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)

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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. 

High dose methotrexate, which is based on body mass and may be more than 10 times the RA dose, is reserved for the treatment of cancers such as leukemia and lymphoma. (Source, Source, Source) 

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
• diabetes 
• 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 

(Source, Source, Source) 

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
• headaches
• 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)

(Source, Source, Source)  

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. 

(Source, Source, Source, Source, Source, Source)

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)

9. How long will it be before I see an improvement in my symptoms after I start methotrexate? 

Methotrexate is a slow-acting drug, so don't panic if you don't experience immediate relief such as a reduction in pain, swelling, and stiffness in your joints, Symptoms usually abate in 6 to 8 weeks, but it can take up to 3 months to get the full benefits. (Source)

10. How will my provider decide if I need a higher dose of methotrexate? 

If after 2 months you haven’t responded well to the dose you've been prescribed, your provider may decide to increase it. Taking more than 15 mg weekly of methotrexate in pill form can be difficult to absorb, so your provider may recommend that you try injections, or that you split the medication into 2 doses to be taken over a 12-hour period. (Source)

11. If I'm on a low dose of methotrexate, will I have to take additional medication for RA? 

Methotrexate is considered a first-line therapy for RA, which means it’s the first treatment prescribed. It can be used on its own, but it can also be combined with other DMARDs, such as  sulfasalazine and hydroxychloroquine. If that's not successful, your provider may prescribe a biologic agent that targets specific molecules on cells of the immune system, joints, and joint fluids. (Source)

12. What is the risk of infection with methotrexate? 

Rheumatoid arthritis comes with an increased risk of infection, and this is affected by your age, the severity of the disease, your overall health, your lifestyle, how often you're hospitalized, and medications you might take to keep your RA in check.

A 2018 review and meta-analysis of studies on methotrexate and RA found that while RA itself increases risk for many kinds of infection, treating RA with methotrexate does not add any additional risk. It is possible, of course, that the risk of infection could be higher if methotrexate is given along with other immunosuppressives. (Source)

In order to reduce your infection risk, it is recommended that you: 

• Get your vaccines. However, keep in mind that methotrexate can cause a reduced immune response to some vaccines, such as those for COVID and the flu, especially for those over the age of 60. Be sure your health care provider is aware of any vaccines you're planning to get, since you may be told to pause methotrexate treatment beforehand, or avoid some vaccines altogether. 

• Wear a mask in crowded places and around people who are or may be sick. 
• Consider taking supplements to build immune support, such as garlic and turmeric. 

Contact your provider immediately if you develop signs of an infection, such as a dry cough, fever, chills, or a sore throat. (Source, Source, Source) 

13. What regular testing do I need while I'm taking methotrexate? 

It’s important that your provider monitor you carefully while you're using methotrexate, which means you will receive testing that includes: 

• liver function tests:  Regular blood tests are recommended to check your liver function, since long term treatment with methotrexate can lead to elevated liver enzymes, scarring, and (rarely) cirrhosis. These tests specifically check levels of alanine transaminase (ALT) and aspartate transaminase (AST), as elevations in these enzymes indicate liver damage or injury. Your serum albumin will also be checked, as low levels of this protein made by your liver can also suggest liver problems. These tests should be administered every 2 to 4 weeks when you begin methotrexate, every 8 to 12 weeks during the third to sixth month of treatment, and after that, every 3 months. 

• a complete blood count: This testing should be done on the same schedule as the liver function tests. It checks for a deficiency in platelets or white or red blood cells, and will also check on your kidney function. If you have untreated kidney disease or a kidney infection your kidneys may not clear methotrexate from your body properly, which may allow the drug to build up and cause bone marrow suppression. 

(Source, Source, Source, Source)

14. What happens if I take too much methotrexate? 

Methotrexate toxicity occurs when there's too much methotrexate in the body, which can happen when: 

• You take your methotrexate incorrectly (for example, you take it daily instead of weekly), or it is prescribed incorrectly.
• You're in kidney failure. 
• You're using drugs that interact with methotrexate and cause a buildup of methotrexate in your body. 
• You have hypoalbuminemia, a lower than normal amount of the protein albumin. Albumin binds methotrexate so it can be cleared from the body, and low albumin levels can mean it takes longer than usual to rid your system of excess methotrexate. 
• You're elderly.

Symptoms of methotrexate toxicity may include: 

• nausea, vomiting, or diarrhea
• mouth sores
• muscle pain
• headache
• fatigue
• difficulty concentrating
• confusion
• dizziness

If you're generally not feeling well, or you're concerned about any symptoms you're having while on methotrexate, consult your provider. Methotrexate toxicity is both preventable and treatable. (Source, Source, Source, Source)

15. What drugs interact with methotrexate? 

If you're using methotrexate, you should avoid: 

• Nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, naproxen, and aspirin, can impair kidney function when they're taken in large amounts and for long periods of time. Your kidneys are important when you're using methotrexate because they help prevent the drug from accumulating in the body. 
• Some antibiotics, such as amoxicillin, bactrim, amphotericin B, and aminoglycoside antibiotics, can also impede your body’s ability to clear methotrexate and increase the risk that you’ll experience side effects. 

• Proton pump inhibitors like Prilosec (omeprazole), which are used to treat gastrointestinal issues like heartburn and gastroesophageal reflux disease (GERD), can reduce your body’s ability to get rid of excess methotrexate. There are other drugs that you can take to treat gastrointestinal conditions that won't interfere with the processing of methotrexate. 

• Medications that can cause stress on the kidneys, such as diuretics, ACE inhibitors, some HIV antivirals, and certain kinds of drugs for type 2 diabetes, can lead to problems clearing extra methotrexate. You won’t necessarily need to avoid these drugs if you're taking low doses of methotrexate. 

• Medications that can be hard on the liver, such as acetaminophen, diclofenac, and some anti-seizure drugs, increase the risk of liver damage when combined with methotrexate, which can itself affect the liver. 

• Protein-bound drugs such as blood thinners, sulfonylureas, and salicylates can keep methotrexate from binding to proteins in the blood, which can lead to excess amounts of the active, unbound form of the drug circulating in the body and cause more severe side effects.

(Source, Source, Source)

The Bottom Line 

Methotrexate is a first-line treatment for rheumatoid arthritis, and most people with the condition will be treated with the drug at some point. When methotrexate is used in low doses, its side effects are usually well tolerated and may be managed by supplementing with folic acid. Your health care provider should be made aware of any liver, kidney, blood, or lung conditions you may have, as methotrexate can aggravate them and lead to more serious side effects. 

It's essential to keep up with regular testing while you're on methotrexate, and to maintain regular communication with your health care provider. Support is vital while you're living with RA, and the care team at WellTheory is here to help you manage your symptoms through changes to lifestyle and diet, as well as connecting you to a community of others with autoimmune conditions.