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Numerous pathogenic processes are mediated by short noncoding RNAs (sncRNA). Twenty percent of inflammatory bowel disease (IBD) patients are labelled as IBD unclassified (IBDU) at disease onset. Most IBDU patients are reclassified as Crohn's disease (CD) or ulcerative colitis (UC) within few years. Since the therapeutic methods for CD and UC differ, biomarkers that can forecast the categorization of IBDU into CD or UC are highly desired. Here, we investigated whether sncRNAs can predict CD or UC among IBDU patients. 35 IBDU patients who were initially diagnosed with IBDU were included in this retrospective investigation; of them, 12, 15, and 8 were reclassified into CD (IBDU-CD), UC (IBDU-UC), or remained as IBDU (IBDU-IBDU), respectively. Eight IBD patients, were included as references. SncRNA profiling on RNA from mucosal biopsies were performed using Affymetrix miRNA 4.0 array. Selected probe sets were validated using RT-qPCR. Among all patients and only adults, 306 and 499 probe sets respectively were differentially expressed between IBDU-CD and IBDU-UC. Six of the probe sets were evaluated by RT-qPCR, of which miR-182-5p, miR-451a and ENSG00000239080 (snoU13) together with age and sex resulted in an AUC of 78.6% (95% CI: 60-97) in discriminating IBDU-CD from IBDU-UC. Based on the three sncRNAs profile it is possible to predict if IBDU patients within 3 years will be reclassified as CD or UC. We showed that the expression profile of IBDU patients differ from that of definite CD or UC, suggesting that a subgroup of IBDU patients may compose a third unique IBD subtype., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 James et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Differential diagnosis of inflammatory bowel disease (IBD) to Crohn's disease (CD) or ulcerative colitis (UC) is crucial for treatment decision making. With the aim of generating a clinically applicable molecular-based tool to classify IBD patients, we assessed whole transcriptome analysis on endoscopy samples. A total of 408 patient samples were included covering both internal and external samples cohorts. Whole transcriptome analysis was performed on an internal cohort of FFPE IBD samples (CD, n = 16 and UC, n = 17). The 100 most significantly differentially expressed genes (DEG) were tested in two external cohorts. Ten of the DEG were further processed by functional enrichment analysis from which seven were found to show consistent significant performance in discriminating CD from UC: PI3, ANXA1, VDR, MTCL1, SH3PXD2A-AS1, CLCF1, and CD180. Differential expression of PI3, ANXA1, and VDR was reproduced by RT-qPCR, which was performed on an independent sample cohort of 97 patient samples (CD, n = 44 and UC, n = 53). Gene expression levels of the three-gene profile, resulted in an area under the curve of 0.84 (P = 0.02) in discriminating CD from UC, and therefore appear as an attractive molecular-based diagnostic tool for clinicians to distinguish CD from UC., (© 2023. The Author(s).)

