Morten H. Vatn

Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohns disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10−12; OR = 1.46 (1.31–1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01–1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

Population-Based Surveillance by Colonoscopy: Effect on the Incidence of Colorectal Cancer: Telemark Polyp Study I

BACKGROUND Most cases of colorectal cancer (CRC) develop from adenomas. Polypectomy is believed to reduce the incidence of CRC, but this effect has never been explored in prospective controlled studies. The aim of the present study was to evaluate the effect of polypectomy on colorectal cancer incidence in a population-based screening program. METHODS In 1983, 400 men and women aged 50-59 years were randomly drawn from the population registry of Telemark, Norway. They were offered a flexible sigmoidoscopy and, if polyps were found, a full colonoscopy with polypectomy and follow-up colonoscopies in 1985 and 1989. A control group of 399 individuals was drawn from the same registry. In 1996 both groups (age, 63-72 years) were invited to have a colonoscopic examination. Hospital files and the files of The Norwegian Cancer Registry were searched to register any cases of CRC in the period 1983-96. RESULTS At screening endoscopy 324 (81%) individuals attended in 1983 and 451 (71%) in 1996. From 1983 to 1996, altogether 10 individuals in the control group and 2 in the screening group were registered to have developed CRC (relative risk, 0.2; 95% confidence interval (CI), 0.03-0.95; P = 0.02). A higher overall mortality was observed in the screening group, with 55 (14%) deaths, compared with 35 (9%) in the control group (relative risk, 1.57; 95% CI, 1.03-2.4; P = 0.03). CONCLUSION Endoscopic screening examination with polypectomy and follow-up was shown to reduce the incidence of CRC in a Norwegian normal population. The possible effect of screening on overall mortality should be addressed in larger studies.

Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study)

Objective. Cohort studies of unselected and newly diagnosed patients are essential for a better understanding of the prognosis in ulcerative colitis (UC). The aim of this study was to evaluate the course of UC in a population-based inception cohort during the first 10 years, and to identify prognostic risk factors based on information gathered at diagnosis. Material and methods. From 1990 to 1994, a population-based cohort of 843 patients with inflammatory bowel disease was enrolled in South-Eastern Norway. The cohort was systematically followed-up at 1, 5 and 10 years after diagnosis. Results. Of 519 patients with UC, 423 completed the 10-year follow-up, 53 died and 43 were lost to follow-up. The mortality risk was not increased compared with that in the general population. The cumulative colectomy rate after 10 years was 9.8% (95% CI: 7.4–12.4%). Initial presentation with extensive colitis and erythrocyte sedimentation rate (ESR) ≥30 mm/h was associated with an increased hazard ratio (HR) (3.57, 95% CI: 1.60–7.96) and age ≥50 years at diagnosis, with reduced HR (0.28, 95% CI: 0.12–0.65) for subsequent colectomy. Relapsing disease was noted in 83%, but half (48%) of the patients were relapse free during the last 5 years. One-fifth (69/288) of patients with proctitis or left-sided colitis had progressed to extensive colitis. Conclusions. The prognosis for UC during the first 10 years was generally good. The colectomy rate was low, and a large proportion of patients were in remission as time progressed. Patients with initially extensive colitis and elevated ESR could benefit from an early potent medical treatment strategy.

Association of NOD2 (CARD 15) genotype with clinical course of Crohn's disease: a cohort study

BACKGROUND Crohns disease is a heterogeneous disorder for which NOD2 (CARD 15) has been identified as a susceptibility gene. We investigate the relation between NOD2 genotype and phenotypic characteristics of patients with Crohns disease. METHODS Hypotheses about the relation between NOD2 genotype and Crohns disease phenotype were generated retrospectively from a group of 446 German patients with this disorder. Positive findings (p<0.10) were verified in prospectively established cohorts of 106 German and 55 Norwegian patients with Crohns disease. All patients were genotyped for the main coding mutations in NOD2, denoted SNP8, SNP12, and SNP13, with Taqman technology. FINDINGS In the retrospective cohort, six clinical characteristics showed noteworthy haplotype association: fistulising, ileal, left colonic and right colonic disease, stenosis, and resection. In the German prospective cohort, these haplotype associations could be replicated for ileal (p=0.006) and right colonic disease (p < or =0.001). A similar trend was noted in the Norwegian patients. INTERPRETATION We recorded a distinct relation between NOD2 genotype and phenotype of Crohns disease. Test strategies with NOD2 variations to predict the clinical course of Crohns disease could lead to the development of new therapeutic paradigms.

