi Takahashi
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kenji Watanabe
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Toshifumi Hibi
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yasuo Suzuki
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Mamoru Watanabe
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kentaro Sugano
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the ''Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease in Japan'', The Japanese Society of Gastroenterology (JSGE), 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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Comparison of Concomitant Mesalamine and Immunomodulator Therapy and Immunomodulator Monotherapy for Crohn's Disease. Gastroenterol Res Pract 2018; 2018:4826973. [PMID: 29576767 PMCID: PMC5822780 DOI: 10.1155/2018/4826973] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 05/03/2017] [Indexed: 12/18/2022] Open
Abstract
Background Although immunomodulators are increasingly used in Crohn's disease (CD), a significant number of gastroenterologists still use 5-aminosalicylate (5-ASA) in combination with azathioprine (AZA) or 6-mercaptopurine (6-MP); there is limited evidence regarding the benefit of concomitant 5-ASA with AZA/6-MP compared with AZA/6-MP monotherapy for the treatment of CD. Study Design A total of 106 patients who received AZA/6-MP for more than 3 months between January 1991 and May 2014 were identified retrospectively. Each patient was matched with 3 randomly selected controls who were treated with concomitant therapy during the same period. Results The cumulative probabilities of steroid use at 5 and 10 years were 24.9% and 75.8% in the 5-ASA + AZA/6-MP group and 31.2% and 87.8% in the AZA/6-MP group, respectively (P = 0.187). The cumulative probabilities of anti-TNF use, resectional surgery, and disease-related hospitalization were comparable between the groups. The younger age and the use of lower doses of immunomodulators were associated with higher requirement of rescue therapy. Conclusions This study did not demonstrate that the concomitant use of 5-ASA with AZA/6-MP showed the proof or effect in terms of steroid requirements, anti-TNF use, resectional surgery, or disease-related hospitalization compared with that of AZA/6-MP alone.
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13
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Drug repurposing: In-vitro anti-glycation properties of 18 common drugs. PLoS One 2018; 13:e0190509. [PMID: 29300762 PMCID: PMC5754062 DOI: 10.1371/journal.pone.0190509] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 12/15/2017] [Indexed: 01/31/2023] Open
Abstract
Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover "new targets" for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 μM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 μM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 μM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 μM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 μM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 μM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents.
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Bermejo San José F, Algaba A, López Durán S, Guerra I, Aicart M, Hernández-Tejero M, Garrido E, de Lucas M, Bonillo D, López Sanromán A. Mercaptopurine and inflammatory bowel disease: the other thiopurine. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 109:10-16. [PMID: 27809554 DOI: 10.17235/reed.2016.4546/2016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Data about use and effectiveness of mercaptopurine in inflammatory bowel disease are relatively limited. AIMS To assess the possible therapeutic indications, efficacy and safety of mercaptopurine as an alternative to azathioprine in inflammatory bowel disease. METHODS Retrospective observational study in patients treated with mercaptopurine in a total cohort of 1,574 patients with inflammatory bowel disease. RESULTS One hundred and fifty-two patients received mercaptopurine, 15.7% of these patients as an initial thiopurine, 5.3% after azathioprine failure, and 79% after azathioprine intolerance. In 52.6% of patients (n = 80), adverse effects of mercaptopurine occurred, resulting in withdrawal in 49 of them. Mercaptopurine was effective in 39% of cases (95% CI 31-48%). In the remaining patients, failure was due mainly to withdrawal due to side effects (55.1%) and therapeutic step-up (33.7%). The average total time of mercaptopurine exposure was 36 months (IQR: 2-60). Myelotoxicity with mercaptopurine was more common in patients with intermediate TPMT activity than in those with normal activity (p = 0.046). CONCLUSIONS In our setting, mercaptopurine is primarily used as a rescue therapy in patients with azathioprine adverse effects. This could explain its modest efficacy and the high rate of adverse effects. However, this drug is still an alternative in this group of patients, before a therapeutic step-up to biologics is considered.
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Affiliation(s)
| | | | - Sergio López Durán
- Servicio de Gastroenterología, Hospital Universitario Ramón y Cajal, España
| | - Iván Guerra
- Digestivo, Hospital Universitario de Fuenlabrada
| | - Marta Aicart
- Gastroenterologia, Hospital Universitario Ramón y Cajal
| | | | - Elena Garrido
- Gastroenterología, Hospital Universitario Ramón y Cajal
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Mosli M, Sabbahi H, Alyousef H, Abdulhaq M, Hadadi A, Aljahdali E, Jawa H, Bazarah S, Qari Y. Risk Stratification of Patients with Crohn's Disease: A Retrospective Analysis of Clinical Decision Making and Its Impact on Long-Term Outcome. Dig Dis 2017; 36:49-55. [PMID: 28654928 DOI: 10.1159/000477613] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 05/15/2017] [Indexed: 02/02/2023]
Abstract
BACKGROUND AND AIMS Complications such as need for bowel resections and hospitalization due to Crohn's disease (CD) occur when disease activity persists due to ineffective therapy. Certain "high-risk" features require an early introduction of anti-tumor necrosis factor-α therapy to prevent such complications. We aim to evaluate the prevalence of "high-risk" features among a cohort of patients with CD and examine the association between discordance of early therapy with baseline risk stratification and disease outcome. PATIENTS AND METHODS All adult patients with CD were retrospectively identified and their medical records were reviewed. Clinical, endoscopic, laboratory, and radiological data were collected. Patients were divided into "low" and "high" risk groups according to the presence or absence of penetrating disease, perianal involvement, foregut involvement, extensive disease seen on endoscopy or cross-sectional imaging, young age at the time of diagnosis (<40), persistent cigarette smoking and frequent early requirements for corticosteroid therapy. Initial treatment selection and treatment approach ("step-up" vs. "accelerated step-up" vs. "top-down") within 6 months of diagnosis were recorded. Rates of CD-related bowel resections and hospitalization within 5 years of diagnosis were calculated. Logistic regression analysis was used to examine the association between "discordance" of early treatment selections and risk stratification categories with outcomes. RESULTS Eighty-five CD patients were included. The median age and duration of disease were 25 (interquartile range [IQR] 19-32) and 5 (IQR 4-6) years, respectively. Sixty five percent were females and 66% were native Saudis. Smoking was reported in 12% of patients and perianal disease in 18%. "High-risk" features were identified in 43 (51%) patients, of which only 6 (14%) were treated with "top-down" therapy and 7 (16%) with "accelerated step-up" care. The risk of requiring a bowel resection, and hospitalization was higher for "high-risk" patients compared to "low-risk" patients (risk ratio [RR] 13.67, 95% CI 1.88-99.41; p = 0.003, and RR 1.86, 95% CI 0.03-0.43; p = 0.0312, respectively). "Discordance" occurred in 34% of cases. Bowel resection was required in 15/85 (18%) patients and 32/85 (38%) required at least one hospitalization within 5 years of diagnosis. Logistic regression analysis identified a statistically significant association between "discordance" and need for bowel resections (OR 6.50, 95% CI 1.59-26.27, p = 0.009), and hospitalizations (OR 3.01, 95% CI 1.08-8.39, p = 0.035) within 5 years of diagnosis. CONCLUSIONS "Discordance" between patient risk-profile and treatment selection early in the course of CD has a significant impact on disease outcome, specifically need for bowel resection and hospitalization, which are more likely to occur in the presence of "high-risk" features. Early identification of "high-risk" features could help prevent long-term complications.
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Affiliation(s)
- Mahmoud Mosli
- Department of Medicine, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia
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Lord JD, Shows DM. Thiopurine use associated with reduced B and natural killer cells in inflammatory bowel disease. World J Gastroenterol 2017; 23:3240-3251. [PMID: 28566883 PMCID: PMC5434429 DOI: 10.3748/wjg.v23.i18.3240] [Citation(s) in RCA: 16] [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: 12/15/2016] [Revised: 01/27/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.
METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease (IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.
RESULTS Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the time of sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer (NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells (Tregs) or naïve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iNKT and MAIT cells than healthy controls.
CONCLUSION Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.
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Abstract
Background and aim The Montreal classification of disease behaviour in Crohn's disease describes progression of disease towards a stricturing and penetrating phenotype. In the present paper, we propose an alternative representation of the long-term course of Crohn’s disease complications, the rolling phenotype. As is commonly observed in clinical practice, this definition allows progression to a more severe phenotype (stricturing, penetrating) but also, regression to a less severe behaviour (inflammatory, or remission) over time. Methods All patients diagnosed with Crohn's Disease between 01/01/1994 and 01/03/2008, managed at a single centre and observed for a minimum of 5 years, had development and resolution of all complications recorded. A rolling phenotype was defined at each time point based on all observed complications in the three years prior to the time point. Phenotype was defined as B1, B2, B3, or B23 (penetrating and stenotic). The progression over time of the rolling phenotype was compared to that of the cumulative Montreal phenotype. Results 305 patients were observed a median of 10.0 (Intraquartile range 7.3–13.7) years. Longitudinal progression of rolling phenotype demonstrated a consistent proportion of patients with B1 (70%), B2 (20%), B3 (5%) and B23 (5%) phenotypes. These proportions were observed regardless of initial phenotype. In contrast, the cumulative Montreal phenotype progressed towards a more severe phenotype with time (B1 (39%), B2 (26%), B3(35%) at 10 years). Conclusion A rolling phenotype provides an alternative view of the longitudinal burden of intra-abdominal complications in Crohn's disease. From this viewpoint, 70% of patients have durable freedom from complication over time (>3 years).
