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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].

Inflammatory Bowel Disease is a chronic relapsing-remitting, immune-mediated condition with increasing prevalence globally [1]. Despite novel agents targeting different disease pathways, the likelihood of achieving sustained clinical remission and mucosal healing remains low [2]. One of the potential reasons may be that patients seek help and clinicians treat IBD once the disease is in its clinical phase. A sub-clinical phase of variable length may precede the symptoms that lead to a diagnosis and perhaps contribute to tissue damage which, once established, is difficult to reverse with currently available medical treatments.

In this study, Torres and colleagues set out to test the hypothesis that a pre-clinical phase of IBD may well be present and could be identified by proteomic markers [3].

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: 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: 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: 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.

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.

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: 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.

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.

The management of Ulcerative Colitis (UC) increasingly involves the use of a biologic agent. Placebo-controlled trials have demonstrated the efficacy of both adalimumab, a tumour necrosis factor (TNF) inhibitor, and vedolizumab, an integrin inhibitor. However, variation in study design makes comparison between such trials difficult. This is particularly evident when comparing rates of clinical remission in the placebo groups of different trials. For example, in the ULTRA 2 trial, which established the superiority of adalimumab over placebo in moderate to severe UC, the 52-week clinical remission rate in the placebo group was just 8.5% compared to 15.9% in GEMINI 1, the placebo-controlled trial of vedolizumab [1,2]. In the absence of head-to-head trials between biologics there is a lack of data to inform clinicians of the best choice of agent. VARSITY is the first head-to-head trial to compare the efficacy and safety of vedolizumab and adalimumab in moderate to severely active UC.

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].

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.

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.