Dana Duricova

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.

Infliximab trough levels may predict sustained response to infliximab in patients with Crohn's disease

BACKGROUND AND AIMS Over 10% of Crohns disease (CD) patients annually lose response to infliximab. Infliximab trough levels (TL), concomitant immunosuppressants and endoscopic healing were proposed as predictors of favourable infliximab outcome. We assessed infliximab TL measured after induction therapy as predictors of sustained clinical response. Furthermore, we tried to identify other predictors of long-term benefit of infliximab therapy. METHODS We included CD patients treated with infliximab between October 2007 and March 2010 who responded to 3-dose induction followed by maintenance therapy and in whom blood samples taken at treatment week 14 or 22 were available in blood bank. Sustained response to infliximab was defined as absence of treatment failure due to loss of response or drug intolerance. RESULTS Eighty four patients were included. Sustained response to infliximab was observed in 47 (56%) patients during a median follow-up of 25 months (14-37). Infliximab TL>3μg/ml were associated with a decreased risk of treatment failure (HR 0.34; 95% CI: 0.16-0.75), whereas the presence of antibodies against infliximab and need for corticosteroids increased this risk (HR 4.34; 95% CI: 1.51-12.5 and HR 2.49, 95% CI: 1.08-5.73, respectively). No impact of concomitant thiopurines was observed, although patients receiving thiopurines had higher infliximab TL than those without immunomodulators (5.51 vs. 0.71μg/ml; p=0.01). CONCLUSION During a median follow up of 2 years sustained response to infliximab was observed in slightly more than half of CD patients. Infliximab TL>3μg/ml at the start of maintenance regime were predicative of sustained response to infliximab.

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.

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

Exogenous alkaline phosphatase for the treatment of patients with moderate to severe ulcerative colitis

Background: Increased activity of intestinal alkaline phosphatase (AP) occurs locally in patients with ulcerative colitis (UC), aimed at repairing inflammatory tissue damage. We evaluated the safety and preliminary efficacy of exogenous AP administered to patients with UC in an open‐label, first‐in‐patient exploratory trial, conducted in the Internal Medicine and Gastroenterology hospital departments in the Czech Republic and Italy. Methods: Twenty‐one patients were enrolled (13 females), age 23–54 years, with steroid‐ and/or immunosuppressant‐refractory, moderate/severe UC (Mayo score 6–11). Oral AP enzyme 30,000 U was administered daily for 7 days, intraduodenally. Efficacy outcomes were changes in Mayo score at Day 21 posttreatment; changes in Modified Truelove–Witts Severity index (MTWSI) at Days 21, 63; C‐reactive protein and stool calprotectin levels at Days 7, 21, 63. Safety evaluations were adverse events and laboratory abnormalities reported up to Day 63 posttreatment. Results: No clinically relevant adverse events causing withdrawal or considered serious, or laboratory abnormalities or antibody formation against AP were observed. Mayo scores were significantly decreased at Day 21, and MTWSI at Days 21 and 63. C‐reactive protein and stool calprotectin levels were decreased at Days 21 and 63. Clinical response on the Mayo score after a single 7‐day AP course was 48% at Day 21. Conclusions: In this uncontrolled trial, administration of exogenous AP enzyme daily over a 7‐day course to patients with UC was associated with short‐term improvement in disease activity scores, with clinical effects being observed within 21 days and associated with reductions in C‐reactive protein and stool calprotectin. AP enzyme treatment was well tolerated and nonimmunogenic. (Inflamm Bowel Dis 2009;)

Bile acid malabsorption in inflammatory bowel disease: Assessment by serum markers