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18
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Wong DR, Coenen MJH, Vermeulen SH, Derijks LJJ, van Marrewijk CJ, Klungel OH, Scheffer H, Franke B, Guchelaar HJ, de Jong DJ, Engels LGJB, Verbeek ALM, Hooymans PM. Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease. J Crohns Colitis 2017; 11:175-184. [PMID: 27402913 DOI: 10.1093/ecco-jcc/jjw130] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 06/10/2016] [Accepted: 06/21/2016] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. METHODS The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 109/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial. RESULTS Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 108 erythrocytes and 3525 pmol/8 × 108 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]). CONCLUSIONS In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.
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Affiliation(s)
- Dennis R Wong
- Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - Marieke J H Coenen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Sita H Vermeulen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.,Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Luc J J Derijks
- Department of Clinical Pharmacy, Máxima Medical Centre, Veldhoven, The Netherlands
| | - Corine J van Marrewijk
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Olaf H Klungel
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands
| | - Hans Scheffer
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Barbara Franke
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Dirk J de Jong
- Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leopold G J B Engels
- Department of Gastroenterology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
| | - André L M Verbeek
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Piet M Hooymans
- Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands
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Wehkamp J, Götz M, Herrlinger K, Steurer W, Stange EF. Inflammatory Bowel Disease. DEUTSCHES ARZTEBLATT INTERNATIONAL 2017; 113:72-82. [PMID: 26900160 DOI: 10.3238/arztebl.2016.0072] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 12/14/2015] [Accepted: 12/14/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Inflammatory bowel diseases are common in Europe, with prevalences as high as 1 in 198 persons (ulcerative colitis) and 1 in 310 persons (Crohn's disease). METHODS This review is based on pertinent articles retrieved by a search in PubMed and in German and European guidelines and Cochrane reviews of controlled trials. RESULTS Typically, the main clinical features of inflammatory bowel diseases are diarrhea, abdominal pain, and, in the case of ulcerative colitis, peranal bleeding. These diseases are due to a complex immunological disturbance with both genetic and environmental causes. A defective mucosal barrier against commensal bowel flora plays a major role in their pathogenesis. The diagnosis is based on laboratory testing, ultrasonography, imaging studies, and, above all, gastrointestinal endoscopy. Most patients with Crohn's disease respond to budesonide or systemic steroids; aminosalicylates are less effective. Refractory exacerbations may be treated with antibodies against tumor necrosis factor (TNF) or, more recently, antibodies against integrin, a protein of the cell membrane. In ulcerative colitis, aminosalicylates are given first; if necessary, steroids or antibodies against TNF-α or integrin are added. Maintenance therapy to prevent further relapses often involves immunosuppression with thiopurines and/or antibodies. Once all conservative treatment options have been exhausted, surgery may be necessary. CONCLUSION The treatment of chronic inflammatory bowel diseases requires individually designed therapeutic strategies and the close interdisciplinary collaboration of internists and surgeons.
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Affiliation(s)
- Jan Wehkamp
- Department of Internal Medicine I - Gastroenterology, Hepatology, Infectiology, University Hospital of Tübingen, Asklepios Klinik Nord - Heidberg, Hamburg, Department of Internal Medicine I (Gastroenterology, Hepatology and Endocrinology), Robert-Bosch-Krankenhaus, Stuttgart
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20
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Holt DQ, Strauss BJ, Moore GT. Weight and Body Composition Compartments do Not Predict Therapeutic Thiopurine Metabolite Levels in Inflammatory Bowel Disease. Clin Transl Gastroenterol 2016; 7:e199. [PMID: 27787512 PMCID: PMC5288590 DOI: 10.1038/ctg.2016.56] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 08/26/2016] [Accepted: 09/13/2016] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVES: Thiopurine drugs are the most commonly used steroid-sparing therapies in moderate-to-severe inflammatory bowel disease (IBD). Their complex metabolism and their narrow therapeutic windows means that optimal dosing is difficult. However, weight-based dosing is the norm. Similar antimetabolites are dosed by body composition parameters. In IBD, treatment response and toxicity has been shown to correlate with thiopurine metabolite levels. We sought to determine whether weight or body composition parameters predicted therapeutic 6-thioguanine nucleotide (6TGN) or toxic 6-methylmercaptopurine (6MMP) levels. METHODS: This single-center retrospective cohort study identified 66 IBD patients who had body composition analysis and thiopurine metabolite levels tested. Statistical analysis was performed using Spearman correlation, Kruskal–Wallis, Mann–Whitney, and unpaired t tests and receiver-operator operating characteristic curves. A P value of <0.05 was considered significant. RESULTS: No correlation was identified between 6TGN and any body composition parameters, absolute drug dose or drug dose/kg of fat mass, fat-free mass (FFM), subcutaneous adipose tissue area, or visceral adipose tissue area. However, 6MMP correlated with azathioprine dose, thiopurine dose/kg of body weight, and with several body composition parameters. CONCLUSIONS: No relationship was found between therapeutic metabolite levels and weight or body composition compartments. Higher thiopurine doses, especially in relation to FFM, are associated with higher levels of potentially hepatotoxic 6MMP and shunting toward this metabolite. Conventional weight-based dosing to attain therapeutic metabolite levels appears unreliable and may be replaced by metabolite level testing.
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Affiliation(s)
- Darcy Q Holt
- Department of Gastroenterology & Hepatology, Monash Health, Clayton, Australia.,School of Clinical Sciences, Monash University, Clayton, Australia
| | - Boyd Jg Strauss
- School of Clinical Sciences, Monash University, Clayton, Australia
| | - Gregory T Moore
- Department of Gastroenterology & Hepatology, Monash Health, Clayton, Australia.,School of Clinical Sciences, Monash University, Clayton, Australia
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21
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González-Lama Y, Gisbert JP. Monitoring thiopurine metabolites in inflammatory bowel disease. Frontline Gastroenterol 2016; 7:301-307. [PMID: 28839871 PMCID: PMC5369498 DOI: 10.1136/flgastro-2015-100681] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Revised: 03/09/2016] [Accepted: 03/16/2016] [Indexed: 02/04/2023] Open
Abstract
Thiopurines (azathioprine and mercaptopurine) are one of the immunosuppressive mainstays for the treatment of inflammatory bowel disease. In spite of its widespread use, thiopurine metabolism is still not fully understood, and a significant proportion of patients suffer toxicity or lack of efficacy. Different enzymatic pathways with individual variations constitute a pharmacogenetic model that seems to be suitable for monitoring and therapeutic intervention. This review is focused on current concepts and recent research that may help clinicians to rationally optimise thiopurine treatment in patients with inflammatory bowel disease.
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Affiliation(s)
- Yago González-Lama
- Gastroenterology and Hepatology Department, Puerta de Hierro University Hospital, Majadahonda, Madrid, Spain
| | - Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Madrid, Spain
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22
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Kirchgesner J, Beaugerie L, Carrat F, Sokol H, Cosnes J, Schwarzinger M. Impact on Life Expectancy of Withdrawing Thiopurines in Patients with Crohn's Disease in Sustained Clinical Remission: A Lifetime Risk-Benefit Analysis. PLoS One 2016; 11:e0157191. [PMID: 27271176 PMCID: PMC4894633 DOI: 10.1371/journal.pone.0157191] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 05/25/2016] [Indexed: 12/26/2022] Open
Abstract
Objective Long-term treatment with thiopurines is associated with a decreased risk of Crohn’s disease (CD) flare but an increased risk of various cancers depending on gender, age, and presence of extensive colitis. We evaluated risks and benefits of withdrawing thiopurines in patients with CD in prolonged remission. Methods We developed a Markov model assessing risks and benefits of withdrawing thiopurines compared to continuing thiopurines in a lifetime horizon. The model was stratified by age (35 and 65 years old at thiopurine withdrawal), gender and presence of extensive colitis. Parameter estimates were taken from French cohorts and hospital databases, cancer and death national registries and published literature. Life expectancy, rates of relapse, serious adverse events, and causes-of-death were evaluated. Results In patients without extensive colitis, continuing thiopurines increased life expectancy up to 0.03 years for 35 year-old men and women but decreased life expectancy down to 0.07 years for 65 year-old men and women. Withdrawal strategy became the preferred strategy at 40.6 years for men, and 45.7 years for women without extensive colitis. In patients with extensive colitis, continuation strategy was the preferred strategy regardless of age. Risk-benefit analysis was not modified by duration of CD activity. Conclusions Factors determining life expectancy associated with withdrawal or continuation of thiopurines in patients with CD and in sustained clinical remission vary substantially according to gender, age and presence of extensive colitis. Individual decisions to continue or withdraw thiopurines in patients with CD in sustained remission should take into account these parameters.
