Rheumatologists have been using low doses of the medication methotrexate to treat rheumatoid arthritis and certain other inflammatory diseases since the 1980s. Since then, it’s become the standard of care and globally the most popular drug for the treatment of rheumatoid arthritis (RA).
Methotrexate is a disease-modifying anti-rheumatic drug (DMARD) that lessens inflammation, which reduces pain and swelling and helps prevent joint damage. It is used to calm the body’s overactive immune system in a host of other autoimmune diseases that cause inflammatory arthritis, including psoriatic arthritis, lupus, Sjögren’s syndrome, scleroderma, and vasculitis, among others.
Because methotrexate is used so often — at different doses, for different conditions, and taken by different routes — people with arthritis hear lots of confusing (and frightening) things about methotrexate and its possible side effects.
We spoke with doctors to separate myths from facts about methotrexate so you can get the most from your treatment, use it safely, and help prevent side effects.
Myth: Methotrexate is chemotherapy
It’s a fact that high doses of methotrexate are chemotherapy, used as far back as the 1940s to treat certain forms of cancer. But don’t think of methotrexate as chemotherapy at the dose you take for inflammatory arthritis.
“Methotrexate is prescribed at a wide range of doses, with low weekly doses for rheumatoid arthritis and much higher doses for treating cancer,” says Ashima Makol, MD, an assistant professor of medicine and a consultant in the division of rheumatology at the Mayo Clinic in Rochester, Minnesota.
As cancer chemotherapy, methotrexate slows the growth of certain cancers by interfering with the cells’ ability to use folic acid in order to divide and make new cells. At the much lower doses of methotrexate used in RA, it works as an anti-inflammatory.
And you’ll still get the anti-inflammatory benefit if you take folic acid supplements with methotrexate to counteract how it interferes with folic acid. This can help you avoid some common methotrexate side effects, such as nausea.
Myth: Methotrexate is only for the worst cases of rheumatoid arthritis
Not at all. American College of Rheumatology (ACR) guidelines call for starting treatment with methotrexate or another DMARD as soon as a diagnosis of RA is made, even if your disease activity is considered low.
Treating early and aggressively can keep the worst from ever happening by preventing joint damage. In a large study published in 2015, McGill University researchers found that patients who spent more time on methotrexate or another DMARD during their first year after diagnosis were more likely to delay or avoid the need for joint replacement.
Myth: Methotrexate can kill you or cause irreversible damage to the liver and other organs
At the doses used to treat RA, methotrexate side effects are rarely life-threatening. The likelihood of severe toxicity to the liver and other organs is low. Still, the possibility of serious side effects is something that rheumatologists pay constant attention to.
Some serious concerns, says Dr. Makol, are “liver damage, bone marrow suppression leading to a shortage of blood cells being produced, a rare form of lung damage, and toxic effects on brain cells.”
Your rheumatologist will watch your liver and kidney function carefully as you take your drug. You’ll need to have regular blood tests to make sure that methotrexate isn’t causing harm. If complications occur, there are many things your doctor can do. “These complications warrant immediate discontinuation of the medication, supportive treatments, sometimes medications such as glucocorticoids, and close monitoring,” says Dr. Makol.
Myth: Methotrexate has horrible side effects for everyone
There’s no getting around the fact that methotrexate can cause a variety of side effects. These can include: gastrointestinal problems, such as nausea, stomach upset, and loose stool; mouth ulcers; hair loss; and liver problems.
The good news is that not everyone experiences all or most of these side effects, and many people find them to be mild.
“Most people tolerate methotrexate fairly well at the doses recommended for the treatment of RA, and most of the side effects improve or are better tolerated over time,” says Dr. Makol.
Speak up about any possible drug-related symptoms you develop, because there are a lot of things you can do to ease or prevent methotrexate side effects. Your doctor may be able to adjust your dosage or switch you to subcutaneous shots of methotrexate instead of pills, which may be easier on your stomach.
You can also take folic acid supplements, which you can buy over the counter, along with methotrexate. These B vitamins help reduce side effects like mouth sores, sun sensitivity, hair loss and stomach upset.
Myth: You can stop taking methotrexate once you feel better
Not necessarily, and not right away. Methotrexate helps control your inflammation. You may feel much better than you did before you started methotrexate: less pain, swelling, morning stiffness or fatigue. If you feel better but still have low disease activity, the ACR’s treatment guidelines recommend against stopping or lowering your dose.
