A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease.

AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.

Intestinal permeability is increased in a proportion of spouses of patients with Crohn's disease.

OBJECTIVE: Increased small intestinal permeability has been found in patients with Crohn's disease and in a proportion of their healthy relatives. This may reflect a shared environment or shared genes. The finding of abnormal permeability in the healthy spouses of patients would favor an environmental cause for this observation. METHODS: The healthy spouses of patients with Crohn's disease attending three gastroenterology clinics were invited to participate. Eligible subjects consumed a 350-ml solution containing lactulose, mannitol, and sucrose before bedtime. All overnight urine was collected, assayed by high performance liquid chromatography, and the ratio of fractional excretion of lactulose to mannitol was calculated as an index of permeability. The results were compared with those of a previously determined control group. RESULTS: Sixty spouses completed the study. Increased permeability was present in eight (13.3%, 95% CI = 6.0-24.6%). The presence of increased permeability was not related to age, gender, duration of cohabitation, alcohol use, nonsteroidal anti-inflammatory drug use or to disease activity in the patient with Crohn's disease. There was a nonsignificant trend for abnormal permeability to occur in those spouses cohabiting with the patient with Crohn's disease at the time of disease diagnosis (p = 0.128). CONCLUSIONS: Small intestinal permeability is increased in a proportion of healthy spouses of patients with Crohn's disease. The presence of abnormal permeability studies in patients with Crohn's disease and a proportion of their healthy close contacts suggests that this phenomenon is caused by environmental factors.

Giant cell myocarditis, in a patient with Crohn's disease, treated with etanercept--a tumour necrosis factor-alpha antagonist.

Cardiac disease in association with inflammatory bowel disease (IBD) is uncommon. Reports include pericarditis, pericardial effusion, myocarditis, myocardial infarction, endocarditis and arrythmias. Myocardial inflammation related to IBD may be due to a drug hypersensitivity reaction or micronutrient deficiency, or may be secondary to the underlying IBD as an extraintestinal manifestation. In this setting, myocarditis usually presents as congestive heart failure and/or refractory arrhythmia. Prognosis varies among reported cases, including complete recovery, remission with recurrence and fatal disease. Treatment of myocarditis has included aminosalicylates and immunosuppressive medications. Recently, newer therapies for IBD have been developed, such as tumour necrosis factor-alpha (TNF-a) antagonists. The present report describes a case of a 46-year-old man with clinical and endoscopic evidence of moderately active colonic Crohn's disease who developed congestive heart failure due to giant cell myocarditis. Little clinical improvement occurred with immunosuppressive therapy. Only after the addition of etanercept, a TNF-a p75 receptor antagonist, did complete clinical resolution occur. These authors conclude that the use of TNF-a antagonists may be considered in the treatment of life-threatening extraintestinal manifestations of inflammatory bowel disease.

Attitudes toward smoking and smoking behaviors of patients with Crohn's disease.

OBJECTIVE: To examine the smoking behaviors of people with Crohn's disease. In active smokers, we measured their willingness to quit, their degree of nicotine dependence, and the proportion that made a quit attempt within 6 months to determine if they were refractory to smoking cessation in comparison to the general population. We also examined factors that were important in their decision to smoke. METHODS: We conducted a cross-sectional survey of out-patients, supplemented by telephone interviews and a 6-month follow-up questionnaire of active smokers. Measures included disease activity, current smoking behaviors, intentions (stage of change), Fagerstrom Test for Nicotine Dependence, and factors related to their decision to smoke (decisional balance). RESULTS: The questionnaire was completed by 115 patients (78% response rate). Forty percent were active smokers. Of active smokers, 59% were considering quitting within the next 6 months, and of these, 15% were planning on quitting within the next 30 days. Those with moderate disease activity were more likely to be considering quitting than those with mild or severe activity. Nicotine dependence was rated as high in 33% and as moderate in 43%. Factors unrelated to Crohn's disease were more important in their decision to smoke than were Crohn's disease-related factors. After 6 months, 23% had made an attempt to quit and this attempt was strongly associated with their stated intentions at the baseline questionnaire. Two of three patients who had recently quit at baseline had resumed smoking. CONCLUSION: When compared to similar data for the general population, patients with Crohn's disease are no more refractory to smoking cessation.

