People who have severe, active Rheumatoid Arthritis (RA) and who are not sufficiently helped by nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed the Drug Methotrexate (Otrexup, Rasuvo, Trexall). It is one of the oldest and most cost-effective medicines available for RA.

Methotrexate Is First-Line Treatment for RA

Methotrexate (MTX) was originally developed in the 1940s as an anti-cancer drug, notes the Arthritis Foundation, but it’s become the first-line treatment for rheumatoid arthritis, as well as other autoimmune and inflammatory conditions. The drug has been hailed as a major success story, and remains the backbone of treatment for RA.

Methotrexate falls in the category of disease-modifying anti-rheumatic drugs, or DMARDs. These drugs do more than deal with symptoms; they actually slow down progression of the disease.

According to scientists who published an article in the International Journal of Molecular Sciences, even though many effective DMARDs have become available for RA, “MTX remains one of the most efficient and most commonly used therapies against which the efficacy of new DMARDs is judged.” The drug has been declared an essential medicine by the World Health Organization (WHO).

Some 90 percent of people with RA use methotrexate at some point in their disease, either alone or in combination with other medicines, according to the Arthritis Foundation.

In addition to being an effective treatment, methotrexate works relatively quickly and has a milder side-effect profile than other medicines used for RA, says Andrew Tenpas, PharmD, a clinical assistant professor of pharmacy practice at Texas A&M University in Kingsville, Texas.

“We have so much experience with methotrexate, and we know it’s effective and safe,” says Bahar Moghaddam, MD, a rheumatologist at the Mount Sinai Hospital in New York City.

RELATED: 8 Things About Rheumatoid Arthritis That Are Difficult to Explain or Understand

How Methotrexate Works to Fight Inflammation

Methotrexate is thought to work by causing cells to release a molecule that blocks chemicals that promote inflammation, according to the Arthritis Foundation. Reducing inflammation helps prevent pain and joint damage otherwise experienced by people with the disease.

Scientists realized early on that the drug could be useful for RA. By the 1980s, well-designed gold-standard studies began to confirm its value for this condition.

Initially, as with many medicines for RA, methotrexate was primarily given late in the course of the disease, when damage to joints were already done. In 2010, the American College of Rheumatology, along with its European counterparts, revamped their diagnostic criteria for the disease so that people could be diagnosed earlier. Their aim was to “refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy,” the scientists wrote in Annals of the Rheumatic Diseases that October.

Related: Early Rheumatoid Arthritis Treatment: Why Is It So Important?

What Are Standard Dosages for Methotrexate?

Most people with RA begin with a 7.5 milligram (mg) dose of methotrexate tablets taken once a week. Over time, if that is not enough to help, your doctor will increase your dosage, perhaps up to 20 mg. According to the Arthritis Foundation, most people take a weekly dose between 10 and 25 mg. (Methotrexate is used in much higher doses to treat certain forms of cancer).

“It is extremely important to understand that the drug is taken once weekly, not once each day,” Dr. Tenpas says, noting that mistaking this dosage has led to toxicity in some patients.

Methotrexate can also be given by injection. People can give the methotrexate shot to themselves using an auto-injector. Taking the drug this way allows more of it to get into your system without increasing unwanted side effects.

Starting dosages for the injected drug are generally similar as for the oral version, notes the Johns Hopkins Arthritis Center.

How Long It Takes for Methotrexate to Start Working

Because methotrexate doesn’t simply suppress pain symptoms, it may take a while for people to see whether the drug is effective.

You may see improvement in symptoms three to six weeks after you starting the drug, but full benefits can take even longer, up to 12 weeks, according to the American College of Rheumatology.

This is faster than with many other RA medicines, but it’s still not fast enough for people in pain. “NSAIDs and steroids are commonly used as ‘bridging’ therapy while the methotrexate takes effect,” Tenpas says.

RELATED: Rheumatoid Arthritis Pain Management

Methotrexate Is Often Prescribed With Others Drugs

Many people with rheumatoid arthritis find that even after they’ve worked up to a higher dose, methotrexate alone is not enough to quell all their symptoms. In this case, other medicines may be added alongside MTX.

