Publications by authors named "Natalia Pedersen"

38 Publications

Validation and update of the Lémann index to measure cumulative structural bowel damage in Crohn's disease.

Gastroenterology 2021 May 27. Epub 2021 May 27.

INSERM U1135 CRESS 'Centre de Recherche Epidémiologie et Statistiques', Equipe ECSTRRA, Université de Paris, Hôpital Saint-Louis, Paris, France.

Background: The Lémann index is a tool measuring cumulative structural bowel damage in Crohn's disease (CD). We here report its validation and updating.

Methods: This was an international, multicenter, prospective, cross-sectional observational study. At each center, 10 inclusions, stratified by CD duration and location, were planned. For each patient, the digestive tract was divided into 4 organs, upper tract, small bowel, colon/rectum, anus, and subsequently into segments, explored systematically by magnetic resonance imaging (MRI), and by endoscopies in relation to disease location. For each segment, investigators retrieved information on previous surgical procedures, identified predefined strictures and penetrating lesions of maximal severity (grades 1-3) at each organ investigational method (gastroenterologist and radiologist for MRI), provided segmental damage evaluation ranging from 0.0 to 10.0 (complete resection). Organ resection-free cumulative damage evaluation was then calculated from the sum of segmental damages. Then, investigators provided a 0-10 global damage evaluation from the 4 organ standardized cumulative damage evaluations. Simple linear regressions of investigator damage evaluations on their corresponding Lémann index were studied, as well as calibration plots. Finally, updated Lémann index was derived through multiple linear mixed models applied to combined development and validation samples.

Results: In 15 centers, 134 patients were included. Correlation coefficients between investigator damage evaluations and Lémann indexes were above 0.80. When analyzing data in 272 patients from both samples and 27 centers, the unbiased correlation estimates were 0.89, 0,97, 0,94, 0.81, 0.91 for the 4 organs and globally, and stable when applied to one sample or the other.

Conclusions: The updated Lémann index is a well-established index to assess cumulative bowel damage in Crohn's disease that can be used in epidemiological studies and disease modification trials.
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http://dx.doi.org/10.1053/j.gastro.2021.05.049DOI Listing
May 2021

Prevalence and Outcomes of COVID-19 Among Patients With Inflammatory Bowel Disease-A Danish Prospective Population-based Cohort Study.

J Crohns Colitis 2021 Apr;15(4):540-550

Gastrounit, Medical Division, Hvidovre University Hospital, Hvidovre, Denmark.

Background And Aims: As no population-based study has investigated the susceptibility and disease course of COVID-19 among patients with inflammatory bowel diseases [IBD], we aimed to investigate this topic in a population-based setting.

Methods: Two cohorts were investigated. First, a nationwide cohort of all IBD patients diagnosed with COVID-19 was prospectively followed to investigate the disease courses of both diseases. Second, within a population-based cohort of 2.6 million Danish citizens, we identified all individuals tested for SARS-CoV-2 to determine the occurrence of COVID-19 among patients with and without IBD and other immune-mediated inflammatory diseases [IMIDs].

Results: Between January 28, 2020 and June 2, 2020, a total of 76 IBD patients with COVID-19 were identified in the national cohort and prospectively followed for 35 days (interquartile range [IQR]: 25-51). A large proportion [n = 19: 25%] required a COVID-19-related hospitalisation for 7 days [IQR: 2-8.5] which was associated with being 65 years or older (odds ratio [OR] = 23].80, 95% confidence interval [CI] 6.32-89.63, p <0.01) and presence of any non-IMID comorbidity [OR = 8.12, 95% CI 2.55-25.87, p <0.01], but not use of immunomodulators [p = 0.52] or biologic therapies [p = 0.14]. In the population-based study, 8476 of 231 601 [3.7%] residents tested positive for SARS-CoV-2; however, the occurrence was significantly lower among patients with IBD [62 of the 2486 patients = 2.5%, p <0.01] and other IMIDs [531 of 16 492 patients = 3.2%, p <0.01] as compared with patients without IMIDs.

Conclusions: Patients with IMIDs, including IBD, had a significantly lower susceptibility to COVID-19 than patients without IMIDs, and neither immunosuppressive therapies nor IBD activity were associated with the disease course of COVID-19.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797764PMC
April 2021

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.

United European Gastroenterol J 2020 10 26;8(8):949-960. Epub 2020 Jul 26.

Hull University Teaching Hospitals NHS Trust, Hull, UK.

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.
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http://dx.doi.org/10.1177/2050640620945949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707880PMC
October 2020

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.

Lancet Gastroenterol Hepatol 2020 05 13;5(5):454-464. Epub 2020 Feb 13.

Hull University Teaching Hospitals NHS Trust, Hull, UK; Hull York Medical School, Hull, UK.

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.
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http://dx.doi.org/10.1016/S2468-1253(20)30012-1DOI Listing
May 2020

Polymorphisms in the NFkB, TNF-alpha, IL-1beta, and IL-18 pathways are associated with response to anti-TNF therapy in Danish patients with inflammatory bowel disease.

Aliment Pharmacol Ther 2019 04 27;49(7):890-903. Epub 2019 Feb 27.

Aabenraa, Denmark.

Background: Anti-tumor necrosis factor-α (TNF-α) is used for the treatment of severe cases of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. We have previously investigated whether single nucleotide polymorphisms (SNPs) in genes involved in inflammation were associated with response to anti-TNF therapy among patients with CD or UC.

Aim: A new cohort of patients was established for replication of the previous findings and to identify new SNPs associated with anti-TNF response.

Methods: Fifty-three SNPs assessed previously in cohort 1 (482 CD and 256 UC patients) were genotyped in cohort 2 (587 CD and 458 UC patients). The results were analysed using logistic regression (adjusted for age and gender).

