D.J. de Jong

High frequency of early colorectal cancer in inflammatory bowel disease

Background and aim: To detect precancerous dysplasia or asymptomatic cancer, patients suffering from inflammatory bowel disease often undergo colonoscopic surveillance based on American or British guidelines. It is recommended that surveillance is initiated after 8–10 years of extensive colitis, or after 15–20 years for left-sided disease. These starting points, however, are not based on solid scientific evidence. Our aim was to assess the time interval between onset of inflammatory bowel disease (IBD) and colorectal carcinoma (CRC), and subsequently evaluate how many patients developed cancer before their surveillance was recommended to commence. Methods: A nationwide automated pathology database (PALGA) was consulted to identify patients with IBD-associated colorectal carcinoma in seven university medical centres in The Netherlands between January 1990 and June 2006. Data were collected retrospectively from patient charts. Time intervals between onset of disease and cancer diagnosis were calculated in months. Results: 149 patients were identified with confirmed diagnoses of IBD and CRC (ulcerative colitis n = 89/Crohn’s disease n = 59/indeterminate colitis n = 1). Taking date of diagnosis as the entry point, 22% of patients developed cancer before the 8 or 15 year starting points of surveillance, and 28% if surveillance was commenced 10 or 20 years after diagnosis for extensive or left-sided disease, respectively. Using onset of symptoms to calculate the time interval, 17–22% of patients would present with cancer prior to the surveillance starting points. Conclusions: These results show that the diagnosis of colorectal cancer is delayed or missed in a substantial number of patients (17–28%) when conducting surveillance strictly according to formal guidelines.

Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort

Background: Crohn’s disease and ulcerative colitis have a complex genetic background. We assessed the risk for both the development and severity of the disease by combining information from genetic variants associated with inflammatory bowel disease (IBD). Methods: We studied 2804 patients (1684 with Crohn’s disease and 1120 with ulcerative colitis) and 1350 controls from seven university hospitals. Details of the phenotype were available for 1600 patients with Crohn’s disease and for 800 with ulcerative colitis. Genetic association for disease susceptibility was tested for the nucleotide-binding and oligomerisation domain 2 gene (NOD2), the IBD5 locus, the Drosophila discs large homologue 5 and autophagy-related 16-like 1 genes (DLG5 and ATG16L1) and the interleukin 23 receptor gene (IL23R). Interaction analysis was performed for Crohn’s disease using the most associated single nucleotide polymorphism (SNP) for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyse disease development and severity. Results: Association with Crohn’s disease was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. Patients with Crohn’s disease carry more risk alleles than controls (p = 3.85 × 10−22). Individuals carrying an increasing number of risk alleles have an increasing risk for Crohn’s disease, consistent with an independent effects multiplicative model (trend analysis p = 4.25 × 10−23). Patients with Crohn’s disease with a more severe disease course, operations or an age of onset below 40 years have more risk alleles compared to non-stricturing, non-penetrating behaviour (p = 0.0008), no operations (p = 0.02) or age of onset above 40 years (p = 0.028). Conclusion: Crohn’s disease is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for the development of Crohn’s disease and with a more severe disease course. Combining information from the known common risk polymorphisms may enable clinicians to predict the course of Crohn’s disease.

Colonoscopic surveillance improves survival after colorectal cancer diagnosis in inflammatory bowel disease

Background:Colonoscopic surveillance provides the best practical means for preventing colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients. Strong evidence for improved survival from surveillance programmes is sparse.Method:The aim of this study was to compare tumour stage and survival of IBD patients with CRC who were a part of a surveillance programme with those who were not. A nationwide pathology database (PALGA (pathologisch anatomisch landelijk geautomatiseerd archief)) was consulted to identify IBD patients with CRC treated in all eight university hospitals in The Netherlands over a period of 15 years. Patients were assigned to the surveillance group when they had undergone one or more surveillance colonoscopies before a diagnosis of CRC. Patients who had not undergone surveillance served as controls. Tumour stage and survival were compared between the two groups.Results:A total of 149 patients with IBD-associated CRC were identified. Twenty-three had had colonoscopic surveillance before CRC was discovered. The 5-year CRC-related survival rate of patients in the surveillance group was 100% compared with 74% in the non-surveillance group (P=0.042). In the surveillance group, only one patient died as a consequence of CRC compared with 29 patients in the control group (P=0.047). In addition, more early tumour stages were found in the surveillance group (P=0.004).Conclusions:These results provide evidence for improved survival from colonoscopic surveillance in IBD patients by detecting CRC at a more favourable tumour stage.

