Longitudinal concordance for clinical characteristics in a Swedish-Danish twin population with inflammatory bowel disease.

BACKGROUND: The genetic influence on disease course in inflammatory bowel disease (IBD) remains unknown. We therefore aimed to study longitudinal concordance for clinical characteristics and longitudinal stability using the Montreal Classification in an IBD twin population. METHODS: A total of 158 twins with ulcerative colitis (UC) (18 belonging to 9 concordant monozygotic pairs) and 141 twins with Crohn's disease (CD) (34 belonging to 17 concordant monozygotic pairs) were enrolled. Medical notes were scrutinized for clinical characteristics at diagnosis and after 10 years. Using the binominal distribution, we tested the hypothesis that clinical characteristics were independent within individuals in disease concordant monozygotic pairs. RESULTS: In CD, location was identical in 11/17 monozygotic concordant pairs at diagnosis (P = 0.008) and in 11/16 pairs after 10 years (P = 0.02). Behavior at diagnosis was identical in 13/17 pairs (P = 0.03) and in 11/16 pairs after 10 years (P = 0.01). Monozygotic UC twins were concordant (within 5 years) for age at diagnosis (6/9 pairs; P < 0.001) and symptomatic onset (4/9 pairs; P = 0.02) but not for extent of disease at diagnosis or after 10 years. The Montreal Classification did not demonstrate longitudinal stability, either regarding location or behavior of CD or extent of UC. CONCLUSIONS: The high phenotypic concordance, both at diagnosis and longitudinally, in monozygotic twins with CD supports a genetic influence not only on disease occurrence but also on disease course. This contrasts with UC, where the genetic impact appears less. Montreal Classification characteristics changed over time and should be used cautiously.

The prevalence of genetic and serologic markers in an unselected European population-based cohort of IBD patients.

BACKGROUND AND AIM: The aetiology of inflammatory bowel disease (IBD) is unknown, but it has become evident that genetic factors are involved in disease susceptibility. Studies have suggested a north-south gradient in the incidence of IBD, raising the question whether this difference is caused by genetic heterogeneity. We aimed to investigate the prevalence of polymorphisms in CARD15 and TLR4 and occurrence of anti-Saccharomyces cerevisiae (ASCA) and antineutrophil cytoplasmic antibodies (pANCA) in a European population-based IBD cohort. METHODS: Individuals from the incident cohort were genotyped for three mutations in CARD15 and the Asp299gly mutation in TLR4. Levels of ASCA and pANCA were assessed. Disease location and behaviour at time of diagnosis was obtained from patient files. RESULTS: Overall CARD15 mutation rate was 23.9% for CD and 9.6% for UC patients (P < 0.001). Mutations were less present in the Scandinavian countries (12.1%) versus the rest of Europe (32.8%) (P < 0.001). Overall population attributable risk was 11.2%. TLR4 mutation rate was 7.6% in CD, 6.7% in UC patients and 12.3% in healthy controls (HC), highest among South European CD patients and HC. ASCA was seen in 28.5% of CD patients with no north-south difference, and was associated with complicated disease. pANCA was most common in North European UC patients and not associated with disease phenotype. CONCLUSION: The prevalence of mutations in CARD15 varied across Europe, and was not correlated to the incidence of CD. There was no association between mutations in TLR4 and IBD. The prevalence of ASCA was relatively low; however related to severe CD.

Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark.

BACKGROUND: It remains uncertain whether the increasing incidence of inflammatory bowel disease (IBD) during the last decades has been accompanied by an alteration in the presentation, course, and prognosis of the disease. To answer this question, 3 consecutive population-based IBD cohorts from Copenhagen, Denmark (1962-2005), were assessed and evaluated. METHODS: Phenotype, initial disease course, use of medications, cumulative surgery rate, standardized incidence ratio of colorectal cancer (CRC), and standardized mortality ratio (SMR) were compared in the 3 cohorts, which had a total of 641 patients with Crohn's disease (CD) and 1575 patients with ulcerative colitis (UC). RESULTS: From 1962 to 2005, the proportion of IBD patients suffering from CD increased (P < 0.001), time from onset of symptoms to diagnosis of CD decreased (P = 0.001), and median age at diagnosis of UC increased (P < 0.01). The prevalence of upper gastrointestinal involvement and pure colonic CD varied significantly between cohorts. UC patients diagnosed in the 1990s had a higher prevalence of proctitis, received more medications, and had a milder initial disease course than did previous patients. The surgery rate decreased significantly in CD but not in UC. The risk of CRC in IBD was close to expected over the entire period, whereas the mortality of patients with CD increased (overall SMR, 1.31; 95% CI, 1.07-1.60). CONCLUSIONS: Despite variations in the presentation and initial course of IBD during the last 5 decades, its long-term prognosis remained fairly stable. Treatment of IBD changed recently, and future studies should address the effect of these changes on long-term prognosis.

Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen county, Denmark and Olmsted county, Minnesota.

OBJECTIVES: Population-based data on risk factors and protective factors for colorectal dysplasia and cancer in patients with inflammatory bowel disease (IBD) are sparse. We conducted a nested case-control study of such factors in two well-described IBD cohorts from Copenhagen County, Denmark and Olmsted County, Minnesota. METHODS: Forty-three neoplasia cases were matched on six criteria to 1-3 controls (N = 102). Medical records were scrutinized for demographic and clinical data. For each variable, the odds of neoplasia were estimated using conditional logistic regression. RESULTS: Primary sclerosing cholangitis (PSC) (odds ratio [OR] 6.9, 95% confidence interval [CI] 1.2-40), percentage of disease course with clinically active disease (OR [per 5% increase] 1.2, 95% CI 0.996-1.4), and >or=1 yr of continuous symptoms (OR 3.2, 95% CI 1.2-8.6) were associated with neoplasia, whereas a borderline association with median number of small-bowel x-rays (OR 1.3, 95% CI 0.96-1.6) was observed. We did not observe a protective effect of frequency of physician visits (OR 1.4, 95% CI 0.96-2.0), number of colonoscopies (OR 1.4, 95% CI 1.0-2.1), cumulative dose of sulfasalazine (OR [per 1,000 g] 1.1, 95% CI 1.0-1.3) and mesalamine (OR [per 1,000 g] 1.3, 95% CI 0.9-1.9), or partial intestinal resections (OR 1.5, 95% CI 0.3-7.1). CONCLUSIONS: Subgroups of IBD patients-those with PSC, severe long-standing disease, and exposure to x-ray-were at greater risk of colorectal neoplasia. The protective effect of close follow-up, colonoscopy, and treatment with 5-aminosalicylates was questionable.

Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population.

BACKGROUND: Genetics and environmental factors are implicated in the etiology of inflammatory bowel disease (IBD). We studied environmental factors in a population-based Swedish-Danish twin cohort using the co-twin control method. SUBJECTS AND METHODS: A questionnaire was sent to 317 twin pairs regarding markers of exposures in the following areas: infections/colonization and diet as well as smoking, appendectomy, and oral contraceptives. Odds ratios (OR) were calculated by conditional logistic regression. When confounding appeared plausible, multivariate conditional logistic regression was added. The questions were also divided into topic groups, and adjustment was made for multiple testing within each of the groups. RESULTS: The response rate to the questionnaire was 83%. In consideration of the study design, only discordant pairs were included (Crohn's disease [CD], n = 102; ulcerative colitis [UC], n = 125). Recurrent gastrointestinal infections were associated with both UC (OR, 8.0; 95% confidence interval [CI], 1.0-64) and CD (OR, 5.5; 95% CI, 1.2-25). Hospitalization for gastrointestinal infections was associated with CD (OR, 12; 95% CI, 1.6-92). Smoking was inversely associated with UC (OR, 0.4; 95% CI, 0.2-0.9) and associated with CD (OR, 2.9; 95% CI, 1.2-7.1). CONCLUSIONS: The observed associations indicate that markers of possible infectious events may influence the risk of IBD. Some of these effects might be mediated by long-term changes in gut flora or alterations in reactivity to the flora. The influence of smoking in IBD was confirmed.

Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) often affects patients in their fertile age. The aim of this study was to describe pregnancy outcome in a European cohort of IBD patients. As data are limited regarding the effect of pregnancy on disease course, our second objective was to investigate whether pregnancy influences disease course and phenotype in IBD patients. METHODS: In a European cohort of IBD patients, a 10-yr follow-up was performed by scrutinizing patient files and approaching the patients with a questionnaire. The cohort comprised 1,125 patients, of whom 543 were women. Data from 173 female ulcerative colitis (UC) and 93 Crohn's disease (CD) patients form the basis for the present study. RESULTS: In all, 580 pregnancies, 403 occurring before and 177 after IBD was diagnosed, were reported. The rate of spontaneous abortion increased after IBD was diagnosed (6.5% vs. 13%, p = 0.005), whereas elective abortion was not significantly different. 48.6% of the patients took medication at the time of conception and 46.9% during pregnancy. The use of cesarean section increased after IBD diagnosis (8.1% vs 28.7% of pregnancies). CD patients pregnant during the disease course, did not differ from patients who were not pregnant during the disease course regarding the development of stenosis (37% vs 52% p = 0.13) and resection rates (mean number of resections 0.52 vs 0.66, p = 0.37). The rate of relapse decreased in the years following pregnancy in both UC (0.34 vs 0.18 flares/yr, p = 0.008) and CD patients (0.76 vs 0.12 flares/yr, p = 0.004). CONCLUSIONS: Pregnancy did not influence disease phenotype or surgery rates, but was associated with a reduced number of flares in the following years.

Disease concordance, zygosity, and NOD2/CARD15 status: follow-up of a population-based cohort of Danish twins with inflammatory bowel disease.

OBJECTIVES: A Danish cohort of twins with inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), has previously been collected. The aim of the present study was to reassess this cohort in order to compare clinical characteristics in concordant versus discordant twin pairs, test twin zygosity genetically, follow-up on disease concordance, and examine NOD2/CARD15 genetic status. METHODS: The Danish cohort is one of two population-based cohorts worldwide and consists of 103 twin pairs. After median 13 yr of follow-up, all twins were contacted and hospital files were scrutinized to reassess disease concordance and obtain phenotype data. DNA was obtained from 123 twins for analysis of zygosity and prevalence of the three common NOD2/CARD15 mutations. RESULTS: Zygosity tested genetically was consistent with the former assessment based on questionnaires. The proband concordance for CD remained fairly stable: 63.6% among monozygotic (MZ) twins and 3.6% among dizygotic (DZ) twins. Clinical characteristics were similar in twins from concordant versus discordant pairs. Forty-four percent of patients with CD were positive for >or=1 mutant allele of NOD2/CARD15 compared to 2% of UC patients (p < 0.001) and 19% of healthy twins (p= 0.02). The allele mutation frequency was 43% among the healthy twins to patients with CD versus 9% among twins to UC patients (p= 0.01). CONCLUSIONS: Previous questionnaire assessment of twin zygosity was confirmed by genetic test. Concordance for CD remained quite stable and was significantly higher among MZ than DZ twins. A high NOD2/CARD15 mutation frequency was observed both among CD twins and their healthy siblings.

Intra- and interobserver variation in the use of the Vienna classification of Crohn's disease.

BACKGROUND: Crohn's disease is a heterogeneous disease, and several classification systems have been developed to classify the patients in more homogeneous groups. Our aim was to assess the intra- and interobserver variation when classifying patients according to the widely used Vifenna classification. METHODS: Ten randomly selected Crohn's disease cases were presented to 11 Danish gastroenterologists with a special interest in inflammatory bowel diseases. Clinical details, together with endoscopic, radiologic, and pathologic reports, were presented to the participants as a PowerPoint slide show, sent by e-mail with a data collection form. The experts were asked to classify the cases according to the Vienna classification and to evaluate intraobserver variation; the participants classified the patients 3 times. The strength of agreement was calculated using kappa statistics. RESULTS: Classification of the patients according to age gave a kappa value of 1.00. The intraobserver kappa value was good, with an average kappa value of 0.75 (range, 0.42-0.86) for location and 0.77 (range, 0.53-1.00) for behavior. The mean overall interobserver kappa value was 0.64 (range, 0.12-1.00), which improved slightly between the first and third rounds. When classifying according to location and behavior, most patients were classified in 2 or 3 different ways, and in no patients was there full agreement among the observers for both location and behavior. CONCLUSIONS: In this study, we found an overall good interobserver agreement when using the Vienna classification, although when looking at individual cases, there was some disagreement.

Long-term risk of cancer in ulcerative colitis: a population-based cohort study from Copenhagen County.