“Probably around 30 to 40 percent of people stay on methotrexate without anything else. The rest need additional medication,” Dr. Moghaddam says.

Most often, methotrexate is combined with other disease-modifying drugs. This includes medicines like leflunomide (Arava), sulfasalazine (Azulfadine), and hydroxychloroquine (Plaquenil).

If this pairing isn’t sufficient, doctors generally move to combining methotrexate with a biologic drug. Common biologics include etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade), certolizumab (Cimzia), abatacept (Orencia), rituximab (Rituxan), and tocilizumab (Actemra).

The goal of this combination treatment is to achieve control of joint inflammation so there’s less risk for long-term damage to the joints.

RELATED: Signs It’s Time to Change Your RA Treatment

What Are the Side Effects of Methotrexate?

As with many drugs, people can experience unpleasant, and in rare cases dangerous, side effects from methotrexate. If you experience anything that concerns you, be sure to speak with your healthcare provider.

Bothersome side effects include dizziness, headache, tiredness, gastrointestinal upset, mouth sores, rash, diarrhea, and the loss of hair, according to MedlinePlus.

According to the American College of Rheumatology, methotrexate may also lower the ability of the immune system to fight infections.

People taking methotrexate should call their physician immediately if they experience more serious side effects. This includes seizures, confusion, weakness on one or both sides of the body, blurred vision or sudden loss of sight, and loss of consciousness.

MTX can cause birth defects or developmental abnormalities in babies. People taking methotrexate should be sure to use effective contraception.

The Best Ways to Minimize Methotrexate Side Effects

Some side effects from this drug result from a drop in folic acid levels in the body. To reduce these effects, doctors generally prescribe folic acid supplements along with the drug.

Many people find taking the oral medicine with food can prevent stomach upset, Tenpas says.

Some recommend splitting the dose, by taking half in the morning and the other half 12 hours later to ease these gastrointestinal side effects. If that doesn’t help, talk to your doctor about switching from the oral to the injectable version of the drug.

To deal with mouth sores, the the Arthritis Foundation suggests using a saltwater rinse or special mouthwash containing a lidocaine pain reliever. If nausea is an issue, you can request a prescription for anti-nausea medicine.

Not all of the negative effects of the drug cause symptoms. This is why routine blood tests are regularly performed for people taking this medication.

Methotrexate Can Impact Vaccine Effectiveness

Because methotrexate affects the immune system, researchers have found that it can blunt the effectiveness of certain vaccines.

A small study published May 25, 2021, in the Annals of the Rheumatic Diseases, for instance, found that up to one-third of people on methotrexate had a weaker immune response to the Pfizer-BioNTech COVID-19 vaccine. More than 90 percent of healthy people or those on TNF-inhibitors or other biologic drugs in the study produced adequate antibody levels with the vaccine, but only 62 percent of methotrexate users did.

A study published in September 2022 in The Lancet Respiratory Medicine concluded that “a two-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination.”

The American College of Rheumatology recommends delaying the dosing of methotrexate for one to two weeks after each shot, as disease allows.

Researchers have also documented diminished effects for the flu vaccine in people on MTX. In follow-ups, Korean research found that stopping the drug for four weeks, either the month after getting the flu shot or two weeks before and two after, increases immune response. (Temporarily going off methotrexate did produce RA disease flares in one-quarter to one-third of the people in the study.)

Anyone who takes methotrexate should work with their physician to discuss their specific drug regimen at the time of any vaccines.

Methotrexate and Risk of Liver Disease

Because methotrexate has been associated with liver damage, people with RA frequently worry about how taking the drug will affect this crucial organ.

Fortunately, people who take this drug for RA appear to have a lower risk for this than people who take it for some other conditions.

A population-based study published in February 2021 in the Journal of the American Academy of Dermatology compared the incidence rate for liver disease among those taking MTX for psoriasis, psoriatic arthritis, and RA and found those with RA were 1 to 3 times less likely to have this problem.

Still, because of the potential for liver problems, regular alcohol use with methotrexate is not considered safe. “People are encouraged to minimize — if not avoid — alcohol consumption,” Tenpas says.