Mechanism of Action: 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 accumulation 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, dendritic 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 proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to rheumatoid synovitis.
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Pharmacokinetics: Methotrexate can be administered either orally or parentally (SC or IM). The drug is approximately 70% absorbed after oral administration (see Chapter 54). Although variable, bioavailability decreased further in one study when more than 25 mg weekly MTX was used. MTX is metabolized to a less active hydroxylated product. 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. Hydroxychloroquine can reduce the clearance or increase the tubular reabsorption of methotrexate. Methotrexate is excreted principally in the urine, but up to 30% may be excreted in bile.
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Dosage and Indications: It is recommended to start treatment with 7.5 mg weekly. According to patient response, methotrexate is increased to the most common dosing regimen for the treatment of RA, which is 15–25 mg weekly. Notably there is an increased effect up to 30–35 mg weekly, although with increased toxicity. 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, PA, AS, polymyositis, dermatomyositis, Wegener’s granulomatosis, giant cell arteritis, SLE, and vasculitis.
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Adverse Effects: 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 hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (<1%). Liver toxicity is not related to serum methotrexate concentrations. A rare hypersensitivity-like lung reaction 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 leucovorin 24 hours after each weekly dose or by the use of folic acid, although this may decrease the efficacy of the methotrexate by about 10%. This drug is contraindicated in pregnancy.
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