Background: Bile acid malabsorption (BAM) is a common feature of Crohns disease (CD). We aimed to determine whether BAM develops only in patients with a resected distal ileum or if it also occurs in patients who have not undergone surgery for CD. Methods: The study included 347 patients with CD or ulcerative colitis (UC) and 119 healthy subjects (controls). BAM was assessed by measurement of serum levels of 7&agr;‐hydroxycholest‐4‐en‐3‐one (C4) and fibroblast growth factor 19 (FGF19). We surveyed members of the European Crohns and Colitis Organization and International Organization for the Study of Inflammatory Bowel Disease to collect current information about BAM diagnosis. Results: The severity of BAM was associated with resection of the distal ileum. Compared with controls, patients who received moderate or extensive ileal resection had significantly increased levels of serum C4 (12 versus 62 versus 243 μg/L, respectively; P < 0.001). However, BAM was also present in a substantial number of the patients with CD who were not treated by surgery who had ileitis or colitis (14% and 11%, respectively). There was an indirect, proportional relationship between levels of C4 and FGF19 (P < 0.001). Conclusions: The most severe BAM occurs in CD patients after resection of the distal ileum, but BAM can occur in surgically untreated CD patients, regardless of disease localization. Laboratory tests for BAM should become a part of the algorithm for diagnosis of CD to identify patients who might respond to therapies such as bile acid sequestrants. FGF19 appears to be a reliable marker of BAM. (Inflamm Bowel Dis 2011;)

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.

Age-related differences in presentation and course of inflammatory bowel disease: an update on the population-based literature☆

Current data indicate a change in the epidemiology of inflammatory bowel diseases. The disease has become more widespread and the rise in the incidence has been reported in all age groups including early childhood and according to recent data also the elderly population. Some earlier studies have suggested that the phenotype and natural history of the disease may be different according to age of onset. Recently the importance of age at onset was reported in two population-based studies from France and Hungary including both paediatric and adult onset inception cohorts. Early onset disease was associated with more frequent disease extension in both Crohns disease and ulcerative colitis and in most but not all studies with higher frequency of complicated disease behaviour. This is also accompanied by striking differences in the medical management with earlier and more prevalent (2-3-fold) use of immunosuppressives and to some extent biologicals in patients with early compared to elderly-onset disease, especially in Crohns disease. However, the results of population-based studies on impact of age on surgery rates in Crohn´s disease as well as ulcerative colitis are conflicting. Furthermore, published data indicate that relative but not absolute risk of developing cancer and mortality is higher in patients with an early onset disease. Critical reviews that focus on the importance of age at onset in inflammatory bowel disease are rare. Therefore, the aim of this review is to describe the differences in epidemiology, clinical characteristics, and natural history of paediatric and elderly-onset inflammatory bowel disease based on studies performed in general population.

Impact of Anti–Tumor Necrosis Factor Alpha Antibodies Administered to Pregnant Women With Inflammatory Bowel Disease on Long-term Outcome of Exposed Children

Background:Prenatal exposure to anti–tumor necrosis factor &agr; (TNF-&agr;) antibodies seems to be safe for fetal development. Data on long-term outcome of exposed children are missing. Our aim was to assess long-term postnatal development of children exposed to anti–TNF-&agr; during pregnancy. Methods:Consecutive children aged ≥12 months exposed to anti-TNFs prenatally for maternal inflammatory bowel disease in 3 centers in the Czech Republic were enrolled. Data on psychomotor development, infections, antibiotics, vaccination, and allergy were retrospectively obtained from mothers, treating pediatricians, and childrens vaccination cards. Furthermore, standardized laboratory tests on humoral and cellular immunity were performed. Results:Twenty-five children exposed to biologicals were included (median age, 34 mo; range, 14–70 mo). All children had normal growth, and all but 1 had normal psychomotor development. Majority (80%) experienced at least 1 infection (mainly respiratory), and 60% of infants received antibiotics, 32% of those within the first year of life. Vaccination was undertaken according to vaccination protocol to 23 infants (92%). Fifteen children also had tuberculosis vaccination without serious complication. Immunological investigation was performed with 17 children (68%). Cellular immunity was normal in all infants, and 7 children had mild decrease in IgA and/or IgG immunoglobulins without clinical significance. All children had a detectable serologic response to vaccination. Conclusions:Exposure to anti–TNF-&agr; antibodies seems to be safe for growth and psychomotor development of children, although clinical significance of relatively high frequency of infections and antibiotic use among infants remains questionable because of the lack of a control group. Continuous follow-up of exposed children is absolutely warranted.