Johan Burisch

East–West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort

Objective The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East–West gradient in the incidence of IBD in Europe exists. Design A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. Results 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohns disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100 000 in 2010 for CD were 6.5 (range 0–10.7) in Western European centres and 3.1 (range 0.4–11.5) in Eastern European centres, for UC 10.8 (range 2.9–31.5) and 4.1 (range 2.4–10.3), respectively, and for IBDU 1.9 (range 0–39.4) and 0 (range 0–1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. Conclusions An East–West gradient in IBD incidence exists in Europe. Among this inception cohort—including indolent and aggressive cases—international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.

Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders

aDepartment of Pharmacology and Therapeutics, University of Porto; MedInUP, Centre for Drug Discovery and Innovative Medicines; Centro Hospitalar São João, Porto, Portugal bIBD Unit, DIMEC, University of Bologna, Bologna, Italy cDepartment of Gastroenterology and Hepatology, Chaim Sheba Medical Center, Tel Hashomer, Israel dGastrointestinal Unit ASST Fatebenefratelli Sacco—University of Milan—Milan, Italy eIBD Unit Complesso Integrato Columbus, Gastroenterological and Endocrino-Metabolical Sciences Department, Fondazione Policlinico Universitario Gemelli Universita’ Cattolica del Sacro Cuore, Rome, Italy fDepartment of Gastroenterology, IBD Unit, University Hospital Santiago De Compostela (CHUS), A Coruña, Spain gDepartment of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark hFirst Department of Medicine, Semmelweis University, Budapest, Hungary iIBD Unit, St Mark’s Hospital, Middlesex, UK jDepartment of Gastroenterology, University Hospital of Ghent, Ghent, Belgium kInstitute of Pathology, Medical University of Graz, Graz, Austria lDepartment of Gastroenterology, Pennine Acute Hospitals NHS Trust; Institute of Inflammation and Repair, University of Manchester, Manchester, UK mUnit of General Surgery, Second University of Naples, Napoli, Italy nMaria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, Department of Oncological Gastroenterology Warsaw; Medical Centre for Postgraduate Education, Department of Gastroenterology, Hepatology and Clinical Oncology, Warsaw, Poland oDepartment of Medicine, University of Cambridge, Cambridge, UK pImperial College London; Chelsea and Westminster Hospital, London, UK qDepartment of Pathobiology /NC22, Lerner Research Institute; Department of Gastroenterology, Hepatology and Nutrition/A3, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

Inflammatory bowel disease epidemiology.

Purpose of review The occurrence of inflammatory bowel disease (IBD) is increasing worldwide, yet the reasons remain unknown. New therapeutic approaches have been introduced in medical IBD therapy, but their impact on the natural history of IBD remains uncertain. This review will summarize the recent findings in the epidemiology of IBD. Recent findings The incidence of IBD in western Europe is twice as high as in eastern Europe, whereas the highest IBD incidence in the world is found in the Faroe Islands. Early intervention with immunosuppressant and biological agents seems to have reduced the colectomy rates for ulcerative colitis, whereas the impact on Crohns disease has yet to be determined. Mortality in Crohns disease has not changed despite improvements in medical and surgical management. Specialized care in IBD centres, treatments to target and obtaining mucosal healing, early intervention at relapse and avoiding Clostridium difficile super infection might reduce the mortality rate in the future. The risk of colorectal cancer in Crohns disease seems to be equivalent to the risk in ulcerative colitis. Patients with small bowel Crohns disease are at increased risk of small bowel adenocarcinoma. Summary The natural disease course of IBD seems to change along with the new ‘treat to target’ goal of achieving intestinal mucosal healing. Future population-based studies of unselected IBD cohorts should be considered the gold standard for studies investigating these issues.

