Mortality of Patients With Inflammatory Bowel Disease in the Faroe Islands From 1966-2020.

BACKGROUND: Increased mortality rates have been found in patients suffering from inflammatory bowel disease (IBD). The Faroe Islands have the highest occurrence of IBD, mainly ulcerative colitis (UC). This study investigated mortality of patients with IBD compared with the general Faroese population. METHODS: All patients diagnosed with IBD from 1966-2020 were included, as well as population mortality data. All-cause and cause-specific mortality in the IBD cohort was compared with the population by standardized incidence ratios (SIRs). Risk factors for death within the cohort were assessed by hazard ratios (HRs) using Cox regression. RESULTS: Overall mortality was not increased in patients with Crohn's disease (CD; SIR 0.9; 95% confidence interval [CI], 0.56-1.35) or UC (SIR 1.0; 95% CI, 0.83-1.25). However, patients with UC had an elevated risk of dying from digestive diseases (SIR 4.3; 95% CI, 2.16-7.74). Patients with IBD had lower risk of death of cardiovascular diseases compared with the background population (SIR 0.7; 95% CI, 0.50-0.93). Risk factors for mortality included male gender, age at diagnosis, and use of steroids. Protective factors were use of 5-aminosalicylic acid (5-ASA), thiopurines, and biological treatment. CONCLUSIONS: No increased risk of all-cause mortality in patients with CD or UC was found in this nationwide study compared with the entire Faroese population over more than 5 decades. The risk of death due to digestive diseases was, however, increased in patients with UC, while mortality risk of cardiovascular diseases was lower in patients with IBD.

Increased mortality exists in IBD patients. The Faroe Islands have the highest occurrence in the world, though mortality risk in Faroese patients compared with the population is unknown. No increased overall risk was found, while mortality risk of digestive diseases was elevated.

Short noncoding RNAs as predictive biomarkers for the development from inflammatory bowel disease unclassified to Crohn's disease or ulcerative colitis.

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.

The Incidence and Prevalence of Inflammatory Bowel Disease Continues to Increase in the Faroe Islands - A Cohort Study from 1960 to 2020.

BACKGROUND AND AIMS: The highest reported incidence rate of inflammatory bowel disease [IBD], and especially of ulcerative colitis [UC], is found in the Faroe Islands. This study aimed to assess the incidence rate and temporal trends in prevalence over six decades. METHODS: All incident and prevalent patients diagnosed with IBD between 1960 and 2020 from the nationwide and population-based Faroese IBD cohort were included in this study. All patients fulfilled the Copenhagen Diagnostic Criteria. RESULTS: Overall, 873 individuals were diagnosed with IBD during the study period, 559 [64%] with UC, 151 [17%] with Crohn's disease, and 163 [19%] with IBD unclassified. A total of 59 patients had paediatric-onset IBD. The incidence of IBD continued to increase throughout the study period, as the age-standardized incidence rate started at 8 per 100 000 person-years [py] [European Standard Population, ESP] in 1960-79 and reached 70 by 2010-20. In 2021, the age-standardized period prevalence was 1414 per 100 000 persons. The IBD incidence was unevenly distributed among the islands with Sandoy having the highest rate of 106 per 100 000 py in 2010-2020. CONCLUSIONS: The incidence of IBD continues to increase in the Faroe Islands, mainly driven by UC. The incidence shows an uneven geographical distribution, which suggests an adverse interaction between unknown environmental factors and genetic traits. The prevalence in 2021 corresponded to 1.3% of the Faroese population. Environmental risk factors are suspected to impact this homogeneous high-risk population; however, the reason for this is unclear.

Mucosal expression of PI3, ANXA1, and VDR discriminates Crohn's disease from ulcerative colitis.

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.

Estimating tissue-specific TNF mRNA levels prior to anti-TNFα treatment may support therapeutic optimisation in IBD patients.

BACKGROUND AND AIMS: Tumour necrosis factor-α (TNF) antagonists have improved the management of inflammatory bowel disease (IBD), however, their usage and administration persist to be suboptimal. Here, we examined the relationship between tissue-specific TNF mRNA expression in mucosal biopsies from IBD patients and anti-TNF treatment response. METHODS: Archived tissue samples from patients with luminal IBD that had all been or were in treatment with anti-TNF were included (18 adults and 24 paediatric patients). Patients were stratified into three groups according to anti-TNF response: responders, primary non-responders (PNR) and secondary loss of response (SLOR). TNF mRNA was detected using RNAscope in situ hybridisation (ISH) and the expression was quantified using image analysis. RESULTS: The ISH analysis showed varying occurrence of TNF mRNA positive cells located in lamina propria and often with increased density in lymphoid follicles (LF). Consequently, expression estimates were obtained in whole tissue areas with and without LF. Significantly higher TNF mRNA expression levels were measured in adults compared to paediatric patients in both the analyses with and without LF (p = .015 and p = .016, respectively). Considering the relation to response, the adult and paediatric patients were evaluated separately. In adults, the TNF expression estimates were higher in PNRs compared to responders with and without LF (p = .017 and p = .024, respectively). CONCLUSION: Our data indicate that adult PNR have significantly higher TNF mRNA levels than responders. This suggests that higher anti-TNF dose may be considered for IBD patients with high TNF mRNA expression estimates from the start of treatment.

