- In patients with complicated Crohn's disease (CD), the combination of a TNF inhibitor and an immunomodulator was associated with a significant 40% reduction in the risk of a composite adverse outcome, compared with TNF inhibitor monotherapy
- The benefit of combination therapy in CD was most striking in patients with the complicated disease (structuring or penetrating), particularly if started within five years of initial evaluation
- Combination therapy was beneficial in complicated CD regardless of the TNF inhibitor used
- In patients with ulcerative colitis, combination therapy was not associated with a reduction in occurrence of the composite adverse outcome
Two landmark clinical trials, SONIC in Crohn's disease (CD) and UC SUCCESS in ulcerative colitis (UC), demonstrated higher rates of clinical and endoscopic remission with the combination of infliximab and azathioprine than with either agent alone. However, these trials were restricted to patients who had never used an immunomodulator.
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It is unclear whether the benefit of combination therapy extends to the real world, where many patients have already been treated unsuccessfully with tumor necrosis factor (TNF) inhibitor or immunomodulator monotherapy. Also, the subgroups of patients most likely to benefit from combination therapy are not well defined.
Ashwin N. Ananthakrishnan, MBBS, MPH, director of the Crohn's and Colitis Center at Massachusetts General Hospital, Robert S. Sandler, MD, at the University of North Carolina, Chapel Hill, and colleagues explored these issues by analyzing prospectively collected data. As they report in Alimentary Pharmacology & Therapeutics, the benefit of combination therapy was strongest in patients with complicated CD, particularly early in the course of the disease.
The researchers examined data of 871 adults from their previously reported prospective, multicenter study of patients with inflammatory bowel disease (IBD). The current analysis involved 707 with CD and 164 with UC, of whom at baseline 492 (56%) were on monotherapy with a TNF inhibitor and 379 (44%) were on combination therapy with a TNF inhibitor and an immunomodulator (methotrexate or a thiopurine).
The primary outcome was a composite of new IBD-related surgery, hospitalization, penetrating complication, need for corticosteroid or need for new biologic at one year from the initial evaluation.
Overall, in patients with CD, combination therapy was not associated with a decrease in the likelihood of the composite adverse outcome, compared with TNF inhibitor monotherapy.
In the subgroup of 111 patients with complicated CD (structuring or penetrating), combination therapy was associated with a significant 40% reduction in the risk of adverse outcomes.
Among patients with complicated CD, the reduction in the risk of adverse outcomes was 60% for those with early CD (duration less than five years) versus 25% in those with the longer-established disease. The reduction in risk of adverse outcomes in complicated CD was evident with both infliximab and other TNF inhibitors.
In patients with UC, combination therapy was not associated with a reduction in the occurrence of the composite adverse outcome. No other variable considered (sex, age at diagnosis, smoking status, disease duration and extent of disease) independently predicted the composite outcome.
Advice for Clinicians
The researchers acknowledge the concerns about the safety of combination immunosuppression in patients with IBD, which some studies have linked to opportunistic infections and malignancy. On the other hand, they say, inadequate control of inflammation can result in disease progression.
They suggest that patients with complicated CD should be considered for combination therapy to prevent irreversible bowel damage and maximize the chance of optimal outcomes.
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