Methotrexate
Of the DMARDs, methotrexate (Rheumatrex) is the most widely
prescribed. It is indicated for the treatment of rheumatoid arthritis and
psoriasis; it is also used for psoriatic arthritis, systemic lupus
erythematosus, andsarcoidosis. It is generally as efficacious as the other
agents, with a low incidence of serious side effects when prescribed on a
low-dose weekly schedule.
Methotrexate is a folate
antimetabolite that inhibits di-hydrofolate reductase and other
folate-dependent en-zymes in cells. When given in high doses, methotrexate
exerts potent suppressing action on cellular and humoral immunity . At the low
doses used in the therapy of rheumatoid arthritis, methotrexate appears to be
act-ing more as an antiinflammatory agent than as an im-munosuppressant.
Methotrexate inhibits folate-depend-ent enzymes involved in adenosine
degradation, increasing concentrations of extracellular adenosine. Adenosine
acts via cell surface receptors to inhibit the production of inflammatory
cytokines such as TNF-αand IFN- . Methotrexate also decreases the production of
inflammatory prostaglandins and proteases, though a direct action on the COX
enzymes has not been noted.
In the low-dose regimen used
for rheumatoid arthritis, most side effects of methotrexate are mild and can be
managed by temporarily stopping the drug or reducing the dose. These include
nausea, stomatitis, GI discom-fort, rash, diarrhea, and headaches. Changes in
liver aminotransferases and mild to moderate immunosup-pression have been
reported in rheumatoid arthritis pa-tients taking methotrexate. Severe toxicity
is possible but rare and may be a function of drug accumulation. These effects
include hepatotoxicity progressing to cir-rhosis, pneumonitis progressing to
pulmonary fibrosis, and bone marrow depression with anemia, leukopenia, and
thrombocytopenia. Folic acid supplementation is of-ten used to alleviate
certain side effects of methotrexate therapy (stomatitis, GI irritation,
hematopoietic effects) but may also contribute to resistance to this therapy.
Methotrexate is teratogenic and is
contraindicated dur-ing pregnancy and breast-feeding. Prior to attempting
pregnancy, women should wait at least one menstrual cycle and men at least 3
months after discontinuing this drug. Additional contraindications to
methotrexate ad-ministration include kidney, liver, and lung disease; moderate
to high alcohol use; immunodeficiency; blood dyscrasias; and hypersensitivity.
Elderly persons may be at increased risk for toxicity because of decreased
renal and hepatic function.
Methotrexate clearance can be
decreased by the coadministration of NSAIDs; however, this not usually a
problem with the low doses of methotrexate used to treat arthritis.
Methotrexate can be displaced from plasma protein binding sites by
phenylbutazone, pheny-toin, sulfonylureas, and sulfonamides and certain other
antibiotics. The antifolate effects of methotrexate are additive with those of
other folate-inhibitory drugs, such as trimethoprim.
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