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What's new in … Gastroenterology
WHAT'S NEW IN GASTROENTEROLOGY Published with Volume 34 May 2006
What’s new in ... Gastroenterology
Medicine
Rakesh Chaudhary Subrata Ghosh
Rapid advances have revolutionized the understanding of the pathogenesis of inflammatory bowel disease and targeted therapy. Further translational advances are anticipated. Management of dyspepsia has de-emphasized reliance on unnecessary endoscopy, and it is likely that the resulting increase in availability of endoscopy capacity will be used in colorectal cancer screening. Wireless capsule endoscopy is now established as the best method to visualize the small intestine either in the diagnosis of gastrointestinal haemorrhage or small intestinal Crohn’s disease. Risk of gastrointestinal haemorrhage while on antiplatelet agents is being re-evaluated. Statins have been found to be useful in prevention of colorectal cancer risk, adding to potential chemopreventive agents available for this common cancer.
NOD2 and Crohn’s disease In patients with Crohn’s disease, up to 15% have homozygous mutations of the CARD15 or NOD2 gene (nucleotide-binding oligomerization domain). 1,2 Three main mutations account for about 75% of double mutations found within the conserved structure of this molecule. Clinically, patients with these mutations are often associated with a fibrostenotic ileal Crohn’s disease phenotype. The NOD2 protein is expressed in the Paneth cells in the base of intestinal crypts as well as in key immune cells such as macrophages and dendritic cells. Considerable work has been undertaken on the innate immune system and to determine the role of NOD2 in the pathogenesis of Crohn’s disease. NOD1 and 2 are intracellular molecules that detect conserved microbial components and, through NF-
κB activation, drive the pro-inflammatory cytokine secretion. Toll-like receptors (TLRs) are the most extensively studied of these pathogen-associated molecular patterns (PAMPs) and these receptors detect bacterial, viral and fungal products at the cell surface and in cellular compartments. Both TLRs and NOD molecules function as microbial sensors and are responsible for mucosal haemostasis – they dampen inflammatory responses to commensal organisms yet elicit a prompt response to invasive pathogens. Extensive cross-talk between NODs and TLRs determine the outcome of bacterial sensing. The NOD2 ligand has been identified as muramyl dipeptide, a component of peptidoglycan found in bacterial cell walls. The exact mechanism by which NOD2 mutations predispose the individual to inflammation remains a matter of debate. Loss of function secondary to mutations in NOD2
Rakesh Chaudhary is Clinical Research Fellow in Gastroenterology at Imperial College London, UK. Professor S Ghosh is the Chief of Gastroenterology at the Hammersmith Hospital, Imperial College London, UK.
MEDICINE 34 (Supplement 5)
1
may result in reduced bacterial clearance via reduced secretion of antimicrobial peptides, thereby propagating inflammation. It may also impair the intestinal barrier and leukocyte chemotaxis. Alternatively, NOD2 mutation may result in increased sensitivity to bacterial components signalling via TLR, potentially predisposing to uncontrolled mucosal inflammation. Not all individuals with NOD2 mutations develop Crohn’s disease and our understanding of the pathogenesis of disease will improve as further predisposing genes are being identified.
