Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study.

BACKGROUND AND AIM: The thiopurines azathioprine and 6-mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long-term use of these agents has been linked to a greatly increased risk of non-melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure. METHODS: We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007. RESULTS: We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non-melanoma skin cancer (seven patients) and non-Hodgkin's lymphoma (five patients). A diagnosis of non-melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1-22.8). Six of seven non-melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3-67.4). CONCLUSIONS: Patients with IBD who receive thiopurines are at increased risk of non-melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.

Effect of severe undernutrition and subsequent refeeding on gut mucosal protein fractional synthesis in human subjects.

OBJECTIVE: Undernutrition has been associated with gut mucosal atrophy, impaired absorption, and increased permeability. This study investigated the effect of severe undernutrition and subsequent refeeding on gastric and duodenal mucosal protein fractional syntheses (MPFS). METHODS: MPFS was investigated in the gastric body, antrum, and duodenum of 23 severely undernourished patients by means of (14)C-leucine incorporation into tissue protein and repeated after a period of refeeding. Results were evaluated in comparison with a group of 22 healthy controls and presented as mean +/- standard error of the mean. RESULTS: The mean body index of the undernourished patients was 13.29 +/- 0.33 kg/m(2) versus 22.67 +/- 0.63 kg/m(2) in the controls (P < 0.001). MPFS in the controls and undernourished patients were similar (gastric body, 36.49 +/- 2.88 versus 33.41 +/- 3.08%/d; gastric antrum, 25.51 +/- 2.20 versus 24.95 +/- 2.32%/d; duodenum, 25.90 +/- 2.58 versus 25.49 +/- 1.99%/d). After refeeding, the body mass index of the undernourished patients increased to 15.87 +/- 0.44 kg/m(2) (P < 0.001). The MPFS increased significantly (gastric body, 51.80 +/- 8.12%/d, P < 0.05; gastric antrum, 33.44 +/- 3.66%/d, P < 0.05; duodenum, 46.27 +/- 8.02%/d, P < 0.01), with the MPFS of the duodenum significantly greater than the control values (P = 0.01). CONCLUSION: Despite severe undernutrition, MPFS of the gastric body, antrum, and duodenum remained similar to control values. Enteral feeding resulted in a significant increase in MPFS, indicating a trophic response.

Treatment of Crohn's disease with certolizumab pegol.

Biologic therapies have revolutionized the treatment of Crohn's disease (CD). Targeting TNF-alpha with monoclonal antibodies has changed the therapeutic landscape for tackling refractory and complicated CD. Intravenous use of infliximab, a chimeric monoclonal antibody to TNF-alpha is, however, limited by the occurrence of adverse events, infusion reactions, infectious complications, aggravation of heart failure, the occurrence of neurological demyelinating conditions and induction of rare malignancies. The incremental development of next-generation TNF-alpha antibodies and binding proteins through antibody-engineering techniques has followed, with the aim of producing efficacious drugs that are less expensive to produce, have a convenient route of administration and have fewer side effects. Certolizumab pegol (CDP870, Cimzia) is an engineered humanized anti-TNF-alpha antibody Fab fragment that minimizes the protein component and is conjugated to polyethylene glycol. Clinical studies have demonstrated efficacy in the treatment of moderate-to-severe active CD. Reported adverse events in the clinical trial program have been largely of mild-to-moderate severity, and occurred at similar frequencies in the active-treatment and placebo groups. Certolizumab pegol will be a useful addition to the armamentarium of biologic agents that can be used for the long-term treatment of CD.

The effects of undernutrition and refeeding on metabolism and digestive function.

PURPOSE OF REVIEW: An intimate interrelationship exists between nutritional status and gut function. This review focuses on the consequences of a poor nutritional state on metabolism and digestive function, and evaluates the effects of refeeding. RECENT FINDINGS: Severe undernutrition has been associated with increased fat and protein catabolism, reflected by a decreased respiratory quotient. Resting energy expenditure assessed in relationship to body weight was increased, probably as a consequence of changes in body composition. Protein synthesis, expressed per kg body weight, was decreased in undernourished patients with coexistent disease, but not in anorexia nervosa patients, indicating the detrimental effects of disease states. Severe undernutrition is associated with malabsorption, which improves following refeeding. Despite a high prevalence of villous atrophy in the duodenal mucosa in undernourished patients, mucosal protein fractional synthesis rates appeared normal. Refeeding resulted in a potent trophic response, and normalization of the mucosal morphology. Gastric and pancreatic secretion was significantly impaired by the undernourished state, with significant improvement following refeeding. SUMMARY: Undernutrition is associated with impairment of digestive function, which is likely to further aggravate the nutritional state. Refeeding corrects this dysfunction, and results in disruption of this vicious circle.

