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St-Pierre J, Rubin DT. Challenging Conventional Care: Ethical Considerations of De-intensification of Therapy in IBD. Gastroenterology 2025; 168:200-204. [PMID: 39692680 DOI: 10.1053/j.gastro.2024.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 09/26/2024] [Accepted: 09/29/2024] [Indexed: 12/19/2024]
Affiliation(s)
- Joëlle St-Pierre
- Department of Medicine, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois
| | - David T Rubin
- Department of Medicine, University of Chicago Medicine Inflammatory Bowel Disease Center, University of Chicago, Chicago, Illinois; The MacLean Center for Clinical Medical Ethics, University of Chicago, Chicago, Illinois
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Bhattaru A, Pundyavana A, Raynor W, Chinta S, Werner TJ, Alavi A. 18F-FDG-PET and other imaging modalities in the diagnosis and management of inflammatory bowel disease. AMERICAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 2024; 14:295-305. [PMID: 39583912 PMCID: PMC11578808 DOI: 10.62347/yxqt2560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 08/22/2024] [Indexed: 11/26/2024]
Abstract
Inflammatory bowel disease (IBD), which encompasses ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory condition of the gastrointestinal (GI) tract that presents complex diagnostic and management challenges. Early detection and treatment of IBD is paramount, as IBD can present with serious complications, including bowel perforation, arthritis, and colorectal cancer. Most forms of diagnosis and therapeutic management, like ileocolonoscopy and upper endoscopy are highly invasive and require extensive preparation at great discomfort to patients. 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) imaging can be a potential solution to the current limitations in imaging for IBD. This review explores the utility and limitations of various imaging modalities used to detect and manage IBD including ileocolonoscopy, magnetic resonance enterography (MRE), gastrointestinal ultrasound (IUS), and 18F-FDG-PET/computed tomography (18F-FDG-PET/CT) and magnetic resonance imaging (18F-FDG-PET/MR). This review has an emphasis on PET imaging and highlights its benefits in detection, management, and monitoring therapeutic response of UC and CD.
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Affiliation(s)
- Abhijit Bhattaru
- Department of Radiology, University of PennsylvaniaPhiladelphia, Pennsylvania, The United States
- Department of Medicine, Rutgers New Jersey Medical SchoolNewark, New Jersey, The United States
| | - Anish Pundyavana
- Department of Radiology, University of PennsylvaniaPhiladelphia, Pennsylvania, The United States
- Department of Medicine, Rutgers New Jersey Medical SchoolNewark, New Jersey, The United States
| | - William Raynor
- Department of Radiology, University of PennsylvaniaPhiladelphia, Pennsylvania, The United States
| | - Sree Chinta
- Department of Radiology, University of PennsylvaniaPhiladelphia, Pennsylvania, The United States
- Department of Medicine, Rutgers New Jersey Medical SchoolNewark, New Jersey, The United States
| | - Thomas J Werner
- Department of Radiology, University of PennsylvaniaPhiladelphia, Pennsylvania, The United States
| | - Abass Alavi
- Department of Radiology, University of PennsylvaniaPhiladelphia, Pennsylvania, The United States
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Schreiber S, Danese S, Dignass A, Domènech E, Fantini MC, Ferrante M, Halfvarson J, Hart A, Magro F, Lees CW, Leone S, Pierik MJ, Peters M, Field P, Fishpool H, Peyrin-Biroulet L. Defining Comprehensive Disease Control for Use as a Treatment Target for Ulcerative Colitis in Clinical Practice: International Delphi Consensus Recommendations. J Crohns Colitis 2024; 18:91-105. [PMID: 37586038 PMCID: PMC10821705 DOI: 10.1093/ecco-jcc/jjad130] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Indexed: 08/18/2023]
Abstract
BACKGROUND AND AIMS Treatment of ulcerative colitis [UC] requires a patient-centric definition of comprehensive disease control that considers improvements in aspects not typically captured by classical landmark trial endpoints. In an international initiative, we reviewed aspects of UC that affect patients and/or indicate mucosal inflammation, to achieve consensus on which aspects to combine in a definition of comprehensive disease control, using a modified Delphi process. METHODS The Delphi panel comprised 12 gastroenterologists and one patient advocate. Two gastroenterologists were elected as chairs and did not vote. To inform statements, we asked 18 patients and the panel members about their experiences of remission and reviewed published literature. Panel members voted on statements anonymously in three rounds, with a live discussion before Round 3. Consensus was met if ≥67% of the panel agreed. Statements without consensus in Rounds 1 and 2 were revised or discarded after Round 3. RESULTS The panel agreed to measure individual patient benefit using a definition of comprehensive disease control that combines aspects currently measured in trials [rectal bleeding, stool frequency, disease-related quality of life, endoscopy, histological inflammatory activity, inflammatory biomarkers, and corticosteroid use] with additional patient-reported symptoms [bowel urgency, abdominal pain, extraintestinal manifestations, fatigue, and sleep disturbance]. The panel agreed on scoring systems and thresholds for many aspects. CONCLUSIONS Using a robust methodology, we defined comprehensive disease control in UC. Next, we will combine the measurement and scoring of these aspects into a multicomponent tool and will adopt comprehensive disease control as a treatment target in clinical practice and trials.
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Affiliation(s)
- Stefan Schreiber
- University Hospital Schleswig-Holstein, Department of Internal Medicine I, Kiel, Germany
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Axel Dignass
- Department of Medicine I, Agaplesion Markus Hospital, Goethe University, Frankfurt, Germany
| | - Eugeni Domènech
- Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol and CIBEREHD, Badalona, Spain
- Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Massimo C Fantini
- Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Ailsa Hart
- IBD Unit, St. Mark’s Hospital, London, UK
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Charlie W Lees
- Edinburgh Inflammatory Bowel Disease Unit, Western General Hospital, Edinburgh, UK
| | - Salvo Leone
- European Federation of Crohn’s & Ulcerative Colitis Associations [EFCCA], Brussels, Belgium
| | - Marieke J Pierik
- Division Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Michele Peters
- Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | | | | | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Inserm, NGERE, University of Lorraine, Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Groupe Hospitalier privé Ambroise Paré – Hartmann, Paris IBD Center, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC, Canada
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Crepaldi M, Maniero D, Massano A, Pavanato M, Barberio B, Savarino EV, Zingone F. Azathioprine monotherapy withdrawal in inflammatory bowel diseases: A retrospective mono-centric study. World J Gastroenterol 2023; 29:4334-4343. [PMID: 37545640 PMCID: PMC10401657 DOI: 10.3748/wjg.v29.i27.4334] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/04/2023] [Accepted: 07/03/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation.
AIM To describe the events following AZA cessation.
METHODS Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups.
RESULTS A total of 133 ulcerative colitis patients and 141 Crohn’s disease patients were included. Therapy with AZA was stopped in the 1st year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years.
CONCLUSION AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.
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Affiliation(s)
- Martina Crepaldi
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua 35128, Italy
| | - Daria Maniero
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua 35128, Italy
| | - Alessandro Massano
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua 35128, Italy
| | - Margherita Pavanato
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua 35128, Italy
| | - Brigida Barberio
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua 35128, Italy
| | | | - Fabiana Zingone
- Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua 35128, Italy
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Crispino F, Michielan A, Grova M, Tieppo C, Mazza M, Rogger TM, Armelao F. Exit strategies in inflammatory bowel disease: Looking beyond anti-tumor necrosis factors. World J Clin Cases 2023; 11:2657-2669. [PMID: 37214561 PMCID: PMC10198103 DOI: 10.12998/wjcc.v11.i12.2657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/10/2023] [Accepted: 03/29/2023] [Indexed: 04/25/2023] Open
Abstract
The long-term management of patients with inflammatory bowel disease (IBD) is still a matter of debate, and no clear guidelines have been issued. In clinical practice, gastroenterologists often have to deal with patients in prolonged remission after immunomodulatory or immunosuppressive therapies. When planning an exit strategy for drug withdrawal, the risk of disease relapse must be balanced against the risk of drug-related adverse events and healthcare costs. Furthermore, there is still a dearth of data on the withdrawal of novel biologics, such as the anti-α4β7 integrin antibody (vedolizumab) and anti-IL12/23 antibody (ustekinumab), as well as the small molecule tofacitinib. Models for estimating the risk of disease relapse and the efficacy of retreatment should be evaluated according to the patient's age and IBD phenotype. These models should guide clinicians in programming a temporary drug withdrawal after discussing realistic outcomes with the patient. This would shift the paradigm from an exit strategy to a holiday strategy.
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Affiliation(s)
- Federica Crispino
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Andrea Michielan
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Mauro Grova
- Inflammatory Bowel Disease Unit, Department of Medicine, Azienda Ospedaliera Ospedali Riuniti, Villa Sofia-Cervello, Palermo 90146, Italy
| | - Chiara Tieppo
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Marta Mazza
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Teresa Marzia Rogger
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
| | - Franco Armelao
- Azienda Provinciale per i Servizi Sanitari, Gastroenterology and Digestive Endoscopy Unit, Santa Chiara Hospital, Trento 38122, Italy
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Miyatani Y, Kobayashi T. De-escalation of Therapy in Patients with Quiescent Inflammatory Bowel Disease. Gut Liver 2023; 17:181-189. [PMID: 36375794 PMCID: PMC10018304 DOI: 10.5009/gnl220070] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 05/25/2022] [Accepted: 06/03/2022] [Indexed: 11/16/2022] Open
Abstract
Inflammatory bowel disease is a chronic disease of unknown origin that requires long-term treatment. The optical duration of maintenance treatment once remission has been achieved remains unclear. When discussing a de-escalation strategy, not only the likelihood of relapse but also, the outcome of retreatment for relapse after de-escalation should be considered. Previous evidence has demonstrated controversial results for risk factors for relapse after de-escalation due to the various definitions of remission and relapse. In fact, endoscopic or histologic remission has been suggested as a treatment target; however, it might not always be indicative of a successful drug withdrawal. For better risk stratification of relapse after de-escalation, it may be necessary to evaluate both the current and previous treatments. Following de-escalation, biomarkers should be closely monitored. In addition to the risk of relapse, a comprehensive understanding of the overall outcome, such as the long-term safety, patient quality of life, and impact on healthcare costs, is necessary. Therefore, a shared decision-making with patients on a case-by-case basis is imperative.