Biological agents in inflammatory bowel disease update Anti-TNF therapy in Crohn’s disease Two subcutaneously administered humanized or human anti-TNF (tumour necrosis factor) antibodies are close to regulatory approval in Crohn’s disease. This will expand the options for anti-TNF therapy in Crohn’s disease. Adalimumab Infliximab, the chimeric murine anti-TNF antibody, has transformed the medical management of Crohn’s disease. The development of immunogenicity over
© 2006 Elsevier Ltd
WHAT'S NEW IN GASTROENTEROLOGY
time can limit the use of infliximab and alternatives are needed. Adalimumab, a fully human anti-TNF antibody, is licensed for use in rheumatoid arthritis but not yet in Crohn’s disease. It is administered as a subcutaneous injection as compared to infliximab which is given as an intravenous infusion. Data from the CLASSIC 1 trial3 (Clinical assessment of adalimumab safety and efficacy studied as induction therapy in Crohn’s disease) confirmed adalimumab is effective in inducing response and remission in active Crohn’s disease. Efficacy was related to the dose of adalimumab with a dose of 160/80 mg found to be the most effective (that is a 160 mg loading dose followed by 80 mg dose at two weeks). The remission rate of this dose at four weeks was 36% compared to 12% for placebo. This is a much higher dose than that currently licensed for adalimumab in rheumatoid arthritis. Injection site reactions were noted to be increased in the treatment group with no other difference in safety profile noted between the groups. Reports of experience with adalimumab in Crohn’s patients with attenuated response to infliximab have been promising.4 However, even fully human antibodies are immunogenic. Certolizumab Certolizumab (CimziaTM) is a pegylated Fab’ fragment humanized anti-TNF antibody which is administered by subcutaneous injection every 4 weeks. In a phase-2 study, 292 patients were randomized to placebo or 3 doses of certolizumab. Certolizumab 400 mg achieved the highest response rate which was significant (p=0.006) at week 10 (52.8% compared to placebo rate 30.1%) but not so at week 12.5 Preliminary data from a phase 3 study, known as PRECiSE 2, found 64% of patients responded to induction therapy with certolizumab at 6 weeks, and with 4-weekly maintenance treatment 62.8% sustained a clinical response throughout the 26 week study compared to a placebo response rate of 36.2%. At 26 weeks, 47.9% of patients achieved clinical remission as compared to 28.8% with placebo. The primary endpoints of the study were statistically significant and response was not affected by previous anti-TNF treatment or dependent on baseline c-reactive protein (CRP) concentrations. Two-year open-label studies to assess long-term safety and tolerability are ongoing.
MEDICINE 34 (Supplement 5)
Natalizumab in Crohn’s disease Lymphocyte infiltration into the intestinal tract in Crohn’s disease is mediated by interaction between α4 integrin expressed on lymphocytes and its specific ligand MAdCAM 1 expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against α4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. The maintenance of response and remission study, ENACT II, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT I) study. This was associated with improvement in quality of life parameters.6 Though the clinical trials showed that inhibition of α4 integrin was well tolerated, use of natalizumab in multiple sclerosis has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML)7 in two patients and the drug has been withdrawn from the market pending further safety evaluation. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with Crohn’s disease receiving open-label natalizumab. Natalizumab may be effective in patients who have previously failed anti-TNF therapy. Infliximab in ulcerative colitis The use of infliximab in the management of ulcerative colitis has been controversial due to conflicting trial data. Recently, however, two large randomised controlled trials have clarified the question of the efficacy of infliximab in ulcerative colitis. The Active Ulcerative Colitis 1 and 2 studies8 (ACT-1 and 2) both evaluated 363 patients each. Patients were randomised to placebo, 5 mg/kg of infliximab and 10 mg/kg of infliximab. For ACT-1 Patients included had moderate to severe colitis despite concomitant steroid alone or in combination with azathioprine or mercaptopurine. ACT-2 patients had moderate-to-severe disease in the presence of steroid therapy alone or combined with aminosalicylates or azathioprine or mercaptopurine. Patients intolerant of steroids or immunosuppressants or who had no response to them within the past 5 years were eligible for inclusion. Following an induction regimen of infusions at week 0, 2 and 6 maintenance
2
therapy with 8 weekly infusions was performed. Response rates at week 8 were 69.4% with 5 mg/kg infliximab, 61.5% for 10 mg/kg and 37.2% for placebo in ACT-1. Corresponding rates in ACT-2 were 64.5% (5 mg/kg), 69.2% (10 mg/kg) and 29.3% for placebo. Remission rates in ACT-1 at 30 weeks were 41% (5 mg/kg), 45% (10 mg/ kg) and 19% (placebo) with rates of 31% (5 mg/kg), 43% (10 mg/kg) and 13% (placebo) in ACT-2. A significant steroid sparing effect was noted in all treatment groups. Mucosal healing was significantly better in all treatment groups compared to placebo at 8 weeks (p<0.001) and this was maintained throughout the follow-up period.8 These studies confirmed the clinical efficacy of infliximab in ulcerative colitis both in terms of significantly increased clinical response and remission rates as well as evidence of mucosal healing. The response was not significantly improved with the increased dose of 10 mg/kg so the authors advocate a dose of 5 mg/kg. The FDA and European regulatory authorities have since licensed infliximab for use in ulcerative colitis. It is likely that infliximab will be valuable in ulcerative colitis patients who are steroid-dependent or refractory and unresponsive or intolerant of immunomodulator therapy.
