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Y-ECCO Literature Review: Incidence and Phenotype of Inflammatory Bowel Disease Based on Results From the Asia-Pacific Crohn’s and Colitis Epidemiology StudyECCO News Issue 3/2013
Year: 2013
Authors: Valérie Pittet

Introduction: High geographical variability of IBD has been observed [1, 2]. In developed countries, incidence of IBD has markedly increased over 50 years suggesting an influence of environmental factors associated with industrialization and urbanization of societies [3, 4]. In developing countries, trends of incidence of IBD are lacking. It seems however that IBD is going to emerge in countries of previously low or rare disease prevalence. This has been observed also in Asia, as regards to previous hospital-based studies showing an increased number of treated patients. It becomes therefore important to perform further epidemiological studies in countries were diseases are emerging for different reasons. The emergence of IBD in developing countries or regions where IBD prevalence was low or inexistent suggests that the development of IBD may be influenced by changing environmental risk factors. Collecting prospective information on environmental and “modern” lifestyle exposure factors over time in developing countries undergoing rapid socioeconomic changes and westernization would thus provide a unique opportunity to study the role of such risk factors on the etiology of IBD. The conjunction of potential increase of IBD in developing countries with wide background population also calls for anticipation in terms of planning and organization of healthcare resources.

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Y-ECCO Literature Review: Natural history of elderly-onset inflammatory bowel disease: a population-based cohort studyECCO News Issue 2/2013
Year: 2013
Authors: Beatrijs Strubbe

Introduction: The incidence of inflammatory bowel disease (IBD) is increasing worldwide. As the worldwide population is ageing, the proportion of elderly onset IBD patients is also on the rise [1, 2]. The management of IBD in this population is complex because of problems with co-morbidities, polypharmacy, impaired mobility and cognition etc. The risk/benefit ratio of medical and surgical therapies should always be taken into account, especially in this fragile population [3, 4]. A better knowledge of the natural history and the further course of the disease at a population-based level could help in making therapeutic decisions, and in improving the quality of care to these patients.

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Y-ECCO Literature Review: Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II studyECCO News Issue 2/2013
Year: 2013
Authors: Loris R. Lopetuso

Introduction: Corticosteroids are effective for inducing rapid remission in active Ulcerative colitis (UC), but due to their adverse effects they are usually reserved for patients who have failed mesalazine, patients who need a prompt response or those with severe disease [1, 2].
Oral budesonide is a topically acting corticosteroid with low bioavailability and few systemic side effects [3, 4] and this local activity in the colonic mucosa is the key to their efficacy. However, current oral pH-modified release formulations of budesonide are able to act only in the distal ileum and proximal colon and so are not optimally designed for anatomical distribution of UC [5]. In fact, a recent study assessed that oral budesonide was significantly less effective than mesalazine for inducing clinical remission in active UC (risk ratio 0.72; 95% CI 0.57 to 0.91) [6]. This lower effect may also be due to the altered intestinal pH of UC patients.
On the other side, the colonic release Multi-Matrix system (MMX) has already been used successfully with oral mesalazine (mesalazine MMX) [7-9]. This technology provides targeted drug delivery to the entire colon, as supported by scintigraphic data [10]. Based on this, the current study assessed whether the use of this technology coupled with budesonide can help to improve the efficacy of corticosteroids while minimizing systemic side effects in UC patients.

