Publications by authors named "Dimitrios K Christodoulou"

85 Publications

Effect of golimumab on health-related quality of life, other patient-reported outcomes and healthcare resource utilization in patients with moderate-to-severe ulcerative colitis: a real-world multicenter, noninterventional, observational study in Greece.

Eur J Gastroenterol Hepatol 2021 May 21. Epub 2021 May 21.

2nd Department of internal Medicine, University General Hospital of Alexandroupoli, Alexandroupoli, W. Thrace Department of Gastroenterology, Medical School and University Hospital of Ioannina, Ioannina, Epirus Department of Gastroenterology, Athens Naval Hospital, Athens Department of Gastroenterology, University General Hospital of Heraklion, Crete Department of Gastroenterology, General Hospital of Nikaia & Piraeus 'Agios Panteleimon' and General Hospital Dytikis Attikis 'Agia Varvara', Nikaia Department of Gastroenterology, 'Venizeleio' General Hospital of Heraklion, Heraklion, Crete Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Peloponnese 2nd Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Ippokration General Hospital, Thessaloniki Gastrointestinal-Liver- Endoscopy Unit, 2nd Department of Internal Medicine, General Hospital of Athens 'Hippocration' Department of Gastroenterology, General Hospital of Athens 'Alexandra' Department of Gastroenterology, Evaggelismos-Polykliniki General Hospital of Athens Merck Sharp & Dohme Pharmaceutical, Industrial and Commercial S.A., Medical Affairs, Athens, Greece.

Background And Aims: This real-world study assessed the impact of golimumab on health-related quality of life (HRQoL) and other patient-reported outcomes (PROs) in patients with ulcerative colitis over 12 months in Greece.

Methods: GO-LIFE was a noninterventional, prospective, multicenter, 12-month study. Patients who had moderately-to-severely active ulcerative colitis were naïve to antitumor necrosis factor (anti-TNFα) therapy and had failed previous conventional therapy. Patients received golimumab as per label. The primary endpoint was patients achieving inflammatory bowel disease questionnaire 32-item (IBDQ-32) remission at 12 months. Secondary endpoints, at 6 and 12 months, included patients achieving IBDQ-32 response; the mean change in the treatment satisfaction questionnaire for medication (TSQM) and the work productivity and activity impairment in ulcerative colitis (WPAI:UC) questionnaires; changes in healthcare utilization; patients achieving clinical response and remission; adherence rates and the percentage of patients who discontinued golimumab.

Results: IBDQ-32 remission was achieved by 76.9% of patients at 12 months. Mean changes in all TSQM and WPAI:UC domain scores at 12 months were statistically significant. Clinical remission was achieved by 49.4 and 50.6% of patients at 6 and 12 months, and clinical response by 59.3 and 56.8%, respectively. All patients but one (80/81) had high adherence (≥80%) to golimumab treatment over 12 months. Ulcerative colitis-related health care resource utilization was reduced during the follow-up period.

Conclusions: In real-world settings, treatment with golimumab resulted in meaningful improvements in HRQoL and other PROs, and in disease activity at 6 and 12 months in patients with moderately-to-severely active ulcerative colitis who were naïve to anti-TNFa therapy.
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http://dx.doi.org/10.1097/MEG.0000000000002182DOI Listing
May 2021

Immuno-oncology: a narrative review of gastrointestinal and hepatic toxicities.

Ann Transl Med 2021 Mar;9(5):423

Medical School, University of Ioannina, Ioannina, Greece.

Vaccines, cytokines, and adoptive cellular therapies (ACT) represent immuno-therapeutic modalities with great development potential, and they are currently approved for the treatment of a limited number of advanced malignancies. The most up-to-date knowledge on the regulation of the anti-cancer immune response has recently led to the development and approval of inhibitors of immune checkpoints, which have produced unprecedented clinical activity in several hard to treat solid malignancies. However, severe adverse events (AEs) represent a limitation to the use of these drugs. Currently approved checkpoint inhibitors block cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand (PD-L1), resulted in increased survival of patients with several solid and hematologic malignancies. The most common treatment AEs associated with these drugs are fatigue, rash, and auto-immune/inflammatory reactions. Many of the immune-related AEs are reversible and the strategies for their management include supportive care either with or without treatment withdrawal; nevertheless, in severe cases, hospitalization and treatment with immune suppressants, and/or immunomodulators may be required. Steroid therapy is a critical component of the treatment algorithm; nevertheless, the associated immunosuppression may compromise the antitumor response. This article provides a comprehensive and narrative review of luminal gastrointestinal and hepatic complications, including recommendations for their investigation and management.
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http://dx.doi.org/10.21037/atm-20-7361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033350PMC
March 2021

New insights into intestinal failure-associated liver disease in adults: A comprehensive review of the literature.

