Participation in colorectal cancer screening trials after first-time invitation: a systematic review.

BACKGROUND AND STUDY AIM: Colorectal cancer (CRC) screening is implemented by an increasing number of countries. Participation rates of screening programs influence the health benefit and cost-effectiveness of the applied method. The aim was to systematically review participation rate after first-time invitation for CRC screening with fecal occult blood test (FOBT), sigmoidoscopy, colonoscopy, and/or computed tomography (CT) colonography. METHODS: A systematic literature search was performed prior to October 1 2009. Prospective CRC screening studies of unselected populations reporting participation rates were included. RESULTS: After meta-analyses, overall participation rates were found to be 47 % for FOBT, 42 % for fecal immunologic tests (FITs), 35 % for sigmoidoscopy, 41 % for sigmoidoscopy combined with FIT/FOBT, 28 % for colonoscopy, and 22 % for CT colonography. Studies comparing screening methods showed higher participation rates for less invasive methods. Studies comparing invitation methods showed higher participation rates with general practitioner involvement, a more personalized recruitment approach, and reduction of barriers that discourage participation. CONCLUSIONS: Knowledge of identified factors affecting CRC screening participation can be used to improve screening programs.

Opportunistic screening of hospital staff using primary colonoscopy: participation, discomfort and willingness to repeat the procedure.

BACKGROUND: Participation in and tolerability of primary colonoscopy screening are presumed to be relatively low. The present study aimed to test its feasibility in a well-informed population of hospital staff using an intensive information campaign, and to identify factors associated with screening colonoscopy rated as uncomfortable. METHODS: Data were collected using standardized forms. RESULTS: Out of 1,090 invited employees (50-65 years), 447 (41.0%) participated. Bowel preparation and colonoscopy were rated as 'somewhat to very uncomfortable' by 79.5 and 21.9%, respectively. 96.3% of participants were willing to repeat colonoscopy in the future. Participants rating colonoscopy as uncomfortable were more likely unwilling to repeat the procedure (OR 8.026, CI 2.667-24.154). Multivariate analysis (age- and gender-adjusted) showed an association of colonoscopy rated as uncomfortable with: abdominal pain during colonoscopy (OR 3.185, CI 1.642-6.178), other pain (OR 2.428, CI 1.335-4.416), flatulence (OR 2.175, CI 1.219-3.881), embarrassment (OR 2.843, CI 1.350-5.989), abdominal pain after colonoscopy (OR 1.976, CI 1.041-3.751), and a prolonged procedure time (OR 1.000, CI 1.000-1.001). CONCLUSIONS: Acceptance of primary colonoscopy screening for colorectal neoplasia was high, although participants with symptoms during and after colonoscopy were more likely to rate colonoscopy as uncomfortable. This type of opportunistic screening procedure is suitable for the introduction of screening programs and may be useful in areas that have no access to population-based screening.

Cardiopulmonary events during primary colonoscopy screening in an average risk population.

BACKGROUND: Large colorectal cancer screening studies using primary colonoscopy have reported a low risk of major complications. Studies on diagnostic and therapeutic colonoscopy have pointed to a frequent occurrence of(minor) cardiopulmonary events, and with the steady increase of colonoscopy screening, it is important to investigate their occurrence in colonoscopy screening. METHODS: This study describes the frequency of bradycardia(pulse rate <60 min-1), hypotension (systolic blood pressure(SB P) <90 mmHg), hypoxaemia (blood oxygenation, SaO2<90%) and ECG changes during colonoscopy screening in an average-risk population (hospital personnel, n=214,mean age 54.0±3.8, 39.3% male), without significant comorbidity) and aims at identifying subject-related and/or endoscopic factors associated with their occurrence. All data were collected prospectively. During 214 consecutive primary screening colonoscopies under conscious sedation(midazolam and pethidine), on top of pulse rate and SaO2,blood pressure and a three-channel ECG were recorded every five minutes. RESULTS: No major complications or relevant ECG changes occurred. Hypoxaemia occurred in 119 (55.6%),hypotension in 19 (8.9%) and bradycardia in 12 subjects(5.6%). In multivariate analysis, the sedation level 3 increased the risk of hypoxaemia (OR 4.8, CI 1.7-13.7), and incomplete colonoscopy (OR 5.3, CI 1.6-18.1) was associated with hypotension. Subjects with bradycardia had a longer mean procedure time (38±12 vs. 29±12 min, p<0.05), which did not turn out as a risk factor in a multivariate analysis. CONCLUSIONS: Mainly procedure-related and not subject-related factors were found to be associated with the occurrence of cardiopulmonary events in primary colonoscopy screening in this relatively healthy screening population.