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Affiliation(s)
- Yusuke Miyatani
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
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Nakase H, Esaki M, Hirai F, Kobayashi T, Matsuoka K, Matsuura M, Naganuma M, Saruta M, Tsuchiya K, Uchino M, Watanabe K, Hisamatsu T, the TRADE consensus group AndohAkiraBambaShigekiEsakiMotohiroFujiyaMikihiroFutamiKitaroHataKeisukeHiraiFumihitoHiraokaSakikohttp://orcid.org/0000-0002-1178-3536HisamatsuTadakazuHokariRyotaIshiharaShunjiIshiharaSoichiroItabashiMichioKakutaYoichiKatoJunKatoShingoKatsuradaTakehikoKitamuraKazuyaKobayashiKiyonoriKobayashiTakuKoganeiKazutakaMaemotoAtsuoMatsuiToshiyukiMatsumotoTakayukiMatsuokaKatsuyoshiMatsuuraMinoruMotoyaSatoshiNagahoriMasakazuNaganumaMakotoNaitoYujiNakamuraShiroNakaseHiroshiOgataHaruhikoOkazakiKazuichiSakurabaHirotakeSarutaMasayukiShinzakiShinichiroSugimotoKenSugitaAkiraSuzukiYasuoTakahashiKenichiTakagiTomohisaTakenakaKentoTakeuchiKenTsuchiyaKiichiroTsujikawaTomoyukiUchinoMotoiUenoFumiakiWatanabeKenjiWatanabeMamoruYamamotoTakayukiYokoyamaKaoruYoshidaAtsushiYoshimuraNaoki. Treatment escalation and de-escalation decisions in Crohn's disease: Delphi consensus recommendations from Japan, 2021. J Gastroenterol 2023; 58:313-345. [PMID: 36773075 PMCID: PMC10050046 DOI: 10.1007/s00535-023-01958-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 01/08/2023] [Indexed: 02/12/2023]
Abstract
BACKGROUND We aimed to develop criteria for treatment intensification in patients with (1) luminal Crohn's disease (CD), (2) CD with perianal disease and/or fistula, (3) CD with small bowel stenosis, (4) in the postoperative setting, and (5) for discontinuing or reducing the dose of treatment in patients with CD. METHODS PubMed and Embase were searched for studies published since 1998 which may be relevant to the five defined topics. Results were assessed for relevant studies, with preference given to data from randomized, controlled studies. For each question, a core panel of 12 gastroenterologists defined the treatment target and developed statements, based on the literature, current guidelines, and relevant additional studies. The evidence supporting each statement was graded using the Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). A modified Delphi process was used to refine statements and gain agreement from 54 Japanese specialists at in-person and online meetings conducted between October 2020 and April 2021. RESULTS Seventeen statements were developed for treatment intensification in luminal CD (targeting endoscopic remission), six statements for treatment intensification in perianal/fistulizing CD (targeting healing of perianal lesions and complete closure of the fistula), six statements for treatment intensification in CD with small bowel stenosis (targeting resolution of obstructive symptoms), seven statements for treatment intensification after surgery (targeting endoscopic remission), and five statements for discontinuing or reducing the dose of treatment in patients with CD. CONCLUSIONS These statements provide guidance on how and when to intensify or de-intensify treatment for a broad spectrum of patients with CD.
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Affiliation(s)
- Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-Ku, Sapporo, Hokkaido 060-8543 Japan
| | - Motohiro Esaki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan
| | - Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-Shi, Tokyo, 181-8611 Japan
| | - Makoto Naganuma
- Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kiichiro Tsuchiya
- Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Motoi Uchino
- Division of Inflammatory Bowel Disease, Department of Gastroenterological Surgery, Hyogo Medical University, Nishinomiya, Hyogo Japan
| | - Kenji Watanabe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Hyogo Japan
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-Shi, Tokyo, 181-8611 Japan
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Miyatani Y, Kobayashi T. Evidence-Based Approach to the Discontinuation of Immunomodulators or Biologics in Inflammatory Bowel Disease. Digestion 2022; 104:66-73. [PMID: 36450267 PMCID: PMC9843544 DOI: 10.1159/000527776] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/22/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Biologics and immunomodulators are key drugs in the long-term treatment of inflammatory bowel diseases, while they may negatively impact patients' quality of life due to concerns of adverse events, need for frequent hospital visits, and medical expenses. The basic concept of drug withdrawal should be based on the risk of relapse and the efficacy of re-treatment. Considering a number of patients may relapse even if treatment is continued, the disadvantage of discontinuation should be recognized not by all relapse after discontinuation, but by the increase in relapse. SUMMARY Discontinuation of immunomodulator monotherapy is associated with an increased risk of relapse. However, prolonged remission might be an indication of withdrawal, concerning the long-term adverse effect including lymphoma and nonmelanoma skin cancers. When considering discontinuation from combination therapy of anti-tumor necrosis factor (TNF) agents with immunomodulators, therapeutic drug monitoring may be useful to understand the pharmacokinetic effect. However, recent randomized controlled trials, as well as large-scale observational studies, demonstrated that discontinuation of anti-TNF agents, but not of immunomodulators, resulted in a significantly higher risk of relapse even in deep remission. Therefore, discontinuation of anti-TNF agents should be considered with caution and close monitoring combined with fecal calprotectin may be necessary. On the other hand, evidence of not only short-term relapse rate but of the true long-term influence on the patient's quality of life should be clarified by a multidimensional approach. KEY MESSAGES Discontinuation of treatment should be implemented based on shared decision-making with careful interpretation of evidence and the condition.
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Affiliation(s)
| | - Taku Kobayashi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
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Gros B, Rodríguez-Lago I. Editorial: thiopurines in the multidrug era-time to rescue our memories over half a century of experience. Aliment Pharmacol Ther 2022; 56:1080-1081. [PMID: 35995737 DOI: 10.1111/apt.17164] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
| | - Iago Rodríguez-Lago
- Hospital Universitario de Galdakao, Biocruces Bizkaia Health Research Institute, Bilbao, Spain
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Ranjan MK, Vuyyuru SK, Kante B, Kumar P, Mundhra SK, Golla R, Sharma R, Sahni P, Das P, Makharia G, Kedia S, Ahuja V. Relapse rates after withdrawal of thiopurines in patients with inflammatory bowel disease. Int J Colorectal Dis 2022; 37:1817-1826. [PMID: 35835862 DOI: 10.1007/s00384-022-04216-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/08/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Withdrawal of thiopurines after remission is associated with an increased risk of relapse in patients with inflammatory bowel disease (IBD). However, long-term data on thiopurine withdrawal is limited, especially from developing countries where the cost of long-term therapy poses a significant burden on patients. METHODS Patients with IBD on thiopurine monotherapy for ≥ 4 months, who stopped thiopurines while in clinical remission and were not on any other immunomodulator or biologics at the time of withdrawal, were included in this retrospective analysis. RESULTS Among 1093 patients with IBD on thiopurine monotherapy, 461 patients stopped thiopurine due to various reasons. Among these, 218 (ulcerative colitis (UC) = 179; Crohn's disease (CD) = 39) patients were in clinical remission and were continued on mesalamine. Overall, 36.7% (n = 80) relapsed after a median duration of 20 months (IQR: 9-49). Relapse rate was higher in UC than CD (39.7% vs 23%, p = 0.055). Cumulative probabilities of relapse were 17%, 34%, and 44% at the end of 1, 3, and 5 years, respectively. The relapse rate at 5 years was significantly lower in patients who had stopped azathioprine after 4 years of therapy (31% vs 54%, p = 0.007). On multi-variate cox regression analysis, male sex [HR: 1.6(1.0-2.6), p = 0.02] and short duration of therapy with thiopurines [HR: 1.02 (1.01-1.02), p = 0.004] before withdrawal were associated with increased risk of relapse. CONCLUSION Approximately 50% patients with IBD in remission would relapse after 5 years of thiopurine withdrawal. Male sex and shorter treatment duration predict relapse. Treatment should be continued in patients who tolerate and maintain remission on long-term thiopurine.
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Affiliation(s)
- Mukesh Kumar Ranjan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Sudheer Kumar Vuyyuru
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Bhaskar Kante
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Peeyush Kumar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Sandeep K Mundhra
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Rithvik Golla
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Raju Sharma
- Department of Radio Diagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Peush Sahni
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Saurabh Kedia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, 3rd Floor, Teaching Block, Ansar Nagar, New Delhi, 110029, India.
