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Methotrexate: What You Need to Know about this Disease Modifying Anti-Rheumatic Drug

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Methotrexate is a standard treatment for inflammatory conditions. It has been in use since 1948 as a treatment for cancer. Oncologists noted that some children with leukemia also had psoriasis or rheumatoid arthritis, and all these conditions improved with methotrexate treatment. Low-dose methotrexate was demonstrated to be effective for rheumatoid arthritis in 1985. It soon became the most popular of the disease modifying anti-rheumatic drugs (DMARDs).

Methotrexate toxicity is a serious concern for long-term use. The authors of Reference 3 reviewed 88 published studies of methotrexate use for more than two years in treating rheumatoid arthritis. They found that 10 to 37 percent of patients in these studies discontinued methotrexate treatment because of toxicity. As arthritis drugs go, this is a good record. Sulfasalazine, D-penicillamine, and gold all had higher dropout rates. Only hydroxychloroquine had a better record, in terms of people who tolerate the treatment long term.

A higher rate of 79 to 85 percent reported some adverse events (side effects), including:

Gastrointestinal. These were the most common, reported by 52 to 65 percent, and include stomatitis (inflammation of the mucous membrane of the mouth), ulcer, abdominal pain, gastrointestinal bleeding, dyspepsia (heartburn), nausea, vomiting, diarrhea, and weight loss.

Liver function. During the first four years of treament, 69 to 88 percent of patients experienced elevation of liver enzymes. After 79 months, the rate dropped to 15 percent.

Skin/hair. Ulcer, pruritis (intense itching), skin rash, alopecia (hair loss), skin itching, moon face, and eczema.

Central nervous system. Headache, depression, blurred vision, transient ischemic attack, stroke, vertigo, lethargy, malaise (general feeling of illness, sometimes called flu-like), fatigue.

Cytopenia. Loss of hemoglobin, platelets, or white blood cells.

Lung. Methotrexate pneumonitis (inflammation of the lung tissue), pulmonary dysfunction, cough, and other unspecified pulmonary adverse reactions.

To me, it seems paradoxical that a drug used to fight inflammation also causes inflammation of the lungs and mouth. But the immune system is so complicated that I have no trouble believing the article from Annals of Rheumatic Disease.

Methotrexate works well for many patients, but if you feel worse taking it, be sure to discuss the side effects with your doctor. There are many alternatives available.


van Dieren JM et al, “Revisiting the immunomodulators tacrolimus, methotrexate, and mycophenolate mofetil: Their mechanisms of action and role in the treatment of IBD”, Inflamm Bowel Dis. 2006 April; 12(4): 311-23.

Tian H et al, “Understanding the mechanisms of action of methotrexate”, Bulletin of the NYU Hospital for Joint Diseases 2007; 65(3): 168-73.

Salliot C et al, “Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature search”, Ann Rheum Dis. 2009; 68: 1100-04.

Linda Fugate is a scientist and writer in Austin, Texas. She has a Ph.D. in Physics and an M.S. in Macromolecular Science and Engineering. Her background includes academic and industrial research in materials science. She currently writes song lyrics and health articles.

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We value and respect our HERWriters' experiences, but everyone is different. Many of our writers are speaking from personal experience, and what's worked for them may not work for you. Their articles are not a substitute for medical advice, although we hope you can gain knowledge from their insight.

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