Saudi J Gastroenterol 2021 Jan-Feb;27(1):3-12

Department of Gastroenterology and Hepatology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina, Ioannina, Greece.

Intestinal failure-associated liver disease (IFALD) remains one of the most common and serious complications of parenteral nutrition (PN), causing a wide spectrum of hepatic manifestations from steatosis and mild cholestasis to portal hypertension and end-stage liver failure. The prevalence of IFALD depends on the diagnostic criteria and ranges from 4.3% to 65%. Moreover, many factors are shown to contribute to its development, including nutrient deficiencies, toxicity of PN, infections, and alterations of bile acid metabolism and gut microbiota. Prevention and management of IFALD aim at ameliorating or eliminating the risk factors associated with IFALD. The use of PN formulations with a lower ratio omega-6-to-omega-3 polyunsaturated fatty acids, cycle PN, optimization of enteral stimulation and prevention and early treatment of infections constitute the main therapeutic targets. However, failure of improvement and severe IFALD with end-stage liver failure should be considered as the indications of intestinal transplantation. The aim of this review is to provide an update of the epidemiology, pathophysiology, and diagnosis of IFALD in the adult population as well as to present a clinical approach of the therapeutic strategies of IFALD and present novel therapeutic targets.
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http://dx.doi.org/10.4103/sjg.sjg_551_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083246PMC
May 2021

Lipidomics in non-alcoholic fatty liver disease.

World J Hepatol 2020 Aug;12(8):436-450

Department of Gastroenterology, School of Health Sciences, Faculty of Medicine, University of Ioannina, Ioannina 45110, Greece.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder in Western countries, comprises steatosis to nonalcoholic steatohepatitis (NASH), with the latter having the potential to progress to cirrhosis. The transition from isolated steatosis to NASH is still poorly understood, but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression. Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD. Changes in glycerophospholipid, sphingolipid, and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD, implicating that specific lipid species are involved in oxidative stress, inflammation, and cell death. In this article, we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.
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http://dx.doi.org/10.4254/wjh.v12.i8.436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475773PMC
August 2020

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

Thromboembolic complications and cardiovascular events associated with celiac disease.

Ir J Med Sci 2021 Feb 20;190(1):133-141. Epub 2020 Jul 20.

Department of Gastroenterology and Hepatology, School of Health Sciences, Faculty of Medicine, University Hospital of Ioannina, University of Ioannina, POBox 1186, 45110, Ioannina, Greece.

Celiac disease (CD) is a chronic intestinal immune-mediated disease occurring in genetically susceptible individuals who are exposed to gluten. Although it primarily affects the small intestine, CD has been associated with a wide spectrum of extraintestinal manifestations, including thromboembolism and cardiovascular events. The risk of ischemic stroke, myocardial infarction, and thromboembolism, such as deep vein thrombosis and pulmonary embolism, is higher in patients with CD, while there is accumulating evidence that gluten-free diet in CD patients decreases the risk of these complications. The pathogenetic mechanism of increasing hypercoagulability in CD is multifactorial and involves hyperhomocysteinemia due to malabsorption of vitamins B12, B6, and folic acid; endothelial dysfunction; acceleration of atherosclerosis; chronic inflammation; thrombocytosis; and thrombophilia. Therefore, in cases of thromboembolic complications and cardiovascular disease of obscure etiology, clinicians' awareness of possible celiac disease is warranted.
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http://dx.doi.org/10.1007/s11845-020-02315-2DOI Listing
February 2021

Clostridium Difficile Infection in Patients Impact Suspected Cytomegalovirus Infection in Patients with Inflammatory Bowel Disease.

Mater Sociomed 2020 Mar;32(1):41-45

Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.

Introduction: infection (CDI) has been reported to be a cause of flare-ups in patients with inflammatory bowel disease (IBD). Cytomegalovirus (CMV) infection can cause severe disease and complications in immunocompromised patients in consequence of disease or therapy.

Aim: Our aim was to describe the prevalence and clinical outcomes of CDI with concomitant CMV infection in IBD patients hospitalized for flare-ups in association with the disease itself and medication used.

Methods: We prospectively identified consecutive patients referred for CDI management during 2015-2017. Stool samples were tested for toxin A and/or B and Glutamate Dehydrogenase in patients with clinical symptoms. CDI patients with IBD history were tested for anti-CMV IgG and IgM antibodies by chemiluminescent microparticle immunoassay and underwent histological analysis for CMV on colon biopsies. Data were collected for demographic characteristics, treatment and outcome.

