Methotrexate is an immunosuppressant medication prescribed for inflammatory arthritis, including rheumatoid arthritis (RA) and psoriatic arthritis.
As a conventional synthetic disease-modifying antirheumatic drug, or DMARD, it broadly suppresses immune system overactivity that underlies inflammatory arthritis, thereby reducing disease activity, slowing progression, and reducing joint damage.
But as you should with all medications, it’s important to understand the potential side effects of methotrexate, as well as the benefits.
“While the list of potential side effects is long and intimidating, the most common side effects such as digestive issues and fatigue are often manageable,” says Cleveland Clinic rheumatologist Stephanie Tancer, MD, MS.
Using Methotrexate
People often take methotrexate “because something is going on with the immune system, and they need to quiet it down,” Dr. Tancer says. Methotrexate is commonly used (and guideline-recommended) as first-line DMARD therapy for a number of rheumatic conditions.
Rheumatologists prescribe it at low doses, but it can also be used at higher doses to treat some cancers.
Side effects can increase with the dose, so most people taking methotrexate for arthritis will experience fewer side effects than those taking it for cancer.
When used for arthritis, methotrexate is administered as one dose, by pill or injection, on the same day every week. It often takes three months to see a positive effect on arthritis symptoms. Rheumatologists monitor routine blood work for kidney and liver function and any other signs of serious side effects. People often take methotrexate indefinitely for arthritis if it helps to relieve symptoms and if the side effects are tolerable.
Managing Methotrexate Side Effects
Serious side effects of methotrexate include allergic reactions, trouble breathing, infection, kidney or liver injury, low red blood cells, and unusual bleeding. More common side effects at low doses include diarrhea, vomiting, nausea and fatigue.
Dr. Tancer employs several strategies to help manage common methotrexate side effects. She can adjust the dose or timing, split or combine doses, or switch to an injected formula. She also may add additional folic acid supplementation—folic acid can help to reduce methotrexate-related side effects. For people who complain of brain fog associated with methotrexate use, some research suggests that dextromethorphan (commonly found in widely used over-the-counter cough remedies) reduces symptoms, usually 60 mg daily (see “Options to Manage Common Methotrexate Side Effects”).
| OPTIONS TO MANAGE COMMON METHOTREXATE SIDE EFFECTS | |
| Common Side Effect | Management Options |
| Diarrhea, vomiting, bloating or nausea | · Take methotrexate in a single dose with food before bed.
· Switch to weekly methotrexate injections. |
| Fatigue | · Increase folic acid supplementation taken every day except the day taking methotrexate. Double folic acid or try a prescription-strength folic acid called leucovorin weekly the day after methotrexate
· Take methotrexate at night before bed. |
| Brain fog | · Add 60 mg daily of dextromethorphan |
Risks of Methotrexate
Several known risks of methotrexate require management. Methotrexate treatment is not compatible with pregnancy, and women of child-bearing age should use effective birth control.
The risk of infections increases because methotrexate suppresses the immune system. Dr. Tancer recommends that people stop taking methotrexate temporarily while they are recovering from an infection. Methotrexate increases the risk of nonmelanoma skin cancers, so Dr. Tancer and other experts recommend undergoing annual skin checks in dermatology during treatment.
Methotrexate carries a low risk of pulmonary fibrosis, which involves serious and permanent lung damage that would require stopping methotrexate treatment. People taking methotrexate should immediately report any difficulty breathing.
Is It Worth It?
Generally, methotrexate is well tolerated and effective and is a first-line treatment. Some people are more sensitive to side effects, and some experience a better reduction in symptoms from methotrexate.
Dr. Tancer describes one patient who was nauseated for an hour after taking methotrexate but decided she could tolerate that because her arthritis symptoms improved so much. Another person became nauseated after taking methotrexate and never wanted to take it again.
“Managing side effects and treatment really depends on the severity of the side effects and also the person. Some people have a higher threshold for what is an acceptable side effect,” Dr. Tancer says.
If people are experiencing side effects and feel no relief from arthritis symptoms after three months, Dr. Tancer tries a different medication. Many other options are available if you can’t tolerate methotrexate side effects or if it does not provide sufficient benefit.
