Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant.[ Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease.][ It can be given by mouth or by injection.][
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Common side effects include nausea, feeling tired, fever, increased risk of infection, leukopenia, and Mucositis.[ Other side effects may include liver disease, lung disease, lymphoma, and severe skin rashes.][ People on long-term treatment should be regularly checked for side effects.][ It is not safe during breastfeeding.][ In those with , lower doses may be needed.][ It acts by blocking the body's use of folic acid.][
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Methotrexate was first made in 1947 and initially was used to treat cancer, as it was less toxic than the then-current treatments.[ In 2023, it was the 130th most commonly prescribed medication in the United States, with more than 4million prescriptions.]
Medical uses
Chemotherapy
Methotrexate was originally developed and continues to be used for chemotherapy, either alone or in combination with other agents. It is effective for the treatment of several cancers, including solid tumours of breast, head and neck, lung, bladder, as well as acute lymphocytic leukemias, non-Hodgkin's lymphoma, osteosarcoma, and choriocarcinoma and other trophoblastic neoplasms. It is also used in the treatment of aggressive fibromatosis (desmoid tumor).
Autoimmune disorders
Although originally designed as a chemotherapy drug, in lower doses methotrexate is a generally safe and well-tolerated drug in the treatment of certain autoimmune diseases.
Methotrexate is used as a disease-modifying treatment for several autoimmune diseases in adults, including rheumatoid arthritis,
Methotrexate is one of the first-line therapies for the treatment of rheumatoid arthritis. Weekly doses of 5–25 mg were found by a Cochrane review to be beneficial for 12–52 weeks duration of therapy, though it is used longer-term in clinical practice. Discontinuation rates are as high as 16% due to adverse effects.
Use of low doses of methotrexate together with NSAIDs such as aspirin or analgesics such as paracetamol is relatively safe in people being treated for rheumatoid arthritis, with appropriate monitoring.
Studies and reviews have found that most rheumatoid arthritis patients treated with methotrexate for up to one year had less pain, functioned better, had fewer swollen and tender joints, and had less disease activity overall as reported by themselves and their doctors. X-rays also showed that the progress of the disease slowed or stopped in many people receiving methotrexate, with the progression being completely halted in about 30% of those receiving the drug.
Results of a systematic review exploring the comparative effectiveness of treatments of early rheumatoid arthritis show that treatment efficacy can be improved with combination therapy with TNF inhibitor or other biologic medications, compared with methotrexate monotherapy.
Likewise, a 2016 study found the use of methotrexate, in combination with TNF inhibitor, is effective for the treatment of ulcerative colitis.
Methotrexate has also been used for multiple sclerosis
Atopic dermatitis
Along with other immunosuppressants, methotrexate is used to treat severe atopic dermatitis (eczema).
During pregnancy
Methotrexate is an abortifacient and is used to treat ectopic pregnancies, provided the fallopian tube has not ruptured.
Administration
Methotrexate can be given by mouth or by injection (intramuscular, intravenous, subcutaneous, or intrathecal).[ Doses are usually taken weekly, not daily, to limit toxicity.][ Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended.][ Measurements of creatinine are recommended at least every two months.][
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Folate is commonly co-prescribed with methotrexate to minimise the risk of adverse effects.
Adverse effects
The most common adverse effects include hepatotoxicity, stomatitis, blood abnormalities (leukopenia, Anemia and thrombocytopenia), increased risk of infection, hair loss, nausea, reduced appetite, abdominal pain, diarrhea, fatigue, fever, dizziness, drowsiness, headache, acute pneumonitis and Kidney failure.
Methotrexate pneumonitis is a rare complication of therapy and appears to be reducing in frequency in most recent rheumatoid arthritis treatment trials.
Methotrexate is Teratology and it is advised to stop taking it at least 4 weeks before becoming pregnant and it should be avoided during pregnancy (pregnancy category X) and while breastfeeding.
Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route (directly into the cerebrospinal fluid), which include Myelopathy and leukoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.
Another little-understood but serious possible adverse effect of methotrexate is neurological damage and memory loss.[ Neurotoxicity may result from the drug crossing the blood–brain barrier and damaging neurons in the cerebral cortex. People with cancer who receive the medication often nickname these effects "chemo brain" or "chemo fog".]
Drug interactions
Penicillins may decrease the elimination of methotrexate and increase the risk of methotrexate toxicity.[ While they may be used together, increased monitoring is recommended.][ The neomycin and paromomycin have been found to reduce gastrointestinal (GI) absorption of methotrexate.][ Likewise, and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively.][
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Other immunosuppressants like Ciclosporin may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity.[ NSAIDs have also been found to fatally interact with methotrexate in numerous case reports.][ Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented.][
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Proton-pump inhibitors such as omeprazole and the anticonvulsant valproate have been found to increase the plasma concentrations of methotrexate, as have nephrotoxic agents such as cisplatin, the GI drug colestyramine, and dantrolene.[
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Vaccine interactions
Taking methotrexate can reduce the effectiveness of vaccinations against various diseases, such as influenza and hepatitis A. It does this by blunting the immune response of the body to the vaccine.
Methotrexate also dampens the immune response to COVID-19 vaccines, making them less effective.
Mechanism of action
Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis.[ Tetrahydrofolate is needed for the de novo synthesis of the nucleoside thymidine, required for DNA replication.][ Also, folate is essential for de-novo purine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, , and .][
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For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather multiple mechanisms appear to be involved, including the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine; inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of ; increasing CD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function.
History
In 1947, a team of researchers led by Sidney Farber showed aminopterin, a chemical analogue of folic acid developed by Yellapragada Subbarao of Lederle, could induce remission in children with acute lymphoblastic leukemia. The development of folic acid analogues had been prompted by the discovery that the administration of folic acid worsened leukaemia, and that a diet deficient in folic acid could, conversely, produce improvement; the mechanism of action behind these effects was still unknown at the time.
In 1951, Jane C. Wright demonstrated the use of methotrexate in , showing remission in breast cancer.
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