Increased eosinophil granule proteins in gut lavage fluid from patients with inflammatory bowel disease.

OBJECTIVE: To explore the potential role of eosinophils in the pathogenesis of inflammatory bowel disease (IBD). DESIGN: We measured the concentrations of eosinophil granule proteins-namely, major basic protein, eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin-in gut lavage fluid. MATERIAL AND METHODS: Ten healthy persons and 17 patients with IBD (9 with Crohn's disease and 8 with ulcerative colitis) underwent gut lavage. Each study subject submitted an early specimen when lavage effluent became liquid and a late specimen when the output became clear. The concentrations of the granule proteins were measured by immunoassay. RESULTS: The median concentrations of eosinophil-derived neurotoxin and eosinophil cationic protein were significantly higher in patients with IBD than in control subjects for both early and late lavage specimens. Excretion of eosinophil peroxidase was also significantly higher in patients with IBD than in the healthy control subjects, but only in the early specimens. No differences were noted in the concentrations of any of the proteins between patients with ulcerative colitis and those with Crohn's disease. CONCLUSION: Concentrations of eosinophil granule proteins were increased in whole gut lavage fluid from patients with IBD in comparison with healthy control subjects. These results encourage further studies of the role of eosinophils in the pathogenesis of IBD.

A placebo-controlled trial of cyclosporine enemas for mildly to moderately active left-sided ulcerative colitis.

BACKGROUND/AIMS: Uncontrolled studies suggest that cyclosporine administered as an enema may be of benefit for left-sided ulcerative colitis and safer than intravenous or oral administration. The efficacy and safety of cyclosporine enemas for left-sided ulcerative colitis in a placebo-controlled trial was assessed. METHODS: Steroid and mesalamine enemas were withdrawn before the study. Forty patients were assigned to 1 of 4 strata: no concomitant therapy, oral steroids, oral salicylates, or oral steroids and salicylates. After stratification, patients were randomized to nightly treatment with 350 mg cyclosporine (n = 20) or placebo (n = 20) enemas. Clinical response was determined at baseline and 4 weeks by endoscopy, physician assessment, and a patient diary of daily symptoms. Trough blood cyclosporine levels were measured by high-performance liquid chromatography. RESULTS: At 4 weeks, 8 of 20 patients (40%) who received cyclosporine showed clinical improvement compared with 9 of 20 patients (45%) who received placebo. One patient receiving cyclosporine had reversible neutropenia attributable to sulfasalazine, and another patient receiving cyclosporine was unable to tolerate the enema vehicle. No other toxicity was noted during the trial. Blood cyclosporine levels were detectable in only two patients. CONCLUSIONS: Cyclosporine enemas administered in a dosage of 350 mg/day for 4 weeks are not efficacious in mildly to moderately active left-sided ulcerative colitis.

Cyclosporine enemas for treatment-resistant, mildly to moderately active, left-sided ulcerative colitis.

Ten patients with treatment-resistant left-sided ulcerative colitis were treated in an open protocol with 350 mg cyclosporine enemas nightly for 4 wk. A 12-point clinical disease activity index (DAI) score was calculated at baseline and after 4 wk. Whole blood and colonic tissue cyclosporine concentrations were determined by HPLC at the end of the study. Five of 10 patients responded to treatment, defined as a decrease in the clinical DAI score > or = 3 points. Responders retained the enemas longer than nonresponders (7.5 +/- 1.3 vs. 3.3 +/- 2.2 h, p = 0.01), and there was a positive correlation between decrease in the clinical DAI score and enema retention time (r = 0.64, p = 0.05). The mean colonic tissue cyclosporine concentration was not significantly higher in responders than in nonresponders (2884 +/- 1635 vs. 2359 +/- 576 ng/g, p = 0.52), and the correlation between decrease in the clinical DAI score index and colonic tissue cyclosporine was weak (r = 0.39, p = 0.26). Cyclosporine was undetectable in whole blood samples from all patients, and there were no apparent side effects with treatment. In conclusion, 50% of patients with treatment-resistant left-sided ulcerative colitis significantly improved during therapy with cyclosporine enemas for 4 wk. Patients with longer enema retention times were more likely to respond. A controlled trial is underway to investigate these findings further.

Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease.

We identified and analyzed 45 patients with asymptomatic primary sclerosing cholangitis to better understand the natural history of this disease. Disease progression was monitored at regular intervals for the development of symptoms and physical signs as well as changes in liver biochemistry, cholangiography, and liver histology. During a median follow-up of 75.2 mo, 34 patients (76%) had evidence of disease progression. Fourteen patients (31%) developed liver failure which resulted in death or referral for liver transplantation. For patients with primary sclerosing cholangitis, survival curves computed using the Kaplan-Meier method were significantly worse than expected when compared to age-, sex-, and race-specific survival rates for the United States north central population (p less than 0.001). These findings indicate that primary sclerosing cholangitis is generally a progressive disease with considerable morbidity and mortality even when detected before the onset of symptoms.