Results: Ten SNPs were associated with anti-TNF response either among patients with CD (TNFRSF1A(rs4149570) (OR: 1.92, 95% CI: 1.02-3.60, P = 0.04), IL18(rs187238) (OR: 1.35, 95% CI: 1.00-1.82, P = 0.05), and JAK2(rs12343867) (OR: 1.35, 95% CI: 1.02-1.78, P = 0.03)), UC (TLR2(rs11938228) (OR: 0.55, 95% CI: 0.33-0.92, P = 0.02), TLR4(rs5030728) (OR: 2.23, 95% CI: 1.24-4.01, P = 0.01) and (rs1554973) (OR: 0.49, 95% CI: 0.27-0.90, P = 0.02), NFKBIA(rs696) (OR: 1.45, 95% CI: 1.06-2.00, P = 0.02), and NLRP3(rs4612666) (OR: 0.63, 95% CI: 0.44-0.91, P = 0.01)) or in the combined cohort of patient with CD and UC (IBD) (TLR4(rs5030728) (OR: 1.46, 95% CI: 1.01-2.11, P = 0.04) and (rs1554973)(OR: 0.80, 95% CI: 0.65-0.98, P = 0.03), NFKBIA(rs696) (OR: 1.25, 95% CI: 1.01-1.54, P = 0.04), NLRP3(rs4612666) (OR: 0.73, 95% CI: 0.57-0.95, P = 0.02), IL1RN(rs4251961) (OR: 0.81, 95% CI: 0.66-1.00, P = 0.05), IL18(rs1946518) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04), and JAK2(rs12343867) (OR: 1.24, 95% CI: 1.01-1.53, P = 0.04)).

Conclusions: The results support that polymorphisms in genes involved in the regulation of the NFκB pathway (TLR2, TLR4, and NFKBIA), the TNF-α signalling pathway (TNFRSF1A), and other cytokine pathways (NLRP3, IL1RN, IL18, and JAK2) were associated with response to anti-TNF therapy. Our multi-SNP model predicted response rate of more than 82% (in 9% of the CD patients) and 75% (in 15% of the UC patients), compared to 71% and 64% in all CD and UC patients, respectively. More studies are warranted to predict response for use in the clinic.
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http://dx.doi.org/10.1111/apt.15187DOI Listing
April 2019

Disease course of inflammatory bowel disease unclassified in a European population-based inception cohort: An Epi-IBD study.

J Gastroenterol Hepatol 2019 Jun 21;34(6):996-1003. Epub 2019 Jan 21.

Department of Gastroenterology, University Hospital of Ioannina, Ioannina, Greece.

Background And Aim: A definitive diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) is not always possible, and a proportion of patients will be diagnosed as inflammatory bowel disease unclassified (IBDU). The aim of the study was to investigate the prognosis of patients initially diagnosed with IBDU and the disease course during the following 5 years.

Methods: The Epi-IBD study is a prospective population-based cohort of 1289 IBD patients diagnosed in centers across Europe. Clinical data were captured prospectively throughout the follow-up period.

Results: Overall, 476 (37%) patients were initially diagnosed with CD, 701 (54%) with UC, and 112 (9%) with IBDU. During follow-up, 28 (25%) IBDU patients were changed diagnoses to either UC (n = 20, 71%) or CD (n = 8, 29%) after a median of 6 months (interquartile range: 4-12), while 84 (7% of the total cohort) remained IBDU. A total of 17 (15%) IBDU patients were hospitalized for their IBD during follow-up, while 8 (7%) patients underwent surgery. Most surgeries (n = 6, 75%) were performed on patients whose diagnosis was later changed to UC; three of these colectomies led to a definitive diagnosis of UC. Most patients (n = 107, 96%) received 5-aminosalicylic acid, while 11 (10%) patients received biologicals, of whom five remained classified as IBDU.

Conclusions: In a population-based inception cohort, 7% of IBD patients were not given a definitive diagnosis of IBD after 5 years of follow-up. One in four patients with IBDU eventually was classified as CD or UC. Overall, the disease course and medication burden in IBDU patients were mild.
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http://dx.doi.org/10.1111/jgh.14563DOI Listing
June 2019

Natural Disease Course of Ulcerative Colitis During the First Five Years of Follow-up in a European Population-based Inception Cohort-An Epi-IBD Study.

J Crohns Colitis 2019 Feb;13(2):198-208

IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic.

Background And Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort.

Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.

Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8].

Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation.
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http://dx.doi.org/10.1093/ecco-jcc/jjy154DOI Listing
February 2019

Vitamin D deficiency in a European inflammatory bowel disease inception cohort: an Epi-IBD study.

Eur J Gastroenterol Hepatol 2018 11;30(11):1297-1303

Pekka Collin Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.

Background: Serum vitamin D level is commonly low in patients with inflammatory bowel disease (IBD). Although there is a growing body of evidence that links low vitamin D level to certain aspects of IBD such as disease activity and quality of life, data on its prevalence and how it varies across disease phenotype, smoking status and treatment groups are still missing.

Materials And Methods: Patients diagnosed with IBD between 2010 and 2011 were recruited. Demographic data and serum vitamin D levels were collected. Variance of vitamin D level was then assessed across different treatment groups, disease phenotype, disease activity and quality of life scores.

Results: A total of 238 (55.9% male) patients were included. Overall, 79% of the patients had either insufficient or deficient levels of vitamin D at diagnosis. Patients needing corticosteroid treatment at 1 year had significantly lower vitamin D levels at diagnosis (median 36.0 nmol/l) (P=0.035). Harvey-Bradshaw Index (P=0.0001) and Simple Clinical Colitis Activity Index scores (P=0.0001) were significantly lower in patients with higher vitamin D level. Serum vitamin D level correlated significantly with SIBQ score (P=0.0001) and with multiple components of SF12. Smokers at diagnosis had the lowest vitamin D levels (vitamin D: 34 nmol/l; P=0.053).