BACKGROUND & AIMS: Ulcerative colitis (UC) is associated with an increased risk for colorectal cancer (CRC) and possibly also increased risk for cancers outside the intestinal tract. We followed-up a population-based cohort of 1160 patients with UC diagnosed in Copenhagen County between 1962 and 1987 for up to 36 years to analyze the overall and site-specific cancer risk. METHODS: Observed vs. expected cancers were presented as standardized morbidity ratio (SMR) with 95% exact confidence intervals (CI) calculated by using individual person-years at risk and sex- and age-specific incidence rates for the Danish background population in 1995. RESULTS: The cohort was followed-up for a median of 19 years, or 22,290 person-years. A total of 124 malignancies were observed compared with 139.85 expected (SMR, .89; 95% CI, .74-1.07). The observed number of CRCs was almost exactly equal to expected: 13 cases vs. 12.42 (SMR, 1.05; 95% CI, .56-1.79). The cumulative probability of CRC was .4% by 10 years, 1.1% by 20 years, and 2.1% by 30 years of disease. Among men, melanoma was increased (SMR, 3.45; 95% CI, 1.38-7.10); otherwise, no increased risk for cancer could be detected. No hepatobiliary cancers and no increased risk for lymphoma or leukemia were found. CONCLUSIONS: Neither the overall cancer risk, nor the CRC risk, were increased in this population-based cohort after a median of 19 years of follow-up evaluation. An active surgical approach in medical treatment failures and long-term use of 5-aminosalicylic acid (5-ASA) as relapse prevention may explain this remarkable result.

Epidemiology of IBD during the twentieth century: an integrated view.

Current incidence figures on ulcerative colitis and Crohn's disease--presented in a recent multicenter study in Europe--are given, and differences in the frequency and clinical appearances of the two conditions are discussed. Trends in the frequency and clinical appearance of inflammatory bowel disease during the twentieth century are summarized, as well as the differences over time and from place to place. Correlations between age, sex, localization of disease and clinical symptoms are given. Risk of progression to more extensive disease in patients with proctitis is shown. Incidences of inflammatory bowel disease in childhood and among migrated ethnic groups are discussed. Survival and cancer risk among patients with ulcerative colitis and Crohn's disease are shown from long-term clinical epidemiological studies of well-defined patient groups. Trends in these important prognostic parameters over time are shown, as well as factors influencing prognosis of the diseases.

Survival and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen County.

BACKGROUND & AIMS: A population-based cohort from Copenhagen County comprising 1160 patients diagnosed with ulcerative colitis between 1962 and 1987 was followed-up until 1997 to describe survival and cause-specific mortality. METHODS: Observed vs. expected deaths were presented as standardized mortality ratio (SMR) with exact 95% confidence intervals (CI) calculated by using individually registered person-years at risk and Danish 1995 mortality rates. Cumulative survival curves were calculated. RESULTS: A total of 261 deaths occurred, not significantly different from the expected number of 249 (SMR, 1.05; 95% CI, 0.92-1.19). The median age at death among men was 70 years (range, 6-96 years) and among women 74 years (range, 25-96 years). Twenty-five deaths (9.6%) were caused by complications to ulcerative colitis, mostly infectious and cardiovascular postoperative complications. Patients older than 50 years of age at diagnosis and with extensive colitis showed an increased mortality within the first 2 years because of ulcerative colitis-associated causes. The mortality from colorectal cancer was not increased and that of cancer in general was significantly lower than expected: 50 vs. 71 (SMR, 0.70; 95% CI, 0.52-0.93). A significantly increased mortality from pulmonary embolism and pneumonia was found. Among women only, death from genitourinary tract diseases and suicide was significantly increased. CONCLUSIONS: Despite an overall normal life expectancy for patients with ulcerative colitis, patients >50 years of age and with extensive colitis at diagnosis had increased mortality within the first 2 years after diagnosis, owing to colitis-associated postoperative complications and comorbidity.

Mortality and causes of death in Crohn's disease: follow-up of a population-based cohort in Copenhagen County, Denmark.

