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TL1A, a protein member of the tumor necrosis factor superfamily 15 (TNFSF15), signaling through its receptor DR3, has been defined as a master regulatory cytokine that plays a key role in human intestinal inflammation. Recent studies have also defined a critical role for TL1A in the pathogenesis of mouse experimental autoimmune encephalomyelitis (EAE), models of allergic lung inflammation and human rheumatoid arthritis. The initial discovery of TL1A has given way to subsequent genetic, human, and animal investigation at the bench and will reach the bedside in the form of a clinical trial in 2011–2012. Furthermore, TNFSF15 and TL1A fit superbly into the personalized medicine paradigm, in which the combination of genetic, biologic, and micro-environmental information may well combine to inform the design of a therapeutic for the subgroup of Crohn΄s disease patients that will be uniquely likely to benefit. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD), encompassing Crohn΄s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders caused by dysregulated immune responses to microbial antigens in a genetically predisposed individual. Recent and accumulating research, including genome-wide association studies (GWAS), has identified over 50 distinct genetic loci that confer susceptibility and begin to define critical molecules and pathways that converge in physiologic processes that lead to mucosal inflammation. Among the several recently discovered IBD associated gene variants in tumor necrosis factor superfamily member 15 (TNFSF15) has been shown to be associated with CD in all ethnic and age groups. TL1A is the product of the TNFSF15 gene and signals through death receptor 3 (DR3). Among the evidence indicating an important functional role of TL1A in mediating gut mucosal inflammation is the finding that neutralizing antibodies to TL1A prevented and treated chronic colitis by decreasing Th1 and Th17 responses in two T cell mediated mouse models. In addition, TL1A expression is elevated in lamina propria mononuclear cells (LPMC) from the mucosa of IBD patients and varies in association with different CD genotypes, as defined by ethnic background, haplotype, and serum microbial antibody expression. One of the etiologic theories on the pathogenesis of IBD is that impaired clearance of foreign material leads to a sustained activation of antigen presenting cells and a compensatory induction of an adaptive immune response. Consistent with the important role of TL1A in IBD, microbial organisms and FcνR signaling induce TL1A in myeloid cells leading to enhanced Th1 responses. These and other studies define TL1A as a master regulatory cytokine that plays a key role in human intestinal inflammation. [ABSTRACT FROM AUTHOR]

The integrity of the intestinal mucosa depends on a functional coordination of the epithelium, lumenal microorganisms, and the local immune system. The mammalian immune system is superbly organized for innate and adaptive recognition of microbial antigens, a defensive capacity that must be balanced against the tissue damage produced by immune activity to preserve normal intestinal function. Inflammatory bowel disease (IBD) is generally thought to reflect an impairment in this balance, due to a combination of host genetic traits that shift the balance of immune and epithelial function to commensal microbiota, and perhaps the composition or activity of certain microbial elements as well. There has been much progress defining the fundamental disorders of these host traits, immunologic processes, and microbial targets in inflammatory bowel disease. Other fields of clinical and geologic microbiology are teaching us about the dynamic interaction of commensal bacteria with their host environment. These lines of investigation have revealed not only important insights about inflammatory bowel disease (IBD) pathogenesis, but also defined technologies and tools useful for its diagnosis and clinical management. This review focuses on these advances at the translational interface. We will first consider the innate anti-microbial response, centering on the utility of NOD2 genotyping for predicting disease susceptibility, prognosis, and therapeutic response profile. We will then turn to the adaptive anti-microbial response, focusing on the application of antibodies to fungal and bacterial species and products for Crohn’s disease (CD) diagnosis and prognosis, and immunogenetics of T cell immunosuppression management. Finally, we will describe autoimmune mechanisms in IBD, with particular attention to autoantibodies in IBD diagnosis and infliximab responsiveness. We will conclude with the concept of multiparameter analysis of patients, to refine patient characterization and stratification in diagnosis and clinical management. [ABSTRACT FROM AUTHOR]

CI is the most common cause of mesenteric ischemia, and encompasses a wide clinical spectrum from mild, reversible disease to life-threatening colonic gangrene. While most commonly seen in elderly patients, younger patients are also at risk, especially if an underlying risk factor such as vasculitis, hyper-coagulability, or certain medication use such as oral contraceptives, pseudoephedrine, cocaine, or ergot, is present. Colonoscopic evaluation is critical in the evaluation of patients with CI, although it must be kept in mind that CI may mimic or be mimicked by other entities, such as IBD or carcinoma. Conservative management usually leads to a full clinical recovery, although several subsets of patients may require segmental resection. Clinicians should always consider CI in the differential diagnosis of acute colitis, especially in elderly patients. [ABSTRACT FROM AUTHOR]

Most women with IBD can expect an uneventful pregnancy. Evidence compiled over many years indicates the importance of controlling disease activity at the time of conception and during pregnancy to optimize the outcome for mother and baby. For this reason drug therapy is often required to treat flare-ups and maintain remission during this time. Where possible, women with IBD should plan a pregnancy to coincide with times when the disease is quiescent, and drug treatment minimal. In practice, however, many pregnancies are unexpected or occur in women with active disease that requires intensive medical therapy. Provided adequate information has been supplied in advance of conception, much of the apprehension that accompanies these events can be substantially reduced. Ongoing supervision by the clinician during pregnancy and the puerperium provides invaluable support, and enables maternal disease flare-ups to be identified and treated as expediently as possible. [ABSTRACT FROM AUTHOR]

NSAID injury can mimic IBC, can exacerbate IBD, and NSAID use may also be more common in the diarrheal syndrome of collagenous colitis, though there is no clear role in pathogenesis. [ABSTRACT FROM AUTHOR]

