Biologics or Methotrexate--What is the Safer and More Effective Therapy?

Systematic Review and Meta-Analysis of the Efficacy and Safety of Existing TNF Blocking Agents in Treatment of Rheumatoid Arthritis, Aaltonen et al, 2012

Full Text of Article

What did they study?

This article is a meta review of 26 clinical trials that evaluated the safety and efficacy of TNF-alpha inhibitors, the most popular biologic therapy for RA patients. Five different therapies were evaluated in these studies:

• Adalimumab, (Humira®) – 8 studies
• Enteracept (Enbrel®) – 7 studies
• Infliximab (Remicade®) – 5 studies
• Golimumab (Simponi®) – 3 studies
• Certolizumab (Cimzia®) – 3 studies

To evaluate efficacy, the researchers evaluated each study to calculate the relative likelihood that study patients would achieve 20, 50, or 70% disease improvement, compared to patients in the control group (placebo or methotrexate), with 50% improvement being the primary goal to define the “risk ratio” of success. They also evaluated the efficacy of a TNF-alpha blocker combined with methotrexate compared to methotrexate alone. Finally, they evaluated whether higher doses of TNF-alpha blocker we associated with improved outcomes.

Safety was evaluated by comparing the risk of an adverse event that required withdrawal from the study for patients treated with the study drug versus patients in the control group (placebo or methotrexate). Combined (TNF-alpha blocker + methotrexate) was also evaluated as well as higher doses of TNF-alpha blocker.

What were the results?

In general, TNF-alpha blockers alone were only marginally (and not statistically significantly) better than methotrexate for achieving a 50% improvement for patients. When compared to control in general, enteracept, adalimumab, and certolizumab had substantially higher relative risk of achieving 50% improvement. Infliximab and golimumab had higher relative risk than controls, but were close. When TNF-alpha blockers were combined with methotrexate, the outcome was substantially better. Increasing the dose of TNF-alpha blocker did not appear to result in an improved outcome.

The primary adverse event observed with TNF-alpha blocker treatment was an injection site reaction, which is expected for biologic products. When compared to control, most of the TNF-alpha blockers had a higher relative risk of an adverse event, with the exception of enteracept. When administered alone, enteracept had a lower relative risk than control of an adverse event. However, when methotrexate was added to enteracept, this improved risk was eliminated. Higher doses of TNF-alpha blockers did not appear to increase the risk of an adverse event.

What does this mean?

From this study, it appears that enteracept is more efficacious and safe compared to other treatments, although not more efficacious that the substantially less expensive methotrexate. From a cost-benefit perspective, a patient would probably benefit more from starting with methotrexate and only adding or switching to enteracept if they don’t see an improvement in their symptoms under this traditional therapy.

There is likely a bias against golimumab and certlizumab in this review, given that there were many fewer studies represented. Furthermore, these are newer products, with both approved for use in RA patients in 2009, compared to enteracept , which was approved in 1998. A longer patient history and more trial data may even out the results.

On a further note, studies of drug efficacy are based on combination therapy with methotrexate. I would be interested in seeing studies evaluating biologic therapy in combination with other DMARD medications, such as hydroxychloroquine (Plaquenil) and especially with Sulfasalazine, which inhibits TNF-alpha on its own.