An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial.

BACKGROUND & AIMS: We evaluated CDP571, a humanized antibody to tumor necrosis factor, for the treatment of active Crohn's disease. METHODS: One hundred sixty-nine patients with moderate-to-severe Crohn's disease were enrolled in a 24-week placebo-controlled trial. Patients were initially randomized to a single dose of 10 or 20 mg/kg CDP571 or placebo to assess dose response. Patients were then retreated with 10 mg/kg CDP571 or placebo every 8 or 12 weeks to assess subsequent dosing intervals. The primary endpoint was clinical response at week 2, defined as a decrease in the Crohn's Disease Activity Index score > or = 70 points. RESULTS: At week 2, clinical response occurred in 45% of CDP571-treated patients compared with 27% of patients in the placebo group (P = 0.023). Patients appeared to benefit from retreatment with CDP571 over 24 weeks, but not all of the results for secondary endpoints were statistically significant. The frequency of severe or serious adverse events was similar among all groups. CONCLUSIONS: CDP571 at an initial dose of 10 or 20 mg/kg is safe and effective for treatment of patients with moderate-to-severe Crohn's disease. Preliminary evidence suggests that retreatment with 10 mg/kg CDP571 at dose intervals of 8 or 12 weeks may also be beneficial, but additional studies are needed.

Medical management of inflammatory bowel disease: old and new perspectives.

The treatment of inflammatory bowel disease is a continually evolving area and a major focus of the current literature in gastroenterology. As further information is gained in the areas of etiology, pathophysiology, and natural history of the disease, new agents are developed, and management strategies are revised. The contribution of this year's clinically based literature is reviewed in this summary and incorporated into specific management strategies.

Determinants of abstract acceptance for the Digestive Diseases Week--a cross sectional study.

BACKGROUND: The Digestive Diseases Week (DDW) is the major meeting for presentation of research in gastroenterology. The acceptance of an abstract for presentation at this meeting is the most important determinant of subsequent full publication. We wished to examine the determinants of abstract acceptance for this meeting. METHODS: A cross-sectional study was performed, based on abstracts submitted to the DDW. All 17,205 abstracts submitted from 1992 to 1995 were reviewed for acceptance, country of origin and research type (controlled clinical trials (CCT), other clinical research (OCR), basic science (BSS)). A random sub-sample (n = 1,000) was further evaluated for formal abstract quality, statistical significance of study results and sample size. RESULTS: 326 CCT, 455 OCR and 219 BSS abstracts were evaluated in detail. Abstracts from N/W Europe (OR 0.4, 95% CI 0.3-0.6), S/E Europe (OR 0.4, 95% CI 0.2-0.6) and non-Western countries (OR 0.3, 95% CI 0.2-0.5) were less likely to be accepted than North-American contributions when controlling for research type. In addition, the OR for the acceptance for studies with negative results as compared to those with positive results was 0.4 (95% CI 0.3-0.7). A high abstract quality score was also weakly associated with acceptance rates (OR 1.4, 95% CI 1.0-2.0). CONCLUSIONS: North-American contributions and reports with statistically positive results have higher acceptance rates at the AGA. Formal abstract quality was also predictive for acceptance.

Quality of life rapidly improves with budesonide therapy for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group.