Although the therapy of CD is primarily medical, surgery still plays an important role in its management. The high incidence of postoperative CD recurrence is, however, a major drawback. We provide a clear and practical algorithm which will help the clinician to decide when and what kind of prophylactic treatment is indicated. Strategies to prevent recurrence start with a careful selection of patients to send for surgery, based on the known risk factors of recurrence. Current evidence suggests only a moderate effect of the known active agents in the prevention of postoperative CD recurrence. Only patients at higher risk for recurrence should continue on, or be treated with, immunosuppressives (6-MP or azathioprine) after surgery. All others can be followed clinically, or alternatively should undergo an ileocolonoscopy 3-12 months after surgery. If severe endoscopic recurrence is seen, therapy is indicated to prevent the imminent clinical symptoms, or eventually a new resection. Much is anticipated from newer biological agents potentially interacting with earlier steps in the pathogenesis of recurrent CD. [ABSTRACT FROM AUTHOR]

Surgery plays an important role in the management of CD, and likely will continue to do so until the etiology of CD is elucidated and more specific medical therapies are available. In most instances surgery leads to an improvement in quality of life and allows patients to regain normal physical well-being without experiencing the side-effects and dysutility of taking medication. Thus, the need for surgery should not be considered a failure of management. Instead, there is a role for both medical therapy and surgical therapy. Because of the variable patterns of disease seen in CD, as well as the individual concerns of patients, treatment may have to be individualized. Optimally, care should be given, using a team approach including gastroenterologists, surgeons and paramedical personnel such as nurses, enterostomal therapists, and psychiatrists. Care should also be provided as a continuum. In order, however, to achieve excellent results, patients require careful preoperative evaluation and management, and surgeons must be familiar with the various patterns of disease and the complications that they may encounter. [ABSTRACT FROM AUTHOR]

Pouchitis is an idiopathic inflammatory disease of the ileal reservoir in patients who have undergone IPAA. Approximately half of all UC patients who undergo this procedure will have at least one episode of pouchitis, with approximately 15% experiencing a chronic course. PSC and other EIM increase the likelihood of developing pouchitis while smoking is protective. Similar genetic and autoimmune mechanisms to UC appear to occur in an ileal reservoir that demonstrates increasingly colon-like adaptations with respect to bacterial content and mucosal characteristics. While most patients have a good response to antibiotic therapy, those with chronic disease become a therapeutic challenge with the specter of dysplasia looming in the foreground. [ABSTRACT FROM AUTHOR]

Initial treatment of mild to moderately active UC may be sulfasalazine, oral or rectal mesalamine, balsalazide, corticosteroid enemas, or oral corticosteroids. Patients with persistent mild to moderate symptoms of active UC in spite of these therapies (treatment-refractory) may require AZA/6-MP, and in some cases intravenous corticosteroid or transder-mal nicotine. Patients with severely active UC should be treated with intravenous conventional corticosteroids, and intravenous cyclosporine may be considered in those who do not respond. Remission should be maintained with sulfasalazine, oral or rectal mesalamine, olsalazine, or balsalazide, and in some cases with AZA/6-MP. [ABSTRACT FROM AUTHOR]

Over the past decade preliminary data regarding the pharmacoeconomics of inflammmatory bowel disease have emerged. The synthesis of this information has culminated in the first models which evaluate the marginal cost-utility of competing therapies. Since the validity of these comparisons is critically dependent upon accurate efficacy, natural history, cost and utility inputs investigators must identify areas where important data are lacking. Through this process, more sophisticated and valid models will be developed. Highly effective, yet costly, new treatments for IBD will soon be in widespread use. Because societal resources are limited, health-care providers must make intelligent choices regarding the introduction of new technologies. Consideration of data from cost-utility models is likely to become an important part of the decision-making process. [ABSTRACT FROM AUTHOR]

Colon biopsies are critical in helping to diagnose diarrhea, to distinguish different forms of colitis, to determine the extent of disease, and to determine if neoplasia has arisen in the setting of chronic colitis. Colon biopsies in some instances can be definitive, but this usually requires the appropriate clinical scenario. For instance, to appreciate that segmental granulomatous colitis is CD and not the much rarer colonic sarcoidosis requires ancillary clinical information. Often colon biopsies may definitively reveal an abnormality, but the findings may be non-specific in regard to a definitive diagnosis. Thus, to utilize colon biopsies most appropriately in patient management usually requires frequent clinician-pathologist interaction, often repeat endoscopy with biopsies at a different time, and the assessment of any prior biopsies or resections. Once a patient has a firm diagnosis of CD he/she rarely converts to a disease that is indistinguishable from UC, and typically continue to behave like CD. Conversely, it is not too uncommon for patients with UC to develop features that strongly suggest that CD is the real underlying disease. These patients also tend to behave like those with CD. The ileum should be intubated whenever possible in cases of undiagnosed diarrhea and in cases of colitis to help distinguish if CD might be present. Gastric biopsies may reveal a pattern of focally active gastritis and this may serve as a clue for CD when the diagnosis is unknown or in doubt. [ABSTRACT FROM AUTHOR]

The nature of UC has changed dramatically over the past five decades. Although the presentation of the disease has remained the same, the impact of the introduction of therapies such as corticosteroids and the aminosalicylates has changed the clinical course of the disease. The course of treated UC offers patients and physicians a much more optimistic out-look than that documented in earlier studies. The advances in medical therapy have been complemented by refinement of surgical techniques, which have improved the quality of life and gained patient acceptance. The new millennium will bring further promise to patients and to those of us who care for these patients. [ABSTRACT FROM AUTHOR]