Results: 125 patients with CDI were enrolled. Among these patients, 14 (11.2%) were diagnosed with IBD. The mean patient age of IBD patients was 52.5±15.4 years at diagnosis of CDI, 85.7% had UC, 14.3% CD, while the age of patients was shared. Eleven of the total of 14 patients (78.6%) tested positive for anti-CMV IgG. Of these, 3 patients (21.4%) exhibited high CMV IgG avidity, without detectable anti-CMV IgM and biopsy-proven CMV colitis. Of the 14 IBD patients with CDI, 8 patients (57.1%) were receiving anti-tumor necrosis factor (anti-TNF) therapy (21.4 % infliximab or golimumab, 7.1% vedolizumab or adalimumab) and 43.5% of patients were being treated with systemic corticosteroids. Four UC patients (28.6%) on steroids of the 14 CDI patients underwent a colectomy whereas none of the not on steroids patients underwent colectomy (p=0.25). Among them, 1 patient (7.1%) had recurrent CDI after 5 months from the first episode of CDI.These patients were treated with vancomycin, metronidazole and fidaxomicin. The mean age of patients that had a colectomy 65.5±9.32 (n=4) was higher than the mean age of those 47.30±14.49 (n=10) who improved (U=6. p=0.04).

Conclusions: Immunosuppressive medications and older age are associated with increased risk of CDI and poor outcome. Although, CMV is a rare colonic pathogen in the immunocompetent patient, it should be included and screened when exacerbation of IBD occurs in patients receiving any type of immunosuppressive therapy.
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http://dx.doi.org/10.5455/msm.2020.32.41-45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219720PMC
March 2020

Correction to: Ocular manifestations in celiac disease: an overview.

Int Ophthalmol 2020 Apr;40(4):1055

Department of Gastroenterology and Hepatology, School of Health Sciences, University Hospital of Ioannina, University of Ioannina, 45100, Ioannina, Greece.

In the original publication, first line of methods under the Abstract section was published incorrectly.
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http://dx.doi.org/10.1007/s10792-020-01327-2DOI Listing
April 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

Ocular manifestations in celiac disease: an overview.

Int Ophthalmol 2020 Apr 8;40(4):1049-1054. Epub 2020 Jan 8.

Department of Gastroenterology and Hepatology, School of Health Sciences, University Hospital of Ioannina, University of Ioannina, 45100, Ioannina, Greece.

Purpose: To review and highlight the ocular manifestations associated with celiac disease (CD) and presentation of their pathogenetic mechanisms.

Methods: A thorough review of the literature was performed using PubMed to identify articles about serrated polyposis syndrome. The search was performed using the search string: ("celiac disease" OR "coeliac disease") AND ("ocular manifestations" OR "eye" OR "orbitopathy" OR "uveitis" OR "neuro-ophthalmic manifestations"). Only articles in English were reviewed.

Results: Several ocular symptoms and disorders have been associated with CD and are a result of defective intestinal absorption and immunological mechanisms. These include nyctalopia, dry eye, cataract, thyroid-associated orbitopathy, uveitis, central retinal vein occlusion and neuro-ophthalmic manifestations. In addition, CD-related ocular disease may represent the first manifestation of CD.

Conclusion: CD may hold accountable for the development of ocular diseases of obscure etiology.
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http://dx.doi.org/10.1007/s10792-019-01254-xDOI Listing
April 2020

T300A polymorphism is associated with Crohn's disease in a Northwest Greek cohort, but T130M and G290S polymorphisms are not associated with ulcerative colitis.

Ann Gastroenterol 2020 Jan-Feb;33(1):38-44. Epub 2019 Nov 21.

Faculty of Medicine, School of Health Sciences, University of Ioannina (Epameinondas V. Tsianos), Greece.

Background: Crohn's disease (CD) and ulcerative colitis (UC) are well-described disease entities with unknown etiopathogenesis. Environmental, genetic, gut microbiota, and host immune response correlations have been implicated. The role of susceptibility gene polymorphisms, such as ATG16L1 T300A and ECM1 T130M and G290S, is well-described, although controversial findings have been reported.

Methods: Two hundred five patients with inflammatory bowel disease (108 CD and 97 UC), and 223 healthy blood donors (control group) from the Northwest Greece region were genotyped for rs2241880 (T300A), rs3737240 (T130M) and rs13294 (G290S) single nucleotide polymorphisms. Genotyping was performed using the real-time polymerase chain reaction method.

Results: The frequency of G allele was significantly higher in CD patients compared to the control group (P=0.029; odds ratio [OR] 1.45, 95% confidence interval [CI] 1.04-2.03). Carriers of two G alleles (T300A), compared to those carrying only one, were 1.3 times more susceptible to CD (P=0.022; OR 2.45, 95%CI 1.14-5.27). In CD patients, the presence of the T300A polymorphism indicates a possible protective effect against developing a penetrating (B3) phenotype, while in UC patients, presence of the T300A polymorphism, indicates a possible protective effect against developing joint-involving extraintestinal manifestations.

