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We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

Tumor necrosis factor-alpha (TNFalpha), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFalpha activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn's disease (CD) and fistulizing CD sufficient to justify recent U.S. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis (RA). Similarly, preliminary controlled trials have suggested efficacy for CDP571 in active CD and RA. Larger controlled trials have demonstrated efficacy for etanercept in RA patients who have failed disease modifying antirheumatic drug (DMARD) therapy leading to FDA approval for RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin's lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti-TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents.

Cyclosporin (CSA) has emerged as a medical alternative to colectomy in severe, steroid-refractory ulcerative colitis (UC) patients. This is the first formal quality-of-life study comparing such patients treated with intravenously administered cyclosporin with those treated surgically with colectomy. Quality-of-life analyses were conducted in all patients who underwent colectomy or received intravenous CSA for severe UC from 1991 to 1995 using the Inflammatory Bowel Disease Questionnaire, a visual-analog scale (VAS), and the Oresland scale, with additional questions regarding health care utilization and medication use. The 18 CSA-treated patients reported a better ability to sleep (p = 0.002; VAS), better stool consistency (p < 0.001; VAS), less abdominal or rectal pain (p = 0.009, VAS), and fewer daytime (p < 0.001; Oresland), nighttime (p = 0.006; Oresland), and daily trips to the toilet (p < 0.001; VAS) than the 46 surgical patients. The mean number and rate of hospitalizations within the first year was also lower in the CSA patients (p < 0.001 for both). The surgical patients reported fewer initial visits to their specialist (p < 0.001) and less medication use (p < 0.001; Oresland). Patients with severe steroid-refractory UC treated with intravenously administered CSA scored as well as or better than their surgical counterparts. The use of CSA in selected patients is substantiated both by clinical results and quality-of-life analysis.

The safety and efficacy of mesalamine enemas were determined ina dose-ranging study enrolling 287 patients with ulcerative proctitis and proctosigmoiditis in a double-blind, placebo-controlled, multicenter trial. Patients were randomized to receive placebo, 1, 2, or 4 g in 100 ml mesalamine (PENTASA) enemas h.s. for 8 weeks. Efficacy was assessed by clinical, sigmoidoscopic, and histologic improvement, as well as by induction of remission. Sixty-seven percent, 65%, and 75% of patients receiving 1-, 2-, and 4-g enemas were markedly improved according to the physician's global assessment compared with 27% of patients treated with placebo. The mean improvement in sigmoidoscopic index was 5.8, 5.9, and 6.4 points (on a 15-point scale) for the 1-, 2-, and 4-g enema groups compared with a decrease of 1.8 points for the placebo group. Improvement in biopsy scores was observed in 47, 55, and 59% of 1-, 2-, and 4-g groups contrasted with 27% of the placebo-treated patients. All three doses were significantly more effective than placebo in reducing symptoms and trips to the toilet compared with placebo. No dose-response relation was demonstrated. The safety profile was similar to that of placebo. In conclusion, mesalamine enemas are effective as a single agent in the short-term treatment of distal ulcerative colitis without an apparent dose response between 1 and 4 g nightly.

Summary: : Crohn's disease and ulcerative colitis are related complex genetic disorders producing chronic intestinal inflammation. A susceptibility locus for Crohn's disease, IBDI (inflammatory bowel disease), has been implicated on chromosome 16. To evaluate IBDI in a different population using alternative methodology, we tested markers in the region of IBDI. Seventy-two relative pairs with Crohn's disease only, 23 mixed relative pairs (one relative having Crohn's disease, the other, ulcerative colitis), and 5 relative pairs with ulcerative colitis were genotyped in the region of IBDI. Our population consisted of white Americans, with 29% of families of Ashkenazi Jewish descent. Among the Crohn's disease pairs, we found evidence for linkage at IBDI using multipoint analysis, p = 0.0082. Negative linkage scores were obtained for mixed and ulcerative colitis-only relative pairs. For the entire data set, including mixed relative pairs and relative pairs with ulcerative colitis, there was no significant evidence of linkage. No difference was observed in the evidence of linkage between Jewish and non-Jewish families. Our studies confirm that IBDI represents a susceptibility locus for Crohn's disease, but not ulcerative colitis.

Infectious complications in 47 patients with hairy cell leukemia were reviewed. Seventeen patients had culture-documented infections, 13 patients had significant clinical infections not documented by culture, and 17 had no serious infections. In the documented group, 64% of the infections were pyogenic and 36% were nonpyogenic. Patients in the two groups with serious infections had an initial median granulocyte count that was significantly lower than the granulocyte count in the uninfected group (P less than 0.05). Ten of the 17 patients with documented infections died, all as a result of their infections. In the uninfected group, two of 17 patients died, both with progressive disease. Four (9%) of the 47 patients had disseminated atypical mycobacterial disease; two of these patients are alive and asymptomatic two and three years, respectively, after the diagnosis of infection.