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...

Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years.

BACKGROUND, AIMS, AND PATIENTS: In a prospective follow up and intervention study of colorectal polyps, leaving all polyps less than 10 mm in situ for three years, analysis of redetection rate, growth, and new polyp formation was carried out in 116 patients undergoing annual colonoscopy. The findings in relation to growth and new polyp formation were applied to 58 subjects who received placebo. RESULTS: Redetection rate varied from 75-90% for each year, and was highest in the rectum and sigmoid colon. There was no net change in size of all polyps in the placebo group, however, polyps less than 5 mm showed a tendency to net growth, and polyps 5-9 mm a tendency to net regression in size, both for adenomas and hyperplastic polyps. This pattern was verified by computerised image analysis. Patients between 50 and 60 years showed evidence of adenoma size increase compared with the older patients, and the same was true for those with multiple adenomas (four to five) compared with those with a single adenoma. The new adenomas were significantly smaller and 71% were located in the right side of the colon. Patients with multiple adenomas had more new polyps at all the follow up examinations than patients with a single adenoma. One patient developed an invasive colorectal carcinoma, which may be evolved from a previously overlooked polyp. Two polyps, showing intramucosal carcinoma after follow up for three years, were completely removed, as judged by endoscopy and histological examination. CONCLUSIONS: The results show that follow up of unresected colorectal polyps up to 9 mm is safe. The consistency of growth retardation of medium sized polyps suggests extended intervals between the endoscopic follow up examinations, but the increased number of new polyps in the proximal colon indicates total colonoscopy as the examination of choice. The growth retardation of the medium sized polyps may partly explain the discrepancy between the prevalence of polyps and the incidence of colorectal cancer.

Geographical variability and environmental risk factors in inflammatory bowel disease

The changing epidemiology of inflammatory bowel disease (IBD) across time and geography suggests that environmental factors play a major role in modifying disease expression. Disease emergence in developing nations suggests that epidemiological evolution is related to westernisation of lifestyle and industrialisation. The strongest environmental associations identified are cigarette smoking and appendectomy, although neither alone explains the variation in incidence of IBD worldwide. Urbanisation of societies, associated with changes in diet, antibiotic use, hygiene status, microbial exposures and pollution have been implicated as potential environmental risk factors for IBD. Changes in socioeconomic status might occur differently in different geographical areas and populations and, consequently, it is important to consider the heterogeneity of risk factors applicable to the individual patient. Environmental risk factors of individual, familial, community-based, country-based and regionally based origin may all contribute to the pathogenesis of IBD. The geographical variation of IBD provides clues for researchers to investigate possible environmental aetiological factors. The present review aims to provide an update of the literature exploring geographical variability in IBD and to explore the environmental risk factors that may account for this variability.

C -Reactive Protein: A Predictive Factor And Marker Of Inflammation In Inflammatory Bowel Disease Results From A Prospective Population-Based Study

