Klaas van der Linde

Association between Toll-like receptor 4 and inflammatory bowel disease.

Background: The human Toll‐like receptor 4 (TLR4) participates in the innate response. Recently, the TLR4 variant Asp299Gly has been described to affect the response of this receptor to lipopolysaccharide. As such, there is a potentially important role of TLR4 in the pathogenesis of inflammatory bowel disease (IBD). We studied the involvement of TLR4 in IBD in a large population of Dutch patients with IBD and in family‐based controls. Methods: In 781 IBD cases and 315 controls, genotyping was performed for Asp299Gly and Thr399Ile variants and for 4 microsatellite markers flanking TLR4. Association analysis and the were applied. In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohns disease (CD). Results: The haplotype sharing statistic showed association at microsatellite marker D9S1864 with IBD (P = 0.0019), and in particular with CD (P = 0.0025) and at TLR406 with ulcerative colitis (UC; P = 0.027). No association was found for Asp299Gly and Thr399Ile. However, the frequencies of both variant allele carriers were higher among CD cases with a disease onset ≥40 years than among controls. No evidence for interaction between TLR4 and CARD15 was found. Conclusions: Haplotype analysis shows that TLR4 is associated with both CD and UC. The Asp299Gly and Thr399Ile variants do not show an association with CD, UC, or IBD as a group, indicating that these polymorphisms are likely not the causal ones. We propose that the 2 polymorphisms are in linkage with (the) disease susceptibility variant(s) located elsewhere on TLR4.

Colonic stenting as bridge to surgery versus emergency surgery for management of acute left-sided malignant colonic obstruction: a multicenter randomized trial (Stent-in 2 study)

BackgroundAcute left-sided colonic obstruction is most often caused by malignancy and the surgical treatment is associated with a high mortality and morbidity rate. Moreover, these operated patients end up with a temporary or permanent stoma. Initial insertion of an enteral stent to decompress the obstructed colon, allowing for surgery to be performed electively, is gaining popularity. In uncontrolled studies stent placement before elective surgery has been suggested to decrease mortality, morbidity and number of colostomies. However stent perforation can lead to peritoneal tumor spill, changing a potentially curable disease in an incurable one. Therefore it is of paramount importance to compare the outcomes of colonic stenting followed by elective surgery with emergency surgery for the management of acute left-sided malignant colonic obstruction in a randomized multicenter fashion.Methods/designPatients with acute left-sided malignant colonic obstruction eligible for this study will be randomized to either emergency surgery (current standard treatment) or colonic stenting as bridge to elective surgery. Outcome measurements are effectiveness and costs of both strategies. Effectiveness will be evaluated in terms of quality of life, morbidity and mortality. Quality of life will be measured with standardized questionnaires (EORTC QLQ-C30, EORTC QLQ-CR38, EQ-5D and EQ-VAS). Morbidity is defined as every event leading to hospital admission or prolonging hospital stay. Mortality will be analyzed as total mortality as well as procedure-related mortality. The total costs of treatment will be evaluated by counting volumes and calculating unit prices. Including 120 patients on a 1:1 basis will have 80% power to detect an effect size of 0.5 on the EORTC QLQ-C30 global health scale, using a two group t-test with a 0.05 two-sided significance level. Differences in quality of life and morbidity will be analyzed using mixed-models repeated measures analysis of variance. Mortality will be compared using Kaplan-Meier curves and log-rank statistics.DiscussionThe Stent-in 2 study is a randomized controlled multicenter trial that will provide evidence whether or not colonic stenting as bridge to surgery is to be performed in patients with acute left-sided colonic obstruction.Trial registrationCurrent Controlled Trials ISRCTN46462267.

