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Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of colorectal cancer (CRC). The association between IBD and CRC is well supported, but reported risk estimates vary widely. Although recent evidence from population-based studies reports a decline in risk, CRC accounts for 10-15% of all deaths in IBD. The potential causes of recent epidemiological trends and the real magnitude of risk of CRC in IBD are subjects of debate. The molecular pathway leading to CRC differs from the classic adenoma-to-CRC sequence. Chronic inflammation contributes to the development of low- and high-grade dysplasia which may further convert into CRC. Patients with a young age at onset, long-standing and extensive colitis with severe inflammatory burden, a family history of sporadic CRC, and concomitant primary sclerosing cholangitis are at greatest risk. The CRC risk in patients with colonic Crohn's disease is similar to that of ulcerative colitis. IBD-associated CRC can frequently be detected at late stages and at a younger age. The long-term prognosis of CRC may be poorer in patients with IBD than in those with sporadic CRC. Regular surveillance colonoscopies may permit earlier detection of CRC, with a corresponding improved prognosis. The interval between surveillance colonoscopies is dependent on each patient's personal risk profile., (© 2014 S. Karger AG, Basel.)

Crohn's disease (CD) is a progressive condition, with most patients developing a penetrating or stricturing phenotype over time. The introduction of anti-tumor necrosis factor (TNF) therapies over the past 10-15 years, which was supported by accumulating evidence both from trials and clinical practice, has led to a significant change in patient management, monitoring, and treatment algorithms. Anti-TNF therapy was demonstrated to be effective for both luminal and fistulizing disease. Regular therapy with both infliximab and adalimumab was shown to increase the likelihood of clinical remission and mucosal healing, as well as to reduce the need for surgery and hospitalization in both clinical trials and clinical practice, especially in patients with pediatric-onset CD, shorter disease duration, and when used in combination with immunosuppressives. This has led to new treatment goals and to the use of early aggressive medical therapy in a selected group of patients with a worse prognosis. Exploratory clinical trials are underway to determine if further optimization of therapies and treatment beyond clinical remission leads to superior disease outcomes. However, more long-term clinical data are needed to assess whether an early, aggressive therapeutic strategy employing anti-TNF, alone or in combination with biologicals, can further improve long-term disease outcomes in both pediatric patients and young adults., (© 2014 S. Karger AG, Basel.)

Background: It has been suggested that matrix metalloproteinases (MMPs) may play a role in the pathogenesis of inflammatory bowel diseases (IBD). However, the impact of serum MMPs and their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] have scarcely been investigated in the same experimental setting in ulcerative colitis (UC) and Crohn's disease (CD) as well as their correlation with IBD activity., Methods: MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 serum antigen levels were determined in 23 patients with UC, 25 patients with CD and 10 healthy control patients by enzyme-linked immunoassay technique. Statistical analysis with one-way ANOVA and Student's t tests was performed. A linear regression analysis or a Spearman's r test was used to assess correlation. Differences were considered significant with p < 0.05., Results: Serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly higher in UC and CD patients compared to controls. MMP-7 was also significantly higher in CD compared with controls. Elevated MMP-9 and TIMP-1 antigen levels showed significant positive correlation with disease activity of IBD. MMP-2 and TIMP-2 levels inversely correlated with CD activity. Significant correlations were found between MMP-9/TIMP-1 and MMP-2/TIMP-2 antigen levels in both UC and CD., Conclusions: We demonstrated that serum antigen concentrations of MMP-9, TIMP-1 and TIMP-2 were significantly increased in patients with UC and CD compared to controls. Our results suggest that MMPs and TIMPs may contribute to the inflammatory and remodeling processes in IBD. Serum MMP-9 and TIMP-1 might be useful as additional biomarkers in the assessment of IBD activity., (Copyright © 2012 S. Karger AG, Basel.)

