The fourth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of intestinal fibrosis in the disease course of inflammatory bowel disease (IBD). The objective was to better understand the pathophysiological mechanisms of intestinal fibrosis, to identify useful markers and imaging modalities of fibrosis in order to assess its presence and progression, and, finally, to point out possible approaches for the prevention and the treatment of fibrosis.

The results of this workshop are presented in three separate manuscripts. This first section describes the most important mechanisms that contribute to the initiation and progression of intestinal fibrosis in IBD including the cellular and molecular mediators, the extracellular matrix molecules and matrix metalloproteinases/tissue inhibitors of metalloproteinases-system, the microbiota products, the role of fat, genetic and epigenetic factors, as well as the currently available experimental models. Furthermore, it identifies unanswered questions in the field of intestinal fibrosis and provides a framework for future research.

The treatment of inflammatory bowel disease (IBD) has been revolutionised over the past decade by the increasing use of immunomodulators. With such immunomodulation, the potential for opportunistic infection is a key safety concern for patients with IBD. Opportunistic infections pose particular problems for the clinician: they are often difficult to recognise and are associated with appreciable morbidity or mortality, because they are potentially serious and hard to treat effectively. This led the European Crohn's and Colitis Organisation (ECCO) to update the previous Consensus meeting on opportunistic infections in IBD.

Background: Recently, two infliximab biosimilar monoclonal antibodies (mAb) have been approved by the European Medical Agency for all immune-mediated inflammatory diseases (IMID), including inflammatory bowel disease (IBD). Current knowledge regarding biosimilars among gastroenterologists and in particular among IBD specialists is unknown. Therefore we developed a web survey to evaluate the awareness of biosimilar mAb among IBD specialists and their readiness to use these therapies.

Methods: A 15-question multiple choice anonymous web survey was conducted with the logistic support of ECCO, with questions covering the most relevant aspects on biosimilars. Randomly selected ECCO members were invited by e-mail to participate. A descriptive analysis of responses was performed and analyzed.

Introduction: Ulcerative Colitis (UC) is an idiopathic chronic inflammatory disease of the colon with episodes of relapses between remissions. Conventional pharmacological treatment relies on aminosalicylates and immunomodulators (thiopurines), with or without corticosteroids. However, up to 16% of patients do not respond to optimal treatment with thiopurines [1]. The ACT-1 and ACT-2 have demonstrated efficacy of infliximab (IFX) for both induction and maintenance of remission in corticosteroid and/or thiopurine refractory moderate to severe UC. However, respectively 51% and 42% of patients that received IFX in the ACT-1 and ACT-2 trial also received thiopurines. It remains unclear whether the efficacy of thiopurine and IFX in combination is superior to either alone in the treatment of moderate to severe UC [2].

Introduction: Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) of unknown etiology, but is generally thought to result from the combination of an exaggerated inflammatory response in a genetically susceptible host exposed to an appropriate environmental trigger.[1] Data on the natural history, namely mortality, of CD from population-based studies is, nevertheless, relatively limited. In light of the evidence published so far, the trend is to believe that CD mortality is still higher than that of the background population. An initial meta-analysis (2007), which included 13 papers (including some from referral centers), found that CD patients had a higher mortality than the control population (pooled estimated standardised mortality ratio, SMR = 1.52; 95%CI: 1.32-1.74). However, the authors noticed that the SMR decreased over time, although this decrease was not statistically significant (p = 0.08).[2] In another meta-analysis (2010), including nine population-based studies (eight were European), mortality in CD was increased, with an SMR of 1.39 (95%CI: 1.30-1.49).[3] A further meta-analysis (2012) concluded the same, with an approximate SMR of 1.5 above background population, especially when the patients were diagnosed at a younger age and required multiple or extensive surgical interventions.[4, 5]