Background and Aims: Few studies have assessed the contemporary patterns of disease activity in patients with inflammatory bowel disease [IBD]. We aimed to describe the disease patterns and their long-term outcomes., Methods: All Danish individuals with IBD between 1995 and 2018 were identified using information about IBD-related hospitalizations, surgeries and redeemed prescriptions. The disease activity patterns for 5- and 10-year periods were assessed., Results: In incident patients with Crohn's disease [CD], severe disease activity occurred in the year of diagnosis in 80% of patients; for ulcerative colitis [UC] this figure was 75%, in addition to 3.4% of UC patients who underwent a colectomy within the first year. After 20 years of disease, the proportion of CD and UC patients in remission increased to 89% and 72%, respectively. The proportion of prevalent patients in remission each year was stable, despite the introduction of biological therapies. A decreasing activity pattern was the most common in both CD and UC patients [both 45%]. The distribution of the disease activity patterns was seen to be stable over time. A quiescent disease pattern was accompanied by a significantly higher risk of intestinal cancer [HR: 3.37, 95% CI: 1.23-9.19] for CD patients, according to a Cox proportional hazards model. In UC patients, increasing disease activity [HR: 0.67, 95% CI: 0.31-1.48] was associated with an increased risk of intestinal cancer., Conclusions: We report the distribution of disease patterns among IBD patients. Patients with quiescent CD, as well as UC patients with chronic continuous or increasing activity, were at increased risk of developing intestinal cancer., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Few population-based studies have investigated the long-term prognosis of Crohn's disease (CD)., Aim: To determine the long-term natural disease course of CD with regard to surgery, cancer and mortality in a population-based cohort followed for more than 50 years., Methods: All patients diagnosed with CD from 1962 to 1987 in Copenhagen County, Denmark were included in a population-based cohort. Information about surgeries, cancers and mortality was collected from patient files from 1962 to 1987 and from the Danish National Patient Registry, Cancer Registry, and from the Register of Causes of Death, 1987-2017. Patients were matched with individuals from the general population., Results: A total of 373 patients were followed for a median of 33 years (range: 0-56 years). The cumulative probability of surgery 10, 20, 30, 40 and 50 years after diagnosis was 62% (CI 95%: 57%-67%), 71% (CI 95%: 66%-75%), 72% (CI 95%: 67%-76%), 74% (CI 95%: 69%-79%) and 74% (CI 95%: 69%-79%), respectively. A total of 142 patients (54%) were operated upon at least twice: 69 (26%) needing two surgeries and 73 (28%) needing three or more. Patients with CD were found to be at increased risk of intestinal (small bowel, rectum and anus) and extra-intestinal (respiratory organs and skin) cancer. All-cause mortality among CD patients was higher than among controls (RR: 1.22, CI 95%: 1.04-1.43), whereas mortality due to gastrointestinal cancer was not., Conclusion: After 50 years of follow-up, 75% CD patients had undergone surgery, with most needing repeat surgery. The risk of intestinal and extra-intestinal cancers, as well as mortality, was higher among CD patients than the background population., (© 2021 John Wiley & Sons Ltd.)

Background: The lack of scientific evidence regarding the effectiveness of 5-aminosalicylate in patients with Crohn's disease is in sharp contrast to its widespread use in clinical practice., Aims: The aim of the study was to investigate the use of 5-aminosalicylate in patients with Crohn's disease as well as the disease course of a subgroup of patients who were treated with 5-aminosalicylate as maintenance monotherapy during the first year of disease., Methods: In a European community-based inception cohort, 488 patients with Crohn's disease were followed from the time of their diagnosis. Information on clinical data, demographics, disease activity, medical therapy and rates of surgery, cancers and deaths was collected prospectively. Patient management was left to the discretion of the treating gastroenterologists., Results: Overall, 292 (60%) patients with Crohn's disease received 5-aminosalicylate period during follow-up for a median duration of 28 months (interquartile range 6-60). Of these, 78 (16%) patients received 5-aminosalicylate monotherapy during the first year following diagnosis. Patients who received monotherapy with 5-aminosalicylate experienced a mild disease course with only nine (12%) who required hospitalization, surgery, or developed stricturing or penetrating disease, and most never needed more intensive therapy. The remaining 214 patients were treated with 5-aminosalicylate as the first maintenance drug although most eventually needed to step up to other treatments including immunomodulators (75 (35%)), biological therapy (49 (23%)) or surgery (38 (18%))., Conclusion: In this European community-based inception cohort of unselected Crohn's disease patients, 5-aminosalicylate was commonly used. A substantial group of these patients experienced a quiescent disease course without need of additional treatment during follow-up. Therefore, despite the controversy regarding the efficacy of 5-aminosalicylate in Crohn's disease, its use seems to result in a satisfying disease course for both patients and physicians.