Dyspepsia guidelines The National Institute of Health and Clinical Excellence (NICE) issued new recommendations on the management of dyspepsia9 in primary care in August 2004 (see Figures 1 and 2). These were amended following the release of the NICE clinical guidelines on referral for suspected cancer10 in June 2005. The guidelines do not advocate routine use of endoscopy to investigate patients with dyspepsia in the absence of alarm symptoms. In cases of uninvestigated dyspepsia an empirical course of proton pump inhibitors (PPIs) or ‘test and treat’ for H Pylori is recommended. H Pylori testing should be by urea breath test or stool antigen test following a two-week washout for those on PPIs. However, in patients who are over 55 years and have persistent or unexplained recent-onset dyspepsia alone, referral for endoscopy is recommended. The guideline provides separate algorithms for the management of diagnosed gastro-oesophageal reflux disease, gastric and duodenal ulcer disease.
© 2006 Elsevier Ltd
WHAT'S NEW IN GASTROENTEROLOGY
Management flowchart for patients with uninvestigated dyspepsia Entry or final state
Action
Management flowchart for patients with non-ulcer dyspepsia
Action and outcome
Entry or final state
Dyspepsia not needing referral
Action and outcome
Non-ulcer dyspepsia
Positive
Review medication1
Lifestyle advice2
Action
Negative H. pylori test result
Response No response or relapse
No response or relapse Response
Full-dose PPI for 1 month3
Low-dose PPI or H2RA for 1 month
No response or relapse Relapse
Test and treat4
Response
Eradication therapy1
No response Response
Low-dose treatment as required
H2RA or prokinetic for 1 month No response
Review6
Response
Return to self care
Return to self care
2 Offer lifestyle advice, including advice on healthy eating, weight reduction and smoking cessation, promoting continued use of antacid/alginates. 3 There is currently inadequate evidence to guide whether full-dose PPI for 1 month or H. pylori test and treat should be offered first. Either treatment may be tried first with the other being offered if symptoms persist or return. 4 Detection: use carbon-13 urea breath test, stool antigen test or, when performance has been validated, laboratory-based serology. Eradication: use a PPI, amoxicillin, clarithromycin 500 mg (PAC500) regimen or a PPI, metronidazole, clarithromycin 250 mg (PMC250) regimen. Do not re-test even if dyspepsia remains unless there is a strong clinical need.
2
5 Offer low-dose treatment with a limited number of repeat prescriptions. Discuss the use of treatment on an as-required basis to help patients manage their own symptoms. 6 In some patients with an inadequate response to therapy it may become appropriate to refer to a specialist for a second opinion. Emphasize the benign nature of dyspepsia. Review long-term patient care at least annually to discuss medication and symptoms.
1
Gastrointestinal bleeding is a common clinical problem. In approximately 5% of cases no cause is identified and bleeding continues either overtly or on an occult basis (often presenting as iron deficiency). Obscure bleeding may be defined as bleeding of unknown origin (after normal
MEDICINE 34 (Supplement 5)
Review3
1 Use a PPI, amoxicillin, clarithromycin 500 mg (PAC500) regimen or a PPI, metronidazole, clarithromycin 250 mg (PMC250) regimen. Do not re-test unless there is a strong clinical need. 2 Offer low-dose treatment, possibly on an as-required basis, with a limited number of repeat prescriptions. 3 In some patients with an inadequate response to therapy or new emergent symptoms it may become appropriate to refer to a specialist for a second opinion. Emphasize the benign nature of dyspepsia. Review long-term patient care at least annually to discuss medication and symptoms.
1 Review medications for possible causes of dyspepsia, for example, calcium antagonists, nitrates, theophyllines, bisphosphonates, steroids and NSAIDs.