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Affiliation(s)
- Julien Kirchgesner
- Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine, Paris, France
- UMR-S 1136, INSERM & UPMC Univ Paris 06, Paris, France
- * E-mail:
| | - Laurent Beaugerie
- Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine, Paris, France
- ERL 1057 INSERM/UMRS 7203 and GRC-UPMC 03, UPMC Univ Paris 06, Paris, France
| | - Fabrice Carrat
- UMR-S 1136, INSERM & UPMC Univ Paris 06, Paris, France
- Department of Public Health, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Harry Sokol
- Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Jacques Cosnes
- Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Michaël Schwarzinger
- THEN, Translational Health Economics Network, Paris, France
- UMR 1137, INSERM, Infection, Antimicrobials, Modelization, Evolution (IAME), Paris, France
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23
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Vögelin M, Biedermann L, Frei P, Vavricka SR, Scharl S, Zeitz J, Sulz MC, Fried M, Rogler G, Scharl M. The Impact of Azathioprine-Associated Lymphopenia on the Onset of Opportunistic Infections in Patients with Inflammatory Bowel Disease. PLoS One 2016; 11:e0155218. [PMID: 27214202 PMCID: PMC4877071 DOI: 10.1371/journal.pone.0155218] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 04/26/2016] [Indexed: 12/18/2022] Open
Abstract
Background Thiopurines are known to cause lymphopenia (<1,500 lymphocytes/μl). As severe lymphopenia (<500C/μl) is associated with opportunistic infections, we investigated severity of thiopurine-related lymphopenia and development of opportunistic infections in our tertiary referral centre. Methods We retrospectively screened medical records of 1,070 IBD patients and identified 100 individuals that developed a total of 161 episodes of lymphopenia during thiopurine treatment between 2002 and 2014. Occurrence of opportunistic infections was documented. A control group consisted of IBD patients receiving thiopurines but without developing lymphopenia. Results Of a total of 161 episodes of lymphopenia, 23% were severe (<500C/μl). In this subgroup, thiopurine dosing was modified in 64% (dosage reduction: 32%, medication discontinued: 32%). We identified 9 cases (5.5%) of opportunistic infections, of which only two occurred during severe lymphopenia. One opportunistic infection (4.5%) was identified in the control group. No association was found between opportunistic infections and severity of lymphopenia. All patients who suffered from opportunistic infections were receiving additional immunosuppressive medication. Conclusion Our patients treated with thiopurines rarely developed severe lymphopenia and opportunistic infections did not occur more often than in the control group. A careful monitoring of lymphocytes and prophylactic adjustment of thiopurine therapy might contribute to this low incidence.
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Affiliation(s)
- Marius Vögelin
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Luc Biedermann
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Pascal Frei
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Stephan R. Vavricka
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Sylvie Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Jonas Zeitz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Michael C. Sulz
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Michael Fried
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Division of Gastroenterology and Hepatology, Stadtspital Triemli, Zurich, Switzerland
- * E-mail:
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24
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Kammermeier J, Morris MA, Garrick V, Furman M, Rodrigues A, Russell RK. Management of Crohn's disease. Arch Dis Child 2016; 101:475-80. [PMID: 26553907 PMCID: PMC4853609 DOI: 10.1136/archdischild-2014-307217] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/09/2015] [Accepted: 10/12/2015] [Indexed: 02/07/2023]
Abstract
Crohn's disease (CD) is rapidly increasing in children so an up to date knowledge of diagnosis, investigation and management is essential. Exclusive enteral nutrition is the first line treatment for active disease. The vast majority of children will need immunosuppressant treatment and around 20% will need treatment with biologics. Recent guidelines have helped make best use of available therapies.
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Affiliation(s)
| | - Mary-Anne Morris
- Department of Paediatrics, Norfolk and Norwich University Hospital, Norwich, UK
| | - Vikki Garrick
- Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, UK
| | - Mark Furman
- Centre for Paediatric Gastroenterology, Royal Free Hospital, London, UK
| | - Astor Rodrigues
- Department of Paediatric Gastroenterology, John Radcliffe Hospital, Oxford, UK
| | - Richard K Russell
- Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, UK
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25
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Thiopurines in the Management of Crohn's Disease: Safety and Efficacy Profile in Patients with Normal TPMT Activity-A Retrospective Study. Can J Gastroenterol Hepatol 2016; 2016:1034834. [PMID: 27446822 PMCID: PMC4904638 DOI: 10.1155/2016/1034834] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 09/24/2015] [Indexed: 12/11/2022] Open
Abstract
Background and Aims. Thiopurines are used in the treatment of Crohn's disease (CD) and thiopurine S-methyltransferase (TPMT) activity can guide thiopurine dosing to avoid adverse events. This retrospective study evaluated the safety and efficacy of starting thiopurines at low dose versus full dose in patients with CD and normal TPMT. Methods. This was a single center retrospective study including adult CD patients with normal TPMT levels (≥25 nmol/hr/g Hgb) who were followed for 1 year. Patients started at full dose of azathioprine (2-2.5 mg/kg) or 6-mercaptopurine (1-1.5 mg/kg) were compared to patients started at low dose. Harvey-Bradshaw index, treatment failure, and drug-related adverse events were recorded. Results. Our study included 134 patients. Both groups had similar incidences of drug-related adverse events and discontinuation of therapy due to side effects. Fifty-six percent of all adverse events occurred within 31 days and 92% occurred within 3 months of therapy. Clinical response favored the full-dose group at 6 months (69% versus 27%, p = 0.0542). Conclusions. Our study indicates that it is safe to start patients on full-dose thiopurine when they have a normal TPMT given its very similar toxicity profile to patients started on low dose. This may also positively impact efficacy.
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26
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Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, Reinisch W. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015; 21:12519-12543. [PMID: 26640330 PMCID: PMC4658608 DOI: 10.3748/wjg.v21.i44.12519] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.
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27
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Chande N, Patton PH, Tsoulis DJ, Thomas BS, MacDonald JK. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2015; 2015:CD000067. [PMID: 26517527 PMCID: PMC9578512 DOI: 10.1002/14651858.cd000067.pub3] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The therapeutic role of 6-mercaptopurine (6-MP) and azathioprine (AZA) remains controversial due to their perceived relatively slow-acting effect and adverse effects. An updated meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission in quiescent Crohn's disease. OBJECTIVES To assess the efficacy of AZA and 6-MP for maintenance of remission in quiescent Crohn's disease. SEARCH METHODS We searched MEDLINE, EMBASE, and the Cochrane Library from inception to June 30, 2015. SELECTION CRITERIA Randomized controlled trials of oral azathioprine or 6-mercaptopurine compared to placebo or active therapy involving adult patients (> 18 years) with quiescent Crohn's disease were considered for inclusion. Patients with surgically-induced remission were excluded. DATA COLLECTION AND ANALYSIS At least two authors independently extracted data and assessed study quality using the Cochrane risk of bias tool. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (CI). The primary outcomes was maintenance of remission. Secondary outcomes included steroid sparing, adverse events, withdrawals due to adverse events and serious adverse events. All data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS Eleven studies (881 participants) were included. Comparisons included AZA versus placebo (7 studies, 532 participants), AZA or 6-MP versus mesalazine or sulfasalazine (2 studies, 166 participants), AZA versus budesonide (1 study, 77 participants), AZA and infliximab versus infliximab (1 study, 36 patients), 6-MP versus methotrexate (1 study, 31 patients), and early AZA versus conventional management (1 study, 147 participants). Two studies were rated as low risk of bias. Three studies were rated as high risk of bias for being non-blinded. Six studies were rated as unclear risk of bias. A pooled analysis of six studies (489 participants) showed that AZA (1.0 to 2.5 mg/kg/day) was significantly superior to placebo for maintenance of remission over a 6 to 18 month period. Seventy-three per cent of patients in the AZA group maintained remission compared to 62% of placebo patients (RR 1.19, 95% CI 1.05 to 1.34). The number needed to treat for an additional beneficial outcome was nine. A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (327 events) and unclear risk of bias. A pooled analysis of two studies (166 participants) showed no statistically significant difference in the proportion of patients who maintained remission between AZA (1.0 to 2.5 mg/kg/day) or 6-MP (1.0 mg/day) and mesalazine (3 g/day) sulphasalazine (0.5 g/15 kg) therapy. Sixty-nine per cent of patients in the AZA/6-MP group maintained remission compared to 67% of mesalazine/sulphasalazine patients (RR 1.09, 95% CI 0.88 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (113 events) and high or unclear risk of bias. One small study found AZA (2.0 to 2.5 mg/kg/day) to be superior to budesonide (6 to 9 mg/day) for maintenance of remission at one year. Seventy-six per cent (29/38) of AZA patients maintained remission compared to 46% (18/39) of budesonide patients (RR 1.65, 95% CI 1.13 to 2.42). GRADE indicated that the overall quality of the evidence supporting this outcome was low due to sparse data (47 events) and high risk of bias. One small study found no difference in maintenance of remission rates at one year between combination therapy with AZA (2.5 mg/kg) and infliximab (5 mg/kg every 8 weeks) compared to infliximab monotherapy. Eighty-one per cent (13/16) of patients in the combination therapy group maintained remission compared to 80% (16/20) of patients in the infliximab group (RR 1.02, 95% CI 0.74 to 1.40). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (29 events) and unclear risk of bias. One small study found no difference in maintenance of remission rates at one year between 6-MP (1 mg/day) and methotrexate (10 mg/week). Fifty per cent (8/16) of 6-MP patients maintained remission at one year compared to 53% (8/15) of methotrexate patients (RR 0.94, 95% CI 0.47 to 1.85). GRADE indicated that the overall quality of the evidence supporting this outcome was very low due to very sparse data (16 events) and high risk of bias. One study (147 participants) failed to show any significant benefit for early azathioprine treatment over a conventional management strategy. In the early azathioprine treatment group 67% (11-85%) of the trimesters were spent in remission compared to 56% (29-73%) in the conventional management group. AZA when compared to placebo had significantly increased risk of adverse events (RR 1.29, 95% CI 1.02 to 1.64), withdrawal due to adverse events (3.12, 95% CI 1.59 to 6.09) and serious adverse events (RR 2.45, 95% CI 1.22 to 4.90). AZA/6-MP also demonstrated a significantly higher risk of serious adverse events when compared to mesalazine or sulphasalazine (RR 9.37, 95% CI 1.84 to 47.7). AZA/6-MP did not differ significantly from other active therapies with respect to adverse event data. Common adverse events included pancreatitis, leukopenia, nausea, allergic reaction and infection. AUTHORS' CONCLUSIONS Low quality evidence suggests that AZA is more effective than placebo for maintenance of remission in Crohn's disease. Although AZA may be effective for maintenance of remission its use is limited by adverse effects. Low quality evidence suggests that AZA may be superior to budesonide for maintenance of remission but because of small study size and high risk of bias, this result should be interpreted with caution. No conclusions can be drawn from the other active comparator studies because of low and very low quality evidence. Adequately powered trials are needed to determine the comparative efficacy and safety of AZA and 6-MP compared to other active maintenance therapies. Further research is needed to assess the efficacy and safety of the use of AZA with infliximab and other biologics and to determine the optimal management strategy for patients quiescent Crohn's disease.