Conclusion: This study demonstrates the high prevalence of low vitamin D levels in treatment-naive European IBD populations. Furthermore, it demonstrates the presence of low vitamin D levels in patients with IBD who smoke.
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http://dx.doi.org/10.1097/MEG.0000000000001238DOI Listing
November 2018

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.

Gut 2019 03 23;68(3):423-433. Epub 2018 Jan 23.

IBD Clinical and Research Centre, ISCARE, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1136/gutjnl-2017-315568DOI Listing
March 2019

Occurrence of Anaemia in the First Year of Inflammatory Bowel Disease in a European Population-based Inception Cohort-An ECCO-EpiCom Study.

J Crohns Colitis 2017 Oct;11(10):1213-1222

Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.

Background And Aims: Anaemia is an important complication of inflammatory bowel disease [IBD]. The aim of this study was to determine the prevalence of anaemia and the practice of anaemia screening during the first year following diagnosis, in a European prospective population-based inception cohort.

Methods: Newly diagnosed IBD patients were included and followed prospectively for 1 year in 29 European and one Australian centre. Clinical data including demographics, medical therapy, surgery and blood samples were collected. Anaemia was defined according to the World Health Organization criteria.

Results: A total of 1871 patients (Crohn's disease [CD]: 686, 88%; ulcerative colitis [UC]: 1,021, 87%; IBD unclassified [IBDU] 164. 81%) were included in the study. The prevalence of anaemia was higher in CD than in UC patients and, overall, 49% of CD and 39% of UC patients experienced at least one instance of anaemia during the first 12 months after diagnosis. UC patients with more extensive disease and those from Eastern European countries, and CD patients with penetrating disease or colonic disease location, had higher risks of anaemia. CD and UC patients in need of none or only mild anti-inflammatory treatment had a lower risk of anaemia. In a significant proportion of patients, anaemia was not assessed until several months after diagnosis, and in almost half of all cases of anaemia a thorough work-up was not performed.

Conclusions: Overall, 42% of patients had at least one instance of anaemia during the first year following diagnosis. Most patients were assessed for anaemia regularly; however, a full anaemia work-up was frequently neglected in this community setting.
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http://dx.doi.org/10.1093/ecco-jcc/jjx077DOI Listing
October 2017

Low-FODMAP diet reduces irritable bowel symptoms in patients with inflammatory bowel disease.

World J Gastroenterol 2017 May;23(18):3356-3366

Natalia Pedersen, Department of Gastroenterology, Slagelse Hospital, 4200 Slagelse, Denmark.

Aim: To investigate the effect of a low-FODMAP diet on irritable bowel syndrome (IBS)-like symptoms in patients with inflammatory bowel disease (IBD).

Methods: This was a randomised controlled open-label trial of patients with IBD in remission or with mild-to-moderate disease and coexisting IBS-like symptoms (Rome III) randomly assigned to a Low-FODMAP diet (LFD) or a normal diet (ND) for 6 wk between June 2012 and December 2013. Patients completed the IBS symptom severity system (IBS-SSS) and short IBD quality of life questionnaire (SIBDQ) at weeks 0 and 6. The primary end-point was response rates (at least 50-point reduction) in IBS-SSS at week 6 between groups; secondary end-point was the impact on quality of life.

Results: Eighty-nine patients, 67 (75%) women, median age 40, range 20-70 years were randomised: 44 to LFD group and 45 to ND, from which 78 patients completed the study period and were included in the final analysis (37 LFD and 41 ND). There was a significantly larger proportion of responders in the LFD group ( = 30, 81%) than in the ND group ( = 19, 46%); (OR = 5.30; 95%CI: 1.81-15.55, < 0.01). At week 6, the LFD group showed a significantly lower median IBS-SSS (median 115; inter-quartile range [IQR] 33-169) than ND group (median 170, IQR 91-288), = 0.02. Furthermore, the LFD group had a significantly greater increase in SIBDQ (median 60, IQR 51-65) than the ND group (median 50, IQR 39-60), < 0.01.

Conclusion: In a prospective study, a low-FODMAP diet reduced IBS-like symptoms and increased quality of life in patients with IBD in remission.
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http://dx.doi.org/10.3748/wjg.v23.i18.3356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434443PMC
May 2017

Follow-up of patients with functional bowel symptoms treated with a low FODMAP diet.

World J Gastroenterol 2016 Apr;22(15):4009-19

Louise Maagaard, Dorit V Ankersen, Pia Munkholm, Department of Gastroenterology, North Zealand University Hospital, 3600 Frederikssund, Denmark.

Aim: To investigate patient-reported outcomes from, and adherence to, a low FODMAP diet among patients suffering from irritable bowel syndrome and inflammatory bowel disease.

Methods: Consecutive patients with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD) and co-existing IBS fulfilling the ROME III criteria, who previously attended an outpatient clinic for low FODMAP diet (LFD) dietary management and assessment by a gastroenterologist, were invited to participate in a retrospective questionnaire analysis. The questionnaires were sent and returned by regular mail and gathered information on recall of dietary treatment, efficacy, symptoms, adherence, satisfaction, change in disease course and stool type, and quality of life. Before study enrolment all patients had to sign an informed written consent.

Results: One hundred and eighty patients were included, 131 (73%) IBS and 49 (27%) IBD patients. Median age was 43 years (range: 18-85) and 147 (82%) were females. Median follow-up time was 16 mo (range: 2-80). Eighty-six percent reported either partial (54%) or full (32%) efficacy with greatest improvement of bloating (82%) and abdominal pain (71%). The proportion of patients with full efficacy tended to be greater in the IBD group than in the IBS group (42% vs 29%, P = 0.08). There was a significant reduction in patients with a chronic continuous disease course in both the IBS group (25%, P < 0.001) and IBD group (23%, P = 0.002) along with a significant increase in patients with a mild indolent disease course of 37% (P < 0.001) and 23% (P = 0.002), respectively. The proportion of patients having normal stools increased with 41% in the IBS group (P < 0.001) and 66% in the IBD group (P < 0.001). One-third of patients adhered to the diet and high adherence was associated with longer duration of dietary course (P < 0.001). Satisfaction with dietary management was seen in 83 (70%) IBS patients and 24 (55%) IBD patients. Eighty-four percent of patients lived on a modified LFD, where some foods rich in FODMAPs were reintroduced, and 16% followed the LFD by the book without deviations. Wheat, dairy products, and onions were the foods most often not reintroduced by patients.