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Y-ECCO Literature Review: Risk of Colorectal High-Grade Dysplasia and Cancer in a Prospective Observational Cohort of Patients With Inflammatory Bowel Disease.ECCO News Issue 3/2013
Year: 2013
Authors: Erik Mooiweer

Introduction: Patients with longstanding ulcerative colitis (UC) and Crohn’s colitis (CD) are at increased risk of developing colorectal cancer (CRC). (1) It is commonly accepted that CRC develops along the inflammation dysplasia carcinoma sequence which is reflected by the fact that extent, severity and duration of colitis are the main risk factors for developing CRC.
Although numerous studies have investigated the risk of CRC in IBD patients, their results show large heterogeneity and therefore there is still debate on whether and to what extent the risk of CRC is increased in patients with IBD. (2) An interesting observation from recently published cohorts is that the CRC risk seems to be declining. (3) A popular hypothesis for this decline in CRC risk is that this is due chemopreventive effects of mesalamine and immunosuppressive agents, although there is no strong evidence to support this. (4, 5)

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Y-ECCO Literature Review: Subcutaneus Golimumab Maintains Clinical Response in Patients with Moderate-To-Severe Ulcerative ColitisECCO News Issue 4/2013
Year: 2013
Authors: Valentina Petito

Introduction: Ulcerative colitis (UC) is one of the main type of inflammatory bowel disease (IBD), characterized by chronic colonic mucosa damage associated to an abnormal immune response against food or bacterial antigens in genetically predisposed individuals[1, 2]. In injured intestinal mucosa chronic inflammation is sustained by activation of mast cells/macrophages, neutrophils, and dendritic cells, followed by the activation of leukocytes, T cells and especially Th2 cells, in course of UC[3]. Among the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) is mainly produced by activated immune cells. It induces several immune reactions, such as an increase of intestinal permeability, endothelium expression of adhesion molecules to recruit immune cells, and matrix metalloproteinase cleavage[4]. Anti-TNF-a are engineered molecules produced using living “biological systems” and not just synthesized in vitro.
New anti-TNF-a agents, like Golimumab, will therefore exert similar but not identical biological functions. Golimumab is a fully humanized IgG1κ monoclonal antibody direct against human TNF-α[5], with potentially low risk of allergic reaction for humans, already approved by Food and Drug Administration (FDA) in April 2009 for the treatment of moderately to severely active RA (in combination with methotrexate), for active psoriatic arthritis and active ankylosing spondylitis[6].

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Y-ECCO Literature Review: The Bacterial Sensor Triggering Receptor Expressed on Myeloid Cells-2 Regulates the Mucosal Inflammatory Response.ECCO News Issue 1/2013
Year: 2013
Authors: Gwenny Fuhler

Introduction: Although a role for the innate immune system in inflammatory bowel disease (IBD) is actively speculated upon, the exact mechanisms remain elusive. Genome wide association studies have identified single nucleotide polymorphisms in several genes involved in innate immunity, which confer risk of developing IBD. Arguably the best known example is the bacterial sensor protein NOD2. Defective bacterial handling by the innate immune system has thus been proposed as one of the contributing factors in IBD pathology[1]. On the other hand, it has also been suggested that activation of Toll-like receptors (TLRs) and NOD-like receptors (NLRs) by pathogen associated molecules triggers an overexaggerated response in IBD, leading to acute and chronic inflammation[2;3]. Recently, a new family of bacterial peptide receptor proteins has been identified: the Triggering Receptor Expressed on Myeloid Cells (TREM) family, which in humans consists of at least 6 members[4]. First characterised in 2000, the two most studied members of this family are TREM-1 and TREM-2. These receptors are predominantly expressed on innate immune cells such as granulocytes and dendritic cells (DCs). The main functions of TREM-1 include augmentation of TLR responses and amplification of inflammatory processes. A role for TREM-1 in IBD has been suggested, as increased numbers of TREM-1+ macrophages have been identified in the mucosa of IBD patients, and TREM-1 signalling in these cells result in IL-6, IL-8 and TNFα production. In contrast, in vitro experimentation so far has suggested a negative regulatory role for TREM-2 in inflammation, although its involvement in IBD remained unknown. Correale et al now provide evidence for a functional role of TREM-2 in IBD.

