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Methotrexate for RA: Safe Use, Side Effects, and What To Expect

Posted on May 25, 2022
Medically reviewed by
Ariel D. Teitel, M.D., M.B.A.
Article written by
Simi Burn, PharmD

Methotrexate is commonly prescribed for the treatment of rheumatoid arthritis (RA). This medication is a disease-modifying antirheumatic drug (DMARD). DMARDs are used to slow the progression of RA by regulating the immune system to reduce inflammation and autoimmune attacks on the joints.

Around 19,000 myRAteam members report they have taken methotrexate, and many have shared their experiences with the drug. “I start taking methotrexate this Sunday,” wrote one member. “I am nervous about the side effects, especially losing some of my hair. Has anyone else had side effects from methotrexate?”

A member replied, “I haven’t lost any hair, but I get bruising that comes and goes. I have been on methotrexate for two years, and it seems to work pretty well for me.”

Another member shared, “I have been on methotrexate for four years with good results so far. However, I have noticed I tire easily.”

Methotrexate— sometimes referred to as MTX — can have a range of potential side effects and drug interactions. People have a wide variety of different experiences with the drug. This article provides information about possible side effects, drug interactions, and how to use methotrexate safely to treat your RA.

How Does Methotrexate Work for RA?

Discovered in 1945 and reintroduced for RA treatment in the 1980s, methotrexate is a traditional DMARD, versus newer DMARD treatments like RA biologics. The Johns Hopkins Arthritis Center notes that around 60 percent of all people diagnosed with RA are currently taking (or have taken) methotrexate. The American College of Rheumatology recommends the drug as the first-line treatment for RA. Sold as Rheumatrex and Trexall, methotrexate is often prescribed along with other medications, such as biologics.

Experts are still unsure about methotrexate’s exact mechanism of action — they don’t know exactly why it’s effective in the treatment of RA. It is believed that methotrexate calms your immune system and reduces inflammation. As a result, methotrexate can help with the symptoms and progression of RA.

How Effective Is Methotrexate for RA?

Studies on methotrexate in people with RA have shown significant improvement in:

  • ACR 50 response, a measure indicating a 50 percent reduction in the number of tender or swollen joints and other outcomes, such as pain and ability
  • Disability levels
  • Quality of life
  • Damage to joints as seen on X-rays

Methotrexate can start working for RA within three to six weeks, and RA symptoms can continue to improve over three months. Methotrexate is most often prescribed as long-term therapy for RA to reduce the progression of the disease, slow joint damage, and help with symptoms. Frequently, methotrexate is used in combination with other RA treatments, depending on your doctor’s assessment of your needs.

How Is Methotrexate Taken?

Methotrexate is usually taken by mouth as a tablet. It is also available as an oral solution. Less often, methotrexate is given as an injection under the skin or in the muscle that may be administered by a health care professional or at home.

Methotrexate is usually prescribed to be taken once per week on the same day. Sometimes, methotrexate is prescribed twice a week or more to help improve absorption and reduce side effects.

Food does not significantly affect the absorption of methotrexate for RA, so you can take it with food or on an empty stomach unless your doctor tells you otherwise. Methotrexate can be taken any time of day.

Your doctor will decide the dose and frequency depending on your needs. If you are prescribed methotrexate, it is important to follow your directions and stick to your treatment carefully to make sure you get the right dose and frequency. When you are taking methotrexate, your doctor will order blood tests to monitor for the development of problems with liver function and other organs.

What Are Side Effects of Methotrexate?

Common side effects of methotrexate include:

  • Gastrointestinal problems — such as nausea, vomiting, and diarrhea — are the most common side effects, affecting between 20 percent and 65 percent of people with RA who take methotrexate.
  • Sores on the lips, mouth, or throat affect up to one-third of people who take methotrexate.
  • “Methotrexate fog” is a feeling of fatigue, headaches, mental fog, and difficulty concentrating, experienced by some people a day after receiving a dose of methotrexate.
  • Hair loss is a relatively uncommon side effect when taking methotrexate at doses commonly prescribed for RA.

Rare but serious side effects of methotrexate include:

  • Liver damage
  • Kidney damage
  • Lung damage
  • Decreased white blood cells, which could increase the risk of infections
  • Decreased blood platelets, which could cause abnormal bleeding
  • Severe birth defects
  • Low sperm cell count

What Are Drug Interactions With Methotrexate?