Capsule endoscopy and obscure GI bleeding
Low-dose PPI or H2RA as required2
upper and lower endoscopy) that persists or recurs. Visualization of the small bowel has been recently advanced by the advent of wireless capsule endoscopy (Figure 3). Each single-use capsule is about the size of a large tablet and can be swallowed with water. It contains a camera, lens, battery, light source and transmitter. Two images per second are transmitted by the
3
capsule to the portable data recorder. The patient has an array of sensors placed on the abdomen that track the location of the capsule as it is propagated through the gut by peristalsis. The capsule is passed in the stool normally in the absence of a stricture causing hold-up. Capsule endoscopy is generally well tolerated by patients and gives excellent views of small intestinal mucosa. A study of 100 consecutive cases of obscure bleeding concluded that the best candidates were patients with ongoing bleeding from an unknown source and secondly, those with iron deficiency and a positive faecal occult test.11 The authors concluded that capsule endoscopy is an effective investigation for obscure bleeding and could shorten the time till diagnosis and total number of investigations if performed early. Notably, this series had
© 2006 Elsevier Ltd
WHAT'S NEW IN GASTROENTEROLOGY
to aspirin with upper GI haemorrhage. Clearly, PPI cover is warranted in patients on both agents with previous upper GI haemorrhage, but perhaps also in high-risk patients (with a previous history of ulcer disease) whilst on aspirin and/or clopridrel. Vigilance in these patients for the occurrence of GI bleeding is important.
Statin use and colorectal cancer
3 Capsule endoscopy showing small intestinal NSAID related ulcer
a 5% complication rate of capsule retention due to unsuspected stenosis (these required surgery). A meta-analysis of capsule endoscopy against other modalities in the investigation of obscure bleeding analyzed the results of 14 studies.12 The authors concluded that capsule endoscopy was superior to both push enteroscopy and small bowel radiography in the diagnosis of small bowel pathology. The absence of any interventional capability with capsule endoscopy means it may be increasingly used early as an investigative tool to make a diagnosis and direct therapy in patients with obscure bleeding. Other recent advances for small intestinal visualization, such as double balloon enteroscopy, may then be used to treat pathology detected at capsule endoscopy.
Clopidogrel and upper GI bleeding in high-risk patients Anti-platelet therapy has become an important part of the medical management of atheromatous vascular disease. More recently, the use of clopidogrel and aspirin has increased in the management of patients with myocardial infarction and transient ischaemic attacks. Clopidoprel has been found to have a safer gastrointestinal safety profile as compared to aspirin in low-to-medium risk patients. However, recent data confirm that, in patients at high risk of peptic ulcer disease haemorrhage, clopidogrel resulted in a greater incidence of GI bleeding when compared to aspirin combined with PPI cover.13 The data do not support widespread practice of prescribing clopidogrel in those with GI intolerance
MEDICINE 34 (Supplement 5)
Colorectal cancer is the second most common cause of cancer-related death in the UK. There has been considerable work on the use of aspirin and non-steroidal drugs in the reduction of the incidence of colorectal adenomas. Recently, a population-based case-control study investigated the effect of statin use on colorectal cancer rates in a population with a previous diagnosis of colorectal cancer (1953 patients) and a control group (2015 individuals).14 They concluded that use of statins for at least five years resulted in a 47% reduction in the risk of colorectal cancer (this was after adjustment for confounding variables e.g. aspirin use). Simvastatin and pravastatin accounted for over 97% of statin use. Randomized trials are necessary (similar to adenoma prevention studies with aspirin) before statins can be advocated for this indication but this study highlights the potentially important development of statins as chemoprotective agents for colorectal cancer. u
REFERENCES 1 Hugot J, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants with susceptibilty to Crohn’s disease. Nature 2001; 411: 599–603. 2 Ogura Y, Bonen D K, Inohara N et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001; 411: 603–6. 3 Hanauer S B, Sandborn W J, Rutgeerts P et al. Human anti–tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease. Gastroenterol 2006; 130: 323–33. 4 Papadakis K A, Shaye O A, Vasiliauskas E A et al. Safety and efficacy of adalimumab (D2E7) in Crohn’s disease patients with an attenuated response to infliximab. Am J Gastroenterol 2005; 100: 75–9. 5 Schreiber S, Rutgeerts P, Fedorak R N et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment
4
of Crohn’s disease. Gastroenterol 2005; 129: 807–18. 6 Sandborn W J, Colombel J F, Enns R et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005; 353: 1912–25. 7 Van Assche G, Van Ranst M, Raf Sciot R et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005; 353: 362–8. 8 Rutgeerts P, Sandborn W J, Feagan B G et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462–76. 9 NICE Clinical Guideline 17. Dyspepsia: management of dyspepsia in adults in primary care.London: NICE, August 2004. 10 NICE Clinical guideline 27. Referral guidelines for suspected cancer.London: NICE, June 2005. 11 Pennazio M, Santucci R, Rondonotti E et al. Outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy: report of 100 consecutive cases. Gastroenterol 2004; 126: 643–53 12 Triester S L, Leighton J A, Leontiadis G I et al. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with obscure gastrointestinal bleeding. Am J Gastroenterol 2005; 100: 2407–18. 13 Chan F K, Ching J Y, Hung L C et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005; 352: 238–44. 14 Poynter J N, Gruber S B, Higgins P D R et al. Statins and the risk of colorectal cancer. N Engl J Med 2005; 352: 2184–92.