Absence of association between the multidrug resistance (MDR1) gene and inflammatory bowel disease

Objective. The multidrug resistance (MDR1) gene encodes for P-glycoprotein, a drug efflux pump. Mice deficient for the MDR1a gene spontaneously develop colitis. In humans, a polymorphism in exon 26 (C3435T) is associated with reduced expression levels and function of MDR1. Currently there are controversial data on the association between MDR1 and inflammatory bowel disease (IBD). The purpose of this study was to examine the involvement of this gene in IBD in a large population of Dutch patients with IBD and family-based controls. Material and methods. A total of 781 IBD cases and 315 controls were investigated. CD phenotypes were determined according to the Vienna Classification. Individuals were genotyped for six single nucleotide polymorphisms (SNPs) close to and in the MDR1 locus. This included the C3435T variant and six microsatellite markers close to and in the MDR1 locus. Single locus association analysis, haplotype association analysis and haplotype sharing statistic (HSS) were used to search for differences between patients and controls. Results. No association was observed for any of the SNPs with IBD as a group, or for ulcerative colitis, Crohns disease and Crohns disease phenotypes, either by single locus or haplotype association analysis or by HSS. Conclusions. No association was observed between the MDR1 gene and IBD. This suggests that it is unlikely that MDR1 plays a role in IBD susceptibility.

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

BackgroundRecent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications.The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas.Methods/designMulticenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma ≥ 3 cm, located between 1–15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment.Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures.Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group.DiscussionThe TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas.Trial registration number(trialregister.nl) NTR1422

CARD15 mutations in Dutch familial and sporadic inflammatory bowel disease and an overview of european studies

Objectives The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohns disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. Methods Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohns disease, 34 probands with ulcerative colitis and 71 inflammatory bowel disease-affected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohns disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. Results In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohns disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohns disease (P=0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohns disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P≥0.38). Inflammatory bowel disease-affected family members of Crohns disease probands carrying L1007fs, however, were carriers significantly more often than expected (P<0.001). In Crohns disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P=0.006 and 0.017, respectively). Conclusion In the Dutch population, CARD15 G908R and L1007fs are associated with Crohns disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohns disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.

Effects of active and passive smoking on Crohn's disease and ulcerative colitis in a cohort from a regional hospital.

Objective Smoking is detrimental for Crohns disease (CD), but beneficial for ulcerative colitis (UC). Earlier, we studied the effects of active and passive smoking in CD and UC patients from a university hospital. This study was conducted to assess the same effects in patients from aregional hospital. Methods A questionnaire focusing on cigarette smoke exposure was sent to 382 patients. Returned questionnaires (84%: 128 CD and 192 UC patients) were incorporated into a retrospective chart review about disease behaviour and received therapy. Results At diagnosis there were 52% (95% confidence interval: 43–60%) smokers among CD patients, 40% in a control population and 25% (95% confidence interval: 18–31%) among UC patients. There were less former (19 vs. 31%, P=0.013) and never smokers at diagnosis (30 vs. 44%, P=0.009) in CD than in UC. No detrimental effects of active or passive smoking on the course of CD were observed. UC patients who continued smoking after diagnosis needed less often two or more hospitalizations than never smokers (5 vs. 25%, P=0.036). Otherwise no clear beneficial effects of active smoking on UC were observed. Passively smoking UC patients experienced more often extraintestinal manifestations (25 vs. 7%, P=0.029) than nonpassive smokers. Conclusion Also in a regional hospital inflammatory bowel disease population smoking is a risk factor to develop CD and protects against developing UC. We found no detrimental effects of smoking on the disease course of CD and no clear beneficial effects on the course of UC.

Diffuse enteritis after colectomy for ulcerative colitis: two case reports and review of the literature.

Ulcerative colitis (UC) is an inflammatory disease of the colon. Involvement of the small bowel is limited to backwash ileitis or pouch-related conditions. Here, we report two men with UC who presented with small bowel inflammation and even perforation, within 1 month after subtotal colectomy. Endoscopy showed diffuse enteritis. Histology showed marked apoptosis of epithelial cells in both cases. One patient responded to steroids and the other to a calcineurin inhibitor. Both patients had no evidence of Crohns disease in the small intestine before this event. Several more cases of small intestinal lesions in patients with well-established UC have been reported. The majority typically presented shortly after colectomy and responded well to steroids. The pathogenesis of this enteritis is unknown, but seems to be distinct from Crohns disease and may be associated with UC and colectomy.

