Hematopoietic Stem Cell Transplantation in Crohn's Disease: State-of-the-Art Treatment.

Both autologous and allogeneic haemopoietic stem cell transplantation (HSCT) have been tried in Crohn's disease (CD). In allogeneic HSCT, the host bone marrow is ablated and replaced by bone marrow from a donor. This substitution of a genetically different bone marrow is effective in a number of conditions including those with an immunological basis such as CD. While the toxicity of allogeneic HSCT has precluded its uptake in idiopathic CD, there is interest in its utility in the management of early onset infantile (inflammatory bowel disease), which behaves as a monogenic disorder, with abnormalities of the interleukin 10 signalling system as the best recognized. In autologous HSCT, the patient's own stem cells are harvested before proceeding to lymphoablation and transplantation of the patient's own uncommitted stem cells, which generate an immune system with an altered T-cell repertoire. In a limited number of cases, this has led to substantial and prolonged remission tantamount to possible cure of CD. However, case series and controlled data from the Autologous Stem Cell International Crohn's Disease study suggest that although this method has its own advantages, most patients are still at risk of redeveloping CD, albeit with an arguably improved response to conventional treatment. The availability of new treatments for CD means that an HSCT is not a suitable treatment method for a majority of patients because of its greater toxicity, even though efficacy may be superior. Wider usage would depend upon the development of protocols that are safer and better targeted.

Stem cells as treatment in inflammatory bowel disease.

BACKGROUND: The Autologous Stem Cell Transplantation International Crohn's Disease (ASTIC) trial is a randomised controlled evaluation of the proposition that immunoablation and haemopoietic stem cell transplantation improves the course of Crohn's disease. Recruitment of all 48 patients in the trial will be completed in early 2012 and the results to date are descriptively presented here. METHODS: Patients with an impaired quality of life due to active Crohn's disease, despite the administration of at least 3 immunosuppressive agents, all received mobilisation treatment (cyclophosphamide 4 g/m(2) over 2 days followed by recombinant human granulocyte colony stimulating factor (filgrastim) 10 µg/kg daily before randomisation to immediate (after 1 month) or delayed (after 1 year) immunoablation and stem cell transplantation. The conditioning regime was cyclophosphamide 50 mg/kg/day for 4 days, anti-thymocyte globulin 2.5 mg/kg/day and methylprednisolone 1 mg/kg on days 3-5. The bone marrow was reconstituted by the infusion of an unselected graft of 3-8 × 10(6)/kg CD34-positive stem cells. Results were compared 1 year after mobilisation alone or after transplantation. RESULTS: Twelve months after stem cell transplantation (early or delayed) the Crohn's Disease Activity Index (CDAI) fell from 324 (median, interquartile range 229-411) to 161 (85-257, n = 17) compared to 351 (287-443) to 272 (214-331) following mobilisation alone (n = 11). Six patients had a normal CDAI after transplantation versus 1 after mobilisation. C-reactive protein fell from 16.6 (6.7-32.0) to 6.5 (3.5-12.5) mg/l versus 14 (8.0-27.0) to 9.0 (2.0-23.4) mg/l following mobilisation alone. The Crohn's Disease Endoscopic Index of Severity (CDEIS) (aggregate for upper and lower endoscopy) fell from 18 (10-25) to 5 (1-11) following transplantation versus 14 (12-16) to 9 (4-22) following mobilisation. Three patients achieved the goal of a normal CDAI, no drug therapy and normal upper and lower endoscopy 1 year after transplantation, but so did 1 patient following mobilisation alone. Serious adverse events were common (n = 100 to date) with 42 infective episodes requiring or prolonging hospitalisation, following both mobilisation and conditioning and transplantation. There were 7 episodes of viral (re)activation. Temporary flare of Crohn's disease activity or a need for surgery occurred in 8 patients. CONCLUSIONS: Immunoablation and haemopoietic stem cell transplantation appear to be an effective treatment for some patients with Crohn's disease, although full results will be required for a firm conclusion. The risks are significant, making it potentially suitable for only a limited number of patients. Data from the whole trial will be needed to judge whether mobilisation alone has any benefits.