© 2006 Elsevier Ltd
What’s new in ... Gastroenterology
Medicine
Rakesh Chaudhary Subrata Ghosh
Rapid advances have revolutionized the understanding of the pathogenesis of inflammatory bowel disease and targeted therapy. Further translational advances are anticipated. Management of dyspepsia has de-emphasized reliance on unnecessary endoscopy, and it is likely that the resulting increase in availability of endoscopy capacity will be used in colorectal cancer screening. Wireless capsule endoscopy is now established as the best method to visualize the small intestine either in the diagnosis of gastrointestinal haemorrhage or small intestinal Crohn’s disease. Risk of gastrointestinal haemorrhage while on antiplatelet agents is being re-evaluated. Statins have been found to be useful in prevention of colorectal cancer risk, adding to potential chemopreventive agents available for this common cancer.
NOD2 and Crohn’s disease In patients with Crohn’s disease, up to 15% have homozygous mutations of the CARD15 or NOD2 gene (nucleotide-binding oligomerization domain). 1,2 Three main mutations account for about 75% of double mutations found within the conserved structure of this molecule. Clinically, patients with these mutations are often associated with a fibrostenotic ileal Crohn’s disease phenotype. The NOD2 protein is expressed in the Paneth cells in the base of intestinal crypts as well as in key immune cells such as macrophages and dendritic cells. Considerable work has been undertaken on the innate immune system and to determine the role of NOD2 in the pathogenesis of Crohn’s disease. NOD1 and 2 are intracellular molecules that detect conserved microbial components and, through NF-
κB activation, drive the pro-inflammatory cytokine secretion. Toll-like receptors (TLRs) are the most extensively studied of these pathogen-associated molecular patterns (PAMPs) and these receptors detect bacterial, viral and fungal products at the cell surface and in cellular compartments. Both TLRs and NOD molecules function as microbial sensors and are responsible for mucosal haemostasis – they dampen inflammatory responses to commensal organisms yet elicit a prompt response to invasive pathogens. Extensive cross-talk between NODs and TLRs determine the outcome of bacterial sensing. The NOD2 ligand has been identified as muramyl dipeptide, a component of peptidoglycan found in bacterial cell walls. The exact mechanism by which NOD2 mutations predispose the individual to inflammation remains a matter of debate. Loss of function secondary to mutations in NOD2
Rakesh Chaudhary is Clinical Research Fellow in Gastroenterology at Imperial College London, UK. Professor S Ghosh is the Chief of Gastroenterology at the Hammersmith Hospital, Imperial College London, UK.
MEDICINE 34 (Supplement 5)
1
may result in reduced bacterial clearance via reduced secretion of antimicrobial peptides, thereby propagating inflammation. It may also impair the intestinal barrier and leukocyte chemotaxis. Alternatively, NOD2 mutation may result in increased sensitivity to bacterial components signalling via TLR, potentially predisposing to uncontrolled mucosal inflammation. Not all individuals with NOD2 mutations develop Crohn’s disease and our understanding of the pathogenesis of disease will improve as further predisposing genes are being identified.