Conclusion: These data suggest that a diet low in FODMAPs is an efficacious treatment solution in the management of functional bowel symptoms for IBS and IBD patients.
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http://dx.doi.org/10.3748/wjg.v22.i15.4009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823251PMC
April 2016

Polymorphisms in the Toll-Like Receptor and the IL-23/IL-17 Pathways Were Associated with Susceptibility to Inflammatory Bowel Disease in a Danish Cohort.

PLoS One 2015 23;10(12):e0145302. Epub 2015 Dec 23.

Medical Department, Viborg Regional Hospital, Viborg, Denmark.

Background: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Previous studies have shown that polymorphisms in the Toll-like receptor (TLR), the apoptosis, the IL-23/IL-17 and the interferon gamma (IFNG) pathways are associated with risk of both CD and UC.

Methods: Using a candidate gene approach, 21 functional single nucleotide polymorphisms (SNPs) in 15 genes were assessed in a clinical homogeneous group of severely diseased ethnic Danish patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression.

Results: The polymorphisms TLR5 (rs5744174) and IL12B (rs6887695) were associated with risk of CD, and TLR1 (rs4833095) and IL18 (rs187238) were associated with risk of both CD and UC (p<0.05). After Bonferroni correction for multiple testing, the homozygous variant genotype of TLR1 743 T>C (rs4833095) was associated with increased risk CD (OR: 3.15, 95% CI: 1.59-6.26, p = 0.02) and CD and UC combined (OR: 2.96, 95% CI: 1.64-5.32, p = 0.005).

Conclusion: Our results suggest that genetically determined high activity of TLR1 and TLR5 was associated with increased risk of both CD and UC and CD, respectively. This supports that the host microbial composition or environmental factors in the gut are involved in risk of IBD. Furthermore, genetically determined high activity of the IL-23/IL-17 pathway was associated with increased risk of CD and UC. Overall, our results support that genetically determined high inflammatory response was associated with increased risk of both CD and UC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689491PMC
July 2016

EHealth: self-management in inflammatory bowel disease and in irritable bowel syndrome using novel constant-care web applications. EHealth by constant-care in IBD and IBS.

Authors:
Natalia Pedersen

Dan Med J 2015 Dec;62(12):B5168

Background: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are chronic gastrointestinal disorders of unknown aetiology of increasing incidence and changing disease activity or severity. Approximately 60-80% of IBD patients suffer from IBS. Monitoring and treatment goals of IBD are to optimise the disease course by prolonging remission periods and preventing or shortening periods of active disease. Constant-care web-monitoring and treatment approaches with active patient involvement have been proven effective in UC, increasing patients' adherence and improving the disease outcomes.  

Aim: To assess the feasibility and efficacy of the novel constant-care eHealth applications in: i) CD patients treated with infliximab (IFX), ii) UC patients with active disease on mesalazine, iii) IBS patients and iv) IBD patients with IBS on a low FODMAP diet (LFD).  

Methods: New constant-care web applications www.cd.constant-care.dk, www.meza.constant-care.dk and www.ibs.constant-care.dk in IBD patients were developed and assessed in this thesis. An integrated inflammatory burden measure of disease activity, consisting of a subjective (clinical indices) and of an objective (faecal calprotectin) part and a treatment guide to drug doses and intervals, was incorporated into the web applications and used by patients.

Results: Web-guided IFX treatment in CD demonstrated patients' inter- and intra-individual variability in infusion intervals and provided patients with individualised treatment according to their needs. Web-guided treatment with multimatrix mesalazine was efficacious in a majority of UC patients with mild-to-moderate disease activity. Web-guided IBS-monitoring in IBD and in IBS patients on LFD was shown to be a feasible method that actively involved patients in their disease management and had a positive short-term impact on the disease. Moreover, the new constant-care concepts were demonstrated to be safe and to have a positive impact on quality of life and adherence to treatment and helped to reduce the costs.  

Conclusions: The novel constant-care web applications have proven feasible in improving the disease outcomes in CD patients on IFX, in UC patients on mesalazine, and in monitoring IBS. These applications are expected to be implemented in the clinical practice of gastroenterology in Denmark in the coming years. Future studies will help to assess whether the natural disease course can be improved in the long-term.
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December 2015

Fecal Calprotectin Measured By Patients at Home Using Smartphones--A New Clinical Tool in Monitoring Patients with Inflammatory Bowel Disease.

Inflamm Bowel Dis 2016 Feb;22(2):336-44

*Gastrounit, Medical Section, Herlev University Hospital, Herlev, Denmark; †Department of Gastroenterology, Slagelse University Hospital, Slagelse, Denmark; ‡Gastrounit, North Zealand Hospital, University of Copenhagen, Frederikssund, Denmark; §Department of Pediatrics, Hvidovre University Hospital, Hvidovre, Denmark; and ‖Gastrounit, Medical section, Hvidovre University Hospital, Hvidovre, Denmark.

Background: Fecal calprotectin is a reliable noninvasive marker for intestinal inflammation usable for monitoring patients with inflammatory bowel disease. Tests are usually performed by enzyme-linked immunosorbent assay (ELISA), which is time consuming and delays results, thus limiting its use in clinical practice. Our aim was to evaluate CalproSmart, a new rapid test for fecal calprotectin performed by patients themselves at home, and compare it to gold standard ELISA.

