Contents
Commentaries
Colon
565 The benefits of diagnostic ERCP in autoimmune pancreatitis
648 Flagellin administration protects gut mucosal tissue from irradiation-induced apoptosis via MKP-7 activity
M M Lerch, J Mayerle
Cover caption: Pancreatic acinar cell. Coloured transmission electron micrograph (TEM) of a slice through several enzyme-secreting acinar cells from a pancreas. The red circles are secretory granules packed with digestive enzymes ready for export to the small intestine. The four round blue and yellow structures are cell nuclei. Each cell is filled with a network of densely folded membrane, called rough endoplasmic reticulum, here coloured light yellow. The membrane’s surface is covered in small dots, called ribosomes. These are protein-manufacturing sites where various digestive enzymes are produced and secreted by the cell. Magnification 31200 at 634.5cm size. Cover credit: SCIENCE PHOTO LIBRARY.
Journal of the British Society of Gastroenterology Impact Factor: 9.35 Editor
Professor Emad El-Omar (UK) Deputy Editor (Hepatology)
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Ramon Bataller (Spain) Guy Boeckxstaens (Belguim) Laurence Egan (Ireland) Thomas Gress (Germany) Ernst Kuipers (The Netherlands) Julian Panes (Spain) Herbert Tilg (Austria) Fabien Zoulim (France) Editorial Office
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[email protected] ISSN: 0017-5749 (print) ISSN: 1468-3288 (online) Disclaimer: Gut is owned and published by BMJ Publishing Group Ltd, a wholly owned subsidiary of the British Medical Association and the British Society of Gastroenterology. The owners grant editorial freedom to the Editor of Gut. Gut follows guidelines on editorial independence produced by the World Association of Medical Editors and the code on good publication practice of the Committee on Publication Ethics. Gut is intended for medical professionals and is provided without warranty, express or implied. Statements in the Journal are the responsibility of their authors and advertisers and not authors’ institutions, the BMJ Publishing Group, the British Society of Gastroenterology or the BMA unless otherwise specified or determined by law. Acceptance of advertising does not imply endorsement. To the fullest extent permitted by law, the BMJ Publishing Group shall not be liable for any loss, injury or damage resulting from the use of Gut or any information in it whether based on contract, tort or otherwise. Readers are advised to verify any information they choose to rely on. Copyright Ó 2011 BMJ Publishing Group and British Society of Gastroenterology. All rights reserved; no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without prior permission Gut is published by BMJ Publishing Group Ltd, typeset by TNQ Books & Journals, Chennai, India and printed in the UK on acid-free paper from sustainable forests by Latimer Trend & Co Ltd, Plymouth, UK Gut (ISSN 0017-5749) is published monthly by BMJ Publishing Group and distributed in the USA by Mercury International Ltd. Periodicals postage paid at Rahway, NJ. POSTMASTER: send address changes to Gut, Mercury International Ltd, 365 Blair Road, Avenel, NJ, 07001, USA.
Volume 60 Issue 5 | GUT May 2011
567 Long-term proton pump inhibitor administration, H pylori and gastric cancer: lessons from the gerbil J G Fox, E J Kuipers
569 Breaking down haem attenuates acute pancreatitis: a new treatment option? J Mayerle, M Sendler, M M Lerch
Guidelines 571 Guidelines for the management of inflammatory bowel disease in adults C Mowat, A Cole, A Windsor, T Ahmad, I Arnott, R Driscoll, S Mitton, T Orchard, M Rutter, L Younge, C Lees, G-t Ho, J Satsangi, S Bloom, On behalf of the IBD Section of the British Society of Gastroenterology
Oesophagus 608 Roles of Kru¨ppel-like factor 4 in oesophageal epithelial cells in Barrett’s epithelium development H Kazumori, S Ishihara, Y Takahashi, Y Amano, Y Kinoshita
Upper GI cancer 618 Prospective study of serum cysteine levels and oesophageal and gastric cancers in China G Murphy, J-H Fan, S D Mark, S M Dawsey, J Selhub, J Wang, P R Taylor, Y-L Qiao, C C Abnet
Helicobacter pylori
R M Jones, V M Sloane, H Wu, L Luo, A Kumar, M V Kumar, A T Gewirtz, A S Neish
658 Accuracy of computed tomographic colonography in a nationwide multicentre trial, and its relation to radiologist expertise D Heresbach, M Djabbari, F Riou, C Marcus, A Le Sidaner, M A Pierredon-Foulogne, T Ponchon, M Boudiaf, J A Seyrig, H Laumonier, D Luet, M Giraud-Cohen, A L Pelletier, A Charachon, F Ramaholimihaso, P Bouillet, M Veyrac, S Ficarelli, K Vahedi, J Keruhel, H Lamouliatte, C Ridereau-Zins, Y Bouhnik, M Tissier, B Diris, A M Zagdanski, J M Josselin, S Hamonic, Y Gandon
Pancreas 666 Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study A Sugumar, M J Levy, T Kamisawa, G J M Webster, M-H Kim, F Enders, Z Amin, T H Baron, M H Chapman, N I Church, J E Clain, N Egawa, G J Johnson, K Okazaki, R K Pearson, S P Pereira, B T Petersen, S Read, R P Sah, N S Sandanayake, N Takahashi, M D Topazian, K Uchida, S S Vege, S T Chari
671 Panhematin provides a therapeutic benefit in experimental pancreatitis A Habtezion, R Kwan, E Akhtar, S P Wanaski, S D Collins, R J Wong, D K Stevenson, E C Butcher, M B Omary
624 Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori T Hagiwara, K-i Mukaisho, T Nakayama, H Sugihara, T Hattori MORE CONTENTS
95% of patients in Asia. Asian physicians therefore have a diagnostic test at hand to immediately confirm or refute their ERCP interpretation. In the present study 30% of patients were included without diagnostic IgG4 levels. Unfortunately, we do not learn from the paper how many of these were recruited before IgG4 became the marker of choice of type I AIP or whether they all represented type II (IDCP) cases. The current paradox is the following. The Japanese consensus guidelines have made ERCP a mandatory diagnostic 565
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Commentary
criterion although an alternative test (serum IgG4) would be diagnostic in the majority of Japanese patients.18 Conversely, the HISORt criteria from the Mayo Clinic,19 derived from experience with mostly Caucasian patients, do not include ERCP as a mandatory diagnostic test although Caucasian patients with AIP often present without diagnostic lab tests and are much more likely to profit from diagnostic ERCP because core biopsy is the only alternative test for confirming the diagnosis (short of obtaining resection specimens) in the prevalent type II AIP. Not surprisingly, a study with mostly Western patients relied for differentiation between cancer and AIP on a protocol that included ERCP20 whereas a Japanese study addressing the same issue made do without it.21 What remains to be addressed in future studies is how well the ERP criteria of Sugumar et al work specifically in type II autoimmune pancreatitis (IDCP) because this is the subgroup which potentially benefits the most from diagnostic ERCP and in which ERCP may prevent most of the unnecessary pancreatic resections. The studies also need to clarify whether concerns about post-ERCP pancreatitis in patients with suspected AIP are unfounded. The good news of the study is that nonAsian pancreas experts can greatly improve their skills in reading ERP-films if given an appropriate teaching module. Moreover, ER(C)P was confirmed as a powerful tool to diagnose AIP and to distinguish it from either chronic pancreatitis or pancreatic cancer. The study supports the Japanese consensus which strongly recommends ERCP for the diagnosis of AIP18 and argues against the Mayo view19 which does not make it a requirement. If the ductal changes reported here can be confirmed in their specificity for type II autoimmune pancreatitis, as well as the superiority of
566
ERCP over MRCP in detecting them, then AIP will side with primary sclerosing cholangitis as a condition in which diagnostic ERCP cannot yet be replaced by less invasive diagnostic test. Whether ERCP can serve in a similar role for monitoring treatment response in AIP will also have to be addressed in future trials. Funding The author’s own work is supported by the Alfried-Krupp-von-Bohlen-und-Hallbach-Foundation (Graduate Schools Tumour Biology and Free Radical Biology), the Deutsche Krebshilfe/ Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFG GRK840-E3/E4, MA 4115/1-2/3, NI 1297/1-1), the Federal Ministry of Education and Research (BMBF GANI-MED 03152061A and BMBF 0314107) and the European Union (EU-FP-7: EPC-TM and EU-FP7-REGPOT-2010-1).
