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Y-ECCO Literature Review: Tofacitinib, an oral Janus kinases inhibitor, in active ulcerative colitis.ECCO News Issue 4/2012
Year: 2012
Authors: Gionata Fiorino

Introduction: Ulcerative colitis (UC) is a chronic life long inflammatory disease of the colon, which can affect daily life by impairment of work and leisure activities. Unfortunately, etiology remains unknown and, differently from Crohn’s disease, few therapies have been shown to be effective in inducing and maintaining long-term remission. Steroids and mesalazine are widely used to treat UC flares, but steroids cannot be used in the long term, and they are not able to change the natural history of the disease. Evidence on efficacy and safety of thiopurines is weak. Biological therapies, directed against Tumor Necrosis Factor (TNF)-α, are effective in inducing and maintaining remission, heal the colonic mucosa and reducing the risk of colectomy, but, up to now, only infliximab and, very recently, adalimumab have been approved for active moderate-to-severe UC1-3. A consistent number of subjects does not respond, or is intolerant to anti TNFs, and therefore cannot be treated appropriately without frequent courses of steroids. New effective therapies other than steroids are urgently needed in UC patients, with different mechanism of action than anti TNFs.
Sandborn et al. conducted a phase 2 prospective multicenter international randomized controlled trial4 to investigate efficacy and safety of tofacitinib, a selective oral inhibitor of Janus kinases (JAK), which can block several pro-inflammatory gamma chain-containing cytokines, and therefore interfere with lymphocyte activation, function and proliferation. They enrolled 194 adults with moderately to severely active ulcerative colitis. Subjects were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome of this study was a clinical response at week 8, defined as an absolute decrease from baseline in the Mayo Score with objective reduction of rectal bleeding.

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Y-ECCO Literature Review: Validation of the Capsule Endoscopy Crohn‘s Disease Activity Index (CECDAI or Niv score): a multicenter prospective study.ECCO News Issue 2/2012
Year: 2012
Authors: Bruno Rosa

Introduction: The concept of deep remission in Crohn’s disease (CD) is being increasingly recognized as a cornerstone predictor of clinical behaviour and prognosis.1,2 Indeed, mucosal healing has been shown to be associated with increased rates of clinical remission, fewer hospitalizations, and fewer abdominal surgeries.1 Therefore, video capsule endoscopy (VCE) has become an attractive noninvasive tool to assess small bowel mucosal damage in patients with CD.3 However, none of the available VCE scoring indices, used to diagnose and measure small bowel involvement in CD, had been prospectively validated.

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Y-ECCO Literature Review: Visceral adipocytes: old actors in obesity and new protagonists in Crohn‘s disease? ECCO News Issue 3/2012
Year: 2012
Authors: Klára Frivolt

Introduction: Crohn‘s disease (CD) is characterized by the presence of expanded adipose tissue located at the mesenteric attachment around areas of inflamed intestine [1]. The inflamed adipose tissue marked with macrophage and T cell infiltration, endothelial cell activation and fibrosis, is an active endocrine and immune organ and serves as a source of pro- and anti-inflammatory cytokines. Microscopically mesenteric adipocytes in CD were described to be small with a 4-fold increased number compared to healthy controls [2]. Adipose tissue in obesity (visceral/omental and subcutaneous) also shows inflammation and is not only characterized by increased numbers of adipocytes, but also by adipocyte enlargement [3].

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Y-ECCO: Flt3 ligand expands CD103+ dendritic cells and FoxP3+ T regulatory cells, and attenuates Crohn‘s-like murine ileitisECCO News Issue 1/2012
Year: 2012
Authors: Sander van der Marel

Introduction: Conventional therapeutics cannot prevent complications in Crohn’s disease (CD) and although novel treatment strategies, including TNF-neutralizing antibodies, have greatly increased the therapeutic armamentarium, many patients still have to undergo surgery (1). For this reason, development of new treatments that induce long-term remission is required.

