IBD Watch®
Timely Information for Practicing Physicians
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SEPTEMBER 2002CROHN'S DISEASE (CD) Long-term fracture risk. Evidence suggests that patients with inflammatory bowel disease are at an increased risk for osteoporosis. Edward Loftus Jr. and colleagues reviewed the records of all residents of Olmstead County, Minnesota, diagnosed with CD between 1940 and 1993 (n = 238) for evidence of subsequent bone fractures. They found that 63 patients had 117 different fractures. The cumulative incidence of any fracture after 20 years of follow-up was 36% for the CD patients compared to 32% for an age- and sex-matched control group of Olmstead County residents (p = 0.792). The overall risk ratio for any fracture compared with controls was 0.9 (95% CI: 0.6 - 1.4). Corticosteroid therapy and surgical resection were not found to predict for risk of fracture. Cox proportional hazards regression identified only age to be an independent predictor of fracture risk. These data indicate that patients with CD do not have an increased long-term risk of fracture. (Loftus EV, et al. Gastroenterology 2002;123:468-475) Combined budesonide and antibiotic therapy. A. Hillary Steinhart and associates for the Crohn's and Colitis Foundation of Canada Inflammatory Bowel Disease Network Investigators conducted a double-blind, multicenter study in which patients with active CD of the ileum, right colon, or both were randomized to receive oral budesonide (9 mg daily) plus either oral ciprofloxacin and metronidazole (both 500 mg twice daily) (n = 64) or placebo (n = 66). After 8 weeks of therapy, the remission rate achieved by the antibiotic group was similar to that of the placebo group (33% vs. 38%; p = 0.55). However, among patients with CD confined to the colon, 53% (9 of 17 patients) of antibiotic-treated patients had a remission compared to 25% (4 of 16 patients) of patients in the placebo group (p = 0.10). Discontinuation of therapy due to adverse events occurred in 13 (20%) of the patients in the antibiotic treatment group while no placebo patients were discontinued from the study for toxicity (p <0.001). This study demonstrated that antibiotics are ineffective treatments for patients with CD of the ileum. A trend toward an improved remission rate was observed for those patients with CD confined to the colon treated with ciprofloxacin and metronidazole plus budesonide and further study of antibiotic therapy for this patient subgroup is warranted. (Steinhart AH, et al. Gastroenterology 2002;123:33-40) Maintenance infliximab therapy. Stephen Hanauer and colleagues from the ACCENT I Study Group conducted a multicenter trial in which 573 patients with active CD were treated with a 5 mg/kg infusion of infliximab and 2 weeks later were then randomized to the following treatment groups: infusions of placebo (group I; n = 110) or infliximab 5 mg/kg (group II; n = 113) at weeks 2 and 6 and then every 8 weeks thereafter until week 46; infusions of infliximab 5 mg/kg at weeks 2 and 6 followed by infusions of infliximab 10 mg/kg every 8 weeks until week 46 (group III). A response (decrease of the Crohn's disease activity index to <150) within 2 weeks of the initial single infusion of infliximab was achieved in 335 (58%) patients. At week 30, the remission rates of treatment groups II (39%) and III (45%) were greater than that of placebo group I (21%) (p = 0.003 and 0.0002, respectively). The median time to loss of response was 38 weeks for group II and >54 weeks for group III compared to 19 weeks for group I (p = 0.002 and 0.0002, respectively). These data showed that patients with CD have greater response rates at weeks 30 and 54 and maintain responses for longer periods of time when maintenance infliximab therapy is administered. (Hanauer SB, et al. Lancet 2002;359;1541-1549) NOD2/CARD15 does not influence response to infliximab. NOD2/CARD15 is a gene that encodes a protein that activates NF-kB-induced apoptosis under normal circumstances. Three independent mutations of NOD2/CARD15 have been found to be associated with an increased risk for developing CD. Severine Vermeire and colleagues genotyped 245 patients with CD receiving infliximab therapy. Mutations of NOD2/CARD15 were identified in 32.6% of CD patients compared to 15% of 95 healthy controls (p <0.001). Short-term clinical response was assessed at 4 weeks (refractory) or 10 weeks (fistulizing) after the first infliximab infusion. There were 77.6% responders and 22.4% non-responders to infliximab. There was no difference in the prevalence of patients with NOD2/CARD15 mutations in either the responder or non-responder groups. In addition, the median duration of response was 12 weeks for patients with or without NOD2/CARD15 variants. These results show that NOD2/CARD15 mutations are more frequent in CD patients than in healthy controls, but that NOD2/CARD15 variants were not predictive of treatment outcome with infliximab therapy. (Vermeire S, et al. Gastroenterology 2002;123:106-111) INFLAMMATORY BOWEL DISEASE (IBD) Effect of smoking on phenotype. Smoking tobacco has been shown to predispose to the development of CD and to be associated with a decreased incidence of ulcerative colitis (UC). S. Bridges et al collected smoking histories by personal interviews from 242 IBD families with a total of 339 sibling pairs with IBD. Smoking was associated with a diagnosis of CD and protection from UC in these familial patients (p <0.001 and <0.001, respectively). Of 89 sibling pairs found to be discordant for smoking at diagnosis, 23 sibling pairs were also discordant for IBD type. In 21 of the 23 pairs, CD occurred in the smoker and UC in the nonsmoker (p <0.0001). These data confirm that smoking is an environmental risk factor for CD and suggest that smoking tobacco may act on IBD genetic predisposition to shift the phenotype from UC towards CD. (Bridges S, et al. Gut 2002;51:21-25) REVIEWTeratogen update of azathioprine (AZA) and 6-mercaptopurine (6-MP). Janine Polifka and J.M. Friedman have recently reviewed the teratogenic effects of AZA and 6-MP. Summaries of the metabolism and pharmacology of these agents as well as animal and human studies are provided and the mechanisms of teratogenicity are discussed. (Polifka JE and Friedman JM. Teratology 2002; 65:240-261) |
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