Introduction: Crohn’s disease (CD) is a chronic, systemic inflammatory disorder that affects mainly the gastrointestinal tract, with a raising incidence in all ethnic and age groups (1).
The primary aim of its treatment is to achieve a sustained clinical and endoscopic remission in order to delay associated complications (1). Although different biologic therapies have been developed and tested in the last decade, anti-TNF remains the only available registrated biological agent for the treatment of CD in Europe (1).
The infiltration of lymphocytes in the intestinal mucosa has previously been described as an important pathogenic pathway in CD. The adhesion of the alfa4beta7 integrin on lymphocytes to MAdCAM-1 on endothelial cells is followed by the infiltration of these lymphocytes from the circulation into the gastrointestinal tract (GI) (3). Vedolizumab is a humanized monoclonal IgG1 antibody that targets integrin alfa4beta7, thereby inhibiting the adhesion of lymphocytes to MAdCAM-1. Natalizumab, a non-gut selective humanized monoclonal antibody against the cell adhesion molecule α4-integrin had already proven its efficacy in the induction and maintenance of remission in active CD, but is associated with systemic side-effects, including a life-threatening progressive multifocal leukoencephalopathy (PML) (3,4).

Introduction: Promising times lie ahead for physicians who are treating IBD patients and some patients are already as excited as their physicians. This excitement is the result of a new class of biologicals that will become available for the treatment of IBD patients more than fifteen years after the introduction of the TNF antagonists. The latter have proven to be very efficacious in both Crohn’s disease and ulcerative colitis but the long-term benefit is hampered by loss of response in almost half of the patients, the formation of antibodies and the increased risk of infections (1). Hence, an alternative therapeutic option is more than welcomed.
Vedolizumab, a humanized monoclonal antibody directed against α4β7 integrin, is a member of this new class of biologicals which are called the leucocyte trafficking inhibitors. These antibodies inhibit the interaction between leukocytes and the intestinal vasculature, thereby decreasing the influx of inflammatory cells into inflamed gastrointestinal mucosa. This class of drugs is not entirely new as a less gut-selective integrin inhibitor, natalizumab, had already been approved by the U.S. Food and Drug Administration (FDA) for both induction of remission and maintenance of remission for moderate to severe Crohn‘s disease. . However, natalizumab has been linked with progressive multifocal leukoencephalopathy (PML), a lethal complication resulting from the reactivation of the JC virus (2), which hampered its registration in Europe. The GEMINI 1 trial is the first randomized, double-blind, placebo-controlled trial to investigate the use of vedolizumab as induction and maintenance therapy in UC patients. Together with the GEMINI 2 trial (3), these are among the largest clinical studies ever performed in patients with IBD.

Endoscopy plays an essential role in the diagnosis, management, prognosis, and surveillance of inflammatory bowel disease (IBD), but surprisingly there are few available guidelines.1,2 This prompted the ECCO Guidelines Committee (GuiCom) members to promote a Consensus on the appropriate indication and application of different endoscopic modalities in IBD. Since the development of guidelines is an expensive and time-consuming process, this Consensus may help to avoid duplication of effort in the future. It may also identify issues where the evidence is lacking and controlled studies are awaited.

Biologics have become key agents for the management of Crohn’s disease and ulcerative colitis. Biosimilars are biological medicines similar to previously authorized biologics and are already available in some countries. This ECCO Position Statement defines the collective view of European specialist in inflammatory bowel disease (IBD) concerning biosimilars. Biosimilars are not comparable to generic small molecules, since both efficacy and toxicity are difficult to predict due to subtle molecular changes that can have profound effects on clinical efficacy and immunogenicity. Direct evidence of safety and benefit from clinical trials in IBD, post-marketing pharmacoviligance, and unequivocal identification of the product as a biosimilar should be requirements before approval. Switching from an established biologic to a biosimilar to save costs is likely to be as inappropriate and inefecctive as switching between current biologics that act on the same target, except when there is loss of response.

The ECCO-ESGAR Consensus on Imaging techniques for assessment of IBD establishes standards for the use of cross-sectional imaging techniques in IBD. Imaging will include MRI, CT and US but not endoscopy or capsule endoscopy, even though these investigations will be at the background of all discussions.