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Colbert RD, Gaya D, Hale G, Rickaby W. Cutaneous Kaposi's sarcoma in an HIV-negative patient with Crohn's disease on thiopurine immunosuppression. BMJ Case Rep 2021; 14:e245321. [PMID: 34764119 PMCID: PMC8587592 DOI: 10.1136/bcr-2021-245321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2021] [Indexed: 11/04/2022] Open
Abstract
We present the rare case of a 61-year-old man with Crohn's disease who developed a cutaneous Kaposi's sarcoma in the setting of long-term treatment with 6-mercaptopurine. Deciding on the best course of management provided a clinical challenge in an 'evidence-light' area. Relevant case reports and guidelines were reviewed. In general, the withdrawal of immunosuppressive therapy is advised; however, a multidisciplinary, case-by-case approach is also emphasised. The patient's lesion was removed and, following collaborative discussion, immunosuppression was continued post resection. This is thought to be the first reported case involving a Kaposi's sarcoma in inflammatory bowel disease where immune therapy was not subsequently discontinued.
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Affiliation(s)
| | - Daniel Gaya
- Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - Gordon Hale
- Dermatology, Glasgow Royal Infirmary, Glasgow, UK
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Crouwel F, Buiter HJC, de Boer NKH. There is still a place for optimised thiopurine therapy in IBD. Gut 2021; 70:2207. [PMID: 33239341 DOI: 10.1136/gutjnl-2020-323481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/09/2020] [Accepted: 11/12/2020] [Indexed: 01/07/2023]
Affiliation(s)
- Femke Crouwel
- Department of Gastroenterology and Hepatology, AGEM Research Insitute, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| | - Hans J C Buiter
- Department of Clinical Pharmacology and Pharmacy, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
| | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, AGEM Research Insitute, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands
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13
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Jorissen C, Verstockt B, Schils N, Sabino J, Ferrante M, Vermeire S. Long-term clinical outcome after thiopurine discontinuation in elderly IBD patients. Scand J Gastroenterol 2021; 56:1323-1327. [PMID: 34399630 DOI: 10.1080/00365521.2021.1965207] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Thiopurines - although used frequently in inflammatory bowel diseases (IBD) - carry a significant safety risk, particularly with prolonged use and/or in elderly patients. Stopping therapy, however, may trigger relapses. We assessed the long-term outcome of elderly IBD patients after discontinuation of thiopurine while in clinical remission. METHODS Electronic medical records from IBD patients >60 years whoever received thiopurine treatment were reviewed. Patients who stopped thiopurine after 60 years of age while in clinical and/or endoscopic remission were included. Long-term outcomes included duration of clinical remission, time to clinical relapse, and development of malignancy. RESULTS In total, 142 patients receiving thiopurines while they were >60 years were identified. Ninety-one patients stopped thiopurines at >60years while in clinical and/or endoscopic remission. After a median follow-up of 66 months, 28 (30.8%) developed a clinical relapse. The median duration of TP therapy in relapses was significantly shorter than in patients who remained in remission (median 45 vs. 103 months, respectively; p = .005). After relapse, 10 patients started a biological (36%) and seven received steroids (25%). Surgery was needed in 36% of patients (10/28). Overall, 26 malignancies developed. CONCLUSION Discontinuation of TP in elderly IBD patients in clinical and/or endoscopic remission results in sustained clinical remission in two-thirds of patients. Patients who flare can mostly be rescued with biologicals although one-third necessitate surgery. A significant proportion of patients developed malignancies under but also after thiopurines discontinuation, indicating that these patients necessitate a continued close follow-up. Decision-making in this vulnerable subgroup of patients remains difficult.
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Affiliation(s)
- C Jorissen
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - B Verstockt
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.,Translational Research in Gastrointestinal Disorders - IBD, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - N Schils
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - J Sabino
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.,Translational Research in Gastrointestinal Disorders - IBD, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - M Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.,Translational Research in Gastrointestinal Disorders - IBD, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - S Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.,Translational Research in Gastrointestinal Disorders - IBD, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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14
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Nguyen ALH, Sparrow MP. Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules. Dig Dis Sci 2021; 66:3250-3262. [PMID: 33073334 DOI: 10.1007/s10620-020-06662-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 10/06/2020] [Indexed: 12/09/2022]
Abstract
In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.
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Affiliation(s)
- Anke L H Nguyen
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia.,Monash University, Melbourne, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health, 55 Commercial Road, Melbourne, 3004, VIC, Australia. .,Monash University, Melbourne, Australia.
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15
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Ochi M, Niikura R, Otsubo T, Yamada A, Kawai T, Koike K. Comparison of inflammatory bowel disease relapse after top-down or step-up therapy: a population-based cohort study. Int J Colorectal Dis 2021; 36:2227-2235. [PMID: 34386841 DOI: 10.1007/s00384-021-04007-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/05/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE The therapeutic effect of top-down therapy for inflammatory bowel disease (IBD) has not been fully evaluated in real-world clinical settings. We compared the effectiveness of top-down and step-up therapies for IBD. METHODS We retrospectively evaluated patients who were admitted with IBD (Crohn's disease [CD] or ulcerative colitis [UC]) between 2012 and 2019 using the nationwide Japan Diagnosis Procedure Combination database. Patients who received immunomodulators or biologic agents at the start of observation were assigned to the top-down group and those who did not were enrolled in the step-up group. Relapse was the primary outcome, a composite outcome defined as surgery, new steroid or immunomodulator use, hospitalization, a new biologic agent, or switching biologic agents. RESULTS We analyzed 6715 patients (CD, N = 3643; UC, N = 3072). Relapse occurred in 1982 CD cases (54.4%). The cumulative CD relapse incidence was 32.9% at 1 year and 61.3% at 5 years in the top-down group and 30.7% at 1 year and 58.6% at 5 years in the step-up group. Relapse occurred in 2032 UC cases (47.8%). The cumulative relapse incidence was 33.5% at 1 year and 50.0% at 5 years in the top-down group and 35.2% at 1 year and 51.6% at 5 years in the step-up group. No clinical factors associated with relapse were identified in patients with CD or UC. CONCLUSION Compared with step-up therapy, top-down therapy was not associated with a decreased relapse risk in a real-world population of patients with CD or UC.
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Affiliation(s)
- Masanori Ochi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Ryota Niikura
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. .,Gastroenterological Endoscopy, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
| | - Tetsuya Otsubo
- The Database Center, National University Hospitals, The University of Tokyo Hospital, Tokyo, Japan.,Division of Medical Information Technology and Administration Planning, Kyoto University Hospital, Kyoto, Japan
| | - Atsuo Yamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Kawai
- Gastroenterological Endoscopy, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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16
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Hirten RP, Lakatos PL, Halfvarson J, Colombel JF. A User's Guide to De-escalating Immunomodulator and Biologic Therapy in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2020; 18:1336-1345. [PMID: 31887444 DOI: 10.1016/j.cgh.2019.12.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 12/05/2019] [Accepted: 12/08/2019] [Indexed: 02/07/2023]
Abstract
De-escalation of immunomodulators and biologic agents in inflammatory bowel disease is frequently discussed with patients and must weigh the risk of continued medical therapy with the risk of disease recurrence. Risk factors for disease flare after withdrawal of inflammatory bowel disease medications such as disease activity at de-escalation, disease prognostic features, and prior course of disease have been identified predominately in retrospective studies, allowing for risk stratification of patients. This review evaluates the published literature regarding therapeutic de-escalation and provides a framework for physicians to apply this to clinical practice. Prospective trials are underway and planned, which should provide further insight into this treatment paradigm and better inform patient selection for this strategy.
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Affiliation(s)
- Robert P Hirten
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Peter L Lakatos
- Division of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada; 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
| | - Jean Frederic Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
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17
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Chapman TP, Gomes CF, Louis E, Colombel JF, Satsangi J. De-escalation of immunomodulator and biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 2020; 5:63-79. [DOI: 10.1016/s2468-1253(19)30186-4] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 12/11/2022]
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18
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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: 1509] [Impact Index Per Article: 251.5] [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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19
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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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20
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Tran V, Limketkai BN, Sauk JS. IBD in the Elderly: Management Challenges and Therapeutic Considerations. Curr Gastroenterol Rep 2019; 21:60. [PMID: 31776797 DOI: 10.1007/s11894-019-0720-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
PURPOSE OF REVIEW Elderly patients with inflammatory bowel disease (IBD) are increasing in prevalence as our population ages and the incidence of IBD increases. The purpose of this review is to describe the management challenges in elderly IBD patients, including comorbid conditions and therapeutic considerations unique to the elderly population. RECENT FINDINGS The elderly experience coexisting comorbidities that complicate IBD management. The disease course and potential side effects of treatments can impact the elderly IBD patient differently than younger IBD patients. The duration for colorectal cancer surveillance (CRC) also remains controversial and should be individualized to determine when discontinuation is appropriate. Given greater safety considerations in the elderly IBD population, treatment targets and management goals require a more personalized approach in the elderly, taking into account coexisting comorbidities, inflammatory burden, and functional limitations.