Our aims were to assess the impact on health-related quality of life (HRQOL) of a controlled ileal release (CIR) formulation of budesonide in active Crohn's disease (CD) and further define the role of HRQOL, using the Inflammatory Bowel Disease Questionnaire (IBDQ), in assessing outcome in CD. A randomized trial was conducted in 258 patients with active ileal or ileocecal CD. Budesonide CIR 1.5 mg, 4.5 mg, 7.5 mg, or placebo was given b.i.d. for 8 weeks. IBDQ score changes were compared among groups. Correlations for IBDQ and Crohn's Disease Activity Index (CDAI) scores were calculated. Mean IBDQ scores improved significantly over placebo by 2 weeks in budesonide 15 mg (155+/-38; p = 0.006) and 9 mg groups (157+/-33; p = 0.0002). Bowel, systemic, social, and emotional subscores were also significantly better (p < 0.002) at 2 and 8 weeks in the 9 mg group. Improved HRQOL scores correlated well with decreased CDAI (-0.8 < r < -0.4). Average per item change in IBDQ at remission was 1.17 to 1.48. Prior surgery (p < 0.005) or current smoker (p < 0.05) status predicted poorer initial HRQOL but not response. Budesonide CIR 9 or 15 mg/day rapidly and significantly improved HRQOL in active CD.

Azathioprine for maintaining remission of Crohn's disease.

OBJECTIVES: To assess the effectiveness of azathioprine in maintaining remission of quiescent Crohn's disease. SEARCH STRATEGY: Pertinent studies were selected using the MEDLINE data base (1966 - May 1998), the Cochrane Controlled Trials Register, the Inflammatory Bowel Disease Trials Register, as well as abstracts from major gastrointestinal research meetings and references from published articles and reviews. SELECTION CRITERIA: Five randomized, double-blind, placebo-controlled trials of azathioprine therapy were identified. Two of these trials consisted solely of patients with quiescent Crohn's disease. Three trials had multiple therapeutic arms for both induction of remission and maintenance of remission. DATA COLLECTION AND ANALYSIS: Data were extracted by three independent observers (GRM, GF, LRS) based on the intention to treat principle. Peto odds ratios for the overall maintenance of remission, steroid sparing, and withdrawals due to adverse effects were calculated, and from these, 95% confidence intervals were derived. Numbers needed to treat or harm (NNT, NNH respectively) for the maintenance of remission, steroid sparing, and withdrawals due to adverse effects were also determined. MAIN RESULTS: Azathioprine had a positive effect on maintaining remission. The Peto odds ratio for maintenance of remission was 2.16 (CI 1.35 - 3.47) with an NNT of 7. A higher dose improved response. A steroid sparing effect was noted, with a Peto odds ratio of 5.22 (CI 1.06 - 25.68) and NNT of 3 for quiescent disease. The Peto odds ratio for withdrawals due to adverse events was 4.36 (CI 1.63 - 11.67), the NNH (Number Needed to Harm) was 19. REVIEWER'S CONCLUSIONS: Azathioprine is effective in maintaining remission. There is evidence for a steroid sparing effect.

Defining the role of fiberoptic sigmoidoscopy in the investigation of patients presenting with bright red rectal bleeding.

OBJECTIVE: This study was done to determine whether sigmoidoscopy could theoretically constitute sufficient investigation for some patients with bright red rectal bleeding. METHODS: One hundred and forty-three patients undergoing investigative colonoscopy for bright red rectal bleeding and whose source of bleeding was identified were studied. The investigation took place in a large urban hospital over an 11-month period. Data obtained included changes in stool pattern, characteristics of the bleeding, lesions identified, and the distance of the lesion from the anus. RESULTS: In patients younger than 55 yr, all serious lesions except for one malignancy in a patient with massive bleeding lay within 60 cm of the anus and theoretically within reach of the fiberoptic sigmoidoscope. The mixing of red blood with stool was commonly due to distal lesions, especially hemorrhoids. CONCLUSIONS: In young persons with bright red rectal bleeding, fiberoptic sigmoidoscopy may prove to constitute appropriate initial investigation.

A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998.

