Methotrexate, a synthetic antimetabolite, is now considered the first-line DMARD for treatment of rheumatoid arthritis and is used in 50–70% of patients. It is active in this condition at much lower doses than those needed in cancer chemotherapy .
Methotrexate’s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of amino-imidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase. AICAR, which accumulates intracellularly, competitively inhibits AMP deaminase, leading to an accumula-tion of AMP. The AMP is released and converted extracellularly to adenosine, which is a potent inhibitor of inflammation. As a result, the inflammatory functions of neutrophils, macrophages, den-dritic cells, and lymphocytes are suppressed. Methotrexate has secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on prolifera-tion and stimulates apoptosis in immune-inflammatory cells. Additionally, it has also been shown to have inhibition of proin-flammatory cytokines linked to rheumatoid synovitis.
The drug is approximately 70% absorbed after oral administration . It is metabolized to a less active hydroxylated metabolite. Both the parent compound and the metabolite are polyglutamated within cells where they stay for prolonged periods. Methotrexate’s serum half-life is usually only 6–9 hours, although it may be as long as 24 hours in some individuals. Methotrexate’s concentration is increased in the presence of hydroxychloroquine, which can reduce the clearance or increase the tubular reabsorp-tion of methotrexate. This drug is excreted principally in the urine, but up to 30% may be excreted in bile.
Although the most common methotrexate dosing regimen for the treatment of rheumatoid arthritis is 15–25 mg weekly, there is an increased effect up to 30–35 mg weekly. The drug decreases the rate of appearance of new erosions. Evidence supports its use in juvenile chronic arthritis, and it has been used in psoriasis, psori-atic arthritis, ankylosing spondylitis, polymyositis, dermatomyosi-tis, Wegener’s granulomatosis, giant cell arteritis, systemic lupus erythematosus, and vasculitis.
Nausea and mucosal ulcers are the most common toxicities. Additionally, many other side effects such as leukopenia, anemia, stomatitis, GI ulcerations, and alopecia are probably the result of inhibiting cellular proliferation. Progressive dose-related hepato-toxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (<1%). Liver toxicity is not related to serum methotrexate concentrations. Rare hypersensitivity-like lung reac-tion with acute shortness of breath has been documented, as have pseudo-lymphomatous reactions. The incidence of GI and liver function test abnormalities can be reduced by the use of leuco-vorin 24 hours after each weekly dose or by the use of daily folic acid, although this may decrease the efficacy of the methotrexate by about 10%. This drug is contraindicated in pregnancy.