Conclusion: Our study found a significant association of the T300A polymorphism with CD susceptibility, suggesting that CD occurrence in our population has a strong genetic background, with the T300A G allele having an additive effect.
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http://dx.doi.org/10.20524/aog.2019.0434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928472PMC
November 2019

New insights into irritable bowel syndrome: from pathophysiology to treatment.

Ann Gastroenterol 2019 Nov-Dec;32(6):554-564. Epub 2019 Oct 22.

School of Medicine, European University Cyprus, Nicosia, Cyprus (Alexandros Hadjivasilis, Constantinos Tsioutis, Adamantios Michalinos, Dimitrios Ntourakis, Aris P. Agouridis).

Irritable bowel syndrome (IBS) is the most common reason to visit a gastroenterologist. IBS was believed to be a functional disease, but many possible pathophysiologic mechanisms can now explain the symptoms. IBS patients are classified into subtypes according to their predominant bowel habit, based on the Rome IV criteria. These include diarrhea-predominant and constipation-predominant IBS, as well as the mixed type, a combination of the two. Usually, IBS treatment is based on the predominant symptoms, with many options for each subtype. A new promising treatment option, fecal microbiota transplantation, seems to have beneficial effects on IBS. However, treating the pathophysiological causative agent responsible for the symptoms is an emerging approach. Therefore, before the appropriate therapeutic option is chosen for treating IBS, a clinical evaluation of its pathophysiology should be performed.
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http://dx.doi.org/10.20524/aog.2019.0428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826071PMC
October 2019

Extrahepatic manifestations of hepatitis E virus: An overview.

Clin Mol Hepatol 2020 01 11;26(1):16-23. Epub 2019 Oct 11.

Department of Gastroenterology and Hepatology, University Hospital of Ioannina, School of Health Sciences, University of Ioannina, Ioannina, Greece.

Hepatitis E virus (HEV) is a significant health problem with approximately 20 million individuals infected annually. HEV infection has been associated with a wide spectrum of extrahepatic manifestations, including neurological, hematological and renal disorders. Guillain-Barré syndrome and neuralgic amyotrophy are the most frequent neurological manifestations. In addition, HEV infection has been observed with other neurological diseases, such as encephalitis, myelitis and Bell's palsy. Hematologic manifestations include anemia due to glucose-6-phospate dehydrogonase deficiency, autoimmune hemolytic anemia and severe thrombocytopenia. Membranoproliferative glomerulonephritis and relapse IgA nephropathy with or without coexisting cryoglobulinemia appear to be the most common renal injuries related with HEV infection. Also, HEV infection has been associated with acute pancreatitis and other immune-mediated manifestations, such as arthritis and myocarditis. However, the pathophysiologic mechanisms of HEV-related extrahepatic manifestations are still largely unclear.
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http://dx.doi.org/10.3350/cmh.2019.0082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940480PMC
January 2020

Exertional heat stroke associated with acute liver failure in a young refugee. Implications in the era of social-economic crisis.

J Gastrointestin Liver Dis 2019 09 1;28(3):364. Epub 2019 Sep 1.

Gastroenterology Department, School of Health Sciences, University Hospital of Ioannina, Ioannina, Greece.

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http://dx.doi.org/10.15403/jgld-302DOI Listing
September 2019

Endoscopic ultrasonography in pancreatic diseases: advances in tissue acquisition.

Endosc Int Open 2019 Jul 11;7(7):E922-E930. Epub 2019 Jul 11.

Department of Gastroenterology, School of Health Sciences, University Hospital of Ioannina, Faculty of Medicine, University of Ioannina, Ioannina, Greece.

 Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) improved the diagnostic performance and upgraded the role of endoscopic ultrasonography (EUS) into an interventional modality, able to guide patient management and treatment.This review aimed to highlight the advances, emerging practices, procedural techniques and technological innovations in EUS tissue acquisition in pancreatic diseases.  A thorough review of the literature was performed using PubMed to identify articles that describe techniques, advances, and practices in EUS tissue acquisition in gastrointestinal diseases.  Since the first EUS-FNA procedure, EUS guided-tissue acquisition has been evolving continuously. Development of needles with innovative tip design enabled procurement of larger samples with preserved histological architecture. Moreover, sampling techniques and complementary methods, such as contrast harmonic imaging and EUS-elastography, have been introduced in an effort to improve diagnostic performance and sample adequacy.
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http://dx.doi.org/10.1055/a-0915-9594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624111PMC
July 2019

Comparison of the Uptake of Screening Colonoscopy between Physicians and the General Population in Greece.

Dig Dis 2020 9;38(1):23-30. Epub 2019 Jul 9.

Department of Gastroenterology, Evangelismos General Hospital, Athens, Greece.

Aim: To evaluate the uptake of screening colonoscopy among physicians as compared to the general population.