Biological agents in inflammatory bowel disease update Anti-TNF therapy in Crohn’s disease Two subcutaneously administered humanized or human anti-TNF (tumour necrosis factor) antibodies are close to regulatory approval in Crohn’s disease. This will expand the options for anti-TNF therapy in Crohn’s disease. Adalimumab Infliximab, the chimeric murine anti-TNF antibody, has transformed the medical management of Crohn’s disease. The development of immunogenicity over
© 2006 Elsevier Ltd
WHAT'S NEW IN GASTROENTEROLOGY
time can limit the use of infliximab and alternatives are needed. Adalimumab, a fully human anti-TNF antibody, is licensed for use in rheumatoid arthritis but not yet in Crohn’s disease. It is administered as a subcutaneous injection as compared to infliximab which is given as an intravenous infusion. Data from the CLASSIC 1 trial3 (Clinical assessment of adalimumab safety and efficacy studied as induction therapy in Crohn’s disease) confirmed adalimumab is effective in inducing response and remission in active Crohn’s disease. Efficacy was related to the dose of adalimumab with a dose of 160/80 mg found to be the most effective (that is a 160 mg loading dose followed by 80 mg dose at two weeks). The remission rate of this dose at four weeks was 36% compared to 12% for placebo. This is a much higher dose than that currently licensed for adalimumab in rheumatoid arthritis. Injection site reactions were noted to be increased in the treatment group with no other difference in safety profile noted between the groups. Reports of experience with adalimumab in Crohn’s patients with attenuated response to infliximab have been promising.4 However, even fully human antibodies are immunogenic. Certolizumab Certolizumab (CimziaTM) is a pegylated Fab’ fragment humanized anti-TNF antibody which is administered by subcutaneous injection every 4 weeks. In a phase-2 study, 292 patients were randomized to placebo or 3 doses of certolizumab. Certolizumab 400 mg achieved the highest response rate which was significant (p=0.006) at week 10 (52.8% compared to placebo rate 30.1%) but not so at week 12.5 Preliminary data from a phase 3 study, known as PRECiSE 2, found 64% of patients responded to induction therapy with certolizumab at 6 weeks, and with 4-weekly maintenance treatment 62.8% sustained a clinical response throughout the 26 week study compared to a placebo response rate of 36.2%. At 26 weeks, 47.9% of patients achieved clinical remission as compared to 28.8% with placebo. The primary endpoints of the study were statistically significant and response was not affected by previous anti-TNF treatment or dependent on baseline c-reactive protein (CRP) concentrations. Two-year open-label studies to assess long-term safety and tolerability are ongoing.
MEDICINE 34 (Supplement 5)
Natalizumab in Crohn’s disease Lymphocyte infiltration into the intestinal tract in Crohn’s disease is mediated by interaction between α4 integrin expressed on lymphocytes and its specific ligand MAdCAM 1 expressed on the endothelial cells of the microvasculature in the inflamed intestinal tract. Development of monoclonal antibodies against α4 integrin permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. The maintenance of response and remission study, ENACT II, has reported impressive efficacy in maintaining response and remission in those who responded in the initial induction of remission (ENACT I) study. This was associated with improvement in quality of life parameters.6 Though the clinical trials showed that inhibition of α4 integrin was well tolerated, use of natalizumab in multiple sclerosis has raised serious concerns about the association with progressive multifocal leukoencephalopathy (PML)7 in two patients and the drug has been withdrawn from the market pending further safety evaluation. Initial safety evaluation suggests that PML is very rare, despite its occurrence in one patient with Crohn’s disease receiving open-label natalizumab. Natalizumab may be effective in patients who have previously failed anti-TNF therapy. Infliximab in ulcerative colitis The use of infliximab in the management of ulcerative colitis has been controversial due to conflicting trial data. Recently, however, two large randomised controlled trials have clarified the question of the efficacy of infliximab in ulcerative colitis. The Active Ulcerative Colitis 1 and 2 studies8 (ACT-1 and 2) both evaluated 363 patients each. Patients were randomised to placebo, 5 mg/kg of infliximab and 10 mg/kg of infliximab. For ACT-1 Patients included had moderate to severe colitis despite concomitant steroid alone or in combination with azathioprine or mercaptopurine. ACT-2 patients had moderate-to-severe disease in the presence of steroid therapy alone or combined with aminosalicylates or azathioprine or mercaptopurine. Patients intolerant of steroids or immunosuppressants or who had no response to them within the past 5 years were eligible for inclusion. Following an induction regimen of infusions at week 0, 2 and 6 maintenance
2
therapy with 8 weekly infusions was performed. Response rates at week 8 were 69.4% with 5 mg/kg infliximab, 61.5% for 10 mg/kg and 37.2% for placebo in ACT-1. Corresponding rates in ACT-2 were 64.5% (5 mg/kg), 69.2% (10 mg/kg) and 29.3% for placebo. Remission rates in ACT-1 at 30 weeks were 41% (5 mg/kg), 45% (10 mg/ kg) and 19% (placebo) with rates of 31% (5 mg/kg), 43% (10 mg/kg) and 13% (placebo) in ACT-2. A significant steroid sparing effect was noted in all treatment groups. Mucosal healing was significantly better in all treatment groups compared to placebo at 8 weeks (p<0.001) and this was maintained throughout the follow-up period.8 These studies confirmed the clinical efficacy of infliximab in ulcerative colitis both in terms of significantly increased clinical response and remission rates as well as evidence of mucosal healing. The response was not significantly improved with the increased dose of 10 mg/kg so the authors advocate a dose of 5 mg/kg. The FDA and European regulatory authorities have since licensed infliximab for use in ulcerative colitis. It is likely that infliximab will be valuable in ulcerative colitis patients who are steroid-dependent or refractory and unresponsive or intolerant of immunomodulator therapy.