[Rehabilitation for digestive and metabolic diseases. Quo vadis?]. / Rehabilitation bei Verdauungs- und Stoffwechselkrankheiten. Quo vadis?

The position of rehabilitation in gastroenterology, hepatology and metabolic diseases has changed little in the last 25 years. Initial improvements in quality are oriented more to the content of rehabilitative measures and less to organizational basic conditions. Nevertheless, there is an urgent need for action if rehabilitation medicine is to achieve an equivalent and recognized position in the interaction between primary care and other medical specialties. In this article suggestions for expedient prerequisites and utilization options of rehabilitation in the fields of hepatogastroenterology and metabolism will be presented, which are also oriented to the exemplary implemented concepts from Sweden and The Netherlands.

Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort.

BACKGROUND: The importance of fatigue in chronic disease has been increasingly recognized; however, little is known about fatigue in inflammatory bowel disease (IBD). The aim of the present study was to investigate the prevalence and severity of fatigue and the impact on health-related quality of life (HRQoL) in patients included in a population-based IBD cohort in the Netherlands. METHODS: IBD patients, diagnosed between January 1st, 1991, and January 1st, 2003, were followed up for a median of 7.1 years. They completed a questionnaire, which included a disease activity score, the Multidimensional Fatigue Inventory (MFI-20), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Short Form health survey (SF-36). Hemoglobin levels were recorded. RESULTS: Data were available in 304 Crohn's disease (CD), 368 ulcerative colitis (UC), and 35 indeterminate colitis (IC) patients. During quiescent disease, the prevalence of fatigue was nearly 40%. MFI-20 and HRQoL scores were significantly worse in IBD patients having active disease. In a multivariate analysis, disease activity was positively related with the level of fatigue in both CD and UC. In UC, anemia influenced the general fatigue score independently of disease activity. Disease activity as well as fatigue were independently associated with an impaired IBDQ. CONCLUSIONS: In IBD, even in remission, fatigue is an important feature. Both in CD and in UC, fatigue determined HRQoL independently of disease activity or anemia. This implies that in IBD patients physicians need to be aware of fatigue in order to better understand its impact and to improve the HRQoL.

Clinical and economic outcomes in a population-based European cohort of 948 ulcerative colitis and Crohn's disease patients by Markov analysis.

BACKGROUND: Forecasting clinical and economic outcomes in ulcerative colitis (UC) and Crohn's disease (CD) patients is complex, but necessary. AIMS: To determine: the frequency of treatment-classified clinical states; the probability of transition between states; and the economic outcomes. METHODS: Newly diagnosed UC and CD patients, allocated into seven clinical states by medical and surgical treatments recorded in serial 3-month cycles, underwent Markov analysis. RESULTS: Over 10 years, 630 UC and 318 CD patients had 22,823 and 11,871 cycles. The most frequent clinical outcomes were medical/surgical remission (medication-free) and mild disease (on 5-aminosalicylates, antibiotics, topical corticosteroids), comprising 28% and 62% of UC cycles and 24% and 51% of CD cycles respectively. The probability of drug-response in patients receiving systemic corticosteroids/immunomodulators was 0.74 in UC, 0.66 in CD. Both diseases had similar likelihood of persistent drug-dependency or drug-refractoriness. Surgery was more probable in CD, 0.20, than UC, 0.08. In terms of economic outcomes, surgery was costlier in UC per cycle, but the outlay over 10 years was greater in CD. Drug-refractory UC and CD cases engendered high costs in the cohort. CONCLUSIONS: Most patients on 5-aminosalicylates, corticosteroids and immunomodulators had favourable clinical and economic outcomes over 10 years. Drug-refractory and surgical patients exhibited greater long-term expenses.

Influence of phenotype at diagnosis and of other potential prognostic factors on the course of inflammatory bowel disease.

