Charles Limonard

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.

High incidence of inflammatory bowel disease in The Netherlands: results of a prospective study. The South Limburg IBD Study Group.

PURPOSE: To gain recent epidemiologic information about inflammatory bowel disease in The Netherlands, a prospective study over four years (1991–1995) was performed. METHODS: The incidence of inflammatory bowel disease and its subgroups was examined using standardized reports of newly diagnosed patients. A separate study compared the Inflammatory Bowel Disease Registration and computerized diagnostic files of a subgroup of general practitioners with the aim of estimating completeness of case ascertainment. RESULTS: The following mean incidence rates (per 100,000 inhabitants and year) were found: 6.9 (95 percent confidence interval, 5.9–7.9) for Crohns disease, 10 (95 percent confidence interval, 8.7–11.2) for ulcerative colitis (23 percent of these with ulcerative proctitis), and 1.1 (95 percent confidence interval, 0.7–1.5) for indeterminate colitis. In the age category 20 to 29 years, the incidence rate of Crohns disease with small-bowel involvement was higher in females than in males. In extended ulcerative colitis, a male preponderance was observed in the older age groups. Estimated case ascertainment was 78 percent. CONCLUSIONS: Compared with recent studies in neighboring countries, the observed age and gender standardized incidence rates are high in the south of The Netherlands. Completeness of case ascertainment might have contributed to this observation; however, case ascertainment was low in ulcerative proctitis. In the study area, differences in age and gender standardized incidence rates and in disease localizations could be compatible with an influence of environmental risk factors.

Disease outcome of inflammatory bowel disease patients: general outline of a Europe-wide population-based 10-year clinical follow-up study

Objective. To give a general outline of a 10-year clinical follow-up study of a population-based European cohort of inflammatory bowel disease (IBD) patients and to present the first results in terms of clinical outcome parameters and risk factors. Materials and methods. A population-based cohort of newly, prospectively, diagnosed cases was initiated between 1991 and 1993. The 2201 patients with IBD (706 had Crohns disease (CD), 1379 had ulcerative colitis (UC) and 116 had indeterminate colitis) originated from 20 different areas in 11 different European countries and Israel. For the 10-year follow-up of this cohort, electronic data-collecting instruments were made available through an Internet-based website. Data concerning vital status, disease activity, medication use, surgical events, cancer, pregnancy, fertility, quality of life and health-care costs were gathered. A blood sample was obtained from patients and controls to perform genotypic characterization. Results. Thirteen centres from eight European countries and Israel participated. In 958 (316 CD and 642 UC) out of a total of 1505 IBD patients (64%) from these 13 centres, a complete dataset was obtained at follow-up. Even though an increased mortality risk was observed in CD patients 10 years after diagnosis, a benign disease course was observed in this patient group in terms of disease recurrence. A correlation between ASCA and CARD15 variants in CD patients and complicated disease course was observed. A north–south gradient was observed regarding colectomy rates in UC patients. Direct costs were found to be highest in the first year after diagnosis and greater in CD patients than in UC patients, with marked differences between participating countries. Conclusions. This 10-year clinical follow-up study of a population-based European cohort of IBD patients provides updated information on disease outcome of these patient groups.

Disease outcome in inflammatory bowel disease: mortality, morbidity and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).

BACKGROUND The course of inflammatory bowel diseases (IBD) has mainly been studied using different methods in single patient cohorts. The aim of the present study was to assess clinical aspects of disease outcome in a population-based cohort of IBD patients over a 4-year period in multiple centres across Europe. METHODS A total of 796 patients with IBD diagnosed in 10 centres between October 1991 and October 1993, registered at the EC IBD study centre (98% of the original cohort), participated in the study. Investigators filled out a standard follow-up form containing questions on the method of follow-up, vital status of the patient, change in diagnosis, extraintestinal manifestations, medical and surgical treatment, and physicians global assessment of disease activity. RESULTS Complete relief of the complaints was reported in 255 (48%) patients with ulcerative colitis (UC), 9 (50%) with indeterminate colitis (IC), but only in 87 (35%) of patients with Crohn disease (CD). Improvement was reported in 195 (37%) patients with UC, 113 (45%) with CD and 6 (33%) with IC. During the 4-year follow-up period, 23 patients died (14 UC, 8 CD. and 1 IC). The mean age at death was 69.3 years (s, 14.9 years). The deaths of three patients were recorded as directly due to IBD. CONCLUSIONS With the present approach to therapeutic management the short-term outcome of patients with IBD seems to be favourable in 10 medical centres in the north and south of Europe. However, more detailed studies including both objective and subjective measures are necessary.Background: The course of inflammatory bowel diseases (IBD) has mainly been studied using different methods in single patient cohorts. The aim of the present study was to assess clinical aspects of disease outcome in a population-based cohort of IBD patients over a 4-year period in multiple centres across Europe. Methods: A total of 796 patients with IBD diagnosed in 10 centres between October 1991 and October 1993, registered at the EC IBD study centre (98% of the original cohort), participated in the study. Investigators filled out a standard follow-up form containing questions on the method of follow-up, vital status of the patient, change in diagnosis, extraintestinal manifestations, medical and surgical treatment, and physicians global assessment of disease activity. Results: Complete relief of the complaints was reported in 255 (48%) patients with ulcerative colitis (UC), 9 (50%) with indeterminate colitis (IC), but only in 87 (35%) of patients with Crohn disease (CD). Improvement was reported in 195 (37%) patients with UC, 113 (45%) with CD and 6 (33%) with IC. During the 4-year follow-up period, 23 patients died (14 UC, 8 CD, and 1 IC). The mean age at death was 69.3 years (s, 14.9 years). The deaths of three patients were recorded as directly due to IBD. Conclusions: With the present approach to therapeutic management the short-term outcome of patients with IBD seems to be favourable in 10 medical centres in the north and south of Europe. However, more detailed studies including both objective and subjective measures are necessary.