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Affiliation(s)
- Nilesh Chande
- London Health Sciences Centre ‐ Victoria HospitalRoom E6‐321A800 Commissioners Road EastLondonONCanadaN6A 5W9
| | - Petrease H Patton
- University of Western OntarioSchulich School of Medicine & DentistryLondonONCanada
| | - David J Tsoulis
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanadaN6A 5K8
| | - Benson S Thomas
- University of Western OntarioDepartment of MedicineLondonONCanada
| | - John K MacDonald
- Robarts Clinical TrialsCochrane IBD Group100 Dundas Street, Suite 200LondonONCanadaN6A 5B6
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Moran GW, Dubeau MF, Kaplan GG, Yang H, Eksteen B, Ghosh S, Panaccione R. Clinical predictors of thiopurine-related adverse events in Crohn's disease. World J Gastroenterol 2015; 21:7795-7804. [PMID: 26167079 PMCID: PMC4491966 DOI: 10.3748/wjg.v21.i25.7795] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 01/10/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the incidence and predictors of thiopurine-related adverse events.
METHODS: Subjects with Crohn’s disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database registry were identified. Retrospective chart review was conducted between August 5th, 2010 and June 1st, 2012. We collected data on: age at diagnosis; sex; disease location and behaviour at time of prescribing thiopurine; perianal fistulising disease at or prior to thiopurine prescription; smoking status at time of thiopurine prescription, use of corticosteroid within 6 mo of diagnosis; dosage, age at onset, and cessation of 5-aminosalicyclic acid (5-ASA); anti-tumour necrosis factor medication exposure and intestinal resection before thiopurine prescription. The primary outcome of interest was the first adverse event that led to discontinuation of the first thiopurine medication used. Logistic regression models were used to associate clinical characteristics with outcomes after adjusting for potential confounders. Risk estimates were presented as odds ratios (OR) with 95% CI. Effect modification by age and sex were explored.
RESULTS: Our cohort had a median follow-up duration of 5.8 years [interquartile range (IQR 25th-75th) 2.7-9.1]. Thiopurine therapy was discontinued in 31.3% of patients because of: hypersensitivity reactions (7.1%), acute pancreatitis (6.2%), gastrointestinal intolerance (5.4%), leucopenia (3.7%), hepatotoxicity (3.4%), infection (1.1%) and other reasons (4.3%). A higher incidence of thiopurine withdrawal was observed in patients over the age of 40 (39.4%, P = 0.007). A sex-by-age interaction (P = 0.04) was observed. Females older than 40 years of age had an increased risk of thiopurine discontinuation due to an adverse event (age above 40 vs age below 40, adjusted OR = 2.8; 95%CI: 1.4-5.6). In contrast, age did not influence thiopurine withdrawal in males (age above 40 vs below 40, adjusted OR = 0.9; 95%CI: 0.4-2.1). Other clinical variables (disease location and phenotype, perianal disease, smoking history, history of intestinal resection and prior 5-ASA or corticosteroid use) were not associated with an increased risk an adverse event leading to therapy cessation.
CONCLUSION: Thiopurine withdrawal due to adverse events is commoner in women over the age of 40 at prescription. These findings need to be replicated in other cohorts.
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Lee KM, Kim YS, Seo GS, Kim TO, Yang SK. Use of Thiopurines in Inflammatory Bowel Disease: A Consensus Statement by the Korean Association for the Study of Intestinal Diseases (KASID). Intest Res 2015; 13:193-207. [PMID: 26130993 PMCID: PMC4479733 DOI: 10.5217/ir.2015.13.3.193] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 04/29/2015] [Accepted: 05/06/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS For decades, thiopurines have been the mainstay of inflammatory bowel disease (IBD) treatment and will play an important role in the future. However, complex metabolism and various side effects limit the use of these potent drugs in clinical practice. The Korean Association for the Study of Intestinal Diseases developed a set of consensus statements with the aim of guiding clinicians on the appropriate use of thiopurines in the management of IBD. METHODS Sixteen statements were initially drafted by five committee members. The quality of evidence and classification of recommendation were assessed according to the Grading of Recommendations Assessment, Development and Evaluation system. The statements were then circulated to IBD experts in Korea for review, feedback, and then finalized and accepted by voting at the consensus meeting. RESULTS The consensus statements comprised four parts: (1) pre-treatment evaluation and management strategy, including value of thiopurine S-methyltransferase screening, dosing schedule, and novel biomarkers for predicting thiopurine-induced leukopenia; (2) treatment with thiopurines with regards to optimal duration of thiopurine treatment and long-term outcomes of combination therapy with anti-tumor necrosis factors; (3) safety of thiopurines, especially during pregnancy and lactation; and (4) monitoring side effects or efficacy of therapy using biomarkers. CONCLUSIONS Thiopurines are an effective treatment option for patients with IBD. Management decisions should be individualized according to the risk of relapse and adverse events.
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Affiliation(s)
- Kang-Moon Lee
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Geom Seog Seo
- Department of Internal Medicine, Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea
| | - Tae Oh Kim
- Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Yoshino T, Matsuura M, Minami N, Yamada S, Honzawa Y, Kimura M, Koshikawa Y, Madian A, Toyonaga T, Nakase H. Efficacy of Thiopurines in Biologic-Naive Japanese Patients With Crohn's Disease: A Single-Center Experience. Intest Res 2015; 13:266-73. [PMID: 26131002 PMCID: PMC4479742 DOI: 10.5217/ir.2015.13.3.266] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 12/31/2015] [Accepted: 04/03/2015] [Indexed: 12/18/2022] Open
Abstract
Background/Aims Early use of biologics in patients with Crohn's disease (CD) improves quality of life. However, the effects of the early use of immunomodulators on long-term outcomes remain unclear. This study aimed to evaluate the effects of immunomodulators in patients with CD. Methods Between January 2004 and December 2011, 47 biologic-naive CD patients treated with thiopurines alone for remission maintenance were analyzed. The patients were classified into 2 groups depending on the presence or absence of digestive complications. We evaluated the efficacy of and predictive factors for thiopurine use for remission maintenance. Results The cumulative relapse rates at 24 and 60 months were 13.7% and 35.4%, respectively. Regarding patient characteristics, there was a significant difference in patient history of surgery between the non-relapse and relapse groups (P=0.021). The cumulative relapse rate was lower in patients without a history of surgery than in those with such a history (27.2% and 52.9% at 60.0 months, respectively). Multivariate analysis suggested that the prevalence of stricturing and penetrating complications is an independent factor for relapse. The cumulative relapse rate in patients without a history of surgery was significantly lower in the non-stricturing and non-penetrating group than in the stricturing and penetrating group (11.8% at 85.0 months vs. 58.5% at 69.0 months; P=0.036). Conclusions Thiopurine use might be beneficial for the long-term maintenance of remission in biologic-naive Crohn's disease patients without digestive complications and a history of surgery.
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Affiliation(s)
- Takuya Yoshino
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Minoru Matsuura
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Naoki Minami
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoshi Yamada
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yusuke Honzawa
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masamichi Kimura
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yorimitsu Koshikawa
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ali Madian
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. ; Department of Internal Medicine, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Takahiko Toyonaga
- The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology & Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Lahad A, Weiss B. Current therapy of pediatric Crohn’s disease. World J Gastrointest Pathophysiol 2015; 6:33-42. [PMID: 25977836 PMCID: PMC4419092 DOI: 10.4291/wjgp.v6.i2.33] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 04/02/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate, antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor (TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy - induction and maintenance of remission while improving the patient’s growth and overall well-being.