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Y-ECCO Literature Review: Ustekinumab induction and maintenance therapy in refractory Crohn’s diseaseECCO News Issue 1/2013
Year: 2013
Authors: Hans Peter Gröchenig

Introduction: Up to the year 2012 treatment of Crohn’s disease (CD) remains a clinical challenge. We are faced on the one side with a chronic relapsing disease with rising incidence all over the world, affecting the entire digestive tract and resulting in stenosis and increased risk of operations. On the other side our medical options are limited. Despite guideline adapted therapy consisting of glucocorticoids, immunosupressants (azathioprine, 6-mercaptopurine, methotrexate) and/or anti-TNF blockers (infliximab, adalimumab) a significant proportion of our treated patients are not achieving clinical response or remission. Focusing on anti-TNF blockers, the to date most potent drug class in the treatment of CD, only one-fifth of all initially treated patients are in remission after one year and secondary nonresponse or intolerance affect one-third of all primary responders. Therefore, we are in urgent need for novel medical treatment options, particulary for patients who failed anti-TNF agents.The presence of Interleukin-12 and interleukin-23 seems to play a major role in gut-driven inflammation resulting in proper T-cell differentiation to mediate cellular immunity. Our understanding about a significant linkage between CD and the IL12/23 pathway increased in the last years due to results of genome-wide association studies, describing multiple susceptibility genes linked to IL12/23 signalling (IL12B, JAK2, STAT3, CCR6, IL18R1, IL12RB1 and TYK2). (1)Ustekinumab, which has shown efficiacy in a previous phase 2a study (2), is a fully human IgG1 monoclonal antibody, targeting the interleukin 12/23 shared p40 subunit.

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Y-ECCO Literature Review: Validation of Endoscopic Activity Scores in Patients With Crohn’s Disease Based on a Post Hoc Analysis of Data From SONIC.ECCO News Issue 4/2013
Year: 2013
Authors: Clifford Kiat

Introduction: Efficacious treatment of Crohn’s disease (CD) is associated with a reduction in endoscopic lesions or even complete mucosal healing in the small intestine and the colon (1), and studies have shown that mucosal healing may change the natural course of the disease by decreasing clinical relapse rates, hospitalization rates, and the need for surgery (2,3). However, it is not known to what degree mucosal healing is required to achieve this beneficial clinical effect. Furthermore, no clear cut-off values have been identified that represent the minimal clinically important improvement in endoscopic disease activity and which could be used to define endoscopic response.
The study by Ferrante et al aimed to answer this question by performing a subgroup analysis of patients from the SONIC trial, a landmark study on the use of immunomodulators and biologics in CD (4), by evaluating the minimal improvement in endoscopic disease activity at week 26 that reliably predicted corticosteroid-free clinical remission at week 50. Both Simple Endoscopic Score for CD (SES-CD) and CD Endoscopic Index of Severity (CDEIS) were evaluated to determine the most appropriate cut-off level of endoscopic response.

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Y-ECCO Literaure Review: Maternal inflammatory bowel disease has short and long-term effects on the health of their offspring: A multicenter study in IsraelECCO News Issue 1/2013
Year: 2013
Authors: Marco Gasparetto

Introduction: Inflammatory Bowel Diseases (IBD) are mainly diagnosed during the second and third decades of life. Therefore, female patients may develop active disease before or during time of pregnancy. As yet, large-scale studies have reported negative effects of IBD on pregnancy, including spontaneous abortions, preterm deliveries and small-for-gestational-age babies. No long-term data are available. In a subgroup of female IBD patients, the fear of potential harm of their offspring is leading to voluntarily remaining childless.