Background: Inflammatory bowel disease (IBD) places a significant burden on health-care systems because of its chronicity and need for expensive therapies and surgery. With increasing use of biological therapies, contemporary data on IBD health-care costs are important for those responsible for allocating resources in Europe. To our knowledge, no prospective long-term analysis of the health-care costs of patients with IBD in the era of biologicals has been done in Europe. We aimed to investigate cost profiles of a pan-European, community-based inception cohort during 5 years of follow-up., Methods: The Epi-IBD cohort is a community-based, prospective inception cohort of unselected patients with IBD diagnosed in 2010 at centres in 20 European countries plus Israel. Incident patients who were diagnosed with IBD according to the Copenhagen Diagnostic Criteria between Jan 1, and Dec 31, 2010, and were aged 15 years or older the time of diagnosis were prospectively included. Data on clinical characteristics and direct costs (investigations and outpatient visits, blood tests, treatments, hospitalisations, and surgeries) were collected prospectively using electronic case-report forms. Patient-level costs incorporated procedures leading to the initial diagnosis of IBD and costs of IBD management during the 5-year follow-up period. Costs incurred by comorbidities and unrelated to IBD were excluded. We grouped direct costs into the following five categories: investigations (including outpatient visits and blood tests), conventional medical treatment, biological therapy, hospitalisation, and surgery., Findings: The study population consisted of 1289 patients with IBD, with 1073 (83%) patients from western Europe and 216 (17%) from eastern Europe. 488 (38%) patients had Crohn's disease, 717 (56%) had ulcerative colitis, and 84 (6%) had IBD unclassified. The mean cost per patient-year during follow-up for patients with IBD was €2609 (SD 7389; median €446 [IQR 164-1849]). The mean cost per patient-year during follow-up was €3542 (8058; median €717 [214-3512]) for patients with Crohn's disease, €2088 (7058; median €408 [133-1161]) for patients with ulcerative colitis, and €1609 (5010; median €415 [92-1228]) for patients with IBD unclassified (p<0·0001). Costs were highest in the first year and then decreased significantly during follow-up. Hospitalisations and diagnostic procedures accounted for more than 50% of costs during the first year. However, in subsequent years there was a steady increase in expenditure on biologicals, which accounted for 73% of costs in Crohn's disease and 48% in ulcerative colitis, in year 5. The mean annual cost per patient-year for biologicals was €866 (SD 3056). The mean yearly costs of biological therapy were higher in patients with Crohn's disease (€1782 [SD 4370]) than in patients with ulcerative colitis (€286 [1427]) or IBD unclassified (€521 [2807]; p<0·0001)., Interpretation: Overall direct expenditure on health care decreased over a 5-year follow-up period. This period was characterised by increasing expenditure on biologicals and decreasing expenditure on conventional medical treatments, hospitalisations, and surgeries. In light of the expenditures associated with biological therapy, cost-effective treatment strategies are needed to reduce the economic burden of inflammatory bowel disease., Funding: Kirsten og Freddy Johansens Fond and Nordsjællands Hospital Forskningsråd., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn's disease (CD)., Design: Patients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis., Results: In total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5)., Conclusion: Despite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation., Competing Interests: Competing interests: JB: consulting fees from Celgene, Janssen-Cilag, AbbVie A/S and Ferring and lecture fees from Abbvie A/S, Pfizer, MSD and Takeda Pharma A/S. VA: consultancy for Janssen and MSD. RS: consulting fees and/or lecture fees from AbbVie, MSD, Takeda, Janssen-Cilag. RD’I: consulting fees from Abbvie, Biocure and lecture fees from Takeda and Mundipharma. MF: speaker/lecture fees for Abbvie, Ferring, MSD, Takeda, Boehringer and Hospira. CG-R: lecture fees from Takeda, MSD, Ferring and Tillots. CE: lecture fees from Takeda. JH: research grants from Janssen, MSD and Takeda and lecture and/or consultancy fees from Abbvie, Cellgene, Ferring, Hospira, Janssen, Medivir, MSD, Pfizer, Vifor Pharma, Takeda and Tillotts Pharma. EL: lecture or consultancy fees from MSD, Abbvie and Ferring Pharmaceuticals. DD: lecture or consultancy fees from AbbVie, Takeda and Janssen. NA: lecture fees from MSD and Jansen. VH: personal fees, non-financial support and other from MSD, AbbVie, Ferring, Faes Farma, Shire, Falk Pharma, Tillots, Otsuka, Hospira Biologicals, Takeda, Jansen and Kernpharma Biologics. AF: personal fees and non-financial support from MSD, AbbVie, Shire and Tillots. SČ-Č: lecture fees from Takeda, MSD, Abbvie., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