The epidemiology of inflammatory bowel disease

Abstract Background and aims. The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing disorders of unknown aetiology. The aim of this review is to present the latest epidemiology data on occurrence, disease course, risk for surgery, as well as mortality and cancer risks. Material and methods. Gold standard epidemiology data on the disease course and prognosis of patients with inflammatory bowel disease (IBD) are based on unselected population-based cohort studies. Results. The incidence of ulcerative colitis (UC) and Crohn’s disease (CD) has increased overall in Europe from 6.0 per 100,000 person-years in UC and 1.0 per 100,000 person-years in CD in 1962 to 9.8 per 100,000 person-years and 6.3 per 100,000 person-years in 2010, respectively. The highest incidence of IBD is found on the Faroe Islands. Overall, surgery rates have been declining over the last decades, partly due to aggressive medical therapy. Among IBD patients, mortality risk is increased by up to 50% in CD when compared to the background population, but this is not the case for UC. In CD, 25 – 50% deaths are disease-specific deaths, e.g. malnutrition, postoperative complications and intestinal cancer. In UC, disease-specific causes of deaths include colorectal cancer (CRC), and surgical and postoperative complications. The risk of CRC and small bowel cancer is increased two- to eightfold among IBD patients. Various subgroups carry increased risk of malignancy, e.g. those with persistent inflammation, long-standing disease, extensive disease, young age at diagnosis, family history of CRC and co-existing primary sclerosing cholangitis. The risk of extra-intestinal cancers, including lymphoproliferative disorders (LD) and intra- and extrahepatic cholangio carcinoma, is significantly higher among IBD patients. Conclusion. In recent years, self-management and patient empowerment, combined with evolving eHealth solutions, has utilized epidemiological knowledge on disease patterns and has been improving compliance and the timing of adjusting therapies, thus optimizing efficacy by individualizing medication in the community setting.

The First European Evidence-based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease.

This is the first European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses extra-intestinal manifestations [EIMs] in inflammatory bowel disease [IBD]. It has been drafted by 21 ECCO members from 13 European countries. Although this is the first ECCO consensus guideline that primarily addresses EIMs, it is partly derived from, updates, and replaces previous ECCO consensus advice on EIMs, contained within the consensus guidelines for Crohn’s disease1 [CD] and ulcerative colitis2 [UC]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, topics were selected by the ECCO guidelines committee [GuiCom]. ECCO members were selected to form working groups. Provisional ECCO Statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds which included national representative participation by ECCO’s 35 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-based Medicine [www.cebm.net]. The ECCO Statements were finalised by the authors at a meeting in Vienna in October 2014 and represent consensus with agreement of at least 80% of participants. Complete consensus [100% agreement] was reached for most statements. The supporting text was then finalised under the direction of each working group leader [VA, SV, FC, MH] before being integrated by the two consensus leaders [MH, FC]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/]. Up to 50% of patients with inflammatory bowel disease [IBD] experience at least one extra-intestinal manifestation [EIM], which can present before IBD is diagnosed.34,5,6 EIMs adversely impact upon patients’ quality of life and some, such as primary sclerosing cholangitis [PSC] or venous thromboembolism [VTE], can be life-threatening. The probability of developing EIMs increases with disease duration and in patients who already have one EIM.7 …

Ehealth: Low FODMAP diet vs Lactobacillus rhamnosus GG in irritable bowel syndrome

