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.

Background Inflammatory bowel disease (IBD) is associated with an increased acute coronary syndrome (ACS) risk. Data are limited regarding the epidemiology and outcomes of ACS in patients with IBD. Methods A retrospective cohort analysis of patients with IBD admitted for ACS in the U.S. Healthcare Cost and Utilization Project National Inpatient Sample for 2005 to 2015 was conducted. We analyzed trends in IBD-ACS admissions and mortality, differences in risk profiles, management strategies, and in-hospital mortality between IBD-ACS and non-IBD ACS and between ulcerative colitis (UC) and Crohn disease (CD). Results We studied 6,872,415 non-IBD ACS and 24,220 IBD-ACS hospitalizations (53% with CD). During the study period, the number of hospitalizations for IBD-ACS increased, particularly those related to CD. Compared with non-IBD ACS, patients with IBD-ACS had a lower prevalence of cardiovascular risk factors and similar rates of coronary angiography and revascularization. The in-hospital mortality rate was lower with IBD-ACS (3.9%) compared with non-IBD ACS (5.3%; odds ratio, 0.81; 95% confidence interval, 0.69-0.96; P = 0.011) and was stable between 2005 and 2015. Risk factors, ACS management strategies, and mortality were similar between CD and UC. Coagulopathy, weight loss, and gastrointestinal bleeding were more frequent in IBD-ACS and were strong independent predictors of mortality. Conclusions Hospitalizations for ACS in patients with IBD increased in recent years but death rates were stable. The ACS-related risk profiles and mortality were modestly favorable with IBD-ACS than with non-IBD ACS and were similar between CD and UC. Complications more frequently associated with IBD were strongly associated with mortality. These findings indicate that aggressive management of IBD and ACS comorbidities is required to improve outcomes.

Epidemiology and Clinical Outcomes of Patients With Inflammatory Bowel Disease Presenting With Acute Coronary Syndrome.

Equipoise, H. pylori, and Musketeers – Choosing an Appropriate Standard Clinical Care Regimen

https://www.gastrojournal.org/article/S0016-5085(03)82629-X/pdf

Management of Crohn's disease (CD) of the ileoanal pouch with infixinab

Failure to yield: Drug resistance in inflammatory bowel disease

The optimal care of patients with inflammatory bowel disease depends on adherence to standards of care regarding diagnosis, informing the patient of potential risks of treatment, obtaining recommended baseline studies, and monitoring the patient for efficacy and adverse effects. In clinical research as well as practice, financial conflicts of interest must be disclosed and managed to insure that patients have sufficient information to make a decision regarding participation in a study and to insure their safety. Medical education of care-givers in training carries the obligation and liability to oversee the care of the IBD patient and insure that safe and optimal care. This review addresses medicolegal issues that can arise in the care of the patient with IBD. Clinicians who provide optimal care for patients with inflammatory bowel diseases (IBD) must employ appropriate diagnostic and therapeutic options and also adhere to standards of care and ethical principles. Ethical and medicolegal issues can arise from the failure to adhere to the standards of medical care, clinical research and education. In a report in the New England Journal of Medicine in 2011, gastroenterologists in the U.S. ranked 6th out of 26 subspecialities as the most commonly sued for malpractice, with the mean payment to the plaintiff of just under $200,000 [1]. It is noteworthy that two other specialties that involve invasive procedures ranked lower on the list than Gastroenterology. For example, Cardiology and Anesthesiology ranked 11th and 17th, respectively. In this review, nine of the pitfalls to adherence to the standards of practice for IBD are reviewed.

William J. Tremaine

Papers

Epidemiology and Clinical Outcomes of Patients With Inflammatory Bowel Disease Presenting With Acute Coronary Syndrome.

Equipoise, H. pylori, and Musketeers – Choosing an Appropriate Standard Clinical Care Regimen

Management of Crohn's disease (CD) of the ileoanal pouch with infixinab

Failure to yield: Drug resistance in inflammatory bowel disease

Nine Medico-Legal Pitfalls in Inflammatory Bowel Disease in the United States