Background and aims: C-reactive protein (CRP) levels are often used in the follow-up of patients with inflammatory bowel disease (IBD). The aims of this study were to establish the relationship of CRP levels to disease extent in patients with ulcerative colitis and to phenotype in patients with Crohn’s disease, and to investigate the predictive value of CRP levels for disease outcome. Methods: CRP was measured at diagnosis and after 1 and 5 years in patients diagnosed with IBD in south-eastern Norway. After 5 years, 454 patients with ulcerative colitis and 200 with Crohn’s disease were alive and provided sufficient data for analysis. Results: Patients with Crohn’s disease had a stronger CRP response than did those with ulcerative colitis. In patients with ulcerative colitis, CRP levels at diagnosis increased with increasing extent of disease. No differences in CRP levels at diagnosis were found between subgroups of patients with Crohn’s disease as defined according to the Vienna classification. In patients with ulcerative colitis with extensive colitis, CRP levels above 23 mg/l at diagnosis predicted an increased risk of surgery (odds ratio (OR) 4.8, 95% confidence interval (CI) 1.5 to 15.1, p = 0.02). In patients with ulcerative colitis, CRP levels above 10 mg/l after 1 year predicted an increased risk of surgery during the subsequent 4 years (OR 3.0, 95% CI 1.1 to 7.8, p = 0.02). A significant association between CRP levels at diagnosis and risk of surgery was found in patients with Crohn’s disease and terminal ileitis (L1), and the risk increased when CRP levels were above 53 mg/l in this subgroup (OR 6.0, 95% CI 1.1 to 31.9, p = 0.03). Conclusions: CRP levels at diagnosis were related to the extent of disease in patients with ulcerative colitis. Phenotype had no influence on CRP levels in patients with Crohn’s disease. CRP is a predictor of surgery in subgroups of patients with either ulcerative colitis or Crohn’s disease.

Epidemiology of Polyps in the Rectum and Colon: Recovery and Evaluation of Unresected Polyps 2 Years after Detection

In an endoscopic population screening study for colorectal polyps among 200 men and 200 women, 50-59 years of age, 215 polyps less than 5 mm in diameter were left in situ for the present 2-year follow-up examination. The attendance rate was 102 of 106 (96%) for polyp patients and 77 of 90 (86%) in the control group. Of 194 polyps, 143 (74%) in the 102 polyp-bearing individuals were recovered for histological evaluation and 57 polyps were registered as new. Ninety-nine (50%) of the polyps were hyperplastic, 45 (23%) were adenomas, and 45 (23%) were mucosal tags. Both growth and regression of polyps were registered. Regression was commoner in the distal part of the rectum than in the proximal part or distal sigmoid colon. Growth was similar for recovered adenomas and hyperplastic polyps, whereas mucosal tags more often showed diminution in size. No polyp had reached a size of more than 5 mm in 2 years, and no case of severe dysplasia or carcinoma was registered. The estimated total polyp mass more than doubled both for adenomas and hyperplastic polyps. It is concluded that the time interval between initial examination with removal of polyps 5 mm or larger in diameter and the first follow-up examination may safely be set at 2 years.

Ulcerative colitis and clinical course: Results of a 5‐year population‐based follow‐up study (the IBSEN study)

Background: The majority of studies concerning the clinical course and prognosis in ulcerative colitis (UC) are old, retrospective in design, or hospital based. We aimed to identify clinical course and prognosis in a prospective, population‐based follow‐up study Materials and Methods: Patients diagnosed with inflammatory bowel disease (IBD) or possible IBD in southeastern Norway during the period 1990–1994 were followed prospectively for 5 years. The evaluation at 5 years included an interview, clinical examination, laboratory tests, and colonoscopy. Results: Of 843 patients diagnosed with IBD, 454 patients who had definite UC and for whom there were sufficient data for analysis were alive 5 years after inclusion in the study. The frequency of colectomy in this population was 7.5%. Forty‐one percent of the patients were not taking any kind of medication for IBD at 5 years. Of the patients initially diagnosed with proctitis, 28% had progressed during the observation period, 10% to extensive colitis. The majority of the patients (57%) had no intestinal symptoms at 5 years, and only a minority (7%) had symptoms that interfered with everyday activities. Among the patients who underwent colonoscopy at the 5‐year visit, symptoms were frequently reported in patients without macroscopic inflammation (44%). A relapse‐free course was observed in 22% of the patients. A decrease in symptoms during the follow‐up period was the most frequent course taken by the disease and was observed in 59% of the cases. The extent of disease was unrelated to symptoms at 5 years and also to relapse rate and course of disease during the 5‐year period. Conclusions: The disease course and prognosis of UC appears better than previously described in the literature. The frequency of surgery was low, and only a minority of the patients had symptoms that interfered with their everyday activities 5 years after diagnosis.