Infliximab | place in therapy review Table 3 | Summary of outcomes with infliximab in adult ulcerative colitis patients Placebo controlled, early termination 11 All patients i.v. steroid refractory 50% infliximab response, 0% placebo response Sands et al. 2001 Design Placebo controlled Placebo controlled Placebo controlled Active comparator, open label Active comparator, open label Open label, retrospective Open label Open label, retrospective Open label, retrospective Open label, retrospective Open label, retrospective i.v., intravenous. No. of patients 43 45 728 20 13 16 27 7 13 8 6 Baseline steroid use Key outcomes All patients steroid refractory Infliximab not superior to placebo All patients i.v. steroid refractory Infliximab superior to placebo 30% steroid refractory Infliximab (5 and 10 mg/kg) superior to placebo Rutgeerts et al. 2005 Steroid-refractory patients excluded Efficacy comparable to oral steroids Steroid-refractory patients excluded Efficacy comparable to oral steroids All patients steroid refractory 88% response Improved response rates in steroid- 66% response, 44% remission responsive disease 6/7 steroid responsive 5/6 response (all steroid responsive) All patients i.v. steroid refractory 77% response rate All patients steroid refractory 50% immediate colectomy, 4/6 response All patients steroid refractory 6/6 improvement, 4/6 remission Reference Probert et al. 2003 Järnerot et al. 2005 Armuzzi et al. 2004 Ochsenkühn et al. 2003 Chey et al. 2001 Su et al. 2002 Bermejo et al. 2004 Kohn et al. 2002 Actis et al. 2002 Kaser et al. 2001 clinical response rate in all six steroid-refractory patients treated with intravenous infliximab has also been observed (Kaser et al. 2001). In contrast, Actis et al. (2002) showed a short-term colectomy rate of 50% and a sustained response rate of only 25% in eight steroid-refractory patients treated with infliximab in an open-label study. Level 2 evidence These conflicting results achieved in open-label studies needed to be challenged or confirmed in controlled studies. In 2003 the results of a European, double-blind, randomized, controlled trial with infliximab in steroid-resistant UC were published. This trial enrolled 43 patients with active UC colitis resistant to oral glucocorticosteroids (prednisolone ≥30 mg) (Probert et al. 2003). Endoscopically active disease was present in all subjects at inclusion. The Barron endoscopic score was used in this trial which includes roughly the same criteria as more recently developed scores (e.g. Mayo score, mentioned below). Mucosal friability, erosions and ulcers, and fading of the vascular pattern constitute the key criteria of most of these endoscopic scores. Patients were treated at weeks 0 and 2 with intravenous infliximab 5 mg/kg or placebo. At 6 weeks no difference in clinical remission was observed between infliximab- and placebo-treated patients (39% vs 30%). Also, the median improvement in the Barron endoscopic activity score or the proportion of patients achieving a score of 0 (endoscopic remission) was not different between both groups (endoscopic remission 26% with infliximab vs 30% with placebo). Patients were offered open-label intravenous infliximab 10 mg/kg once and every 8 weeks thereafter if they did not respond after 6 weeks, but the investigators were not unblinded at this time point. Of the patients treated in this open- label phase with infliximab, remission was achieved in 27% (3/11) and 11% (1/9) of the original infliximab and the placebo groups, 156 respectively. No differences in the occurrence of serious adverse events were noted and one patient in the placebo group had a colectomy during the intervention period. Two large multicenter trials sufficiently powered to assess the true therapeutic potential of infliximab in active, moderate to severe UC have now been published (Rutgeerts et al. 2005). The Active Colitis Trials, ACT-1 and ACT-2, enrolled 728 patients in 171 centers worldwide. Each of the trials recruited patients with clinically and endoscopically active disease. Patients were randomized to receive infliximab 5 mg/kg, infliximab 10 mg/kg, or placebo at week 0, 2, and 6 and than every 8 weeks thereafter for 22 weeks (ACT-1) or 46 weeks (ACT-2) in total. Apart from the duration of treatment, the main difference between the two trials was the fact that patients in ACT-2 were allowed to fail only mesalamine whereas in ACT-1 only patients failing steroids and/or purine analogs were eligible. All these drugs were continued for the entire treatment phase of the two trials, except for steroids, which were tapered from week 8. Efficacy assessment was based on an intention-to-treat analysis and the primary endpoint was clinical response at week 8 based on the Mayo disease activity score (Schroeder et al. 1987). This score has been developed to assess the efficacy of mesalamine and encompasses criteria of stool frequency, rectal bleeding, findings at endoscopy, and physician’s global assessment (Table 4). Again, the clinical criteria used in the Mayo score are based on the clinical activity index developed earlier and used in other trials with infliximab in UC. The score can vary between 0 and 12, and patients with scores of 6 to 10 inclusive were eligible. Endoscopic activity of at least 2 (loss of vascular pattern and at least mucosal erosions) on the Mayo scale was also a necessary inclusion criterion. The primary endpoint of clinical response was defined as a decrease of at least 3 points and at least 30% in the total Mayo score. Secondary endpoints were clinical remission (total Mayo score of 2 points or lower with a maximum of 1 in any of the subscores) © 2007 Core Medical Publishing Limited