OBJECTIVES: Disease course in inflammatory bowel disease (IBD) is variable and difficult to predict. To optimize prognosis, it is of interest to identify phenotypic characteristics at disease onset and other prognostic factors that predict disease course. The aim of this study was to evaluate such factors in a population-based IBD group. METHODS: IBD patients diagnosed between 1 January 1991 and 1 January 2003 were included. A follow-up questionnaire was developed and medical records were reviewed. Patients were classified according to phenotype at diagnosis and risk factors were registered. Disease severity, cumulative medication use, and "surgical" and "nonsurgical" recurrence rates were calculated as outcome parameters. RESULTS: In total, 476 Crohn's disease (CD), 630 ulcerative colitis (UC), and 81 indeterminate colitis (IC) patients were diagnosed. In CD (mean follow-up 7.6 years), 50% had undergone resective surgery. In UC (mean follow-up 7 years), colectomy rate was 8.3%. First year cumulative recurrence rates per 100 patient-years for CD, UC, and IC were 53, 44, and 42%, respectively. In CD, small bowel localization and stricturing disease were negative prognostic factors for surgery, as was young age. Overall recurrence rate was increased by young age and current smoking. In UC, extensive colitis increased surgical risk. In UC, older age at diagnosis initially increased recurrence risk but was subsequently protective. CONCLUSIONS: This population-based IBD study showed high recurrence rates in the first year. In CD, small bowel localization, stricturing disease, and young age were predictive for disease recurrence. In UC, extensive colitis and older age at diagnosis were negative prognostic predictors.

Communication of information to patients with inflammatory bowel disease: A European Collaborative Study in a multinational prospective inception cohort.

BACKGROUND AND AIMS: Communication to patients of information about their disease has become increasingly important in modern medicine, and particularly with chronic nonfatal disorders like inflammatory bowel disease (IBD), but the subject is not adequately researched or understood. METHODS: We studied the media and preferences for communication of information in a multi-national community-based inception cohort of European and Israeli patients with IBD and 10 years follow-up, using structured questionnaires categorizing demographics, disease status, current and preferred sources of information, use of electronic media, role of patients' associations, and satisfaction level. RESULTS: The 917 patients completing the questionnaire were derived from northern (60%) and southern (40%) countries. The mean age was 48.3 years (62% under 50 years); 51% were males; 67% had ulcerative colitis, 33% Crohn's disease. Sixty-six percent of patients designated the specialist as their primary source of information, 77% indicated satisfaction with their current information, and 65% reported not receiving information about medical treatment in the past year. Patient concerns were about new research into their illness (64%), medical treatments (58%), risks and complications (51%) and genetics (42%). Preferred sources of information were paper bulletin (76%), electronic media (30%) and international organization (79%). Diagnosis (ulcerative colitis or Crohn's disease), gender, education level and country impacted significantly on patients' choices. CONCLUSIONS: In providing health care information to patients with IBD their individual attitudes and preferences must be considered. There should be greater roles for IBD patients' associations and international IBD-research organizations, and an increasing use of electronic media.

Dysplasia and cancer in inflammatory bowel disease 10 years after diagnosis: results of a population-based European collaborative follow-up study.

OBJECTIVE: To determine dysplasia and cancer in the 1991-2004 European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort. PATIENTS AND METHODS: A patient questionnaire and a physician per patient form were completed for each of the 1,141 inflammatory bowel disease patients (776 ulcerative colitis/365 Crohn's disease) from 9 centers (7 countries) derived from the EC-IBD cohort. Rates of detection of intestinal cancer and dysplasia as well as extra-intestinal neoplasms were computed. RESULTS: Patient follow-up time was 10.3 +/- 0.8 (range 9.4-11) years. The mean age of the whole group of IBD patients was 37.8 +/- 11.3 (range 16-76) years. Thirty-eight patients (3.3%; 26 with ulcerative colitis/12 with Crohn's disease, 21 males/17 females, aged 61.3 +/- 13.4, range 33-77 years), were diagnosed with 42 cancers. Cancers occurred 5.4 +/- 3.3 (range 0-11) years after inflammatory bowel disease diagnosis. Colorectal cancer was diagnosed in 8 (1 Crohn's disease and 7 ulcerative colitis patients--0.3 and 0.9% of the Crohn's disease and ulcerative colitis cohort, respectively) of 38 patients and 30 cancers were extra-intestinal. Four of 38 patients (10.5%) were diagnosed as having 2 cancers and they were younger compared to patients with one cancer (p = 0.0008). There was a trend for a higher prevalence of intestinal cancer in the northern centers (0.9%) compared to southern centers (0.3%, p = NS). Southern centers had more cases of extra-intestinal cancer compared to northern centers (2 vs. 3.8%, p = 0.08). Ten patients (0.9%; 8 with ulcerative colitis/2 with Crohn's disease, 8 males, aged 62.3 +/- 14.1 years) had colorectal dysplasia. CONCLUSIONS: In the first decade of the EC-IBD Study Group cohort follow-up study, the prevalence of cancer was as expected with most patients having a single neoplasm and an extra-intestinal neoplasm. In northern centers there was a trend for more intestinal cancers, while in southern centers there was a trend for more extra-intestinal cancers compared to northern centers.

