Faculty Bibliography

OBJECTIVES: Budesonide controlled ileal release (CIR) capsules deliver budesonide, a glucocorticosteroid with high topical and low systemic activity, to the distal ileum and the proximal colon. In four previous controlled trials in Crohn's disease, remission rates ranged from 51% to 69%. We sought to evaluate the efficacy and safety of this drug in a population of patients in the United States with Crohn's disease. METHODS: In this multicenter, double blind, randomized trial, 200 patients in the United States with mild to moderate Crohn's disease (Crohn's Disease Activity Index [CDAI] between 200 and 450) involving the distal ileum and/or ascending colon received 9 mg of budesonide CIR once daily, 4.5 mg b.i.d., or placebos for 8 wk. The primary outcome was remission defined by a CDAI of 150 or less. RESULTS: Remission was achieved in 48%, 53%, and 33% with 9 mg once daily, 4.5 mg b.i.d., and placebos, respectively, after 8 wk of treatment. Differences between the groups were not significant. The differences in mean change from baseline CDAI between the combined budesonide and placebo groups was significant (p < 0.05). There was no difference in observed adverse events between treatment groups, although a modest decrease in plasma cortisol levels was observed relative to the placebo (p < 0.01). CONCLUSIONS: Treatment of symptomatic Crohn's disease with budesonide CIR capsules (9 mg daily) was safe, and remission rates were similar to those achieved in previous trials. Although the remission rate did not significantly differ from the placebo response in this study, there was a significant change in the mean CDAI from baseline in the combined treatment groups relative to the placebo

The bewildering array of medications in the therapy of inflammatory bowel disease (IBD) often confounds the clinician in the choice of specific agents regarding the balance between safety and efficacy. This review surveys and evaluates currently available IBD therapies as well as those used in clinical trials of ulcerative colitis. The primary purpose is to provide the busy clinician with a practical guide to the use of established and newly emerging medical therapies of IBD

BACKGROUND & AIMS: We evaluated etanercept, a human soluble tumor necrosis factor receptor: Fc fusion protein, for the treatment of active Crohn's disease. METHODS: Forty-three patients with moderate to severe Crohn's disease were enrolled in an 8-week placebo-controlled trial. Patients were randomized to subcutaneous etanercept 25 mg or placebo twice weekly. The primary outcome measure was clinical response at week 4, defined as a decrease in the baseline Crohn's Disease Activity Index score > or =70 points or a Crohn's Disease Activity Index score <150 points. RESULTS: At week 4, 39% of etanercept-treated patients had clinical response as compared with 45% of placebo-treated patients (P = 0.763). The frequency of common adverse events including headache, new injection site reaction, asthenia, abdominal pain, Crohn's disease-related anemia, and skin disorders was similar in both groups. Likewise, the frequency of severe or serious adverse events was similar in both groups. CONCLUSIONS: Subcutaneous etanercept at a dose of 25 mg twice weekly is safe, but not effective, for the treatment of patients with moderate to severe Crohn's disease. The dose of etanercept administered in this study is that approved for rheumatoid arthritis. Higher doses or more frequent dosing may be required to attain a response in patients with active Crohn's disease.

A 67-yr-old woman with a 25-yr history of Crohn's disease, maintained on near-continuous corticosteroids (prednisone 10 mg daily) over a 6-yr period, underwent ileocolic resection for obstruction. Pathology revealed Crohn's disease, multiple nodules of Kaposi's sarcoma, and cytomegalic inclusion bodies with confirmation of cytomegalovirus by shell vial immunofluorescence. Testing for HIV serum antibody has been repeatedly negative. Crohn's disease, Kaposi's sarcoma, and cytomegalovirus have been clinically in remission for 5 yr

OBJECTIVE: Recent studies have suggested that a susceptibility gene located on chromosome 16 and designated IBD1 may contribute to the development of Crohn's disease (CD). However, these findings were observed in predominantly non-Jewish populations; in the three studies where Ashkenazi Jews were included for analysis, the results have been widely divergent. Because Ashkenazi Jews are known to have a higher incidence of the disease than non-Jews, we sought to determine whether this previously reported linkage could be extended to the Ashkenazi population. In addition, we examined whether Ashkenazi Jewish patients with an early age of onset (< or = 21 yr) showed greater evidence of linkage to this locus. METHODS: Linkage analysis for the IBD1 region was performed on 123 Ashkenazi Jewish CD patients distributed among 53 families. Only patients with four Jewish grandparents were considered to be Jewish. Of the 123 Ashkenazi Jewish patients, 75 (61%) had an age of onset < or = 21 yr. RESULTS: Ashkenazi Jews showed only modest evidence of linkage (nonparametric linkage 1.63, p = 0.05) to the IBD1 locus. However, when the Ashkenazi population was subdivided on the basis of age of onset, there was a striking increase in linkage in families where affected individuals had an age of onset < or = 21 yr (nonparametric linkage 3.02, p = 0.002). In contrast, there was no evidence of linkage in the Jewish families where all affected individuals had an age of onset > 21 yr. CONCLUSIONS: The IBD1 gene plays a greater role in conferring susceptibility to CD in Jews with early onset disease than in Jews with late onset disease

Previous studies have suggested that susceptibility to Crohn's disease (CD) is associated with the histocompatibility complex (HLA) class II alleles DR1, DQ5, and DR13 in the Caucasian population, DR7 in the French and German populations, and DR4 and DQ4 in the Japanese population. However, little is known about the relationship between HLA class II alleles and CD in the Jewish population since these previous studies included few Jewish individuals. In order to determine whether the HLA associations observed with predominantly non-Jewish populations were also present in the Jewish CD population and whether there were any HLA class II alleles uniquely associated with CD in the Jewish population, 132 CD patients, of which 82 were Ashkenazi Jewish, were HLA-typed using serologic and DNA methods. Ethnically matched controls were similarly typed. No association with DR1 or DR13 was observed in the Jewish CD population although an association with DR13 (OR [odds ratio] = 5.3, p = 0.02) was observed in the non-Jewish CD population. However, an association with DR15 (OR = 2.7, p = 0.03), which is normally associated with ulcerative colitis, was observed in the Jewish, but not non-Jewish, CD group. In addition, a strong negative association was observed with DR3, which was especially striking in the Jewish population (OR = 0.35, p = 0.025); similar negative associations with DR3 have been observed by others using non-Jewish populations. Furthermore, a significant negative association with DR7 (OR = 0.45, p = 0.04) was observed in the Jewish, but not non-Jewish, population. Consistent with this was the negative association with DQ2 (OR = 0.38, p = 0.005), which is in strong linkage disequilibrium with both DR3 and DR7, in the Jewish, but not non-Jewish, population. These studies support previous suggestions that susceptibility to CD in Jewish and non-Jewish populations is determined by distinct genes and provide further support to the hypothesis that a gene on the DR3 haplotype may protect against CD. Furthermore, protection is conferred by the same or another gene found on Jewish, but not non-Jewish, DR7 haplotypes

We report a 74-yr-old woman with Crohn's disease and acute pancreatitis who, 3 yr after resolution of the latter, developed cystadenocarcinoma of the pancreas. No drug, toxin, or other etiologies including contiguous duodenal involvement were identified as responsible for the pancreatitis, suggesting that pancreatitis was an extraintestinal manifestation of her Crohn's disease. Could Crohn's-associated pancreatitis be a premalignant state for cystadenocarcinoma of the pancreas?

BACKGROUND & AIMS: Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity. METHODS: A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. RESULTS: Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. CONCLUSIONS: Short-term treatment with rhIL-11 is well tolerated in patients with active Crohn's disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohn's disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.