The histologic examination of endoscopic biopsies or resection specimens remains a key step in the work-up of affected inflammatory bowel disease (IBD) patients and can be used for diagnosis and differential diagnosis, particularly in the differentiation of UC from CD and other non-IBD related colitides. The introduction of new treatment strategies in inflammatory bowel disease (IBD) interfering with the patients' immune system may result in mucosal healing, making the pathologists aware of the impact of treatment upon diagnostic features. The European Crohn's and Colitis Organisation (ECCO) and the European Society of Pathology (ESP) jointly elaborated a consensus to establish standards for histopathology diagnosis in IBD. The consensus endeavors to address: (i) procedures required for a proper diagnosis, (ii) features which can be used for the analysis of endoscopic biopsies, (iii) features which can be used for the analysis of surgical samples, (iv) criteria for diagnosis and differential diagnosis, and (v) special situations including those inherent to therapy. Questions that were addressed include: how many features should be present for a firm diagnosis? What is the role of histology in patient management, including search for dysplasia? Which features if any, can be used for assessment of disease activity? The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas.

The N-ECCO Consensus provides clarity on the different nursing roles in caring for patients with Crohn’s disease and ulcerative colitis within Europe. The intention is to identify the position of IBD nurses and provide a consensus on the ideal standard of nursing care that patients with IBD can expect, irrespective of level of training or title.

Introduction: The aetiopathogenesis of inflammatory bowel disease (IBD) remains poorly understood. However, recent advances through genome wide association studies implicate both the immune response to the intestinal microbiome and disruption of intestinal epithelial barrier function as factors likely to influence disease development (1). In addition to host composition, environmental factors can influence the microbiome or alter epithelial barrier function; hence pre-morbid diet is an obvious candidate for study in understanding factors which may predispose to, or protect from disease (2,3).
Dietary fibre is a plausible area for study given in vitro evidence that fermentable fibre can play a role in maintaining epithelial barrier function (4). However the complexity of diet, which, in addition to composition of both macro and mirconutrients, is also influenced by socioeconomic and health behaviours, makes study difficult. This study aimed to use a large prospective cohort of patients to examine the role of dietary fibre in the development of IBD.

Introduction: The development of perianal fistulas is a common complication of Crohn’s disease (CD), with a reported cumulative incidence of about 25% after a disease duration of 20 years (1,2). Although a range of medical and surgical options are available today, the treatment of perianal fistulas remains challenging. Achieving complete closure of the fistulous tract is a long process and relapses are common.
Antibiotics such as ciprofloxacin and metronidazole are widely used as first-line therapy for perianal fistulas; however, re-exacerbations are common after discontinuation of this treatment (3). Several trials clearly demonstrated the benefit of anti-TNF for the induction and maintenance of remission in perianal fistulizing disease (4,5,6).
West et al. (7) combined infliximab therapy with ciprofloxacin or placebo for 12 weeks and found a non-significant difference in response to the treatment in favour of the combination group.

Introduction:Ulcerative colitis (UC) is a chronic relapsing disease with incomplete understanding of its pathogenesis [1], and, consequently, a currently missing causal therapy which is pressingly needed. In 2006, infliximab, as the first anti-TNF antibody, has extended the therapeutic armamentarium for UC after efficacy was proven in both induction and maintenance therapy [2].
However, due to insufficient long-term response rates in case of maintenance therapy and potentially severe side-effects associated with the use of anti-TNF antibodies, there is still an urgent need for new therapeutic approaches in UC. The ongoing search for new therapeutics beyond anti-TNF based strategies is documented by an abundance of drugs currently being evaluated in a vast number of preclinical and clinical studies3.
Interferon-g-inducible protein-10 (IP-10; CXCL10) is a chemokine which both directly and indirectly participates in inflammatory cell migration (e.g. Th1 and Th17 cells, as well as monocytes) and epithelial cell survival through binding to the G protein-coupled CXCR3 receptor. High IP-10 expression levels were found in colonic biopsies and plasma from patients with active UC as compared to healthy controls. In addition, preclinical in vivo studies demonstrated therapeutic activity of anti-IP10 treatment in several murine models of colitis [4, 5].

Introduction: Crohn`s disease (CD) and ulcerative colitis (UC) are the two main subtypes of inflammatory bowel disease (IBD). Although the etiology of both diseases still remains unsolved, we have seen significant progress concerning new therapies for both diseases within the last years [1,2]. Especially novel therapeutics, such as anti-TNF agents are promising in the therapy of IBD. Unfortunately, only about 2/3 of the patients show initial response to the new therapies. A cross analysis indicates a loss of infliximab response with a mean of 37% with an annual risk for loss of response about 13% per patient-year [3]. Due to this, further and new therapeutic strategies are still needed.
In refractory cases of IBD, hematopoietic stem cell transplantation has successfully been used in a rare number of patients. However, only a limited subgroup of patients seems eligible for this therapy so far due to a quite risky therapy with potential huge side effects [4,5].

