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Methotrexate: its use in the rheumatic diseases
Abstract:
Methotrexate in a low dose intermittent regimen has become popular as a therapeutic choice for refractory psoriatic arthritis, polymyositis, Reiter's disease and more recently rheumatoid arthritis. As a folate analogue, it inhibits the formation of reduced folate cofactors which participate in a host of important reactions including DNA synthesis. It has been shown to have both immunosuppressive and anti-inflammatory properties although its precise mechanism of action in these diseases is not known. It may be variably absorbed especially in psoriatics and its action may be antagonized by folate supplements. Its major route of metabolism appears to be via the enterohepatic circulation. Numerous drugs, including salicylates, may increase serum levels by displacing the drug from protein binding sites and by competing for renal excretion. It has fewer short term side effects than the other immunosuppressives used in rheumatic disease. Its major long term toxicity is liver fibrosis or cirrhosis which appears to increase with greater cumulative dosage and treatment duration. Several recent reports of hypersensitivity pneumonitis reinforce the previous literature on this topic. Pulmonary toxicity may be more common than suggested as more patients are treated with methotrexate for rheumatic diseases. Clinical studies in general have been uncontrolled and lacking in scope and size. Nevertheless, the literature to date appears to show this to be an excellent drug for use in the diseases mentioned. Prospective double blind controlled studies on psoriatic arthritis and rheumatoid arthritis should help establish this drug as the immunosuppressive of choice in these diseases.
Insights
Low-dose methotrexate is an effective immunosuppressive for rheumatic diseases like rheumatoid arthritis. While generally safe short-term, long-term use carries risks of liver fibrosis and pulmonary toxicity.
Area of Science:
- Rheumatology
- Pharmacology
Background:
- Methotrexate (MTX) is increasingly used for refractory psoriatic arthritis, polymyositis, Reiter's disease, and rheumatoid arthritis.
- As a folate antagonist, MTX inhibits DNA synthesis, exerting immunosuppressive and anti-inflammatory effects.
- Its precise mechanisms in rheumatic diseases and potential drug interactions require further elucidation.
Purpose of the Study:
- To review the efficacy and safety of low-dose intermittent methotrexate in rheumatic diseases.
- To highlight the pharmacokinetic properties and potential toxicities of methotrexate therapy.
- To assess the current evidence supporting methotrexate as a preferred immunosuppressive agent.
Main Methods:
- Literature review of clinical studies on methotrexate in rheumatic diseases.
- Analysis of pharmacokinetic data, including absorption, metabolism, and drug interactions.
- Evaluation of reported short-term and long-term adverse events, including liver and pulmonary toxicity.
Main Results:
- Methotrexate demonstrates efficacy in various rheumatic conditions, with fewer short-term side effects than other immunosuppressants.
- Variable absorption and potential antagonism by folate supplements can affect MTX efficacy.
- Long-term toxicity includes liver fibrosis/cirrhosis, increasing with cumulative dose and duration; hypersensitivity pneumonitis is also a concern.
Conclusions:
- Low-dose methotrexate is a valuable therapeutic option for specific rheumatic diseases.
- Careful monitoring for long-term toxicities, particularly liver and pulmonary, is crucial.
- Further prospective, double-blind controlled studies are needed to solidify methotrexate's role as a first-line immunosuppressive.