For this study, the researchers re-analyzed the data to compare the outcome of three groups: 1) those who were treated throughout the whole study with methotrexate alone, 2) those who were stepped up after 6 months to more aggressive therapy (either methotrexate plus etanercept or methotrexate plus sulfasalazine and hydroxychloroquine), and 3) those who were treated from the start with one of the two more aggressive therapies.

Of the 370 patients who were started on methotrexate alone, 81 (28 percent) achieved low disease activity within six months and did not need to take additional medications for the remainder of the trial.

The remaining 234 were stepped up to combination therapy, while 315 were started immediately on combination therapy. By the end of the trial, there were no significant differences in DAS28 scores (a measure of disease activity) between the three groups. Importantly, those who had to step up to combination therapy had similar DAS28 scores and similar disease progression (as seen on X-rays) as those who were treated with combination therapy from the start.

Dr. O’Dell says this analysis shows “you don't lose anything radiographically or in terms of mobility” by first trying methotrexate alone – even if it turns out you need stronger drugs down the road. 

But Dr. O'Dell says doctors need to give methotrexate a chance to work. "Clinicians often don't use the drug to its best effect," he says, noting that some try doses that are too low or give up on it after only a month, assuming it's not working.

The findings also support the ACR’s contribution to the Choose Wisely campaign designed to cut back on unnecessary medical costs by reducing unnecessary medical procedures, tests and drugs. The ACR recommends trying methotrexate alone, before adding or switching to a biologic.

Yusuf Yazici, MD, assistant professor of medicine at the NYU Langone School of Medicine calls this a well-done study, because it is double-blind, which means neither the doctor nor the patient knew which medication the patient was getting. "There were several [previous] studies showing the same thing. This is a better-designed trial because of the double blind nature of it, so it’s a very good confirmation that bolsters previous conclusions," he notes.

But while methotrexate may be “the cornerstone” of RA treatment, Megan E. B. Clowse, MD, an assistant professor of medicine in the division of rheumatology and immunology at Duke University School of Medicine in Durham, N.C., has a reminder that it’s not for everyone. She says this study does not address the patients who cannot take methotrexate. This includes women who are pregnant, nursing or trying to become pregnant, as well as patients with liver disease, renal disease or those who consume a lot of alcohol.

So what’s the bottom line? "This [study] contradicts the belief that you are running out the clock," says Eric Matteson, MD, chair of rheumatology at Mayo Clinic in Rochester, Minnesota. "It’s entirely appropriate to treat patients with methotrexate without thinking that you need to start severe patients first on biologics. This study shows it’s not a necessary or obligatory strategy."