Methotrexate

Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant.<ref name=AHFS2016>Template:Cite web</ref> It is used to treat cancer, autoimmune diseases, and ectopic pregnancies.<ref name="AHFS2016" /> Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma.<ref name=AHFS2016/> Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease.<ref name=AHFS2016/> It can be given by mouth or by injection.<ref name=AHFS2016/>

Common side effects include nausea, feeling tired, fever, increased risk of infection, low white blood cell counts, and breakdown of the skin inside the mouth.<ref name=AHFS2016/> Other side effects may include liver disease, lung disease, lymphoma, and severe skin rashes.<ref name=AHFS2016/> People on long-term treatment should be regularly checked for side effects.<ref name=AHFS2016/> It is not safe during breastfeeding.<ref name=AHFS2016/> In those with kidney problems, lower doses may be needed.<ref name=AHFS2016/> It acts by blocking the body's use of folic acid.<ref name=AHFS2016/>

Methotrexate was first made in 1947 and initially was used to treat cancer, as it was less toxic than the then-current treatments.<ref>Template:Cite book</ref> In 1956 it provided the first cures of a metastatic cancer.<ref>Template:Cite news</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> Methotrexate is available as a generic medication.<ref name=AHFS2016/> In 2023, it was the 130th most commonly prescribed medication in the United States, with more than 4Template:Nbspmillion prescriptions.<ref name="Top 300">Template:Cite web</ref><ref>Template:Cite web</ref>

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).<ref name=AHFS2016/><ref name="medicines.org.uk" /><ref>Template:Cite journal</ref>

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,<ref name="Donahue_2018" /> psoriasis and psoriatic arthritis, reactive arthritis, enteropathic arthritis, myositis, systemic sclerosis, lupus, sarcoidosis, Crohn's disease,<ref>Template:Cite journal</ref><ref name="pmid9782534">Template:Cite journal</ref> and many forms of vasculitis. In children, it can be used for juvenile dermatomyositis, juvenile idiopathic arthritis, uveitis and localised scleroderma.<ref name="AMH" /><ref name="BNF">Template:Cite book</ref><ref name="Arthritis UK" />

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.<ref>Template:Cite journal</ref><ref name="AMH">Template:Cite book</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> Methotrexate is also sometimes used in combination with other conventional DMARDs, such as sulfasalazine and hydroxychloroquine.<ref>Template:Cite web</ref>

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.Template:Citation needed 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.<ref>Template:Cite journal</ref> Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as myocardial infarctions and strokes.<ref>Template:Cite journal</ref>

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 anti-TNF or other biologic medications, compared with methotrexate monotherapy.<ref name="Donahue_2018">Template:Cite book</ref><ref>Template:Cite journal</ref>

Likewise, a 2016 study found the use of methotrexate, in combination with anti-TNF agents, is effective for the treatment of ulcerative colitis.<ref>Template:Cite journal</ref>

Methotrexate has also been used for multiple sclerosis<ref name="AHFS2016" /> and is used occasionally in systemic lupus erythematosus, with tentative evidence to support such use.<ref>Template:Cite journal</ref>

Atopic dermatitis

Along with other immunosuppressants, methotrexate is used to treat severe atopic dermatitis (eczema).<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="NIHR Evidence-2024">Template:Cite report</ref>

During pregnancy

Methotrexate is an abortifacient and is used to treat ectopic pregnancies, provided the fallopian tube has not ruptured.<ref name=AHFS2016/><ref name="pmid18522946">Template:Cite journal</ref> Methotrexate with dilation and curettage is used to treat molar pregnancy. Rarely, it is used in combination with misoprostol to abort intrauterine pregnancies.<ref>Template:Cite web</ref>

Administration

Methotrexate can be given by mouth or by injection (intramuscular, intravenous, subcutaneous, or intrathecal).<ref name=AHFS2016/> Doses are usually taken weekly, not daily, to limit toxicity.<ref name=AHFS2016/> Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended.<ref name=AHFS2016/> Measurements of creatinine are recommended at least every two months.<ref name=AHFS2016/>

Folic acid is commonly co-prescribed with methotrexate to minimise the risk of adverse effects.<ref name="Arthritis UK">Template:Cite web</ref>

Adverse effects

The most common adverse effects include hepatotoxicity, stomatitis, blood abnormalities (leukopenia, anaemia and thrombocytopenia), increased risk of infection, hair loss, nausea, reduced appetite, abdominal pain, diarrhea, fatigue, fever, dizziness, drowsiness, headache, acute pneumonitis and renal impairment.<ref name=AHFS2016/><ref name = AMH/><ref>Template:Cite web</ref><ref name="medicines.org.uk">Template:Cite web</ref> Methotrexate can also cause mucositis.<ref>Template:Cite journal</ref>