AIM To investigate the effects of a low fermentable, oligosaccharides, disaccharides, monosaccharides and polyols diet (LFD) and the probiotic Lactobacillus rhamnosus GG (LGG) in irritable bowel syndrome (IBS). METHODS Randomised, unblinded controlled trial on the effect of 6-wk treatment with LFD, LGG or a normal Danish/Western diet (ND) in patients with IBS fulfilling Rome III diagnostic criteria, recruited between November 2009 and April 2013. Patients were required to complete on a weekly basis the IBS severity score system (IBS-SSS) and IBS quality of life (IBS-QOL) questionnaires in a specially developed IBS web self-monitoring application. We investigated whether LFD or LGG could reduce IBS-SSS and improve QOL in IBS patients. RESULTS One hundred twenty-three patients (median age 37 years, range: 18-74 years), 90 (73%) females were randomised: 42 to LFD, 41 to LGG and 40 to ND. A significant reduction in mean ± SD of IBS-SSS from baseline to week 6 between LFD vs LGG vs ND was revealed: 133 ± 122 vs 68 ± 107, 133 ± 122 vs 34 ± 95, P < 0.01. Adjusted changes of IBS-SSS for baseline covariates showed statistically significant reduction of IBS-SSS in LFD group compared to ND (IBS-SSS score 75; 95%CI: 24-126, P < 0.01), but not in LGG compared to ND (IBS-SSS score 32; 95%CI: 18-80, P = 0.20). IBS-QOL was not altered significantly in any of the three groups: mean ± SD in LFD 8 ± 18 vs LGG 7 ± 17, LFD 8 ± 18 vs ND 0.1 ± 15, P = 0.13. CONCLUSION Both LFD and LGG are efficatious in patients with IBS.

Initial disease course and treatment in an inflammatory bowel disease inception cohort in Europe: The ECCO-EpiCom cohort

Background:The EpiCom cohort is a prospective, population-based, inception cohort of inflammatory bowel disease (IBD) patients from 31 European centers covering a background population of 10.1 million. The aim of this study was to assess the 1-year outcome in the EpiCom cohort. Methods:Patients were followed-up every third month during the first 12 (±3) months, and clinical data, demographics, disease activity, medical therapy, surgery, cancers, and deaths were collected and entered in a Web-based database (www.epicom-ecco.eu). Results:In total, 1367 patients were included in the 1-year follow-up. In western Europe, 65 Crohn’s disease (CD) (16%), 20 ulcerative colitis (UC) (4%), and 4 IBD unclassified (4%) patients underwent surgery, and in eastern Europe, 12 CD (12%) and 2 UC (1%) patients underwent surgery. Eighty-one CD (20%), 80 UC (14%), and 13 (9%) IBD unclassified patients were hospitalized in western Europe compared with 17 CD (16%) and 12 UC (8%) patients in eastern Europe. The cumulative probability of receiving immunomodulators was 57% for CD in western (median time to treatment 2 months) and 44% (1 month) in eastern Europe, and 21% (5 months) and 5% (6 months) for biological therapy, respectively. For UC patients, the cumulative probability was 22% (4 months) and 15% (3 months) for immunomodulators and 6% (3 months) and 1% (12 months) for biological therapy, respectively in the western and eastern Europe. Discussion:In this cohort, immunological therapy was initiated within the first months of disease. Surgery and hospitalization rates did not differ between patients from eastern and western Europe, although more western European patients received biological agents and were comparable to previous population-based inception cohorts.

eHealth: individualisation of infliximab treatment and disease course via a self‐managed web‐based solution in Crohn's disease

Infliximab (IFX) maintenance therapy for Crohns disease (CD) is administered every 8 weeks, but inter‐patient variation in optimal treatment intervals may exist.

Polymorphisms in the Inflammatory Pathway Genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG Are Associated with Susceptibility of Inflammatory Bowel Disease in a Danish Cohort

Background The inflammatory bowel diseases (IBD), Crohns disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage. Methods Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. Results Sixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p≤0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (ORCD,adj: 0.38, 95% CI: 0.21–0.67, p = 0.03; ORIBD,adj 0.43, 95% CI: 0.28–0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (ORCD,unadj 0.54, 95% CI: 0.41–0.72, p = 7*10−4; ORIBD,unadj: 0.61, 95% CI: 0.48–0.77, p = 0.001) were associated with reduced risk of CD. Conclusion The biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals.

Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease

Antitumor necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NFκB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-α signaling (TNFA (TNF-α) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFκB (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P⩽0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFκB through the Toll-like receptor (TLR) pathways, genes regulating TNF-α signaling and cytokines regulated by NFκB are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1β, IL-6 and IFN-γ may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting.