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.

Summary
Background

Anti-TNFα biologics induce and maintain remission in inflammatory bowel disease (IBD). Also, they have been reported to induce or unmask idiopathic inflammatory demyelinating disease of the central nervous system (IIDD).



Aim

To determine if anti-TNFα biologics increased the risk of IIDD in a large cohort of patients with IBD.



Methods

We retrospectively identified adult patients referred to the Mayo Clinic, Rochester, MN for management of IBD from a five state capture area (Minnesota, Wisconsin, North Dakota, South Dakota and Iowa) between 1996 and 2010. IIDDs were identified in both Crohn's disease (CD) and ulcerative colitis (UC) patients with and without anti-TNFα exposure using the 2010 McDonald MRI criteria. The risk of IIDDs in patients with and without anti-TNFα exposure was estimated for IBD; CD and UC groups separately.



Results

A total of 9095 patients with IBD were identified (4342 CD and 4753 UC). Four patients with CD with exposure to anti-TNFα agents (4/2054) and five patients with CD without anti-TNFα exposure (5/2288) developed a confirmed IIDD. One patient with UC with exposure to anti-TNFα agents (1/1371) and five patients with UC without anti-TNFα agents developed a confirmed IIDD (5/3382). The per cent of IIDDs in patients with and without anti-TNFα exposure was; IBD: 0.15% and 0.18% (RR = 0.83, 95% CI: 0.28–2.42; P = 0.729); CD: 0.19% and 0.22% (RR = 0.89, 95% CI: 0.24–3.31; P = 0.863); UC: 0.07% and 0.15% (RR = 0.49, 95% CI: 0.06–4.22; P = 0.510).



Conclusion

Anti-TNFα biologics do not appear to impact the risk of developing clinical idiopathic inflammatory demyelinating disease in patients with inflammatory bowel disease.

Idiopathic inflammatory demyelinating disease of the central nervous system in patients with inflammatory bowel disease: retrospective analysis of 9095 patients.

Revisión técnica sobre corticosteroides, inmunomoduladores, e infliximab en enfermedad inflamatoria intestinal del Instituto de la Asociación de Gastroenterología Americana

Update on incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in olmsted county, minnesota

The development of practice guidelines is problematic because guidelines that are too broad have no value and guidelines that are highly specific cannot address the nuances of every patient's illness. In this article, we present the hypothesis that practice guidelines that provide specific objectives for assessment and intervention in inflammatory bowel disease can be used to measure practice variation. These guidelines are proposed as 15 specific objectives with options for intervention. These objectives could be used as an instrument to quantify variations in clinical practice and to assess the benefits of practice guidelines.

Practice guidelines for inflammatory bowel disease: an instrument for assessment.

Collagenous colitis is part of the spectrum of disorders known as microscopic colitis, which also include lymphocytic colitis and a mixed disorder with both a collagen band present and also intra-epithelial lymphocytes. Collagenous colitis appears to be caused by mucosal injury from toxins in the faecal stream. The collagen band is a result of the underlying inflammatory process and not the cause of symptoms. The diagnosis is based on colonic mucosal pathology and a compatible clinical presentation. Treatment is empiric and ranges from no therapy, to anti-inflammatory or anti-secretory agents, to diverting ileostomy.

William J. Tremaine

Papers

Idiopathic inflammatory demyelinating disease of the central nervous system in patients with inflammatory bowel disease: retrospective analysis of 9095 patients.

Revisión técnica sobre corticosteroides, inmunomoduladores, e infliximab en enfermedad inflamatoria intestinal del Instituto de la Asociación de Gastroenterología Americana

Update on incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC) in olmsted county, minnesota

Practice guidelines for inflammatory bowel disease: an instrument for assessment.

Diagnosing collagenous colitis: does it make a difference?