It is increasingly admitted that Crohn's disease and ulcerative colitis, the two entities of inflammatory bowel disease, are initiated and reactivated by environmental factors in genetically susceptible hosts, and result from aberrant immune response to specific intestinal microbes, in the context of altered composition of intestinal microbiota, called dysbiosis. We hypothesize that the role of the gut microbiota in Crohn's disease pathogenesis is linked to early-life abnormal crosstalk with the host immune system under construction. By contrast, in ulcerative colitis, the detrimental effect of intestinal dysbiosis could occur at any time of life, due to instant environment. This hypothesis could explain why the incidence of Crohn's disease raises many years later than that of ulcerative colitis in developing countries that adopt the Western lifestyle. This would also explain why many early-life events, such as caesarean section, increased hygiene and repeated antibiotic exposure, are risk factors for subsequent development of Crohn's disease, but not ulcerative colitis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This ECCO Topical Review of the European Crohn's and Colitis Organisation [ECCO] focuses on the role of environmental factors with respect to the development of inflammatory bowel disease [IBD] as well as their influence on the course of established IBD. The objective was to reach expert consensus to provide evidence-based guidance for clinical practice., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: The aim of the present study was to validate the IBD (inflammatory bowel diseases) incidence reported in the 2010 ECCO-EpiCom (European Crohn's and Colitis Organization-Epidemiological Committee) inception cohort by including a second independent inception cohort from participating centers in 2011 and an Australian center to investigate whether there is a difference in the incidence of IBD between Eastern and Western European countries and Australia., Methods: Fourteen centers from 5 Eastern and 9 Western European countries and one center from Australia participated in the ECCO-EpiCom 2011 inception cohort. Patients' data regarding disease type, socio-demographic factors, extraintestinal manifestations and therapy were entered into the Web-based EpiCom database, www.ecco-epicom.eu., Results: A total of 711 adult patients were diagnosed during the inclusion year 2011, 178 (25%) from Eastern, 461 (65%) from Western Europe and 72 (10%) from Australia; 259 (37%) patients were diagnosed with Crohn's disease, 380 (53%) with ulcerative colitis and 72 (10%) with IBD unclassified. The mean annual incidence rate for IBD was 11.3/100,000 in Eastern Europe, 14.0/100,000 in Western Europe and 30.3/100,000 in Australia. Significantly more patients were diagnosed with complicated disease at diagnosis in Eastern Europe compared to Western Europe (43% vs. 27%, p=0.02)., Conclusion: Incidence rates, disease phenotype and initial treatment characteristics in the 2011 ECCO-EpiCom cohort were not significantly different from that reported in the 2010 cohort., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Introduction: Treatment possibilities have changed in inflammatory bowel disease (IBD). We assessed changes in medical treatment and surgery over time and impact of medications on risk of surgery in a population-based cohort., Methods: 48 967 individuals were diagnosed with IBD (Crohn's disease (CD), 13 185; ulcerative colitis (UC), 35 782) during 1979-2011. Cumulative probability of receiving 5-aminosalicylic acids (5-ASA), topical, oral corticosteroids, thiopurines, and tumour necrosis factor-α (TNF-α) blockers, and of first minor or major surgery according to period of diagnosis, was estimated. Medication use and risk of surgery was examined by Cox regression., Results: 5-year cumulative probability of first major surgery decreased from 44.7% in cohort (1979-1986) to 19.6% in cohort (2003-2011) (p < 0.001) for CD, and from 11.7% in cohort (1979-1986) to 7.5% in cohort (2003-2011) (p < 0.001) for UC. Minor surgery risk decreased significantly in CD. From cohort (1995-2002) to cohort (2003-2011), a significant increase in use of thiopurines and TNF-α blockers was observed, paralleled by a significant decrease in use of 5-ASA and corticosteroids. Comparing use of azathioprine (or oral corticosteroids) to never-use, no convincing surgery-sparing effect was found. Comparing use in 3+ months of a given drug with use <3 months, only 3+ months use of oral corticosteroids reduced the risk of surgery in patients with disease duration of >1 year., Conclusions: Parallel to an increasing use of thiopurines and TNF-α blockers in IBD over time, a persistent significant decrease in surgery rates was observed along with a significant decrease in use of 5-ASA and corticosteroids. However, no convincing surgery-sparing effect of newer medications was found., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Aims: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe possibly due to changes in environmental factors towards a more "westernised" standard of living. The aim of this study was to investigate differences in exposure to environmental factors prior to diagnosis in Eastern and Western European IBD patients., Methods: The EpiCom cohort is a population-based, prospective inception cohort of 1560 unselected IBD patients from 31 European countries covering a background population of 10.1 million. At the time of diagnosis patients were asked to complete an 87-item questionnaire concerning environmental factors., Results: A total of 1182 patients (76%) answered the questionnaire, 444 (38%) had Crohn's disease (CD), 627 (53%) ulcerative colitis (UC), and 111 (9%) IBD unclassified. No geographic differences regarding smoking status, caffeine intake, use of oral contraceptives, or number of first-degree relatives with IBD were found. Sugar intake was higher in CD and UC patients from Eastern Europe than in Western Europe while fibre intake was lower (p<0.01). Daily consumption of fast food as well as appendectomy before the age of 20 was more frequent in Eastern European than in Western European UC patients (p<0.01). Eastern European CD and UC patients had received more vaccinations and experienced fewer childhood infections than Western European patients (p<0.01)., Conclusions: In this European population-based inception cohort of unselected IBD patients, Eastern and Western European patients differed in environmental factors prior to diagnosis. Eastern European patients exhibited higher occurrences of suspected risk factors for IBD included in the Western lifestyle., (Copyright © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: Infliximab (IFX) maintenance therapy for Crohn's disease (CD) is administered every 8 weeks, but inter-patient variation in optimal treatment intervals may exist., Aim: To assess, in a prospective pilot study, the efficacy, safety and quality of life (QoL) of IFX maintenance treatment scheduled through web-based self-monitoring of disease activity., Methods: Twenty-seven CD patients in IFX maintenance therapy were enrolled and received a standardised disease education and web-training. Using the http://www.cd.constant-care.dk concept, patients recorded their disease activity and faecal calprotectin weekly. From this, the inflammatory burden (IB) score was calculated, placing patients in the green, yellow or red zones of a ‘traffic light’ system. If placed in the yellow or red zones, the computer directed these patients to consult their physician for IFX infusion., Results: Seventeen patients (63%) completed 52 weeks of follow-up, 6 (22%) completed 26 weeks and 4 (15%) were excluded due to loss of response, patient decision or non-adherence. In total, 121 IFX infusions were given with a median interval of 9 (range: 4–18) weeks. Only 10% of infusions were given at 8-week intervals, whereas 39% were administered with shorter and 50% with longer intervals respectively. The mean IB and the QoL remained stable during the web-treatment. One mild infusion reaction and one case of folliculitis were observed, while three patients underwent surgery., Conclusions: The program http://www.cd.constant-care.dk appears to be a practical and safe concept for the individualised scheduling of maintenance treatment with IFX in patients with Crohn's disease. Larger studies are awaited to confirm this preliminary outcome.