Methods: A total of 221 patients with inflammatory bowel disease (115 ulcerative colitis and 106 Crohn's disease) were included. The CalproSmart test involves extraction of feces, application to the lateral flow device, and taking a picture with a smartphone after 10 minutes of incubation. Results appear on the screen within seconds. Patients were instructed at inclusion and had a video guide of the procedure as support. When using CalproSmart at home, patients also sent in 2 fecal samples to be analyzed by ELISA.

Results: Totally, 894 fecal calprotectin results were obtained by ELISA, and 632 of them from CalproSmart. The correlation coefficient was 0.685, higher for academics than nonacademics (0.768 versus 0.637; P = 0.0037). The intra-assay and interassay coefficients of variation of the CalproSmart test were 4.42% and 12.49%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value were 82%, 85%, 47%, and 97%, respectively, with an optimal cutoff at 150 μg/g.

Conclusions: The CalproSmart test performed by patients with inflammatory bowel disease for fast assessment of gut inflammation seems a reliable alternative to ELISA and presents a new way of monitoring patients by eHealth.
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http://dx.doi.org/10.1097/MIB.0000000000000619DOI Listing
February 2016

Reply to Methodological Approach to Mesalazine Treatment in Patients with Mild-to-moderate Ulcerative Colitis.

Inflamm Bowel Dis 2015 Aug;21(8):E15-6

*Department of Gastroenterology, Slagelse Hospital, University of Copenhagen, Slagelse, Denmark; and †Gastrounit, Medical Section, North Sealand Hospital, University of Copenhagen, Frederikssund, Denmark.

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http://dx.doi.org/10.1097/MIB.0000000000000484DOI Listing
August 2015

Effectiveness of anti-tumour necrosis factor-α therapy in Danish patients with inflammatory bowel diseases.

Dan Med J 2015 Mar;62(3)

Medical Department, Viborg Regional Hospital, 8800 Viborg.

Introduction: The objective of this study was to evaluate the outcome of anti-tumour necrosis factor-α (anti-TNF) treatment in a large cohort of patients with inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) in clinical practice and to establish a cohort for future studies of genetic markers associated with treatment response.

Methods: A national, clinically based cohort of previously naïve anti-TNF treated patients from 18 medical departments was established. The patients were screened for tuberculosis prior to treatment initiation. By combining the unique personal identification number of Danish citizens (the CPR number) from blood samples with data from the National Patient Registry, patients with International Classification of Diseases, Version 10 (ICD-10) codes K50-K63 were identified. Treatment efficacy reflected the maximum response within 22 weeks.

Results: Among 492 patients with CD and 267 patients with UC, 74%/13%/14% and 65%/12%/24% were responders, partial responders and non-responders to anti-TNF therapy, respectively. More patients with UC than with CD were non-responders (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.34-2.87, p = 0.001). Young age was associated with a beneficial response (p = 0.03), whereas smoking ≥ 10 cigarettes/day was associated with non-response among patients with CD (OR = 2.33, 95% CI: 1.13-4.81, p = 0.03).

Conclusion: In this clinically based cohort of Danish patients with IBD treated with anti-TNF, high response rates were found. Heavy smoking was associated with non-response, whereas young age at treatment initiation was associated with a beneficial response among patients with CD. Thus, the results obtained in this cohort recruited from clinical practice were similar to those previously obtained in clinical trials.

Funding: The work was funded by Health Research Fund of Central Denmark Region, Colitis-Crohn Foreningen and the University of Aarhus (PhD grant).

Trial Registration: Clinicaltrials NCT02322008.
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March 2015

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

World J Gastroenterol 2014 Nov;20(43):16215-26

Natalia Pedersen, Johan Burisch, Pia Munkholm, Digestive Disease Centre, Medical Section, Herlev University Hospital, 2730 Copenhagen, Denmark.

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.
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http://dx.doi.org/10.3748/wjg.v20.i43.16215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239510PMC
November 2014

Costs and resource utilization for diagnosis and treatment during the initial year in a European inflammatory bowel disease inception cohort: an ECCO-EpiCom Study.

Inflamm Bowel Dis 2015 Jan;21(1):121-31

1Digestive Disease Centre, Medical Section, Herlev University Hospital, Copenhagen, Denmark; 2Department of Public Health, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel; 3Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia; 4Private Practice, Nicosia, Cyprus; 5IBD Center ISCARE, Charles University, Prague, Czech Republic; 6Department of Gastroenterology, Hospital České Budějovice, České Budějovice, Czech Republic; 7Department of Medicine, Amager Hospital, Amager, Denmark; 8Department of Medicine, Herning Central Hospital, Herning, Denmark; 9Medical Department, Viborg Regional Hospital, Viborg, Denmark; 10Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark; 11Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; 12Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Arhus, Denmark; 13Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; 14Division of Endocrinology and Gastroenterology, Tartu University Hospital, Tartu, Estonia; 15Medical Department, The National Hospital of the Faroe Islands, Torshavn, Faroe Islands; 16Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland; 17First Division of Internal Medicine and Hepato-Gastroenterology Unit, University Hospital, Ioannina, Greece; 18Medical Department, Dronning Ingrids Hospital, Nuuk, Greenland; 19First Department of Medicine, Semmelweis University, Budapest, Hungary; 20Department of Gastroenterology, Adelaide and Meath Hospital, TCD, Dublin, Ireland; 21Department of Gastroenterology and Hepatology, Soroka Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel; 22U.O. di Gastroenterologia e Endoscopia Digestiva, Az.Ospedaliera Ospedale Maggiore di Crema, Crema, Italy; 23EpiCom Northern Italy centre based in Crema a

Background: No direct comparison of health care cost in patients with inflammatory bowel disease across the European continent exists. The aim of this study was to assess the costs of investigations and treatment for diagnostics and during the first year after diagnosis in Europe.