A drunk and disorderly country: a nationwide cross-sectional survey of alcohol use and misuse in Great Britain.

OBJECTIVES: To explore current alcohol drinking patterns, behaviours and attitudes in Great Britain. DESIGN AND SETTING: Independent online cross-sectional survey. PATIENTS AND INTERVENTIONS: Survey of 2221 individuals from a representative panel. MAIN OUTCOME MEASURES AND RESULTS: Excessive alcohol consumption is a widespread problem across Great Britain. Binge-drinking is common among 18-24 year olds, with 19% reporting drinking 10+ drinks on the same drinking day. 'Pre-loading' with alcohol at home before going out was reported by 30% of 18-24-year-old drinkers, of whom 36% get drunk twice or more a month, with 27% having injured themselves while drunk. Among older drinkers, 25% regularly drink to excess, 8% drink seven or more drinks on a typical drinking day and 9% self-reported drink-driving. Male gender was an independent risk factor for heavy (>40 units/week) alcohol abuse (odds ratio 3.05 (95% CI 1.82 to 5.10)). Men (19%) were more likely than women (8%, p<0.001) to report binge-drinking, drink-driving (11% vs 3%, p<0.001), or to have missed work owing to alcohol consumption (12% vs 7%, p<0.001). Young drinkers said they were heavily influenced by overall alcohol price and drink promotions. Increasing average weekly alcohol consumption, age <55 years, male gender, never having been married and being in full-time employment were all independently associated with a history of alcohol-related self-harm. Alcohol abuse was not related to socioeconomic status. CONCLUSIONS: Alcohol abuse remains common across all socioeconomic strata and geographical areas of Great Britain. Minimum pricing strategies and interventions that target cheap on-trade alcohol products seem likely to bring major public health benefits.

High definition colonoscopy vs. standard video endoscopy for the detection of colonic polyps: a meta-analysis.

BACKGROUND AND STUDY AIMS: High definition colonoscopy may improve adenoma detection rates but studies report conflicting results. The aim of this meta-analysis was to compare the diagnostic yield of colonic polyps between high definition colonoscopy and standard video endoscopy (SVE). METHODS: Various electronic databases were searched for articles reporting on high definition colonoscopy. The pooled incremental yield and pooled weighted mean difference of high definition colonoscopy over SVE for polyp detection was determined. RESULTS: Five studies involving 4422 patients provided data on the total number of polyps detected. The incremental yield of high definition colonoscopy for the detection of any polyp was 3.8 % (95 % confidence interval [CI] 1 % - 6.7 %) with a number needed to treat (NNT) of 26. For the detection of adenomatous polyps the incremental yield was 3.5 % (95 %CI 0.9 % - 6.1 %) with an NNT of 28. There were no differences between high definition and SVE in the detection of high risk adenomas, with an incremental yield of -0.1 % (95 %CI -1.7 % to 1.6 %). When grouped according to the overall adenoma detection rate of the studies (> 50 % or < 50 %) the pooled weighted mean difference in small adenoma detection was better with high definition colonoscopy ( P = 0.035). CONCLUSIONS: There were marginal differences between high definition colonoscopy and SVE for the detection of colonic polyps/adenomas. High definition colonoscopy did not improve the detection of high risk adenomas. Due to differences in the adenoma detection rate between the studies and the nonrandomized study design of three of the five studies, these results need to be interpreted with caution. Prospective randomized trials looking at long term outcomes such as rates of interval or missed cancers are needed to clarify the clinical implications.

What you need to know when you prescribe a proton pump inhibitor.

Ever since they were launched, proton pump inhibitors (PPIs) have been regarded as profligate prescription interventions and have become a favourite target for pharmacy advisers. Now that they are cheap, with generic omeprazole 20 mg daily costing £1.88 per month (£24.51 per annum) in the UK, it is time to ask whether this status should be reviewed, whether there are areas where the message should be reversed and whether there are any circumstances in which the extra cost of branded PPIs or combined preparations is justified. Equally, with the recognition of an extended toxicity profile, is prescribing profligacy not an economic but a safety issue?