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Competing interests None declared. Patient consent Obtained.
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Provenance and peer review Commissioned; externally peer reviewed. Published Online First 11 February 2011
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Sarles H, Sarles JC, Muratore R, et al. Chronic inflammatory sclerosis of the pancreas e an autonomous pancreatic disease? Am J Dig Dis 1961;1:688e98. Yoshida K, Toki F, Takeuchi T, et al. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci 1995;40:1561e8. Varadarajulu S, Cotton PB. Autoimmune pancreatitis: is it relevant in the west? Gastroenterology 2003;125:1557. Pickartz T, Mayerle J, Lerch MM. Autoimmune pancreatitis. Nat Clin Pract Gastroenterol Hepatol 2007;4:314e23. Keim V, Bauer N, Teich N, et al. Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. Am J Med 2001;111:622e6. Gress TM, Mu¨ller-Pillasch F, Lerch MM, et al. Balance of expression of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in chronic pancreatitis. Z Gastroenterol 1994;32:221e5. Moon SH, Kim MH, Park DH, et al. Is a 2-week steroid trial after initial negative investigation for
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malignancy useful in differentiating autoimmune pancreatitis from pancreatic cancer? A prospective outcome study. Gut 2008;57:1704e12. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732e8. Aparisi L, Farre A, Gomez-Cambronero L, et al. Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis. Gut 2005;54:703e9. Chari ST, Kloeppel G, Zhang L, et al; Autoimmune Pancreatitis International Cooperative Study Group (APICS). Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document. Pancreas 2010;39:549e54. Klo¨ppel G, Detlefsen S, Chari ST, et al. Autoimmune pancreatitis: the clinicopathological characteristics of the subtype with granulocytic epithelial lesions. J Gastroenterol 2010;45:787e93. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 2008;134:706e15. Menges M, Lerch MM, Zeitz M. The double duct sign in patients with malignant and benign pancreatic lesions. Gastrointest Endosc 2000;52:74e7. Frulloni L, Lunardi C, Simone R, et al. Identification of a novel antibody associated with autoimmune pancreatitis. N Engl J Med 2009;361:2135e42. Halangk W, Kru¨ger B, Ruthenbu¨rger M, et al. Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation. Am J Physiol Gastrointest Liver Physiol 2002;282:G367e74. Lo¨hr JM, Faissner R, Koczan D, et al. Autoantibodies against the exocrine pancreas in autoimmune pancreatitis: gene and protein expression profiling and immunoassays identify pancreatic enzymes as a major target of the inflammatory process. Am J Gastroenterol 2010;105:2060e71. Sugumar A, Levy MJ, Kamisawa T, et al. Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicenter study. Gut 2011;60:666e70. Kamisawa T, Okazaki K, Kawa S, et al. Japanese consensus guidelines for management of autoimmune pancreatitis: III. Treatment and prognosis of AIP. J Gastroenterol 2010;45:471e7. Chari ST. Diagnosis of autoimmune pancreatitis using its five cardinal features: introducing the Mayo Clinic’s HISORt criteria. J Gastroenterol 2007;42 (Suppl 18):39e41. Chari ST, Takahashi N, Levy MJ, et al. A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer. Clin Gastroenterol Hepatol 2009;7:1097e103. Kamisawa T, Imai M, Yui Chen P, et al. Strategy for differentiating autoimmune pancreatitis from pancreatic cancer. Pancreas 2008;37:e62e7.
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Long-term proton pump inhibitor administration, H pylori and gastric cancer: lessons from the gerbil James G Fox,1 Ernst J Kuipers2 The association between chronic active gastritis and pre-neoplastic conditions as well as invasive cancer of the stomach was established several decades ago. The risk of progression depended on the severity and distribution of gastritis, with cancer, in particular, occurring in subjects with pan-gastritis. Subsequently, Helicobacter pylori was recognised as the primary cause of chronic active gastritis, and it was demonstrated that the pattern of gastritis corresponded with the colonisation pattern of H pylori. We and others then showed both in animals and in humans that this pattern of colonisation and associated gastritis primarily depended on the level of acid output.1 2 Although this hypothesis was widely accepted, it led to intense debate when dealing with the safety of long-term treatment with profound acid suppressors. An elegant, long-awaited study from Japan published in this issue of Gut (see page 624) provides compelling evidence that the pattern of H pylori colonisation depends on acid output and that this influences the long-term progression to neoplasia.3 The current study was based on experiments in gerbils, one of the well-established animal models for the study gastric disease induced by Helicobacter spp.4 Gerbils, used sparingly for biomedical research, were first reported as a model for experimental H pylori infection in 1991.5 Interestingly, the gerbil has been shown to have particular relevant features that can be used to address whether H pylori can induce gastric cancer. Japanese investigators
1
Division of Comparative Medicine and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA; 2 Departments of Internal Medicine, and Gastroenterology & Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands Correspondence to Dr James G Fox, Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Bldg 16-825, Cambridge, MA 02139, USA;
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have noted intestinal metaplasia, atrophy and gastric ulcers in gerbils experimentally infected with H pylori.6 7 Following these findings, others noted that gerbils infected with H pylori from periods ranging from 15 to 18 months develop gastric adenocarcinoma.8 9 The gastric cancers were clearly documented histologically. Vascular invasion and metastases were not observed in either study. The histological progression of H pyloriassociated disease in the gerbil closely resembles that observed in humans, including the early appearance of intestinal metaplasia, well-differentiated histological patterns of gastric malignancy, and antral location of the gastric cancers. The development of cancer in the gerbil is also preceded by invagination of atypical glands (cystica profunda) into the submucosa. The association with gastric ulcers in this model continues to be of interest, given clinical studies in human patients indicating a link between gastric ulcer disease and gastric cancer.10 Although most of the tumours in the H pylori gerbil model originate in the pyloric region of the stomach, significant changes in the oxyntic mucosa consistent with chronic atrophic gastritis are also observed. Glandular tissues in the gastric body and fundus are replaced by atrophy and hyperplastic epithelium of the pseudopyloric type. A similar type of gastric atrophy (loss of oxyntic glands and neck cell hyperplasia) has also been reported in Helicobacter felis or H pylori-infected C57BL mice.11 12 The gerbil appears to be uniquely susceptible to H pylori-induced gastric neoplasia, and further characterisation of the gerbil model has provided important clues on gastric cancer progression and hostebacteria interaction. The unusual susceptibility of this animal species to gastric cancer using fairly standard H pylori strains underscores once again the over-riding importance of host factors in determining the outcome from gastric