Nutritional factors, as sources of luminal antigens, have been thought to be important factors in the immunopathogenesis of numerous gastrointestinal diseases. In some diseases, the role of the nutritional component is causal in the susceptible host. Such diseases include celiac disease, a common heritable chronic inflammatory condition of the small intestine induced by dietary wheat, rye and barley, in susceptible individuals. Specific HLA-DQ2 and HLA-DQ8 risk alleles are necessary, but not sufficient, for disease development. The well-defined role of HLA-DQ heterodimers encoded by these alleles is to present cereal peptides to CD4+ T cells, activating an inflammatory immune response in the intestine. Genome-wide association studies have been performed which identified the IL2-IL21 risk locus and other genes with immune functions and key roles in thymic T-cell selection. Another example for this group is Wilson's disease, an autosomal recessive disorder of copper metabolism caused by mutation of the ATP7B gene, resulting in a defect of biliary copper excretion and toxic accumulation in the body, especially in the liver, brain and cornea, resulting in hepatic and/or neurological symptoms. In other diseases, however, the association is less well established. In such endeavor, epidemiological observations may become a valuable part of the overall investigations aimed at identifying dietary factors, which are involved in the initiation and perpetuation of the specific disease. As an example, relationships between nutrition and colorectal cancer have been hypothesized early on (e.g. folate, calcium, vitamin D, red meat). Similarly, intake of certain diet constituents like fat, refined sugar, fruits, vegetables and fiber was reported to be associated with the expression of inflammatory bowel diseases. In addition, in children with active Crohn's disease, enteral nutrition was found to be equally effective as corticosteroids in induction of remission, with mucosal healing induced by downregulation of mucosal pro-inflammatory cytokine profiles in both the ileum and the colon after enteral nutrition. However, the particular effect of the consumption of each type of food remains questionable in most cases, at least in part because of insufficient data and serious methodological limitations (e.g. recall bias, heterogeneity between collected data, lack of correction for covariates, difficulties in double blinding)., (Copyright © 2011 S. Karger AG, Basel.)

Patients with longstanding ulcerative colitis (UC) and Crohn's disease (CD) have an increased risk of colorectal cancer (CRC). CRC accounts for approximately 15% of all deaths in patients with inflammatory bowel disease (IBD). The molecular pathway leading to CRC in IBD appears to differ from the well-known adenoma-to-CRC sequence, given the fact that these cancers appear to arise from either flat dysplastic tissue or dysplasia-associated lesions or masses. The risk of CRC for patients with IBD increases by 0.5-1% yearly, 8-10 years after diagnosis. Patients with a young age at disease onset, more extensive colitis, greater inflammatory burden, concomitant primary sclerosing cholangitis, and a family history of CRC are at greatest risk. Most cancers arise in pancolitis and there is little or no increased risk associated with proctitis while left-sided colitis carries an intermediate cancer risk. The CRC risk in patients with colonic CD is similar to that of UC. Colonic dysplasia is a precursor to CRC in IBD. There is no clear evidence that surveillance colonoscopy prolongs survival in patients with extensive colitis. Newer endoscopic and molecular techniques are being assessed for their effectiveness in augmenting conventional surveillance., (2007 S. Karger AG, Basel)

Background: Tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role in the pathogenesis of inflammatory bowel diseases and bone resorption as well. Limited data exist about the effect of anti-TNF-alpha infliximab on bone metabolism in inflammatory-type Crohn's disease (CD)., Aim: Our aim was to evaluate the effect of infliximab treatment on rapid changes of bone metabolism in fistulizing CD patients., Methods: 27 patients with fistulizing CD were treated with three series of infliximab. Serum osteocalcin (OC) and beta-CrossLaps (bCL) were measured before administration of each infliximab infusion. 54 patients with inactive CD were controls., Results: In treated patients, there were significant differences in bCL concentrations on days 0 and 14 (p < 0.01) and days 0 and 42 (p < 0.05). OC levels increased significantly between day 0 and 42 (p < 0.05). The values of bCL and OC of control groups differed from serum levels in active patients before the treatment, but not on day 42. Bone markers improved significantly in responder patients, but not in non-responders., Conclusion: The beneficial effect of infliximab to the bone metabolism is more expressive in patients whose fistulizing disease improves with this therapy. Our results suggest that TNF-alpha has an important role in the alteration of bone metabolism in fistulizing CD patients., (Copyright 2006 S. Karger AG, Basel.)