Methotrexate Use for Rheumatoid Arthritis

The Gold Standard Treatment for RA

A Little History

  • In the 1940s, methotrexate was developed for leukemia therapy.
  • The first attempt to use it to treat rheumatoid arthritis was reported in 1951.
  • In the years that followed, studies were conducted to determine the effectiveness and safety of methotrexate as a treatment for rheumatoid arthritis.
  • In the 1970s, methotrexate was considered an experimental treatment for rheumatoid arthritis.
  • In 1988, methotrexate was approved by the FDA as a treatment for rheumatoid arthritis.

Initially, methotrexate was prescribed for patients who did not respond to other therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or other disease-modifying antirheumatic drugs (DMARDs, such as:

Over time, the trend for rheumatoid arthritis treatment has gone from a conservative approach to the belief that early, aggressive treatment is imperative. Methotrexate has become the gold standard treatment (i.e., most reliable treatment against which others are compared) for patients who have moderate to severe rheumatoid arthritis with pain, stiffness, swelling, and fatigue.

Treatment Schedule

Methotrexate may be taken orally in tablet form. The entire weekly dose is usually given once a week, either in divided doses over a 24-hour period or in one dose. Methotrexate is usually prescribed in addition to other treatments, not instead of them.

Many patients choose Saturday as their treatment day so that potential side effects (i.e., nausea or fatigue) do not interrupt their work week. Methotrexate can also be injected intramuscularly and this eliminates the gastrointestinal upset for many people.

Studies have indicated that for some people, methotrexate used in combination with another cytotoxic drug (i.e., Imuran, Cytoxan), or in combination with a biologic drug may be more beneficial than methotrexate used alone.

Studies have also revealed that methotrexate given earlier in the course of treatment may provide a better result.

  • Combination Treatment for Rheumatoid Arthritis

How Methotrexate Works

Methotrexate is an antimetabolite. It interferes with the way cells utilize essential nutrients. As a result, methotrexate inhibits the activity of the immune system and reduces inflammation. As a cytotoxic drug, it may slow the rapid growth of cells in the synovial membrane that lines the joints.

Methotrexate is a potent drug and many have feared its potential toxicity and questioned its safety. Over the last decade, the drug has proved to be safer than expected. The toxic reactions have not appeared as frequently or severely as had been feared due probably to the low dosage level used for arthritis, 1/100 the amount used for cancer chemotherapy.

Methotrexate is a long-term treatment. Dramatic improvement seems to occur in patients within the first month or two. Steady improvement continues for many people over months or even years.

When the drug is withdrawn, as has been done in studies, all signs of improvement disappear and a flare-up of symptoms occurs within a few weeks.

Side Effects

The most common side effect of methotrexate is nausea. Nausea from methotrexate use often disappears on its own. It may also be controlled by lowering the dose or spreading the dose out.

The drug can cause hidden problems, such as liver toxicity, and tests are performed to monitor whether or not these problems are occurring. Complete blood counts are done since methotrexate can suppress the production of new blood cells and lead to severe forms of anemia. Liver-chemistry profiles are done to watch for possible effects on the liver. Liver damage is among the worst potential problems, since once the damage is done, it is irreversible. Because most serious damage to the liver is not revealed by a blood test, a liver biopsy may be recommended periodically.

Another potential threat from methotrexate use is lung disease. A dry cough accompanied by fever and shortness of breath could indicate such a problem. Hair loss is seen in some patients. Some people who use methotrexate develop sores on their skin and inside their mouths. These are signs of a toxic reaction to the drug and its use may need to be discontinued.

According to the American College of Rheumatology, "the use of folate supplements (folic and folinic acid), which are B vitamins, can decrease side effects during methotrexate treatment."


Women should not take methotrexate if they are pregnant or plan to become pregnant. Men planning to become fathers also are warned that the drug may cause birth defects and sterility. Methotrexate use is also ruled out for people who drink a lot of alcohol since the danger of liver cirrhosis rises significantly.


Arthritis What Works. Dava Sobel and Arthur C. Klein

The Duke University Medical Center Book of Arthritis. David S. Pisetsky, M.D. 1995.

Methotrexate. American College of Rheumatology. 4/2004.

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