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Infliximab: rescue therapy in severe UC▸
The Th1/Th2 hypothesis to explain the pattern of cytokine activation in Crohn’s and ulcerative colitis (UC) predicted that anti-tumour necrosis factor therapy would not be useful in UC. However, a number of cases of refractory colitis responding well to infliximab encouraged randomised trials in UC, and this Swedish study evaluated infliximab in hospitalised patients with severe UC. Patients were recruited if they scored eight or more on the SEO activity index at day 3 of standard intravenous corticosteroid therapy (indicating a 72% chance of colectomy) or if they had a Seo index indicating severe or moderately severe disease between days 5 and 7. Patients were randomised to a single infusion of infliximab 5 mg/kg or placebo, and corticosteroid therapy continued. Although the trial was stopped early because of slow recruitment, 45 patients were randomised. The primary end point was colectomy rate at three months, and this was significantly lower on infliximab (7/24 (29%)) compared with placebo (14/21 (67%)) (p = 0.017). Unfortunately there were significantly more patients with a first attack in the placebo group (43% v 22% in the infliximab group) and this might bias against the placebo group but correction for this still gave a statistically significant result for infliximab. The benefit of infliximab appeared more marked in the group with less severe disease, with no colectomies on infliximab versus 62.5% on placebo, whereas those with fulminant disease had a 47% colectomy rate on infliximab versus 67% on placebo.
This positive study in severe UC means that infliximab, once funding is improved, could become an alternative salvage therapy to ciclosporin, and may be preferable for ease of use and possibly safety. The ACT1 and ACT2 studies, presented at the Digestive Disease Week in Chicago in May 2005, provide more controlled evidence of benefit in UC.
Do statins do more than lower cholesterol?▸
Colon cancer is the second commonest cause of cancer mortality in many Western countries. Colorectal cancer screening is being instituted but a strategy of chemoprevention may have a greater impact. Candidates include aspirin and calcium but other agents are needed. Statins may protect against neoplasia as cancer cells over express HMG-CoA reductase and statins induce apoptosis in cancer cell lines. Poynter et al addressed this hypothesis in a case control study. They reported that 120/1953 (6%) colorectal cancer cases were taking statins compared with 234/2015 (12%) controls (odds ratio (OR) 0.5 (95% confidence interval (CI) 0.4–0.63)). This association remained after adjusting for age, sex, NSAID/aspirin use, history of colon cancer, and level of vegetable consumption (OR 0.57 (95% CI 0.44–0.73)). The investigators relied on self reporting and did not obtain information on dose of statin, and therefore dose-response could not be assessed. Randomised controlled trial data have provided inconsistent results on the effect of statins when colorectal cancer was evaluated in post hoc analyses so the results of this case control study could be due to bias or residual confounding. Nevertheless, these are interesting data suggesting statins may do more than protect against ischaemic heart disease.
One small step for womankind▸
Obesity increases peripheral insulin resistance while physical activity results in upregulation of insulin receptors in muscle tissue. Although central obesity and type 2 diabetes are well known risk factors for non-alcoholic fatty liver disease (NAFLD), the association of physical activity with NAFLD, independent of obesity, has not been well established. In a random sample of 3789 British women aged 60–79 years, the authors investigated the association of physical activity, body mass index (BMI), and waist:hip ratio with alanine transaminase (ALT) and gamma-glutamyltransferase (GGT). A questionnaire that has been validated in studies of cardiovascular and diabetes outcome was used to assess physical activity. The effect of frequency of moderate intensity activities was analysed. Both BMI and waist:hip ratio had a strong linear and positive association with ALT and GGT. Similar strong linear associations were seen with indices of obesity (BMI and waist:hip ratio) and diabetes. Lower levels of physical activity were associated with higher levels of GGT independent of measures of adiposity and other confounders. However, the inverse relationship of physical activity with ALT was attenuated in a fully adjusted model.
Based on these findings, the authors conclude that NAFLD mediates development of diabetes in subjects with central obesity. Although such conclusions regarding pathogenesis are debatable, the study highlights the influence of physical activity on insulin resistance and hence the accumulation of fat within the liver. Increase in physical activity may have a therapeutic benefit in NAFLD, even in the absence of weight reduction.
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