Randomized, placebo-controlled trial of low molecular weight heparin in active ulcerative colitis.

BACKGROUND: In several open and 1 controlled trial, unfractionated heparin was effective in the treatment of active ulcerative colitis (UC). Low molecular weight heparin (LMWH) had a similar effect in several open studies. METHODS: We studied the efficacy, safety, and tolerability of LMWH in mild to moderately active UC in a randomized, double-blind, placebo-controlled trial. In all, 29 patients with a mild or moderate recurrence of UC during salicylate treatment were randomized to receive either reviparin 3,436 IU (n = 15) subcutaneously twice daily or placebo (n = 14). The study period was 8 weeks. Treatment was discontinued if there was no improvement at 4 weeks or at any disease progression. Primary outcome measure was clinical improvement at 8 weeks measured by the Colitis Activity Index (CAI) and the Clinical Symptoms Grading (CSG, based on the CAI). Endoscopic and histologic grading and quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) were secondary outcome measures. Patients were closely monitored for adverse events. RESULTS: Twenty of 29 patients finished the 8-week treatment period (reviparin versus placebo: 11 versus 9; P = 0.70). There was no difference in CSG, CAI, endoscopic and histologic grading, or IBDQ. Treatment was well tolerated and no serious adverse events occurred. CONCLUSION: In this study, treatment with LMWH showed no significant clinical advantage compared to placebo in mild to moderately active UC.

Ulcerative colitis: no rise in mortality in a European-wide population based cohort 10 years after diagnosis.

BACKGROUND: Population based studies have revealed varying mortality for patients with ulcerative colitis but most have described patients from limited geographical areas who were diagnosed before 1990. AIMS: To assess overall mortality in a European cohort of patients with ulcerative colitis, 10 years after diagnosis, and to investigate national ulcerative colitis related mortality across Europe. METHODS: Mortality 10 years after diagnosis was recorded in a prospective European-wide population based cohort of patients with ulcerative colitis diagnosed in 1991-1993 from nine centres in seven European countries. Expected mortality was calculated from the sex, age and country specific mortality in the WHO Mortality Database for 1995-1998. Standardised mortality ratios (SMR) and 95% confidence intervals (CI) were calculated. RESULTS: At follow-up, 661 of 775 patients were alive with a median follow-up duration of 123 months (107-144). A total of 73 deaths (median follow-up time 61 months (1-133)) occurred compared with an expected 67. The overall mortality risk was no higher: SMR 1.09 (95% CI 0.86 to 1.37). Mortality by sex was SMR 0.92 (95% CI 0.65 to 1.26) for males and SMR 1.39 (95% CI 0.97 to 1.93) for females. There was a slightly higher risk in older age groups. For disease specific mortality, a higher SMR was found only for pulmonary disease. Mortality by European region was SMR 1.19 (95% CI 0.91 to 1.53) for the north and SMR 0.82 (95% CI 0.45-1.37) for the south. CONCLUSIONS: Higher mortality was not found in patients with ulcerative colitis 10 years after disease onset. However, a significant rise in SMR for pulmonary disease, and a trend towards an age related rise in SMR, was observed.

Colorectal cancer screening: results of a 5-year program in asymptomatic subjects at increased risk.