Inflammatory Bowel Disease in South Limburg (the Netherlands) 1991–2002: Incidence, diagnostic delay, and seasonal variations in onset of symptoms

BACKGROUND AND AIMS Increasing incidence in Inflammatory Bowel Disease (IBD) has been suggested. Recent data on population based incidence rates within Europe are however scarce. Primary aim was to investigate prospectively the incidence of IBD within a well-defined geographical and administrative area of the Netherlands, the South Limburg IBD registry. Secondary aims were to study the duration of symptoms before diagnosis (lag time) and seasonal influences on the incidence of IBD. METHODS The incidence was examined using standardized registration of all newly diagnosed IBD patients, between 1-1-1991 and 1-1-2003. Medical records were reviewed to verify the diagnosis. At inclusion, diagnostic lag time was registered in months. RESULTS Age standardized incidence rates per 100,000 person-years (p-y) were: Crohns Disease, male 4.84, female 7.58; Ulcerative Colitis, male 8.51, female 6.92; and Indeterminate Colitis, male 1.05, female 0.93. Incidence rates did not significantly changes over time in either Crohns Disease, Ulcerative Colitis or Indeterminate Colitis. Lag time was 5 (0-360) months in Crohns Disease, 3.0 (0-480) months in Ulcerative Colitis and 3.0 (0-180) months in Indeterminate Colitis. Lag time was not significantly different between the periods 1991-1993 and 2000-2002, and no statistical differences in the onset of symptoms per calendar month or season were found. CONCLUSIONS Our results, from the South Limburg region (the Netherlands), show no significant change in incidence rates of IBD. The incidence found is relatively high compared to other European countries. Lag time did not change during the study period, and seasonal influence of incidence rates could not be confirmed.

Mortality in inflammatory bowel disease in the Netherlands 1991-2002: results of a population-based study: the IBD South-Limburg cohort.

Background: The aim was to evaluate overall and disease‐specific mortality in a population‐based inflammatory bowel disease (IBD) cohort in the Netherlands, as well as risk factors for mortality. Methods: IBD patients diagnosed between 1 January 1991 and 1 January 2003 were included. Standardized mortality ratios (SMRs) were calculated overall and with regard to causes of death, gender, as well as age, phenotype, smoking status at diagnosis, and medication use. Results: At the censoring date, 72 out of 1187 patients had died (21 Crohns disease [CD], 47 ulcerative colitis [UC], and 4 indeterminate colitis [IC] patients). The SMR (95% confidence interval [CI]) was 1.1 (0.7–1.6) for CD, 0.9 (0.7–1.2) for UC and 0.7 (0.2–1.7) for IC. Disease‐specific mortality risk was significantly increased for gastrointestinal (GI) causes of death both in CD (SMR 7.5, 95% CI: 2.8–16.4) and UC (SMR 3.4, 95% CI: 1.4–7.0); in CD patients, especially in patients <40 years of age at diagnosis. For UC, an increased SMR was noted in female patients and in patients <19 years and >80 years at diagnosis. In contrast, UC patients had a decreased mortality risk from cancer (SMR 0.5, 95% CI; 0.2–0.9). Conclusions: In this population‐based IBD study, mortality in CD, UC, and IC was comparable to the background population. The increased mortality risk for GI causes might reflect complicated disease course, with young and elderly patients at diagnosis needing intensive follow‐up. Caution in interpreting the finding on mortality risk from cancer is needed as follow‐up was probably to short to observe IBD‐related cancers. (Inflamm Bowel Dis 2010)

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.

