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.

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.

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.

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)

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].

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.

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.

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.

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.

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.

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.

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.

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 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.

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.