Understanding Methotrexate 

Updated by Linda Rath | March 18, 2024

More than 900,000 people in the U.S. take methotrexate, often as a first-line treatment for rheumatoid arthritis (RA). It’s also used at much higher doses to treat some forms of cancer. In RA and certain other autoimmune diseases, including psoriatic arthritis and juvenile idiopathic arthritis (JIA), it’s an anti-inflammatory, reducing pain and the production of inflammatory proteins. As a disease-modifying antirheumatic drug (DMARD), methotrexate can also slow joint damage and the progress of the disease. This, as well as its long track record and inexpensive price tag, explains why it’s usually the first drug prescribed for RA and JIA.  
 

How to take it

Most people take methotrexate in pill form, starting at 7.5 mg to 15 mg once a week, which can be increased to a maximum of 25 mg weekly. Some rheumatologists recommend taking half the dose twice a week to improve absorption or reduce side effects. Another option is to use an injectable form, although a 2023 analysis of several large studies and two meta-analyses found no solid evidence that injectable methotrexate was better absorbed or had fewer side effects than pills. The American College of Rheumatology (ACR) recommends pills over injections because they’re cheaper, more convenient and have similar absorption at starting doses. Pills and injectable solutions are available as low-cost generics, and most insurers cover needles and syringes for prescribed medications. Auto injector pens only come in more expensive brand-name versions (Rasuvo, Otrexup).  
 

Changing guidelines

The ACR’s 2012 guidelines for managing rheumatoid arthritis recommended combining methotrexate with other DMARDs, particularly sulfasalazine and hydroxychloroquine, a combination called triple therapy. By the time the ACR issued its 2021 guidelines, a lot had changed. Triple therapy or any DMARD combination is no longer suggested for RA patients who have moderate to high disease activity. Instead, the emphasis is on using only methotrexate and avoiding corticosteroids as “bridge” drugs as much as possible due to their serious side effects. Doctors say most patients do well on methotrexate alone, a drug that’s been used for RA since the 1980s, and want to avoid the added expense and toxicity of unnecessary medications. Hydroxychloroquine is recommended over methotrexate for patients with low disease activity because it has fewer side effects.

The ACR also doesn’t recommend adding a biologic like a tumor necrosis factor (TNF) blocker to methotrexate. This is a conditional recommendation, meaning the evidence is less certain. The ACR strongly, with good evidence, advises against combining methotrexate with any biologic other than a TNF blocker.

The ACR guidelines are recommendations, so it’s important that you and your doctor work together to decide on a treatment plan. If you have severe symptoms or other serious health problems and don’t want to wait six to 12 weeks for methotrexate to take effect, you and your doctor might choose to start with a TNF blocker. Before making any decision, it’s important to know the effectiveness, potential side effects and price of all possible options.
 

Effectiveness

As many as 20% to 50% of people don’t respond to methotrexate, according to various studies, but there is no way to know beforehand who will benefit and who won’t. Because it can take weeks or months for symptoms to improve, non-responder patients lose valuable time and experience side effects. Researchers are actively trying to find useful biomarkers that can predict patient response to methotrexate.
 

Side effects

Despite its reputation as a relatively safe medication, methotrexate is not a “benign drug,” according to rheumatologist Daniel Solomon, MD, of Brigham and Women’s Hospital in Boston. Dr. Solomon was an investigator on the Cardiovascular Inflammation Reduction Trial (CIRT), which was undertaken to discover if low-dose (15 mg to 20 mg per week) methotrexate could prevent heart attack and stroke in high-risk patients without rheumatic disease. Although methotrexate didn’t improve heart health, it was associated with several troubling side effects compared to placebo, including:

• A 23% higher rate of gastrointestinal (GI) symptoms, such as nausea and vomiting
• A 42% higher rate of lung problems, including cough, trouble breathing and in a small percentage of people, pneumonitis, a potentially fatal lung inflammation
• A 15% increase in infections
• A doubled risk of skin cancer, although the overall rate was low

Other common side effects include mouth sores, lost or thinning hair and potential liver and kidney damage. People taking methotrexate should have frequent blood tests to check liver and kidney function. Taking 1mg of the B vitamin folic acid (synthetic folate) every day helps relieve some but not all methotrexate side effects. Talk to your doctor about ways to manage side effects.

Two kinds of side effects can occur in children who take methotrexate for JIA: symptoms, particularly nausea and vomiting, caused by the drug itself and by anticipating taking it. One small study found that giving kids and teens levofolinic acid – a prescription form of folic acid – 48 hours before and after methotrexate reduced or eliminated GI side effects. Reducing physical nausea and vomiting might help kids who struggle with anticipatory symptoms.

Who shouldn’t take methotrexate

Some diseases and conditions take methotrexate off the table, including

• Liver disease or cirrhosis
• Alcohol use disorder (Some doctors recommend avoiding even small amounts of alcohol while taking methotrexate. Talk to your doctor about whether drinking alcohol is safe.)
• Kidney disease
• Blood disorders
• HIV/AIDS
• Radiation therapy

You shouldn’t take methotrexate if you’re pregnant or may become pregnant; it can cause serious birth defects. Folic acid is essential for a fetus to develop normally, and methotrexate interferes with the body’s ability to break down and use folic acid. You should also avoid methotrexate if you’re breastfeeding because it passes into breast milk. If you’re of child-bearing age, it’s important to use at least two methods of contraception while you take methotrexate and for at least three months after you stop.

There’s some debate about whether men taking methotrexate should avoid trying to conceive; many experts advise holding off for at least three months after stopping the drug. Discuss the risks with your doctor.
 

Is methotrexate in short supply?

Methotrexate isn’t an abortion drug, but it’s commonly used to treat ectopic pregnancies (those outside the uterus), so the 2022 Dobbs decision overturning a woman’s right to reproductive choice caused a tremendous amount of confusion for women, doctors and pharmacists. At the time, there were anecdotal reports of women being unable to fill methotrexate prescriptions for RA and other rheumatic diseases, even if they’d been taking the drug for years. The expected shortage of the drug never really materialized, although there have been shortages of some generic vials for injection, mainly due to manufacturing issues or increased demand.
 

Vitamin D and methotrexate

Low vitamin D is associated with an increased risk of early death in the general population and in people with RA. A recent study involving more than 15,000 RA patients found that those with vitamin D levels in a normal range before starting methotrexate had a 28% lower risk of early death. Most with adequate levels were supplementing with vitamin D, suggesting vitamin supplements may improve immune health in people with RA, especially when taking methotrexate.