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 Crohn's 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.

Gastroduodenal Crohn's disease is associated with NOD2/CARD15 gene polymorphisms, particularly L1007P homozygosity.

Limited data exist on the specific association between gastroduodenal Crohn's disease (GDCD) and NOD2/CARD15 gene polymorphisms. The aim of this study was to assess the association between NOD2 polymorphisms and GDCD, and to assess the specific association between each of the 3 major allelic variants G908R, L1007P, and R702W and the clinical features of Crohn's disease. We retrospectively reviewed the records of 202 patients with confirmed Crohn's 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 L1007P homozygous 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). G908R heterozygosity 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 L1007P homozygosity was associated with GDCD (OR 5.8; 95% CI 2.6-10.8). L1007P variation was associated with younger age at diagnosis as well. There was no specific association between R702W homo- or heterozygosity and any of the characteristics examined. In conclusion, GDCD is associated with double dose of the NOD2/CARD15 gene variants, particularly L1007P homozygosity. There is evidence of specific variant-phenotype associations. G908R heterozygosity is associated with ileal involvement and smoking, whereas L1007P homozygosity is strongly associated with GDCD and younger age at diagnosis.

Gastric and duodenal mucosal protein fractional synthesis and growth factor expression in patients with H. pylori-associated gastritis before and after eradication of the organism.

Our purpose was to study the effect of Helicobacter pylori (HP) on mucosal protein fractional synthesis (MPFS) and growth factor expression. 14C-leucine incorporation, and TGF-alpha, beta-FGF, and EGF-receptor levels were assessed in gastric and duodenal mucosa in 20 patients with HP-associated gastritis and repeated after treatment of the gastritis, with or without eradication of the organism. At entry, MPFS in the fundus, antrum, and duodenum was 43.1, 38.2, and 28.3%/day, respectively. Following HP eradication, fundal and antral rates fell to 28.1 and 21.4%/day (P < 0.05), whereas the duodenum was unchanged. MPFS in the patient subset not eradicated remained similar to entry values (35.9, 31.6, and 25.4%/day). Expression of TGF-alpha, beta-FGF, and EGF receptors was unchanged. Eradication of HP results in reduction of gastric, but not duodenal, MPFS and has no effect on the growth factors measured. Increased MPFS associated with HP gastritis may relate to the potential for neoplastic transformation.

Investigation of HLA-DPA1 genotypes as predictors of inflammatory bowel disease in the German, South African, and South Korean populations.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a polygenic disorder, as demonstrated by epidemiological evidence, genetic linkage, and the identification of the first susceptibility gene, NOD2. Genetic linkage analysis has identified and replicated several genomic regions as locations for susceptibility genes, including chromosome 6p (termed IBD3). The HLA-DP genes play an important role in antigen presentation and are located within the chromosome 6p linkage region. PATIENTS AND METHODS: We investigated HLA-DPA1 as a positional and functional candidate gene for IBD using 249 German multiplex IBD families, 174 unrelated German controls, 48 monoplex families from a mixed South African population, 87 IBD patients, and 71 controls from a South Korean sample. Polymorphisms in exon 2 at amino acid positions 31, 37-38 and 50 were genotyped using direct sequencing. Analyses were performed using chi(2) statistics, multipoint transmission disequilibrium test and nonparametric linkage analysis. RESULTS: A marginally significant association for Crohn's disease was detected in the German family cohort for DPA1*02021. This finding was not replicated in ulcerative colitis or any of the other populations. CONCLUSION: HLA-DPA1 is not a major determinant of IBD risk in any of the three populations. The transmission distortion observed in the German cohort may indicate an extended haplotype, suggesting another disease relevant gene in the vicinity of HLA-DPA.