Clinical Efficacy: Moderate-to-Severe Disease and Maintenance Therapy

Infliximab has also been evaluated for use in patients with ongoing moderate to severely active UC, despite conventional therapy. In 2005, infliximab became the first anti-TNF agent approved by the US Food and Drug Administration (FDA) for use in moderate-to-severe UC. A year later, this approval was extended to include maintenance, as well as induction therapy, and European approval was also granted. This evidence was generated in 2 large, randomized, placebo-controlled, double-blind trials : A ctive Ulcerative C olitis T rials 1 and 2 (ACT 1 and ACT 2). The 2 trials ran concurrently for 3 years at multiple sites over 4 continents. Each trial included 364 patients and studied the effect of infliximab given at doses of 5 or 10 mg/kg at weeks 0, 2, and 6 followed by maintenance treatment scheduled at 8 weekly intervals. Both studies included patients with moderate-to-severe disease activity (defined as a Mayo score >6, with an endoscopic subscore of ≥2) and their inclusion criteria regarding concomitant medications differed only slightly. Both included patients taking corticosteroids and/or thiopurines as well as those who were no longer taking them but had previously failed or had contraindications (or intolerance) to these medications in the past. In addition to these groups, ACT 2 also included 5-aminosalicylate drugs using the same criteria. Therefore, patients did not necessarily need to be receiving corticosteroids at baseline (61% and 51% were in ACT 1 and 2, respectively). Although the 2 studies had identical induction regimens, the duration of treatment and follow-up period differed. Patients were given maintenance treatment until week 46 in ACT 1 and followed until 56 weeks. In ACT 2, the corresponding time points were week 22 and 30. Clinical response at week 8 was the primary endpoint of the ACT trials. The authors defined this as a decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Both trials showed that patients treated with infliximab (at either dose) were significantly more likely to have a clinical response at week 8 and 30. The 2 dosing regimens delivered similar efficacy, and response rates at these time points in treated patients were greater than 60% at week 8 and greater than 47% at week 30. Placebo response rates were less than 38% and 30% at the corresponding time points. With its extended follow-up period, ACT 1 showed this response to be durable at week 54 with 45.5% and 44.3% of treated patients (5 mg/kg and 10 mg/kg, respectively) responding compared with 19.8% on placebo. Clinical remission rates followed a similar pattern to clinical response and the effect of infliximab was again significant. In ACT 1, remission rates at 54 weeks were 34.7%, 34.4%, and 16.5% of patients treated with infliximab 5 mg/kg, 10 mg/kg, or placebo, respectively ( P = .01).

Corticosteroid-Free Remission

Remission in the absence of corticosteroid treatment has become an important endpoint for clinical trials in UC. Of the 61% of patients in ACT 1 on steroids at baseline, the proportion in clinical remission following corticosteroid cessation at week 30 was significantly higher with infliximab 5 mg/kg than with placebo (24.3% vs 10.1%, respectively; P = .03). The durability of this effect was evident at week 54 when the corresponding corticosteroid-free remission rates were 25.7% versus 8.9%, respectively ( P = .006). Furthermore, at baseline, the median dose was 20 mg/d in all groups. By week 54, this had fallen to 5 mg/d in the group given infliximab 5 mg/kg, whereas it remained at 20 mg/d in the placebo group.

Mucosal Healing

MH is an outcome measure with important implications for remission rates, future steroid use, and risk of colectomy in UC. Evidence is growing that complete mucosal reconstitution or significant improvement of endoscopic appearance can have multiple clinical benefits. MH was defined in the trials as a Mayo endoscopic subscore of 0 or 1 following treatment. Analysis of data from ACT 1 using this definition showed that at all time points, 5 mg/kg infliximab was significantly superior to placebo in this regard. At week 8, 62% achieved MH on this dose compared with 33.9% on placebo. This difference was maintained at weeks 30 (50.4% vs 24.8%, respectively) and 54 (45.5% vs 18.2%, respectively) with all comparisons reaching statistical significance ( P <.001).

As debate is on-going regarding whether Mayo grade 1 (abnormal vascular pattern and some friability but no erosions, ulcerations, or active bleeding) should be included in the group achieving MH, subgroup analysis including only those with grade 0 (completely normal mucosa) has subsequently been carried out. Using this more stringent definition, MH was achieved in 22.3% of infliximab patients and 12.4% of placebo patients at week 8, and 32.2% and 15.7%, respectively, at week 54.

Hospitalizations, Colectomy, and Long-Term Efficacy

Hospitalization and colectomy rates from the ACT trials were studied in a post-hoc analysis, which included 630 (87%) of the original 728 patients. When assessed at week 54, the cumulative incidence of colectomy was 10% in the infliximab-treated group compared with 17% in the placebo group ( P = .02). Infliximab therefore delivers an absolute risk reduction of 7% for colectomy in patients with moderate-to-severe UC. In their post-hoc analysis, the authors also showed that infliximab halved the rate of hospital admissions compared with placebo. Through week 54, there were 40 hospitalizations per 100 patient-years (PY) in the placebo group and 20 per 100 PY with infliximab ( P = .003).

To assess the long-term efficacy, effect on quality of life (QoL), and safety of infliximab, a 3-year open-label extension to the ACT trials was carried out. Any patient participating in the original trials who could benefit from ongoing treatment, as deemed by the investigator (without specific criteria), was eligible for inclusion. Ongoing infliximab, given at 8 weekly intervals, was shown to deliver maintained clinical benefit and health-related QoL while reducing corticosteroid use.