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Ulcerative Colitis (UC) Consensus Part 1 - Definitions and diagnosis (2012)JCC, Volume 6, Issue 10, 2012
Year: 2012
Authors: Axel Dignass, Rami Eliakim, Fernando Magro, Christian Maaser, Yehuda Chowers, Karel Geboes, Gerassimos Mantzaris, Walter Reinisch, Jean-Frederic Colombel, Severine Vermeire, Simon Travis, James O. Lindsay, Gert Van Assche

Ulcerative colitis is a lifelong disease arising from an interaction between genetic and environmental factors, observed predominantly in the developed countries of the world. The precise aetiology is unknown and therefore medical therapy to cure the disease is not yet available. Within Europe there is a North–South gradient, but the incidence appears to have increased in Southern and Eastern countries in recent years. Patients may live with a considerable symptom burden despite medical treatment (66% describe interference with work and 73% with leisure activities) in the hope that the aetiology of ulcerative colitis will shortly be revealed and a cure emerge. Although this is conceivable in the next decade, clinicians have to advise patients on the basis of information available today. Despite randomised trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries.

Management of Pediatric Ulcerative Colitis: Joint ECCO and ESPGHAN Evidence-based Consensus GuidelinesJPGN: Volume 55, Issue 3, 2012
Year: 2012
Authors: Turner, Dan; Levine, Arie; Escher, Johanna C.; Griffiths, Anne M.; Russell, Richard K.; Dignass, Axel; Dias, Jorge Amil; Bronsky, Jiri; Braegger, Christian P.; Cucchiara, Salvatore; de Ridder, Lissy; Fagerberg, Ulrika L.; Hussey, Séamus; Hugot, Jean-Pierre; Kolacek, Sanja; Kolho, Kaija Leena; Lionetti, Paolo; Pærregaard, Anders; Potapov, Alexander; Rintala, Risto; Serban, Daniela E.; Staiano, Annamaria; Sweeny, Brian; Veerman, Gigi; Veres, Gabor; Wilson, David C. Ruemmele, Frank M.

The aim of this new consensus is to establish standards for the diagnosis and management of Paediatric UC. It will include the use of immunosuppressors and biologics.

Results of the 2nd scientific workshop of the ECCO (III): Basic mechanisms of intestinal healing JCC: Volume 6, Issue 3, 2012
Year: 2012
Authors: Florian Rieder, Thomas Karrasch, Shomron Ben-Horin, Anja Schirbel, Robert Ehehalt, Jan Wehkamp, Colin de Haar, Dominique Velin, Giovanni Latella, Franco Scaldaferri, Gerhard Rogler, Peter Higgins, Miquel Sans

The second scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal healing for the disease course of inflammatory bowel disease (IBD). The objective was to better understand basic mechanisms, markers for disease prediction, detection and monitoring of intestinal healing, impact of intestinal healing on the disease course of IBD as well as therapeutic strategies. The results of this workshop are presented in four separate manuscripts. This section describes basic mechanisms of intestinal healing, identifies open questions in the field and provides a framework for future studies.

Results of the 2nd scientific workshop of the ECCO (IV): Therapeutic strategies to enhance intestinal healing in inflammatory bowel diseaseJCC: Volume 6, Issue 4, 2012
Year: 2012
Authors: Alessandro Armuzzi, Gert Van Assche, Walter Reinisch, Guillaume Pineton de Chambrun, Anne Griffiths, Malgorzata Sladek, Jan C. Preiss, Milan Lukas, Geert D'Haens

Evidence supporting the importance of assessment of mucosal healing in inflammatory bowel disease has increased in the last years. Mucosal healing has been integrated in the assessment of treatment efficacy in ulcerative colitis, but in Crohn's disease this thought has arised after biological agents have been evaluated in clinical trials. Although a validated definition of mucosal healing still does not exist, its use is also assuming an increasingly important role in the follow-up of individual patients in clinical practice. Corticosteroids induce mucosal healing in a small proportion of patients with Crohn's disease and are of no benefit to maintain it. By contrast, mucosal healing in Crohn's disease can be achieved and maintained, with varying degrees of evidence and success, with thiopurines and biological agents. In ulcerative colitis, the ability of corticosteroids to induce mucosal healing is well recognized. 5-aminosalicylates, thiopurines and biological agents are also able to induce mucosal healing and, additionally, to maintain it. Mucosal healing assessment should be considered in clinical practice when symptoms persist despite therapy or when treatment discontinuation is being considered. Conversely, in patients whose clinical remission is not associated with mucosal healing, intensification of treatment is not currently recommended because of lack of evidence.