Thiopurines Are Associated with a Reduction in Surgical Re-resections in Patients with Crohn's Disease: A Long-term Follow-up Study in a Regional and Academic Cohort

Background:Combination therapy of thiopurines and anti–tumor necrosis factor alpha (TNF-&agr;) antibodies is the most effective medical treatment of Crohns disease (CD). Data on thiopurines and anti-TNF-&agr; antibodies in preventing surgical recurrence (need for re-resection) of CD are scarce. Therefore, we analyzed which factors were involved in surgical recurrence of CD in a large cohort of patients with CD operated in a regional and a university hospital. Methods:This is a retrospective cohort study of 567 patients who underwent surgery for CD. Clinical data and risk factors for surgical recurrence were analyzed, focusing on medical therapy and hospital type. Results:Overall, 237 (41.8%) patients developed a surgical recurrence, after a median of 70 (2–482) months. Before surgical recurrence, 235 patients (41.4%) and 116 patients (20.5%) used thiopurines and anti-TNF-&agr; antibodies, respectively. Multivariate analysis identified 3 independent risk factors associated with surgical recurrence of CD. A higher risk was seen in patients with colonic disease compared with patients with ileal disease (hazard ratio, 1.56; 95% confidence interval, 1.10–2.21; P = 0.012) and in patients using multiple types of medication (hazard ratio, 1.38; 95% confidence interval, 1.25–1.54; P < 0.001). However, a lower risk was seen in patients using thiopurines (hazard ratio, 0.51; 95% confidence interval, 0.34–0.77; P = 0.001). Conclusions:Thiopurines are effective in preventing surgical recurrence of CD. The role of anti-TNF-&agr; antibodies seems promising as well. Combination therapy of thiopurines and anti-TNF-&agr; antibodies for prevention of surgical recurrence of CD should be studied in a randomized trial.

Maternal imprinting and female predominance in familial Crohn's disease ☆

BACKGROUND AND AIM Although the genetic risk factors for familial and sporadic inflammatory bowel disease (IBD) seem identical, the relative risk for contracting IBD in the familial setting is larger as that seen in the population at large, suggesting an important role of epi- and/or paragenetic factors in familial IBD. Epidemiological data indicate a female predominance in IBD, but how this relates to familial IBD has not been assessed. METHODS Familial IBD patients (N=608) were compared with a cohort of 415 sporadic IBD patients with regards to the patterns of sex and disease type distribution. The imprinting pattern in 87 families in which both a parent and a child had IBD was tested using Galton binominal statistics. RESULTS The percentage of females in familial IBD population was significantly higher (61%; female/male ratio 1.5) compared with sporadic IBD (54%; female/male ratio 1.2; p=0.011). The analysis of offspring sex distribution pattern revealed significantly higher female to female transmission compared with female to male transmission rate (36 vs. 18, respectively; p=0.02). A significantly higher number of mother to child transmissions (55 vs. 32 of father to child transmissions) was observed (p=0.018). The female imprinting was specifically related to Crohns disease (31 vs. 14 mother vs. father to child transmissions, respectively; p=0.016). CONCLUSION We propose that a female sex-specific epigenetic inheritance pattern for Crohns disease is a major contributing factor in the family-specific risk in Crohns disease. Sex-specific manifestation of familial Crohns disease can partly explain the epidemiologically observed increased relative risk for females for contracting IBD.

A solitary tuberculous ulcer in the oesophagus

A 48-year-old woman born in Pakistan was evaluated for dysphagia. Endoscopy showed a solitary ulcerative oesophageal lesion. Cultures were positive for mycobacterium tuberculosis. Additional imaging showed no other manifestations of tuberculosis. Oesophageal tuberculosis is a rare entity, especially as a primary manifestation defined as involvement of the oesophagus without signs of disseminated disease. Therefore, this case was classified as primary oesophageal tuberculosis.