Helicobacter spp. infection.13 Further, a possible role for altered gastrin physiology in the pathogenesis of gastric cancer has been raised by several recent studies. In Mongolian gerbils, H pylori leads to marked elevation of serum gastrin levels which coincide temporally with increases in gastric mucosal proliferation rates.14 This is consistent with experiments in inbred (FVB/N) mice that were rendered moderately hypergastrinaemic through an insulinegastrin (INS-GAS) transgene. In this model there is increased mucosal proliferation and progressive atrophy, and gastric carcinomas develop in 20-monthold INS/GAS mice.15 Infection of these hypergastrinaemic mice with H felis and H pylori accelerates tumorigenesis, with the majority (85%) of infected male mice developing gastric cancer within 8 months after colonisation. We recently reported that this chronic, progressive process is enhanced by co-colonisation with enteric flora.16 Using this well-described and reproducible gerbil model, Japanese investigators have conducted a very important study, examining the potential effect of proton pump inhibitor (PPI) therapy on progression of H pylori-associated disease.3 The male gerbils were divided into four groups: H pylori (ATCC43504) positives and negatives, with and without administration of a PPI (omeprazole 100 mg/kg body weight/day). At the end point of the 6-month experiment, the authors provided detailed analysis of gastric pathology including morphometric severity of parietal cell loss. The authors made a concerted effort to address confusion in the literature with respect to what constitutes a ‘gastric adenocarcinoma’ in a Mongolian gerbil model and how to differentiate an ‘invasive carcinoma’ from ‘heterotopic glands’ that are frequently encountered in these models during the early course of the disease. The ability to differentiate glandular herniation into the submucosa from the true invasion is an important consideration in evaluating rodent models of gastric cancer induced by Helicobacter spp. Indeed with these histopathological criteria in mind the results were remarkable and provide considerable support for previously published literature in humans. H pylori-negative male gerbils did not develop gastritis, metaplasia, or cancer irrespective of PPI treatment. H pylori-positive gerbils all developed gastritis, and most also developed metaplasia during the later stages of disease. Treatment with omeprazole in H pyloripositive animals accelerated progression to atrophy and enhanced hypergastrinaemia, 567
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resulting in a significantly increased incidence of gastric cancer.3 The authors emphasise that hypergastrinaemia might be promoting the development of H pylori gastric cancer. Given gender susceptibility to H pylori-associated gastric cancer in humans and rodent models, additional studies using H pylori female gerbils on chronic PPI therapy should provide additional interesting insights. Overall, the findings in the current paper support previous findings by us and others showing the increased risk of gastric atrophy in H pylori-infected patients on PPI therapy.2 17e19 In humans, it remains to be shown whether chronic PPI therapy in H pylori-infected individuals also increases the further progression to metaplasia, dysplasia and neoplasia. These studies will require longer-term follow-up of this subset of patients. In the meantime, the current findings in this paper support the argument regarding the importance of considering H pylori eradication in patients on long-term PPI treatment to cure gastritis, lower gastrin levels, and prevent progression to atrophy, dysplasia and gastric cancer. This recommendation is consistent with European guidelines on H pylori treatment in humans.20 Competing interests None. Provenance and peer review Commissioned; not externally peer reviewed.
Published Online First 17 February 2011
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Danon SJ, O’Rourke JL, Moss ND, et al. The importance of local acid production in the distribution of Helicobacter felis in the mouse stomach. Gastroenterology 1995;108:1386e95. Kuipers EJ, Uyterlinde AM, Pena AS, et al. Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapy: implications for long-term safety. Am J Gastroenterol 1995;90:1401e6. Hagiwara T, Mukaisho K, Nakayama T, et al. Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori. Gut 2011;60:624e30. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest 2007;117:60e9. Yokota K, Kurebayashi Y, Takayama Y, et al. Colonization of Helicobacter pylori in the gastric mucosa of Mongolian gerbils. Microbiol Immunol 1991;35:475e80. Hirayama F, Takagi S, Kusuhara H, et al. Induction of gastric ulcer and intestinal metaplasia in mongolian gerbils infected with Helicobacter pylori. J Gastroenterol 1996;31:755e7. Honda S, Fujioka T, Tokieda M, et al. Gastric ulcer, atrophic gastritis, and intestinal metaplasia caused by Helicobacter pylori infection in Mongolian gerbils. Scand J Gastroenterol 1998;33:454e60. Honda S, Fujioka T, Tokieda M, et al. Development of Helicobacter pylori-induced gastric carcinoma in Mongolian gerbils. Cancer Res 1998;58:4255e9. Watanabe T, Tada M, Nagai H, et al. Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology 1998;115:642e8.
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Hansson LE, Nyren O, Hsing AW, et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N Engl J Med 1996;335:242e9. Wang TC, Goldenring JR, Dangler C, et al. Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection. Gastroenterology 1998;114:675e89. Fox JG, Dangler CA, Taylor NS, et al. High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res 1999;59:4823e8. Wang TC, Fox JG. Helicobacter pylori and gastric cancer: Koch’s postulates fulfilled? Gastroenterology 1998;115:780e3. Peek RM Jr, Wirth HP, Moss SF, et al. Helicobacter pylori alters gastric epithelial cell cycle events and gastrin secretion in Mongolian gerbils. Gastroenterology 2000;118:48e59. Wang TC, Dangler CA, Chen D, et al. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 2000;118:36e47. Lofgren JL, Whary MT, Ge Z, et al. Lack of commensal flora in Helicobacter pylori-infected INSGAS mice reduces gastritis and delays intraepithelial neoplasia. Gastroenterology 2011;140:210e20. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996;334:1018e22. Lundell L, Havu N, Miettinen P, et al. Changes of gastric mucosal architecture during long-term omeprazole therapy: results of a randomized clinical trial. Aliment Pharmacol Ther 2006;23:639e47. Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006;55:1217e21. Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III consensus report. Gut 2007;56:772e81.