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ECCO-ESPGHAN Consensus for managing Acute Severe Ulcerative Colitis in children (2011)The American Journal of Gastroenterology volume 106, pages 574–588 (2011)
Year: 2011
Authors: Dan Turner MD, PhD, Simon P L Travis FRCP, Anne M Griffiths MD, Frank M Ruemmele MD, PhD, Arie Levine MD, Eric I Benchimol MD, PhD, Marla Dubinsky MD, George Alex MBBS, FRACP, PhD, Robert N Baldassano MD, Jacob C Langer MD, Robert Shamberger MD, Jeffrey S Hyams MD, Salvatore Cucchiara MD, PhD, Athos Bousvaros MD, MPH, Johanna C Escher MD, PhD, James Markowitz MD, David C Wilson MD, Gert van Assche MD, PhD & Richard K Russell PhD

Acute severe ulcerative colitis (ASC) is a potentially life-threatening disease. We aimed to formulate guidelines for managing ASC in children based on systematic review of the literature and robust consensus process. This manuscript is a product of a joint effort of the ECCO (European Crohn's and Colitis Organization), the Pediatric Porto Inflammatory Bowel Disease (IBD) Working group of ESPGHAN (European Society of Pediatric Gastroenterology, Hepatology, and Nutrition) and ESPGHAN.

Results from the 2nd Scientific Workshop of the ECCO (I): Impact of mucosal healing on the course of inflammatory bowel diseaseJCC: Volume 5, Issue 5 2011
Year: 2011
Authors: Laurent Peyrin-Biroulet, Marc Ferrante, Fernando Magro, Simon Campbell, Denis Franchimont, Herma Fidder, Hans Strid, Sandro Ardizzone, Gigi Veereman-Wauters, Jean-Baptiste Chevaux, Mathieu Allez, Silvio Danese, Andreas Sturm

Over the past years, mucosal healing has emerged as a major therapeutic goal in clinical trials in inflammatory bowel diseases. Accumulating evidence indicates that mucosal healing may change the natural course of the disease by decreasing the need for surgery and reducing hospitalization rates in both ulcerative colitis and Crohn's disease. Mucosal healing may also prevent the development of long-term disease complications, such as bowel damage in Crohn's disease and colorectal cancer in ulcerative colitis. Histologic healing may be the ultimate therapeutic goal in ulcerative colitis, whereas its impact on the course of Crohn's disease is unknown. Complete mucosal healing may be required before considering drug withdrawal. Targeting early Crohn's disease is more effective than approaches aimed at healing mucosa in longstanding disease. Several questions remain to be answered: should mucosal healing be systematically used in clinical practice? Should we optimize therapies to achieve mucosal healing? What is the degree of intestinal healing that is required to change the disease course? Large prospective studies addressing these issues are needed.

Results of the 2nd part Scientific Workshop of the ECCO (II): Measures and markers of prediction to achieve, detect, and monitor intestinal healing in Inflammatory Bowel DiseaseJCC: Volume 5, Issue 5, 2011
Year: 2011
Authors: Marco Daperno, Fabiana Castiglione, Lissy de Ridder, Iris Dotan, Martti Färkkilä, Jon Florholmen, Gerald Fraser, Walter Fries, Xavier Hebuterne, Peter Laszlo Lakatos, Julián Panés, Jordi Rimola, Edouard Louis

The healing of the intestine is becoming an important objective in the management of inflammatory bowel diseases. It is associated with improved disease outcome. Therefore the assessment of this healing both in clinical studies and routine practice is a key issue. Endoscopy for the colon and terminal ileum and computerized tomography or magnetic resonance imaging for the small bowel are the most direct ways to evaluate intestinal healing. However, there are many unsolved questions about the definition and the precise assessment of intestinal healing using these endoscopic and imaging techniques. Furthermore, these are relatively invasive and expensive procedures that may be inadequate for regular patients' monitoring. Therefore, biomarkers such as C-reactive protein and fecal calprotectin have been proposed as surrogate markers for intestinal healing. Nevertheless, the sensitivity and specificity of these markers for the prediction of healing may be insufficient for routine practice. New stool, blood or intestinal biomarkers are currently studied and may improve our ability to monitor intestinal healing in the future.

Y-ECCO Literature Review: 3g mesalazine granules are superior to 9mg budesonide for achieving remission in active ulcerative colitis: A double-blind, double-dummy, randomized trial.ECCO News Issue 2/2011
Year: 2011
Authors: Anja Schirbel

Clinical trials with the objective of direct comparison of two or more different therapeutics for the treatment of IBD are rare. Often medication is used without knowing the exact mode of action or one drug is preferred without having evidence for better efficacy. Although budesonide and mesalazine are both often used in the treatment of ulcerative colitis, only three small studies have compared these medications when administered orally. Usually budesonide is administered rectally in distal colitis with very good success, while mesalazine can be delivered orally or rectally.