Dyspepsia guidelines The National Institute of Health and Clinical Excellence (NICE) issued new recommendations on the management of dyspepsia9 in primary care in August 2004 (see Figures 1 and 2). These were amended following the release of the NICE clinical guidelines on referral for suspected cancer10 in June 2005. The guidelines do not advocate routine use of endoscopy to investigate patients with dyspepsia in the absence of alarm symptoms. In cases of uninvestigated dyspepsia an empirical course of proton pump inhibitors (PPIs) or ‘test and treat’ for H Pylori is recommended. H Pylori testing should be by urea breath test or stool antigen test following a two-week washout for those on PPIs. However, in patients who are over 55 years and have persistent or unexplained recent-onset dyspepsia alone, referral for endoscopy is recommended. The guideline provides separate algorithms for the management of diagnosed gastro-oesophageal reflux disease, gastric and duodenal ulcer disease.
© 2006 Elsevier Ltd
WHAT'S NEW IN GASTROENTEROLOGY
Management flowchart for patients with uninvestigated dyspepsia Entry or final state
Action
Management flowchart for patients with non-ulcer dyspepsia
Action and outcome
Entry or final state
Dyspepsia not needing referral
Action and outcome
Non-ulcer dyspepsia
Positive
Review medication1
Lifestyle advice2
Action
Negative H. pylori test result
Response No response or relapse
No response or relapse Response
Full-dose PPI for 1 month3
Low-dose PPI or H2RA for 1 month
No response or relapse Relapse
Test and treat4
Response
Eradication therapy1
No response Response
Low-dose treatment as required
H2RA or prokinetic for 1 month No response
Review6
Response
Return to self care
Return to self care
2 Offer lifestyle advice, including advice on healthy eating, weight reduction and smoking cessation, promoting continued use of antacid/alginates. 3 There is currently inadequate evidence to guide whether full-dose PPI for 1 month or H. pylori test and treat should be offered first. Either treatment may be tried first with the other being offered if symptoms persist or return. 4 Detection: use carbon-13 urea breath test, stool antigen test or, when performance has been validated, laboratory-based serology. Eradication: use a PPI, amoxicillin, clarithromycin 500 mg (PAC500) regimen or a PPI, metronidazole, clarithromycin 250 mg (PMC250) regimen. Do not re-test even if dyspepsia remains unless there is a strong clinical need.
2
5 Offer low-dose treatment with a limited number of repeat prescriptions. Discuss the use of treatment on an as-required basis to help patients manage their own symptoms. 6 In some patients with an inadequate response to therapy it may become appropriate to refer to a specialist for a second opinion. Emphasize the benign nature of dyspepsia. Review long-term patient care at least annually to discuss medication and symptoms.
