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.

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].

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.

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.

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.

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.

Introduction: The conventional thiopurines, azathioprine (AZA) and mercaptopurine (MP), are the cornerstone of immunosupressive maintenance therapy in inflammatory bowel disease (IBD). Unfortunately, up to half of patients have no benefit from this antimetabolite therapy due to lack of efficacy but mainly because intractable side-effects develop (1). The majority of these thiopurine failing patients is subsequently treated in a step-up regime with methotrexate (in Crohn’s disease) or biologicals. The unfavorable outcome of thiopurine administration can in part be explained by the complex metabolism and its generated metabolites (especially the metabolites 6-thioguaninenucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP)). Thiopurine metabolism can be optimized by co-administration of allopurinol (a xanthine oxidase inhibitor, regularly used in the treatment of gout), leading to a striking decrease in 6-MMP levels and mild increase in 6-TGN levels.
Several small scaled studies have demonstrated earlier that low-dose thiopurine (approximately 25-33% of its original weight-based dosage) in combination with allopurinol (100mg/day) can overcome several side effects (especially those associated with high 6-MMP levels, like transaminitis) that developed during regular thiopurine monotherapy. Moreover combination therapy showed good clinical efficacy (2,3). The study by the Sanderson group provides essential data on safety and success in a large real life cohort of 110 IBD patients using this combination therapy with an average follow-up of 16 months.

Introduction: In this descriptive retrospective single-centre study, Katsanos and colleagues searched the records of all their IBD patients receiving EPO therapy between 1994 and 2009. The list included 26 IBD patients (16 UC, 10 CD) with particular refractory disease in need of immunomodulators (65%), or infliximab (27%). These subjects were receiving EPO therapy because their anemia was not responding to I.V. iron therapy or because of a poor tolerance, or severe adverse reaction, to I.V. iron therapy. The paper summarizes 15 years of experiences of a single centre with EPO therapy.

Introduction: : Inflammatory bowel disease (IBD) is a well known risk factor for thromboembolic events. There is clear evidence in the literature indicating a significant correlation between coagulation and inflammation in Crohn‘s disease and ulcerative colitis, leading to an increased risk for venous thromboembolism (VTE) 1, 2.
The association between VTE and malignancy has also been recognized and is widely accepted for more than a century now. In recent years, there is increasing evidence that thromboembolic complications commonly occur before a cancer is diagnosed, and that primary VTE might be a useful marker of an occult tumor 3.
In contrast to primary VTE, the role of secondary VTE as a suitable tool to predict the onset of cancer is still unknown. It remains controversial whether thromboembolic complications occurring in patients with secondary VTE (i.e. in patients with known risk factors such as IBD) can also be used as a marker of an occult tumor. A better understanding of the correlation between IBD and VTE is required to clarify the usefulness of detecting hidden cancers in patients with IBD.

Introduction: Several studies have shown that patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC)[1-3]. Among IBD patients, greater duration of disease, extent of disease and severity of disease are all associated with higher risks of CRC.
Primary sclerosing cholangitis (PSC) is characterized by bile duct inflammation, fibrosis and stricturing that may lead to cirrhosis, hepatic failure and cholangiocarcinoma. A large proportion of PSC patients, have co-existing ulcerative colitis (UC), with a smaller proportion having Crohn’s disease (CD) with colonic involvement. It is well documented that patient with UC and concomitant PSC have a significant higher risk of developing CRC with an adjusted relative risk from 3.1 to 6.9 [4,5].
However, little is known whether PSC also increases the risk of developing CRC in patients with colonic CD. To address this issue, Braden et al. conducted a retrospective analysis on the occurrence of CRC or colorectal dysplasia in patients with colonic CD with and without PSC (n=149) , in patients with indeterminate colitis and PSC (n=11) and also in patients with UC with and without PSC (n=222).

Introduction: Inflammatory bowel disease (IBD) is characterized by a dysregulated immune system. Immunomodulating therapies (e.g. thiopurines and anti-tumor necrosis factor α (anti-TNF) agents) are widely used in treatment of both Crohn’s disease (CD) and ulcerative colitis (UC). Patients with immune dysfunction and immunosuppressive therapies are at increased risk of developing neoplasia. Thiopurine use, especially long term, has been associated with increased risk of non-melanoma skin cancer (NMSC), including in patients with IBD [1, 2]. Anti-TNF therapy often is used in combination with thiopurines to treat IBD, leading to an even more immunocompromised state. Little is known about the potential of anti-TNF drugs to promote malignancy when used alone or in combination with other immunosuppressants. Whether, anti-TNF agents are associated with NMSC and melanoma is unclear. Some cases of basal cell carcinoma and melanoma have recently been reported in IBD patients treated with biologics [3, 4]. NMSC incidence was raised in patients with CD on adalimumab therapy [5], especially, those on prolonged treatment regimens [2]. However, long term safety report for adalimumab has shown that overall malignancy rates were comparable to the general population [5].

Introduction: Infliximab (IFX) and adalimumab (ADA) are both effective in inducing and maintaining clinical and endoscopic remission in Crohn’s disease (CD) (1). In the ACCENT 1 trial, patients who underwent IFX administration as maintenance therapy were more likely to sustain clinical remission until week 54 (28% and 38% for 5 mg/kg and 10 mg/kg) compared with placebo (14%, p=0.007 and <0.001) (2). In the CHARM trial a greater percentage of patients who received ADA (36% and 41% for administration every other week or weekly) were in clinical remission at week 56 compared with placebo (12%, p< 0.001) (3). Similar results emerged from the CLASSIC II trial, in which 79% (ADA administration every other week) and 83% (ADA administration weekly) of patients were in remission at week 56 compared with 44% of patients receiving placebo (p<0.05) (4). Switch to ADA has been evaluated in patients presenting with loss of response or intolerance to IFX. In this patient population ADA induced remission in 21% of patients compared with 7% in the placebo group (p<0.05), representing a valid alternative in case loss of response or intolerance to IFX occur (5). For practical and economical reasons, switch from intravenous (IFX) to subcutaneous (ADA) administration has entered clinical practice and is being frequently requested by patients, who usually prefer self-administration at home.

Introduction: Diagnosis of IBD is still made by endoscopic assessment and histology. Due to long waiting lists for endoscopy, a procedure considered invasive and uncomfortable, and the rising incidence of IBD in children, a good screening tool is necessary.
Calprotectin is a calcium-binding protein and is found in neutrophil granulocytes. Measured in stool samples, it is a stable marker of mucosal inflammation.
Similar to the development of new drugs, diagnostic test development goes through several phases.1 In phase I of the development of a calprotectin test, researchers showed that patients with IBD have different test results from healthy individuals. In Phase II studies researchers compare fecal calprotectin levels between preselected groups of healthy individuals and of individuals with severe IBD and show that the test can discriminate under ideal circumstances. Phase III studies evaluate whether fecal calprotectin can discriminate in routine pediatric practice. In this type of studies, patients in whom it is clinically reasonable to suspect IBD are consecutively enrolled. All patients are included, regardless of lost results or indeterminate diagnosis. In Phase II studies, the same reference standard is used for patients with and without IBD. Phase III studies more often use different standards for patients with and without the disease.