Ulcerative Colitis (UC) Consensus Part 2 - Current management (2012)JCC, Volume 6, Issue 10, 2012
Year: 2012
Authors: Axel Dignass, Rami Eliakim, Fernando Magro, Christian Maaser, Yehuda Chowers, Karel Geboes, Gerassimos Mantzaris, Walter Reinisch, Jean-Frederic Colombel, Severine Vermeire, Simon Travis, James O. Lindsay, Gert Van Assche

Ulcerative colitis is a lifelong disease arising from an interaction between genetic and environmental factors, observed predominantly in the developed countries of the world. The precise aetiology is unknown and therefore medical therapy to cure the disease is not yet available. Within Europe there is a North–South gradient, but the incidence appears to have increased in Southern and Eastern countries in recent years.1,2 Patients may live with a considerable symptom burden despite medical treatment (66% describe interference with work and 73% with leisure activities3) in the hope that the aetiology of ulcerative colitis will shortly be revealed and a cure emerge. Although this is conceivable in the next decade, clinicians have to advise patients on the basis of information available today. Despite randomised trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries.

Y-ECCO Literature Review: Abnormal activation of Autophagy-induced crinophagy in Paneth cells from patients with Crohn’s diseaseECCO News Issue 4/2012
Year: 2012
Authors: J. Jasper Deuring

Introduction: Intestinal epithelial cells (IEC) have the difficult task to protect the host from potentially harmful luminal content and promoting the uptake of water and nutrients. Specialised IEC such as, Paneth cells, are protective cells located at the small intestine in the crypt base. These cells produce anti-microbial substances such as defensins and lysozyme, but also produce growth factors that are indispensable for the intestinal stem cell niche. Highly secretory cells, such as Paneth cells need to be able to cope with high endoplasmic reticulum (ER)-dependent protein production causing chronic ER stress. As such, micro and macro engulfment of intracellular compartments (e.g. autophagy) is part of the ER stress response to protect cells from noxious ER stress levels.
Defects in Paneth cell function, including impeded defensin production and secretion, have been reported in Crohn’s Disease (CD) patients. The mechanisms behind this phenomenon are still largely unknown. However, a recent short report by Thachil et al. in Gastroenterology from January 2012 elegantly shows that this impeded Paneth cell function in CD patients may be due to increased autophagy-related engulfment of the secretory granules, known as crinophagy. This finding further strengthens in the importance of IEC, in particular the Paneth cells, in a normal gut homeostasis.

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Y-ECCO Literature Review: Local barrier dysfunction identified by confocal laser endomicroscopy predicts relapse in inflammatory bowel diseaseECCO News Issue 1/2012
Year: 2012
Authors: Pascal Juillerat

Introduction: Increased intestinal permeability has been reported in inflammatory bowel disease (IBD) patients and is associated with occurrence of relapses [1]. An intestinal barrier function defect is thought to be one of the mechanisms leading to the pathogenesis of IBD development and subsequent flare. Measurement of small-molecular-weight saccharides1, chromium-EDTA or in vitro techniques (trans-epithelial electrical resistance and 3H-mannitol flux) are the methods currently used to evaluate it, but no in vivo evidence of these defects has so far been available. Whether this suggested tight junction dysfunction has a clinical impact also needs to be demonstrated [2].

