Methotrexate has been approved for the treatment of refractory rheumatoid arthritis by several regulatory agencies, including the Food and Drug Administration. The tendency is now to prescribe it at earlier stages of the disease.
Methotrexate is a well known antifolate. Its exact mechanism of action in rheumatoid arthritis remains uncertain. The polyglutamated derivatives of methotrexate are potent inhibitors of various enzymes, including dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Inhibitory effects on cytokines, particularly interleukin-1, and on arachidonic acid metabolism, as well as effects on proteolytic enzymes, have been reported. Some of them may be linked to the antifolate properties of methotrexate. Overall, the drug appears to act in rheumatoid arthritis as an anti-inflammatory agent with subtle immunomodulating properties. Direct inhibitory effects on rapidly proliferating cells in the synovium have also been suggested.
Methotrexate is usually given orally. Marked interindividual variation in its bioavailability has been found. Food intake has no significant effect on the pharmacokinetics of oral methotrexate.
Methotrexate undergoes significant metabolism. The functionally important metabolites are the polyglutamated derivatives of methotrexate, which are selectively retained in the cells. Less than 10% of a dose of methotrexate is oxidised to 7-hydroxy-methotrexate, irrespective of the route of administration. This metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (35 to 50% bound). Methotrexate is mainly excreted by the kidneys. It undergoes tubular secretion and may thereby compete with various organic acid compounds.
Early placebo-controlled trials demonstrated that weekly low dosage methotrexate produced early symptomatic improvement in most rheumatoid arthritis patients. Two meta-analyses showed that methotrexate is among the most efficacious of slow-acting antirheumatic agents, together with parenteral gold (sodium aurothiomalate), penicillamine and sulfasalazine. Furthermore, in the short term context of clinical trials, methotrexate has one of the best efficacy/toxicity ratios.
There is little evidence that methotrexate, or any available slow-acting antirheumatic agent, is a true disease-modifying drug. However, the probability that a patient will continue methotrexate therapy over time appears quite favourable compared with any other slow-acting antirheumatic drug. Combination therapy with slow-acting drugs has been advised for the management of rheumatoid arthritis, but the evidence currently available does not support general use of combination therapy including methotrexate.
Almost all investigations indicated that toxic effects, rather than lack of response, were the major reason for discontinuing methotrexate therapy. An analysis of more than 3000 courses of therapy with 6 slow-acting drugs indicated that the overall toxicity of methotrexate was similar to that of penicillamine and azathioprine. Hydroxychloroquine was the least toxic, followed by sodium aurothiomalate, whereas auranofin was the most toxic.
Few predisposing factors to methotrexate toxicity have been clearly identified, and individual susceptibility plays a primary role in determining toxicity. Folate supplementation may decrease the incidence of common adverse effects, but whether it prevents more serious adverse reactions remains to be answered. Gastrointestinal symptoms, stomatitis, increased levels of liver enzymes and mild cytopenia are frequent adverse effects associated with methotrexate therapy. Further-more, severe, and possibly life-threatening, complications have been reported. These include advanced liver fibrosis and cirrhosis, interstitial pneumonitis, severe neutropenia and pancytopenia, as well as opportunistic infections. Epstein-Barr virus-associated lymphomas have also been reported. Finally, a variety of other adverse events, such as central nervous system and cutaneous reactions, have been ascribed to methotrexate use.
Numerous drug interactions may occur in patients receiving low dosage methotrexate. Most are probably not clinically significant. Conversely, methotrexate toxicity may be precipitated by concurrent use of cotrimoxazole (trimethoprim/sulfamethoxazole), probenecid, and possibly non-steroidal anti-inflammatory drugs (NSAIDs).
On the basis of the available data, methotrexate should generally not be the first slow-acting antirheumatic drug to be used. However, unlike other cytotoxic agents, it should no longer be regarded as tertiary therapy for rheumatoid arthritis. Low dosage methotrexate may become one of the drugs considered earlier in the course of rheumatoid arthritis not controlled by NSAIDs alone.