NEW YORK (Reuters Health) – In adults with moderate-to-severe active Crohn’s disease, treatment with infliximab plus azathioprine, or infliximab alone, led to significantly higher rates of corticosteroid-free clinical remission and mucosal healing than treatment with azathioprine alone.
“The development of infliximab has been a major advance in the management of Crohn’s disease (CD), yet many key questions remain regarding optimization of therapeutic strategies,” lead author Dr. Jean Frederic Colombel, from Hopital Claude Huriez, Lille, France told Reuters Health by email. “These include when to start infliximab, how to use it and especially whether it should be used before, started with, added to, or used after conventional immunomodulators and finally for how long treatment should be maintained.”
The SONIC trial, involving 508 adults with moderate-to-severe active Crohn’s disease naïve to immunomodulators, was performed to address some of these questions. Study patients were either dependent on corticosteroids, were being considered for a second course of steroids, or had not responded to at least 4 weeks of either mesalamine or budesonide.
The investigators randomly assigned them to three groups: intravenous infliximab, 5 mg/kg plus daily oral placebo; oral azathioprine, 2.5 mg/kg plus placebo infusions; or a combination of the two drugs. Infusions were given at weeks 0, 2, and 6 and then every 8 weeks through week 30, after which patients could continue in a blinded extension through week 50.
As reported April 15th in The New England Journal of Medicine, the proportion of patients in steroid-free remission at week 26 (the primary endpoint) was higher with combination therapy (56.8%; 96 of 169) than with infliximab (44.4%; 75 of 169) or azathioprine (30.6%; 51 of 170). The p values were < 0.001 for combination therapy vs. azathioprine; p=0.006 for infliximab vs azathioprine; and p=0.02 for combination therapy vs. infliximab.
At baseline, 325 patients had mucosal ulcerations — 111 of 169 (65.7%) in the combination therapy group, 99 of 169 (58.6%) in the infliximab group and 115 of 170 patients (67.6%) in the azathioprine group.
The proportion of patients with complete mucosal healing at week 26 (the secondary endpoint) was 43.9% (47 of 107 patients) with combination therapy; 30.1% (28 of 93 patients) with infliximab; and 16.5% (18 of 109 patients) with azathioprine (p<0.001 for combination therapy versus azathioprine; p=0.02 for infliximab versus azathioprine; p=0.06 for combination therapy vs infliximab).
In post hoc analyses, the researchers observed that patients with objective evidence of inflammation – such as a high C-reactive protein (CRP) level or mucosal lesions — had the best clinical results with infliximab.
On the other hand, “in patients with normal CRP or no endoscopic lesions, no significant differences were observed among treatments,” Dr. Colombel reported. These observations suggest that “CRP and endoscopy may serve as predictors of patients who are most likely to respond to infliximab or combination therapy,” he said.
The results of the extension study at week 50 confirmed the superiority of infliximab over azathioprine and of combination therapy over infliximab alone for achieving long-term steroid-free clinical remission.
Safety, including the proportion of patients with serious infections, was similar in all treatment groups. Thirty-eight azathioprine patients, 20 infliximab patients, and 28 combination therapy patients withdrew because of adverse events. Rates of serious infections, including tuberculosis, were 3.9% in the combination arm, 4.9% with infliximab, and 5.6% with azathioprine.
Dr. Colombel told Reuters Health that the results of this trial “provide the best evidence so far that positioning biologics early in the (inflammatory bowel disease) treatment algorithm (a ‘top-down’ strategy) results in superior outcomes compared with the current step-up strategy, in which biologics are used only in patients failing conventional therapies or who are steroid dependent.”
The results also “support the use of combination dual therapy with infliximab and azathioprine in patients naïve to immunomodulators.”
“The concern that remains with the long-term top-down dual approach,” Dr. Colombel continued, “is an increased risk of toxicity with infectious complications as well as an increased risk of lymphoma. Crohn’s disease is a heterogeneous disease and ultimately, we must weigh the safety and efficacy of the therapies with the risks of the disease itself in each patient.”
The study was supported by research grants from Centocor Ortho Biotech and Schering-Plough.
N Engl J Med 2010;362:1383-1395.