This paper by Gross et al. provides a direct comparison of orally administered budesonide 9mg once daily (OD) and mesalazine 3g OD in mild-to-moderate ulcerative colitis with the aim of demonstrating non-inferiority of budesonide for inducing clinical remission. 288 patients completed the study. Physician’s Global Assessment and laboratory tests were performed. At baseline and week 8, endoscopy was performed and biopsies were taken to determine endoscopic and histological indices.

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Y-ECCO Literature Review: A population-based study of fatigue and sleep difficulties in inflammatory bowel diseaseECCO News Issue 4/2011
Year: 2011
Authors: Antonina Mikocka-Walus

Introduction: Fatigue has long been linked to inflammatory bowel disease (IBD) and is frequently reported by patients. This symptom has been commonly explained as a consequence of chronic inflammation, anaemia, prevalent sleep problems and psychological co-morbidities such as anxiety and depression.

To date, only a few studies have explored fatigue in IBD and those available have largely involved small samples, in particular hospitalised populations, and have focussed on either active or inactive disease only. As part of their ongoing Manitoba IBD cohort study, Graff et al. conducted the first comprehensive investigation on fatigue in IBD. Their sample of 318 participants was representative of the larger local IBD population, with a mean age of 43 years (SD=14.06), an average disease duration of 6.4 years (SD=2.1), 51% of participants having Crohn’s Disease (CD) and 46% having current active disease.

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Y-ECCO Literature Review: A population-based study of fatigue and sleep difficulties in inflammatory bowel diseaseECCO News Issue 4/2011
Year: 2011
Authors: Gianluca Pellino

Introduction:There is no known cure for Ulcerative Colitis (UC), but several agents are frequently used for control of inflammation. High doses of corticosteroids (CS) are administered in acute flares of UC and achieve a high response rate, but this success has the trade-off of a higher risk of complications after surgery. The anti-tumour necrosis factor (TNF)-α antibody infliximab (IFX) is now used in both induction and maintenance therapy for moderate to severe UC. The number of UC patients undergoing surgery after treatment with IFX is increasing. It has been hypothesized that IFX treatment may increase the risk of postoperative complications in patients with UC. Recent investigations have tried to assess this dilemma, with conflicting conclusions. A study on a 10-year experience from Belgium concluded that use of CS, but not IFX, increases the risk of early postoperative complications [1]. On the other hand, two large series globally comparing 132 patients who received IFX as a treatment before surgery with 692 who did not, found that IFX was associated with a higher rate of complications post surgery [2,3].

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Y-ECCO Literature Review: Alterations in mucin glycosylation are associated with spontaneous colitisECCO News Issue 3/2011
Year: 2011
Authors: Sebastian Zeissig

Mucus covers the intestinal epithelium along the entire gastrointestinal tract and is a central part of the intestinal barrier. Enteric mucus contains goblet cellderived mucins, antimicrobial peptides and immunoglobulins and thus forms both a functional and a physical barrier that prevents the translocation of microbial organisms into the intestinal lamina propria [1]. The composition of mucus varies along the intestinal tract and increases in depth towards the distal colon, where an inner, sterile layer adjacent to the epithelium and an outer non-sterile layer can be distinguished [1, 2]. These structural features are dependent on mucins, a family of oligomerising and non-oligomerising heavily O-glycosylated glycoproteins [1, 2].

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Y-ECCO Literature Review: Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitisECCO News Issue 4/2011
Year: 2011
Authors: Johanne Brooks

Introduction: In terms of the number of investigations into the use of biologics to induce and maintain clinical remission, Ulcerative Colitis (UC) has been a ‘neglected cousin’ to Crohn’s Disease. ACT-1 and ACT-2 [1] assessed the efficacy and safety of infliximab versus conventional treatment in patients with moderately to severely active UC. UC patients in the infliximab arm were more likely to achieve clinical response, remission or mucosal healing at weeks 8, 30 and 54 than those receiving conventional treatment. In addition, maintenance infliximab reduced the risk of colectomy in this UC patient population [2]. Colombel et al. have undertaken a subgroup efficacy analysis of ACT-1 and ACT-2 to evaluate a possible correlation between endoscopy subscores at 8 weeks of treatment with infliximab or placebo and subsequent long-term clinical outcomes at week 54. The outcomes assessed included colectomy rates, commercial infliximab use, symptomatic remission (Mayo Stool Frequency of 0 or 1 and a rectal bleeding subscore of 0), corticosteroid-free symptomatic remission, corticosteroid-free status and sustained mucosal healing. In effect they asked the question: Does the patient’s response at 8 weeks predict what will happen in a year’s time?
ACT-1 and ACT-2 [1] enrolled UC patients with moderately to severely active colitis despite conventional treatment and placed them into one of three arms: placebo, infliximab (5 mg/kg) and infliximab (10 mg/kg). Colombel et al. separated each of these arms into their Mayo endoscopy subscores at week 8.

