Nearly 40 years have passed since Sidney Truelove and Derek Jewell1 first reported that intravenous steroid hormones were effective in the treatment of severe ulcerative colitis. However, once steroid hormone therapy fails, the likelihood of colectomy increases and few other treatment options are available. Cyclosporine and infliximab have emerged as major rescue drugs for the treatment of hormone-resistant acute severe ulcerative colitis, but the relative efficacy of these two drugs is unclear. The efficacy of intravenous cyclosporine in the treatment of severe ulcerative colitis was first identified in a preliminary uncontrolled study. In a subsequent placebo-controlled trial of 20 patients,3 intravenous cyclosporine was found to be effective in treating hormone-resistant ulcerative colitis at doses up to 4 mg/kg. This study was terminated prematurely because the favorable effects of cyclosporine were much greater than originally envisioned, thus not yielding an accurate assessment of the drug’s efficacy. In subsequent dose exploration trials, the results were similar for intravenous cyclosporine 2 mg/kg and 4 mg/kg per day.5 Many clinicians believe that intravenous cyclosporine is the most effective drug for the treatment of hormone-resistant ulcerative colitis, but the drug’s toxic side effects limit its use. In all these studies of cyclosporine, patient selection and assessment of disease activity were based on an unvalidated evaluation method, the Lichtiger score, or a modified Truelove and Witts index.2 The Lichtiger score for disease activity correlates poorly with other evaluation methods, and the clinical significance is not clear. In the outpatient setting, infliximab is effective in patients with moderately to severely active ulcerative colitis. Although infliximab has been included in clinical guidelines as an alternative to cyclosporine in the treatment of severe ulcerative colitis, there is no literature demonstrating the efficacy of infliximab for this indication. In an earlier placebo-controlled trial of 11 patients, infliximab had better results than placebo (not statistically significant). A placebo-controlled study consisting of 45 patients showed that in patients with hormone-resistant severe ulcerative colitis given infliximab, the rate of colon resection was significantly lower in these patients. The lack of clinical evidence on the relative effectiveness of cyclosporine and infliximab, and the application of different methods to evaluate their effectiveness in clinical trials, limits the optimal evidence-based treatment of hormone-resistant severe ulcerative colitis. In The Lancet, David Laharie and colleagues answer this question with the results of a long-awaited, multi-national trial comparing intravenous cyclosporine with infliximab in the treatment of severe ulcerative colitis. The trial established a well-defined target population, comparing the efficacy of cyclosporine and infliximab, and treatment failure was defined by several clinical endpoints and disease activity parameters. Laharie and colleagues defined acute severe colitis as a Lichtiger score of more than 10 and enrolled patients with hormone-resistant colitis who had received at least 5 days of intravenous steroid hormone therapy. Patients were randomly assigned to receive intravenous cyclosporine 2 mg/kg daily or infliximab 5 mg/kg at weeks 0, 2, and 6. All patients were given azathioprine therapy. Treatment failure (primary endpoint) at any time period was defined more broadly as clinical non-response by day 7, relapse of disease between days 7 and 98, failure to remit after discontinuation of hormones at day 98, serious adverse events leading to treatment discontinuation, colectomy, or death. At day 98, treatment failure occurred in 35 of 58 patients (60%) in the cyclosporine group and in 31 of 57 patients (54%) in the infliximab group (absolute risk difference 6%, 95% CI -7-19, OR 1.3, 95% CI 0.6-2.7). In both groups approximately 85% of patients experienced a clinical reaction at day 7 according to the Lichtiger score (secondary endpoint). The rate of serious adverse reactions in patients was similar in both groups (9 [16%] in the cyclosporine group vs. 14 [25%] in the infliximab group), with no deaths and few cases of serious infections. In previous trials, the efficacy of cyclosporine in severe ulcerative colitis has usually been evaluated solely on the basis of the Lichtiger score, which certainly overestimates efficacy. the study by Laharie and colleagues comparing the efficacy of infliximab and cyclosporine was somewhat limited by the small sample size (30% difference detected with 80% statistical power). However, the importance of this potential type II error (e.g., missing differences in efficacy between the two drugs) requires several points in the article to be explained in context. First, the application of cyclosporine is limited to clinical centers that are able to test concentrations regularly and have sufficient experience with the drug, rather than routinely using it in an outpatient setting. Second, a high rate of adverse reactions (nephrotoxicity, hirsutism, opportunistic infections, mortality of 1-2%) was reported in patients to whom cyclosporine was applied, thus limiting the use of this drug.12 Finally, the regimen of infliximab may not have been the optimal dose for all patients in this trial, whereas the maximum dose was applied for cyclosporine. Patients with hormone-resistant severe ulcerative colitis who proved to be treatment failures in the infliximab group had accelerated drug clearance in their bodies; these patients may require larger doses or multiple dosing. Similarly, post-hoc analyses in the ACT1 and ACT2 trials showed14 that higher infliximab trough concentrations showed better response, remission, and mucosal healing compared with lower infliximab. Laharie and colleagues provided clinicians with a randomized controlled trial for the treatment of severe hormone-resistant ulcerative colitis that gave clinicians the primary efficacy endpoint that actually worked thereby guiding their decision. Because cyclosporine lacks significant advantages, is difficult to administer, is unsafe, and cannot be used as maintenance therapy (due to toxicities), we estimate that most physicians would prefer infliximab for treating this patient population. In the future, we need to develop a proven method for assessing disease activity in hospitalized patients with ulcerative colitis, monitor the effects of infliximab in real-time therapy to determine the optimal dose for patients with enhanced clearance; and compare the efficacy of intravenous hormone alone with hormone in combination with infliximab as the primary induction therapy for treating patients with severe ulcerative colitis. In the meantime, Laharie and his colleagues’ experimental results were sufficient to change clinical practice.