Meta-analysis: the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with colonic inflammatory bowel disease.

BACKGROUND: Dysplasia in inflammatory bowel disease (IBD) is often multifocal and flat. Dye spraying is believed to enhance visualisation of subtle mucosal abnormalities. AIM: To perform a meta-analysis of the published studies to compare the diagnostic yield of dysplastic lesions in patients with IBD undergoing surveillance colonoscopy between chromoendoscopy and standard white light endoscopy. METHODS: We searched electronic databases for full journal articles reporting on chromoendoscopy in patients with IBD. Pooled incremental yield of chromoendoscopy over white light endoscopy for dysplasia detection was determined. A fixed effects model was used unless there was significant heterogeneity. Publication bias was assessed using Funnel plots or Egger's test. RESULTS: Six studies involving 1277 patients provided data on a number of dysplastic lesions detected. The difference in yield of dysplasia between chromoendoscopy and white light endoscopy was 7% (95% CI 3.2-11.3) on a per patient analysis with an NNT of 14.3. The difference in proportion of lesions detected by targeted biopsies was 44% (95% CI 28.6-59.1) and flat lesions was 27% (95% CI 11.2-41.9) in favour of chromoendoscopy. CONCLUSIONS: Chromoendoscopy is significantly better than white light endoscopy in detecting dysplasia in patients with colonic IBD. This holds true for all dysplastic lesions, proportion of targeted lesions and proportion of flat lesions detected.

Narrow band imaging for characterization of high grade dysplasia and specialized intestinal metaplasia in Barrett's esophagus: a meta-analysis.

BACKGROUND AND STUDY AIM: Narrow band imaging (NBI), a novel endoscopic technique that highlights mucosal surface structures and microvasculature is increasingly advocated as a tool to detect and characterize neoplasia and intestinal metaplasia in patients with Barrett's esophagus. We aimed to assess the diagnostic accuracy of NBI with magnification for the diagnosis of high grade dysplasia (HGD) and specialized intestinal metaplasia (SIM) in patients with Barrett's esophagus. METHODS: We performed a meta-analysis of studies which compared NBI-based diagnosis of HGD and SIM with histopathology as the gold standard. RESULTS: Eight studies including 446 patients with 2194 lesions met the inclusion criteria. For diagnosing HGD, the pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.96 (95 % confidence interval [CI] 0.93-0.99), 0.94 (95 %CI 0.84-1.0), 342.49 (95 %CI 40.49 - 2896.89) and 0.99 (SE 0.01) on a per-lesion analysis with similar results on per-patient analysis.. For the characterization of SIM, the pooled sensitivity, specificity, DOR, and AUC were 0.95 (95 %CI 0.87-1.0), 0.65 (95 %CI 0.52-0.78), 37.53 (95 %CI 6.50-217.62) and 0.88 (SE 0.08) on a per-lesion analysis. CONCLUSION: NBI with magnification is accurate with high diagnostic precision for diagnosis of HGD in Barrett's esophagus on the basis of irregular mucosal pit patterns and/or irregular microvasculature. NBI has high sensitivity but poor specificity for characterizing SIM.

Predictors of gastroduodenal erosions in patients taking low-dose aspirin.