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Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn's disease. Dig Dis Sci 2015; 60:1414-23. [PMID: 25381202 DOI: 10.1007/s10620-014-3419-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 10/29/2014] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIM Many patients with quiescent Crohn's disease are maintained on long-term treatment with azathioprine (AZA), but controlled data are limited. We aimed to evaluate the efficacy of AZA therapy for more than 4 years to maintain clinical remission. METHODS We performed a randomized double-blind placebo-controlled AZA withdrawal trial with a follow-up period of 24 months. Patients had to have continuous AZA therapy ≥ 4 years without exacerbation of disease during the 12 months before enrollment, and a Crohn's disease activity index < 150 at baseline. Patients were randomized to continue on AZA or switch to placebo. The primary endpoint was time to clinical relapse during follow-up. RESULTS After inclusion of 52 patients, the trial was stopped prematurely due to slow recruitment. During the 2-year follow-up, clinical relapse occurred in 4 of 26 (15 %) patients on continued AZA and in 8 of 26 (31 %) patients on placebo. Time to clinical relapse averaged 22.3 months (95 % CI 20.6-24.0) on AZA and 19.2 months (95 % CI 16.4-22.1) on placebo (p = 0.20). According to life-table analysis, the proportion of patients in remission after 12 and 24 months was 96 ± 4 and 86 ± 7 % in patients receiving AZA versus 76 ± 8 and 68 ± 9 % in patients receiving placebo (month 12, p = 0.035; month 24, p = 0.30). A higher AZA dose at enrollment was an independent predictor for relapse (p < 0.05). CONCLUSIONS AZA withdrawal resulted in a significantly increased relapse risk after 1 year and a nonstatistically significant trend for relapse after 2 years. Our results are in line with previous observations.
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Heap GA, Weedon MN, Bewshea CM, Singh A, Chen M, Satchwell JB, Vivian JP, So K, Dubois PC, Andrews JM, Annese V, Bampton P, Barnardo M, Bell S, Cole A, Connor SJ, Creed T, Cummings FR, D'Amato M, Daneshmend TK, Fedorak RN, Florin TH, Gaya DR, Greig E, Halfvarson J, Hart A, Irving PM, Jones G, Karban A, Lawrance IC, Lee JC, Lees C, Lev-Tzion R, Lindsay JO, Mansfield J, Mawdsley J, Mazhar Z, Parkes M, Parnell K, Orchard TR, Radford-Smith G, Russell RK, Reffitt D, Satsangi J, Silverberg MS, Sturniolo GC, Tremelling M, Tsianos EV, van Heel DA, Walsh A, Watermeyer G, Weersma RK, Zeissig S, Rossjohn J, Holden AL, Ahmad T. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet 2014; 46:1131-4. [PMID: 25217962 DOI: 10.1038/ng.3093] [Citation(s) in RCA: 153] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 08/22/2014] [Indexed: 12/16/2022]
Abstract
Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.
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Affiliation(s)
- Graham A Heap
- 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK. [3]
| | - Michael N Weedon
- 1] Precision Medicine Exeter, University of Exeter, Exeter, UK. [2]
| | - Claire M Bewshea
- 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK
| | - Abhey Singh
- IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK
| | - Mian Chen
- Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK
| | - Jack B Satchwell
- Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK
| | - Julian P Vivian
- Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
| | - Kenji So
- IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK
| | - Patrick C Dubois
- Department of Gastroenterology, King's College Hospital, London, UK
| | - Jane M Andrews
- IBD Service, Department of Gastroenterology and University of Adelaide at Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Vito Annese
- Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Peter Bampton
- Flinders Medical Centre, Flinders University of South Australia, Adelaide, South Australia, Australia
| | - Martin Barnardo
- Oxford Transplant Centre, Oxford University Hospital National Health Service (NHS) Trust, Oxford, UK
| | - Sally Bell
- Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia
| | - Andy Cole
- Gastroenterology and Hepatology, Royal Derby Hospital, Derby, UK
| | - Susan J Connor
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, New South Wales, Australia
| | - Tom Creed
- Joint Clinical Research Unit, University Hospitals Bristol NHS Foundation Trust, Bristol, UK
| | - Fraser R Cummings
- Department of Gastroenterology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Mauro D'Amato
- Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
| | | | - Richard N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Timothy H Florin
- The University of Queensland School of Medicine, South Brisbane, Queensland, Australia
| | - Daniel R Gaya
- Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Emma Greig
- Department of Gastroenterology, Taunton and Somerset NHS Foundation Trust, Taunton, UK
| | - Jonas Halfvarson
- Division of Gastroenterology, Örebro University Hospital and School of Health and Medical Sciences, Örebro University, Örebro, Sweden
| | - Alisa Hart
- Department of Medicine, St. Mark's Hospital and Academic Institute, North West London Hospitals NHS Trust, London, UK
| | - Peter M Irving
- Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Gareth Jones
- Department of Gastroenterology, Western General Hospital, Edinburgh, UK
| | - Amir Karban
- Department of Gastroenterology, Rambam Medical Center, Haifa, Israel
| | - Ian C Lawrance
- Centre for Inflammatory Bowel Diseases, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia
| | - James C Lee
- Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | - Charlie Lees
- Department of Gastroenterology, Western General Hospital, Edinburgh, UK
| | - Raffi Lev-Tzion
- Paediatric Gastroenterology and Nutrition Unit, Shaare Zedek Medical Centre, Jerusalem, Israel
| | - James O Lindsay
- Department of Gastroenterology, Barts and The London NHS Trust, London, UK
| | - John Mansfield
- Department of Gastroenterology, Newcastle University Hospitals NHS Trust, Newcastle, UK
| | - Joel Mawdsley
- Department of Gastroenterology, West Middlesex University Hospital NHS Trust, Isleworth, UK
| | - Zia Mazhar
- Department of Gastroenterology, Basildon and Thurrock Hospital NHS Trust, Basildon, UK
| | - Miles Parkes
- Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK
| | | | | | - Graham Radford-Smith
- 1] Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. [2] IBD Group, Queensland Institute of Medical Research and University of Queensland School of Medicine, Herston Campus, Brisbane, Queensland, Australia
| | - Richard K Russell
- Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK
| | - David Reffitt
- Department of Gastroenterology, Lewisham and Greenwich NHS Trust, London, UK
| | - Jack Satsangi
- Department of Gastroenterology, Western General Hospital, Edinburgh, UK
| | - Mark S Silverberg
- Inflammatory Bowel Disease Group, Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada
| | | | - Mark Tremelling
- Department of Gastroenterology, Norfolk and Norwich Hospital NHS Trust, Norwich, UK
| | - Epameinondas V Tsianos
- 1st Division of Internal Medicine and Division of Gastroenterology, Faculty of Medicine, University of Ioannina, Ioannina, Greece
| | - David A van Heel
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Alissa Walsh
- Department of Gastroenterology, St. Vincent's Hospital, Sydney, New South Wales, Australia
| | - Gill Watermeyer
- Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town, South Africa
| | - Rinse K Weersma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen and the University of Groningen, Groningen, the Netherlands
| | - Sebastian Zeissig
- Department of Internal Medicine, University Medical Center Schleswig-Holstein, Kiel, Germany
| | - Jamie Rossjohn
- Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
| | - Arthur L Holden
- The International Serious Adverse Events Consortium, Chicago, Illinois, USA
| | | | | | - Tariq Ahmad
- 1] IBD Pharmacogenetics, Royal Devon and Exeter Hospital, Exeter, UK. [2] Precision Medicine Exeter, University of Exeter, Exeter, UK
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Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, Haritunians T, Ye BD, Kim KJ, Park SH, Park SK, Yang DH, Dubinsky M, Lee I, McGovern DPB, Liu J, Song K. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 2014; 46:1017-20. [PMID: 25108385 PMCID: PMC4999337 DOI: 10.1038/ng.3060] [Citation(s) in RCA: 409] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 07/16/2014] [Indexed: 01/01/2023]
Abstract
Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; P(combined) = 4.88 × 10(-94)). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10(-4)). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.
