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.

/pdf/a-frameshift-mutation-in-nod2-associated-with-susceptibility-48m0thlgj6.pdf

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.

BACKGROUND Data on the differences in inpatient treatment approaches and outcomes between younger and older patients with inflammatory bowel disease (IBD) are limited. Therefore, we used a parallel cohort study design to compare outcomes between younger and older patients with IBD. METHODS All anti-tumor necrosis factor (TNF)-naive patients aged 60 years and older hospitalized at our institution between 2003 and 2011 and treated with corticosteroids for an IBD flare were matched 1:1 to younger patients aged 18 to 50 years. Rates of corticosteroid response, colectomy, and initiation of anti-TNF therapy were compared. RESULTS Sixty-five patients were identified in each cohort. Median ages were 70 years (range, 60-94) and 30 years (range, 18-50) for the older and younger groups, respectively. Twenty-three percent of older patients were refractory to corticosteroids compared with 38% of the younger cohort (odds ratio, 0.5; 95% confidence intervals, 0.2-1.1). Older corticosteroid-refractory patients had surgery (80% versus 72%) and were started on anti-TNF therapy (20% versus 12%; P = 0.71), at a similar frequency as younger patients. Older steroid-responsive patients were less likely to start an anti-TNF agent during the first year of follow-up than younger patients (7% versus 31%, P = 0.006), but there was no difference in 1-year colectomy rates (27% versus 28%, P = 0.63). CONCLUSIONS Corticosteroid response was similar in older and younger patients hospitalized for IBD. Inpatient treatment for corticosteroid-refractory patients was similar between cohorts. Older corticosteroid-responsive patients were less likely to be treated with an anti-TNF than younger patients.

https://www.gastrojournal.org/article/S0016-5085(13)62360-4/pdf

Comparative outcomes of younger and older hospitalized patients with inflammatory bowel disease treated with corticosteroids.

https://www.gastrojournal.org/article/S0016-5085(13)60381-9/pdf

561 Inflammatory Bowel Disease and Non-Relaxing Pelvic Floor Dysfunction

Cross-sectional study of IBD patients taking aza-thioprine (AZA) or 6-mercaptopurine (6-MP): Lack of correlation between disease activity and 6-thioguanine nucleotide (6TGN) concentration

Su1887 - Impact of Obesity on Future IBD-Related Complications in a Population-Based Cohort of Crohn's Disease (CD) and Ulcerative Colitis (UC) Patients

William J. Tremaine

Papers

Comparative outcomes of younger and older hospitalized patients with inflammatory bowel disease treated with corticosteroids.

561 Inflammatory Bowel Disease and Non-Relaxing Pelvic Floor Dysfunction

Cross-sectional study of IBD patients taking aza-thioprine (AZA) or 6-mercaptopurine (6-MP): Lack of correlation between disease activity and 6-thioguanine nucleotide (6TGN) concentration

Su1887 - Impact of Obesity on Future IBD-Related Complications in a Population-Based Cohort of Crohn's Disease (CD) and Ulcerative Colitis (UC) Patients

Su1872 - Trends in the Prevalence of Overweight and Obesity at the Time of Inflammatory Bowel Disease Diagnosis: A Population-Based Study