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Y-ECCO Literature Review: Loss of Interleukin-10 Signaling and Infantile Inflammatory Bowel Disease – Implications for Diagnosis and TherapyECCO News Issue 3/2012
Year: 2012
Authors: Donata Lissner

Introduction: Although identification of a single cytokine responsible for the pathogenesis of a chronic inflammatory condition seems promising for providing targeted curative treatment, this cannot be achieved for inflammatory bowel disease (IBD) with its complex and heterogeneous etiology. However, for a subgroup of IBD patients – children with very early onset IBD – one such cytokine seems to be Interleukin-10 (IL-10), known for its anti-inflammatory properties. First evidence for a role of IL-10 in IBD emerged yet nearly 20 years ago, when IL-10-/- mice had been shown to develop severe enterocolitis (1), an effect that could be reversed by IL-10 gene therapy (2). In 2009, three mutations in genes encoding for the IL-10 receptor (IL10R1 and IL10R2) were identified in children with early onset IBD (3). As a consequence, peripheral blood mononuclear cells (PBMCs) of affected children produced higher amounts of pro-inflammatory cytokines. As a proof of principle, one patient was successfully treated with allogeneic stem-cell transplantation, and sustained remission could be achieved.

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Y-ECCO Literature Review: Low-dose smoking resumption in ex-smokers with refractory ul-cerative colitisECCO News Issue 4/2012
Year: 2012
Authors: Razvan Zaro

Introduction: Cigarette smoke contains hundreds of potentially toxic (or therapeutic) compounds, many of which have unknown action in the human body [1]. Ulcerative colitis (UC) and Crohn’s disease (CD) show an inverse association with cigarette smoking exposure. Non- or ex-smokers have a higher risk for UC while smokers are more likely to suffer from CD. Anecdotal evidence suggested that smoking resumption may improve the clinical outcome of ex-smokers with refractory UC.Cigarette smoking has a negative impact on most autoimmune disorders, being associated with a high risk of cardiovascular, lung and digestive diseases; notwithstanding of this, cigarette smoking appears to have beneficial effects in UC. Studies showed that carbon monoxide (CO) is one candidate that may concur to this helpful effect [3-4]. Nicotine could also be responsible for most of the immunoregulatory effects of cigarette smoke. Also it is worth mentioning that considering the bimodal distribution of UC [5-6], the second older-age peak (between 50 and 80 years of age) is characterized by higher rates of former smokers [7-9], thus suggesting that smoking suspends the onset of the UC rather than fully protecting it.

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Y-ECCO Literature Review: Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn’s diseaseECCO News Issue 1/2012
Year: 2012
Authors: Dirk P. van Asseldonk

Introduction: A substantial number of patients with acute severe ulcerative colitis are glucocorticoid resistant. Before cyclosporine (CsA) and infliximab (IFX) were introduced as rescue therapies colectomy rates were 46% at 3 months and 64% at 10 years.(1) Both CsA and IFX are effective in reducing colectomy rates to around 36%.(2;3)
It is not clear whether one of these drugs is superior to the other, although a single infusion of IFX seems less effective than CsA induction therapy. (4) On the other hand, preliminary results of a randomized controlled trial comparing CsA (2 week intravenous (IV) infusion followed by a daily oral formulation) with scheduled IV IFX (Week 0, 2, 6 followed by every 8 weeks) show equal clinical response rates and colectomy rates at 1 and 14 weeks.(5) Long-term data, including data on the role of antimetabolite co-treatment are awaited.

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Y-ECCO Literature Review: Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn’s diseaseECCO News Issue 1/2012
Year: 2012
Authors: Peter Bossuyt

Introduction: The CRP response in Crohn’s disease (CD) is stronger than in ulcerative colitis (UC). For current treatment decisions in Crohn’s disease, the level of C-reactive protein (CRP) is a major biochemical guide. However, CRP and endoscopic findings correlate poorly. The mechanism of CRP production is still poorly understood. Recently, adipocytes were identified as a source of CRP aside the liver. Since CD is characterized by mesenteric fat hyperplasia, the authors focused on the role of mesenteric fat in CRP production and the inflammatory process CD.

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