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Affiliation(s)
- Vivy Tran
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Berkeley N Limketkai
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- UCLA Center for Inflammatory Bowel Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jenny S Sauk
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
- Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
- UCLA Center for Inflammatory Bowel Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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21
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Withdrawal of Azathioprine in Inflammatory Bowel Disease Patients Who Sustain Remission: New Risk Factors for Relapse. Dig Dis Sci 2019; 64:1612-1621. [PMID: 30604371 DOI: 10.1007/s10620-018-5429-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 12/12/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND The benefits of immunosuppressants for sustaining remission and preventing flares of IBD are well known. However, optimal timing for withdrawal has not been determined. AIMS The objective of this study was to calculate the risk of relapse and predictors after withdrawal of azathioprine (AZA) monotherapy in patients who sustain deep remission. METHODS This was a multicenter observational study of patients with IBD in remission whose immunosuppressant had been withdrawn. We recorded demographic variables, disease data, laboratory values, and the results of imaging tests performed at withdrawal and, in patients who relapsed, time to relapse and the efficacy of reintroducing the drug. RESULTS Ninety-five patients were included (35 UC and 60 CD). The mean duration of AZA treatment was 87 and 77 months for UC and CD, respectively. Endoscopic remission was evaluated in 23 patients with UC and 35 with CD. After AZA withdrawal, 91% patients with UC and 67% with CD received high doses of salicylates. A total of 26 patients relapsed. The cumulative relapse rate at 5 years was 46% for CD and UC. AZA was reintroduced in 19 patients, of whom 14 responded. Predictors of relapse were corticosteroid dependence, early introduction of AZA (CD), and late introduction of AZA (UC). CONCLUSIONS Almost half of the patients in whom AZA was withdrawn were in remission at 5 years. The candidates for withdrawal could be better identified based on corticosteroid dependence, previous surgery, timing of initiation, and indication for AZA.
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22
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Israel A, Jurdi KE, Rubin DT. Treatment De-Escalation in Patients With Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 2019; 15:335-341. [PMID: 31391803 PMCID: PMC6676361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Inflammatory bowel disease follows a relapsing and remitting course that can be augmented with the use of various pharmacologic therapies. Treatments used to induce or maintain remission may not be required indefinitely. The associated side-effect profile, adverse events, and costs are additional motivators for providers to treat patients with the lowest dose of effective medications. De-escalation of therapy, whether dose reduction or drug discontinuation, must be carefully considered on an individual patient basis. The steps for de-escalation include confirmation of deep remission, development of a maintenance strategy, discussion of the rescue threshold and treatment options in the event of relapse, and appropriate discussion with the patient of this plan.
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Affiliation(s)
- Amanda Israel
- Dr Israel is an advanced inflammatory bowel disease fellow, Dr El Jurdi is a clinical research coordinator, and Dr Rubin is a professor of medicine and chief of gastroenterology at the University of Chicago Medicine in Chicago, Illinois
| | - Katia El Jurdi
- Dr Israel is an advanced inflammatory bowel disease fellow, Dr El Jurdi is a clinical research coordinator, and Dr Rubin is a professor of medicine and chief of gastroenterology at the University of Chicago Medicine in Chicago, Illinois
| | - David T Rubin
- Dr Israel is an advanced inflammatory bowel disease fellow, Dr El Jurdi is a clinical research coordinator, and Dr Rubin is a professor of medicine and chief of gastroenterology at the University of Chicago Medicine in Chicago, Illinois
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23
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Actis GC, Pellicano R, Ribaldone DG. A Concise History of Thiopurines for Inflammatory Bowel Disease: From Anecdotal Reporting to Treat-to-Target Algorithms. Rev Recent Clin Trials 2019; 14:4-9. [PMID: 30198438 DOI: 10.2174/1574887113666180910120959] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 08/28/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The need for immune suppressive strategies in the control of chronic inflammatory bowel diseases originated in the 1960s following the perception of a relative inefficacy of salazopyrin and its derivatives. In some 50 years upon an anecdotal claim, the indication for thiopurines in the management of inflammatory bowel diseases has come of age. OBJECTIVE The aim of this minireview is to give an overview, after the historical premises, of the current use of thiopurines in the context of inflammatory bowel diseases. METHOD Through MEDLINE searches, we reviewed the literature of the last two decades. RESULTS For Crohn's disease, the 1980 trial of 6-mercaptopurine for steroid sparing and fistula closure proved pivotal. The analysis of withdrawal experiments and of numerous open trials has established the efficacy of thiopurines for ulcerative colitis. In this indication, cutting-edge data are now showing that because targeting dysplasia, thiopurines can induce mucosal/histological healing, thus abolishing or delaying the need for pre-emptive (tumor prophylactic) colectomy. CONCLUSION In UC thiopurines may be recognized to effect a treat-to-target strategy, joining the modern algorithms of rheumatologic disorders.
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24
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Mezzina N, Campbell Davies SE, Ardizzone S. Nonbiological therapeutic management of ulcerative colitis. Expert Opin Pharmacother 2018; 19:1747-1757. [DOI: 10.1080/14656566.2018.1525361] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Nicolò Mezzina
- Gastrointestinal Unit, ASST Fatebenefratelli Sacco – Department of Biochemical and Clinical Sciences “L. Sacco”, University of Milan, Milano, Italy
| | | | - Sandro Ardizzone
- Gastrointestinal Unit, ASST Fatebenefratelli Sacco – Department of Biochemical and Clinical Sciences “L. Sacco”, University of Milan, Milano, Italy
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25
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Turner D, Ruemmele FM, Orlanski-Meyer E, Griffiths AM, de Carpi JM, Bronsky J, Veres G, Aloi M, Strisciuglio C, Braegger CP, Assa A, Romano C, Hussey S, Stanton M, Pakarinen M, de Ridder L, Katsanos K, Croft N, Navas-López V, Wilson DC, Lawrence S, Russell RK. Management of Paediatric Ulcerative Colitis, Part 1: Ambulatory Care-An Evidence-based Guideline From European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018; 67:257-291. [PMID: 30044357 DOI: 10.1097/mpg.0000000000002035] [Citation(s) in RCA: 316] [Impact Index Per Article: 45.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ∼20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points. METHODS These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate. RESULTS These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines. CONCLUSIONS These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.
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Affiliation(s)
- Dan Turner
- Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Frank M Ruemmele
- Université Paris Descartes, Sorbonne Paris Cité, APHP, Hôpital Necker Enfants Malades, Paris, France
| | | | - Anne M Griffiths
- The Hospital for Sick Children, University of Toronto, Toronto, Canada
| | | | - Jiri Bronsky
- Department of Paediatrics, University Hospital Motol, Prague, Czech Republic
| | - Gabor Veres
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Marina Aloi
- Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli," Napoli, Italy
| | | | - Amit Assa
- Schneider Children's Hospital, Petach Tikva, Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Claudio Romano
- Pediatric Department, University of Messina, Messina, Italy
| | - Séamus Hussey
- National Children's Research Centre, Royal College of Surgeons of Ireland and University College Dublin, Dublin, Ireland
| | | | - Mikko Pakarinen
- Helsinki University Children's Hospital, Department of Pediatric Surgery, Helsinki, Finland
| | - Lissy de Ridder
- Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands
| | | | - Nick Croft
- Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - Victor Navas-López
- Pediatric Gastroenterology and Nutrition Unit. Hospital Materno, IBIMA, Málaga, Spain
| | - David C Wilson
- Child Life and Health, University of Edinburgh, Edinburgh, UK
| | - Sally Lawrence
- BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada
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Abstract
PURPOSE OF REVIEW Currently, inflammatory bowel disease treatment is based on immunomodulators (IM) and/or biologic as this strategy may prevent the development of irreversible damage. Nevertheless, long-term treatment may be associated with non-negligible side effects and with high costs, and therefore the question on whether therapy can be de-escalated is often posed in clinical practice. RECENT FINDINGS Recent studies have shown a predictable rate of relapse after stop biologic or IM therapy withdrawal. Overall, around 40-50% of patients will eventually relapse over the following year after drug withdrawal, and the rates will increase over time. Stratification of patients and therapeutic drug monitoring could be promising alternatives to guide therapeutic management. We reviewed the current evidence on de-escalation strategy and summarised the recent results on discontinuation and dose reduction. Nowadays, de-escalation strategy is still a case-by-case decision in highly selected patients.
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Affiliation(s)
- Catarina Frias Gomes
- Surgical Department, Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
| | - Jean-Frédéric Colombel
- Medicine Department, Gastroenterology Division, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
| | - Joana Torres
- Surgical Department, Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal
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Migliore F, Macchi R, Landini P, Paroni M. Phagocytosis and Epithelial Cell Invasion by Crohn's Disease-Associated Adherent-Invasive Escherichia coli Are Inhibited by the Anti-inflammatory Drug 6-Mercaptopurine. Front Microbiol 2018; 9:964. [PMID: 29867868 PMCID: PMC5961443 DOI: 10.3389/fmicb.2018.00964] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 04/24/2018] [Indexed: 12/22/2022] Open
Abstract
Adherent-invasive Escherichia coli (AIEC) strains are overrepresented in the dysbiotic microbiota of Crohn’s disease (CD) patients, and contribute to the onset of the chronic inflammation typical of the disease. However, the effects of anti-inflammatory drugs used for CD treatment on AIEC virulence have not yet been investigated. In this report, we show that exposure of AIEC LF82 strain to amino-6-mercaptopurine (6-MP) riboside, one of the most widely used anti-inflammatory drugs in CD, impairs its ability to adhere to, and consequently to invade, human epithelial cells. Notably, phagocytosis of LF82 treated with 6-MP by human macrophages is also reduced, suggesting that 6-MP affects AIEC cell surface determinants involved both in interaction with epithelial cells and in uptake by macrophages. Since a main target of 6-MP in bacterial cells is the inhibition of the important signal molecule c-di-GMP, we also tested whether perturbations in cAMP, another major signaling pathway in E. coli, might have similar effects on interactions with human cells. To this aim, we grew LF82 in the presence of glucose, which leads to inhibition of cAMP synthesis. Growth in glucose-supplemented medium resulted in a reduction in AIEC adhesion to epithelial cells and uptake by macrophages. Consistent with these results, both 6-MP and glucose can affect expression of cell adhesion-related genes, such as the csg genes, encoding thin aggregative fimbriae (curli). In addition, glucose strongly inhibits expression of the fim operon, encoding type 1 pili, a known AIEC determinant for adhesion to human cells. To further investigate whether 6-MP can indeed inhibit c-di-GMP signaling in AIEC, we performed biofilm and motility assays and determination of extracellular polysaccharides. 6-MP clearly affected biofilm formation and cellulose production, but also, unexpectedly, reduced cell motility, itself an important virulence factor for AIEC. Our results provide strong evidence that 6-MP can affect AIEC-host cell interaction by acting on the bacterial cell, thus strengthening the hypothesis that mercaptopurines might promote CD remission also by affecting gut microbiota composition and/or physiology, and suggesting that novel drugs targeting bacterial virulence and signaling might be effective in preventing chronic inflammation in CD.