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Affiliation(s)
- Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Myunghee Hong
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Jiwon Baek
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyunchul Choi
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Wanting Zhao
- Human Genetics Group, Genome Institute of Singapore, Singapore
| | - Yusun Jung
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Talin Haritunians
- The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung-Jo Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo-Kyung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Marla Dubinsky
- Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Inchul Lee
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dermot P B McGovern
- The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jianjun Liu
- Human Genetics Group, Genome Institute of Singapore, Singapore
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
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Patel V, Wang Y, MacDonald JK, McDonald JWD, Chande N. Methotrexate for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2014; 2014:CD006884. [PMID: 25157445 PMCID: PMC8202560 DOI: 10.1002/14651858.cd006884.pub3] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Safe and effective long-term treatments that reduce the need for corticosteroids are needed for Crohn's disease. Although purine antimetabolites are moderately effective for maintenance of remission patients often relapse despite treatment with these agents. Methotrexate may provide a safe and effective alternative to more expensive maintenance treatment with TNF-α antagonists. This review is an update of a previously published Cochrane review. OBJECTIVES To conduct a systematic review of randomized trials examining the efficacy and safety of methotrexate for maintenance of remission in Crohn's disease. SEARCH METHODS The Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, EMBASE, and the Cochrane IBD/FBD Group Specialized Trials Register were searched from inception to June 9, 2014. Study references and review papers were also searched for additional trials. SELECTION CRITERIA Randomised controlled trials (RCTs) that compared methotrexate to placebo or any other active intervention for maintenance of remission in Crohn's disease were eligible for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently reviewed studies for eligibility, extracted data and assessed study quality using the Cochrane risk of bias tool. The primary outcome measure was the proportion of patients maintaining clinical remission as defined by the studies and expressed as a percentage of the total number of patients randomized (intention-to-treat analysis). We calculated the pooled risk ratio (RR) and corresponding 95% confidence intervals (95% CI) for dichotomous outcomes. The overall quality of the evidence supporting the primary outcome was assessed using the GRADE criteria. MAIN RESULTS Five studies (n = 333 patients) were included in the review. Three studies were judged to be at low risk of bias. Two studies were judged to be at high risk of bias due to blinding. Intramuscular methotrexate was superior to placebo for maintenance of remission at 40 weeks follow-up. Sixty-five per cent of patients in the intramuscular methotrexate group maintained remission compared to 39% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 76 patients).The number needed to treat to prevent one relapse was four. A GRADE analysis indicated that the overall quality of evidence supporting this outcome was moderate due to sparse data (40 events). There was no statistically significant difference in maintenance of remission at 36 weeks follow-up between oral methotrexate (12.5 mg/week) and placebo. Ninety per cent of patients in the oral methotrexate group maintained remission compared to 67% of placebo patients (RR 1.67, 95% CI 1.05 to 2.67; 22 patients). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to very sparse data (17 events). A pooled analysis of two small studies (n = 50) showed no statistically significant difference in continued remission between oral methotrexate (12.5 mg to 15 mg/week) and 6-mercaptopurine (1 mg/kg/day) for maintenance of remission. Seventy-seven per cent of methotrexate patients maintained remission compared to 57% of 6-mercaptopurine patients (RR 1.36, 95% CI 0.92 to 2.00). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was very low due to high risk of bias in one study (no blinding) and very sparse data (33 events). One small (13 patients) poor quality study found no difference in continued remission between methotrexate and 5-aminosalicylic acid (RR 2.62, 95% CI 0.23 to 29.79). A pooled analysis of two studies (n = 145) including one high quality trial (n = 126) found no statistically significant difference in maintenance of remission at 36 to 48 weeks between combination therapy (methotrexate and infliximab) and infliximab monotherapy. Fifty-four percent of patients in the combination therapy group maintained remission compared to 53% of monotherapy patients (RR 1.02, 95% CI 0.76 to 1.38, P = 0.95). A GRADE analysis indicated that the overall quality of evidence supporting this outcome was low due to high risk of bias in one study (no blinding) and sparse data (78 events). Adverse events were generally mild in nature and resolved upon discontinuation or with folic acid supplementation. Common adverse events included nausea and vomiting, symptoms of a cold, abdominal pain, headache, joint pain or arthralgia, and fatigue. AUTHORS' CONCLUSIONS Moderate quality evidence indicates that intramuscular methotrexate at a dose of 15 mg/week is superior to placebo for maintenance of remission in Crohn's disease. Intramuscular methotrexate appears to be safe. Low dose oral methotrexate (12.5 to 15 mg/week) does not appear to be effective for maintenance of remission in Crohn's disease. Combination therapy (methotrexate and infliximab) does not appear to be any more effective for maintenance of remission than infliximab monotherapy. The results for efficacy outcomes between methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Large-scale studies of methotrexate given orally at higher doses for maintenance of remission in Crohn's disease may provide stronger evidence for the use of methotrexate in this manner.
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Affiliation(s)
| | - Yongjun Wang
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
| | - John K MacDonald
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
| | - John WD McDonald
- Robarts Research InstituteRobarts Clinical TrialsP.O. Box 5015100 Perth DriveLondonONCanada
| | - Nilesh Chande
- London Health Sciences Centre ‐ Victoria HospitalRoom E6‐321A800 Commissioners Road EastLondonONCanadaN6A 5W9
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Gordon M, Taylor K, Akobeng AK, Thomas AG. Azathioprine and 6-mercaptopurine for maintenance of surgically-induced remission in Crohn's disease. Cochrane Database Syst Rev 2014; 2014:CD010233. [PMID: 25081347 PMCID: PMC6486089 DOI: 10.1002/14651858.cd010233.pub2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Crohn's disease (CD) is a chronic relapsing inflammatory condition. Many patients fail to achieve remission with medical management and require surgical interventions. Purine analogues have been used to maintain surgically-induced remission in CD, but the effectiveness of these agents is unclear. OBJECTIVES The objectives were to evaluate the efficacy and safety of purine analogues for maintenance of surgically-induced remission in CD. SEARCH METHODS We searched the following databases from inception to 30 April 2014: PubMed, MEDLINE, EMBASE, CENTRAL, and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register). We also searched the reference lists of all included studies, and contacted personal sources and drug companies to identify additional studies. The searches were not limited by language. SELECTION CRITERIA Randomised controlled trials (RCTs) that compared purine analogues to placebo or another intervention, with treatment durations of at least six months were considered for inclusion. Participants were patients of any age with CD in remission following surgery. DATA COLLECTION AND ANALYSIS Two authors independently assessed trial eligibility and extracted data. Methodological quality was assessed using the Cochrane risk of bias tool. The primary outcome measures were clinical and endoscopic relapse as defined by the primary studies. Secondary outcomes included adverse events, withdrawal due to adverse events and serious adverse events. Data were analysed on an intention-to-treat basis where patients with missing final outcomes were assumed to have relapsed. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes. The Chi(2) and I(2) statistics were used to assess heterogeneity. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS Seven RCTs (n = 584 patients) were included in the review. Three studies compared azathioprine to 5-aminosalicylic acid (5-ASA). One small study compared azathioprine to both 5-ASA and adalimumab. One study compared azathioprine to placebo and another study compared 6-mercaptopurine to 5-ASA and placebo. One small study compared azathioprine to infliximab. Three studies were judged to be at low risk of bias. Four studies were judged to be at high risk of bias due to blinding. The study (n = 22) comparing azathioprine to infliximab found that the effects on the proportion of patients who had a clinical (RR 2.00, 95% CI 0.21 to 18.98) or endoscopic relapse (RR 4.40, 95% CI 0.59 to 3.07) were uncertain. One study (n = 33) found decreased clinical (RR 5.18, 95% CI 1.35 to 19.83) and endoscopic relapse (RR 10.35, 95% CI 1.50 to 71.32) rates favouring adalimumab over azathioprine. A pooled analysis of two studies (n = 168 patients) showed decreased clinical relapse rates at one or two years favouring purine analogues over placebo. Forty-eight per cent of patients in the purine analogue group experienced a clinical relapse compared to 63% of placebo patients (RR 0.74, 95% CI 0.58 to 0.94). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to high risk of bias (one study was single-blind) and sparse data (93 events). One study (87 patients) found a reduction in endoscopic relapse rates favouring 6-mercaptopurine over placebo. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse at two years compared to 42% of placebo patients (RR 0.40, 95% CI 0.19 to 0.83). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (25 events). A pooled analysis of five studies (n = 425 patients) showed no difference in clinical relapse rates at one or two years between purine analogues and 5-ASA agents. Sixty-three per cent of patients in the purine analogues group experienced a clinical relapse compared to 54% of 5-ASA patients (RR 1.15, 95% CI 0.99 to 1.34). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was very low due to high risk of bias (two open-label studies), sparse data (249 events) and moderate heterogeneity (I(2) = 45%). There was no difference in endoscopic relapse at 12 months between azathioprine and 5-ASA (RR 0.78, 95% CI 0.52 to 1.17; 1 study, 35 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to high risk of bias (open-label study) and very sparse data (26 events). There was a reduction in endoscopic relapse at 24 months favouring 6-mercaptopurine over 5-ASA patients. Seventeen per cent of 6-mercaptopurine patients had an endoscopic relapse compared to 48% of 5-ASA patients (RR 0.36, 95% CI 0.18 to 0.72; 1 study, 91 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (29 events). Adverse events that required withdrawal were more common in the purine analogue group compared to 5-ASA. Twenty per cent of patients in the purine analogue group withdrew due to adverse events compared to 10% of 5-ASA patients (RR 2.07, 95% CI 1.26 to 3.39; 5 studies, 423 patients).The results for withdrawal due to adverse events between purine analogues and placebo or for other comparisons were uncertain. Commonly reported adverse events across all studies included leucopenia, arthralgia, abdominal pain or severe epigastric intolerance, elevated liver enzymes, nausea and vomiting, pancreatitis, anaemia, exacerbation of Crohn's disease, nasopharyngitis, and flatulence. AUTHORS' CONCLUSIONS Purine analogues may be superior to placebo for maintenance of surgically-induced remission in patients with CD, although this is based on two small studies. The results for efficacy outcomes between purine analogues and 5-ASA agents were uncertain. However, patients taking purine analogues were more likely than 5-ASA patients to discontinue therapy due to adverse events. No firm conclusions can be drawn from the two small studies that compared azathioprine to infliximab or adalimumab. Adalimumab may be superior to azathioprine but further research is needed to confirm these results. Further research investigating the efficacy and safety of azathioprine and 6-mercaptopurine in comparison to other active medications in patients with surgically-induced remission of CD is warranted.