Methods: The EpiCom cohort is a prospective population-based inception cohort of unselected inflammatory bowel disease patients from 31 Western and Eastern European centers. Patients were followed every third month from diagnosis, and clinical data regarding treatment and investigations were collected. Costs were calculated in euros (€) using the Danish Health Costs Register.

Results: One thousand three hundred sixty-seven patients were followed, 710 with ulcerative colitis, 509 with Crohn's disease, and 148 with inflammatory bowel disease unclassified. Total expenditure for the cohort was €5,408,174 (investigations: €2,042,990 [38%], surgery: €1,427,648 [26%], biologicals: €781,089 [14%], and standard treatment: €1,156,520 [22%)]). Mean crude expenditure per patient in Western Europe (Eastern Europe) with Crohn's disease: investigations €1803 (€2160) (P = 0.44), surgery €11,489 (€13,973) (P = 0.14), standard treatment €1027 (€824) (P = 0.51), and biologicals €7376 (€8307) (P = 0.31). Mean crude expenditure per patient in Western Europe (Eastern Europe) with ulcerative colitis: investigations €1189 ( €1518) (P < 0.01), surgery €18,414 ( €12,395) (P = 0.18), standard treatment €896 ( €798) (P < 0.05), and biologicals €5681 ( €72) (P = 0.51).

Conclusions: In this population-based unselected cohort, costs during the first year of disease were mainly incurred by investigative procedures and surgeries. However, biologicals accounted for >15% of costs. Long-term follow-up of the cohort is needed to assess the cost-effectiveness of biological agents.
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http://dx.doi.org/10.1097/MIB.0000000000000250DOI Listing
January 2015

eHealth: individualization of mesalazine treatment through a self-managed web-based solution in mild-to-moderate ulcerative colitis.

Inflamm Bowel Dis 2014 Dec;20(12):2276-85

*Gastroenterology Unit, Herlev University Hospital, Copenhagen, Denmark; †Department of Gastroenterology, Nykoebing Falster Hospital, Nykoebing Falster, Denmark; ‡Department of Gastroenterology, Nordsjaellands Hospital, Frederikssund, Denmark; §Department of Gastroenterology, Gentofte Hospital, Gentofte, Denmark; ‖IBD Clinical and Research Center, ISCARE a. s., Charles University, Prague, Czech Republic; ¶Department of Epidemiology Research, States Serum Institute, Copenhagen, Denmark; and **Department of Gastroenterology, St. Vincent's University Hospital, Melbourne, Australia.

Background: To individualize treatment with mesalazine for ulcerative colitis relapses through a self-managed, web-based solution to optimize the short-term disease course.

Methods: Prospective, open-label, web-guided study with 3 months mesalazine therapy among patients with mild-to-moderate ulcerative colitis. Once a week, patients completed the simple clinical colitis activity index (SCCAI) and registered fecal calprotectin (FC) on the web application: www.meza.constant-care.dk. SCCAI and FC were summed and resulted in a total inflammatory burden score (TIBS). Deep remission was defined as SCCAI ≤1; FC = 0, and TIBS ≤1.

Results: A total of 95 patients (62% females; median age 45 yr) were included in the study and allocated 4.8 g mesalazine per day. Of these, 82 (86%) patients were adherent to web therapy, completing 3 months of web-guided mesalazine therapy. Of the 82 adherent patients, 72 (88%) continued mesalazine and 10 (12%) needed rescue therapy. From weeks 0 to 12, patients had experienced a significant reduction in mean SCCAI (4.6 versus 1.6, P < 0.001), mean FC (437 versus 195, P < 0.001), and mean TIBS (6.7 versus 2.4, P < 0.001). Based on TIBS values (≤1), the dose of mesalazine was reduced to 2.4 g in 25% of patients at week 3 in 50% of subjects at week 5 and in 88% of patients at week 12.

Conclusions: Web-guided therapy with mesalazine in mild-to-moderate ulcerative colitis helps to individualize the dose and improve adherence to therapy. The study confirms mesalazine efficacy in mild-to-moderate UC, significantly improving TIBS values in majority of the patients.
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http://dx.doi.org/10.1097/MIB.0000000000000199DOI Listing
December 2014

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.

PLoS One 2014 27;9(6):e98815. Epub 2014 Jun 27.

Medical Department, Viborg Regional Hospital, Viborg, Denmark; Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; Organ Centre, Hospital of Southern Jutland Aabenraa, Aabenraa, Denmark; OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark.

Background: The inflammatory bowel diseases (IBD), Crohn's 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) (OR(CD,adj): 0.38, 95% CI: 0.21-0.67, p = 0.03; OR(IBD,adj) 0.43, 95% CI: 0.28-0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (OR(CD,unadj) 0.54, 95% CI: 0.41-0.72, p = 7*10-4; OR(IBD,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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074037PMC
October 2015

Ehealth monitoring in irritable bowel syndrome patients treated with low fermentable oligo-, di-, mono-saccharides and polyols diet.

World J Gastroenterol 2014 Jun;20(21):6680-4

Natalia Pedersen, Johan Burisch, Lisbeth Jensen, Pia Munkholm, Digestive Disease Centre, Medical Section, Herlev University Hospital, Copenhagen 2730, Denmark.