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Affiliation(s)
- Federica Migliore
- Dipartimento di Bioscienze, Università degli studi di Milano, Milan, Italy
| | - Raffaella Macchi
- Dipartimento di Bioscienze, Università degli studi di Milano, Milan, Italy
| | - Paolo Landini
- Dipartimento di Bioscienze, Università degli studi di Milano, Milan, Italy
| | - Moira Paroni
- Dipartimento di Bioscienze, Università degli studi di Milano, Milan, Italy
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28
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de Boer NKH, Peyrin-Biroulet L, Jharap B, Sanderson JD, Meijer B, Atreya I, Barclay ML, Colombel JF, Lopez A, Beaugerie L, Marinaki AM, van Bodegraven AA, Neurath MF. Thiopurines in Inflammatory Bowel Disease: New Findings and Perspectives. J Crohns Colitis 2018; 12:610-620. [PMID: 29293971 DOI: 10.1093/ecco-jcc/jjx181] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/20/2017] [Indexed: 02/08/2023]
Abstract
Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.
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Affiliation(s)
- Nanne K H de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Hepatology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Bindia Jharap
- Department of Gastroenterology, Meander Medical Centre, Amersfoort, The Netherlands
| | - Jeremy D Sanderson
- Department of Gastroenterology, Guy's and St Thomas' Hospitals, London, UK
| | - Berrie Meijer
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands
| | - Imke Atreya
- Department of Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Germany
| | - Murray L Barclay
- Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand
| | | | - Anthony Lopez
- Department of Gastroenterology and Hepatology and Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Laurent Beaugerie
- Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine,UPMC University, Paris, France
| | | | - Adriaan A van Bodegraven
- Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, The Netherlands.,Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine [Co-MIK], Zuyderland Medical Centre, Heerlen-Sittard-Geleen, The Netherlands
| | - Markus F Neurath
- Department of Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Germany
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29
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Kaymak T, Moriconi F, Niess JH, Beglinger C, Hruz P. Low Discontinuation Rate of Infliximab Treatment in Steroid-Dependent/Refractory Crohn's Disease Patients. Inflamm Intest Dis 2018; 2:171-179. [PMID: 30018967 DOI: 10.1159/000486676] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 01/03/2018] [Indexed: 12/17/2022] Open
Abstract
Background Many patients with moderate to severe Crohn's disease (CD) are treated with infliximab (IFX). As most of these patients experience a long-lasting therapy, the outcome and withdrawal of IFX treatment are important clinical questions. Methods In this retrospective study, we analyzed the treatment outcome in moderate to severe CD patients with a steroid-dependent/refractory disease course started on IFX. Withdrawal of IFX was evaluated in patients with deep remission defined as clinical (Harvey-Bradshaw Index ≤4), biochemical (fecal calprotectin [FC] ≤150 μg/g stool) over a period of 2 years, and endoscopic and histological remission before discontinuation of IFX. Results After induction with IFX, clinical remission was observed in 45/109 patients (41.3%) and clinical response in 61/109 patients (56.0%). Only 8/109 patients (7.3%) achieved deep remission and therefore could be discontinued from IFX therapy. In 4 of these patients (50%), relapse was observed after discontinuation of IFX treatment. FC decreased in these 8 patients in deep remission from 652 ± 168 μg/g stool (mean ± SE) at baseline to 24.9 ± 8.1 μg/g stool at 14 weeks. When compared to patients in deep remission, FC had decreased significantly less at 14 weeks in patients in clinical remission after induction with IFX (n = 31; 154 ± 55 μg/g stool; p = 0.01), in patients with clinical response after induction achieving clinical remission during the maintenance phase (n = 11; 352 ± 67 μg/g stool; p = 0.004), or in patients with chronic active disease course on maintenance therapy (n = 50; 645 ± 93 μg/g stool; p < 0.001). Conclusion A low discontinuation rate was observed for steroid-dependent/refractory moderate to severe CD patients with IFX treatment. As FC showed a more or less pronounced decrease depending on the response to the IFX treatment, monitoring of FC may become a noninvasive tool for tailoring biological therapy in CD patients.
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Affiliation(s)
- Tanay Kaymak
- Department of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - Federico Moriconi
- Department of Gastroenterology and Hepatology, Triemli Hospital Zürich, Zürich, Switzerland
| | - Jan H Niess
- Department of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - Christoph Beglinger
- Department of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - Petr Hruz
- Department of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
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30
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Doherty G, Katsanos KH, Burisch J, Allez M, Papamichael K, Stallmach A, Mao R, Berset IP, Gisbert JP, Sebastian S, Kierkus J, Lopetuso L, Szymanska E, Louis E. European Crohn's and Colitis Organisation Topical Review on Treatment Withdrawal ['Exit Strategies'] in Inflammatory Bowel Disease. J Crohns Colitis 2018; 12:17-31. [PMID: 28981623 DOI: 10.1093/ecco-jcc/jjx101] [Citation(s) in RCA: 143] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 07/31/2017] [Indexed: 12/12/2022]
Abstract
Clinically effective therapies now exist for remission maintenance in both ulcerative colitis [UC] and Crohn's Disease [CD]. For each major class of IBD medications [5-aminosalicyclates, immunomodulators, and biologic agents], used alone or in combination, there is a risk of relapse following reduction or cessation of treatment. A consensus expert panel convened by the European Crohn's and Colitis Organisation [ECCO] reviewed the published literature and agreed a series of consensus practice points. The objective of the expert consensus is to provide evidence-based guidance for clinical practice so that physicians can make informed decisions in partnership with their patients. The likelihood of relapse with stopping each class of IBD medication is reviewed. Factors associated with an altered risk of relapse with withdrawal are evaluated, and strategies to monitor and allow early identification of relapse are considered. In general, patients in clinical, biochemical, and endoscopic remission are more likely to remain well when treatments are stopped. Reintroduction of the same treatment is usually, but not always, successful. The decision to stop a treatment needs to be individualized, and shared decision making with the patient should take place.
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Affiliation(s)
- Glen Doherty
- Centre for Colorectal Disease, St Vincent's University Hospital & University College Dublin, Dublin, Ireland
| | - Konstantinos H Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Johan Burisch
- Department of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark
| | - Matthieu Allez
- Department of Gastroenterology and Hepatology, Hôpital Saint-Louis, APHP, INSERM UMRS 1160, Université Denis Diderot, Paris, France
| | | | - Andreas Stallmach
- Department of Internal Medicine IV [Gastroenterology, Hepatology and Infectious Disease], University Hospital Jena, Jena, Germany
| | - Ren Mao
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ingrid Prytz Berset
- Gastroenterology Department, Alesund Hospital, Helse More Romsdal Hospital Trust, Alesund, Norway
| | - Javier P Gisbert
- Department of Gastroenterology, Hospital Universitario de la Princesa, Instituto de Investigaciun Sanitaria Princesa (IIS-IP) and Centro de Investigaciun Biomédica en Red de Enfermedades Heprticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Shaji Sebastian
- IBD Unit, Department of Gastroenterology, Hull & East Yorkshire Hospitals NHS Trust, Hull, UK
| | - Jaroslaw Kierkus
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Loris Lopetuso
- Department of Gastroenterology and Internal Medicine, Catholic University of Rome-A. Gemelli Hospital, Rome, Italy
| | - Edyta Szymanska
- Department of Pediatrics, Nutrition, and Metabolic Disorders, Children's Memorial Health Institute, Warsaw, Poland
| | - Edouard Louis
- Department of Gastroenterology, CHU Liège, Sart Tilman, Liège, Belgium
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31
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Warner B, Johnston E, Arenas-Hernandez M, Marinaki A, Irving P, Sanderson J. A practical guide to thiopurine prescribing and monitoring in IBD. Frontline Gastroenterol 2018; 9:10-15. [PMID: 29484155 PMCID: PMC5824765 DOI: 10.1136/flgastro-2016-100738] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/05/2016] [Accepted: 08/08/2016] [Indexed: 02/04/2023] Open
Abstract
Thiopurines are often the mainstay of treatment for many patients with inflammatory bowel disease. As such, a general understanding of the evidence behind their use and of their metabolism is extremely useful in clinical practice. This review gives a practical overview of thiopurine metabolism, the importance of thiopurine S-methyltransferase testing prior to the start of therapy and the monitoring of thioguanine nucleotide levels while on treatment, guiding a personalised approach to optimising thiopurine therapy.
