Methotrexate

Common indications

1. As a disease-modifying treatment for rheumatoid arthritis.
2. As part of chemotherapy regimens for cancers including leukaemia, lymphoma and some solid tumours.
3. To treat severe psoriasis (including psoriatic arthritis) that is resistant to other therapies.

 

Mechanisms of action

• Methotrexate inhibits dihydrofolate reductase, which converts dietary folic acid to tetrahydrofolate (FH4). FH4 is required for DNA and protein synthesis, so lack of FH4 prevents cellular replication. Actively dividing cells are particularly sensitive to the effects of methotrexate, accounting for its efficacy in cancer. Methotrexate also has anti-inflammatory and immunosuppressive effects. 
• These are mediated in part by inhibition of inflammatory mediators such as interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α, although the underlying mechanisms are not fully understood.

 

Important adverse effects

• Dose-related adverse effects of methotrexate include mucosal damage (e.g. sore mouth, gastrointestinal upset) and bone marrow suppression (resulting most significantly in neutropenia and an increased risk of infection). Rarely, hypersensitivity reactions including cutaneous reactions, hepatitis or pneumonitis may occur. Long-term use can cause hepatic cirrhosis or pulmonary fibrosis.
• As methotrexate is usually administered once weekly, there is a risk of accidental overdose if patients take treatment daily. Overdose causes severe dose-related adverse effects with renal impairment and hepatotoxicity. Neurological effects such as headache, seizures and coma may also occur. Treatment is with folinic acid, which ‘rescues’ normal cells from methotrexate effects, and with hydration and urinary alkalinisation to enhance methotrexate excretion.

 

Warnings

• Methotrexate is teratogenic and must be avoided in pregnancy. 
• Both men and women taking the drug should use effective contraception during and for 3 months after stopping treatment. 
• As methotrexate is renally excreted, it is contraindicated in severe renal impairment. 
• As it can cause hepatotoxicity, methotrexate should be avoided in patients with abnormal liver function.

 

Important interactions

• Methotrexate toxicity is more likely if it is prescribed with drugs that inhibit its renal excretion, e.g. NSAIDs, penicillins. 
• Co-prescription with other folate antagonists, e.g. trimethoprim and phenytoin, increases the risk of haematological abnormalities. 
• The risk of neutropenia is increased if methotrexate is combined with clozapine.