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 , especially, those on prolonged treatment regimens . However, long term safety report for adalimumab has shown that overall malignancy rates were comparable to the general population .
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.
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: 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 characterized by the presence of expanded adipose tissue located at the mesenteric attachment around areas of inflamed intestine . 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 . 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 .
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.
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.
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.
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.
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.
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.
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 . 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].
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 . 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].
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  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 . 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  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.
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.