In the present study we report on changes in irritable bowel syndrome-severity scoring system (IBS-SSS) and irritable bowel syndrome-quality of life (IBS-QoL) in 19 IBS patients, aged 18 to 74 years (F/M: 14/5), during 12 wk registering their symptoms on the web-application (www.ibs.constant-care.dk). During a control period of the first 6-wk patients were asked to register their IBS-SSS and IBS-QoL on the web-application weekly without receiving any intervention. Thereafter, low fermentable oligo-, di-, mono-saccharides and polyols (FODMAP) diet (LFD) was introduced for the next 6 wk while continuing the registration. Though a small sample size a significant improvement in disease activity (IBS-SSS) was observed during both the control period, median: 278 (range: 122-377), P = 0.02, and subsequently during the LFD period, median: 151 (range: 29-334), P < 0.01. The IBS-QoL solely changed significantly during the LFD period, median: 67 (37-120), P < 0.01. The significant reduction in disease activity during the control period shows a positive effect of the web-application on IBS symptoms when presented as a "traffic light". However adding the diet reduced IBS-SSS to < 150, inactive to mild symptoms. In the future results from larger scale trials are awaited.
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http://dx.doi.org/10.3748/wjg.v20.i21.6680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047359PMC
June 2014

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

Inflamm Bowel Dis 2014 Jan;20(1):36-46

1Medical Section, Digestive Disease Centre, Medical Section, Herlev University Hospital, Copenhagen, Denmark; 2Division of Gastroenterology and Hepatology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia; 3Nicosia Private Practice, Nicosia, Cyprus; 4IBD Center ISCARE, Charles University, Prague, Czech Republic; 5Gastroenterology Department, Hospital České Budějovice, České Budějovice, Czech Republic; 6Department of Medicine, Amager Hospital, Amager, Denmark; 7Department of Medicine, Herning Central Hospital, Herning, Denmark; 8Medical Department, Viborg Regional Hospital, Viborg, Denmark; 9Medical Department, Hospital of Southern Jutland, Aabenraa, Denmark; 10Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark; 11Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Arhus, Denmark; 12Department of Medical Gastroenterology, Odense University Hospital, Odense, Denmark; 13Division of Endocrinology and Gastroenterology, Tartu University Hospital, Tartu, Estonia; 14Medical Department, The National Hospital of the Faroe Islands, Torshavn, Faroe Islands; 15Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland; 161st Division of Internal Medicine and Hepato-Gastroenterology Unit, University Hospital, Ioannina, Greece; 17Medical Department, Dronning Ingrids Hospital, Nuuk, Greenland; 18Department of Medicine, Csolnoky F. Province Hospital, Veszprem, Hungary; 19Department of Gastroenterology, Adelaide and Meath Hospital, Trinity College of Dublin, Dublin, Ireland; 20Department of Gastroenterology and Hepatology, Soroka Medical Center and Ben Gurion University of the Negev, Beer Sheva, Israel; 21U.O. Gastroenterologia, Azienda Ospedaliera, Università di Padova, Padova, Italy; 22EpiCom Northern Italy Centre based in Crema & Cremona, Padova and Reggio Emilia, Italy; 23UO Medicina 3° e Gastroenterologia, Azie

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.
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http://dx.doi.org/10.1097/01.MIB.0000436277.13917.c4DOI Listing
January 2014

Auditory hallucinations in a deaf patient: a case report.

Case Rep Psychiatry 2013 9;2013:659698. Epub 2013 Jul 9.

Team for Psychotic Disorders, Aalborg Psychiatric Hospital, Aalborg University Hospital, Brandevej 5, 9000 Aalborg, Denmark.

This case report describes the progression of symptoms in a young deaf female. Her initial psychotic symptoms occur at the age of 16, but she did not come into contact with a psychiatric treatment facility before the age of 27, where she felt symptoms were distressing. The case report describes the difficulties in evaluating psychotic symptoms in a deaf patient, as well as the use of specialized scales in combination with the standard psychiatric evaluation. The current evidence, concerning the prevalence of psychotic symptoms, as well as the influence of deafness on the understanding of psychosis, is described.
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http://dx.doi.org/10.1155/2013/659698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722972PMC
August 2013

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

Inflamm Bowel Dis 2012 Dec 29;18(12):2334-41. Epub 2012 Mar 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Background: Crohn's 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.
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http://dx.doi.org/10.1002/ibd.22956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812910PMC
December 2012

Cancer in inflammatory bowel disease 15 years after diagnosis in a population-based European Collaborative follow-up study.

J Crohns Colitis 2011 Oct 18;5(5):430-42. Epub 2011 May 18.

Department of Hepato-Gastroenterology, Medical School of Ioannina, Greece.

Aim Of The Study: To determine the occurrence of intestinal and extraintestinal cancers in the 1993-2009 prospective European Collaborative Inflammatory Bowel Disease (EC-IBD) Study Group cohort.

Patients-methods: A physician per patient form was completed for 681 inflammatory bowel disease patients (445UC/236CD) from 9 centers (7 countries) derived from the original EC-IBD cohort. For the 15-year follow up period, rates of detection of intestinal and extraintestinal cancers were computed.

Results: Patient follow-up time was fifteen years. In total 62/681 patients (9.1%) [41 with ulcerative colitis/21 with Crohn's disease, 36 males/26 females] were diagnosed with sixty-six cancers (four patients with double cancers). Colorectal cancer was diagnosed in 9/681 patients [1.3%] (1 Crohn's disease and 8 ulcerative colitis). The remaining 53 cancers were extraintestinal. There was a higher prevalence of intestinal cancer in the Northern centers compared to Southern centers [p=NS]. Southern centers had more cases of extraintestinal cancer compared to Northern centers [p=NS]. The frequency of all observed types of cancers in Northern and in Southern centers did not differ compared to the expected one in the background population.

Conclusions: In the fifteen-year follow up of the EC-IBD Study Group cohort the prevalence of cancer was 9.1% with most patients having a single neoplasm and an extraintestinal neoplasm. In Northern centers there were more intestinal cancers while in Southern centers there were more extraintestinal cancers compared to Northern centers. In this IBD cohort the frequency of observed cancers was not different from that expected in the background population.
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http://dx.doi.org/10.1016/j.crohns.2011.04.013DOI Listing
October 2011

Alpha-defensin DEFA1A3 gene copy number elevation in Danish Crohn's disease patients.

Dig Dis Sci 2011 Dec 24;56(12):3517-24. Epub 2011 Jun 24.

Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark.

