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

Background Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. Methods The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas. Results Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue. Conclusions Infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.

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Infliximab for the treatment of fistulas in patients with Crohn's disease.

Erroneous communication between the innate and adaptive immune systems through cytokines results in exaggerated or attenuated immune response. It is not known whether the pathologic immune response in inflammatory bowel disease has its origin in a dysbalance of pro- and anti-inflammatory cytokine release or whether it is secondary in subsequence of a defective intestinal barrier or the destructive power of aggressive microbiota in the gut lumen.

Cytokines in inflammatory bowel disease

The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Enormous progress has been made recently in understanding the pathogenesis of these diseases. Through the study of patients and mouse models, it has emerged that Crohn's disease is driven by the production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), whereas ulcerative colitis is probably driven by the production of IL-13. A second area of progress is in the identification of specific genetic abnormalities that are responsible for disease. The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. Here, we discuss these recent findings and the implications for therapy.

The immunological and genetic basis of inflammatory bowel disease.

TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases

https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.2287

TNF‐mediated inflammatory disease

https://www.gastrojournal.org/article/0016-5085(94)90398-0/pdf

Tumor necrosis factor α-producing cells in the intestinal mucosa of children with inflammatory bowel disease

Intestinal permeability, diet, and growth

Paediatricians often estimate liver size by palpating and percussing the liver edge in the right mid-clavicular line (RMCL). This measure is awkward in children, as determination of the RMCL is difficult - is measurement of the liver edge more accurate in the midline? 20 children aged between 6 months and 5 years were examined ‘blind’ by 5 practisinig clnicians on 3 separate occasions We observed poor repeatablity in measuring the RMCL between observers (15%>2standard deviations, SD), although the length ol the sternum, with defined, bony anatomical points, showed less variability (0.5%>2SD). Measurement in the midline showed greater repeatability between observers than in the RMCL (4%>2SD vs 8%>2SD). Estimation of the upper edge of the liver by percussion showed greatest variability (15%>2SD) Intra-observer variation followed the same pattern. Two children with exacerbations of asthma were followed by the examiners over 30 days: changes in the liver position were more accurately documented by measures made in the midline. We conclude that manual measurement of the hepar in the midline in children under 5 is more accurate than that in the RMCL.

/pdf/how-should-we-estimate-liver-size-clinically-2githdpp8l.pdf

Colin A Michie

Papers

Tumor necrosis factor α-producing cells in the intestinal mucosa of children with inflammatory bowel disease

Intestinal permeability, diet, and growth

How should we estimate liver size clinically

Vitamin A deficiency and lymphocyte subsets.