BACKGROUND AND AIMS: The province of Ferrara has one of the highest incidences of colorectal cancer (CRC) in Italy. In January 2000, we set up a colonoscopy screening program focussing on first-degree relatives of CRC patients. We now report the results 5 years after the beginning of the project. SCREENEES AND METHODS: In October 1999, we started a campaign stressing the usefulness of colonoscopy for the first-degree relatives of CRC patients. Subjects included in the screening program were aged between 45 and 75 years with at least one first-degree relative affected by CRC. They were invited to an interview where a physician suggested colonoscopy as a screening option. RESULTS: In 5 years, 776 subjects were interviewed and 733 (94.4%) agreed to an endoscopic examination (M/F:375/401; mean age 55 years): 562 colonoscopies were performed. Adenomas and cancers were found in 122 (21.7%) and 12 (2.1%) subjects, respectively. Histological examination in 181 persons with lesions (32.8%) showed (most serious lesion quoted) 47 hyperplastic polyps (26% of all lesions), 2 serrated adenomas (1.1%), 68 tubular adenomas (48%), 24 tubulovillous adenomas (13.3%), 9 adenomas with high grade dysplasia (5%) and 12 adenocarcinomas (6.6%). The majority of the cancers were at an early stage (8 Dukes A and 3 Dukes B). Sedation was used in only 42 colonoscopies (7.5%). CONCLUSIONS: A colonoscopy-based screening in this selected high-risk population is feasible. Even without sedation subjects readily agreed to the endoscopic procedure. We identified a significant number of advanced neoplasms and cancers at an early stage suggesting that this could be a useful tool in early identification of CRC.

Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects?

BACKGROUND: 6-Thioguanine is used in inflammatory bowel disease since 2001, with promising short-term results. In 2003, liver histology of some 6-thioguanine treated patients showed nodular regenerative hyperplasia. Recently, magnetic resonance imaging revealed nodular regenerative hyperplasia in patients with normal histology. AIMS: Investigating the presence of nodular regenerative hyperplasia in long-term 6-thioguanine treated patients. PATIENTS AND METHODS: Inflammatory bowel disease patients, using 6-thioguanine minimally 24 months, were asked to undergo liver biopsy and magnetic resonance imaging. RESULTS: Fourteen patients used 6-thioguanine minimally 24 months, 13 participated. Mean 6-thioguanine therapy duration, daily dose and 6-thioguanine nucleotide levels were: 36 months, 18.8 mg (0.28 mg/kg) and 705 pmol/8x10(8) erythrocytes, respectively. Liver histology and magnetic resonance imaging showed no nodular regenerative hyperplasia. DISCUSSION: Liver biopsy and magnetic resonance imaging showed no nodular regenerative hyperplasia in these long-term 6-thioguanine treated inflammatory bowel disease patients. 6-thioguanine dose and metabolite levels were lower compared with previous nodular regenerative hyperplasia reports, suggesting dose or metabolite level-dependent effects. Otherwise, nodular regenerative hyperplasia is related with inflammatory bowel disease itself and immunosuppressives, including azathioprine and 6-mercaptopurine. CONCLUSION: 6-Thioguanine is debated due to nodular regenerative hyperplasia. We found no nodular regenerative hyperplasia in inflammatory bowel disease patients with long-term, low dosed 6-thioguanine, suggesting metabolite level-dependent effects. Therefore, 6-thioguanine still seems useful, but in selected patients, intolerant for other immunosuppressives, low dosed and under close surveillance of metabolite levels and hepatotoxity.

Review article: Probiotics in gastrointestinal and liver diseases.

BACKGROUND: Probiotics, defined as live micro-organisms with beneficial effects for the host, are widely applied in gastrointestinal and liver diseases. AIM AND METHOD: To review the available evidence of clinical trials on probiotics in gastrointestinal and liver diseases, with a major focus on irritable bowel syndrome, inflammatory bowel disease, pancreatitis and chronic liver diseases. RESULTS: Evidence for the therapeutic or preventive application of particular probiotic strains is available for antibiotic-associated diarrhoea, rota-virus-associated diarrhoea and pouchitis. Results are encouraging for irritable bowel syndrome, ulcerative colitis and for reducing side effects by Helicobacter pylori eradication therapies, but are less clear for Crohn's disease, lactose intolerance and constipation. In general, for most of these patient groups, more placebo-controlled methodologically well-designed studies that pay attention to both clinical outcome and mechanistic aspects are required. The application in liver disease and pancreatitis is promising, but more human trials have to be awaited. Possible mechanisms of probiotics include modulation of the intestinal microbiota and the immune system, but different bacterial may have different effects. CONCLUSION: Further insight into disease entities and the functioning of probiotic strains is required to be able to select disease-specific strains, which have to be tested in well-designed placebo-controlled studies.