Disease Activity Patterns of Inflammatory Bowel Disease-A Danish Nationwide Cohort Study 1995-2018.

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.

Therapeutic drug monitoring in inflammatory bowel disease: implementation, utilization, and barriers in clinical practice in Scandinavia.

BACKGROUND AND AIMS: Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. METHODS: A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. RESULTS: In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01-0.09], p < 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p < 0.001), and by physicians managing >10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. CONCLUSION: TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.

Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: a randomised, double-blind, active-comparator, non-inferiority clinical trial.

BACKGROUND: Bile acid diarrhoea is an underdiagnosed disease estimated to affect 1-2% of the general population. Case reports indicate that the glucagon-like peptide 1 receptor agonist liraglutide might be an effective treatment for bile acid diarrhoea. We aimed to investigate the safety and efficacy of liraglutide for the treatment of bile acid diarrhoea. METHODS: We conducted a randomised, double-blind, active-comparator, double-dummy, non-inferiority clinical trial at the Center for Clinical Metabolic Research at Copenhagen University Hospital-Herlev and Gentofte, Hellerup, Denmark. Patients aged 18-75 years with 75selenium-homotaurocholic acid test (SeHCAT)-verified moderate-to-severe primary bile acid diarrhoea were randomly assigned (1:1) to receive liraglutide (one daily subcutaneous injection uptitrated from 0·6-1·8 mg per day over 3 weeks) or colesevelam (three capsules of 625 mg twice daily), the standard of care, for 6 weeks following one run-in week with no treatment. The primary endpoint was the proportion of participants experiencing a reduction in daily stool frequency of 25% or greater after 6 weeks. Data from all participants were included in the analysis of the primary outcome. The non-inferiority limit was set to 15% in favour of colesevelam. This trial is registered with EudraCT (2018-003575-34) and is completed. FINDINGS: Between April 1, 2019, and Jan 31, 2021, 52 patients were enrolled; 26 were assigned to liraglutide and 26 to colesevelam. 20 (77%) of 26 participants on liraglutide and 13 (50%) of 26 on colesevelam experienced a 25% or greater reduction in stool frequency, corresponding to a significant risk difference of -27% in favour of liraglutide (one-sided 95% CI -100 to -6). Liraglutide was therefore superior to colesevelam in reducing daily stool frequency. Mild nausea with a duration of 10-21 days was reported by six participants in the liraglutide group and by one participant in the colesevelam group. No other adverse events were reported. INTERPRETATION: The superiority of liraglutide compared with colesevelam in reducing stool frequency suggests consideration of liraglutide as a potential new treatment modality for bile acid diarrhoea, although larger confirmatory trials powered for superiority are warranted. FUNDING: Novo Nordisk, Novo Nordisk Foundation, Foundation for the Advancement of Medical Science under The A.P. Møller and Chastine Mc-Kinney Møller Foundation.

Therapeutic management and outcomes in inflammatory bowel diseases, 2010 to 2017 in cohorts from Denmark, Sweden and Norway.

BACKGROUND: Despite the increasing use of biologics in patients with inflammatory bowel disease (IBD), real-world data about outcomes in the era of biologics remain inconclusive. AIMS: To investigate trends in surgeries, hospitalisations and medication use in patients with IBD in a multinational, population-based cohort METHODS: We included 42,894 patients with ulcerative colitis (UC) and 24,864 with Crohn's disease (CD) who were diagnosed between 2010 and 2017 in Denmark, Norway and Sweden. We extracted data about surgeries, hospitalisations and medications from national registries and compared across countries and diagnosis years. RESULTS: Between 2010 and 2017, 2-year surgery rates were 4-7% in UC and 10-15% in CD and were stable over time. Two-year hospitalisation rates increased in Denmark (UC: 20% to 35%; CD: 27% to 32%) but were stable in Norway and Sweden (fluctuating between 33% and 37% in UC, and 46% and 52% in CD). Two-year rates of biologic use increased in both UC (7% to 16% in Denmark, 8% to 18% in Norway) and CD (22% to 26% in Denmark; 21% to 35% in Norway). Two-year rates of immunomodulator use increased in Norway (from 14% to 23% in UC; 37% to 45% in CD) and Sweden (from 41% to 52% in CD), but were stable in Denmark (between 17% and 21% in UC; 39% to 46% in CD). CONCLUSION: Between 2010 and 2017, surgery rates among Scandinavian patients with IBD remained stable, with no clear changes in hospitalisation rates despite the increasing use of immunomodulators and biologics.

The clinical course of Crohn's disease in a Danish population-based inception cohort with more than 50 years of follow-up, 1962-2017.

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.

Surgery, cancer and mortality among patients with ulcerative colitis diagnosed 1962-1987 and followed until 2017 in a Danish population-based inception cohort.