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.

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.

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.

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.

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 Crohn's 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.

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.

Aim: To determine the long-term risk of intestinal and extra-intestinal malignancies in Crohn's disease patients in Copenhagen County, Denmark., Methods: In Copenhagen County, a strictly population-based cohort of 374 patients with Crohn's disease diagnosed between 1962 and 1987 was followed until 1997 in order to determine the long-term risk of intestinal and extra-intestinal malignancies. Information on cancer occurrence was provided by the Danish National Cancer Registry and confirmed by the examination of hospital files. The observed number of cases was compared with the expected number, calculated from individually computed person-years at risk and 1995 cancer incidence rates for the background population., Results: The risk of small bowel adenocarcinoma was significantly increased, independent of age and gender (standardized morbidity ratio, 66.7; 95% confidence interval, 18.1-170.7). The risk of colorectal cancer was not increased, either in the total group of patients or in patients with colonic Crohn's disease exclusively (standardized morbidity ratio, 1.64; 95% confidence interval, 0.20-5.92). Extra-intestinal cancer did not occur more frequently than expected., Conclusions: This population-based study of patients with Crohn's disease revealed no increase in colorectal cancer risk, possibly due to maintenance treatment with 5-aminosalicylic acid preparations and surgery in treatment failure. In contrast, the risk of small bowel cancer was increased more than 60-fold, but the numbers were small. The risk of extra-intestinal cancer was not increased and no lymphomas were observed.

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.