Methotrexate pneumonitis is a rare complication of therapy and appears to be reducing in frequency in most recent rheumatoid arthritis treatment trials.<ref name="pmid31709258">Template:Cite journal</ref> In the context of rheumatoid arthritis interstitial lung disease, methotrexate treatment may be associated with a lower incidence of ILD over time.Template:Cn

Methotrexate is teratogenic and it is advised to stop taking it at least four weeks before becoming pregnant and it should be avoided during pregnancy (pregnancy category X) and while breastfeeding.<ref>Template:Cite journal</ref> Guidelines have been updated to state that it is safe for a male partner to take at any point while trying to conceive.<ref name="pmid36318965">Template:Cite journal</ref>

Central nervous system reactions to methotrexate have been reported, especially when given via the intrathecal route (directly into the cerebrospinal fluid), which include myelopathies and leukoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.<ref>Template:Cite journal</ref>

Another little-understood but serious possible adverse effect of methotrexate is neurological damage and memory loss.<ref name=Haf2009/> 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".<ref name=Haf2009>Template:Cite journal</ref>

Drug interactions

Penicillins may decrease the elimination of methotrexate and increase the risk of methotrexate toxicity.<ref name=AHFS2016/> While they may be used together, increased monitoring is recommended.<ref name=AHFS2016/> The aminoglycosides neomycin and paromomycin have been found to reduce gastrointestinal (GI) absorption of methotrexate.<ref name = MD>Template:Cite web</ref> Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.<ref name = MD/> Likewise, retinoids and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively.<ref name = MD/>

Other immunosuppressants like cyclosporins may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity.<ref name = MD/> NSAIDs have also been found to fatally interact with methotrexate in numerous case reports.<ref name = MD/> Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented.<ref name = MD/>

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.<ref name = MD/>

Trimethoprim/sulfamethoxazole taken together with methotrexate can cause organ toxicity, hepatotoxicity, kidney injury and mucositis due to both medications inhibiting folic acid and TMP-SMX decreasing the renal excretion of methotrexate. This toxicity can be rapid and life-threatening, even when taking doses as low as 5-25mg of methotrexate per week.<ref>Template:Cite journal</ref>

Vaccine interactions

Methotrexate might reduce the effectiveness of COVID-19 vaccines.

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.<ref name="Wroński_2023">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Methotrexate also dampens the immune response to COVID-19 vaccines, making them less effective.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Pausing methotrexate for two weeks following COVID-19 vaccination may result in improved immunity. Not taking the medicine for two weeks might result in a minor increase of inflammatory disease flares in some people.<ref name="Wroński_2023" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name="Raja">Template:Cite journal</ref><ref name="Goodsell">Template:Cite journal</ref> The affinity of methotrexate for DHFR is about 1000-fold that of dihydrofolate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate.<ref name = Raja/> Tetrahydrofolate is needed for the de novo synthesis of thymidine and purine bases, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.<ref name = Raja/>

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 B cells; increasing CD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor.<ref name="pmid8292668">Template:Cite journal</ref> Thereby, it acts as anticytokine.

• 
  The coenzyme folic acid (top) and the anticancer drug methotrexate (bottom) are very similar in structure. As a result, methotrexate is a competitive inhibitor of many enzymes that use folates.
• 
  Methotrexate (green) complexed into the active site of DHFR (blue)

History

Image shows open bottle of methotrexate drug—one of the first chemotherapeutic drugs used in the early 1950s

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.<ref name=Bertino2000>Template:Cite bookTemplate:Page needed</ref> Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia.<ref>Template:Cite journal</ref> Animal studies published in 1956 showed the therapeutic index of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate.Template:Cn

In 1951, Jane C. Wright demonstrated the use of methotrexate in solid tumors, showing remission in breast cancer.<ref>Template:Cite journal</ref> Wright's group was the first to demonstrate use of the drug in solid tumors, as opposed to leukemias, which are a cancer of the marrow. Min Chiu Li and his collaborators then demonstrated complete remission in women with choriocarcinoma and chorioadenoma in 1956,<ref>Template:Cite journal</ref> and in 1960 Wright et al. produced remissions in mycosis fungoides.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Template:Clear

External links

• Methotrexate Injection MedlinePlus article from NIH