Methods: Asymptomatic physicians, aged 45-67 years, at average risk for colorectal cancer (CRC), working in the participating National Health System hospitals were asked to complete a questionnaire regarding the uptake of screening colonoscopy. The results were compared to those in a background healthy population, aged 50-75 years, inhabitants of a Greek county, who were offered a free access to a screening colonoscopy program for CRC. High-risk adenomas were those ≥10 mm in diameter or any adenoma, regardless of size, with villous histology or high-grade dysplasia.

Results: Overall, 267 of 782 physicians and 402 of 6,534 nonphysicians underwent a screening colonoscopy (uptake rates 34.2 and 6.2% respectively, p = 0.00001). Screening colonoscopy has yielded 4 adenocarcinomas (1.6%), 14 high-risk adenomas (5.5%), and 61 low-risk adenomas (25.7%) in the physicians' group. Corresponding figures in the nonphysician arm were 4 (1), 26 (6.5), and 107 (26.6%), respectively. The main reason among physicians for nonadherence was indifference/negligence (n = 213).

Conclusion: The proportion of physicians undergoing screening colonoscopy for CRC is significantly higher compared to the general population; however, it does remain suboptimal.
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http://dx.doi.org/10.1159/000501266DOI Listing
March 2020

Has the time been reached for pseudopolyps to be re-enrolled in endoscopic inflammatory bowel disease scores?

World J Gastrointest Endosc 2019 Jun;11(6):424-426

Department of Gastroenterology, University Hospital of Ioannina, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina 45110, Greece.

Patients with inflammatory bowel diseases (IBD) represent heterogeneous groups with different characteristics and different clinical course. A great deal of effort is made to discover proxies for more severe disease needing more intense treatment and early intervention to gain the maximum therapeutic benefit. Endoscopy remains an invaluable method in assessment of patients with IBD. Pseudopolyps are often encountered during endoscopy and, although they are a well described entity, their presence is of unclear importance. In one of our recent studies and in conjunction with one study with a large cohort of patients with IBD and pseudopolyps, patients with pseudopolyps were found to face a higher inflammatory burden in terms of receiving more intense biological treatment. This letter comes as a comment and proposition regarding the concept of re-evaluation of pseudopolyps as a promising marker in IBD scores.
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http://dx.doi.org/10.4253/wjge.v11.i6.424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580305PMC
June 2019

Hepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study.

BMC Gastroenterol 2019 Apr 3;19(1):48. Epub 2019 Apr 3.

Department of Gastroenterology and Hepatology, Medical school and University of Ioannina, Ioannina, Greece.

Background: Hepatobiliary and pancreatic manifestations have been reported in patients with Crohn's disease or ulcerative colitis. Our aim was to describe the prevalence of hepatobiliary and pancreatic manifestations in inflammatory bowel disease and their association with the disease itself and the medications used.

Methods: Data were retrospectively extracted from the clinical records of patients followed up at our tertiary IBD referral Center.

Results: Our study included 602 IBD patients, with liver function tests at regular intervals. The mean follow-up was 5.8 years (Std. Dev.: 6.72). Abdominal imaging examinations were present in 220 patients and revealed findings from the liver, biliary tract and pancreas in 55% of examined patients (120/220). The most frequent findings or manifestations from the liver, biliary tract and pancreas were fatty liver (20%, 44/220), cholelithiasis (14.5%, 32/220) and acute pancreatitis (0.6%, 4/602), respectively. There were 7 patients with primary sclerosing cholangitis. Regarding hepatitis viruses, one-third of the patients had been tested for hepatitis B and C. 5% (12/225) of them had positive hepatitis B surface antigen and 13.4% had past infection with hepatitis B virus (positive anti-HBcore). In addition, most of the patients were not immune against hepatitis B (negative anti-HBs), while 3% of patients were anti-HCV positive and only one patient had active hepatitis C. Furthermore, 24 patients had drug-related side effects from the liver and pancreas. The side effects included 21 cases of hepatotoxicity and 3 cases of acute pancreatitis. Moreover, there were two cases of HBV reactivation and one case of chronic hepatitis C, which were successfully treated.

Conclusion: In our study, approximately one out of four patients had some kind by a hepatobiliary or pancreatic manifestation. Therefore, it is essential to monitor liver function at regular intervals and differential diagnosis should range from benign diseases and various drug related side effects to severe disorders, such as primary sclerosing cholangitis.
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http://dx.doi.org/10.1186/s12876-019-0967-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446300PMC
April 2019

Perioperative Use of Anti-TNFa Biological Agents in Open and Laparoscopic Surgery for Inflammatory Bowel Disease.

Surg Technol Int 2019 May;34:107-114

1st Division of Internal Medicine & Hepato-Gastroenterology Unit University of Ioannina School of Medicine, Ioannina, Greece.