Role of ASCA and the NOD2/CARD15 mutation Gly908Arg in predicting increased surgical costs in Crohn's disease patients: A project of the European Collaborative Study Group on Inflammatory Bowel Disease

Background: NOD2/CARD15, the first identified susceptibility gene in Crohns disease (CD), is associated with ileal stenosis and increased frequency of surgery. Anti‐Saccharomyces cerevisiae antibody (ASCA), a serological marker for CD, is associated with ileal location and a high likelihood for surgery. We hypothesized that the presence of ASCA and NOD2/CARD15 mutations could predict increased health care cost in CD. Methods: CD patients in a prospectively designed community‐based multinational European and Israeli cohort (n = 228) followed for mean 8.3 (SD 2.6) years had blood drawn for measurement of ASCA (IgG, IgA), Arg702Trp, Gly908Arg, and Leu1007fsinsC. Days spent in the hospital and the costs of medical and surgical hospitalizations and medications were calculated. Results: The median duration of surgical hospitalizations was longer in Gly908Arg‐positive than ‐negative patients, 3.5 and 1.5 days/patient‐year (P < 0.01), and in ASCA‐positive than ‐negative patients, 1.1 and 0 days/patient‐year (P < 0.001). Median surgical hospitalization cost was 1,580 &U20AC;/patient‐year in Gly908Arg‐positive versus 0 &U20AC;/patient‐year in ‐negative patients (P < 0.01), and 663 &U20AC;/patient‐year in ASCA‐positive versus 0 &U20AC;/patient‐year in ‐negative patients (P < 0.001). Differences in cost of medications between groups were not significant. The effect of Gly908Arg was expressed in countries with higher Gly908Arg carriage rates. ASCA raised surgical costs independently of the age at diagnosis of disease. Arg702Trp and Leu1007fsinsC did not affect the cost of health care. Conclusions: Since CD patients positive for Gly908Arg and ASCA demonstrated higher health care costs, it is possible that measurement of Gly908Arg and ASCA at disease diagnosis can forecast the expensive CD patients. (Inflamm Bowel Dis 2007)

Effect of phenotype on health care costs in Crohn’s disease: A European study using the Montreal classification

BACKGROUND Crohns disease (CD) is a chronic inflammation of the gastrointestinal tract associated with life-long high health care costs. We aimed to determine the effect of disease phenotype on cost. METHODS Clinical and economic data of a community-based CD cohort with 10-year follow-up were analyzed retrospectively in relation to Montreal classification phenotypes. RESULTS In 418 patients, mean total costs of health care for the behavior phenotypes were: nonstricturing-nonpenetrating 1690, stricturing 2081, penetrating 3133 and penetrating-with-perianal-fistula 3356 €/patient-phenotype-year (P<0.001), and mean costs of surgical hospitalization 215, 751, 1293 and 1275 €/patient-phenotype-year respectively (P<0.001). Penetrating-with-perianal-fistula patients incurred significantly greater expenses than penetrating patients for total care, diagnosis and drugs, but not surgical hospitalization. Total costs were similar in the location phenotypes: ileum 1893, colon 1748, ileo-colonic 2010 and upper gastrointestinal tract 1758 €/patient-phenotype-year, but surgical hospitalization costs differed significantly, 558, 209, 492 and 542 €/patient-phenotype-year respectively (P<0.001). By multivariate analysis, the behavior phenotype significantly impacted total, medical and surgical hospitalization costs, whereas the location phenotype affected only surgical costs. Younger age at diagnosis predicted greater surgical expenses. CONCLUSIONS Behavior is the dominant phenotype driving health care cost. Use of the Montreal classification permits detection of cost differences caused by perianal fistula.

Treatment inferred disease severity in Crohn's disease: Evidence for a European gradient of disease course

Objective. Geographic differences in disease course of Crohns disease (CD) might possibly be related to differences in genetic and environmental factors encountered in different parts of the world. The aim of this study was to assess differences in treatment regimens within a European cohort of CD patients as a reflection of disease course, and to identify associated phenotypic risk factors at diagnosis. Material and methods. A prospective European population-based inception cohort of 380 CD patients was studied. The patients were classified for phenotype according to the Vienna classification. Differences between Northern and Southern European centres in treatment over the first 10 years of disease were analysed using a competing risks survival analysis method. Results. Patients in the North were more likely to have had surgery (p<0.01), whereas patients in the South were more likely to have been treated medically (p<0.01). Phenotype at diagnosis was not predictive of differences in treatment regimens between North and South. Conclusions. In this study, a difference in management of CD was observed between Northern and Southern European centres. This suggests that there may be a North–South disease severity gradient across Europe. Phenotypic differences between patients in the North and South did not explain this observed difference.