From an incidence cohort diagnosed during 1962-1987 we identified all patients with onset of IBD before the age of 15 in order to describe the course and to compare course and prognosis with adult onset IBD. The mean incidence of IBD among children below 15 years was 2.2/10(5), 2.0 for ulcerative colitis (UC), and 0.2 for Crohns disease (CD). At diagnosis, UC children had more extensive disease compared to adults (p < 0.05). Abdominal pains were also more frequent. The cumulative colectomy probability was 6% after one year and 29% after 20 years, not different from adults. Regarding disease activity, it was found that 60-70% of UC patients were in remission in the first 10 years of disease, for CD about 50% were in remission. One UC patient developed carcinoma of the sigmoid colon. Time between onset and development of carcinoma was 12 years. For CD no differences in clinical appearance at diagnosis and course between children and adults were found. No deaths occurred among CD patients. Three CD patients were found to have severe growth retardation already at diagnosis. In conclusion, the incidence of IBD is low in childhood. At diagnosis children with UC have more widespread disease than adults. Children with CD do not differ in clinical presentation, course or prognosis compared to adult onset CD. However, growth retardation is a problem among CD patients.

Objectives: Inflammatory bowel disease is characterized by T cell activation. Activated T cells shed interleukin-2 receptors (IL-2R) in a soluble form. A positive correlation between sIL-2R alpha (CD25) and disease activity in inflammatory bowel disease has been shown previously, whereas IL-2R beta (CD122) has never before been investigated in this respect. Serum from 27 patients with ulcerative colitis (UC), 31 with Crohn's disease (CD), and 29 healthy volunteers was obtained., Methods: Disease activity was scored according to a semiquantitative score for UC and by Crohn's disease activity index for CD. sIL-2R alpha and -beta chains were assessed by a sandwich ELISA technique using monoclonal antibodies specific for CD25 and CD122, respectively., Results: The median concentration of sIL-2R alpha was 4424 pg/ml in healthy controls, 6460 in UC (p < 0.004), and 6371 in CD (p < 0.01). The corresponding value of sIL-2R beta in healthy volunteers was 605 pg/ml; in active UC, significantly lower levels were found at 233 pg/ml (p < 0.01), whereas in inactive UC, no such difference was observed at 725 pg/ml (p > 0.05). In CD, the levels were 839 pg/ml in inactive and 920 pg/ml in active disease stages (p > 0.05 vs controls). A positive and significant correlation existed between sIL-2R levels of alpha and beta chains in CD (r = 0.64; p < 0.01) but not in UC (r = -0.32; p > 0.05) or in healthy volunteers (r = 0.16; p > 0.05)., Conclusion: Future longitudinal studies will be necessary to learn whether this newly assessed sIL-2R beta (CD122), which may interfere with IL-15R, could be used to predict disease exacerbation and to monitor anti-inflammatory therapy in UC.

Background: The study was a follow-up of an inception cohort of 373 patients with Crohn's disease., Methods: Annual assessments, life table analyses, and Markov chain analyses, estimating the probability for remission and relapse with time, and working capacity were carried out., Results: The clinical course of Crohn's disease differs markedly over time, from ever-relapsing cases to a quiescent course with remission for several years, interrupted by years with relapse. No predictive factors have been found for the subsequent course with regard to age, sex, extent of disease at diagnosis, and treatment in the year of diagnosis. The relapse rate within the year of diagnosis and the following 2 years, however, does correlate positively (p = 0.00001) with the relapse rate in the following 5 years. Furthermore, the relapse rate for 1 year during the disease course influences the relapse rate the following year, indicating a disease pattern over time with waves of at least 2 years' duration. A slight tendency towards burning out was found. The disease course reflected in working capacity for the patients showed that a minor part--up to 15% after 15 years--will become incapable and obtain disablement pension, while 75% of the patients each year are fully capable of work. Within 10 years 50% of the patients will not have experienced any year with impaired capacity for work.

Intercellular adhesion molecule (ICAM)-1 promotes the initial interaction between macrophages and T cells during immune activation. We have measured serum levels of soluble ICAM-1 (sICAM-1) by ELISA in 27 patients with ulcerative colitis (UC), 31 with Crohn's disease (CD), and 29 healthy subjects. The median sICAM-1 serum concentration was significantly increased in inflammatory bowel disease (IBD) patients (355 ng/ml, range 195-855) compared to controls (245 ng/ml, 155-580) (P = 0.001). Variance analysis for trend showed that sICAM-1 levels were significantly higher in patients with active CD and UC, compared to those with inactive disease and controls (P = 0.00002). The concentration of sICAM-1 was higher in CD patients (365 ng/ml 230-470) compared to UC (300 ng/ml 195-855) (P = 0.01). Furthermore, weak but significant correlations were found between serum levels of sICAM-1 and: soluble IL-2 receptors, orosomucoid, and C-reactive protein. It is suggested that increased circulating sICAM-1 levels may reflect increased adhesiveness and signal transmission across cells, probably as a result of shedding of the parent molecule during local cellular immunoresponses in vivo.

