Hendrik M. van Dullemen

Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2)

BACKGROUND & AIMS Increased concentrations of tumor necrosis factor (TNF), a potent proinflammatory cytokine, can be shown in the mucosa of patients with active Crohns disease. Neutralization of TNF has been shown to decrease recruitment of inflammatory cells and granuloma formation in several animal models. The aim of this study was to investigate the safety and potential efficacy of an anti-TNF monoclonal antibody in the treatment of active Crohns disease. METHODS Ten patients with active Crohns disease that was unresponsive to therapy were administered a single infusion of an anti-TNF human/mouse chimeric monoclonal antibody (cA2) in an open-label treatment protocol while the baseline anti-inflammatory therapy was continued. RESULTS Eight patients showed normalization of Crohns Disease Activity Index scores and healing of ulcerations as judged by colonoscopy within 4 weeks after treatment. One patient had a perforation after colonoscopy and recovered completely after surgery. One elderly patient showed a poor response. The average duration of response after a single infusion was 4 months. No adverse experiences related to cA2 were observed. CONCLUSIONS The results support the hypothesis that TNF is of major importance in the pathogenesis of Crohns disease. Treatment with cA2 was safe and may be useful in patients with Crohns disease that is unresponsive to steroid treatment.

Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: A pooled analysis

BACKGROUND Pancreatic cystic tumors commonly include serous cystadenoma (SCA), mucinous cystadenoma (MCA), and mucinous cystadenocarcinoma (MCAC). A differential diagnosis with pseudocysts (PC) can be difficult. Radiologic criteria are not reliable. The objective of the study is to investigate the value of cyst fluid analysis in the differential diagnosis of benign (SCA, PC) vs. premalignant or malignant (MCA, MCAC) lesions. METHODS A search in PubMed was performed with the search terms cyst, pancrea, and fluid. Articles about cyst fluid analysis of pancreatic lesions that contained the individual data of at least 7 patients were included in the study. Data of all individual patients were combined and were plotted in scatter grams. Cutoff levels were determined. RESULTS Twelve studies were included, which comprised data of 450 patients. Cysts with an amylase concentration <250 U/L were SCA, MCA, or MCAC (sensitivity 44%, specificity 98%) and, thus, virtually excluded PC. A carcinoembryonic antigen (CEA) <5 ng/mL suggested a SCA or PC (sensitivity 50%, specificity 95%). A CEA >800 ng/mL strongly suggested MCA or MCAC (sensitivity 48%, specificity 98%). A carbohydrate-associated antigen (CA) 19-9 <37 U/mL strongly suggested PC or SCA (sensitivity 19%, specificity 98%). Cytologic examination revealed malignant cells in 48% of MCAC (n = 111). DISCUSSION Most pancreatic cystic tumors should be resected without the need for cyst fluid analysis. However, in asymptomatic patients, in patients with an increased surgical risk, and, in patients in whom there is a diagnostic uncertainty about the presence of a PC, cyst fluid analysis helps to determine the optimal therapeutic strategy.

Endosonographic imaging of pancreatic pseudocysts before endoscopic transmural drainage

BACKGROUND Endoscopic drainage of pancreatic pseudocysts has become an established alternative to surgery. We performed endosonography before endoscopic drainage to find out whether detailed anatomic information would help in the selection of appropriate candidates and result in a reduction of complications. PATIENTS AND METHODS Between April 1992 and July 1995 endosonography was performed in 32 patients, referred for endoscopic pseudocyst drainage, to determine the minimal distance between the pseudocyst and the gut, to identify interposed vascular structures, and to determine the optimal site for drainage. RESULTS Endosonography failed to identify a pseudocyst in 3 patients and in 2 patients the lesion was inconsistent with a pseudocyst. In 7 patients transmural drainage was considered inappropriate: in 4 the distance between the gut and the cyst was too large, in 2 varices were present between the cyst and the gut, and in 1 patient normal pancreatic parenchyma was present between the cyst and the gut. In 20 patients endosonography was followed by ERCP, and in 19 endoscopic drainage was attempted. Transmural drainage was successful in 16 patients. Endosonography changed management in 37.5% of the patients. CONCLUSION Endosonography provides essential information prior to endoscopic drainage of pseudocysts, leading to a change in therapy in one third of patients.

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.

