Trevor Winter

A COMPARISON OF BUDESONIDE AND MESALAMINE FOR ACTIVE CROHN'S DISEASE

Background Crohns disease is often treated with glucocorticoids or mesalamine. We compared the efficacy and safety of controlled-ileal-release budesonide capsules and slow-release mesalamine tablets in patients with active Crohns disease affecting the ileum, the ascending colon, or both. Methods In a double-blind, multicenter trial, we enrolled 182 patients with scores of 200 to 400 on the Crohns Disease Activity Index (with higher scores indicating greater disease activity) and randomly assigned 93 to receive 9 mg of budesonide once daily and 89 to receive 2 g of mesalamine twice daily for 16 weeks. The primary efficacy variable was clinical remission, defined as a score of 150 or less on the Crohns Disease Activity Index. Results In the analysis of all patients who received at least one dose of study drug, the rates of remission after 8 weeks of treatment were 69 percent in the budesonide group and 45 percent in the mesalamine group (P=0.001); the respective rates after 16 weeks of treatment were 62...

Intravenous CDP870, a PEGylated Fab′ fragment of a humanized antitumour necrosis factor antibody, in patients with moderate‐to‐severe Crohn's disease: an exploratory study

Background : CDP870 is a PEGylated Fab′ fragment of a humanized monoclonal antibody that neutralizes tumour necrosis factor‐α.

Switch from systemic steroids to budesonide in steroid dependent patients with inactive Crohn's disease

BACKGROUND Steroid dependent patients with Crohns disease are at high risk of developing glucocorticosteroid induced side effects. AIMS We evaluated the possibility of switching from systemic steroids to budesonide (Entocort) in prednisolone/prednisone dependent patients with inactive Crohns disease affecting the ileum and/or ascending colon. PATIENTS Steroid dependent patients with a Crohns disease activity index ⩽200 were included. METHODS In a double blind multicentre trial, 120 patients were randomly assigned to receive budesonide 6 mg once daily or placebo. Prednisolone was tapered to zero during the first 4–10 weeks and budesonide or placebo was given concomitantly and for a further 12 weeks. Relapse was defined as an index >200 and an increase of 60 points from baseline or withdrawal due to disease deterioration. RESULTS After one and 13 weeks without prednisolone, relapse rates were 17% and 32%, respectively, in the budesonide group, and 41% and 65% in the placebo group (95% confidence intervals for the difference in percentages −41%, −8% and −51%, −16%; p=0.004 and p<0.001, respectively). The number of glucocorticosteroid side effects was reduced by 50% by switching from prednisolone and was similar in the budesonide and placebo groups. Basal plasma cortisol increased in both groups. CONCLUSIONS The majority of patients with steroid dependent ileocaecal Crohns disease may be switched to budesonide controlled ileal release capsules 6 mg without relapse, resulting in a sharp decrease in glucocorticosteroid side effects similar to placebo, and with an increase in plasma cortisol levels.

The effect of severe undernutrition, and subsequent refeeding on digestive function in human patients.

Background Severe undernutrition may adversely affect gut function. Aims To investigate the effects of severe undernutrition and subsequent refeeding on human digestive function. Methods Severely undernourished patients (body mass index (BMI) < 17 kg/m2) were studied before, and after a period of intensive nutritional support. Standard intestinal absorption tests (faecal fat and urinary xylose excretion), pentagastrin‐stimulated acid secretion, and cholecystokinin octapeptide (CCK‐8)‐stimulated pancreatic enzyme secretion tests were performed. In addition, duodenal biopies were taken to assess gut mucosal morphology. Findings were evaluated in comparison to a group of normal healthy volunteers. Results Mean BMI of the patients prior to nutritional support was 13.41 kg/m2, with improvement to 16.12 kg/m2 after. Duodenal histology showed evidence of villous atrophy in six of 14 (43%) undernourished patients. Mean xylose excretion following a 5 g oral dose was 0.62 g/5 h in the group of undernourished patients prior to nutritional support (normal > 1 g/5 h), with improvement to 1.40 g/5 h (P < 0.01) after feeding. Maximal gastric acid output was significantly impaired in the undernourished group, as compared to the controls (6.94 mEq/l vs 25.53 mEq/l, P < 0.02), with a significant improvement to 12.30 mEq/I (P < 0.05) following nutritional support. Pancreatic enzyme output was significantly reduced (amylase 830.9 U/h vs 2304 U/h, P < 0.01; lipase 38.0 U/h vs 118.6 U/h, P < 0.01; trypsin 119.7 U/h vs 341.4 U/h, P < 0.01). Following a period of nutritional support there was a significant improvement in amylase and lipase outputs to 1819 U/h and 85.5 U/h, respectively (P < 0.01). These levels were not significantly different from the normal controls. Trypsin output, however, remained significantly impaired at 174.3 U/h (P < 0.01). Conclusions Severe undernutrition is associated with significant impairment of digestive function, with improvement occurring following nutritional support. These changes may affect initial tolerance to enteral feeding, particularly in those patients with co‐existent gut disease. Eur J Gastroenterol Hepatol 12:191‐196

Budesonide and mesalazine in active Crohn's disease: a comparison of the effects on quality of life.