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Breaking down haem attenuates acute pancreatitis: a new treatment option? Julia Mayerle, Matthias Sendler, Markus M Lerch The premature intracellular activation of digestive proteases can result in autodigestion of the pancreas and has long been regarded as the initial and a rate-limiting step in the development of acute pancreatitis.1 Recent evidence suggests, however, that inflammatory cells infiltrating the pancreasdrather than the extent of initial protease activationddetermines the ultimate severity of acute pancreatitis.2 3 All attempts to target the inflammatory response of acute pancreatitis therapeutically have unfortunately been unsuccessful. One reason for this failure may lie in the type of inflammatory cells that were targeted.4 Macrophages orchestrate both the initiation and the resolution of inflammation and would therefore be an interesting therapeutic target for modulating the inflammatory response in acute pancreatitis. Selective depletion of the proinflammatory M1 macrophages has been found to reduce the severity in acute pancreatitis.5 Nature has provided a potent protective strategy to counter an overwhelming inflammatory response. Haemoxygenase-1 (HO-1) is an inducible isoform of the initial and rate-controlling enzyme used in the degradation of haem into iron, carbon monoxide and biliverdin. The latter is subsequently converted to bilirubin.6 HO-1 is expressed in various inflammatory cells including macrophages and has recently gained considerable attention for exerting anti-inflammatory, anti-apoptotic, angiogenic and cytoprotective actions. Haem that is either released from resolved erythrocytes or therapeutically applied as haemin (or in its water soluble form panhaematin) induces HO-1 expression in inflammatory cells. HO-1 will, in turn, break down the haem and trigger different cellular events: (1) the haem breakdown product carbon monoxide is a potent Department of Medicine A, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany Correspondence to Dr Julia Mayerle, Department of Medicine A, Ernst-Moritz-Arndt-University, Greifswald, Friedrich-Loeffler-Str 23a, Greifswald 17475, Germany;
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vasodilator and can resolve the microcirculatory disturbances associated with acute pancreatitis and promote angiogenesis during the recovery from necrosis. It will also mediate anti-apoptotic effects via the activation of the PERK-Nrf2-HO-1 axis and PERK-eIF2a-ATF4 pathways resulting in the downregulation of CHOP (DNA damage-inducible transcript 3); (2) haem is also broken down into bilirubin which can act as a potent antioxidant; and (3) during haem degradation, iron is released which is then sequestered into the acute phase protein ferritin.7 HO-1 is induced in macrophages as early as 2 h after intraperitoneal or intravenous haemin or panhaematin treatment. Macrophages then home to the inflamed pancreas and start the resolution phase of pancreatitis. Macrophages with induced HO-1 activity respond to lipopolysaccharide (LPS) stimulation with decreased secretion of proinflammatory cytokines interleukin (IL)-6, tumour necrosis factor a, IL-1b and macrophage inflammatory protein 1b but increased IL-10 secretion. The latter results in an autoregulatory loop in which IL-10 again induces HO-1 and can thereby protect mice from LPS-induced septic shock.6 IL-10-mediated HO-1 activity may also add to the beneficial role of IL-10 treatment in acute pancreatitis.8 In this manner, HO-1 contributes to the shift from M1 (proinflammatory) to M2 (anti-inflammatory, profibrogenic) macrophages.9 HO-1 upregulation reduces the rolling, sticking and transmigration of inflammatory cells from the vascular compartment.6 This immunoregulatory role of HO-1 has already been implicated in a variety of diseases ranging from type 1 diabetes and allergic asthma to different infectious diseases such as malaria, listeria, salmonella and pneumococcal infections. Ischaemiareperfusion damage and acute or chronic rejection after organ transplantation are also affected by HO-1 activity.6 In 2005 Omary et al showed that prophylactic haemin treatment reduces the mortality in choline-deficient-dietinduced (CDD) pancreatitis in mice from 45% to 0%.10 HO-1 upregulation in
macrophages occurred as early as 2 h after haemin treatment and was shown to be responsible for the beneficial treatment effect. Translation to the human situation was accomplished late last year when the same group demonstrated that HO-1 is upregulated in peripheral blood mononuclear cells during the course of pancreatitis and that monocytes from patients with acute pancreatitis are primed for HO-1 induction by panhaematin treatment.11 The final evidence for a beneficial action of panhaematin in the treatment of experimental pancreatitis is reported in this issue of Gut (see page 671).12 In this study, Habtezion and co-workers used two different models of acute pancreatitis (CDD, L-arginine) and treated animals with panhaematin up to 24 h after disease onset. In this late treatment window of pancreatitis, which corresponds to a frequent clinical situation, the authors achieved a significant reduction in mortality. They excluded a direct effect of panhaematin or of macrophages with upregulated HO-1 on pancreatic acinar cells and concluded that the beneficial effect is the result of reduced infiltration of inflammatory cells. This was supported by the results of CD45 staining of the pancreas and reduced levels of the neutrophil chemoattractant CXCL1. What remained unresolved in this is study is whether the antioxidant effect of bilirubin13 or a vascular effect of carbon monoxide also added to the beneficial effect of panhaematin treatment. Antioxidant treatment has been suggested to prevent organ failure in severe acute pancreatitis,14 but clinical trials have reported conflicting results.15 16 The therapeutic potential of antioxidants in clinical acute pancreatitis has therefore remained an open question. Regardless of the underlying mechanism by which the upregulation of HO-1 in macrophages or the therapeutic application of panhaematin exert a beneficial effect on the course of two animal models of severe pancreatitis, Habtezion and co-workers have established haem as a novel treatment option for pancreatitis. Haem, or its soluble pharmaceutical equivalent panhaematin or haemin, is already an FDA approved agent for the treatment of acute intermittent porphyria. Prospective clinical trials for pancreatitis are therefore a realistic possibility in the near future. Whether the presently substantial treatment costs of haemin or its nephrotoxicity will limit the enthusiasm for introducing this interesting pathophysiological discovery 569
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of Habtezion and co-workers into clinical practice will remain to be seen. Funding The authors’ own work is supported by the Alfried-Krupp-von-Bohlen-und-Hahlbach-Foundation (Graduate Schools Tumour Biology and Free Radical Biology), the Deutsche Krebshilfe/ Dr. Mildred-Scheel-Stiftung (109102), the Deutsche Forschungsgemeinschaft (DFG GRK840-E3/E4, MA 4115/1-2/3, NI 1297/1-1), the Federal Ministry of Education and Research (BMBF GANI-MED 03152061A and BMBF 0314107) and the European Union (EU-FP-7: EPC-TM and EU-FP7-REGPOT-2010-1).
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Competing interests None. Provenance and peer review Commissioned; externally peer reviewed. Published Online First 11 February 2011
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Halangk W, Kruger B, Ruthenburger M, et al. Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation. Am J Physiol Gastrointest Liver Physiol 2002;282:G367e74. Mayerle J, Schnekenburger J, Kruger B, et al. Extracellular cleavage of E-cadherin by leukocyte elastase during acute experimental pancreatitis in rats. Gastroenterology 2005;129:1251e67. Sendler MDA, Weiss FU, Brandt-Nedelev B, et al. Tissue damage and protease activation in acute pancreatitis via TNF alpha secretion. Pancreas 2009;38:1045. Blancou P, Tardif V, Simon T, et al. Immunoregulatory properties of heme oxygenase-1. Methods Mol Biol 2011;677:247e68. Kim HP, Pae HO, Back SH, et al. Heme oxygenase-1 comes back to endoplasmic reticulum. Biochem Biophys Res Commun 2011;404:1e5. Deviere J, Le Moine O, Van Laethem JL, et al. Interleukin 10 reduces the incidence of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography. Gastroenterology 2001;120:498e505. Shrivastava P, Bhatia M. Essential role of monocytes and macrophages in the progression of acute pancreatitis. World J Gastroenterol 2010;16:3995e4002. Nakamichi I, Habtezion A, Zhong B, et al. Hemin-activated macrophages home to the pancreas
11.
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and protect from acute pancreatitis via heme oxygenase-1 induction. J Clin Invest 2005;115:3007e14. Habtezion A, Kwan R, Yang AL, et al. Heme oxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: a potential therapeutic target. Am J Physiol Gastrointest Liver Physiol 2011;300:G12e20. Habtezion A, Kwan R, Akhtar E, et al. Panhematin provides a therapeutic benefit in experimental pancreatitis. Gut 2011;60:671e79. MacLean PD, Drake EC, Ross L, et al. Bilirubin as an antioxidant in micelles and lipid bilayers: its contribution to the total antioxidant capacity of human blood plasma. Free Radic Biol Med 2007;43:600e9. Johnson CD. Antioxidants in acute pancreatitis. Gut 2007;56:1344e5. Sateesh J, Bhardwaj P, Singh N, et al. Effect of antioxidant therapy on hospital stay and complications in patients with early acute pancreatitis: a randomised controlled trial. Trop Gastroenterol 2009;30:201e6. Siriwardena AK, Mason JM, Balachandra S, et al. Randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in severe acute pancreatitis. Gut 2007;56:1439e44.
