Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.

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A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases With Time, Based on Systematic Review

https://www.ualberta.ca/~loewen/Medicine/GIM%20Residents%20Core%20Reading/IBD,%20CROHN'S%20AND%20U.C/accent%20i%20trial.pdf

Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

Background Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor α, is an established treatment for Crohn's disease but not ulcerative colitis. Methods Two randomized, double-blind, placebo-controlled studies — the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) — evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. Results In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0...

/pdf/infliximab-for-induction-and-maintenance-therapy-for-4v31zm5xxu.pdf

Infliximab for induction and maintenance therapy for ulcerative colitis.

Mo1010 The Epidemiology of Microscopic Colitis: A Population-Based Update

Tu1367 Effectiveness and Safety of Certolizumab Pegol for Crohn's Disease in a Large Cohort Followed at a Tertiary Care Center

Mo1855 - Certolizumab Trough Levels and Antibodies in Inflammatory Bowel Disease: A Single-Center Experience

Clinical practice guidelines are “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances” (1). Guidelines are proliferating in all aspects of medicine, with the purpose of reducing practice variation so that patients with similar problems receive the same care and the most appropriate care. For medicine in general, it has been estimated that inappropriate treatment rates range from 15 to 30% (2) and that one-fourth of hospital days, one-fourth of procedures, and 40% of medications are unnecessary (3). Such estimates have not gone unnoticed by health care payers, who are eager to trim costs by eliminating unnecessary services, but who determines what services are necessary’? IBD is a prime example of the current shift in medicine from the heuristic approach, in which decisions are based on clinical experience and intuition (4), to evidence-based medicine, in which decisions are based on relevant scientific data (5,6). Controlled therapeutic trials in IBD have been around for more than 40 years, and the results have at times been equivocal, conflicting, or unconvincing because of small sample sizes. In the past 5 years, meta-analyses have brought together the data from many studics for a variety of clinical situations, and these have provided more convincing evidence for the efficacy or lack of efficacy of

William J. Tremaine

Papers

Mo1010 The Epidemiology of Microscopic Colitis: A Population-Based Update

Tu1367 Effectiveness and Safety of Certolizumab Pegol for Crohn's Disease in a Large Cohort Followed at a Tertiary Care Center

Mo1855 - Certolizumab Trough Levels and Antibodies in Inflammatory Bowel Disease: A Single-Center Experience

Issues in the development of practice guidelines for inflammatory bowel disease.

W1240 Adalimumab for Crohn's Disease in Clinical Practice At An Academic Medical Center: the First 118 Patients