Infliximab Helpful for Moderate to Severe Crohn's Disease

Laurie Barclay, MD

April 14, 2010

April 14, 2010 — Patients with moderate to severe Crohn's disease treated with infliximab with or without azathioprine are more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy, according to the results of a randomized, double-blind trial reported in the April 15 issue of the New England Journal of Medicine.

"Anti-TNF [tumor necrosis factor] biologics and combination therapy are clearly superior to azathioprine in patients with moderate to severe Crohn's disease who are failing first-line therapy with mesalamine and/or steroids," coauthor William J. Sandborn, MD, vice chairman, Division of Gastroenterology and Hepatology, Mayo Clinic, and professor of medicine, Mayo Clinic College of Medicine in Rochester, Minnesota, told Medscape Gastroenterology. "Combination therapy is the most effective strategy."

Jean Frédéric Colombel, MD, from Centre Hospitalier Universitaire de Lille, Université Lille Nord de France, and colleagues from the Study of Etiologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) Study Group note that before this study, the comparative efficacy and safety of infliximab and azathioprine used alone or in combination for Crohn's disease were unknown.

The purpose of this study was to determine the efficacy of infliximab monotherapy, azathioprine monotherapy, and infliximab plus azathioprine in 508 adults with moderate to severe Crohn's disease who were not previously treated with immunosuppressive or biologic therapy. Patients were randomly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; 2.5 mg of oral azathioprine per kilogram daily plus a placebo infusion on the standard schedule; or combination therapy with both drugs. Study medication was administered through week 30, and patients were permitted to continue in a blinded study extension through week 50.

The primary endpoint of corticosteroid-free clinical remission at week 26 was noted in 96 (56.8%) of the 169 patients receiving combination therapy, 75 (44.4%) of 169 patients receiving infliximab alone (P = .02), and 51 (30.0%) of 170 patients receiving azathioprine alone (P < .001 vs combination therapy and P = .006 vs infliximab). At week 50, findings were similar.

Mucosal healing at week 26 was noted in 47 (43.9%) of 107 patients in the combination-therapy group, 28 (30.1%) of 93 patients in the infliximab group (P = .06), and 18 (16.5%) of 109 patients in the azathioprine group (P < .001 vs combination therapy and P = .02 vs infliximab). Serious infections occurred in 3.9% of patients receiving combination therapy, 4.9% of those receiving infliximab, and 5.6% of those receiving azathioprine.

"Side effects were similar in all 3 treatment groups," Dr. Sandborn said. "Clinical practice should change such that combination therapy is used in many if not most patients who are failing first-line therapy."

On the basis of these findings, the investigators concluded that patients with moderate to severe Crohn's disease who received infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission vs those receiving azathioprine monotherapy.

"In light of these results, the most important clinical implication is that physicians may be authorized to treat Crohn's disease patients with infliximab without any prior treatment with immunosuppressant," Antonio Tursi, MD, from the Gastroenterology Service, Azienda Sanitaria Locale Barletta-Andria-Trani (ASL BAT) in Andria, Italy, told Medscape Gastroenterology when asked for independent comment. "It is probable that this approach may increase the cases of early inflammatory bowel disease that may benefit from this treatment, and that it may modify the clinical course of the disease."

Study Limitations and Strengths

The authors acknowledged limitations of this study. First, by excluding patients who had a heterozygous thiopurine methyltransferase phenotype, the investigators may have excluded patients who were more likely to have a response to azathioprine.

However, these patients are also more likely to be intolerant to azathioprine, so the investigators suggest the net effect of these competing forces was unlikely to affect the findings significantly. Second, they also note that the benefits shown for combination therapy may not apply to patients in whom azathioprine has already failed.

"In my opinion, the main strength of this study is that it showed for the first time the efficacy of infliximab alone in inducing and maintaining remission," Dr. Tursi said. "The main limitation is that only about 40% of patients treated with infliximab alone were steroid-free at 26th week of treatment."

Strengths of the study noted by Dr. Sandborn are that this is the first prospective, randomized trial to evaluate the comparative efficacy of azathioprine, anti-TNF biologic, and combination therapy and to show that anti–TNF-based strategies are clearly superior. This study is also the first prospective, randomized trial to evaluate the comparative safety of azathioprine, anti-TNF biologic, and combination therapy and to show that the 3 treatment strategies have generally comparable safety profiles.

"This is the first study in Crohn's disease to require a colonoscopy at baseline in all patients, and to do follow-up colonoscopies in most patients," Dr. Sandborn said. "The benefits of the anti-TNF biologic and combination therapy primarily were seen in the 82% of patients who had ulcers in the colon and/or terminal ileum at the baseline colonoscopy."

Other limitations noted by Dr. Sandborn are that the 1-year study duration is too short to evaluate the impact of the therapies on surgery and disease progression and that with 508 patients, the study may be too small to detect differences in very rare adverse effects, such as lymphoma.

"Patients with symptoms of moderate to severe Crohn's disease should undergo evaluation for objective measures of inflammation such as C-reactive protein (CRP) and colonoscopy," Dr. Sandborn said. "Only patients who have objective evidence of inflammation should undergo therapy intensification with azathioprine, anti-TNF biologics, or combination therapy."

More Research Needed

Regarding additional research, Dr. Tursi recommends confirming these findings in patients with ulcerative colitis and performing further investigation on combined treatment.

"The combined treatment (infliximab plus azathioprine) seems to be better than infliximab alone in obtaining and maintaining remission, and it was also better in assessing several other secondary endpoints," Dr. Tursi said. "Further studies are needed to investigate the costs and the long-term side-effects profile of the combined treatment compared to infliximab alone. Moreover, further studies should investigate whether it is better to start with a combined therapy and to stop azathioprine after some months (e.g. after 6 months) or to start directly with infliximab alone."

"Longer term studies (18 - 24 months or longer) with larger sample size (1000 patients or more) should be undertaken to determine if combination therapy is more effective then azathioprine for preventing disease progression (development of the complications of stricture, fistula, abscess) and for preventing surgery," Dr. Sandborn concluded.

Research grants from Centocor Ortho Biotech and Schering-Plough supported this study. Dr. Sandborn has served as a consultant for Centocor Ortho Biotech (fees paid to Mayo Clinic) and has received research support from Centocor Ortho Biotech. Several of the other study authors have disclosed various financial relationships with the study sponsors and other pharmaceutical companies. Complete details of these disclosures are available in the original article.

Dr. Tursi has disclosed no relevant financial relationships.

N Engl J Med. 2010;362:1383-1395.

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