In the early 1950s, doctors conducted the first trials of methotrexate for treating RA, believing that the disease was linked to uncontrolled cell proliferation, or rapid growth, in the joints. However, the research fizzled and interest in methotrexate for RA largely faded. Some three decades later, scientists resurrected this abandoned line of research in a series of successful clinical trials, including a 1985 study published in the New England Journal of Medicine indicating that methotrexate relieved pain, swelling and other symptoms in people with RA.

Methotrexate soon won FDA approval for treating RA and within a few years became the treatment of choice for people with this condition.

“There’s great data to show that it’s extremely effective and safe,” says Prabha Ranganathan, MD, an associate professor of medicine in the division of rheumatology at Washington University School of Medicine. “Most rheumatologists, once they’re convinced that a patient really has rheumatoid arthritis, will use methotrexate as first-line therapy.”


Pairing With Other Drugs

About 40 to 50 percent of people with RA who take methotrexate gain adequate relief from joint pain, swelling, morning stiffness and other symptoms. “The rest of the patients need something else,” says Yusuf Yazici, MD, an assistant professor of medicine at the New York University School of Medicine’s Hospital for Joint Diseases in New York City.

Fortunately for patients who need more relief, combining methotrexate with other medications will usually do the job, says Dr. Yazici. In fact, many studies have found that methotrexate is particularly effective when paired with biologic agents, particularly tumor necrosis factor (TNF) inhibitors such as etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade). These drugs block TNF, a protein that promotes inflammation and damages joints. Meanwhile, methotrexate helps to regulate inflammation, too, apparently by stimulating the release of a compound called adenosine and through other pathways.

“TNF inhibitors and methotrexate appear to be synergistic,” says Arthur Kavanaugh, MD, a professor of medicine in the rheumatology division at the University of California at San Diego.