1
Gastrointestinal bleeding is a common clinical problem. In approximately 5% of cases no cause is identified and bleeding continues either overtly or on an occult basis (often presenting as iron deficiency). Obscure bleeding may be defined as bleeding of unknown origin (after normal
MEDICINE 34 (Supplement 5)
Review3
1 Use a PPI, amoxicillin, clarithromycin 500 mg (PAC500) regimen or a PPI, metronidazole, clarithromycin 250 mg (PMC250) regimen. Do not re-test unless there is a strong clinical need. 2 Offer low-dose treatment, possibly on an as-required basis, with a limited number of repeat prescriptions. 3 In some patients with an inadequate response to therapy or new emergent symptoms it may become appropriate to refer to a specialist for a second opinion. Emphasize the benign nature of dyspepsia. Review long-term patient care at least annually to discuss medication and symptoms.
1 Review medications for possible causes of dyspepsia, for example, calcium antagonists, nitrates, theophyllines, bisphosphonates, steroids and NSAIDs.
Capsule endoscopy and obscure GI bleeding
Low-dose PPI or H2RA as required2
upper and lower endoscopy) that persists or recurs. Visualization of the small bowel has been recently advanced by the advent of wireless capsule endoscopy (Figure 3). Each single-use capsule is about the size of a large tablet and can be swallowed with water. It contains a camera, lens, battery, light source and transmitter. Two images per second are transmitted by the
3
capsule to the portable data recorder. The patient has an array of sensors placed on the abdomen that track the location of the capsule as it is propagated through the gut by peristalsis. The capsule is passed in the stool normally in the absence of a stricture causing hold-up. Capsule endoscopy is generally well tolerated by patients and gives excellent views of small intestinal mucosa. A study of 100 consecutive cases of obscure bleeding concluded that the best candidates were patients with ongoing bleeding from an unknown source and secondly, those with iron deficiency and a positive faecal occult test.11 The authors concluded that capsule endoscopy is an effective investigation for obscure bleeding and could shorten the time till diagnosis and total number of investigations if performed early. Notably, this series had
© 2006 Elsevier Ltd
WHAT'S NEW IN GASTROENTEROLOGY
to aspirin with upper GI haemorrhage. Clearly, PPI cover is warranted in patients on both agents with previous upper GI haemorrhage, but perhaps also in high-risk patients (with a previous history of ulcer disease) whilst on aspirin and/or clopridrel. Vigilance in these patients for the occurrence of GI bleeding is important.
Statin use and colorectal cancer
3 Capsule endoscopy showing small intestinal NSAID related ulcer
a 5% complication rate of capsule retention due to unsuspected stenosis (these required surgery). A meta-analysis of capsule endoscopy against other modalities in the investigation of obscure bleeding analyzed the results of 14 studies.12 The authors concluded that capsule endoscopy was superior to both push enteroscopy and small bowel radiography in the diagnosis of small bowel pathology. The absence of any interventional capability with capsule endoscopy means it may be increasingly used early as an investigative tool to make a diagnosis and direct therapy in patients with obscure bleeding. Other recent advances for small intestinal visualization, such as double balloon enteroscopy, may then be used to treat pathology detected at capsule endoscopy.
Clopidogrel and upper GI bleeding in high-risk patients Anti-platelet therapy has become an important part of the medical management of atheromatous vascular disease. More recently, the use of clopidogrel and aspirin has increased in the management of patients with myocardial infarction and transient ischaemic attacks. Clopidoprel has been found to have a safer gastrointestinal safety profile as compared to aspirin in low-to-medium risk patients. However, recent data confirm that, in patients at high risk of peptic ulcer disease haemorrhage, clopidogrel resulted in a greater incidence of GI bleeding when compared to aspirin combined with PPI cover.13 The data do not support widespread practice of prescribing clopidogrel in those with GI intolerance
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Colorectal cancer is the second most common cause of cancer-related death in the UK. There has been considerable work on the use of aspirin and non-steroidal drugs in the reduction of the incidence of colorectal adenomas. Recently, a population-based case-control study investigated the effect of statin use on colorectal cancer rates in a population with a previous diagnosis of colorectal cancer (1953 patients) and a control group (2015 individuals).14 They concluded that use of statins for at least five years resulted in a 47% reduction in the risk of colorectal cancer (this was after adjustment for confounding variables e.g. aspirin use). Simvastatin and pravastatin accounted for over 97% of statin use. Randomized trials are necessary (similar to adenoma prevention studies with aspirin) before statins can be advocated for this indication but this study highlights the potentially important development of statins as chemoprotective agents for colorectal cancer. u
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