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Affiliation(s)
- Ben Warner
- 1st Floor College House, St Thomas’ Hospital, London, UK
| | - Emma Johnston
- Department of Gastroenterology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
| | | | | | - Peter Irving
- Department of Gastroenterology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
| | - Jeremy Sanderson
- Department of Gastroenterology, Guy's and St Thomas’ NHS Foundation Trust, London, UK
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32
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Dart RJ, Irving PM. Optimising use of thiopurines in inflammatory bowel disease. Expert Rev Clin Immunol 2017; 13:877-888. [DOI: 10.1080/1744666x.2017.1351298] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Robin J. Dart
- IBD Centre, Department of Gastroenterology, St Thomas’ Hospital, London, UK
- Immunosurveillance Lab, Francis Crick Institute, London, UK
- Immunobiology, DIIID, King’s College London, Guy’s Hospital, London, UK
| | - Peter M. Irving
- IBD Centre, Department of Gastroenterology, St Thomas’ Hospital, London, UK
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33
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Sturm A, Maaser C, Mendall M, Karagiannis D, Karatzas P, Ipenburg N, Sebastian S, Rizzello F, Limdi J, Katsanos K, Schmidt C, Jeuring S, Colombo F, Gionchetti P. European Crohn's and Colitis Organisation Topical Review on IBD in the Elderly. J Crohns Colitis 2017; 11:263-273. [PMID: 27797918 DOI: 10.1093/ecco-jcc/jjw188] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/17/2016] [Accepted: 10/18/2016] [Indexed: 12/12/2022]
Abstract
This ECCO topical review of the European Crohn's and Colitis Organisation [ECCO] focuses on the epidemiology, pathophysiology, diagnosis, management and outcome of the two most common forms of inflammatory bowel disease, Crohn's disease and ulcerative colitis, in elderly patients. The objective was to reach expert consensus to provide evidence-based guidance for clinical practice.
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Affiliation(s)
- Andreas Sturm
- Department of Gastroenterology, DRK Kliniken Berlin I Westend. Akademisches Lehrkrankenhaus der Charite, Spandauer Damm 130, 14050 Berlin, Germany
| | - Christian Maaser
- Outpatients Department of Gastroenterology and Department of Geriatrics, Hospital Lüneburg, Bögelstraße 1, 21339 Lüneburg, Germany
| | - Michael Mendall
- Croydon University Hospital, Mayday Road, CR4 7YE Thornton Heath; & St George's Medical School, Cranmer Terrace SW17 ORE, UK
| | - Dimitrios Karagiannis
- Department of Gastroenterology, Iatriko Kentro Athinon, Dervenakion St. 3, 14572 Athens, Greece
| | - Pantelis Karatzas
- Department of Gastroenterology, Evangelismos Hospital, 45-47 Ypsilantou Street, 10676 Athens, Greece
| | - Nienke Ipenburg
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Shaji Sebastian
- IBD Unit, Hull & East Yorkshire NHS Trust, Anlaby Road, Hull HU3 2JZ, UK
| | - Fernando Rizzello
- IBD Unit, DIMEC, University of Bologna, Via Massarenti, 9, 40138 Bologna, BO, Italy
| | - Jimmy Limdi
- Department of Gastroenterology, Pennine Acute Hospitals NHS Trust, Manchester M8 5RB, Institute of Inflammation and Repair, Manchester Academic Health Sciences, University of Manchester, UK
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, PO Box 1186, 45110 Ioannina, Greece
| | - Carsten Schmidt
- Department of Internal Medicine IV, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany
| | - Steven Jeuring
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center (MUMC), PO Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Francesco Colombo
- Dipartimento di Area Chirurgica, Ospedale "Luigi Sacco"- Polo Universitario, ASST Fatebenefratelli Sacco, Milano, Italy
| | - Paolo Gionchetti
- IBD Unit, DIMEC, University of Bologna, Via Massarenti, 9, 40138 Bologna, BO, Italy
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34
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Mantzaris GJ. Thiopurines and Methotrexate Use in IBD Patients in a Biologic Era. ACTA ACUST UNITED AC 2017; 15:84-104. [DOI: 10.1007/s11938-017-0128-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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35
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Minami N, Matsuura M, Koshikawa Y, Yamada S, Honzawa Y, Yamamoto S, Nakase H. Maternal and fetal outcomes in pregnant Japanese women with inflammatory bowel disease: our experience with a series of 23 cases. Intest Res 2017; 15:90-96. [PMID: 28239318 PMCID: PMC5323313 DOI: 10.5217/ir.2017.15.1.90] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 08/31/2016] [Accepted: 09/05/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS Our physicians work to expand the possibilities to treat female patients with inflammatory bowel disease (IBD) who wish to become pregnant. Although many drugs, including 5-aminosalicylate (5-ASA), corticosteroids, immunomodulators, and biologics, are used safely during pregnancy, few reports have described the therapeutic regimen throughout pregnancy and the management of patients who relapse during pregnancy precisely. The aim of this study was to assess the management of patients with IBD during pregnancy. METHODS We identified 19 patients (five with Crohn's disease and 14 with ulcerative colitis [UC]) who became pregnant with a total of 23 pregnancies between May 2005 and May 2015 by reviewing the medical records of Kyoto University Hospital. The following data were collected: the maternal variables, the IBD treatment type, the disease activity, the pregnancy outcome, and the mode of delivery. RESULTS Among the 19 patients, 18 had become pregnant after being diagnosed with IBD, while one had developed UC newly after pregnancy. Throughout the gestation, all patients were treated with probiotics, 5-ASA, prednisolone, cytapheresis, or infliximab. The relapse rate during pregnancy was 21.7% (5/23 cases). The five patients who experienced a relapse were able to pursue their pregnancy after intensification of their treatments. There were no adverse fetal or neonatal problems, except in one case that required an emergency Caesarean section because of placental dysfunction and in which a very low-birth-weight infant was born preterm. CONCLUSIONS Our present data confirmed that even if the disease flares up during pregnancy, good pregnancy outcomes can be achieved with an optimal intensification of the patient's treatment.
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Affiliation(s)
- Naoki Minami
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Yorimitsu Koshikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Satoshi Yamada
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Yusuke Honzawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Shuji Yamamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
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36
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Kirchgesner J, Lemaitre M, Rudnichi A, Racine A, Zureik M, Carbonnel F, Dray-Spira R. Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014. Aliment Pharmacol Ther 2017; 45:37-49. [PMID: 27781286 DOI: 10.1111/apt.13835] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 06/21/2016] [Accepted: 09/28/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Management of inflammatory bowel disease (IBD) has evolved in the last decade. AIM To assess IBD therapeutic management, including treatment withdrawal and early treatment use in the current era of anti-TNF agents (anti-TNFs). METHODS All patients affiliated to the French national health insurance diagnosed with IBD were included from 2009 to 2013 and followed up until 31 December 2014. Medication uses, treatment sequences after introduction of thiopurine or anti-TNF monotherapies or both (combination therapy), surgical procedures and hospitalisations were assessed. RESULTS A total of 210 001 patients were diagnosed with IBD [Crohn's disease (CD), 100 112; ulcerative colitis (UC), 109 889]. Five years after diagnosis, cumulative probabilities of anti-TNF monotherapy and combination therapy exposures were 33.8% and 18.3% in CD patients and 12.9% and 7.4% in UC patients, respectively. Among incident patients who received thiopurines or anti-TNFs, the first treatment was thiopurine in 69.1% of CD and 78.2% of UC patients. Among patients treated with anti-TNFs, 45.2% and 54.5% of CD patients and 38.2% and 39.9% of UC patients started monotherapy and combination therapy within 3 months after diagnosis, respectively; 31.3% of CD and 27.1% of UC incident patients withdrew from thiopurine or anti-TNFs for more than 3 months after their first course of treatment. Five years after diagnosis, the cumulative risks of first intestinal resection in CD patients and colectomy in UC patients were 11.9% and 5.7%, respectively. CONCLUSIONS Step-up approach remains the predominant strategy, while exposure to anti-TNFs is high. Surgery rates are low. Treatment withdrawal in IBD is more common than expected.
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Affiliation(s)
- J Kirchgesner
- Department of Epidemiology of Health Products, French National Agency for Medicines and Health Products Safety, Saint-Denis, France.,UMR-S 1136, INSERM & UPMC Univ Paris 06, Paris, France
| | - M Lemaitre
- Department of Epidemiology of Health Products, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
| | - A Rudnichi
- Department of Epidemiology of Health Products, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
| | - A Racine
- Université Paris-Sud, Assistance Publique-Hôpitaux de Paris and Gastroenterology Unit, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France
| | - M Zureik
- Department of Epidemiology of Health Products, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
| | - F Carbonnel
- Université Paris-Sud, Assistance Publique-Hôpitaux de Paris and Gastroenterology Unit, Hôpitaux Universitaires Paris Sud, Le Kremlin Bicêtre, France
| | - R Dray-Spira
- Department of Epidemiology of Health Products, French National Agency for Medicines and Health Products Safety, Saint-Denis, France
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37
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Experts Opinion on the Practical Use of Azathioprine and 6-Mercaptopurine in Inflammatory Bowel Disease. Inflamm Bowel Dis 2016; 22:2733-2747. [PMID: 27760078 DOI: 10.1097/mib.0000000000000923] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The relevance of azathioprine and 6-mercaptopurine therapy in inflammatory bowel disease, Crohn's disease, and ulcerative colitis, has been challenged in recent publications. In this article, a panel of experts gives advice, based on the relevant literature, on indications and practical use of azathioprine/6-mercaptopurine, prevention, and management of drug adverse reactions and special situations such as vaccination, pregnancy, and lactation.