BACKGROUND & AIMS: A population-based cohort comprising 374 patients with Crohn's disease diagnosed in Copenhagen County between 1962 and 1987 was observed until 1997 for mortality and causes of death. METHODS: Observed deaths were compared with expected deaths calculated by using individually computed person-years at risk and 1995 rates for Copenhagen County. Cumulative survival curves were calculated. RESULTS: A total of 84 deaths occurred vs. 67 expected (standardized mortality ratio [SMR], 1.3; 95% confidence interval [CI], 1.01-1.56): 45 women vs. 31.8 expected (SMR, 1.4; 95% CI, 1.03-1.89) and 39 men vs. 35.2 expected (SMR, 1.1; 95% CI, 0.79-1.51). An excess mortality was observed among women observed for 21-25 years after diagnosis. Among women aged <50 years at diagnosis, 25 deaths were observed vs. 7.3 expected (SMR, 3.42; 95% CI, 2.21-5.04). Fourteen (31%) of the observed deaths among women and 8 (21%) among men had a certain or possible connection to Crohn's disease. Among causes of death unrelated to Crohn's disease, an overrepresentation of gastrointestinal diseases, infections, and diseases of the urinary organs was observed. CONCLUSIONS: An increased mortality was observed late in the disease course that was most pronounced among women younger than 50 years at diagnosis and was attributed to death associated with severe Crohn's disease.

CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease.

CARD15/NOD2 encodes a protein involved in bacterial recognition by monocytes. Mutations in CARD15 have recently been found in patients with Crohn disease (CD), a chronic inflammatory condition of the digestive tract. Here, we report the mutational analyses of CARD15 in 453 patients with CD, including 166 sporadic and 287 familial cases, 159 patients with ulcerative colitis (UC), and 103 healthy control subjects. Of 67 sequence variations identified, 9 had an allele frequency >5% in patients with CD. Six of them were considered to be polymorphisms, and three (R702W, G908R, and 1007fs) were confirmed to be independently associated with susceptibility to CD. Also considered as potential disease-causing mutations (DCMs) were 27 rare additional mutations. The three main variants (R702W, G908R, and 1007fs) represented 32%, 18%, and 31%, respectively, of the total CD mutations, whereas the total of the 27 rare mutations represented 19% of DCMs. Altogether, 93% of the mutations were located in the distal third of the gene. No mutations were found to be associated with UC. In contrast, 50% of patients with CD carried at least one DCM, including 17% who had a double mutation. This observation confirmed the gene-dosage effect in CD. The patients with double-dose mutations were characterized by a younger age at onset (16.9 years vs. 19.8 years; P=.01), a more frequent stricturing phenotype (53% vs. 28%; P=.00003; odds ratio 2.92), and a less frequent colonic involvement (43% vs. 62%; P=.003; odds ratio 0.44) than were seen in those patients who had no mutation. The severity of the disease and extraintestinal manifestations were not different for any of the CARD15 genotypes. The proportion of familial and sporadic cases and the proportion of patients with smoking habits were similar in the groups of patients with CD with or without mutation. These findings provide tools for a DNA-based test of susceptibility and for genetic counseling in inflammatory bowel disease.

A Genetic Study of Ulcerative Colitis.

A group of 152 patients with a verified diagnosis of ulcerative colitis (including haemorrhagic proctitis) was compared with a control group with an identical sex ratio, age, and social class distribution. All patients attended an ulcerative colitis out-patient clinic, and had been examined and followed by the members of the team. By the use of questionnaires information was gathered concerning familial incidence of the following diseases: ulcerative colitis, regional ileitis, cancer of the colon and rectum, allergic diseases of the immediate type (bronchial asthma, urticaria, allergic rhinitis, and atopic dermatitis), diseases presumably caused by delayed hypersensitivity (erythema nodosum), or auto-allergy (rheumatoid arthritis and ankylosing spondylarthritis). Eight families with more than one case of ulcerative colitis were found in the patient group (5.3 per cent) compared to only one case in the control group (0.7 per cent). This difference is significant. No cases of regional ileitis were observed, either in the patient group or in the control group. Cancer of the colon and rectum did not occur significantly more often among the relatives of patients with ulcerative colitis. The preponderance of urticaria and allergic rhinitis in the ulcerative colitis families and the even distribution of rheumatoid arthritis, erythema nodosum, and ankylosing spondylarthritis in the two groups compared tends to support the hypothesis that an allergic pathogenesis of ulcerative colitis is of the immediate type.