BACKGROUND: Gastroduodenal ulcers are common in patients taking low-dose aspirin. However, the factors predisposing to mucosal erosions, the precursor lesions, are not well known. AIMS: To examine the potential risk factors for the development of erosions in patients chronically taking low-dose aspirin. METHODS: Patients included were taking aspirin 75-325 mg daily for >28 days. Exclusion criteria included use of nonsteroidal anti-inflammatory and ulcer-healing drugs. Demographic data were collected at baseline, prior to endoscopy to determine the frequency and number of erosions and Helicobacter pylori status. In those without ulcer or other exclusions, endoscopy was repeated at 3 months. RESULTS: Fewer patients had gastric erosions if they were H. pylori +ve (48.5% vs. 66.4% in H. pylori-ve patients at baseline, P = 0.17; 40.0% vs. 64.1% at 3 months, P = 0.029). If gastric erosions were present, they were also less numerous in H. pylori +ve patients (3.61 +/- 0.83 vs. 4.90 +/- 0.53 at baseline, P = 0.026; 2.17 +/- 0.68 vs. 5.68 +/- 0.86 at 3 months, P = 0.029). There was a trend (0.1 > P > 0.05) for more gastric erosions in those taking >100 mg/day aspirin. Males had more duodenal erosions at baseline (25.2% vs. 7.5%, P = 0.016). Patient age did not affect the presence or number of erosions. H. Pylori was not significantly associated with duodenal erosion numbers. CONCLUSIONS: Helicobacter pylori infection may partially protect against low-dose aspirin-induced gastric erosions; damage to the stomach appears weakly dose-related; and older age does not increase the risk of erosions.

Clinical trial: a randomized trial of early endoscopy, Helicobacter pylori testing and empirical therapy for the management of dyspepsia in primary care.

BACKGROUND: Early endoscopy, Helicobacter pylori eradication and empirical acid suppression are commonly used dyspepsia management strategies in primary care but have not been directly compared in a single trial. AIM: To compare endoscopy, H. pylori test and refer, H. pylori test and treat and empirical acid suppression for dyspepsia in primary care. METHODS: Patients presenting to their general practitioner with dyspepsia were randomized to endoscopy, H. pylori'test and treat', H. pylori test and endoscope positives, or empirical therapy with symptoms, patient satisfaction, healthcare costs and cost effectiveness at 12 months being the outcomes. RESULTS: At 2 months, the proportion of patients reporting no or minimal dyspeptic symptoms ranged from 74% for those having early endoscopy to 55% for those on empirical therapy (P = 0.009), but at 1 year, there was little difference among the four strategies. Early endoscopy was associated with fewer subsequent consultations for dyspepsia (P = 0.003). 'Test and treat' resulted in fewer endoscopies overall and was most cost-effective over a range of cost assumptions. Empirical therapy resulted in the lowest initial costs, but the highest rate of subsequent endoscopy. Gastro-oesophageal cancers were found in four patients randomized to the H. pylori testing strategies. CONCLUSIONS: While early endoscopy offered some advantages 'Test and treat' was the most cost-effective strategy. In older patients, early endoscopy may be an appropriate strategy in view of the greater risk of malignant disease.

Narrow-band imaging with magnification in Barrett's esophagus: validation of a simplified grading system of mucosal morphology patterns against histology.

BACKGROUND AND STUDY AIMS: Validation of a simplified classification of mucosal morphology in prediction of histology in Barrett's esophagus using narrow-band imaging with magnification (NBI-Z) and assessing its reproducibility by endoscopists experienced in the use of NBI (NBI-experts) and by endoscopists who were new to NBI (non-NBI-experts). PATIENTS AND METHODS: In a prospective cohort study of 109 patients with Barrett's esophagus at a single tertiary referral center, mucosal patterns visualized in Barrett's esophagus on NBI-Z were classified into four easily distinguishable types: A, round pits with regular microvasculature; B, villous/ridge pits with regular microvasculature; C, absent pits with regular microvasculature; D, distorted pits with irregular microvasculature. The NBI-Z grading was compared with the final histopathological diagnosis, and positive (PPV) and negative predictive values (NPV) were calculated. The reproducibility of the grading was then assessed by NBI-expert and non-NBI-expert endoscopists, and interobserver and intraobserver agreement were calculated using kappa statistics. RESULTS: Per-biopsy analysis: In 903 out of 1021 distinct areas (87.9%) the NBI-Z grading corresponded to the histological diagnosis. Per-patient analysis: The PPV and NPV for type A pattern (columnar mucosa without intestinal metaplasia) were 100% and 97% respectively; for types B and C (intestinal metaplasia) they were 88% and 91% respectively, and for type D (high-grade dysplasia) 81% and 99% respectively. Inter- and intraobserver agreement: The mean kappa values in assessing the various patterns were 0.71 and 0.87 in the non-expert group; 0.78 and 0.91 in the expert group. CONCLUSIONS: This study has validated a simplified classification of the various morphologic patterns visualized in Barrett's esophagus and confirmed its reproducibility when used by NBI-expert and non-NBI-expert endoscopists.