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Gut May 2011 Vol 60 No 5
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Guidelines
Guidelines for the management of inflammatory bowel disease in adults Craig Mowat,1 Andrew Cole,2 Al Windsor,3 Tariq Ahmad,4 Ian Arnott,5 Richard Driscoll,6 Sally Mitton,7 Tim Orchard,8 Matt Rutter,9 Lisa Younge,10 Charlie Lees,5 Gwo-tzer Ho,5 Jack Satsangi,5 Stuart Bloom,11 on behalf of the IBD Section of the British Society of Gastroenterology 1
Gastrointestinal Unit, Ninewells Hospital, Dundee, UK 2 Derby Digestive Disease Centre, Royal Derby Hospital, Derby, UK 3 Department of Surgery, University College London Hospitals, UK 4 Department of Gastroenterology, Royal Devon & Exeter Hospital, UK 5 Gastrointestinal Unit, Western General Hospital, Edinburgh, UK 6 Crohn’s and Colitis UK (NACC), St. Albans, UK 7 Department of Paediatrics, St George’s Hospital, London, UK 8 Department of Gastroenterology, St. Mary’s Hospital, London, UK 9 Department Gastroenterology, University Hospital of North Tees, UK 10 Endoscopy Unit, Royal London Hospital, UK 11 Department of Gastroenterology, University College London Hospitals, UK Correspondence to Dr Craig Mowat, Gastrointestinal Unit, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK;
[email protected] Revised 22 November 2010 Accepted 7 December 2010
ABSTRACT The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: < The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. < The publication of ‘Quality Care: service standards for the healthcare of people with IBD’ in 2009. < The introduction of the Montreal classification for Crohn’s disease and ulcerative colitis. < The revision of recommendations for the use of immunosuppressive therapy. < The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohn’s disease and ulcerative colitis. < The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. < The availablity of new data on the role of reconstructive surgery in ulcerative colitis. < The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. < Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohn’s and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).
1.0 INTRODUCTION These guidelines have been commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) for clinicians and allied professionals caring for patients Gut 2011;60:571e607. doi:10.1136/gut.2010.224154
with inflammatory bowel disease in the United Kingdom. The authors of these guidelines were members of the BSG IBD Committee at the time. This committee is elected by fellow members of the IBD section of the Society. They replace the guidelines published in 2004 by Carter et al.1 They have been written with close reference to the recent European evidence-based consensus documents on Crohn’s disease2e4 and ulcerative colitis5e7 produced by the European Crohn’s and Colitis Organisation (ECCO) (https://www.ecco-ibd.eu/ index.php (accessed Oct 2010)). Although these consensus documents provide a comprehensive and authoritative review of the evidence base underlying definitions, diagnosis and current management we believe there are still compelling reasons to issue a set of up-to-date guidelines for UK practice: 1. These diseases are complex and recent UK-wide audits have demonstrated wide variation in clinical practice.8 9 2. There may be important differences between guidelines and consensus. Clinical practice guidelines are ‘systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances’. Their specific purpose is to make explicit recommendations with an intent to influence what clinicans do.10 Recommendations for practice with particular reference to one country may not always be identical to consensus statements (eg, use of maintenance anti-tumour necrosis factor (TNF) antibodies in Crohn’s disease). 3. The recent publication of a set of UK Service Standards for the healthcare of people who have IBD is very relevant to guidelines for UK practice. http://www.ibdstandards.org.uk (accessed Oct 2010).11 4. UK practice is influenced by guidance from the National Institute for Clinical Excellence (NICE) http://www.nice.org.uk/ (accessed Oct 2010). 5. In some areas, the approach of UK physicians differs from the European consensus, and indeed from North American practice, and the present document provides an appropriate and necessary addition to the current literature. This is particular necessary at the present time, when new therapies are being introduced in IBD, and previously accepted management paradigms are being extensively revised. 6. Publication of these guidelines will be supported by the establishment of a discussion forum on the 571
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Guidelines BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010).
1.1 Guideline development The guidelines were drafted shortly after the ECCO consensus was published in the knowledge of the extremely rigorous nature and literature review accompanying that process; throughout the current document, reference is made to the ECCO consensus statements. Each author responsible for drafting sections carried out a further literature review and the draft and accompanying evidence base was extensively discussed in committee. The ECCO recommendations were formally compared to the 2004 BSG guidance at the outset, in order to identify areas of disparity in opinion and content. The important issue of assessing guideline quality has been addressed by use of the AGREE tool (see section 1.2). We feel readers will want to assess the recommendations as they would for other guidelines, including a judgement based on accompanying levels of evidence, which are included throughout the text. A preliminary document was drafted by contributing authors (coordinated by CM). Recommendations were submitted by contributing authors and voted on before being incorporated into the guidelines. Draft guidelines were submitted for review by the BSG Clinical Services and Standards Committee before being submitted for further review by BSG council members and simultaneously by external reviewers chosen by the editor of Gut. The format of the first edition of the guidelines has largely been retained with modifications to emphasise aspects of service delivery and patient expectations relevant to UK practice. Sections have been added on UK standards of care and principles of nutrition. Drug therapies have been given a separate section rather than being included in disease management and guidelines have been extensively re-written to take account of developments in use of immunosuppressive and biological treatments.
1.2 Assessing the quality of guidelines: The AGREE instrument There have been attempts to develop external validation for clinical practice guidelines; the best characterised of these is the AGREE instrument developed by the AGREE collaboration (http://www.agreecollaboration.org/intro/ (accessed Oct 2010)). The audit department of the Royal College of Physicians has adopted this tool. It identifies six criteria of quality which are addressed here.
1. Scope and purpose The guidelines are intended for use by clinicians and other healthcare professionals in managing patients with ulcerative colitis and Crohn’s disease in the light of recent guidance published by NICE and the development of the IBD standards of care. They are primarily aimed at management of adult patients: there are separate guidelines published for the care of children with IBD (http://bspghan.org.uk/IBDGuidelines (accessed Oct 2010)). They contain reference to specific issues relating to management of adolescents with IBD.
2. Guideline development group membership and stakeholder involvement Membership of the group is detailed at the end of the document: it includes medical and surgical gastroenterologists, IBD specialist nurses, members of the British Dietetic Association, 572
and patient representative groups. The section on imaging has been approved by the British Society of Gastrointestinal and Abdominal Radiology committee.
3. Rigour of development The published literature has been searched using Pubmed, Medline and the Cochrane database. The guidelines rely considerably on consensus statements published by the European Crohn’s and Colitis Organisation (ECCO).2e7 In order to harmonise management guidelines with the ECCO consensus statements, we have adopted a similar style of graded recommendations (graded AeD), determined by the level of supporting evidence (graded level 1e5) as described by the Oxford Centre For Evidence Based Medicine (table 1). Areas of disagreement about the recommendation grade were subjected to discussion and if necessary voting by members of the guidelines group. Where possible, the health benefits, side effects and risks of recommendations have been discussed. The guidelines have been peer reviewed according to the editorial policy of Gut.
4. Clarity and presentation Recommendations are intended to be specific to particular situations and patient groups; where necessary, different options are listed. Key recommendations are linked to discussion threads on a discussion forum hosted on the BSG website.