Review article: Non-alcoholic fatty liver disease in morbidly obese patients and the effect of bariatric surgery.

BACKGROUND: Morbid obesity is strongly associated with non-alcoholic fatty liver disease. The effects of bariatric surgery on liver tests an histological abnormalities after weight loss are controversial. AIM: To review the literature on the prevalence of non-alcoholic fatty liver disease in patients with morbid obesity with respect to laboratory and histopathological parameters and the effect of weight loss on these parameters after bariatric surgery. RESULTS: Standard liver tests do not seem to be a sensitive tool for the assessment and follow-up of non-alcoholic fatty liver disease in obesity. In nearly all patients with morbid obesity, histological abnormalities reflecting non-alcoholic fatty liver disease are present. Bariatric surgery in these patients will decrease the grade of steatosis. However, there are some concerns about the effect of bariatric surgery on hepatic inflammation and fibrosis. In particular, older follow-up studies reported negative results as opposed to more recent studies, which also showed improvement in hepatic inflammation and fibrosis. Unfortunately, most studies had limitations because of the selection of patients. CONCLUSION: Despite limitations in many studies, bariatric surgery seems to be a promising treatment in patients with obesity presenting with non-alcoholic fatty liver disease.

The effect of a probiotic drink with Lactobacillus plantarum 299v on the bacterial composition in faeces and mucosal biopsies of rectum and ascending colon.

BACKGROUND: Studies on probiotics mainly base their results on faecal samples, which may not represent the situation in the mucosa of distal and proximal colon. AIM: In a placebo-controlled study, to assess the effect of Lactobacillus plantarum 299v on the bacterial composition of faecal vs. mucosal samples. METHODS: Twenty-nine patients undergoing colonoscopic examination for polyps consumed a twice-daily drink with or without L. plantarum 299v (10(11) CFU/day) for 2 weeks. Faecal samples were collected before and after consumption. During colonoscopy, biopsies were collected from the ascending colon and rectum. The faecal and mucosal bacterial concentrations and prevalence were determined. RESULTS: L. plantarum 299v significantly increased the concentration of faecal lactic acid bacteria, lactobacilli and clostridia, and was identified in two rectal biopsies but not in the ascending colon biopsies of probiotic-treated subjects. Concentrations and prevalence in ascending colon and rectum biopsies were comparable, but were significantly lower compared with faecal samples. CONCLUSIONS: After probiotic consumption, a significant increase in the faecal concentration of lactobacilli was found but concentrations were low in biopsies. The bacterial composition in biopsies of the ascending colon and rectum did not differ based on culture techniques. To further elucidate the modes of action of probiotics, it might be necessary to study differences in colonization with molecular techniques.

Crohn's disease: increased mortality 10 years after diagnosis in a Europe-wide population based cohort.

BACKGROUND: No previous correlation between phenotype at diagnosis of Crohn's disease (CD) and mortality has been performed. We assessed the predictive value of phenotype at diagnosis on overall and disease related mortality in a European cohort of CD patients. METHODS: Overall and disease related mortality were recorded 10 years after diagnosis in a prospectively assembled, uniformly diagnosed European population based inception cohort of 380 CD patients diagnosed between 1991 and 1993. Standardised mortality ratios (SMRs) were calculated for geographic and phenotypic subgroups at diagnosis. RESULTS: Thirty seven deaths were observed in the entire cohort whereas 21.5 deaths were expected (SMR 1.85 (95% CI 1.30-2.55)). Mortality risk was significantly increased in both females (SMR 1.93 (95% CI 1.10-3.14)) and males (SMR 1.79 (95% CI 1.11-2.73)). Patients from northern European centres had a significant overall increased mortality risk (SMR 2.04 (95% CI 1.32-3.01)) whereas a tendency towards increased overall mortality risk was also observed in the south (SMR 1.55 (95% CI 0.80-2.70)). Mortality risk was increased in patients with colonic disease location and with inflammatory disease behaviour at diagnosis. Mortality risk was also increased in the age group above 40 years at diagnosis for both total and CD related causes. Excess mortality was mainly due to gastrointestinal causes that were related to CD. CONCLUSIONS: This European multinational population based study revealed an increased overall mortality risk in CD patients 10 years after diagnosis, and age above 40 years at diagnosis was found to be the sole factor associated with increased mortality risk.

