Methotrexate for Rheumatoid Arthritis

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Methotrexate for Rheumatoid Arthritis


Generic Name

Methotrexate is given weekly either as a shot (injection) or by mouth (orally).

How It Works

Methotrexate interferes with the production and maintenance of DNA, the genetic material in the cells of your body. It is not known exactly how methotrexate works in rheumatoid arthritis, but it can reduce inflammation and slow the progression of the disease. Methotrexate is considered a disease-modifying antirheumatic drug (DMARD). DMARDs are also called immunosuppressive drugs or slow-acting antirheumatic drugs (SAARDs).

Why It Is Used

Methotrexate reduces inflammation caused by rheumatoid arthritis. It is the most common DMARD used to treat rheumatoid arthritis.5 Methotrexate may be used:

  • In the early stages of rheumatoid arthritis to prevent disease progression.
  • In combination with other medicines such as other DMARDs.

How Well It Works

Methotrexate is effective in relieving joint inflammation and pain, slowing disease progression, and preventing disability by delaying joint destruction.1 People with rheumatoid arthritis may be more likely to continue treatment with methotrexate than with other DMARDs because of favourable results and tolerable side effects. Studies indicate that more than 50% of people who take methotrexate for rheumatoid arthritis continue taking the medicine for more than 3 years, which is longer than any other DMARD.2

Methotrexate is often the first DMARD prescribed for rheumatoid arthritis and usually provides relatively fast relief of at least some symptoms. If you can tolerate methotrexate, but it is not effective, your doctor will recommend that you take another DMARD along with methotrexate (combination therapy). Several recent studies report that treatment results are improved when methotrexate is given with another DMARD. For example, one study found that methotrexate used in combination with etanercept, a new DMARD, is more effective at reducing disease activity than methotrexate alone.3 Studies with infliximab and adalimumab have shown similar results.6

Combination therapy may allow for lower doses of an individual drug to be used, which may reduce the risk of adverse effects that can occur with higher doses. In one large review of studies, various combinations of DMARDs plus methotrexate were more effective than either methotrexate or another DMARD alone.4

Side Effects

Common side effects, which are reversible once the medicine is stopped, include:

  • Nausea.
  • Hair loss.
  • Skin rash.
  • Mild liver inflammation (elevation of liver enzyme blood test).
  • Fatigue and feeling like you have the flu.
  • Mouth sores.
  • Diarrhea.
  • Low blood counts.

Folic acid supplements may help prevent some of these minor side effects. But do not take folic acid without consulting your health professional first.

Risk of infection

Methotrexate decreases the activity of your body's immune system, which increases the risk of a serious bacterial infection. Some people who take methotrexate develop an infection that requires oral antibiotics; a smaller number of people will develop an infection that requires intravenous antibiotics and hospitalization. Contact your health professional if you develop any of the following symptoms:

  • Fever or chills
  • Increased frequency of or burning during urination
  • A cough with yellow sputum or shortness of breath
  • A skin infection
  • Severe abdominal pain or diarrhea
  • A severe sore throat
  • Sinus pain with yellow mucus
  • A painful, burning rash in a band across one side of your body (shingles)
  • Painful, widespread mouth sores

Rare side effects include:

  • Liver damage (not reversible).
  • Lung inflammation or damage.

Regular blood tests may help detect liver damage early so that the dose can be adjusted accordingly. If you develop any of the more serious side effects listed above, call your health professional immediately.

People with rheumatoid arthritis have a slightly higher risk of getting cancer of the lymph glands, called lymphoma, than people without the disease. But lymphoma is rare even for people with rheumatoid arthritis. Experts do not know why this risk is higher for people with rheumatoid arthritis—it may be because the disease is severe or because of the medicines used to treat it. Studies are currently under way to explain this. Talk with your health professional about the benefits of DMARD therapy and the potential risks of treatment.

Your health professional may want you to have a chest X-ray taken before starting treatment with methotrexate. If you develop a cough and shortness of breath while on methotrexate, contact your health professional immediately.

See Drug Reference for a full list of side effects. (Drug Reference is not available in all systems.)

What To Think About

Avoid using alcohol if you are taking methotrexate for rheumatoid arthritis.5

Methotrexate should not be used by pregnant women or women of child-bearing age who are not using reliable birth control. If you are going to take methotrexate, you should be on some form of reliable birth control. If you plan to become pregnant, check with your health professional before stopping birth control and trying to become pregnant.

If you are taking methotrexate, talk to your health professional before taking any other medicines, including:

  • Penicillin antibiotics.
  • Sulfa-based medicines.

While it is generally safe to take non-steroidal anti-inflammatory drugs (NSAIDs), such as ASA (Aspirin), with methotrexate, it is best to talk with your health professional if you plan to do so. Methotrexate is eliminated by the kidney, and NSAIDs could decrease kidney function, so it is possible that clearance of methotrexate from the body could be affected by NSAIDs.

There may be a slight increase in the risk of developing certain infections, such as shingles and pneumonia.

If you have a history of liver disease, such as viral or alcoholic hepatitis, talk with your doctor before taking methotrexate.

Complete the new medication information form (PDF) (What is a PDF document?) to help you understand this medication.



  1. Walker-Bone K, Fallow S (2007). Rheumatoid arthritis, search date June 2005. Online version of BMJ Clinical Evidence. Also available online:
  2. Kwoh CK, et al. (2002). Guidelines for the management of rheumatoid arthritis. Arthritis and Rheumatism, 46(2): 328–346.
  3. Klareskog L, et al. (2004). Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rhumatoid arthritis: Double-blind randomised controlled trial. Lancet, 363: 675–681.
  4. Donahue KE, et al. (2008). Systematic review: Comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Annals of Internal Medicine, 148(2): 124–134.
  5. Kremer JM (2001). Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Annals of Internal Medicine, 134(8): 695–706.
  6. Kremer JM, et al. (2002). Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. Annals of Internal Medicine, 137: 726–733.


By Healthwise Staff
Primary Medical Reviewer Anne C. Poinier, MD - Internal Medicine
Primary Medical Reviewer Brian D. O'Brien, MD - Internal Medicine
Specialist Medical Reviewer Stanford M. Shoor, MD - Rheumatology
Last Revised September 30, 2010

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