METHOTREXATE
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.
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