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Lelli F, Nuhoho S, Lee XY, Xu W. Systematic review: treatment pattern and clinical effectiveness and safety of pharmaceutical therapies for Crohn's disease in Europe. Clin Exp Gastroenterol 2016; 9:311-323. [PMID: 27785086 PMCID: PMC5063598 DOI: 10.2147/ceg.s109696] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Although many clinical trials have been conducted in treatments of Crohn’s disease (CD), whether the trial results were representative of daily practice needs to be supported by studies conducted in real-world settings. Aim This study aims to identify how CD is treated and what are the clinical effectiveness and safety of the pharmaceutical therapies of CD in real-world settings. Methods A systematic literature review was conducted based on Medline®, Embase®, and Cochrane. All publications were assessed for title/abstract and full-text according to a predefined study protocol. Data were extracted and reported. Results A total of 1,998 publications were identified. Fifty studies including six publications reporting treatment pattern and 44 studies reporting clinical effectiveness and safety of pharmaceutical therapies in CD management in Europe were included. 5-Aminosalicylic acid and corticosteroids were reported to be used among 14%–74% of CD patients. Immunomodulators were used by 14%–25% and 29%–31% of CD patients as an initial and follow-up treatment, respectively. Biological therapies were used by 25%–33% of CD patients. A trend toward an increasing use of immunomodulators and biological therapies in Europe has been reported in recent years. Approximately 50% of patients achieved remission on immunomodulator or biologic treatment, although a relapse rate of up to 23% has been reported. Conclusion There is a trend of treatment shift to immunomodulators and biologics in CD management. Clinical effectiveness of immunomodulators and biologics has been demonstrated, though with a lack of sustainability of the effectiveness.
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Affiliation(s)
| | - Solomon Nuhoho
- Health Economics, Market Access and Reimbursement, Johnson & Johnson Middle East FZ LLC, Dubai, United Arab Emirates
| | | | - Weiwei Xu
- Pharmerit International, Rotterdam, the Netherlands
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Abstract
Therapeutic advances in the management of IBD have led to a paradigm shift in the assessment of IBD disease activity. Beyond clinical remission, objective assessment of inflammation is now critical to guiding subsequent therapy as part of a 'treat to target' strategy. Multiple domains of disease activity assessment in IBD exist, each of which has its merits, although none are perfect. The aim of this Review is to comprehensively evaluate measures of disease activity in both ulcerative colitis and Crohn's disease, including clinical, endoscopic, histological and radiological assessment tools, as well as the use of biomarkers and quality of life evaluation. A subjective appraisal of the best indices for use in clinical practice is provided, based on index validation, responsiveness and experience in clinical trials, international specialist opinion, and practicality and suitability for use in clinical practice. This Review aims to enable the reader to gain confidence in IBD disease activity assessment and to give ready access to the necessary tools.
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Basaranoglu M, Ertan A, Mathew S, Najjar SM, Ala A, Demirbag AE, Senturk H. Rate and Predictors of Endoscopic Mucosal Healing in Biologic Naive Patients with Inflammatory Bowel Disease by Azathioprine Treatment: A Real World, 10 Years' Experience from a Single Centre in Turkey. ACTA ACUST UNITED AC 2016; 6. [PMID: 29057149 DOI: 10.4172/2161-069x.1000467] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND There is increasing evidence that endoscopic mucosal healing (EMH) is a key target in inflammatory bowel disease (IBD) therapy. However, there is limited evidence of EMH rates with conventional IBD therapy outside of Western population groups. AİM To evaluate the role of azathioprine (AZA) in inducing EMH in IBD patients. METHODS Patients with inflammatory bowel disease were evaluated in terms of endoscopic mucosal healing and the incidence of surgical interventions during the azathioprine treatment between 1995 to 2014. RESULTS A total of 120 inflammatory bowel disease patients were enrolled. Endoscopic mucosal healing was found in 37% patients with inflammatory bowel disease (42% in chronic ulcerative colitis and 33% in Crohn's disease). Male gender had a negative impact on the efficacy of azathioprine (P<0.05). Responder inflammatory bowel disease patients were older (age at the IBD diagnose) than the nonresponder (P<0.05). Azathioprine therapy reduced the number of the surgical interventions (P<0.05). CONCLUSİON We showed that azathioprine therapy significantly induced endoscopic mucosal healing in biologic naïve patients with active inflammatory bowel disease as well as decreasing the surgical interventions, with negative predictive factors identified by a younger age at IBD presentation and male gender.
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Affiliation(s)
- Metin Basaranoglu
- Department of Internal Medicine, Gastroenterology Division, Bezmialem Vakif University Faculty Hospital, Fatih, 34000, Istanbul, Turkey.,Gastroenterology and Gastrointestinal Surgery Divisions, Türkiye Yüksek Ihtisas Hospital, Sihhiye, 06010, Ankara, Turkey
| | - Atilla Ertan
- Department of Internal Medicine, Gastroenterology Division, Ertan Digestive Center, The University of Texas Medical School, Houston, 6414, Texas, USA
| | - Sanju Mathew
- Department of Gastroenterology and Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, GU2 7XX, UK.,Faculty of Health Medical Sciences, Health Management University of Surrey Guildford, Surrey, GU2 7XH, UK
| | - Sonia Michael Najjar
- Associate Dean of Research and Innovation, Heritage College of Osteopathic Medicine Office of Research and Grants Irvine Hall, Room 220B, 1 Ohio University, USA
| | - Aftab Ala
- Department of Gastroenterology and Hepatology, Royal Surrey County Hospital NHS Foundation Trust, Guildford, Surrey, GU2 7XX, UK.,Faculty of Health Medical Sciences, Health Management University of Surrey Guildford, Surrey, GU2 7XH, UK
| | - Ali Eba Demirbag
- Gastroenterology and Gastrointestinal Surgery Divisions, Türkiye Yüksek Ihtisas Hospital, Sihhiye, 06010, Ankara, Turkey
| | - Hakan Senturk
- Department of Internal Medicine, Gastroenterology Division, Bezmialem Vakif University Faculty Hospital, Fatih, 34000, Istanbul, Turkey
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41
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Utility of surrogate markers for the prediction of relapses in inflammatory bowel diseases. J Gastroenterol 2016; 51:531-47. [PMID: 26975751 DOI: 10.1007/s00535-016-1191-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 02/21/2016] [Indexed: 02/04/2023]
Abstract
Patients with diagnosed inflammatory bowel disease (IBD) will commonly experience a clinical relapse in spite of a prolonged therapy-induced period of clinical remission. The current methods of assessing subclinical levels of low-grade inflammation which predispose patients to relapse are not optimal when considering both cost and patient comfort. Over the past few decades, much investigation has discovered that proteins such as calprotectin that are released from inflammatory cells are capable of indicating disease activity. Along with C-reactive protein and erythrocyte sedimentation rate, calprotectin has now become part of the current methodology for assessing IBD activity. More recently, research has identified that other fecal and serum biomarkers such as lactoferrin, S100A12, GM-CSF autoantibodies, α1-antitrypsin, eosinophil-derived proteins, and cytokine concentrations have variable degrees of utility in monitoring gastrointestinal tract inflammation. In order to provide direction toward novel methods of predicting relapse in IBD, we provide an up-to-date review of these biomarkers and their potential utility in the prediction of clinical relapse, given their observed activities during various stages of clinical remission.
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42
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Cintolo M, Costantino G, Pallio S, Fries W. Mucosal healing in inflammatory bowel disease: Maintain or de-escalate therapy. World J Gastrointest Pathophysiol 2016; 7:1-16. [PMID: 26909224 PMCID: PMC4753175 DOI: 10.4291/wjgp.v7.i1.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/16/2015] [Accepted: 12/07/2015] [Indexed: 02/06/2023] Open
Abstract
In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing (MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis (UC) and Crohn's disease (CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.
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43
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Xu L, Ma L, Lian J, Yang J, Chen S. Gene expression alterations in inflamed and unaffected colon mucosa from patients with mild inflammatory bowel disease. Mol Med Rep 2016; 13:2729-35. [PMID: 26861951 DOI: 10.3892/mmr.2016.4880] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 01/13/2016] [Indexed: 11/06/2022] Open
Abstract
An endoscopic examination is currently the most reliable method for monitoring disease activity in patients with inflammatory bowel disease (IBD). However, endoscopic evaluations are unable to detect mucosal inflammation at the earliest stages. The present study aimed to evaluate the molecular profiles of inflamed and unaffected colon mucosa from patients with mild Crohn's disease (CD) and ulcerative colitis (UC), in order to identify a more sensitive method for monitoring mucosal impairment. Patients were recruited and colon biopsies from the inflamed and the normal‑appearing mucosa of patients with mild IBD were obtained by colonoscopy. Gene expression analysis was performed using microarrays, after which Gene Ontology and clustering were performed using bioinformatics. In addition, the levels of inflammatory cytokines were analyzed by reverse transcription‑quantitative polymerase chain reaction. A total of 620 genes in the inflamed and 210 genes in the unaffected colon mucosa with at least a 3‑fold change, as compared with healthy controls, were detected in patients with mild CD, and 339 genes in the inflamed and 483 genes in the unaffected colon mucosa were detected in patients with mild UC. Heat mapping demonstrated a similarity in the gene alteration patterns, and altered transcripts overlapped, between the inflamed and unaffected colon mucosa. Interferon‑γ and interleukin‑17 mRNA levels were comparably elevated in the inflamed and unaffected colon mucosa from patients with IBD. Marked gene expression alterations were detected in the inflamed and unaffected colon mucosa from patients with mild IBD, and these showed marked similarity and overlap between the two groups. The results of the present study suggested that inflammation was not limited to the endoscopic lesions and that gene expression profiling may be considered a sensitive tool for monitoring mucosal inflammation, predicting relapses and optimizing therapeutic strategies for patients with IBD.