ATG16L1 and IL23R Are Associated With Inflammatory Bowel Diseases but Not With Celiac Disease in The Netherlands

BACKGROUND:Inflammatory bowel disease (IBD)—Crohns disease (CD) and ulcerative colitis (UC)—and celiac disease are intestinal inflammatory disorders with a complex genetic background. Recently, two novel genes were found to be associated with IBD susceptibility. One, an uncommon coding variant (rs11209026) in the gene encoding for the interleukin-23 receptor (IL23R), conferred strong protection against CD. The other, rs2241880 in the autophagy-related 16-like 1 gene (ATG16L1), was associated with CD. We performed a case-control study for the association of IBD with IL23R and ATG16L1 in a Dutch cohort. We also looked at the association of IL23R and ATG16L1 with celiac disease.METHODS:Five hundred eighteen Dutch white IBD patients (311 CD and 207 UC, including 176 trios of patients with both parents), 508 celiac disease patients, and 893 healthy controls were studied for association with the rs11209026 (IL23R) and rs2241880 (ATG16L1) single nucleotide polymorphisms (SNP).RESULTS:The rs11209026 SNP in IL23R had a protective effect for IBD in the case-control analysis (odds ratio [OR] 0.19, 95% confidence interval [CI] 0.10–0.37, P = 6.6E-09). Both CD (OR 0.14, CI 0.06–0.37, P = 3.9E-07) and UC (OR 0.33, CI 0.15–0.73, P = 1.4E-03) were associated with IL23R. For ATG16L1, the rs2241880 SNP was associated with CD susceptibility (OR 1.36, CI 1.12–1.66, P = 0.0017). The population-attributable risk of carrying allele G is 0.24 and is 0.19 for homozygosity for allele G in CD. No association was found between IL23R or ATG16L1 and celiac disease.CONCLUSIONS:We confirmed the association of IL23R and ATG16L1 with CD susceptibility and also the association of IL23R with UC. We found IL23R and ATG16L1 were not associated with celiac disease susceptibility.

Adalimumab combined with ciprofloxacin is superior to adalimumab monotherapy in perianal fistula closure in Crohn's disease: a randomised, double-blind, placebo controlled trial (ADAFI)

Objective To assess whether a combination of adalimumab and ciprofloxacin is superior to adalimumab alone in the treatment of perianal fistulising Crohns disease (CD). Design Randomised, double-blind, placebo controlled trial in eight Dutch hospitals. In total, 76 CD patients with active perianal fistulising disease were enrolled. After adalimumab induction therapy (160/80 mg week 0, 2), patients received 40 mg every other week together with ciprofloxacin 500 mg or placebo twice daily for 12 weeks. After 12 weeks, adalimumab was continued. Follow-up was 24 weeks. Primary endpoint (clinical response) was defined as 50% reduction of fistulas from baseline to week 12. Secondary endpoints included remission (closure of all fistulas), Perianal Crohns Disease Activity Index, Crohns Disease Activity Index (CDAI) and Inflammatory Bowel Disease Questionnaire (IBDQ). Results Clinical response was observed in 71% of patients treated with adalimumab plus ciprofloxacin and in 47% treated with adalimumab plus placebo (p=0.047). Likewise, remission rate at week 12 was significantly higher (p=0.009) in the combination group (65%) compared with adalimumab plus placebo (33%). Combination treatment was associated with a higher mean CDAI change and mean IBDQ change at week 12 (p=0.005 and p=0.009, respectively). At week 24, no difference in clinical response between the two treatment groups was observed (p=0.22). No difference in safety issues was observed. Conclusions Combination therapy of adalimumab and ciprofloxacin is more effective than adalimumab monotherapy to achieve fistula closure in CD. However, after discontinuation of antibiotic therapy, the beneficial effect of initial coadministration is not maintained. Trial registration ClinicalTrials.gov Identifier: NCT00736983.

Positron emission tomography with F-18-fluorodeoxyglucose in a combined staging strategy of esophageal cancer prevents unnecessary surgical explorations

Distant metastases or local invasion are frequently found during the explorative phase of surgery for esophageal cancer. This study was performed to determine the rate of patients with incurable disease encountered during exploration and to examine the impact of preoperative staging, including positron emission tomography (PET), on the number of unnecessary explorations. The records of 203 patients with esophageal cancer who were eligible for curative resection were retrospectively reviewed. The surgical reports were analyzed to obtain the reasons for abandoning resection. Furthermore, the different staging modalities according to the related time interval were reviewed for each patient to analyze the influence of them on the number of explorations. After exploratory surgery, resection was abandoned in 78 of the 203 patients (38%) because of distant metastases (n = 59; 29%), metastatic spread and local irresectability (n = 5; 2%), and local irresectability (n = 14; 7%). In a logistic regression model with all preoperative staging modalities and the year of examination as independent variables, F-18-fluorodeoxyglucose (FDG)-PET) was the only modality that predicts intended curative resection in these patients (P < 0.001). In patients with esophageal cancer who are suitable for potentially curative surgery, resection was abandoned mainly because of distant metastases encountered during exploration. The addition of FDG-PET may have reduced the rate of unnecessary surgery in this group of patients.

Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease

Objective Patients with IBD display substantial heterogeneity in clinical characteristics. We hypothesise that individual differences in the complex interaction of the host genome and the gut microbiota can explain the onset and the heterogeneous presentation of IBD. Therefore, we performed a case–control analysis of the gut microbiota, the host genome and the clinical phenotypes of IBD. Design Stool samples, peripheral blood and extensive phenotype data were collected from 313 patients with IBD and 582 truly healthy controls, selected from a population cohort. The gut microbiota composition was assessed by tag-sequencing the 16S rRNA gene. All participants were genotyped. We composed genetic risk scores from 11 functional genetic variants proven to be associated with IBD in genes that are directly involved in the bacterial handling in the gut: NOD2, CARD9, ATG16L1, IRGM and FUT2. Results Strikingly, we observed significant alterations of the gut microbiota of healthy individuals with a high genetic risk for IBD: the IBD genetic risk score was significantly associated with a decrease in the genus Roseburia in healthy controls (false discovery rate 0.017). Moreover, disease location was a major determinant of the gut microbiota: the gut microbiota of patients with colonic Crohns disease (CD) is different from that of patients with ileal CD, with a decrease in alpha diversity associated to ileal disease (p=3.28×10−13). Conclusions We show for the first time that genetic risk variants associated with IBD influence the gut microbiota in healthy individuals. Roseburia spp are acetate-to-butyrate converters, and a decrease has already been observed in patients with IBD.

Dieulafoy's disease : endosonographic detection and endosonography-guided treatment

Abstract Background: To investigate whether endosonography can help in the detection and treatment of Dieulafoys disease, we examined eight patients with suspicion of Dieulafoys disease. Methods: Between December 1992 and April 1995, eight patients were referred because of suspicion of Dieulafoys disease. Seven presented with upper gastrointestinal bleeding and one with a tiny ulcer. In all eight patients the stomach was examined with an Olympus GF-UM20 echoendoscope. The stomach was filled with 200 to 400 ml of water after which the body, fundus, and cardia were carefully visualized. Results: In all eight patients a clearly visible, relatively large caliber (2 to 3 mm) vessel was seen to penetrate the muscularis propria and could be followed running through the submucosa for 2 to 4 cm. Subsequently four patients received sclerotherapy, three under endosonographic guidance. Follow-up of all patients (median 10 months), showed recurrent bleeding in two patients, 3 and 5 months after sclerotherapy. One was then diagnosed with a duodenal ulcer and one with recurrent bleeding from the Dieulafoys lesion. Conclusions: Endosonography is useful in the detection of Dieulafoys disease in patients with unexplained upper gastrointestinal bleeding. Sclerotherapy can be performed during the same procedure, with endosonography-guided injection of the sclerosing agent near the abnormal vessel. (Gastrointest Endosc 1996;44:437-42.)

Clinical outcome of Crohn's disease according to the Vienna classification: disease location is a useful predictor of disease course.

Objectives Crohns disease (CD) is a complex genetic disease with multiple clinical patterns. Clinical classifications may help to identify subgroups of patients that have a distinct pattern of disease, and they are also a prerequisite for the conduction of genetic and therapeutic studies. The aim of this study was to determine the usefulness of the Vienna classification in patient care and clinical studies. Methods The clinical data of patients were carefully reviewed retrospectively. The behaviour and location of the disease were determined according to the Vienna classification and additional clinical characteristics including surgical data, vitamin B12 status and medication were also assessed. Results Data according to the Vienna classification of 292 CD cases were available. The mean age at diagnosis was 31.4 years. The operation rate was higher in patients with ileocolonic localization (P<0.05) and stricturing and penetrating disease behaviour (P<0.001). The incidence of vitamin B12 deficiency was 41.9% in cases with ileal involvement and 20.7% in cases with disease confined to the colon. In 187 cases (64.0%) an operation was performed because of CD-related complications, in a majority (126, 67.4%) this took place within 5 years after diagnosis. Intolerance of azathioprine occurred in 36 cases (22.0%). Conclusions Ileocolonic disease localization is associated with a complicated course of disease. Vitamin B12 deficiency occurs frequently, also in patients with disease apparently confined to the colon. We propose that location parameters can be used for the prediction of disease course in clinical settings and in interventional studies.