Crohn's disease is a heterogeneous entity. Previous attempts of classification have been based primarily on anatomic location and behavior of disease. However, no uniform definition of patient subgroups has yet achieved broad acceptance. The aim of this international Working Party was to develop a simple classification of Crohn's disease based on objective variables. Eight outcome-related variables relevant to Crohn's disease were identified and stepwise evaluated in 413 consecutive cases, a database survey, and by clinical considerations. Allocation of variables was conducted with well-defined Crohn's disease populations from Europe and North America. Cross-table analyses were performed by chi-square testing. Three variables were finally elected: Age at Diagnosis [below 40 years (A1), equal to or above 40 years (A2)], Location [terminal ileum (L1), colon (L2), ileocolon (L3), upper gastrointestinal (L4)], and Behavior [nonstricturing nonpenetrating (B1), stricturing (B2), penetrating (B3)]. The allocation of patients to these 24 subgroups proved feasible and resulted in specific disease clusters. Cross-table analyses revealed associations between Age at Diagnosis and Location, and between Behavior and Location (all p < 0.001). The Vienna classification of Crohn's disease provides distinct definitions to categorize Crohn's patients into 24 subgroups. Operational guidelines should be used for the characterization of patients in clinical trials as well as for correlation of particular phenotypes with putative biologic markers or environmental factors.

Helping patients with Crohn's disease quit smoking.

Smoking is not only a risk factor for Crohn's disease, but ongoing smoking is associated with a poorer disease course. Therefore, smoking cessation should be an important treatment strategy for Crohn's disease patients who smoke tobacco. Recent improvements in understanding how people quit smoking and the development of pharmacological interventions, such as nicotine patches and bupropion, have improved cessation rates. In this article, we first briefly review the evidence supporting the adverse effects of smoking on the disease course. We next review the current understanding of how people change addictive behaviors, such as smoking. We then describe how the gastroenterologist can aid the patient with Crohn's disease to quit smoking, including appropriate and brief counseling strategies and the use of adjunctive treatments. Given the improvements in smoking cessation strategies, all patients with Crohn's disease should be strongly advised to quit smoking and be aided in doing so.

Prevention of relapse of Crohn's disease.

Until a cure for Crohn's disease(s) is found, strategies that prolong the time spent in remission offer the greatest hope for reducing the morbidity and significant social costs associated with the disease. Medical therapy to date has been disappointing, and the search for a safe, effective therapy that could be offered at low cost continues. The aminosalicylates, so effective in ulcerative colitis, have shown, at best, minimal efficacy in maintaining remission in Crohn's disease. Conventional corticosteroids are not effective, and any reduction in time to relapse for budesonide-treated patients is measured in weeks not months. Azathioprine, 6-mercaptopurine, and methotrexate are effective in maintaining remission, but all three have significant side effects. Antibiotics may have a role to play. Biological therapy may be considered, but the issues of cost and long-term safety require evaluation. Future studies should segregate patients into two groups, those with a medically induced remission and patients whose concern is the prevention of postoperative recurrence.

Gastric cancer and other endoscopic diagnoses in patients with benign dyspepsia.

BACKGROUND: It has been suggested that endoscopy could be replaced with non-invasive assessment of helicobacter status in the initial work up of young dyspeptic patients without sinister symptoms. AIMS: To determine the incidence of gastro-oesophageal malignancy in young dyspeptic patients. METHODS: The Alberta Endoscopy Project captured clinical and demographic data on all endoscopies performed from April 1993 to February 1996 at four major adult hospitals in Alberta. The endoscopic and histological diagnosis in a subgroup of patients under 45 years of age without alarm symptoms that had undergone gastroscopy was reviewed. In addition, a random list of 200 patients was generated and their medical records reviewed in order to assess the proportion with symptoms suitable for a non-invasive management strategy. RESULTS: Gastroscopy was performed in 7004 patients under 45 years. In 3634 patients (56% female) alarm type symptoms were absent; 78.9% of patients had symptoms amenable to a non-invasive initial approach, giving a corrected sample size of 2867 patients (correction factor 0.789). Three gastric cancers, one case of moderate dysplasia, 10 biopsy proved cases of Barrett's oesophagus, and 19 oesophageal strictures/rings were detected within this sample. The corrected prevalence of gastric cancer in this select population was 1.05 per thousand patients. DISCUSSION: Endoscopy yielded three gastric cancers in this sample of under 45 year old dyspeptic patients without sinister symptoms. While initial non-invasive screening with one-week triple therapy for helicobacter positive individuals is unlikely to have a detrimental outcome the physician is advised to consider endoscopy in patients with persisting, recurrent, or sinister symptoms.

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of