DDW: Methotrexate Adds No Benefit to Infliximab (Remicade) in Crohn's Disease
By John Gever, Staff Writer, MedPage Today
Published: May 23, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine
Action Points
Explain to interested patients that the study found no benefit from adding methotrexate to infliximab (Remicade) therapy in Crohn's disease.
Explain that infliximab and methotrexate are each approved individually for Crohn's disease.
Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
SAN DIEGO, May 23 -- Although both methotrexate and infliximab (Remicade) are known to be effective against Crohn's disease, combining them provides no extra benefit, a researcher said here.
Patients receiving the combination had the same treatment success rate as others treated with infliximab alone in a 50-week, placebo-controlled trial, reported Brian Feagan, M.D., of the Robarts Research Institute in London, Ontario, at Digestive Disease Week.
"Triple induction therapy with methotrexate was not more effective than dual induction therapy followed by infliximab maintenance therapy," he said.
Treatment success was defined by three criteria: score of less than 150 on the Crohn's Disease Activity Index and no clinical need for prednisone supplements at week 14, and no relapse though week 50.
At week 14, 76.2% of patients receiving the combination met the success definition, compared with 77.8% of those taking infliximab and placebo (P=0.83). There were 63 patients in each arm.
Relapse rates were also nearly identical, with 55.6% of combination-treated patients meeting the final success definition at week 50 versus 57.1% of those receiving infliximab and placebo (P=0.86).
Disease duration had no bearing on responses to the combination versus infliximab alone. There were no differences in response rates in patients whose disease onset was less than two years earlier, nor in patients with disease duration of more than 12 years.
Patients in the study were adults with an established Crohn's diagnosis and active symptoms requiring 15 to 40 mg/day of prednisone. Lactating or pregnant women and patients with risk factors for toxicity from the study drugs or recent serious infections were excluded.
Infliximab was given at 5 mg/kg by infusion at weeks one, three, and seven, and every eight weeks thereafter through week 50, with 200 mg of hydrocortisone prior to each infusion. Methotrexate was started at 10 mg weekly by subcutaneous injection, then increased to 25 mg by week seven and continued until week 14. Prednisone was gradually withdrawn over the 14-week induction phase.
Median disease activity scores over the first 14 treatment weeks suggested that the methotrexate-infliximab combination was actually inferior to infliximab alone, although the difference did not reach statistical significance.
Dr. Feagan said that if any advantage for the combination was going to be evident, it would most likely have been in this measure. In fact, the mean score in the combination group at week 14 was about 125, compared with about 100 with infliximab.
Secondary measures of effectiveness, such as scores on the SF-36 health survey instrument, also showed no significant differences between treatments.
There were no major differences in adverse effects in the study, Dr. Feagan said. The most important was that 14 patients in the combination group had disease exacerbations versus four in the infliximab-only group. Infection rates were nearly identical.
Despite the lack of benefit for the combination in the trial, Dr. Feagan said it deserves additional research.
"In my opinion, future studies should concentrate on combination therapy in patients with early disease and in steroid-resistant patients," he said.
Gary Lichtenstein, M.D., of the University of Pennsylvania in Philadelphia, commented that the findings were no surprise.
Earlier studies in his own lab and elsewhere had suggested that combinations of drugs do not add benefit to individual biologic therapies in Crohn's disease, he said.
"In most patients you don't need to add anything. These biologic agents are wonderful drugs by themselves. By adding drugs such as methotrexate or steroids you are just increasing the risk of serious adverse events," he said.
The study was investigator-initiated with support from Schering Canada.
Dr. Feagan reported relationships with Abbott, UCB Pharma, Centocor, Schering-Plough, Novartis, Celgene, Chemocentryx, Procter & Gamble Pharmaceuticals, Otsuka America, Berlex, Santarus, Synta, Genentech, PDL Biopharma, and Elan.
Dr. Lichtenstein reported relationships with Salix, Procter & Gamble, Shire, Axcan, Centocor, UCB, Schering-Plough, Abbott, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Elan, Serono, Wyeth, Millennium, and Protein Design Labs.
Primary source: Digestive Disease Week
Source reference:
Feagan B, "A randomized trial of methotrexate in combination with infliximab for the treatment of Crohn's disease" Digestive Disease Week 2008; Abstract 682c.