5. Applicability Where necessary, we have discussed organisational changes that may be needed in order to apply recommendations. We have attempted to identify key criteria for monitoring and audit purposes.
6. Editorial independence and conflict of interest Guideline group members have declared any conflicts of interest.
1.3 Scheduled review of guidelines The content and evidence base for these guidelines should be revised within 4 years of publication, to take account of new evidence. We anticipate the guidelines will continue to evolve through evidence gathered by regular national audit of IBD standards and services. Guidelines, by their nature, will become outdated as new evidence is published. With this in mind (and also to provide user feedback) links to the BSG discussion forum relating to specific sections of these guidelines are included in this document. These forums are accessible to any member of the BSG who are encouraged to contribute citing the appropriate new evidence. In line with the agree tool the BSG forum will also provide some user feedback on the guidelines. The links will be at http://www.bsg.org.uk/forum/ and the links for specific sections are also imbedded within this document.
2.0 SERVICE DELIVERY 2.1 Impact of inflammatory bowel disease on patients and society With a reported prevalence of 400 per 100 00012 there are approximately 240 000 patients with IBD in the UK (ulcerative colitis: 243/100 000¼146 000 people in UK population of 60 million; Crohn’s disease: 145/100 000¼87 000 people in UK). The incidence of Crohn’s disease in the UK increased markedly between the 1950s and the 1980s.13 14 Since the 1980s the incidence of Crohn’s disease has continued to increase in the UK at a rather slower rate.15 16 Most patients are referred to hospital clinics for evaluation, and approximately 30% of patients are under regular hospital follow-up.12 About 2000 people undergo colectomy for IBD each Gut 2011;60:571e607. doi:10.1136/gut.2010.224154
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Guidelines Table 1 Evidence levels (EL) and recommendation grades (RG) (adapted from the Oxford Centre for Evidence Based Medicine, http://www.cebm.net/index.aspx?o¼1025 (accessed Oct 2010)) EL
Individual study
Technique
1a 1b 1c
Systematic review (SR) with homogeneity of level 1 diagnostic studies Validating cohort studies with good reference standards Specificity is so high that a positive result rules in the diagnosis (SpPIn) or sensitivity is so high that a negative result rules out the diagnosis (SnNout) SR with homogeneity of >level 2 diagnostic studies Exploratory cohort study with good reference standards
Systematic review (SR) with homogeneity of randomised controlled trials (RCTs) Individual RCT (with narrow CI) All or none
2a 2b 2c 3a 3b 4 5 RG A B C D
SR with homogeneity of 3b and better studies Non-consecutive study; or without consistently applied reference standards Caseecontrol study, poor or non-independent reference standard Expert opinion without explicit critical appraisal, or based on physiology, ’bench research’ or ’first principles’ GRADES OF EVIDENCE Consistent level 1 studies Consistent level 2 or 3 studies or extrapolation from level 1 studies Level 4 studies or extrapolation from level 2 or 3 studies Level 5 evidence or troublingly inconsistent or inconclusive studies of any level
year. The lifetime risk for surgery may be as high as 70e80% for Crohn’s disease and 20e30% for ulcerative colitis, depending on disease severity and location.17e21 Costs of caring for patients with IBD in UK hospitals have recently been assessed.22 Lifetime costs for IBD are comparable to a number of major diseases, including heart disease and cancer. This implies a substantial burden of disease and disability that is mirrored by the large amount of academic and commercial activity currently being expended to develop better treatments. Patients find symptoms of ulcerative colitis or Crohn’s disease embarrassing and humiliating. IBD can result in loss of education and difficulty in gaining employment or insurance. It can cause psychological problems and growth failure or retarded sexual development in young people. Medical treatments (steroids, immunosuppressants) can cause secondary health problems, and surgery may result in complications such as impotence or intestinal failure. The impact of IBD on society is disproportionately high as presentation often occurs at a young age and has the potential to cause lifelong ill health.
2.2 UK IBD service standards Historically, practice guidelines have focused on evidence-based therapeutics. This addresses only one aspect of care. Since the 2004 BSG guidelines were published, two significant steps have been taken to address the quality of care provided to patients with IBD in the UK. First, The UK IBD National Audit programme was developed in partnership by the British Society of Gastroenterology, the Association of Coloproctology of Great Britain and Ireland, the National Association for Colitis and Crohn’s Disease (NACC) and the Clinical Effectiveness Unit at the Royal College of Physicians, (http://www.rcplondon.ac.uk/resources/ inflammatory-bowel-disease-audit (accessed Feb 2011)). The inaugural audit was performed in 2006. It assessed the structure; organisation, processes and outcomes of care for patients with IBD admitted to UK hospitals and found a wide variation in all aspects across the country. The second round audit in 2008 has demonstrated an improvement in many aspects of basic care such as the provision of specialist wards, availability of IBD nurses, the prescription of prophylactic heparin and the collection of stool specimens for culture Clostridium difficile toxin. However, there remains wide variation, with some key deficits in fundamental aspects of IBD care. Gut 2011;60:571e607. doi:10.1136/gut.2010.224154
SR (with homogeneity) of cohort studies Individual cohort study (including low quality RCT; eg, 40 years (A3)
Colonic (L2) Ileo-colonic (L3) *Isolated upper GI disease (L4)
Non-stricturing, Non-penetrating (B1) Stricturing (B2) Penetrating (B3) + ‘p’ if peri-anal disease
*L4 is a modifier that can be added to L1 e 3 when concomitant upper gastrointestinal (GI) disease is present.
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Guidelines which attempts to more accurately characterise the clinical patterns of IBD.23 24 Ulcerative colitis is characterised by diffuse mucosal inflammation limited to the colon. It is classified according to the maximal extent of inflammation observed at colonoscopy because this is most clearly related to the risk of complications, including dilatation and cancer. The implications of limited macroscopic disease with extensive microscopic inflammation remain unclear. Crohn’s disease is characterised by patchy, transmural inflammation, which may affect any part of the gastrointestinal tract. It may be defined by: age of onset, location, or behaviour. About 5% of patients with IBD affecting the colon are unclassifiable after considering clinical, radiological, endoscopic and pathological criteria, because they have some features of both conditions. This is now termed as ‘IBD, type unclassified (IBDU)’. The term ‘indeterminate colitis (IC)’ should be reserved for cases where colectomy has been performed and the pathologist remains unable to classify the disease after a full examination.23 If all patients are characterised in this standard fashion, this should facilitate data collection for an IBD registry and clinical research.