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Y-ECCO Literature Review: IL-22+ CD4+ T cells are associated with therapeutic Trichuris trichiura infection in an ulcerative colitis patient.ECCO News Issue 2/2011
Year: 2011
Authors: Christine Breynaert

No increased risk of SBA or CRC was demonstrated in this study despite the long follow-up and the large number of patients. Young age at diagnosis, male gender and stricturing disease at diagnosis were identified as possible risk factors. This suggests that young males with CD should be monitored more carefully from the start, independent of disease location. Studies of colitis in mice as well as clinical trials have suggested that helminth infection can prevent and/or treat IBD.

This article by Broadhurst et al. describes the disease course of a 35-year-old patient diagnosed with severe UC in 2003, refractory to medical treatment. In early 2004, he chose to infect himself with T. trichiura eggs, followed by a completely symptom-free period. In 2008, after deterioration of disease, he chose again to infect himself with T. trichiura eggs, followed by a progressive improvement of the symptoms and histopathological findings. During the whole disease course, the cellular and molecular portrait of changes in the intestinal mucosa was followed with special attention to IL-22, which promotes wound healing and proliferation and Th17 cells.

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Y-ECCO Literature Review: Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileumECCO News Issue 1/2011
Year: 2011
Authors: Jan Wehkamp

Reflecting the programme of the 2011 ECCO Congress in Dublin there are different lines of current understanding and research. The classical and probably most established investigation line is the role of the adaptive immune system including the role of Th-1 driven inflammation. The more recent but already very dominant area of interest is the role of the microbiota, which is generally accepted to trigger the inflammation in both Crohn’s Disease and Ulcerative Colitis. Another translational research driven achievement of the past years is the acknowledgment of different clinical phenotypes and disease locations, most importantly the understanding that ileal inflammation is likely due to different factors than inflammation in the colon. The newest and – by some – still controversially discussed field is the understanding of host antimicrobial defense and especially the understanding that – at least – different types of IBD are caused by a barrier problem. In the lines of a barrier problem, different mechanisms including NOD2 mutations, stem cell differentiation WNT signaling defects, Autophagy as well as endosomal stress pinpoint to an important role of the small intestinal crypt – epithelial Paneth cell, especially in case of small intestinal disease involvement.

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Y-ECCO Literature Review: Induction of Colonic Regulatory T Cells by Indigenous Clostridium SpeciesECCO News Issue 1/2011
Year: 2011
Authors: James Lee

For some time it has been recognised that alterations in the gut bacteria are associated with Inflammatory Bowel Disease. However, it is unclear which is the chicken and which is the egg – does this “dysbiosis” arise due to genetic differences in affected individuals or because of the inflammatory conditions present in the intestine, or is it causative and a prerequisite for disease to develop, and if so how?

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Y-ECCO Literature Review: Influence of ileal pouch anal anastomosis on bone loss in ulcerative colitis patientsECCO News Issue 3/20111
Year: 2011
Authors: Alexander Esser

Low bone mineral density (BMD) is both prevalent and frequently unrecognised in patients with inflammatory bowel disease (IBD). With osteoporosis occurring at a rate of 10–14% in the IBD population already at a median age of 33–41 years, low BMD can well be considered an extra intestinal manifestation of IBD. Despite this, and the availability of guidelines from the American Gastroenterological Association and the American College of Gastroenterology, testing rates for osteoporosis have been reported to be low in IBD patients [1, 2].

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Y-ECCO Literature Review: Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitisECCO
Year: 2011
Authors: Colin de Haar