Clinical trial: comparison of the gastrointestinal safety of lumiracoxib with traditional nonselective nonsteroidal anti-inflammatory drugs early after the initiation of treatment--findings from the Therapeutic Arthritis Research and Gastrointestinal Event Trial.

BACKGROUND: The large (n = 18 325) Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) study demonstrated a significant gastrointestinal benefit with lumiracoxib 400 mg o.d. (4x the recommended dose in osteoarthritis) vs. naproxen 500 mg b.d. or ibuprofen 800 mg t.d.s. AIM: To investigate how early a reduction in ulcer complications could be detected with lumiracoxib vs. nonselective nonsteroidal anti-inflammatory drugs in TARGET. METHODS: Pointwise 95% confidence intervals were generated for the between-treatment differences in Kaplan-Meier estimates for definite or probable upper gastrointestinal ulcer complications (ulcer complications) and for all ulcers. RESULTS: In patients not on aspirin, there was a significant reduction in all ulcers by day 8 and in ulcer complications by day 16 with lumiracoxib compared with both nonselective nonsteroidal anti-inflammatory drugs combined, by day 6 (all ulcers) and day 14 (ulcer complications) vs. naproxen and by day 32 (all ulcers) and day 33 (ulcer complications) vs. ibuprofen. CONCLUSION: Even with short-term use, there are gastrointestinal safety benefits for lumiracoxib vs. nonselective nonsteroidal anti-inflammatory drugs.

Clinical trial: healing of NSAID-associated gastric ulcers in patients continuing NSAID therapy - a randomized study comparing ranitidine with esomeprazole.

BACKGROUND: The use of non-steroidal anti-inflammatory drugs (NSAID) is associated with an increased risk of gastric ulcer (GU) development. METHODS: This multicentre, randomized, double-blind, parallel-group trial compared endoscopic healing rates at 4 and 8 weeks after treatment with oral esomeprazole 40 or 20 mg once daily, or ranitidine 150 mg twice daily, in patients with 1 baseline GU > or = 5 mm but no GUs or duodenal ulcers >25 mm in diameter who received continued cyclooxygenase-2-selective or non-selective NSAID therapies. The primary outcome was the percentage of patients in each treatment group who had no GUs at week 8. RESULTS: Four hundred and forty patients were randomized to treatment. At week 8, GU healing rates (95% CI) with esomeprazole 40 mg, esomeprazole 20 mg and ranitidine were 85.7 (79.8-91.7)%, 84.8 (78.8-90.8)% and 76.3 (69.2-83.3)%, respectively; between-group differences were not statistically significant. Week-4 GU healing rates were 70.7 (62.9-78.4)% and 72.5 (65.0-79.9)% with esomeprazole 40 and 20 mg, respectively, and were significantly higher (P < 0.01 for both doses) than those with ranitidine [55.4 (47.1-63.7)%]. CONCLUSION: In patients who require continued NSAID therapy, GU healing rates at 8 weeks numerically favoured esomeprazole but were not significantly different from ranitidine.

A randomized, double-blind, placebo-controlled trial of lenalidomide in the treatment of moderately severe active Crohn's disease.