Phenotype at diagnosis predicts recurrence rates in Crohn's disease.

BACKGROUND: In Crohn's disease (CD), studies associating phenotype at diagnosis and subsequent disease activity are important for patient counselling and health care planning. AIMS: To calculate disease recurrence rates and to correlate these with phenotypic traits at diagnosis. METHODS: A prospectively assembled uniformly diagnosed European population based inception cohort of CD patients was classified according to the Vienna classification for disease phenotype at diagnosis. Surgical and non-surgical recurrence rates throughout a 10 year follow up period were calculated. Multivariate analysis was performed to classify risk factors present at diagnosis for recurrent disease. RESULTS: A total of 358 were classified for phenotype at diagnosis, of whom 262 (73.2%) had a first recurrence and 113 patients (31.6%) a first surgical recurrence during the first 10 years after diagnosis. Patients with upper gastrointestinal disease at diagnosis had an excess risk of recurrence (hazard ratio 1.54 (95% confidence interval (CI) 1.13-2.10)) whereas age >/=40 years at diagnosis was protective (hazard ratio 0.82 (95% CI 0.70-0.97)). Colonic disease was a protective characteristic for resective surgery (hazard ratio 0.38 (95% CI 0.21-0.69)). More frequent resective surgical recurrences were reported from Copenhagen (hazard ratio 3.23 (95% CI 1.32-7.89)). CONCLUSIONS: A mild course of disease in terms of disease recurrence was observed in this European cohort. Phenotype at diagnosis had predictive value for disease recurrence with upper gastrointestinal disease being the most important positive predictor. A phenotypic North-South gradient in CD may be present, illustrated by higher surgery risks in some of the Northern European centres.

The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients.

BACKGROUND: In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S-methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6-methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites. AIM: To examine the in vivo pharmacokinetic interaction between mesalazine and mercaptopurine. METHODS: A prospective study was performed in quiescent inflammatory bowel disease patients using the combination of mercaptopurine and mesalazine. Laboratory parameters, 6-methylmercaptopurine ribonucleotide and tioguanine levels and thiopurine S-methyltransferase activity in erythrocytes were measured at stable medication, after mesalazine discontinuation and mesalazine reintroduction, further mercaptopurine was continued. RESULTS: Seventeen patients were participated. Mean mercaptopurine dose was 0.78 mg/kg/day and median of mesalazine dose was 3000 mg/day. After mesalazine discontinuation, mean tioguanine levels changed significantly from 262 to 209 pmol/8 x 10(8) red blood cell, increasing to 270 after reintroduction. Mean 6-methylmercaptopurine ribonucleotide levels were 1422, 2149 and 1503 pmol/8 x 10(8) red blood cell respectively. Mean 6-methylmercaptopurine ribonucleotide/tioguanine ratio increased significantly from 6.3 at baseline to 11.2. Mean baseline thiopurine S-methyltransferase activity was 0.58 pmol/10(6) red blood cell/h and stable. All patients had wild-type thiopurine S-methyltransferase genotypes however, leucocyte counts were stable. DISCUSSION: A significantly higher tioguanine levels and improving 6-methylmercaptopurine ribonucleotide/tioguanine ratio were found during mesalazine/mercaptopurine combination. Theoretically, mesalazine inhibits thiopurine S-methyltransferase activity. In vivo thiopurine S-methyltransferase activity did not change, however. CONCLUSION: Mesalazine has synergistic effects on mercaptopurine therapy, but the mechanism is unclear. Combining these drugs may be further indication for mesalazine in inflammatory bowel disease treatment.