Introduction: Acute severe colitis (ASC) is a potentially life-threatening condition with estimated rates of colectomy of up to 40%(1). Patients presenting with ASC should be admitted to the hospital and started on intravenous (iv) corticosteroids(2). However, around 15 to 57% of patients will be refractory to this therapy (3); in those who fail to respond within 3–5 days, or who present with frank deterioration at any earlier point, rescue therapy with either ciclosporin 2 mg/kg or infliximab (IFX) 5 mg/kg is generally considered as an alternative to surgery.
The efficacy of ciclosporin in the treatment of ASC was demonstrated more than 15 years ago. In a small randomised placebo-controlled trial, 9 out of 11 patients treated with 4 mg/kg ciclosporin has a response compared to none of the 9 placebo-treated patients(4). Later on, in a dose-finding trial, ciclosporin doses of 2 mg/kg and 4 mg/kg per day were found to be equivalent (5). IFX was shown to be an effective salvage therapy in patients with steroid-refractory ASC in a pivotal randomised controlled study conducted by Jarnerot et al. In this trial, 67% (14/21) of patients in the placebo-treated group required colectomy by 3 months as compared to 29% (7/24) of those treated with a single dose of infliximab 5 mg/kg (6).
The decision on whether to select ciclosporin or IFX in the setting of steroid-refractory ASC, in the absence of a specific contra-indication to each particular drug, usually depends on centre and physician’s personal experience and patient’s preference. Arguments supporting IFX are its ease of use and better safety profile. Besides that, because patients previously failing azathioprine are more prone to colectomy following initial response to ciclosporin(7), previous thiopurines-failures may be considered better candidates to IFX. In the other hand, arguments favouring ciclosporin are its reported high and rapid response rates, and its short half-life. Ciclosporin clears more rapidly from the circulation than IFX, and therefore some physicians may prefer its use in patients where colectomy is felt to be more imminent, to prevent septic complications.
So far no clear guidance for the choice between both agents was possible due to the lack of comparative trials. In this recently published manuscript, Laharie et al. present the results of the first trial comparing ciclosporin and IFX for ASC.

Introduction: Therapy with immunomodulators has no clear affect on disease progression and rate of surgery in Crohn’s disease (CD), although efficiency has been demonstrated long time ago [1,2]. In children the early treatment with azathioprine resulted in reduced need for prednisolone and lower relapse rates [3,4].
The reason for this lack of affect on disease progression might be a delayed prescription of the drug, therefore the aim of the presented study was to evaluate the concept of early azathioprine therapy in adult patients with Crohn’s disease.

Introduction: The aetiology of Inflammatory Bowel Disease (IBD) is still incompletely understood. Epidemiological observations may be helpful in identifying the true causative factors of this disease. Historically, the prevalence and incidence of IBD have been higher in developed countries, with a decreasing gradient from North to South gradient and, to a lesser degree, from West to East [1]. However, more recent data demonstrate changes in demography as countries become more developed and immigration increases [2]. Several hypotheses have been put forward to explain these changing demographics, but direct experimental evidence is lacking in most cases [2,3]. Racial and ethnic relations in different populations and immigration studies offer interesting data which reflect a complex interplay between genetic, environmental and behavioural factors [1–3]. Diet, alterations in the bowel microflora, smoking habits and the influence of hormonal status and drugs are viewed as contributing factors in the manifestation of the disease [1,3]. However, these factors may differ for Western and Eastern European countries. In fact, some articles report that the Western-Eastern discrepancy can be merely attributed to a difference in life styles [1].
Understanding the discrepancies between data from populations with different genetic backgrounds and environmental factors may reveal fundamental aspects of IBD pathogenesis [3].
Recent studies from Eastern Europe have reported acute increases in the incidence of IBD in some countries, comparable with Western European incidence rates, whereas in other Eastern European centres, IBD incidence has not been investigated [4,5]. It remains unknown whether these changes represent true increases in IBD incidence, rising awareness of the disease or differences in diagnostic practices.

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.