Once you’re in remission, there isn’t solid evidence about what to do and the ACR considers tapering methotrexate or other DMARDs to be an option but not mandatory. As you make that decision with your rheumatologist, the doctor will consider how long you’ve been in remission, how tolerable you find it to keep taking your meds, and your concerns about the possibility of developing a flare or not sustaining your remission if you lower your dose.
Don’t be surprised if your rheumatologist wants you to keep taking methotrexate, possibly at a lower dosage or less frequently than you do when your RA is active. You don’t want to risk a painful flare or your disease becoming active again.
Read more about achieving remission in rheumatoid arthritis.
Myth: Taking methotrexate means you can’t have children
Methotrexate, like many other drugs, can cause serious birth defects, including fetal death. So you absolutely should not get pregnant while you’re taking methotrexate.
Why is methotrexate so dangerous during pregnancy? Folic acid is important for normal fetal development (the reason women are often put on folic acid supplements when they conceive) and methotrexate reduces the body’s ability to break down and use folic acid.
“Methotrexate is commonly used to treat ectopic pregnancies [those outside the uterus]. It can increase the risk of miscarriage, and exposure in the first trimester of pregnancy has been associated with serious birth defects in the offspring,” says Dr. Makol. “When women of childbearing age take methotrexate, strict contraception is advised [using two different methods] and methotrexate should be stopped at least three months prior to attempting pregnancy. This should be attempted at a time when their arthritis is generally well controlled, but there are medications that are safe to use during pregnancy if needed,” she says.
You also shouldn’t breastfeed while you’re taking methotrexate. But you can work with your rheumatologist to go off methotrexate for a period of time to clear it from your system, and then conceive a baby once your rheumatologist says it’s OK to proceed.
Myth: Men on methotrexate shouldn’t even be around pregnant women
When it comes to pregnancy and methotrexate, there’s plenty to worry about, but not this. A 2014 study from Berlin found that the partners of men taking low-dose methotrexate for RA delivered no more babies with birth defects than those whose partners were not on the drug.
The evidence on prospective fathers taking methotrexate is less clear. Higher doses of methotrexate can temporarily reduce sperm counts until the drug is stopped.
“Although multiple studies have demonstrated no birth defects resulting from fathers using methotrexate, given the theoretical concern and some prior reports of miscarriages, it may be best for men to hold off any attempts at conception until three months after stopping methotrexate,” says Dr. Makol.
Myth: You have to stop drinking alcohol when you take methotrexate
Not necessarily. There are reasons to be concerned about this alcohol/drug combo, but you may not have to become a teetotaler if you enjoy an occasional beer, cocktail, or glass of wine.
“Alcohol doesn’t make methotrexate less effective. The problem is that methotrexate can be toxic to the liver and has the potential to accelerate toxicity when mixed with alcohol, which is also metabolized by the liver. We ask our patients to limit the amount of alcohol they drink, but it doesn’t have to be zero. If you drink, don’t miss your lab tests so any liver abnormalities can be caught early. If there is any question about liver issues, then further testing with imaging and possible biopsy can be very informative,” says Rebecca L. Manno, MD, MHS, assistant professor of medicine in the Johns Hopkins Arthritis Center in Baltimore.
Your doctor can advise on whether drinking any alcohol while on methotrexate is safe for you. Read more about alcohol and methotrexate.
Myth: You should stop non-steroidal anti-inflammatory drugs (NSAIDs) once you start methotrexate
The scary things you may read about the dangers of combining NSAIDs and methotrexate are primarily aimed at people taking high-dose methotrexate to treat cancer. “Methotrexate is eliminated from the body by the kidneys, and if your kidney function is impaired [a known complication of NSAIDs], then methotrexate levels may increase to dangerous amounts resulting in severe consequences such as bone marrow and liver damage,” says Bryant England, MD, assistant professor in the division of rheumatology and immunology at the University of Nebraska Medical Center in Omaha.
On low-dose methotrexate you won’t be forbidden from using NSAIDs. “However, regular blood work to monitor for these complications is essential while on methotrexate and may need to be more frequent when NSAIDs are also used,” says Dr. England.
You may also find that you don’t need NSAIDs as much as you used to before you started methotrexate. “Patients and providers should regularly evaluate whether there is an ongoing need for NSAIDs or if alternative medications or non-drug therapies for pain relief could be substituted,” Dr. England says.
Myth: Methotrexate can cure your RA
At this time, there’s no “cure” for RA. Methotrexate is the first line of treatment for most people with active disease, and it can help you get your inflammation under control so you feel much better. Your treatment goal is to get your RA into remission, but that’s not the same as a cure. Methotrexate can help you lower your disease activity — measured with various tests your rheumatologist will give you — but it doesn’t technically cure your RA.