Combination infliximab/azathioprine may be superior to monotherapy for UC

In anti-tumor necrosis factor-alpha–naive patients with moderate to severe ulcerative colitis, combination treatment with infliximab plus azathioprine appears to yield a greater likelihood of corticosteroid-free remission at 16 weeks compared with monotherapy with either agent, according to findings from the UC Success trial.

However, these findings were called into question in a subsequent letter to the editor, which cautioned against prematurely drawing conclusions from the study.

In the randomized, double-blind study conducted at 62 centers, researchers evaluated 239 patients, aged 18 years and older, with moderate to severe ulcerative colitis (UC) as determined by baseline Mayo scores of 6 to 8 (moderate UC) and 9 to 12 (severe UC). To be eligible for enrollment, patients were required to have responded inadequately to a regimen of corticosteroids with or without mesalamine within the previous 12 weeks. Patients were randomly assigned in 1:1:1 fashion to undergo treatment with infliximab (Remicade, Centocor Inc.; IFX), azathioprine (AZA) or combination IFX/AZA.

The IFX regimen consisted of 5 mg/kg intravenous IFX at weeks 0, 2, 6 and 14, plus daily placebo capsules. Those in the IFX group who were nonresponders at week 8 were given placebo infusions at weeks 8 and 10.

The AZA regimen consisted of 2.5 mg/kg AZA capsules daily, plus IV placebo infusions at weeks 0, 2 and 6. Patients who achieved a response to AZA at week 8 underwent a placebo infusion at week 14. Patients who failed to respond to AZA at week 8 underwent IFX rescue infusions at weeks 8, 10 and 14 while continuing the AZA regimen.

Patients in the combined IFX/AZA cohort received IFX 5 mg/kg at weeks 0, 2, 6 and 14 and also were given 2.5 mg/kg AZA capsules per day. Those in this group who did not respond at week 8 also underwent placebo infusions at weeks 8 and 10.

The researchers found that at week 16, corticosteroid-free remission occurred in 39.7% (31 of 78) of patients receiving IFX/AZA vs. 22.1% (17 of 77) in the IFX alone group (P=.017) and 23.7% (18 of 76) of those in the AZA alone group (P=.032). Of patients in the combination IFX/AZA group, mucosal healing was achieved in 62.8% of patients vs. 54.6% in the IFX alone group (P =.295) and 36.8% in the AZA alone group (P=.001).

There were two cases of serious infections, one in the IFX group and one in the AZA group. Adverse events that resulted in discontinuation were numerically higher in the AZA group (8%) than in the IFX group (3%) or the combination group (4%), although this was not statistically significant.

In a letter subsequently published in Gastroenterology, YeongYeh Lee, MD, of the Department of Medicine, Section of Gastroenterology & Hepatology at Georgia Regents University, cited concerns regarding the study’s findings. Specifically, Lee questioned the higher incidence of adverse events in the AZA arm than in the combination arm despite comparable doses, as well as the lower prevalence of infusion reactions noted in IFX and combination arms, which “does not align with previous reports.”

“Based on these concerns, we are skeptical of our readiness for combination therapy in moderate to severe UC,” Lee wrote. “Moreover, it may be misleading for the authors to suggest that combination therapy is superior to monotherapy with ‘either’ agent, when the study did not actually demonstrate a clear superior. Until we have a more robust study, the decision to pursue combination therapy should be individualized and weighed against the risk-benefit ratio, as well as cost.”

For more information:

Panaccione R. Gastroenterology. 2014;doi:10.1053/j.gastro.2013.10.052.

Lee YY. Gastroenterology. 2014;doi:10.1053/j.gastro.2014.03.053.

Disclosure: Please see the full study for a complete list of relevant financial disclosures. Lee reports no relevant financial disclosures.