The outcome of the first steroid treatment course was prospectively studied in a regional cohort of 196 patients with Crohn's disease diagnosed 1979-1987. The immediate outcome after 30 days, and the prolonged outcome 30 days after treatment had stopped, are described. In all 109 patients treatment was analysed. Complete remission was obtained in 48%, partial remission in 32%, and no response in 20% within 30 days of treatment. Among primary responders (complete and partial remission), 55% remained in prolonged response after treatment had finished, while 45% relapsed or could not be withdrawn from treatment within one year. Localisation of disease, age, sex or clinical symptoms did not significantly correlate with outcome, which can be summarised as prolonged steroid response in 44%, steroid dependency in 36%, and steroid resistant in 20% of the patients.

Increased intestinal permeability in patients with Crohn's disease and their first degree relatives has been proposed as an aetiological factor. The nine hour overnight urinary excretion of polyethyleneglycol-400 (PEG-400) and three inert sugars (lactulose, l-rhamnose, and mannitol) was used to test the permeation in 47 patients with Crohn's disease of whom 18 had at least one first degree relative with inflammatory bowel disease (2BD) and 52 patients with ulcerative colitis of whom 16 had at least one first degree relative with IBD. A total of 17 first degree relatives with IBD and 56 healthy first degree relatives were included. Thirty one healthy subjects not related to patients with IBD served as controls. No significant differences in PEG-400 permeation were found between the groups of patients, relatives, and controls, or between diseased and healthy relatives. The permeability to lactulose, rhamnose, and mannitol similarly did not differ between the three groups. This study challenges the previously reported findings of increased PEG-400 permeation in patients with Crohn's disease and in their healthy and diseased first degree relatives. There was no increase in permeability in a similar group of ulcerative colitis patients and their families.

Background: It is important to know about mortality, risk of intestinal cancer, and surgical intervention as well as possible predictive factors for patients with Crohn's disease. These prognostic parameters were estimated by regular follow-up of a complete, regional incidence cohort of 373 patients., Methods: Annual assessments of clinical conditions were the basis for statistical evaluation with life table analysis, calculations of relative risk, and lifetime cancer risk., Results: Survival curves for the total group of patients with Crohn's disease and the background population did not differ. However, a subgroup of patients aged 20-29 years at diagnosis (P = 0.04) and a subgroup of patients with extensive small bowel disease (P = 0.03) showed slightly increased mortality within the first 5 years. Cancer in small and/or large bowel occurred in 3 patients vs. an expected 1.8(P = NS). Small bowel cancer was found in 2 patients vs. the 0.04 expected (P = 0.001). Lifetime risk of intestinal cancer was 4.1% compared with 3.8% for the Danish population in general (P = NS). Probability of surgical resection within 15 years after diagnosis was 70%. The initial extent of disease significantly influenced the probability for resection, which was 78% in ileocecal enteritis and 44% in all other localizations within 5 years after diagnosis., Conclusions: The overall mortality and life-time risk of cancer in patients with Crohn's disease was not found increased, although the risk of rare small bowel cancer was significantly increased.

The incidence of Crohn's disease was assessed in a population based study in Copenhagen County from 1962-1987. The incidence increased six fold during the study period from 0.62/10(5) in 1962 to a mean of 4.1/10(5) from 1979-1987, equally in both sexes. The highest incidence was found in the age group 15-24 years: 12.8/10(5) for women and 6.0/10(5) for men (as mean of the period 1979-1987). The prevalence at the end of the study was 54/10(5). The clinical symptoms and extent of disease at diagnosis did not change over the time, but a significantly higher disease activity was found in the 1980's, 74% (1962-1979) vs 84% (1980-1987), p = 0.04. The increase in incidence of Crohn's disease is well established in most parts of the industrialized world. The analysis shows that it is not due to a new disease entity, since the extent of disease, the age and sex distribution, and the symptoms remained unchanged during the 26 year study period.