BACKGROUND: Therapy targeted at tumour necrosis factor-alpha has an established role in Crohn's disease. Lenalidomide, an analogue of thalidomide, is an oral immunomodulatory agent with powerful antitumour necrosis factor-alpha properties. It is licensed for myeloma and myelodysplastic syndrome. Based upon reports of thalidomide efficacy, lenalidomide was evaluated in Crohn's disease. AIM: To evaluate the efficacy and safety of lenalidomide in subjects with moderately severe active Crohn's disease. METHODS: In a multicentre, double-blind, placebo-controlled parallel group study 89 subjects were randomized to lenalidomide 25 mg daily, 5 mg daily or placebo. Subjects were treated for 12 weeks. The primary end point was a 70-point reduction in Crohn's Disease Activity Index. RESULTS: The overall clinical response rate was not significantly different between the three groups: lenalidomide 25 mg 26%, lenalidomide 5 mg 48% and placebo 39%. Lenalidomide was generally well tolerated with only one serious adverse event, a deep vein thrombosis, being attributed to treatment. CONCLUSION: Lenalidomide, an oral agent with antitumour necrosis factor-alpha properties, was not effective in active Crohn's disease in contrast to reports of benefit from thalidomide. The reasons for this lack of efficacy are speculative, other physiological activities may offset its action on inflammatory cytokines, or its antitumour necrosis factor-alpha action without apoptosis may be insufficient for activity in Crohn's disease.

Novel endoscopic observation in Barrett's oesophagus using high resolution magnification endoscopy and narrow band imaging.

BACKGROUND: High resolution magnification endoscopy with narrow band imaging (NBI) may improve the detection of specialised intestinal metaplasia (SIM) and dysplasia in Barrett's oesophagus. AIMS: To describe the magnified endoscopic features with the use of NBI in Barrett's oesophagus. METHODS: Three hundred and forty-four areas from 50 patients with Barrett's oesophagus were studied using high resolution magnification endoscopy (HRME) with NBI and targeted biopsies were obtained. The sensitivity, specificity, predictive values of the various patterns for the prediction of SIM and dysplasia were calculated. RESULTS: The magnified endoscopic features of Barrett's oesophagus with the use of NBI consist of microstructural/microvascular patterns. The yield of SIM according to the patterns was: (i) Regular microstructural pattern with tubular/linear/villous pattern 90.6% and with circular pattern 0%; and (ii) Absent microstructural pattern 98.9%. The sensitivity, specificity, positive and negative predictive values of the combination of regular microstructural pattern (tubular/villous/linear) and absent microstructural pattern to detect SIM were 100%, 78.8%, 93.5% and 100%, respectively. The sensitivity, specificity, positive and negative predictive values of the irregular microvascular/microstructural pattern for the prediction of high grade dysplasia were 90%, 100%, 99.2% and 100%, respectively. CONCLUSION: High resolution magnification endoscopy with NBI allows clear visualisation of microstructural and microvascular patterns within Barrett's oesophagus, and allows targeted biopsy with a high yield of SIM and high grade dysplasia.

Efficacy of esomeprazole for resolution of symptoms of heartburn and acid regurgitation in continuous users of non-steroidal anti-inflammatory drugs.

BACKGROUND: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with upper gastrointestinal symptoms such as heartburn and acid regurgitation. AIM: To assess the efficacy of esomeprazole 20 and 40 mg for resolution of heartburn and acid regurgitation in continuous NSAIDs. METHODS: A post hoc analysis of five clinical trials was performed. Two identically designed, placebo-controlled, 4-week studies (NASA1, SPACE1) enrolled non-ulcer, NSAIDs-treated patients with upper abdominal pain, discomfort or burning. PLUTO and VENUS were identically designed, placebo-controlled, 6-month studies that enrolled patients at risk of NSAIDs-induced ulcers. Study 285 was an 8-week comparative study with ranitidine (300 mg/day) in patients with NSAIDs-induced gastric ulcers. Resolution of investigator-assessed heartburn and acid regurgitation was defined as symptom severity of 'none' in the last 7 days. RESULTS: In NASA1/SPACE1, heartburn resolved in 61% and 62% of patients taking esomeprazole 20 and 40 mg, respectively (vs. 36% on placebo, P < 0.001), and acid regurgitation resolved in 65% and 67% (vs. 48%, P < 0.001). Resolution of both symptoms was greater with esomeprazole than with placebo in PLUTO/VENUS (P