3.2 Clinical features and course of disease17e19 Ulcerative colitis
21 25e27
The cardinal symptom of ulcerative colitis is bloody diarrhoea. Associated symptoms of colicky abdominal pain, urgency, or tenesmus may be present. It is a severe disease that used to carry a high mortality and major morbidity. With modern medical and surgical management, the disease now has a slight excess of mortality in the first 2 years after diagnosis, but little subsequent difference from the normal population. However, severe colitis is still a potentially life-threatening illness. The clinical course is marked by exacerbation and remission. About 50% of patients have a relapse in any year. An appreciable minority has frequently relapsing or chronic, continuous disease and overall, 20e30% of patients with pancolitis come to colectomy. After the first year approximately 90% of patients are fully capable of work (defined by 3 g/day. Clinical improvement characteristically occurs at twice the remission rate. In a meta-analysis of oral 5-ASA for active ulcerative colitis, of 19 trials involving 2032 patients, nine were placebo controlled and 10 compared mesalazine with sulfasalazine. The outcome of interest on an intention-to-treat principle was the failure to induce remission, so that a pooled OR 2 g/day has a modest effect in reducing relapse after surgery (NNT 10e12), especially after Gut 2011;60:571e607. doi:10.1136/gut.2010.224154
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Guidelines small bowel resection (40% reduction at 18 months). However the cost of therapy and the pill burden for patients are such that it should probably be reserved for specific patientsdnormally those with small-bowel disease, and only after more effective measures such as smoking cessation have been instituted.84
Adverse effects of 5-ASA103e105 Side effects of sulfasalazine occur in 10e45% of patients, depending on the dose. Headache, nausea, epigastric pain, diarrhoea, and oligospermia in men are most common and dose related. Serious idiosyncratic reactions (including Stevense Johnson syndrome, pancreatitis, agranulocytosis, or alveolitis) are rare. Mesalazine intolerance occurs in up to 15% of patients. Diarrhoea (3%), headache (2%), nausea (2%) and rash (1%) are reported, but a systematic review has confirmed that all new 5-ASA agents are safe, with adverse events that are similar to placebo for mesalazine or olsalazine. No comparison between balsalazide and placebo has been published, but events were lower than with sulfasalazine. Acute intolerance to all 5-ASAs in 3% may resemble a flare of colitis since it includes bloody diarrhoea. Recurrence on rechallenge provides the clue. All aminosalicylates have been associated with nephrotoxicity (including interstitial nephritis and nephrotic syndrome), which appears both to be idiosyncratic and, in part, dose related.106 Reactions are rare, but patients with pre-existing renal disease are at higher risk. A population-based study found the risk (OR 1.60, CI 1.14 to 2.26 compared to normal) to be associated with disease severity rather than the dose or type of mesalazine. For patients on maintenance 5-ASA, annual measurement of creatinine is sensible, although there is no evidence that monitoring is necessary or effective at preventing renal impairment. Aminosalicylates should be stopped if renal function deteriorates.
4.4.2 Antibiotics Antibiotics have an important role in treating secondary complications in IBD, such as abscess and bacterial overgrowth.107 There is some evidence that metronidazole and ciprofloxacin have specific uses in Crohn’s disease. There is no clear-cut evidence to support the use of these antibiotics in ulcerative colitis as disease modifying therapy.
Metronidazole Metronidazole in a synthetic nitroimidazole antibiotic and antiprotozoal drug.
Efficacy in Crohn’s disease. Early trials of metronidazole to treat Crohn’s disease showed reductions in blood markers of inflammation (ESR and orosomucoid levels).108e110 Following ileocaecal resection, 20 mg/kg/day for 3 months reduces the risk of endoscopic recurrence in the short term only.111 (see section 6.6.4) Metronidazole is used to treat perianal disease. The evidence is from case series, it has not been subject to adequately powered controlled studies and recent data suggests it is less effective than ciprofloxacin.112 Metronidazole treatment of pouchitis improves diarrhoea without a clear effect on pouch inflammation.113 It appears less effective than ciprofloxacin. Adverse effects. Metronidazole should be used with caution in the long term as peripheral neuropathy can occur after a mean duration of 6 months.114 Ciprofloxacin
This drug is a fluoroquinolone antibiotic with a broad spectrum of activity against Gram positive and negative bacteria including many enteric pathogens. Gut 2011;60:571e607. doi:10.1136/gut.2010.224154
Efficacy in Crohn’s disease. There are no placebo-controlled studies of ciprofloxacin to treat active Crohn’s disease though comparisons have been made with other drugs showing similar response rates to mesalazine and steroids respectively.115 116 Studies in ulcerative colitis show weak or no effect.117 118 The evidence suggests a greater benefit than metronidazole in perianal Crohn’s disease and pouchitis.112 119 Adverse effects. Ciprofloxacin is recognised to cause tendon weakness and this effect may be aggravated by steroids.
Antituberculous chemotherapy and other antibiotics in Crohn’s disease These drugs are not discussed here. The reader is referred to the ECCO consensus statement.3
4.4.3 Corticosteroids Corticosteroids are used in the form of oral prednisolone, prednisone, budesonide (among others), or intravenous hydrocortisone and methylprednisolone. Topical suppositories, foam or liquid enemas include hydrocortisone, prednisolone metasulfobenzoate, betamethasone and budesonide. Many strategies attempt to maximise topical effects while limiting systemic side-effects of steroids. Budesonide (EntocortÒ, BudenofalkÒ) is a poorly absorbed corticosteroid with limited bioavailability and extensive first-pass metabolism that has therapeutic benefit with reduced systemic toxicity in ileo-caecal Crohn’s disease, or ulcerative colitis.120 Beclometasone dipropionate has been studied in oral and enema forms in ulcerative colitis, and is no better than 5-ASA.121 122
Choice and mechanism123 Corticosteroids are potent anti-inflammatory agents for moderate to severe relapses of both ulcerative colitis and Crohn’s disease. They have no role in maintenance therapy for either disease. They act through inhibition of several inflammatory pathways: suppressing interleukin transcription, induction of Ikb that stabilises the NFkb complex, suppression of arachidonic acid metabolism and stimulation of apoptosis of lymphocytes within the lamina propria of the gut. The anti-inflammatory dose equivalence of prednisolone 5 mg is betamethasone 0.75 mg, methylprednisolone 4 mg and hydrocortisone 20 mg though with differing mineralocorticoid effects (British National Formulary, http://bnf.org/bnf/index.htm (accessed Oct 2010)).
Efficacy for active ulcerative colitis124e126 Oral prednisolone (starting at 40 mg daily) induced remission in 77% of 118 patients with mild-to-moderate disease within 2 weeks, compared to 48% treated with 8 g/day sulfasalazine. A combination of oral and rectal steroids is better than either alone. Adverse events are significantly more frequent at a dose of 60 mg/day compared to 40 mg/day, without added benefit, so 40 mg appears optimal for outpatient management of acute ulcerative colitis. Too rapid reduction in the dose of steroids can be associated with early relapse and doses of prednisolone 12 weeks, but sometimes less) include posterior subcapsular cataracts, 580
osteoporosis, osteonecrosis of the femoral head, myopathy and susceptibility to infection. Steroids have been associated with impaired growth velocity in some conditions. However, when strategies are taken to avoid steroids in Crohn’s disease, the main influence on growth velocity is disease activity.138 < Effects during withdrawal include acute adrenal insufficiency (from sudden cessation), corticosteroid withdrawal syndromea syndrome of myalgia, malaise and arthralgia (similar to recrudesence of Crohn’s disease), or raised intracranial pressure.
Monitoring for side effects Other guidelines recommend monitoring for eye, bone and other side effects particularly in patients on steroids for more than 3 months139 (see also section 7.6: Osteoporosis).
4.4.4 Thiopurines Azathioprine (AZA) or mercaptopurine (MP) are widely used in ulcerative colitis and Crohn’s disease as adjunctive therapy and as corticosteroid-sparing therapies although they are unlicensed therapies for IBD. Their slow onset of action precludes usage as sole therapy for active disease. Purine antimetabolites inhibit ribonucleotide synthesis, but the mechanism of immunomodulation is by inducing T cell apoptosis by modulating cell (Rac1) signalling.140 AZA is non-enzymatically metabolised to MP, which involves loss of a nitro-imidazole side chain; this is thought to explain some of the side effects seen with AZA and which may be less of a problem with MP.141 142 MP is subsequently metabolised to 6-thioguanine nucleotides (6-TGN). 6-TGN has been used for treatment of IBD, but caution is appropriate because of potential hepatotoxicity.