Objective: To investigate the mode of inheritance of ulcerative colitis and Crohn's disease by complex segregation analysis., Design: Cross sectional population based survey of familial occurrence of chronic inflammatory bowel disease., Setting: Population of the Copenhagen county in 1987., Subjects: 662 patients in whom inflammatory bowel disease had been diagnosed before 1979, of whom 637 (96%) provided adequate information. Of 504 patients with ulcerative colitis, 54 had 77 relatives with ulcerative colitis and of 133 patients with Crohn's disease, five had seven relatives with Crohn's disease., Main Outcome Measures: Patterns of segregation of either disease as assessed by complex segregation analysis performed with the computer program POINTER., Results: The analysis suggested that a major dominant gene with a penetrance of 0.20-0.26 is present in 9-13% of adult patients with ulcerative colitis. The analysis did not allow for other components in the familial aggregation. For Crohn's disease the best fitting model included a major recessive gene with complete penetrance, for which 7% of the patients are homozygous. However, this model was not significantly different from a multifactorial model., Conclusions: The segregation pattern indicates that a major dominant gene has a role in ulcerative colitis, and suggests that a major recessive gene has a role in Crohn's disease.

Fusidic acid is an antibiotic with T-cell specific immunosuppressive effects similar to those of cyclosporin. Because of the need for the development of new treatments for Crohn's disease, a pilot study was undertaken to estimate the pharmacodynamics and tolerability of fusidic acid treatment in chronic active, therapy-resistant patients. Eight Crohn's disease patients were included. Fusidic acid was administered orally in a dose of 500 mg t.d.s. and the treatment was planned to last 8 weeks. The disease activity was primarily measured by a modified individual grading score. Five of 8 patients (63%) improved during fusidic acid treatment: 3 at two weeks and 2 after four weeks. There were no serious clinical side effects, but dose reduction was required in two patients because of nausea. Biochemically, an increase in alkaline phosphatases was noted in 5 of 8 cases (63%), and the greatest increases were seen in those who had elevated levels prior to treatment. All reversed to pre-treatment levels after cessation of treatment. The results of this pilot study suggest that fusidic acid may be of benefit in selected chronic active Crohn's disease patients in whom conventional treatment is ineffective. Because there seems to exist a scientific rationale for the use of fusidic acid at the cytokine level in inflammatory bowel disease, we suggest that the role of this treatment should be further investigated.

The incidence of Crohn's disease increased sixfold from 1962 to 1987 in the county of Copenhagen. The mean annual incidence for 1979-87 was 4.1 per 10(5) inhabitants. The increase was found equally in both sexes, with an approximately 40% higher incidence in women. The maximal incidence was found in the 15- to 24-year age group, being 12.8 per 10(5) per year for women and 6.0 per 10(5) per year for men, as mean of the period 1979-87. The prevalence at the end of the study was 54 per 10(5) inhabitants, 46 per 10(5) in men and 63 per 10(5) in women. The clinical appearance of the disease at the time of diagnosis was remarkably similar during the study period with regard to both the localization of disease and the clinical symptoms and signs. A slightly higher percentage of the patients, however, were in high disease activity at diagnosis in the later years of the study.

An epidemiologic study was performed 1) to estimate the occurrence of epithelioid granulomas in the appendix wall among patients in whom an appendectomy had been performed, 2) to identify patients with granulomas in the appendix who had symptoms and history compatible with Crohn's disease, and 3) to estimate the long-term prognosis. Within a 5-year period 6051 patients in Copenhagen County underwent appendectomy. Six patients (0.1%) had epithelioid granulomas of the appendix (0.2 per 10(5) inhabitants per year). Follow-up of the six patients for 9-11 years (median, 9.5 years) showed that all had been free of gastrointestinal symptoms since the operation. Among the 373 patients diagnosed as having Crohn's disease in Copenhagen County between 1962 and 1987, 3 patients had their disease initially confined to the appendix. Follow-up in these patients showed no recurrence within a median of 6 years (range, 4-7 years). Patients with epithelioid granulomas of the appendix have an excellent long-term prognosis, which could be explained by the fact that the condition seems to be unrelated to Crohn's disease.