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Affiliation(s)
| | - Kelly Taylor
- North Manchester General HospitalDepartment of PaediatricsCrumpsallUK
| | | | - Adrian G Thomas
- Royal Manchester Children's HospitalOxford RoadManchesterUKM13 9WL
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Abstract
Crohn disease (CD) is one of the major subtypes of inflammatory bowel disease and can occur in any segment of the alimentary tract. There have been significant advances in the medical therapy of CD over the past several decades. For mild CD, the oral corticosteroid derivative budesonide has demonstrated superior efficacy compared with traditional therapies such as 5-aminosalicylic acid, and can be used concurrently with these agents. For the management of moderate to severe disease, the immunomodulators azathioprine, 6-mercaptopurine, and methotrexate, as well as the antitumor necrosis factor-alpha (TNF-α) agents infliximab, adalimumab, and certolizumab pegol, have become the mainstay of therapy, with growing interest in combining these agents for maximal effect. Immunomodulators and anti-TNF-α agents have also demonstrated benefit in fistulizing CD. There has been growing evidence suggesting that both of these agents, along with the antibiotics metronidazole and ornidazole, are also effective in preventing postoperative recurrence of CD.
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Affiliation(s)
- Frank I Scott
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Penn Presbyterian Medical Center, Philadelphia, Pennsylvania
| | - Mark T Osterman
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Penn Presbyterian Medical Center, Philadelphia, Pennsylvania
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Abstract
A key aim in the management of Crohn's disease is to maintain disease remission, whether this has been achieved by medical or surgical treatment. The reasons for doing this are to maintain quality of life, to avoid steroid dependence and to maintain mucosal healing with a view to preventing relapse, hospital admission and surgery, and improving disease natural history. Options for remission maintenance include smoking cessation, thiopurines, methotrexate, anti-TNF-α drugs and surgery. Evidence suggests that in some places now, and in most places in the past, too few patients are/were appropriately treated when in remission, and, in many instances, treatment regimens are/were insufficiently tailored to the patient's individual phenotype, prognosis and/or genotype.
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Affiliation(s)
- David Rampton
- Centre for Digestive Diseases, Institute of Cellular and Molecular Science, Barts and the London, Queen Mary School of Medicine and Dentistry, London, UK
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Abstract
The use of biologics and thiopurines in patients with inflammatory bowel disease has increased rapidly over the last 2 decades with both classes of drugs being used more frequently and earlier in the disease course. This vogue has come about through a realisation that for some patients Crohn's disease and ulcerative colitis are progressive diseases and that use of these therapies can sometimes prevent that progression. However, knowledge about the optimal way in which to use these drugs continues to evolve. In this paper, the evidence regarding optimal timing and dosing of thiopurines and biologics will be reviewed as will the role of thiopurine methyltransferase testing along with therapeutic drug monitoring of both thiopurines and biologics. In addition, possible future applications of biologic drug level and anti-drug antibody testing will be considered.
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Affiliation(s)
- Peter M Irving
- Department of Gastroenterology, Guy's and St Thomas' Hospital, and Division of Diabetes and Nutritional Sciences, School of Medicine, King's College London, London, UK
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Bewtra M, Johnson FR. Assessing patient preferences for treatment options and process of care in inflammatory bowel disease: a critical review of quantitative data. PATIENT-PATIENT CENTERED OUTCOMES RESEARCH 2014; 6:241-55. [PMID: 24127239 DOI: 10.1007/s40271-013-0031-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD), consisting of both Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions of the intestinal tract. As there is no cure for either CD or UC, patients with these conditions face numerous treatment decisions regarding their disease. The aim of this review is to evaluate literature regarding quantitative studies of patient preferences in therapy for IBD with a focus on the emerging technique of stated preference and its application in IBD. Numerous simple survey-based studies have been performed evaluating IBD patients' preferences for medication frequency, mode of delivery, potential adverse events, etc., as well as variations in these preferences. These studies are limited, however, as they are purely descriptive in nature with limited quantitative information on the relative value of treatment alternatives. Time trade-off and standard-gamble studies have also been utilized to quantify patient utility for various treatment options or outcomes. However, these types of studies suffer from inaccurate assumptions regarding patient choice behavior. Stated preference is an emerging robust methodology increasingly utilized in health care that can determine the relative utility for a therapy option as well as its specific attributes (such as efficacy or adverse side effects). Stated preference techniques have begun to be applied in IBD and offer an innovative way of examining the numerous therapy options these patients and their providers face.
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Affiliation(s)
- Meenakshi Bewtra
- Department of Gastroenterology, University of Pennsylvania, 423 Guardian Drive, 724 Blockley Hall, Philadelphia, PA, 19104-6021, USA,
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Abstract
Crohn's disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-α and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered.
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Affiliation(s)
- Leon P McLean
- Department of Medicine, Division of Gastroenterology and Hepatology University of Maryland, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA
| | - Raymond K Cross
- Department of Medicine, Division of Gastroenterology and Hepatology University of Maryland, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA
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Garg SK, Croft AM, Bager P. Helminth therapy (worms) for induction of remission in inflammatory bowel disease. Cochrane Database Syst Rev 2014; 2014:CD009400. [PMID: 24442917 PMCID: PMC10767620 DOI: 10.1002/14651858.cd009400.pub2] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic, globally-occurring gastrointestinal disorder and a major cause of illness and disability. It is conventionally classified into Crohn's disease (CD) and ulcerative colitis (UC). Helminths are parasitic worms with complex life cycles involving tissue- or lumen-dwelling stages in their hosts, and causing long-lasting or chronic infections that are frequently asymptomatic. Helminths modulate immune responses of their hosts, and many observational and experimental studies support the hypothesis that helminths suppress immune-mediated chronic inflammation that occurs in asthma, allergy and IBD. OBJECTIVES The objective was to evaluate the efficacy and safety of helminth treatment for induction of remission in IBD. SEARCH METHODS We searched the following databases from inception to 13 July 2013: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register. We also searched four online trials registries, and abstracts from major meetings. There were no language restrictions. SELECTION CRITERIA Randomised controlled trials (RCTs) where the intervention was any helminth species or combination of helminth species, administered in any dose and by any route and for any duration of exposure to people with active CD or UC, confirmed through any combination of clinical, endoscopic and histological criteria were eligible for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed eligibility using a standardized data collection form. We used the RevMan software for analyses. The primary outcome was induction of remission as defined by the included studies. Secondary outcomes included clinical, histologic, or endoscopic improvement as defined by the authors, endoscopic mucosal healing, change in disease activity index score, change in quality of life score, hospital admissions, requirement for intravenous corticosteroids, surgery, study withdrawal and the incidence of adverse events. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for dichotomous outcomes. We calculated the mean difference (MD) and 95% CI for continuous outcomes. We assessed the methodological quality of included studies using the Cochrane risk of bias tool. The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. MAIN RESULTS Two RCTs (90 participants) were included. One trial assessed the efficacy and safety of Trichuris suis (T. suis) ova in patients with UC (n = 54). The other RCT was a phase one that assessed the safety and tolerability of T. suis ova in patients with CD (n = 36). The risk of bias in both studies was judged to be low. In the UC study, during the 12-week study period, participants in the active arm received 2-weekly aliquots of 2500 T. suis eggs, added to 0.8 mL of saline; those in the placebo arm received 0.8 mL saline only. There were sparse data available for the outcomes clinical remission and clinical improvement. Ten per cent (3/30) of patients in the T. suis arm entered remission compared to 4% (1/24) of patients in the placebo arm (RR 2.40, 95% CI 0.27 to 21.63). Forty-three per cent (13/30) of patients in the T. suis group achieved clinical improvement compared to 17% (4/24) of placebo patients (RR 2.60, 95% CI 0.97 to 6.95). The mean ulcerative colitis disease activity index (UCDAI) score was lower in the T. suis group (6.1 +/- 0.61) compared to the placebo group (7.5 +/- 0.66) after 12 weeks of treatment (MD -1.40, 95% CI -1.75 to -1.05). There was only limited evidence relating to the proportion of patients who experienced an adverse event. Three per cent (1/30) of patients in the T. suis group experienced at least one adverse event compared to 12% (3/24) of placebo patients (RR 0.27, 95% CI 0.03 to 2.40). None of the adverse events reported in this study were judged to be related to the study treatment. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission and improvement) as low due to serious imprecision. In the CD study, participants received a single treatment of T. suis ova at a dosage of 500 (n = 9), 2500 (n = 9), or 7500 (n = 9) embryonated eggs or matching placebo (n = 9). The CD study did not assess clinical remission or improvement as outcomes. There were sparse data on adverse events at two weeks. Thirty-seven per cent (10/27) of patients in the T. suis group experienced at least one adverse event compared to 44% (4/9) of placebo patients (RR 0.83, 95% CI 0.35 to 2.01). Only one adverse event (dysgeusia) was judged to be possibly related to treatment in this study. Dysgeusia was reported in one patient in the T. suis group and in one patient in the placebo group. AUTHORS' CONCLUSIONS Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of helminths used to treat patients with IBD. The evidence for our primary efficacy outcomes in this review comes from one small study and is of low quality due to serious imprecision. We do not have enough evidence to determine whether helminths are safe when used in patients with UC and CD. Further RCTs are required to assess the efficacy and safety of helminth therapy in IBD.
