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.

SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking.

Over the past 15 years, SCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies recently provided the proof-of-concept that restoration of immunological tolerance can be achieved by haematopoietic SCT in chronic autoimmunity through eradication of the pathologic, immunologic memory and profound reconfiguration of the immune system, that is, immune 'resetting'. Nevertheless, a number of areas remain unresolved and warrant further investigation to refine our understanding of the underlying mechanisms of action and to optimize clinical SCT protocols. Due to the low number of patients transplanted in each centre, it is essential to adequately collect and analyse biological samples in a larger cohort of patients under standardized conditions. The European society for blood and marrow transplantation Autoimmune Diseases and Immunobiology Working Parties have, therefore, undertaken a joint initiative to develop and implement guidelines for 'good laboratory practice' in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after SCT. The aim of this document is to provide practical recommendations for biobanking of samples and laboratory immune monitoring in patients with ADs undergoing SCT, both for routine supportive care purposes and investigational studies.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Endoscopic evaluation of the gastro-duodenal tolerance of short-term analgesic treatment with 25 mg diclofenac-K liquid capsules.

BACKGROUND: Diclofenac-potassium (diclofenac--K) 25 mg liquid capsule is absorbed more quickly than the tablet formulation. It offers potential for rapid pain relief, but may alter gastro-duodenal tolerability. AIM: To evaluate the gastro-duodenal tolerance of diclofenac-K 25 mg liquid capsules vs. diclofenac-K 12.5 mg tablets, acetylsalicylic acid (ASA) 500 mg tablets and ibuprofen 200 mg liquid capsules. METHODS: In an endoscopist-blinded, randomised, parallel-group study, volunteers received 15 doses of diclofenac-K 25 mg liquid capsules (n = 36), diclofenac-K 2 × 12.5 mg tablets (n = 36), ibuprofen 2 × 200 mg liquid capsules (n = 24) or ASA 2 × 500 mg tablets (n = 36) over 5 days. The primary outcome was the incidence of erosive gastro-duodenal lesions at Day 6. Secondary outcomes included modified Lanza score and change in gastric mucosal prostaglandin synthesis. RESULTS: The lowest incidence of erosive gastro-duodenal lesions was with diclofenac-K liquid capsules (53%), compared to 61% with diclofenac-K tablets (P = 0.52), 75% with ibuprofen (P = 0.08) and 94% with ASA (P = 0.001). Results were similar for the Lanza scores, although diclofenac-K liquid capsules were significantly superior to ibuprofen liquid capsules (P = 0.04). Diclofenac-K liquid capsules inhibited prostaglandin synthesis by 52% compared to 64% for diclofenac-K tablets (P = 0.10), 50% for ibuprofen (P = 0.85) and 79% for ASA (P = 0.002). With respect to safety, adverse events were most frequent in the ASA group, predominantly gastrointestinal events. CONCLUSIONS: Mucosal injury with diclofenac-K liquid 25 mg liquid capsules was similar to diclofenac-K 25 mg tablets, significantly lower than ASA 1 g tablets and showed some superiority over ibuprofen 400 mg liquid capsules (EudraCT Number 2009-011278-14).

Haematopoietic SCT in severe autoimmune diseases: updated guidelines of the European Group for Blood and Marrow Transplantation.

In 1997, the first consensus guidelines for haematopoietic SCT (HSCT) in autoimmune diseases (ADs) were published, while an international coordinated clinical programme was launched. These guidelines provided broad principles for the field over the following decade and were accompanied by comprehensive data collection in the European Group for Blood and Marrow Transplantation (EBMT) AD Registry. Subsequently, retrospective analyses and prospective phase I/II studies generated evidence to support the feasibility, safety and efficacy of HSCT in several types of severe, treatment-resistant ADs, which became the basis for larger-scale phase II and III studies. In parallel, there has also been an era of immense progress in biological therapy in ADs. The aim of this document is to provide revised and updated guidelines for both the current application and future development of HSCT in ADs in relation to the benefits, risks and health economic considerations of other modern treatments. Patient safety considerations are central to guidance on patient selection and HSCT procedural aspects within appropriately experienced and Joint Accreditation Committee of International Society for Cellular Therapy and EBMT accredited centres. A need for prospective interventional and non-interventional studies, where feasible, along with systematic data reporting, in accordance with EBMT policies and procedures, is emphasized.

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.

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.

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.

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.

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?

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.

Recall of informed consent information by healthy volunteers in clinical trials.

BACKGROUND: Information sheets for clinical research are becoming increasingly complex but the extent to which they are understood is uncertain. AIMS: To assess, as our primary outcome, recall by healthy volunteers of key facts in a patient information sheet in a phase 3 clinical trial. As secondary outcomes, we examined whether there was a difference between medical student and non-medically trained volunteers. DESIGN: Questionnaire to determine recall by healthy volunteers of informed consent information. METHODS: Eighty-two healthy volunteers participating in a capsule endoscopy study were given a 13 page written information sheet and allowed to asked questions. After indicating they were ready to give consent they were asked to complete a 6-item questionnaire covering the identity and adverse effects of trial treatments and of the procedure, the duration of the trial and value of the inconvenience allowance. RESULTS: All 82 healthy volunteers were questioned. Of the volunteers, 74 (90%) had university level education and 49 (60%) were clinical medical students. However, only 10 subjects (12%) could name the three trial drugs. The maximum number of risks remembered was 6 (n = 2) of 23. Only 14 (17%) could name three or more potential risks of the medication they might be exposed to, whilst 17 (20%) could identify none. Most subjects (77/82, 90%) identified capsule endoscopy as the trial procedure and impaction/obstruction as its main risk (52/82, 64%). All but one subject (98.8%) could recall the exact value of the inconvenience payment. CONCLUSION: A comprehensive information sheet resulted in limited recall of trial risks. Shorter information sheets with a test and feedback session should be trialled so that informed consent becomes valid informed consent.

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.