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.

Left-sided ulcerative colitis: True extent of disease and risk of pouchitis

Crohn's disease is a chronic inflammatory intestinal disorder characterized in most patients by repeated episodes of diminished and exacerbated symptoms. Recent controlled trials demonstrated that oral preparations of 5-aminosalicylic acid decrease recurrence rates by approximately 40% when administered long-term to patients with quiescent Crohn's disease. Orally administered corticoste­ roids, sulfasalazine, metronidazole, azathioprine, and cyclosporine have not proved of benefit in the prevention of recurrences of Crohn's disease. Nonetheless, corticosteroids, metronidazole, and azathioprine can control chronically active disease. Methotrexate may have some benefit in the treatment of active Crohn's disease, but its role in maintenance of remission has not been investigated. Elimination diets seem to prolong periods of symptomatic remission. Further studies are needed to define subgroups of patients who are most likely to benefit from preventive therapy. Of patients with Crohn's disease who have not previously undergone surgical treatment and who are in symptomatic remission, 25 to 50% will experience symptomatic recur­ rences after 1 year, and 40 to 65% will have recurrences by 2 years.!-' Of patients who have undergone surgical resection of intestinal segments involved with Crohn's disease, 30 to 50% will have symptomatic recurrences during the first 5 postoperative years, and 50 to 80% will have symptomatic recurrences by 10 years postoperatively.' Increasing the length of the margins of normal intestine removed at the time of resection does not decrease the frequency of recurrent disease."? Because of the high rate of recurrence, a safe and effective regimen has long been sought for maintaining re­ mission in patients with Crohn's disease.

https://www.mayoclinicproceedings.org/article/S0025-6196(12)60070-6/pdf

William J. Tremaine

Papers

Left-sided ulcerative colitis: True extent of disease and risk of pouchitis

Subject Review Maintenance of Symptomatic Remission in Patients With Crohn's Disease

Tu2006 Clinical Features and Outcomes of Ischemic Colitis in a Population-Based Cohort

Diarrhea: Diagnostic and Therapeutic Advances

Hereditary Angioedema and Hormones—Reply