BACKGROUND: Long-term data on the natural disease course of unselected patients with ulcerative colitis (UC) are limited. AIMS: To determine the long-term course and prognosis of UC, including patients' risks of surgery, cancer and mortality, in a population-based cohort followed for over 50 years METHODS: All incident patients with UC diagnosed between 1962 and 1987 in Copenhagen County, Denmark were included in a population-based cohort. We extracted information about IBD-related surgeries, cancers and mortality from patient files from 1962 to 1987, and from the Danish National Patient Registry, Cancer Registry, and Register of Causes of Death during 1988-2017. Patients were matched with up to 50 individuals from the general population. RESULTS: We followed 1161 patients for a median of 34 years (range: 0.1-56.0). Median age at diagnosis was 33 years (range: 2-88). The cumulative probability of colectomy 10, 20, 30, 40 and 50 years after diagnosis was 22% (95% CI: 20%-25%), 27% (95% CI: 25%-30%), 31% (95% CI: 28%-34%), 34% (95% CI: 31%-37%), and 40% (95% CI: 36%-44%), respectively. The risk of small intestinal, colon, rectal and anal cancer was higher than among controls, as was cancer of the skin, pancreas and thyroid. All-cause mortality was lower than controls (adjusted RR: 0.90, 95% CI: 0.82-0.99). CONCLUSION: In this population-based cohort of UC patients diagnosed between 1962 and 1987, 40% underwent colectomy within 50 years of diagnosis. Physicians need to be aware that UC patients are at increased risk of intestinal and extra-intestinal cancers. However, UC patients' risk of mortality is comparable to that of the background population.

Gut Mucosal Gene Expression and Metabolic Changes After Roux-en-Y Gastric Bypass Surgery.

OBJECTIVE: Changes in the secretion of gut-derived peptide hormones have been associated with the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. In this study, the effects of RYGB on anthropometrics, postprandial plasma hormone responses, and mRNA expression in small intestinal mucosa biopsy specimens before and after RYGB were evaluated. METHODS: In a cross-sectional study, 20 individuals with obesity undergoing RYGB underwent mixed meal tests and upper enteroscopy with retrieval of small intestinal mucosa biopsy specimens 3 months before and after surgery. Concentrations of circulating gut and pancreatic hormones during mixed meal tests as well as full mRNA sequencing of biopsy specimens were evaluated. RESULTS: RYGB-induced improvements of body weight and composition, insulin resistance, and circulating cholesterols were accompanied by significant changes in postprandial plasma responses of pancreatic and gut hormones. Global gene expression analysis of biopsy specimens identified 2,437 differentially expressed genes after RYGB, including changes in genes that encode prohormones and G protein-coupled receptors. CONCLUSIONS: RYGB affects the transcription of a wide range of genes, indicating that the observed beneficial metabolic effects of RYGB may rely on a changed expression of several genes in the gut. RYGB-induced changes in the expression of genes encoding signaling peptides and G protein-coupled receptors may disclose new gut-derived treatment targets against obesity and diabetes.

MicroRNA Biomarkers in IBD-Differential Diagnosis and Prediction of Colitis-Associated Cancer.

Inflammatory bowel disease (IBD) includes Crohn's disease (CD) and ulcerative colitis (UC). These are chronic autoimmune diseases of unknown etiology affecting the gastrointestinal tract. The IBD population includes a heterogeneous group of patients with varying disease courses requiring personalized treatment protocols. The complexity of the disease often delays the diagnosis and the initiation of appropriate treatments. In a subset of patients, IBD leads to colitis-associated cancer (CAC). MicroRNAs are single-stranded regulatory noncoding RNAs of 18 to 22 nucleotides with putative roles in the pathogenesis of IBD and colorectal cancer. They have been explored as biomarkers and therapeutic targets. Both tissue-derived and circulating microRNAs have emerged as promising biomarkers in the differential diagnosis and in the prognosis of disease severity of IBD as well as predictive biomarkers in drug resistance. In addition, knowledge of the cellular localization of differentially expressed microRNAs is a prerequisite for deciphering the biological role of these important epigenetic regulators and the cellular localization may even contribute to an alternative repertoire of biomarkers. In this review, we discuss findings based on RT-qPCR, microarray profiling, next generation sequencing and in situ hybridization of microRNA biomarkers identified in the circulation and in tissue biopsies.

The use of 5-aminosalicylate for patients with Crohn's disease in a prospective European inception cohort with 5 years follow-up - an Epi-IBD study.

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.

Health-care costs of inflammatory bowel disease in a pan-European, community-based, inception cohort during 5 years of follow-up: a population-based study.

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.

Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery.

CONTEXT: After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1). OBJECTIVE: To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut. DESIGN AND SETTING: Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark. PARTICIPANTS: Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes. INTERVENTIONS: Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB. MAIN OUTCOME MEASURES: The 29-amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry-validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry. RESULTS: Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon. CONCLUSION: Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB.

Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study.

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.