Natalia Pedersen

Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005 : A population-based study from the danish crohn colitis database

OBJECTIVES:A continuous increase in the incidence of inflammatory bowel disease (IBD), Crohns disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC) has been suggested. Since Denmark provides excellent conditions for epidemiological research, we aimed to describe contemporary IBD incidence rates and patient characteristics in Copenhagen County and City.METHODS:All patients diagnosed with IBD during 2003–2005 were followed prospectively. Demographic and clinical characteristics, such as disease extent, extraintestinal manifestations, smoking habits, medical treatment, surgical interventions, cancer, and death, were registered.RESULTS:Five-hundred sixty-two patients were diagnosed with IBD, resulting in mean annual incidences of 8.6/105 for CD, 13.4/105 for UC, and 1.1/105 for IC. Time from onset to diagnosis was 8.3 months in CD and 4.5 months in UC patients. A family history of IBD, smoking, and extraintestinal manifestations was significantly more common in CD than in UC patients. Only 0.6% of UC patients had primary sclerosing cholangitis. In CD, old age at diagnosis was related to pure colonic disease, whereas children significantly more often had proximal and extensive involvement. Twelve percent of CD patients and 6% of UC patients underwent surgery during the year of diagnosis, significantly less than earlier reported.CONCLUSIONS:The incidence of IBD in Copenhagen increased noticeably during the last decades. Time from onset of symptoms until diagnosis decreased markedly, extent of CD was related to age at diagnosis, and the risk of surgery was low in UC.

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.

Symptomatic Effect of Pancreatic Enzyme Therapy in Patients with Chronic Pancreatitis

The symptomatic effect of pancreatic enzyme substitution therapy was examined in a 4-week double-blind crossover study. Twenty patients, 11 with and 9 without steatorrhoea, were examined. Pancreatic steatorrhoea was reduced from a median of 24 g/day to 10 g/day by the enzyme therapy (P less than 0.01). No significant pain reduction was found in either of the two groups, although there was a tendency to reduction in pain and analgetic consumption in the patients with steatorrhoea when treated with pancreatic enzymes. It is concluded that pancreatic steatorrhoea is still the only indication for pancreatic enzyme therapy.

Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies.

OBJECTIVES:Extra-intestinal manifestations of inflammatory bowel disease (IBD) are relatively common, whereas the risk of extra-intestinal cancer (EIC) remains uncertain. The aim of this study was to obtain a reliable estimate of the risk of EIC in Crohns disease (CD) and ulcerative colitis (UC) by performing a meta-analysis of population-based cohort studies.METHODS:A systematic literature review was performed using MEDLINE (1966–2009) and abstracts from recent international conferences. Eight population-based cohort studies comprising a total of 17,052 patients with IBD were available. Standardized incidence ratios (SIRs) of EICs were pooled in a meta-analysis approach using STATA software.RESULTS:Overall, IBD patients were not at increased risk of EIC (SIR, 1.10; 95% confidence interval (CI) 0.96–1.27). However, site-specific analyses revealed that CD patients had an increased risk of cancer of the upper gastrointestinal tract (SIR 2.87, 95% CI 1.66–4.96), lung (SIR 1.82, 95% CI 1.18–2.81), urinary bladder (SIR 2.03, 95% CI 1.14–3.63), and skin (SIR 2.35, 95% CI 1.43–3.86). Patients with UC had a significantly increased risk of liver–biliary cancer (SIR 2.58, 95% CI 1.58–4.22) and leukemia (SIR 2.00, 95% CI 1.31–3.06) but a decreased risk of pulmonary cancer (SIR 0.39, 95% CI 0.20–0.74).CONCLUSIONS:Although the overall risk of EIC was not significantly increased among patients with IBD, the risk of individual cancer types differed from that of the background population as well as between CD and UC patients. These findings may primarily be explained by smoking habits, extra-intestinal manifestations of IBD, and involvement of the upper gastrointestinal tract in CD.

Infliximab for Inflammatory Bowel Disease in Denmark 1999–2005: Clinical Outcome and Follow-Up Evaluation of Malignancy and Mortality