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Affiliation(s)
- Lili Xu
- Division of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Lili Ma
- Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jingjing Lian
- Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jiayin Yang
- Division of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Shiyao Chen
- Division of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
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44
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Torres J, Boyapati RK, Kennedy NA, Louis E, Colombel JF, Satsangi J. Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. Gastroenterology 2015; 149:1716-30. [PMID: 26381892 DOI: 10.1053/j.gastro.2015.08.055] [Citation(s) in RCA: 166] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/10/2015] [Accepted: 08/13/2015] [Indexed: 12/14/2022]
Abstract
Little is known about the optimal duration of therapy with an anti-tumor necrosis factor (TNF) agent and/or an immunomodulator for patients with inflammatory bowel disease (IBD). We performed a systematic search of the literature to identify studies reporting after de-escalation (drug cessation or dose reduction) of anti-TNF agents and/or immunomodulators in patients in remission from IBD. Studies were reviewed according to the type of IBD and drug. Rates of relapse, factors associated with relapse, and response to re-treatment were determined. Our search yielded 6315 unique citations; we analyzed findings from 69 studies (18 on de-escalation [drug cessation or dose reduction] of immunomodulator monotherapy, 8 on immunomodulator de-escalation from combination therapy, and 43 on de-escalation of anti-TNF agents, including 3 during pregnancy) comprising 4672 patients. Stopping immunomodulator monotherapy after a period of remission was associated with high rates of relapse in patients with Crohn's disease or ulcerative colitis (approximately 75% of patients experienced a relapse within 5 years after therapy was stopped). Most studies of patients with Crohn's disease who discontinued an immunomodulator after combination therapy found that rates of relapse did not differ from those of patients who continued taking the drug (55%-60% had disease relapse 24 months after they stopped taking the immunomodulator). The only study in patients with ulcerative colitis supported continued immunomodulator use. Approximately 50% of patients who discontinued anti-TNF agents after combination therapy maintained remission 24 months later, but the proportion in remission decreased with time. Markers of disease activity, poor prognostic factors, and complicated or relapsing disease course were associated with future relapse. In conclusion, based on a systematic review, 50% or more of patients with IBD who cease therapy have a disease relapse. Further studies are required to accurately identify subgroups of patients who are good candidates for discontinuation of treatment. The decision to withdraw a drug should be made for each individual based on patient preference, disease markers, consequences of relapse, safety, and cost.
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Affiliation(s)
- Joana Torres
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Ray K Boyapati
- Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland.
| | - Nicholas A Kennedy
- Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland
| | - Edouard Louis
- Department of Gastroenterology, University Hospital CHU of Liège, Liège, Belgium
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jack Satsangi
- Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland
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45
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Martínez-Montiel MP, Casis-Herce B, Gómez-Gómez GJ, Masedo-González A, Yela-San Bernardino C, Piedracoba C, Castellano-Tortajada G. Pharmacologic therapy for inflammatory bowel disease refractory to steroids. Clin Exp Gastroenterol 2015; 8:257-69. [PMID: 26316792 PMCID: PMC4544729 DOI: 10.2147/ceg.s58152] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Although corticosteroids are an effective treatment for induction of remission in inflammatory bowel disease (IBD), many patients are dependent on or refractory to corticosteroids. This review is based on scrutinizing current literature with emphasis on randomized controlled trials, meta-analyses, and Cochrane reviews on the management of IBD refractory to corticosteroids. Based on this evidence, we propose algorithms and optimization strategies for use of immunomodulator and biologic therapy in IBD refractory to corticosteroids.
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Affiliation(s)
| | - B Casis-Herce
- Division of Gastroenterology, Hospital 12 de Octubre, Madrid, Spain
| | - G J Gómez-Gómez
- Division of Gastroenterology, Hospital 12 de Octubre, Madrid, Spain
| | | | | | - C Piedracoba
- Division of Gastroenterology, Hospital 12 de Octubre, Madrid, Spain
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46
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Abstract
BACKGROUND The ideal length of treatment with thiopurines in patients with ulcerative colitis (UC) in sustained remission remains unknown. It is widely accepted that the drug withdrawal is associated with a worse outcome. The aim of this study was to analyze the outcome after this withdrawal and to identify predictors of relapse. METHODS A multicenter and retrospective study was designed. A total of 102 patients with UC who discontinued thiopurines in a situation of sustained remission were included. All the patients were followed up until last revision or until relapse (understood as the occurrence of signs and symptoms of UC that required a rescue treatment). RESULTS After thiopurines withdrawal, overall relapse was recorded in 32.35% of the patients: 18.88% in the first year, 36.48% in the third, and 43.04% in the fifth year after withdrawal. On multivariate analysis, predictors of relapse were the time from diagnosis of UC until the starting of thiopurines (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01-1.02; P = 0.039), the number of relapses before the withdrawal (HR, 1.3; 95% CI, 1.01-1.66; P = 0.029), pancolitis (HR, 5.01; 95% CI, 1.95-26.43; P = 0.028), the duration of treatment with thiopurines (HR, 0.15; 95% CI, 0.03-0.66; P = 0.013) and the situation of biological remission at withdrawal (HR, 0.004; 95% CI, 0.0001-0.14; P = 0.002). CONCLUSIONS The withdrawal of thiopurines in patients with UC, although in sustained remission, is related to a high relapse rate. Clinical variables such as the extent of the disease, the duration of treatment or time from diagnosis to the start of thiopurines should be considered before stopping these drugs.
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47
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Lee KM, Kim YS, Seo GS, Kim TO, Yang SK, IBD Study Group of the Korean Association for the Study of Intestinal Diseases. 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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48
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Goldberg R, Irving PM. Toxicity and response to thiopurines in patients with inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2015; 9:891-900. [PMID: 25915575 DOI: 10.1586/17474124.2015.1039987] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The use of thiopurines is well established in the management of inflammatory bowel disease. A wealth of data and experience, amassed over several decades, supporting their efficacy has recently been challenged by trials that failed to show a benefit in Crohn's disease when used early in the disease course, although other trials continue to support their role both as monotherapy and in combination with anti-TNF. Recent reports of previously unrecognized toxicity have also emerged. Fortunately, the absolute incidence of serious toxicity remains low, and an improved understanding of how best to minimize risk and the recognition of groups of patients at higher risk of toxicity from thiopurines means that they remain a relatively safe therapy in the majority of patients. In this paper, we review the literature evaluating the role of thiopurines in inflammatory bowel disease as well as their toxicity. We conclude that education regarding the spectrum of thiopurine side effects and optimal monitoring during therapy may help with optimizing safety and efficacy of these important medications.
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Affiliation(s)
- Rimma Goldberg
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
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49
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Goel RM, Blaker P, Mentzer A, Fong SCM, Marinaki AM, Sanderson JD. Optimizing the use of thiopurines in inflammatory bowel disease. Ther Adv Chronic Dis 2015; 6:138-46. [PMID: 25954498 PMCID: PMC4416969 DOI: 10.1177/2040622315579063] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Immunomodulator drugs, of which thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of thiopurine therapy are also discussed.
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Affiliation(s)
- Rishi M Goel
- Guy's & St Thomas' Hospitals - Gastroenterology, Westminster Bridge Road, London SE1 7EH, UK
| | - Paul Blaker
- Guy's & St Thomas' Hospitals - Gastroenterology, London, UK
| | - Alex Mentzer
- Guy's & St Thomas' Hospitals - Gastroenterology, London, UK
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50
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Tanida S, Ozeki K, Mizoshita T, Tsukamoto H, Katano T, Kataoka H, Kamiya T, Joh T. Managing refractory Crohn's disease: challenges and solutions. Clin Exp Gastroenterol 2015; 8:131-40. [PMID: 25914555 PMCID: PMC4401331 DOI: 10.2147/ceg.s61868] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The goals of treatment for active Crohn’s disease (CD) are to achieve clinical remission and improve quality of life. Conventional therapeutics for moderate-to-severe CD include 5-aminosalicylic acid, corticosteroids, purine analogs, azathioprine, and 6-mercaptopurine. Patients who fail to respond to conventional therapy are treated with tumor necrosis factor (TNF)-α inhibitors such as infliximab and adalimumab, but their efficacy is limited due to primary nonresponse or loss of response. It is suggested that this requires switch to another TNF-α inhibitor, a combination therapy with TNF-α blockade plus azathioprine, or granulocyte and monocyte adsorptive apheresis, and that other therapeutic options having different mechanisms of action, such as blockade of inflammatory cytokines or adhesion molecules, are needed. Natalizumab and vedolizumab are neutralizing antibodies directed against integrin α4 and α4β7, respectively. Ustekinumab is a neutralizing antibody directed against the receptors for interleukin-12 and interleukin-23. Here, we provide an overview of therapeutic treatments that are effective and currently available for CD patients, as well as some that likely will be available in the near future. We also discuss the advantages of managing patients with refractory CD using a combination of TNF-α inhibitors plus azathioprine or intensive monocyte adsorptive apheresis.
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Affiliation(s)
- Satoshi Tanida
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Keiji Ozeki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Tsutomu Mizoshita
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Hironobu Tsukamoto
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Takahito Katano
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Takeshi Kamiya
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
| | - Takashi Joh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan
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