Methotrexate has drug interactions with many other medications that can sometimes increase the side effects or toxicity of methotrexate, including:

  • Sulfamethoxazole-trimethoprim, sold under the brand names Bactrim and Septra, an antibiotic used to treat bacterial infections such as upper respiratory and urinary tract infections
  • Nonsteroidal anti-inflammatory drugs such as ibuprofen and aspirin, used to treat mild to moderate pain
  • Barbiturates such as phenobarbital or butalbital, used to reduce anxiety, aid sleep, or relieve headaches
  • Phenytoin (sold as Dilantin), used to treat seizures
  • Retinoids — such as acitretin (Soriatane) and tretinoin (Retin-A) — used to treat acne, psoriasis, and other skin conditions

Make sure that your doctors and specialists are aware of every drug you take for each condition, including any dietary or herbal supplements. Your health care team can help catch potential problems and keep you safe from dangerous interactions.

Tips for Staying Safe While on Methotrexate

While you’re on methotrexate, your doctor may advise that you take precautions, including the following.

Take Folic Acid

Doctors usually prescribe folic acid to people who are taking methotrexate for RA to reduce common side effects of the drug. These include nausea, vomiting, and mouth sores. Folic acid can also help lower the risk of developing liver problems while taking methotrexate. Usually, folic acid is prescribed once daily for people taking methotrexate. It is important to take folic acid exactly as prescribed by your doctor.

Avoid Pregnancy and Use Contraception

Your doctor may recommend that you avoid pregnancy and use contraception if you’re taking methotrexate. Taking the drug can result in severe birth defects, both for women and men. Effective contraception methods could include abstinence, oral contraceptives, IUDs, or condoms plus spermicidal foam.

Avoid Sun Exposure

Avoiding sun exposure may be important for people taking methotrexate. According to Arthritis Research Canada, methotrexate is often listed as causing sun sensitivity. Although it’s technically not a sun-sensitizing drug, it can be irritating for some people who have had past sunburns. Precautions such as limiting sun exposure, wearing clothing that covers more skin, and using sunscreen are recommended.

Abstain From Alcohol

Because methotrexate can damage the liver, people taking it are usually advised to stop drinking alcohol.

Talk With Others Who Understand

On myRAteam, the social network for people with rheumatoid arthritis, more than 189,000 members come together to ask questions, give advice, and share their stories with others who understand life with RA.

Are you taking methotrexate for RA? Share your experience and tips in the comments below or by posting on myRAteam.

References
  1. DMARDs — Arthritis Foundation
  2. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis — American College of Rheumatology
  3. Methotrexate Drug Information Sheet — Johns Hopkins Arthritis Center
  4. Methotrexate Mechanism in Treatment of Rheumatoid Arthritis — Joint Bone Spine
  5. Methotrexate for Treating Rheumatoid Arthritis — The Cochrane Database of Systematic Reviews
  6. ACR 50 Response — The Free Dictionary by Farlex
  7. Methotrexate (Rheumatrex, Trexall, Otrexup, Rasuvo) — American College of Rheumatology
  8. Effect of Food on the Bioavailability of Low-Dose Methotrexate in Patients With Rheumatoid Arthritis — Arthritis and Rheumatism
  9. Is There an Optimal Time To Administer Methotrexate in the Treatment of Rheumatoid Arthritis? — The Journal of Rheumatology
  10. A Family Physician’s Guide to Monitoring Methotrexate — American Family Physician
  11. Methotrexate: Managing Side Effects — Arthritis Foundation
  12. Long-Term Safety of Methotrexate Monotherapy in Patients With Rheumatoid Arthritis: A Systematic Literature Research — Annals of the Rheumatic Diseases
  13. Systematic Review on the Safety of Methotrexate in Rheumatoid Arthritis Regarding the Reproductive System (Fertility, Pregnancy, and Breastfeeding) — Clinical and Experimental Rheumatology
  14. The Toxicity of Methotrexate in Male Fertility and Paternal Teratogenicity — Expert Opinion on Drug Metabolism & Toxicology
  15. Folate Supplementation for Methotrexate Therapy in Patients With Rheumatoid Arthritis: A Systematic Review — Journal of Clinical Rheumatology: Practical Reports on Rheumatic & Musculoskeletal Diseases
  16. Methotrexate Drug Interactions in the Treatment of Rheumatoid Arthritis: A Systematic Review — The Journal of Rheumatology
  17. Sun Exposure, Medications, and Rheumatoid Arthritis — Arthritis Research Canada
  18. Methotrexate — NHS

All updates must be accompanied by text or a picture.
Ariel D. Teitel, M.D., M.B.A. is the clinical associate professor of medicine at the NYU Langone Medical Center in New York. Review provided by VeriMed Healthcare Network. Learn more about him here.
Simi Burn, PharmD is a seasoned pharmacist with experience in long-term care, geriatrics, community pharmacy, management, herbal medicine, and holistic health.. Learn more about her here.

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