Efficacy in ulcerative colitis AZA is more effective than mesalazine at induction of clinical and endoscopic remission in steroid dependent ulcerative colitis143 and should be first-choice therapy in this situation providing other causes of persistent symptoms such as cytomegalovirus or cancer have been excluded. Thiopurines are effective maintenance therapy for patients with ulcerative colitis who have failed or who cannot tolerate mesalazine and for patients who require repeated courses of steroids, although the data quality has been cited as poor in a recent Cochrane review144 and the evidence for using thiopurines in ulcerative colitis is weaker than in Crohn’s disease: probably the best study to date is Ardizzone et al143 which found steroid-free, clinical and endoscopic remission in 53% patients on AZA compared with 21% given 5-ASA (OR on ITT 4.78, 95% CI 1.57 to 14.5).
Efficacy in Crohn’s disease Thiopurines are effective for both induction and maintenance of remission in Crohn’s disease. A Cochrane review of the efficacy of AZA and MP for inducing remission in active Crohn’s disease demonstrated a benefit for thiopurine therapy compared to placebo with an OR of 2.43 (95% CI 1.62 to 3.64). This equates to a number needed to treat (NNT) of about five and a number needed to harm (NNH) of 14.145 Their efficacy at maintaining remission is confirmed in another Cochrane review. The OR for maintenance of remission with AZA was 2.32 (95% CI 1.55 to 3.49) with a NNT of six. The OR for maintenance of remission with MP was 3.32 (95% CI 1.40 to 7.87) with a NNT of four. Higher doses of AZA improved response. Withdrawals due to adverse events were more common in patients treated with AZA (OR 3.74; 95% CI 1.48 to 9.45, NNH¼20) than with placebo.146 For those who relapse once immunosuppressants are stopped, current evidence suggests that AZA/MP can be safely restarted Gut 2011;60:571e607. doi:10.1136/gut.2010.224154
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Guidelines and continued. The efficacy of thiopurines for post-operative prophylaxis of Crohn’s disease is discussed in section 6.6.4.
Dosing Tailoring or optimisation of thiopurine therapy can occur prior to or during treatment. The appropriate maintenance dose of AZA is 2e2.5 mg/kg/day and of MP is 0.75e1.5 mg/kg/day in both ulcerative colitis and Crohn’s disease. The ‘maximum’ dose will differ between individuals and effectively means that level at which leucopenia develops. There is some evidence that mesalazine has synergistic effects on thiopurine therapy but the mechanism of this effect is unclear.147e149
Is measurement of thiopurine methyl-transferase necessary? AZA induced myelosuppression linked to thiopurine methyltransferase (TPMT) deficiency and elevation of thioguanine nucleotide cytotoxic metabolites has been documented in many patient groups including those with IBD.150 TPMT activity in human tissues is under the control of a common genetic polymorphism. About 90% of the population have normal or high enzyme activity and are homozygous for the wild-type allele, 10% inherit intermediate levels of enzyme activity with one wild-type and one variant allele, and one in 300 subjects have no functional TPMT activity. Patients with leukaemia who are TPMT deficient are at increased risk of myelotoxicity. This does not necessarily apply in IBD; in one study the majority (77%) of 41 patients with IBD with AZA-induced bone marrow suppression did not carry a TPMT mutation. Evidence that TPMT activity predicts other side effects or outcome is limited.151 Patients with high levels of TPMT may convert the majority of 6-MP into 6-MMP with inadequate production of 6-TGNs to provide therapeutic efficacy. The precise role of measuring TPMT levels in starting AZA/ MP therapy is still controversial. At the start of AZA/MP therapy, measuring TPMT has a role in identifying the one in 300 patients at risk of severe immunosuppression when treated with standard doses. Most patients who develop leucopenia will have a normal TPMT. During the initial months of AZA therapy a knowledge of low TPMT activity warns of possible early bone marrow toxicity (probability of myelotoxicity in high TPMT group is 3.5% compared 14.3% in the TPMT intermediate group.152 In patients established on AZA, there is no good evidence to suggest that TPMT is predictive of clinical response or drug toxicity, suggesting a role for TPMT in the prediction of early events rather than long-term control.153
Risk of malignancy Organ transplant recipients who are prescribed thiopurines as part of their immunosuppression are recognised to have an increased risk of developing lymphoproliferative disorders.158 In IBD, large population-based studies have shown no increased risk.159 160 However, the data from studies examining patients prescribed thiopurines has been conflicting. One meta-analysis suggested no increased risk of malignancy,161 whereas a second suggested a fourfold increased risk of lymphoma in patients with IBD treated with AZA/MP compared with background population.162 More recently, a large prospective study followed almost 20 000 consecutive patients over a 3-year period for the incidence of lymphoproliferative disorders. Those patients receiving maintenance thiopurines had a fivefold increased risk compared to those who had previously or never received the drug.163 In absolute terms, the risk remains very small (0.001). Significantly higher rates of mucosal healing were also demonstrated. Despite these positive findings, only 20.9% in the ACT1 study were in corticosteroid-free remission at 1 year follow-up. Colectomy rates at 54 weeks have recently been published and show an absolute risk reduction of 7% in the IFX treated group.221 There are no published RCTs examining the efficacy of ADA in ulcerative colitis. However, case series suggest that ADA may have a role in treating mildemoderate ulcerative colitis patients who are intolerant, or have lost response to IFX.222e225
Efficacy for corticosteroid-refractory ulcerative colitis In a RCT involving 43 patients, Probert et al showed that IFX was not superior to placebo in inducing remission at week 6 (39% vs 30% remission rates in IFX and placebo groups respectively; p¼0.76).226 In this study, 77% of patients had received Gut 2011;60:571e607. doi:10.1136/gut.2010.224154
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Guidelines corticosteroids for more than 14 days. In the ACT1/2 studies, a third of the patients were considered to be refractory to corticosteroids at the time of recruitment. Contrary to the earlier study, the response (not remission) rates were significantly higher than placebo at week 8 (77% vs. 35%, p45 mg/l at 3 days appears to predict the need for surgery in 85% of cases.270 Surgical review and input from specialist colorectal nurse or stoma therapist is appropriate at this stage. < Intravenous steroids are generally given for up to 5 days. There is no benefit beyond 7e10 days.272 < Consideration of colectomy or rescue therapy with either intravenous ciclosporin (CsA) 2 mg/kg/day OR infliximab (IFX) if there is no improvement by day 3 or there is subsequent deterioration (EL1b, RG B). NICE recommends CsA as first-line (and IFX use only if CsA is contraindicated) based on health economic analyses and the paucity of data to support the use of IFX over CsA (http://www.nice.org.uk/ 588
nicemedia/pdf/TA163Guidance.pdf (accessed Oct 2010)). For patients already on immunosuppressive therapy such as AZA/MP at the time of presentation, surgery should be considered as the first option (EL4, grade D). < Rescue with intravenous CsA: e 2 mg/kg/day is as effective as 4 mg/kg/day with decreased toxicity e Magnesium, cholesterol and creatinine should be measured within 48 h of starting CsA e Beware contraindications (Mg2+