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Affiliation(s)
- Sushil K Garg
- University of MinnesotaDepartment of Surgery420 Delaware Street SEMayo Mail Code 195MinneapolisMNUSA55455
| | - Ashley M Croft
- Ministry of DefenceSurgeon General's DepartmentLondonUKSW1A 2HA
| | - Peter Bager
- Statens Serum InstitutDepartment of Epidemiology ResearchØrestads Boulevard 5CopenhagenDenmarkDK‐2300
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Awareness of adverse effects of azathioprine in patients with inflammatory bowel disease--more to be done? THE ULSTER MEDICAL JOURNAL 2014; 83:56-7. [PMID: 24757277 PMCID: PMC3992102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Lund JL, Cook SF, Allen JK, Carroll CF, Kappelman MD. Patterns of 6-mercaptopurine and azathioprine maintenance therapy among a cohort of commercially insured individuals diagnosed with Crohn's disease in the United States. Clin Epidemiol 2013; 5:501-12. [PMID: 24348071 PMCID: PMC3857068 DOI: 10.2147/clep.s51625] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND AND AIMS Thiopurines, including 6-mercaptopurine (6-MP) and azathioprine (AZA), are the mainstay of maintenance therapy for Crohn's disease (CD). However, studies examining their effectiveness in routine practice among diverse patient populations are lacking. Among a cohort of new users of 6MP/AZA, we described treatment patterns and changes in subsequent therapy. METHODS Using the Truven Health Analytics databases, we identified all individuals diagnosed with CD and initiating 6-MP/AZA monotherapy from 2001-2008 (n=3,657). We estimated the proportion of CD patients remaining on 6-MP/AZA monotherapy, using Kaplan-Meier methods, and identified predictors of treatment noncontinuation, using multivariable Cox regression. Among the "noncontinuers," we described subsequent patterns of maintenance therapy and summarized the diagnosis and procedure codes and prescription drug claims preceding treatment discontinuation. RESULTS The 1-year 6-MP/AZA treatment continuation rate was 42%. Children (age ≤18 years) and individuals with no prior anti-tumor necrosis factor (TNF) use were more likely to continue 6-MP/AZA, while those dispensed more (>4) outpatient prescriptions for any drug before initiation of 6-MP/AZA were less likely to continue maintenance treatment. Overall, 1,128 (39%) and 105 (4%) individuals experienced a clinical event potentially indicating active disease or 6-MP/AZA-intolerance prior to discontinuation, respectively. Most patients discontinued therapy; among the remaining patients who failed to continue 6-MP/AZA, most augmented with an anti-TNF. CONCLUSION Most patients initiating 6-MP/AZA monotherapy did not continue beyond 1 year. In contrast to trial evidence showing 1-year remission rates of 40%-80%, this study observed a lower effectiveness of 6-MP/AZA treatment, possibly due to differences in disease severity, patient demographics, comorbidity, adherence, and health care utilization.
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Affiliation(s)
- Jennifer L Lund
- Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark
| | - Suzanne F Cook
- Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC, USA
| | - Jeffery K Allen
- Worldwide Epidemiology, GlaxoSmithKline, Research Triangle Park, NC, USA
| | | | - Michael D Kappelman
- Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Wu J, Gao Y, Yang C, Yang X, Li X, Xiao S. Low-dose azathioprine is effective in maintaining remission among Chinese patients with Crohn's disease. J Transl Med 2013; 11:235. [PMID: 24070341 PMCID: PMC3849559 DOI: 10.1186/1479-5876-11-235] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2013] [Accepted: 09/24/2013] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Azathiopurine (AZA) is efficacious for maintenance remission of Crohn's disease (CD) at the standard dose of 2.0-2.5 mg/kg for Caucasian. It has been reported that the lower dose (1.0-2.0 mg/kg) in some Asian countries was as effective as the standard dose. In the present study we analyzed the efficacy of <1.0 mg/kg AZA in maintaining remission for Chinese patients. METHODS The clinical data of all CD patients were reviewed from 1993 to December 2012. The patients who initiated AZA treatment and were followed for ≥ 2 years with complete medical data were included. We divided the patients into two groups according to their initial dose: <1.0 mg/kg group and 1.0-2.0 mg/kg group. RESULTS Among 77 patients, 39 (50.6%) started treatment with <1.0 mg/kg AZA and 38 (49.4%) with 1.0-2.0 mg/kg. The mean dose of <1.0 mg/kg group remained under 1.0 mg/kg at 6, 12 and 24 months, even if the doses were adjusted according to efficacy and tolerance. The remission rate in patients of <1.0 mg/kg group was significantly higher than that in those of 1.0-2.0 mg/kg group (P = 0.025). A dose of <1.0 mg/kg AZA was more commonly associated with male gender, older age, heavier body weight and L1 location. Adverse events were observed in 21 of 77 patients (27.3%) and no significant difference in occurrence of adverse events or leucopenia between two groups. CONCLUSIONS <1.0 mg/kg AZA was effective as 1.0-2.0 mg/kg in maintaining remission among Chinese patients with CD.
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Affiliation(s)
- Jianghong Wu
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), Shanghai, China.
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Luo FY, Bai AP. Risk of lymphoma after treatment of inflammatory bowel disease with azathioprine. Shijie Huaren Xiaohua Zazhi 2013; 21:2121-2127. [DOI: 10.11569/wcjd.v21.i22.2121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory disease of the intestine, characterized by excessive activation of the immune system. Immunosuppressive therapy has been widely and effectively used in IBD patients. However, the occurrence of lymphoma after immunosuppressive therapy for IBD, especially azathioprine, has been recently reported. This article reviews the clinical application of azathioprine in IBD, the possible mechanisms responsible for lymphoma induction by azathioprine, and the assessment of benefit and risk of immunosuppressive therapy for IBD.
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Abstract
IMPORTANCE Treatment of Crohn disease is rapidly evolving, with the induction of novel biologic therapies and newer, often more intensive treatment approaches. Knowing how to treat individual patients in this quickly changing milieu can be a challenge. OBJECTIVE To review the diagnosis and management of moderate to severe Crohn disease, with a focus on newer treatments and goals of care. EVIDENCE REVIEW MEDLINE was searched from 2000 to 2011. Additional citations were procured from references of select research and review articles. Evidence was graded using the American Heart Association level-of-evidence guidelines. RESULTS Although mesalamines are still often used to treat Crohn disease, the evidence for their efficacy is lacking. Corticosteroids can be effectively used to induce remission in moderate to severe Crohn disease, but they do not maintain remission. The mainstays of treatment are immunomodulators and biologics, particularly anti-tumor necrosis factor. CONCLUSION AND RELEVANCE Immunomodulators and biologics are now the preferred treatment options for Crohn disease.
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Affiliation(s)
- Adam S Cheifetz
- Division of Gastroenterology, Rabb-Rose 425, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, USA.
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Abstract
Crohn's disease (CD) is a heterogeneous disorder that can involve any segment of the gastrointestinal tract. The pathogenesis of CD is unknown but is thought to involve an uncontrolled immune response triggered by an environmental factor in a genetically susceptible host. The heterogeneity of disease pathogenesis and clinical course, combined with the variable response to treatment and its associated side effects, creates an environment of complex therapeutic decisions. Despite this complexity, significant progress has been made which allows physicians to start and predict disease behavior and natural course, response to therapy, and factors associated with significant side effects. In this manuscript the data pertaining to these variables including clinical, endoscopic and the various biological and genetic markers are reviewed, and the possibility of tailoring personal treatment is discussed.
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Gene expression and thiopurine metabolite profiling in inflammatory bowel disease - novel clues to drug targets and disease mechanisms? PLoS One 2013; 8:e56989. [PMID: 23437289 PMCID: PMC3578787 DOI: 10.1371/journal.pone.0056989] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 01/16/2013] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND AND AIMS Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity. METHODS Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0-14.0 and ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately. RESULTS Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (PLCB2, HVCN1, CTSS, and DEF8) and one purine/thiopurine related gene (NME6) correlated significantly with the clinical activity of Crohn's disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes. CONCLUSIONS Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD.
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Abstract
For more than a decade, methotrexate has been known to be an effective therapeutic agent in the treatment of steroid-dependent active Crohn's disease. However, international data on medication utilization suggest that this drug is rarely used in clinical practice for an indication of Crohn's disease. This review investigates the potential reasons for the underuse of methotrexate in patients with inflammatory bowel diseases.
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Affiliation(s)
- Hans H Herfarth
- Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC 27599, USA. hherf @ med.unc.edu
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