More Right-sided IBD-associated Colorectal Cancer in Patients with Primary Sclerosing Cholangitis

Background: Patients with inflammatory bowel disease (IBD) and concurrent primary sclerosing cholangitis (PSC) have a higher risk of developing colorectal cancer (CRC) than IBD patients without PSC. The aim of this study was to investigate potential clinical differences between patients with CRC in IBD and those with CRC in IBD and PSC, as this may lead to improved knowledge of underlying pathophysiological mechanisms of CRC development. Methods: The retrospective study from 1980–2006 involved 7 Dutch university medical centers. Clinical data were retrieved from cases identified using the national pathology database (PALGA). Results: In total, 27 IBD‐CRC patients with PSC (70% male) and 127 IBD‐CRC patients without PSC (59% male) were included. CRC‐related mortality was not different between groups (30% versus 19%, P = 0.32); however, survival for cases with PSC after diagnosing CRC was lower (5‐year survival: 40% versus 75% P = 0.001). Right‐sided tumors were more prevalent in the PSC group (67% versus 36%, P = 0.006); adjusted for age, sex, and extent of IBD, this difference remained significant (odds ratio: 4.8, 95% confidence interval [CI] 2.0–11.8). In addition, tumors in individuals with PSC were significantly more advanced. Conclusions: The right colon is the predilection site for development of colonic malignancies in patients with PSC and IBD. When such patients are diagnosed with cancer they tend to have more advanced tumors than patients with IBD without concurrent PSC, and the overall prognosis is worse. Furthermore, the higher frequency of right‐sided tumors in patients with PSC suggests a different pathogenesis between patients with PSC and IBD and those with IBD alone. (Inflamm Bowel Dis 2009)

Risk of Malignant Lymphoma in Patients with Inflammatory Bowel Diseases: A Dutch Nationwide Study

Background: Immune suppressant medications such as thiopurines and anti‐tumor necrosis factor agents are important for maintaining disease control in most patients with inflammatory bowel diseases (IBDs); however, their use has been associated with the development of malignant lymphoma. The purpose of this Dutch nationwide study was to estimate the relative risk of malignant lymphoma in IBD patients. Methods: IBD patients who developed a lymphoma between 1997 and 2004 were identified using the Dutch National Database of PALGA. Data from confirmed cases were collected from individual hospitals, including data on Epstein–Barr virus (EBV). The age‐adjusted 8‐year incidence of malignant lymphoma in the Netherlands was retrieved from the Central Bureau of Statistics. Results: Forty‐two hospitals were visited and 285 matches evaluated in the total cohort of 17,834 IBD patients. Forty‐four lymphomas were observed, resulting in a relative risk of 1.27 (95% confidence interval [CI]: 0.92–1.68). Only 19 of 44 patients (43%) were exposed to azathioprine/6‐mercaptopurine (AZA/6‐MP). Remarkably, 92% of patients (11/12) with EBV‐positive lymphoma used AZA/6‐MP, in contrast to only 19% patients (4/21) with EBV‐negative lymphoma, suggesting a strong relation between EBV‐positive lymphoma and thiopurine use. Conclusions: This nationwide study does not suggest a significant overall increased risk for lymphoma in IBD patients. A distinct correlation between EBV‐positive lymphoma and AZA/6‐MP use was observed. (Inflamm Bowel Dis 2011;)

Safety of thiopurines in the treatment of inflammatory bowel disease.

BACKGROUND Thiopurines have proven efficacy in inflammatory bowel disease. However, concerns regarding toxicity have limited the use of these agents as first line of medical therapy. METHODS Review of the literature regarding metabolism, efficacy and side effects. RESULTS In clinical trials, up to 15% of patients discontinued 6-mercaptopurine or its pro-drug azathioprine prematurely due to adverse events. These events may be divided into dose-independent idiosyncratic reactions and dose-related, pharmacologically explainable toxicity. Dose-independent reactions include skin rash, fever, diarrhoea and pancreatitis. Most frequently observed dose-dependent adverse events are nausea, malaise and myelotoxicity. Furthermore, dose-dependent and dose-independent hepatotoxicity may occur. Recent insights obtained by therapeutic drug monitoring in patients on azathioprine or 6-mercaptopurine have led to strategies to reduce toxicity. One strategy is to detect poor metabolisers of thiopurines by establishing the activity of the key enzyme thiopurine methyltransferase. However, the clinical relevance of this strategy is still a point of debate. Another strategy is to administer 6-thioguanine, which is an agent close to the effective 6-thioguanine nucleotides. CONCLUSION Therapeutic drug monitoring of thiopurines resulted in strategies to reduce toxicity. The value of these strategies has yet to be proven in prospective randomized trials.