Introduction: The IL-12 family of cytokines plays an important role in the pathogenesis of IBD. It consists of pro-inflammatory cytokines enhancing inflammation by induction of Th1/ Th17 responses, like IL-12 and IL-23, but also of members with an immunosuppressive function, like IL-27 and IL-35.
Interestingly, the IL-12 family consists of heterodimeric cytokines composed of two subunits, some of which are shared amongst family members. IL-27 is composed of EBI3 (Epstein-Barr virus-induced gene 3) and the IL-27p28 subunit, whereas IL-35 is composed of EBI3 and IL-12p35. In contrast to the well-defined function of IL-12 and IL-23 in IBD, the function of IL-27 and IL-35 is still unclear. In particular, functional studies of IL-35 are hampered by the current limitations in our ability to detect it and the fact that knockout of the EBI3 subunit will also affect IL-27 expression and knock-out of the IL-12p35 unit will also affect IL-12 expression.
Wirtz et al. elegantly circumvented this problem by using mice deficient in both EBI3 (lacking both IL-27 and IL-35) and IL-27p28 (lacking only IL-27) to gain insight into the role of IL-35. The differences between the EBI3 and IL-27p28 deficiency were studied in a variety of established mouse colitis models, using state of the art imaging tools, i.e. murine endoscopy and bioluminescence, to assess colonic inflammation in vivo.

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Y-ECCO Literature Review: Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stoppedECCO News 4/2011
Year: 2011
Authors: Monica Cesarini

Introduction:Infliximab (IFX) has dramatically changed the approach to the management of patients with Crohn’s Disease (CD) [1]. IFX induces rapid and profound endoscopic healing, improves quality of life and allows patients to avoid hospitalisation and surgery [2]. The ACCENT I [3] and ACCENT II [4] trials have shown that scheduled maintenance therapy with IFX is superior to episodic therapy in maintaining response and remission both in luminal and in fistulising CD. Nonetheless, approximately 60% of patients cannot reach remission and 25–40% of patients on an IFX maintenance regimen experience a loss of response to the drug [5].
It has been demonstrated that the combination of IFX and azathioprine is more effective than IFX alone in inducing steroid-free remission and mucosal healing of the bowel in luminal CD in patients not treated previously with azathioprine. The Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) also showed that IFX monotherapy is significantly better at inducing steroid-free remission and mucosal healing than azathioprine alone in azathioprine-naive patients [6].
It is important, however, to determine whether IFX therapy can be safely interrupted in patients with CD who have undergone a period of prolonged remission, and the timing of IFX withdrawal in patients who receive combination therapy is one of the most controversial topics in IBD management.

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Y-ECCO Literature Review: Risk of colorectal cancer and small bowel adenocarcinoma in Crohn’s disease: A population-based study from western HungaryECCO News Issue 2/2011
Year: 2011
Authors: Catherine Rennaers

Colorectal cancer (CRC) and small bowel adenocarcinoma (SBA) are severe com-plications of inflammatory bowel dis-eases (IBD) and represent a major concern in the follow-up of these patients. The association between CRC and ulcerative colitis has been well established since the first case was described in 1925, whereas conflicting data about the risk of CRC in Crohn’s disease (CD) have been reported in the literature. A strong association between CD and small bowel cancer has been established without any reduction of this risk in recent decades. The risk of CRC in CD is less clear. An increase in risk of about 2.5-fold has been reported in several studies, including two recent meta-analyses, whereas other studies reported no increased risk of CRC in the CD population. The well-established risk factors for CRC in IBD are disease duration, an early age at diagnosis (usually associated with long disease duration), the disease location (colonic loca-tion and extensive disease), a familial history of CRC, concomitant primary sclerosing cholangitis and male gender. Environmental, dietary and genetic factors can influence the risk of CRC and small bowel adenocarcinoma. Geo-graphic variations have been reported, with an increased risk in North America and the United Kingdom.

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Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: Definitions, frequency and pharmacological aspectsJCC: Volume 4, Issue 4, 2010
Year: 2010
Authors: Matthieu Allez, Konstantinos Karmiris, Edouard Louis, Gert Van Assche, Shomron Ben-Horin, Amir Klein, Janneke Van der Woude, Filip Baert, Rami Eliakim, Konstantinos Katsanos, Jørn Brynskov, Flavio Steinwurz, Silvio Danese, Severine Vermeire, Jean-Luc Teillaud, Marc Lémann, Yehuda Chowers

The first ECCO pathogenesis workshop focused on anti-TNF therapy failures in inflammatory bowel diseases (IBDs). The overall objective was to better understand and explore primary non response and loss of response to anti-TNF agents in IBD. The outcome of this workshop is presented into two parts. This first section addresses definitions, frequency and pharmacological aspects of anti-TNF therapy failure, including pharmacokinetics of anti-TNF monoclonal antibodies and immune and non-immune mediated clearance of anti-TNF mAbs. The second section concerns the biological roles of TNF and TNF antagonists, including mechanisms of action of anti-TNF agents, and discuss hypothesis regarding their failures and phenomenon of paradoxical inflammation, including the potential role of TNF independent inflammatory pathways.