Inflammatory bowel disease (IBD) consists of two disorders: Crohn's disease (CD) and ulcerative colitis (UC). Over the past few decades, a great body of knowledge has accumulated regarding the pathogenesis of IBD, and effective pharmaceutical agents, such as inhibitors of tumor necrosis factor (anti-TNF), have been introduced. Although these agents have dramatically improved the outcome of IBD, up to 70% of patients with CD and 10-30% of those with UC still undergo surgery within 10 years from diagnosis. Because of their young age and high recurrence rates, these patients are appropriate candidates for laparoscopic surgery as an alternative to laparotomy. Recently, considerable attention has been focused on perioperative outcomes of patients who are receiving anti-TNF agents and require surgery. The aim of this narrative review is to discuss the current evidence regarding the impact of perioperative anti-TNF treatment on post-operative complication rates with a special focus on laparoscopic surgery.
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May 2019

Presence of pseudopolyps in ulcerative colitis is associated with a higher risk for treatment escalation.

Ann Gastroenterol 2019 Mar-Apr;32(2):168-173. Epub 2019 Jan 23.

Department of Gastroenterology, University Hospital of Ioannina, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece (Dimitrios S. Politis, Konstantinos H. Katsanos, Epameinondas V. Tsianos, Dimitrios K. Christodoulou).

Background: Pseudopolyps in ulcerative colitis (UC) are considered as indicators of previous episodes of severe inflammation and ulceration of the mucosa. The aim of the study was to investigate the long-term outcomes of patients treated for UC, with or without pseudopolyps.

Methods: This was a retrospective single-center study. Consecutive patients with UC and available endoscopic data from 2000 until 2016 were eligible for the study and were followed until June 2017. Patients with incomplete medical/endoscopic charts or interrupted follow up were excluded from the study. Primary outcomes included time to treatment escalation, treatment escalation to biological agents or surgery, and UC-related hospitalization.

Results: Eighty-three UC patients were included in the study, of whom 25 (30%) had pseudopolyps. The median duration of follow up was 2.8 years (interquartile range: 1.1-4.9). Multiple Cox regression analysis identified the presence of pseudopolyps as the only variable independently associated with treatment escalation (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.2-4.3; P=0.014) and escalation to biological agents or surgery (HR 6.3, 95%CI 1.9-20.7; P=0.002).

Conclusion: This retrospective single-center study provides the first preliminary evidence that patients with UC and pseudopolyps may represent a subpopulation with a higher inflammatory burden and a greater need for treatment escalation, including to biological agents or surgery. Large, prospective multicenter studies are certainly warranted to confirm these findings.
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http://dx.doi.org/10.20524/aog.2019.0357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394261PMC
January 2019

The Developing Story of Predictive Biomarkers in Colorectal Cancer.

J Pers Med 2019 Feb 7;9(1). Epub 2019 Feb 7.

Medical School, University of Ioannina, Stavros Niarchou Avenue, 45110 Ioannina, Greece.

Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the genomics of CRC has recently been achieved thanks to the widespread use of next generation sequencing with potential future therapeutic implications. Microsatellite instability (MSI) has been suggested as a predictive marker for response to anti-programmed-cell-death protein 1 (PD-1) therapy in solid tumors, including CRC. It should be noted that not all cancers with MSI phenotype respond to anti-PD-1 immunotherapy, highlighting the urgent need for even better predictive biomarkers. Mitogen-Activated Protein Kinase () pathway genes , , and represent important molecular targets and could serve as independent prognostic biomarkers in CRC, and identify those who potentially benefit from anti-epidermal growth factor receptor (EGFR) treatment. Emerging evidence has attributed a significant role to inflammatory markers including blood cell ratios in the prognosis and survival of CRC patients; these biomarkers can be easily assessed in routine blood exams and be used to identify high-risk patients or those more likely to benefit from chemotherapy, targeted therapies and potentially immunotherapy. Analysis of cell-free DNA (cfDNA), circulating tumor cells (CTC) and/or micro RNAs (miRNAs) could provide useful information for the early diagnosis of CRC, the identification of minimal residual disease and, the evaluation of the risk of recurrence in early CRC patients. Even the selection of patients suitable for the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Finally, the development of treatment resistance with the emergence of chemo-resistance clones after treatment remains the most important challenge in the clinical practice. In this context it is crucial to identify potential biomarkers and therapeutic targets which could lead to development of new and more effective treatments.
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http://dx.doi.org/10.3390/jpm9010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463186PMC
February 2019

Specific Features of Patients With Inflammatory Bowel Disease and Primary Sclerosing Cholangitis.

J Clin Med Res 2019 Feb 5;11(2):81-88. Epub 2019 Jan 5.

Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Ioannina, Ioannina, Greece.