BACKGROUND & AIMS Data on safety and long-term follow-up evaluation of population-based cohorts of inflammatory bowel disease (IBD) patients treated with infliximab are sparse. The aim of this article is to describe the use of infliximab in a national Danish population-based IBD cohort during 1999-2005. METHODS Medical records of all infliximab-treated IBD patients were scrutinized to abstract information on patient demographics, treatment efficacy, and adverse events. RESULTS A total of 651 patients (619 with Crohns disease, 15 with ulcerative colitis, and 17 with colonic IBD type unclassified) received infliximab during 1999-2005. A total of 3351 infusions were administered, with a median of 3 infusions per patient. A positive clinical response was observed in 82.7% (95% confidence interval, 79.9-85.5) of patients. Infusion reactions were observed after 146 of 3351 infusions (4.4%). Significantly fewer infusion reactions were seen in patients also receiving azathioprine or methotrexate (63 of 2079; 3.0%), compared with patients not receiving azathioprine or methotrexate (83 of 1272; 6.5%) (P < .0001). Severe adverse events were observed after 112 of 3351 infusions (3.3%) in a total of 95 patients (14.6%). Four patients developed cancer versus 5.9 expected (standardized incidence ratio, 0.7; 95 confidence interval, 0.2-1.7) and 13 patients died versus 6.9 expected (standardized mortality ratio, 1.9; 95% confidence interval, 1.0-3.2). Two deaths caused by infections were possibly related to infliximab. CONCLUSIONS Infliximab seemed effective in IBD and generally was well tolerated. However, rare but severe adverse events occurred, and patients receiving infliximab therefore should be selected carefully and monitored closely. No lymphomas and no increased risk of cancer were observed.

Overall and cause-specific mortality in Crohn's disease: A meta-analysis of population-based studies

Background: An overview of mortality risk among unselected patients with Crohns disease (CD) is lacking. We therefore performed a systematic review and meta‐analysis of population‐based studies on overall and cause‐specific mortality in CD. Methods: MEDLINE (January 1965 to February 2008), abstracts from international conferences and reference lists of selected articles were searched systematically. All articles fulfilling the predefined inclusion criteria were scrutinized for data on population size, time of follow‐up, gender, age, and observed to expected deaths. STATA meta‐analysis software was used to calculate overall and cause‐specific pooled standardized mortality ratios (SMR, observed/expected). Results: Nine studies were included with overall SMRs ranging from 0.72–3.2, resulting in a significantly increased pooled SMR of 1.39 (95% confidence interval [CI]: 1.30–1.49). Regarding cause‐specific mortality, a significantly increased risk of death from cancer (SMR 1.50, 95% CI: 1.18–1.92), in particular of pulmonary cancer (SMR 2.72, 95% CI: 1.35–5.45), as well as chronic obstructive pulmonary disease (SMR 2.55, 95% CI: 1.19–5.47), gastrointestinal diseases (SMR 6.76, 95% CI: 4.37–10.45), and genitourinary diseases (SMR 3.28, 95% CI: 1.69–6.35) was observed. Conclusions: Among unselected patients with CD, overall mortality was slightly but significantly higher than in the general population—primarily explained by deaths from gastrointestinal, respiratory, and genitourinary diseases. Notably, mortality from colorectal cancer was not increased. Inflamm Bowel Dis 2009

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.

Genome‐wide peripheral blood leukocyte DNA methylation microarrays identified a single association with inflammatory bowel diseases

Background: Crohns disease (CD) and ulcerative colitis (UC) are common forms of inflammatory bowel disease (IBD). Monozygotic (MZ) twin discordance rates and epidemiologic data implicate that environmental changes and epigenetic factors may play a pathogenic role in IBD. DNA methylation (the methylation of cytosines within CpG dinucleotides) is an epigenetic modification, which can respond to environmental influences. We investigated whether DNA methylation might be connected with IBD in peripheral blood leukocyte (PBL) DNA by utilizing genome‐wide microarrays. Methods: Two different high‐throughput microarray‐based methods for genome‐wide DNA methylation analysis were employed. First, DNA isolated from MZ twin pairs concordant (CD: 4; UC: 3) and discordant (CD: 4; UC: 7) for IBD was interrogated by a custom‐made methylation‐specific amplification microarray (MSAM). Second, the recently developed Illumina Infinium HumanMethylation450 BeadChip arrays were used on 48 samples of PBL DNA from discordant MZ twin pairs (CD: 3; UC: 3) and treatment‐naive pediatric cases of IBD (CD: 14; UC: 8), as well as controls (n = 14). The microarrays were validated with bisulfite pyrosequencing. Results: The MSAMs did not yield significant IBD associations. The Methylation BeadChip approach identified a single DNA methylation association of IBD at TEPP (testis, prostate and placenta‐expressed protein) when DNA isolated selectively from peripheral blood mononuclear cells was analyzed (8.6% increase in methylation between CD and control, FDR = 0.0065). Conclusions: Microarray interrogation of IBD‐dependent DNA methylation from PBLs appears to have limited ability to detect significant disease associations. More detailed and/or selective approaches may be useful for the elucidation of connections between the DNA methylome and IBD in the future. (Inflamm Bowel Dis 2012;)

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.