A routine visit to the drug store became frustrating and worrisome for some people with rheumatoid arthritis (RA) in recent months. That’s because injectable methotrexate, which some RA patients use to control joint pain and stiffness, was suddenly unavailable at many pharmacies. The problem: The largest maker of injectable methotrexate, Ben Venue Laboratories, was forced to shut down several plants due to manufacturing problems. As a result, the nationwide supply of this important drug dwindled, which meant some pharmacies were unable to keep it in stock.

The majority of people with RA who use methotrexate – and most patients with this form of arthritis do use the drug at some point – take an oral version, which was not affected by the recent shortage. Moreover, injectable methotrexate is once again widely available, since the Food and Drug Administration asked several other manufacturers to step up production of the drug. That was especially good news for patients with certain forms of childhood leukemia and other types of cancer, since injectable methotrexate is also used in much higher doses as life-saving chemotherapy for these diseases. However, this hiccup in the drug supply chain shined a light on the importance of methotrexate, which over the last generation has become the cornerstone of treatment for RA.

Better Than Gold?

Prior to the 1980s, patients with RA had limited treatment options. Injections of gold salts were the most commonly used therapy. However, gold salts were only modestly effective and caused a variety of side effects such as mouth sores and potentially severe skin rashes; about one in three patients couldn’t tolerate the treatments and had to stop receiving them. Eager to find better therapies for RA, some researchers chose to look backward.

Methotrexate was initially developed as a cancer drug. In the 1940s, famed physician Sidney Farber, MD, developed a theory that blocking folic acid, a form of vitamin B, would stop cancer cells from spreading and induce remission in children with acute leukemia. Farber created several folic acid antagonists, or “blockers,” including methotrexate, which proved successful and became one of the first forms of cancer chemotherapy.

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.

In one study Dr. Kavanaugh coauthored, about half of RA patients who received methotrexate and adalimumab had their disease go into remission after two years, making them twice as likely to be symptom-free as other patients given either of the drugs alone. What’s more, X-rays showed that patients receiving the tandem of drugs also experienced less joint deterioration.

Research also indicates that methotrexate combines effectively with newer biologic agents, such as abatacept (Orencia) and rituximab (Rituxan).

A Long Record of Safety

Methotrexate is widely regarded as one of the safest of all arthritis drugs, though it carries some potential downsides. Gastrointestinal symptoms such as nausea and vomiting are the most frequent side effects linked to the drug. About one in 10 patients experience a “post-dosing reaction” – sometimes called “methotrexate fog” – soon after taking the medication, which is administered once a week (whether injected or taken orally).

“It’s hard to quantify, but some people just don’t feel good the day after they take methotrexate,” says Dr. Kavanaugh. Patients who have this reaction complain of fatigue and malaise, though these side effects usually only last a day or so.

Other possible side effects include hair loss, swollen and tender gums, headaches, drowsiness, and dizziness. Most physicians recommend taking 1 milligram of folic acid daily, which can help to offset these problems. Certain people, notably women who are or may become pregnant, should not take methotrexate. Learn more about methotrexate side effects here.

Injectable methotrexate is just one of many prescription drugs used to treat a variety of medical conditions that has gone on short supply in recent years due to a complex web of economic and regulatory factors. Last October, President Barack Obama issued an executive order that gave the FDA greater authority to take actions that could help to prevent drug shortages, while Congress is considering legislation that would give the agency more power to ensure that needed medications don’t disappear.

“It’s a big issue,” says Dr. Kavanaugh. “This shortage didn’t seem to affect a lot of our patients. But I hope it doesn’t happen again.”