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New Drug Superior to Methotrexate in Reducing RA Symptoms

July 03, 2014

Patients taking Xeljanz (tofacitinib) experienced greater reductions in the signs and symptoms of rheumatoid arthritis (RA) than individuals taking methotrexate in a recent 2-year, phase 3 study. Tofacitinib was also superior to methotrexate in reducing the progression of structural joint damage in the study participants.

“While these results were not necessarily unexpected, they were important in that they provide confirmation that there is another effective oral therapy for moderate to severe RA patients that have had an inadequate response to methotrexate,” said author Dr. Bethanie Wilkinson of Pfizer.

Researchers compared the effects of tofacitinib monotherapy, a novel oral, small-molecule Janus kinase inhibitor, with methotrexate monotherapy, the most widely used first-line antirheumatic drug, in 956 patients with active moderate to severe RA. Subjects had not previously taken methotrexate.

“This was the first time that tofacitinib was compared directly head-to-head with methotrexate,” said Dr. Wilkinson.

Patients were randomly assigned to the group that received tofacitinib, 5 mg or 10 mg twice daily, or the group that received methotrexate, which was incrementally increased to 20 mg weekly over an 8-week period.

Individuals taking tofacitinib experienced significantly smaller mean changes from baseline in the modified total Sharp score, which indicated less radiographic progression of joint damage, at 6, 12, and 24 months compared with individuals taking methotrexate.

Researchers also found that the participants’ American College of Rheumatology (ACR) 70 response rates were 25.5%, 37.7%, and 12% in the tofacitinib 5-mg group, tofacitinib 10-mg group, and methotrexate group, respectively, at 6 months, indicating a superior response in reducing the signs and symptoms of RA with the use of tofacitinib.

“This Phase 3 study in patients with moderately to severely active RA who had not previously received methotrexate or therapeutic doses of methotrexate met its primary endpoints,” said Dr. Wilkinson. “This study showed that XELJANZ [tofacitinib] taken by itself was statistically significantly superior to methotrexate in measures of clinical, radiographic and functional efficacy RA outcomes, and these results were measured at 6 months as the primary endpoint and sustained over two years,” said Dr. Wilkinson. “This is important since some people don’t adequately respond, eventually stop responding, or have intolerance to methotrexate.”

A limitation of the study, as noted by Dr. Wilkinson, is that methotrexate could only be adjusted every 3 months.

“Furthermore, this trial was conducted in methotrexate-naïve patients; however, Xeljanz is only approved for use in moderate to severe RA patients that have had an inadequate response to methotrexate,” she said.

In terms of side effects, researchers found that herpes zoster developed in 4.0% of patients taking tofacitinib and in 1.1% of patients taking methotrexate, and that cancer developed in 6 patients (5 in the tofacitinib group and 1 in the methotrexate group). In addition, increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels were observed in patients taking tofacitinib.

The authors concluded that the benefits of tofacitinib should be considered in the context of the risks of adverse events.

When questioned about future research, Dr. Wilkinson explained, “Future studies of the comparison on methotrexate in other populations as well as continuing pharmacovigilance will provide additional information on the risk:benefit profile of this therapy.”

This study was supported by Pfizer, maker of Xeljanz, and was published in the New England Journal of Medicine.


-Meredith Edwards White



1. Lee EB, Fleischmann R, Hall S, et al; ORAL Start Investigators. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377-2386.

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