Heterozygosity for IL23R p.Arg381Gln confers a protective effect not only against Crohn’s disease but also ulcerative colitis

Background  A recent study reported that a non‐synonymous single nucleotide polymorphism (rs11209026, p.Arg381Gln) located in the IL23R gene is a protective marker for inflammatory bowel disease.

Long-term follow-up of children exposed intrauterine to maternal thiopurine therapy during pregnancy in females with inflammatory bowel disease.

Inflammatory bowel disease (IBD) affects a substantial number of female patients in their reproductive years. Therefore, many physicians face the dilemma whether thiopurines, prescribed to maintain remission, can be taken safely during pregnancy. Data on long‐term development outcome of children exposed to maternal thiopurine therapy are very limited.

Risk factors of work disability in patients with inflammatory bowel disease - A Dutch nationwide web-based survey: Work disability in inflammatory bowel disease.

BACKGROUND Inflammatory bowel disease (IBD) is associated with high costs to society. Few data on the impact of IBD on work disability and potential predictive factors are available. AIM To assess the prevalence of and predictive factors for work disability in Crohns disease (CD) and ulcerative colitis (UC). METHODS A web-based questionnaire was sent out in seven university hospitals and seven general hospitals in the Netherlands. Initially, 3050 adult IBD patients were included in this prospective, nationwide cohort study, whereof 2629 patients were within the working-age (18-64 years). We used the baseline questionnaire to assess the prevalence rates of work disability in CD and UC patients within working-age. Prevalence rates were compared with the Dutch background population using age- and sex-matched data obtained from Statistics Netherlands. Multivariable logistic regression analyses were performed to identify independent demographic- and disease-specific risk factors for work disability. RESULTS In CD, 18.3% of patients was fully disabled and 8.8% partially disabled, compared to 9.5% and 5.4% in UC patients (p<0.01), respectively. Compared to Dutch controls, the prevalence was significantly higher, especially in CD patients. Higher age, low education, depression, chronic back pain, joint manifestations and typical disease-related risk factors such as penetrating disease course and surgery in the past were all found to be associated with work disability. CONCLUSION We report high work disability rates in a large sample of IBD patients in the Netherlands. CD patients suffer more frequently from work disability than UC patients. A combination of demographic and disease-related factors is predictive of work disability.

Malignant transformation of perianal and enterocutaneous fistulas is rare: results of 17 years of follow-up from The Netherlands

Abstract Objective. Malignant transformation of fistulas has been observed, particularly in perianal fistulas in Crohns disease (CD) patients. The prevalence of adenocarcinoma in enterocutaneous fistulas and non-CD-related fistulas, however, is unknown. We investigated adenocarcinoma originating from perianal and enterocutaneous fistulas in both CD patients and non-CD patients from nine large, mostly tertiary referral, hospitals in The Netherlands. Methods. Patients suffering from fistulizing disease and either dysplasia or adenocarcinoma between January 1990 and January 2007 were identified using the nationwide automated pathology database (PALGA). Clinical and histopathological data were collected and verified using hospital patient-charts and reported by descriptive statistics. The total CD-population comprised 6058 patients. Results. In a study-period of 17 years, 2324 patients with any fistula were reported in PALGA. In 542 patients, dysplasia or adenocarcinoma was also mentioned. After initial review and additional detailed chart review, 538 patients were excluded, mainly because the adenocarcinoma was not related to the fistula. In the remaining four patients, all suffering from CD, adenocarcinoma originating from the fistula-tract was confirmed. The malignancies developed 25 years (IQR 10–38) after CD diagnosis, and 10 years (IQR 6–22) after fistula diagnosis. Median age at time of adenocarcinoma diagnosis was 48.3 years (IQR 43–58). Only one patient had clinical symptoms indicative for adenocarcinoma. In three other patients, the adenocarcinoma was found coincidently. Conclusions. Adenocarcinoma complicating perianal or enterocutaneous fistula-tracts is a rare finding. Only 4 out of 6058 CD patients developed a fistula-associated adenocarcinoma. We could not identify any malignant transformations in non-CD-related fistulas in our 17 years study-period.