Methotrexate is eliminated almost entirely by the kidneys. The risk of
methotrexate toxicity is therefore increased in patients with poor renal function, most likely as a result of
drug accumulation. Declining renal function with age may thus be an important predictor of toxicity to
methotrexate. Up to 60% of all patients who receive
methotrexate for
rheumatoid arthritis (RA) discontinue taking it because of adverse effects, most of which occur during the first year of
therapy. Gastrointestinal complications are the most common adverse effects of
methotrexate, but hepatotoxicity, haematological toxicity, pulmonary toxicity,
lymphoproliferative disorders and exacerbation of
rheumatic nodules have all been reported. Decreased renal function as a result of disease and/or aging appears to be an important determinant of hepatic, lymphoproli ferative and haematological toxicity. Concomitant use of low doses of
folic acid has been recommended as an approach to limiting toxicity. Interactions between
methotrexate and several nonsteroidal anti-inflammatory drugs have been reported, but they may not be clinically significant. However, caution is advised in the use of such combinations in patients with reduced renal function. More serious toxicities (e.g.
pancytopenia) may result when other inhibitors of
folate utilisation [e.g.
cotrimoxazole (
trimethoprim-sulfamethoxazole)] or inhibitors of renal tubular secretion (e.g.
probenecid) are combined with
methotrexate. Before starting low dose
methotrexate therapy in patients with RA, a full blood count, liver function tests, renal function tests and chest radiography should be performed. Blood counts and liver function tests should be repeated at regular intervals. Therapeutic
drug monitoring of
methotrexate has also been suggested as a means of limiting toxicity. Patients with RA usually respond very favourably to low dose
methotrexate therapy, and the probability of patients continuing their treatment beyond 5 years is greater than for other slow-acting
antirheumatic drugs. Thus, given its sustained clinical utility and relatively predictable toxicity profile, low dose
methotrexate is a useful addition to the
therapy of RA.