Combination Therapy Versus Monotherapy

Panaccione and colleagues conducted the UC SUCCESS trial to compare the efficacy of infliximab monotherapy with the combination of infliximab and azathioprine. To compare these 2 approaches, they recruited 239 biologic-naïve patients with moderate-to-severe UC (Mayo score ≥6). Ninety percent were azathioprine-naïve and 10% had stopped azathioprine more than 3 months before trial entry. The original trial design had planned the enrollment of 600 patients to the first phase (described here) to allow 200 to subsequently enter a longer-term observational study in the second phase. However, enrollment was terminated prematurely by the sponsor, because of higher than expected serious infusion reactions with an intermittent infliximab regimen in an unrelated study of patients with psoriasis. Patients were randomized to 1 of 3 treatment arms: azathioprine and placebo; infliximab and placebo; infliximab and azathioprine. A standard induction regimen of 5 mg/kg infliximab and/or 2.5 mg/kg azathioprine was administered to the relevant groups and endpoints were judged at week 16. The primary endpoint investigated was steroid-free remission (defined as total Mayo score ≤2 with no subscore >1). In this regard, combination therapy performed significantly better than either infliximab (40% vs 22%, P = .017) or azathioprine (40% vs 24%, P = .032) alone. Patients on combination therapy were significantly more likely to achieve MH (endoscopic Mayo of 0 or 1) than those on azathioprine monotherapy. MH rates were 63% with combination therapy compared with 55% with infliximab monotherapy ( P = .295) and 37% with azathioprine monotherapy ( P = .001).

Safety

The TREAT (Crohn T herapy, R esource, E valuation, and A ssessment T ool) registry was designed specifically to investigate the long-term safety of anti-TNF therapy in patients with Crohn disease (CD). More than 5 years of data from this ongoing, prospective, observational study was published in 2012 and, although the study only includes patients with CD, results are certainly relevant to anti-TNF-treated patients with UC. Based on analysis of more than 6000 patients, the authors demonstrated no increase in mortality or neoplasia between patients receiving infliximab and those receiving other treatments only. Analysis of this data also confirmed the increased risk of serious infections that had been previously seen (hazard ratio 1.98; 95% confidence interval [CI] 1.11, 1.84; P = .006). It should be noted, however, that increased risk was not relative to cumulative infliximab dose because neither the number of infusions nor the dose escalation to 10 mg/kg significantly impacted it.

Of significant concern in the treatment of fulminant colitis with infliximab is its possible effect on postoperative complication rates among nonresponder who require colectomy. This group of patients are often already at increased risk of infectious complications owing to the use of immunomodulators and corticosteroids. A literature review and meta-analysis of trials have been conducted to examine this issue. Although the studies included are all retrospective, use different endpoints, and report mixed results, limited conclusions can be drawn. It seems that if the use of preoperative infliximab increases the risk of postoperative complications (infectious or otherwise) at all, the effect is minimal.

Clinical Efficacy: Rescue Therapy

Before infliximab, therapeutic options for patients with severe or fulminant colitis unresponsive to IV corticosteroids were only cyclosporin or colectomy. Given the risks for toxicity with cyclosporin, the benefit of infliximab in clinical trials of moderate-to-severe UC suggested a potential alternative for patients hospitalized with severe UC. However, until recently the 2 agents had not been compared in a head-to-head trial to assess their relative efficacy. This comparison was recently carried out in a study involving 27 centers in France and Belgium as part of a parallel, open-label, RCT. Patients experiencing a severe flare (defined as a Lichtiger score >10) with an insufficient response to IV corticosteroids received either cyclosporin (2 mg/kg/d for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg at 0, 2, and 6 weeks). All 115 patients included were naïve to the trial agents and those with a satisfactory response to either drug commenced azathioprine at day 7. The primary outcome was “treatment failure,” and the authors defined this as the absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Failure of therapy was seen in 60% (35) of those receiving cyclosporin and 54% (31) given infliximab (absolute risk difference 6%, 95% CI −7 to 19; odds ratio 1.3, 95% CI 0.6–2.7). Roughly 85% of patients in both groups had a clinical response at day 7 measured by the Lichtiger score (a secondary endpoint). The proportion of severe adverse events was also similar among the 2 arms with 9 (16%) and 14 (25%) suffering these in the cyclosporin and infliximab groups, respectively. No deaths and few serious infections were reported. Overall, the authors concluded that treatment choice should be guided by physician and center experience. When considered in the context of the monitoring cyclosporin blood levels, the significant potential toxicity of cyclosporin, and the emerging evidence regarding the pharmacodynamics of infliximab, infliximab may soon become the rescue therapy of choice for many practitioners. The overriding practical issue in relation to cyclosporin is that its use is restricted to centers that can regularly monitor concentrations and have sufficient clinical experience in the use of drugs not routinely used in outpatient practices. Evidence has also emerged demonstrating that patients with severe, steroid-refractory colitis may fail to respond to infliximab because of accelerated clearance of the drug. Dose optimization with higher or more frequent doses may therefore improve response rates, an aspect that was not studied in the head-to-head comparison. This theory is supported by post-hoc analysis from the ACT 1 and 2 demonstrating that higher infliximab trough concentrations were associated with greater likelihood of response, remission, and MH than were low or absent trough concentrations.

It is also important to consider the patient who has a severe flair despite thiopurine maintenance therapy in whom there is no subsequent maintenance option if rescue cyclosporin is chosen and succeeds. Infliximab, therefore, has a significant advantage in this group. Further data regarding the efficacy and cost-effectiveness of each agent will be available when the UK-wide CONSTRUCT trial ( CO mparison of i N fliximab and cyclosporin in ST eroid R esistant U lcerative C olitis: a T rial) is completed in August 2014.