Primary sclerosing cholangitis (PSC) is a chronic and progressive disease of the biliary tract. PSC is strongly associated with inflammatory bowel disease (IBD), mainly with ulcerative colitis, and most PSC patients have underlying IBD. The pathophysiological interactions between IBD and PSC are unclear, although it seems that the patients with IBD and PSC have a distinct phenotype. IBD with coexisting PSC is more extensive and is characterized by milder activity compared to IBD alone. The coexistence of PSC increases the risk for colorectal cancer in IBD patients and lifelong annual surveillance colonoscopy is recommended. Also, liver transplantation (LT) for PSC may affect the course of IBD. In addition, the management of IBD after LT includes many specific problems. On the other hand, the effect of IBD on the natural history of PSC appears to be milder. However, IBD may increase the risk of postsurgical complications after LT and is a risk factor for recurrent PSC after LT. Overall, the coexistence of IBD with PSC changes the management, natural history and prognosis of both diseases.
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http://dx.doi.org/10.14740/jocmr3680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340671PMC
February 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

A multicentre Study of Nutrition Risk Assessment in Adult Patients with Inflammatory Bowel Disease Attending Outpatient Clinics.

Ann Nutr Metab 2019 28;74(1):18-23. Epub 2018 Nov 28.

Human Nutrition, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom,

Background: Overnutrition and undernutrition can affect patients with inflammatory bowel disease (IBD). Although all IBD outpatients should be screened for nutrition risk, screening is not routinely performed, potentially leading to reduced identification and treatment. This study aimed to estimate the prevalence of nutrition risk in adult IBD outpatients and the proportion of cases who discussed diet and/or nutrition during their routine clinical appointment.

Methods: Adults with IBD attending outpatient clinics at 4 hospitals in Greece and in UK were recruited. Demographic and anthropometric data were collected using face-to-face patient interviews and clinical records. Patients were classified as high (i.e., body mass index [BMI] < 18.5 or 18.5-20 kg/m2 and weight loss > 5%), moderate (i.e., BMI 20-25 kg/m2 and weight loss > 5%) or low risk of undernutrition and high risk of obesity (i.e., BMI 25-30% and weight gain > 5%). The proportion of patients who discussed diet and/or nutrition during their clinical appointment was calculated.

Results: In total, 390 IBD patients participated. Sixteen (4%) patients were underweight, 113 (29%) were overweight and 71 (18%) were obese. Twenty-one (5%) patients were at high risk of undernutrition; of these 4 (19%) were under dietetic care. Of those at high risk of undernutrition, 11 (52%) had discussed diet and/or nutrition during their routine clinical appointment. Fifty-six (14%) patients had gained more than 5% weight since their last recorded/reported weight and 19 (5%) were at high risk of obesity.

Conclusions: Few patients were identified to be at high risk of undernutrition and less than a fifth of these were under dietetic care. Overnutrition is a growing problem in IBD with almost half of adult patients being overweight or obese. Diet and/or nutrition were not routinely discussed in this group of IBD outpatients.
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http://dx.doi.org/10.1159/000495214DOI Listing
March 2020

Malignant peritoneal mesothelioma: clinical aspects, and therapeutic perspectives.

Ann Gastroenterol 2018 Nov-Dec;31(6):659-669. Epub 2018 Sep 14.

Department of Gastroenterology, University Hospital of Ioannina, Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece (Konstantinos H. Katsanos, Dimitrios K. Christodoulou).

Malignant peritoneal mesothelioma (MPM) is a rare disease with a wide clinical spectrum. It arises from the peritoneal lining and commonly presents with diffuse, extensive spread throughout the abdomen and, more rarely, metastatic spread beyond the abdominal cavity. Computed tomography, magnetic resonance imaging and positron-emission tomography are important diagnostic tools used for the preoperative staging of MPM. The definitive diagnosis is based on histopathological analysis, mainly via immunohistochemistry. In this regard, negativity represents a useful diagnostic biomarker for differentiating MPM from ovarian carcinoma. In addition, loss is specific to MPM and allows it to be distinguished from both benign mesothelial lesions and ovarian serous tumors. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has become an increasingly important therapeutic approach, while systemic therapies are still being developed. Histology, Ki-67, completeness of cytoreduction, age, sex, and baseline thrombocytosis are commonly used to optimize patient selection for CRS with HIPEC. Additionally, it is well recognized that, compared to other subtypes, an epithelial morphology is associated with a favorable prognosis, whereas baseline thrombocytosis predicts an aggressive biologicalbehavior. Platelets and other immunologic cytokines have been evaluated as potential novel therapeutic targets. Epigenetic modifiers, including BAP1, SETD2 and DDX3X, are crucial in mesothelial tumorigenesis and provide opportunities for targeted treatment. Overexpression of the closely interacting phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways appears crucial in regulation of the malignant phenotype. The use of targeted therapies with PI3K-mTOR-based inhibitors requires further clinical assessment as a novel approach.
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http://dx.doi.org/10.20524/aog.2018.0305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191875PMC
September 2018

Alcohol and narcotics use in inflammatory bowel disease.

