If you've recently been diagnosed with rheumatoid arthritis (RA), your health care provider may have prescribed methotrexate. Methotrexate is a disease‐modifying anti-rheumatic drug (DMARD) that reduces immune system activity to lessen inflammation, reduce RA symptoms, and slow the progression of the condition.
Methotrexate is recommended as the first method of treatment for RA by the American College of Rheumatology, and around 90% of RA patients will take methotrexate at some point. As with any medication that's new to you, though, it's essential to be informed about it, so let's get into some basics about methotrexate, including some frequently asked questions about dosing. (Source, Source)
Frequently Asked Questions About Methotrexate
1. What dose of methotrexate would I be given to begin my RA treatment?
The methotrexate dosing schedule varies, but most RA patients begin with an initial dose of 7.5 mg to 10 mg taken by mouth (3 or 4 pills) weekly. If needed, the dose can be incrementally increased to up to 25 mg per week. (Source)
2. What is considered a high dose of methotrexate for RA?
Some studies have indicated that a weekly dose of between 25 mg and 30 mg of methotrexate is the optimal dosage for RA, although this comes with a risk of bone marrow suppression and other serious side effects. Bone marrow suppression is not associated with a low dose of methotrexate.
3. Is methotrexate for RA considered chemotherapy?
When it's used to treat patients with rheumatoid arthritis, methotrexate is not considered chemotherapy. Methotrexate is used to treat cancer in medium to high doses, determined by the type of cancer, body size, and the function of one’s kidneys. A low dose of methotrexate for cancer treatment is considered to be under 50 mg per square meter of body mass (written as 50 mg/m2), doses up to 500 mg/m2 are considered intermediate, and 500 mg/m2 or more is considered high. (Source)
4. Which is more effective: the methotrexate injection, or the pills?
There are two means of administering methotrexate for the treatment of rheumatoid arthritis. The oral form comes in 2.5 mg tablets with variable dosing, usually starting with 7.5 mg to 10 mg per week and increasing up to 25 mg per week. The tablets may be taken all at once or broken up into smaller doses. Injectable methotrexate is formulated to be given in similar doses, but is given just once per week.
There is some evidence that the injection is more effective than the oral route, without an increase in side effects. In a study published in the journal Arthritis & Rheumatism, RA patients with high disease activity — those with symptoms such as inflammation and joint damage — were randomly assigned to receive methotrexate either by injection or by mouth.
After 24 weeks, participants receiving methotrexate by injection were found to have significantly greater improvement in symptoms than participants who took the drug orally. This adds to previous research which has shown that giving the drug by injection tends to make treatment more effective, in part because it reduces gastrointestinal side effects and patients are more willing to stick with the treatment. (Source, Source, Source)
5. What tests should my provider conduct before I start methotrexate?
You should let your provider know about your medical history and any medications you’re taking before you start methotrexate. Tell your provider if you have:
- alcoholic liver disease, long-term liver disease, or hepatitis B or C
- an immunological condition such as HIV
- stomach or bowel problems, such as ulcerative colitis or ulcers
- bacterial, viral, or fungal infection
- pulmonary problems, such as scarring on the lungs
Additionally, your provider should perform:
- a pregnancy test (in women of childbearing age): Methotrexate is toxic to a fetus and can also affect sperm, so you should wait 90 days after stopping methotrexate before trying to conceive. If you're breastfeeding, you should not use methotrexate.
- blood tests to check for pre-existing blood disorders, such as severe anemia, bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia. If you have any of these conditions, caution must be exercised when taking methotrexate.
- renal function test: Low-dose methotrexate is considered safe for those with normal kidney function or mild to moderate chronic kidney disease, but not for those with advanced kidney disease.
- liver function test: Your provider should evaluate your liver for any pre-existing problems, since this can affect how methotrexate works and whether it can be used.
- a chest x-ray to check for pulmonary conditions
6. What are the side effects of a low dose of methotrexate?
A low dose of methotrexate does come with side effects, which are generally mild and controllable and go away with time. They include:
- gastrointestinal toxicity, with symptoms such as nausea and vomiting (the most common side effects, reported by up to 65% of methotrexate users)
- shortness of breath
- the "methotrexate fog,” or feeling of fatigue and general malaise, which can occur a day after receiving a dose
If you experience any of the following side effects, contact your health care provider immediately:
- a sore throat
- raised temperature or fever
- flushing or sweating
- stomachache or signs of stomach bleeding (bloody stools, vomiting of blood or a substance that looks like coffee grounds)
- changes in urine and/or frequency of urination
- a dry cough
- loss of appetite
- unexplained bruising or bleeding
- jaundice (yellowing of the skin or eyes)
- changes in vision
- signs of an allergic reaction (hives, difficulty breathing, swelling in the mouth, throat, tongue or throat, a rash that is large or spreads quickly)
7. What can I do to off-set methotrexate side effects?
The side effects of methotrexate can be managed. Here are some things you can do to prevent and relieve symptoms.
- Consider avoiding alcohol. Methotrexate can contribute to problems with the liver, as can alcohol. While a moderate amount of alcohol may be permissible while you are taking methotrexate, if you already have liver problems it’s recommended that you avoid it altogether. Alcohol can also cause lower bone density, for which you're already at risk if you have RA.
- Don’t skip your tests. To help you maintain optimal health while you’re taking methotrexate, your health care provider will test your liver function, renal function, and more. These tests will take place at regular intervals, so be sure you stay on top of the schedule, show up, and ask any questions you may have at your visits.
- Incorporate anti-inflammatory foods into your diet. Because RA is an inflammatory condition, eliminating foods that encourage inflammation, as well as foods that are actively inflammatory, may help your RA symptoms.
Foods that may be pro-inflammatory include gluten, fried foods, sugary foods, and dairy products.
Foods with anti-inflammatory properties include turmeric, ginger, fatty fish, green tea, berries, and walnuts.
- Get your vitamin E. A 2020 study published in the International Journal of Rheumatology suggested that taking vitamin E alongside methotrexate may help reduce methotrexate’s adverse effects on the liver. You can find vitamin E in mangoes, avocados, greens, and asparagus.
- Eat foods rich in folate (but don't stop there). Taking methotrexate reduces the amount of folate in the body, so it’s essential that you refill and maintain those levels. You can get folate from dark leafy greens like kale and spinach, as well as liver, beets, broccoli, Brussels sprouts, asparagus, bananas, strawberries, raspberries, and cantaloupe. However, taking a folic acid supplement while you're on methotrexate may also help reduce common side effects.
8. Why is folate (or folic acid) so important to take while on methotrexate?
Methotrexate’s mechanism of action in treating cancer involves blocking folate, also known as vitamin B9, so people receiving the drug as a cancer treatment don’t supplement with folic acid. It works differently in treating RA, though, and supplementing with folic acid (a synthetic form of folate used in supplements) is recommended to lessen the intensity and occurrence of methotrexate side effects when it’s used as a DMARD. Folate deficiency can lead to anemia and has been associated with an increased risk of cardiovascular disease, and folic acid supplementation is vital when taking methotrexate for RA.
Once you start taking folic acid alongside methotrexate, it's important that you stick with it in order to keep consistent levels in the blood. Folic acid is usually given to methotrexate users as a 5 mg dose, which is taken the day after methotrexate. Another option is to take a 1 mg dose every day, and skip it on the day you take methotrexate. (Source, Source, Source)