OBJECTIVES:Controlled ileal release budesonide and slow release mesalazine are both used to treat mild to moderate active Crohns disease, although data show that budesonide is more effective in inducing remission. When comparing different treatment options, the effects of agents on health-related quality of life must be considered as well as efficacy. In this study, we sought to compare the effects of budesonide and mesalazine on the health-related quality of life of patients with active Crohns disease.METHODS:The study included 182 patients with Crohns Disease Activity Index scores between 200 and 400. Patients were randomized in a double blind, double dummy, multicenter study to receive 9 mg of budesonide, once daily (n = 93), or 2 g of mesalazine, b.i.d. (n = 89), for 16 wk. Quality of life was assessed at baseline and after 2, 4, 8, 12, and 16 wk of treatment using the Psychological General Well-Being index. In addition, a physicians global evaluation was used to assess how symptoms affected patients’ normal activities.RESULTS:Patients treated with budesonide experienced significantly greater improvement in Psychological General Well-Being scores than the group treated with mesalazine after 2, 8, 12, and 16 wk. All components of this index showed greater improvements in the budesonide-treated group than in the mesalazine group at 12 and 16 wk. The physicians global evaluation showed significantly greater improvements in the budesonide group than in the mesalazine group at all visits.CONCLUSION:Budesonide (9 mg once daily) improves health-related quality of life to a greater extent than mesalazine (2 g b.i.d.) in patients with mild to moderate active Crohns disease.

The −237C→T promoter polymorphism of the SLC11A1 gene is associated with a protective effect in relation to inflammatory bowel disease in the South African population

The purpose of this study was to assess the likelihood that variation in the promoter region of the solute carrier family 11 member 1 gene (SLC11A1) contributes to inflammatory bowel disease (IBD) susceptibility in the South African population. The study cohort included 102 IBD patients, 47 with Crohns disease (CD) and 55 with ulcerative colitis, and 192 population-matched controls. Mutation analysis revealed two novel alleles for the 5′-(GT)n repeat polymorphism, t(gt)5ac(gt)5ac(gt)6ggcaga(g)6 (allele 8) and t(gt)5ac(gt)5ac(gt)8ggcaga(g)6 (allele 9), and one previously documented point mutation −237C→T. A significantly decreased frequency of the −237C→T promoter polymorphism was observed in the patient group with IBD (p<0.001) and CD (p<0.0006) compared with the population-matched control group. These findings may be related to previous in vitro studies, which demonstrated that the point mutation at nucleotide position −237 represents a functional polymorphism that affects regulation of the upstream 5′-(GT)n repeat polymorphism differentially upon iron loading. Our findings raise the possibility that iron dysregulation mediated by allelic effects of SLC11A1 may contribute to IBD susceptibility.

Sucralfate and Methylprednisolone Enemas in Active Ulcerative Colitis (A Prospective, Single-Blind Study)

In order to investigate the role of sucralfatein active ulcerative colitis, 60 patients wererandomized to receive either sucralfate enemas (20 g/100ml) or methylprednisolone enemas (20 mg/100 ml). The enemas were administered twice daily for oneweek, and then once daily for three weeks. Clinicalevaluation was documented at entry and at two weeks andfour weeks. The sigmoidoscopic appearance of the rectal mucosa was scored, and rectal biopsiestaken at entry and at four weeks. Results indicatedsimilar reduction in diarrhea and rectal bleeding at twoweeks and at four weeks. Sigmoidoscopy demonstrated similar significant improvement in themacroscopic appearance of the rectal mucosa in bothgroups (8.28 to 6.20 in sucralfate group, P < 0.02;and 8.72 to 6.36 in the methylprednisolone treatedgroup, P < 0.04). Histologic assessment, likewise,showed similar improvements in the two groups. Thisstudy indicates that sucralfate enemas may be useful inthe treatment of ulcerative proctosigmoiditis.

The Effect of Severe Undernutrition and Subsequent Refeeding on Whole-Body Metabolism and Protein Synthesis in Human Subjects

