Weighing the Benefits of Combination Therapy in Crohn's Disease

Recent studies suggest that combination therapy with infliximab and azathioprine is more effective than monotherapy in patients with newly diagnosed Crohn's disease, but patients with more established Crohn's disease do not derive any extra benefit from triple therapy with infliximab, methotrexate, and prednisone compared to double therapy with infliximab and prednisone.

Inflammatory bowel diseases (IBD) comprising Crohn’s disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases that are associated with considerable morbidity. The therapeutic advances over the past decade have significantly improved our ability to achieve control of these diseases.

In particular, the monoclonal antibodies to tumor necrosis factor α (anti-TNF) have been very effective in achieving remission, and reducing the need for hospitalization and surgery. Recent studies have shown that when these agents are used early on in the course of disease or in combination with more traditional immunomodulator agents like azathioprine, there is an increase in likelihood of achieving disease remission.

While the data on the incremental risks associated with combination therapy, particularly with regard to infection and cancers, have been conflicting, it remains an important concern to patients and providers. The results from the SONIC trial published in the New England Journal of Medicine in 2010 showed that in patients who were naive to immunomodulator therapy, a combination of azathioprine and infliximab performed significantly better than either agent when used alone.

Results from a randomized controlled trial by Feagan and colleagues, the COMMIT study, examining the role of adding methotrexate to infliximab in the treatment of Crohn’s disease was published in the March issue of Gastroenterology. This study was conducted at 15 centers in Canada and included patients with active Crohn’s disease who had initiated between 15-40 mg/day of prednisone within 6 weeks before entry into the trial. Patients who had been treated previously with methotrexate or infliximab were excluded as were patients who had recently had surgery, had a stoma, or had other serious chronic diseases or risk factors that placed them at a high risk for complications.

Patients were then randomized to receive either 25 mg weekly of methotrexate injected subcutaneously (with this dosing gradually achieved over 5 weeks) in conjunction with infliximab 5 mg/kg every 8 weeks (after the standard week 0, 2, and 6 induction dosing) or infliximab alone. A tapering schedule of prednisone was begun at week 1 and the study ran for a total of 50 weeks.

A total of 126 patients entered the study with the median Crohn's Disease Activity Index (CDAI) score at entry for both groups being 207 and just under half the patients having a CDAI score > 150 (which would be considered active disease).

At the end of the study, there was no difference between groups in proportion of patients who were in remission free of corticosteroid use (76% vs. 78%), or in patients who achieved normalization of their CRP. Investigators also found no real differences between the groups in quality of life measures. Patients who were on methotrexate were less likely to develop antibodies and had higher serum trough infliximab concentrations.

What are the implications of this study? And how should these results be interpreted in the context of the SONIC study last year that demonstrated that combination azathioprine-infliximab therapy worked better than either agent alone? The key differences between SONIC and the COMMIT study is that patients who entered this study were less sick than those in the SONIC trial and had all likely already started feeling better by the entry into this trial.

Thus, it appears that in patients who are being induced with corticosteroids, adding an immunosuppressant to a biologic seems to be less effective than in patients in whom this is the primary therapy. However, consistent across both trials, patients who are on both treatments have lower levels of antibody formation to infliximab and higher trough levels, both of which have been linked to better long-term outcomes. Reassuringly, neither trial showed any safety concerns with combination therapy.

In summary, in terms of efficacy, the literature so far suggests that in patients with newly diagnosed Crohn’s disease, double therapy (infliximab+azathioprine) is better than monotherapy, but that in patients with more established Crohn’s disease, triple therapy (infliximab+methotrexate+prednisone) is not any better in terms of clinical endpoints when compared to double therapy (infliximab+prednisone). The effect of combination therapy on pharamacokinetics continues to suggest that this has an important role in optimizing the performance of biologic therapy but that continued study is warranted to define the right patient population for this approach.

Ashwin Ananthakrishnan, MD, is an assistant professor of medicine at Harvard Medical School and the Massachusetts General Hospital. He practices at the MGH Crohn’s and Colitis center and specializes in clinical care of patients with inflammatory bowel diseases. He is also an active clinical researcher, supported by various research grants.