Background And Purpose Of Study: Extensive copy number variation is observed for the DEFA1A3 gene encoding alpha-defensins 1-3. The objective of this study was to determine the involvement of alpha-defensins in colonic tissue from Crohn's disease (CD) patients and the possible genetic association of DEFA1A3 with CD.

Methods: Two-hundred and forty ethnic Danish CD patients were included in the study. Reverse transcriptase PCR assays determined DEFA1A3 expression in colonic tissue from a subset of patients. Immunohistochemical analysis identified alpha-defensin peptides in colonic tissue. Copy number of DEFA1A3 and individual alleles, DEFA1 and DEFA3, were compared with those for controls, by use of combined real-time quantitative PCR and pyrosequencing, and correlated with disease location.

Results: Inflammatory-dependent mRNA expression of DEFA1A3 (P < 0.001), and the presence of alpha-defensin peptides, were observed in colonic tissue samples. Higher DEFA1A3 gene copy number (CD: mean copy number, 7.2 vs. controls 6.7; P < 0.001) and individual DEFA1 alleles (CD mean copy number 5.6 vs. controls 5.1; P < 0.01) were associated with CD, with strong association with colonic location (P < 0.001).

Conclusions: Alpha-defensins are involved in the inflammation of CD, with local mRNA and peptide expression. In combination with the findings that a high DEFA1A3 copy number is significantly linked to CD, these results suggest that a high DEFA1A3 copy number might be important in hindering the normal inflammatory response in CD, particularly colonic CD.
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http://dx.doi.org/10.1007/s10620-011-1794-8DOI Listing
December 2011

Construction and validation of a web-based epidemiological database for inflammatory bowel diseases in Europe An EpiCom study.

J Crohns Colitis 2011 Aug 2;5(4):342-9. Epub 2011 Apr 2.

Digestive Disease Centre, Medical Section, Herlev University Hospital, Copenhagen, Denmark.

Background: The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration.

Aim: To construct and validate a web-based inception cohort database available in both English and Russian language.

Method: The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments.

Results: The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database.

Conclusion: A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu.
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http://dx.doi.org/10.1016/j.crohns.2011.02.016DOI Listing
August 2011

The clinical implication of drug dependency in children and adults with inflammatory bowel disease: a review.

J Crohns Colitis 2011 Apr 23;5(2):81-90. Epub 2011 Feb 23.

Clinical and Research Centre for Inflammatory Bowel Disease, ISCARE a.s., Charles University in Prague, Czech Republic.

Drug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review. Dependent patients maintain remission while on the treatment, but they relapse shortly after drug cessation or dose decrease. However, a quick restoration of remission and sustained response is achieved when the therapy is re-introduced or dose increased. Population-based studies have demonstrated that 22-36% of adults and 14-50% of children become corticosteroid dependent. Approximately 1/4-1/3 of treated patients undergo surgery ≤1 year after treatment start, although newer paediatric studies reported lower risk of surgery (5-11%), including dependent patients. The frequent use of immunosuppressants (68-80% of children) might explain this favourable outcome and thus reduce importance of the term corticosteroid dependency. Infliximab dependency was described in 42-66% of children and 29% of adults with Crohn's disease. The risk of surgery 50 and 40 months after treatment start was 10% and 23% in infliximab dependent children and adults, respectively. Maintenance of infliximab in dependent patients was suggested to postpone if not avoid the need of surgery. Lastly, mesalazine dependency was identified in 23% of adults with Crohn's disease. These patients were characterized by mild disease course and lower surgical risk compared to non-responders to mesalazine (32 vs. 61%). Identification of drug dependency is useful for prediction of a certain disease course and surgery. An adjustment of medical therapy may alter the prognosis and disease course.
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http://dx.doi.org/10.1016/j.crohns.2010.12.006DOI Listing
April 2011

5-aminosalicylic acid dependency in Crohn's disease: a Danish Crohn Colitis Database study.

J Crohns Colitis 2010 Nov 2;4(5):575-81. Epub 2010 Aug 2.

Clinical and Research Center for Inflammatory Bowel Disease, ISCARE a.s. and Charles University in Prague, Czech Republic.

Background And Aims: The role of 5-aminosalicylic acid (5-ASA) in Crohn's disease is unclear. The outcome of the first course of 5-ASA monotherapy with emphasis on 5-ASA dependency was retrospectively assessed in consecutive cohort of 537 Crohn's disease patients diagnosed 1953-2007.

Methods: Following outcome definitions were used: Immediate outcome (30 days after 5-ASA start) defined as complete/partial response (total regression/improvement of symptoms) and no response (no regression of symptoms with a need of corticosteroids, immunomodulator or surgery). Long-term outcome defined as prolonged response (still in complete/partial response 1 year after induction of response); 5-ASA dependency (relapse on stable/reduced dose of 5-ASA requiring dose escalation to regain response or relapse ≤1 year after 5-ASA cessation regaining response after 5-ASA re-introduction).

Results: One hundred sixty-five (31%) patients had monotherapy with 5-ASA. In 50% 5-ASA monotherapy was initiated ≤1 year after diagnosis (range 0-49 years). Complete/partial response was obtained in 75% and no response in 25% of patients. Thirty-six percent had prolonged response, 23% developed 5-ASA dependency and 38% were non-responders in long-term outcome. Female gender had higher probability to develop prolonged response or 5-ASA dependency (OR 2.89, 95%CI: 1.08-7.75, p=0.04). The median duration (range) of 5-ASA monotherapy was 34 months (1-304) in prolonged responders, 63 (6-336) in 5-ASA dependent and 2 (0-10) in non-responders.

Conclusions: A selected phenotype of Crohn's disease patients may profit from 5-ASA. Fifty-nine percent of patients obtained long-term benefit with 23% becoming 5-ASA dependent. Prospective studies are warranted to assess the role of 5-ASA in Crohn's disease.
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http://dx.doi.org/10.1016/j.crohns.2010.06.002DOI Listing
November 2010