ORLANDO — Infliximab, alone or in combination with azathioprine, was superior to azathioprine monotherapy for inducing steroid-free remission and mucosal healing in a study of 508 patients with moderate to severe Crohn's disease.
Many physicians who treat Crohn's disease patients with the anti-tumor necrosis factor-? agent infliximab (Remicade) do not use it first line, Dr. William J. Sandborn said. However, based on the study findings, doctors might want to consider prescribing the agent sooner, forgoing the classic step-up therapy, he said.
“We have compelling evidence that anti-tumor necrosis factor therapy should be considered in patients [earlier],” Dr. Sandborn said at the annual meeting of the American College of Gastroenterology.
The multicenter, phase IIIb Study of Biologic and Immunomodulator-Naive Patients with Crohn's Disease (SONIC) included people who had previously failed 5-aminosalicylate therapy and/or who were steroid dependent. A total of 41% of participants were taking steroids at baseline; 52% were men, and the mean age was 34 years. The median baseline Crohn's Disease Activity Index was 275.
As the study name suggests, participants had no prior exposure to biologic or immunomodulator agents, including azathioprine (Imuran), 6-mercaptopurine, and methotrexate. A meeting attendee commented that many previous trials showed no significant benefit when azathioprine was added to infliximab. “All other trials were retrospective and looked at patients who failed azathioprine previously, whereas if you are naive to the drugs, you have a better chance of getting synergy,” Dr. Sandborn replied. Use of azathioprine in the United States is off label for Crohn's disease.
“As early as week 6, infliximab (either as monotherapy or in combination with azathioprine) was superior to azathioprine for corticosteroid remission, and in addition the combination was also superior to infliximab monotherapy after 10 weeks,” said Dr. Sandborn, professor of medicine and vice chair of the division of gastroenterology and hepatology, Mayo Clinic, Rochester, Minn.
Participants were randomized into three groups. In all, 170 received azathioprine 2.5 mg/kg per day plus a placebo infusion; another 169 received a placebo capsule and infliximab 5 mg/kg infusions; and the 169 others in the combination group received azathioprine 2.5 mg/kg and infliximab 5 mg/kg infusions. The infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through 30 weeks.
At 26 weeks, corticosteroid-free clinical remission was achieved by 31% of the azathioprine monotherapy group, 44% of the infliximab monotherapy patients, and 57% of the combination group.
Also at 26 weeks, a secondary end point of mucosal healing was achieved by 17% of the azathioprine monotherapy group, 30% of the infliximab monotherapy patients, and 44% of the combination group.
“Infliximab and azathioprine, when started together, are superior to azathioprine alone. Infliximab monotherapy was superior to azathioprine monotherapy,” said Dr. Sandborn, the principal investigator for the SONIC trial. Centocor Inc., manufacturer of infliximab, funded this research. Mayo Clinic receives consulting fees for work provided by Dr. Sandborn from Centocor, Abbott Laboratories, and UCB Pharma. Dr. Sandborn had no disclosures related to azathioprine.
A subgroup of 204 patients had both elevated C-reactive protein levels and lesions on baseline examination. In this subgroup, corticosteroid-free clinical remission was attained by 28% of the azathioprine monotherapy group, 57% of the infliximab monotherapy group, and 69% of the combination group. Dr. Sandborn said this was “a very significant finding.”
At week 30, a higher proportion of patients in the azathioprine monotherapy group, 24%, experienced at least one serious adverse event, compared with 16% of the infliximab monotherapy group and 14% of the combination therapy group.
The rate of serious infections was relatively low and was similar across treatment groups, Dr. Sandborn said. Specifically, eight serious infections were reported in the azathioprine monotherapy group, four occurred in the infliximab monotherapy group, and there were six in the combination therapy group.
'Anti-tumor necrosis factor therapy should be considered in patients [earlier].' DR. SANDBORN