BACKGROUND To determine the consequences of severe undernutrition and refeeding on whole-body metabolism and protein synthesis. METHODS Respiratory quotient (RQ), resting energy expenditure (REE), and whole-body protein synthesis (WBPS) were assessed in undernourished patients, with anorexia nervosa (n = 8) or with coexistent disease (n = 17). Results were compared with 17 healthy controls. Six anorexic patients and 13 disease patients consented to study after nutrition support. RESULTS Mean body mass index was 12.46 +/- 0.53 kg/m2 in the anorexia patients and 13.81 +/- 0.40 kg/m2 in the disease patients (controls 23.71 +/- 0.72 kg/m2; p < .001). Compared with controls, RQ was similar in anorexia patients (0.85 +/- 0.05 vs 0.90 +/- 0.05) but lower in the disease patients (0.76 +/- 0.03 vs 0.90 +/- 0.05; p = .02). REE was lower in the patients (anorexia 1058 +/- 134.0 kcal/d, disease 1189 +/- 101.4 kcal/d vs 1828 +/- 89.76 kcal/d; p < .001); however, expressed as kcal/kg/d, it was higher (anorexia 32.17 +/- 4.25, disease 31.30 +/- 2.14 vs 25.07 +/- 1.00; p < .05). WBPS was lower in the patients (anorexia 140.9 +/- 10.54 g/d, disease 119.8 +/- 8.57 g/d vs 305.0 +/- 21.64 g/d; p < .001); however, when expressed as g/kg/d, the anorexia patients were similar to controls, whereas the disease patients were lower (3.11 +/- 0.24 vs 4.27 +/- 0.32; p < .05). Refeeding increased RQ in the disease patients (0.84 +/- 0.03 vs 0.76 +/- 0.03; p < .05), and normalized REE (anorexia 27.65 +/- 3.05 kcal/kg/d, disease 28.90 +/- 1.85 kcal/kg/d). WBPS increased in the disease patients (173.6 +/- 16.38 g/d vs 116.5 +/- 10.15 g/d; p < .01). CONCLUSIONS Undernutrition is associated with increased REE (kcal/kg/d). Reduction in RQ and protein synthesis (g/kg/d) was evident in those patients with coexistent disease. Refeeding resulted in normalization of RQ, REE (kcal/kg/d), and protein synthesis (g/kg/d).

Gastroduodenal Crohn's Disease Is Associated With NOD2/CARD15Gene Polymorphisms, Particularly L1007PHomozygosity

Limited data exist on the specific association between gastroduodenal Crohns disease (GDCD) and NOD2/CARD15gene polymorphisms. The aim of this study was to assess the association between NOD2polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702Wand the clinical features of Crohns disease. We retrospectively reviewed the records of 202 patients with confirmed Crohns disease and complete data was performed. Seventy-one patients (35%) had at least 1 allelic variant: 55 had 1 variant, 4 were homozygous for L1007fs, 2 homozygous for R702W, and 10 were compound heterozygous. Eighteen patients with confirmed GDCD were identified; 10 (56%) had wild type, 4 (22%) had 1 variant, and 4 (22%) had 2 allelic variants (2 were L1007Phomozygous and 2 compound heterozygous). Compared to patients without gastroduodenal involvement, those with GDCD were more likely to have 2 allelic variants (22% vs. 6%; odds ratio [OR] 2.7; 95% confidence interval [CI] 1.6–7.3) and to be homozygous for L1007P(11% vs. 1%; OR 5.2; 95% CI 2.5–9.4). G908Rheterozygosity was associated with ileal involvement (OR 1.4; 95% CI 1.1–2.9) and smoking habits (OR 2.4; 95% CI 1.2–3.8), whereas L1007Phomozygosity was associated with GDCD (OR 5.8; 95% CI 2.6–10.8). L1007Pvariation was associated with younger age at diagnosis as well. There was no specific association between R702Whomo- or heterozygosity and any of the characteristics examined. In conclusion, GDCD is associated with double dose of the NOD2/CARD15gene variants, particularly L1007Phomozygosity. There is evidence of specific variant-phenotype associations. G908Rheterozygosity is associated with ileal involvement and smoking, whereas L1007Phomozygosity is strongly associated with GDCD and younger age at diagnosis.

Impaired gastric acid and pancreatic enzyme secretion in patients with Crohn's disease may be a consequenece of a poor nutritional state

Introduction:Impaired pancreatic function has been reported in Crohn’s disease, the cause of which is uncertain. This study investigated the effect of malnutrition, and subsequent re-feeding, on digestive function and protein synthesis in Crohn’s disease patients. Methods:Gastric acid and pancreatic secretion studies were performed on malnourished Crohn’s patients before, and after a period of intensive nutritional support. Whole body, as well as pancreatic enzyme protein synthesis was investigated by [14C]leucine isotope incorporation studies. Results were evaluated in comparison to normal healthy volunteers. Results:The mean body mass index (BMI) of the Crohn’s patients was 14.14 kg/m2. The Crohn’s patients had reduction in the secretion of gastric acid (7.36 versus 25.53 mEq/h; P < 0.01), and the pancreatic enzymes, amylase (759.6 versus 2305 U/h; P < 0.01), lipase (33.01 versus 118.6 U/h; P < 0.01) and trypsin (97.43 versus 341.4 U/h; P < 0.01). Resting energy expenditure (REE), expressed in relation to body mass, was greater in the malnourished Crohn’s disease patients (38.25 versus 25.36 kcal/kg/d; P = 0.01). Total body protein synthesis was reduced (2.82 versus 4.39 g protein/kg/d; P < 0.05), with significant impairment in the synthesis of pancreatic enzymes, and reduction of zymogen stores. Following re-feeding, the BMI of the Crohn’s patients improved to 16.80±0.66 kg/m2. Pancreatic enzyme synthesis improved, with significant increase in pancreatic enzyme stores and secretion, to levels similar to control values. Gastric acid secretion also improved, although still lower than the control value. Conclusion:Malnutrition may play a significant role in the impairment of gastric acid and pancreatic secretion in Crohn’s disease patients.