Ann Gastroenterol 2018 Nov-Dec;31(6):649-658. Epub 2018 Aug 1.

Department of Gastroenterology, University of Ioannina, Medical School (George Mantzouranis, Eleftheria Fafliora, Athina Tatsioni, George Glantzounis, Konstantinos H. Katsanos, Dimitrios K. Christodoulou), Greece.

The aim of this study was to evaluate alcohol consumption and narcotics use among patients with inflammatory bowel diseases (IBD). A comprehensive literature search was conducted in Medline using relevant keywords. The references of the retrieved articles were also searched to identify additional articles. Only English-language studies that provided evidence on alcohol consumption and/or narcotics use among non-hospitalized IBD patients were included in the present review. Twelve studies were included that examined the use of alcohol among IBD patients. The prevalence of alcohol consumption among IBD patients appeared to be similar to that of the general population. The majority of the studies reported worsening of IBD symptoms among patients who consumed alcoholic beverages. Four studies were identified that evaluated narcotics use as analgesia among IBD patients. Narcotics use was prevalent among IBD patients and correlated with a longer disease duration and comorbid mental illnesses. The available evidence suggests that alcohol consumption may have a deleterious effect on IBD symptoms. Furthermore, a considerable proportion of IBD patients are reported to use a narcotic as analgesia and this was correlated with their mental health status. Further studies are needed to address these important facets of IBD.
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http://dx.doi.org/10.20524/aog.2018.0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191867PMC
August 2018

Vitamin D and Ulcerative Colitis: Is There a Relationship with Disease Extent?

Dig Dis 2019 1;37(3):208-213. Epub 2018 Nov 1.

Division of Gastroenterology, Mater Dei Hospital, Msida, Malta.

Introduction: Patients with ulcerative colitis (UC) can suffer from low serum vitamin D that can result in complications such as low bone mineral density. It can also reflect underlying disease severity.

Methods: One hundred and ninety-seven patients previously diagnosed with UC from 2 European centers were prospectively recruited through the out-patient clinics. Clinical features (Montreal Classification, age, gender, previous and current medications, surgery), disease activity (Simple Clinical Colitis Activity Index [SCCAI]), blood investigations including serum inflammatory markers, and serum vitamin D were analyzed. The vitamin D levels were compared to a group of age- and gender-matched healthy controls.

Results: Mean vitamin D levels were lower in patients with UC (54.6 nmol/L) than in controls (80.7 nmol/L; p = 0.0001). Mean vitamin D levels was lowest in patients with extensive UC (E3; p = 0.0001). Serum vitamin D was not significantly different across treatment groups (p = 0.876). There was no statistical difference in vitamin D levels across patients receiving calcium and vitamin D supplements (p = 0.35) and there was no statistical correlation with SCCAI (p = 0.22).

Conclusions: This study confirms the existence of low serum vitamin D in patients with UC when compared to healthy controls. It also provides evidence of an existing relationship between disease extent and serum vitamin D.
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http://dx.doi.org/10.1159/000494439DOI Listing
March 2019

Dermal Lesions and Skin Cancer in Patients with Inflammatory Bowel Disease Receiving Immunosuppressive Therapy

Asian Pac J Cancer Prev 2018 Oct 26;19(10):2845-2851. Epub 2018 Oct 26.

Department of Cardiology, University Hospital of Ioannina, Greece. Email:

Background: Anti-TNFa medications represent the first effective biologic therapy for IBD that has largely revolutionized treatment. The aim of this study was to quantify the risk of MM and other skin cancers among patients from Northern Greece area with IBD who take immunosuppressive or biologic anti-TNF medications. Methods: The current study was conducted during a 3-year period (2014-2016). Clinical history and metabolic data of all patients were extracted from the IBD database that is kept since 1980. 101 patients with IBD from Northwestern Greece, were studied. Results: The mean age of enrolled patients was 44.2±15.9 years old ranging from 17 years to 77 years old. No sun burn was reported from the 44.6% of the patients, 53.5% presented mild reticular veins in the face, and lack of any elastosis was noticed in 60.4%. The occurrence of two cases with squamous and basal cell carcinoma is an important finding. The absence of any case with MM should not quiet down but should strengthen our efforts for further implementation of preventive measures. Conclusions: Furthermore, education of patients to avoid deleterious sun exposure may help decrease MM incidence.
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http://dx.doi.org/10.22034/APJCP.2018.19.10.2845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291021PMC
October 2018

Sexual Dysfunction in Patients With Inflammatory Bowel Disease.

Inflamm Bowel Dis 2018 10;24(11):2348-2349

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

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http://dx.doi.org/10.1093/ibd/izy206DOI Listing
October 2018

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