Methotrexate was first made in 1947 and initially was used to treat cancer, as it was less toxic than the then-current treatments.[8] In 1956 it provided the first cures of a metastatic cancer.[9] It is on theWorld Health Organization's List of Essential Medicines.[10] Methotrexate is available as ageneric medication.[4] In 2023, it was the 130th most commonly prescribed medication in the United States, with more than 4million prescriptions.[11][12]
Methotrexate was originally developed and continues to be used forchemotherapy, 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 asacute lymphocytic leukemias, non-Hodgkin's lymphoma, osteosarcoma, andchoriocarcinoma and othertrophoblastic neoplasms. It is also used in the treatment ofaggressive fibromatosis (desmoid tumor).[4][13][14]
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 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.[21][18][22][23]
Use of low doses of methotrexate together withNSAIDs such asaspirin or analgesics such asparacetamol is relatively safe in people being treated for rheumatoid arthritis, with appropriate monitoring.[24] Methotrexate is also sometimes used in combination with other conventionalDMARDs, such as sulfasalazine and hydroxychloroquine.[25]
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.[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.[26] Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such asmyocardial infarctions andstrokes.[27]
Results of a systematic review exploring the comparative effectiveness of treatments of earlyrheumatoid arthritis show that treatment efficacy can be improved with combination therapy withanti-TNF or otherbiologic medications, compared with methotrexate monotherapy.[15][28]
Methotrexate pneumonitis is a rare complication of therapy and appears to be reducing in frequency in most recent rheumatoid arthritis treatment trials.[38] In the context of rheumatoid arthritisinterstitial lung disease, methotrexate treatment may be associated with a lower incidence of ILD over time.[citation needed]
Methotrexate isteratogenic 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.[39] Guidelines have been updated to state that it is safe for a male partner to take at any point while trying to conceive.[40]
Central nervous system reactions to methotrexate have been reported, especially when given via theintrathecal route (directly into thecerebrospinal fluid), which includemyelopathies andleukoencephalopathies. It has a variety of cutaneous side effects, particularly when administered in high doses.[41]
Another little-understood but serious possible adverse effect of methotrexate is neurological damage and memory loss.[42] Neurotoxicity may result from the drug crossing theblood–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".[42]
Penicillins may decrease the elimination of methotrexate and increase the risk of methotrexate toxicity.[4] While they may be used together, increased monitoring is recommended.[4] Theaminoglycosidesneomycin andparomomycin have been found to reduce gastrointestinal (GI) absorption of methotrexate.[43]Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.[43] Likewise,retinoids andtrimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively.[43]
Other immunosuppressants likecyclosporins may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity.[43]NSAIDs have also been found to fatally interact with methotrexate in numerous case reports.[43]Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented.[43]
Trimethoprim/sulfamethoxazole taken together with methotrexate can cause organ toxicity, hepatotoxicity, kidney injury and mucositis due to both medications inhibiting folic acid andTMP-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.[44]
Methotrexate might reduce the effectiveness of COVID-19 vaccines.
Taking methotrexate can reduce the effectiveness of vaccinations against various diseases, such asinfluenza andhepatitis A. It does this by blunting theimmune response of the body to the vaccine.[45][46]
Methotrexate also dampens the immune response toCOVID-19 vaccines, making them less effective.[47][48] 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.[45][49][50]
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 inpurine metabolism, leading to accumulation ofadenosine; inhibition ofT cell activation and suppression ofintercellular adhesion molecule expression by T cells; selective down-regulation ofB cells; increasingCD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function.[53][54] Another mechanism of MTX is the inhibition of the binding ofinterleukin 1-beta to its cell surface receptor.[55] Thereby, it acts asanticytokine.
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)
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 bySidney Farber showedaminopterin, a chemicalanalogue offolic acid developed byYellapragada Subbarao of Lederle, could induceremission in children withacute 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; themechanism of action behind these effects was still unknown at the time.[56] Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia.[57] Animal studies published in 1956 showed thetherapeutic index of methotrexate was better than that of aminopterin, and clinical use of aminopterin was thus abandoned in favor of methotrexate.[citation needed]
^World Health Organization (2023).The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Cronstein BN (June 2005). "Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis".Pharmacological Reviews.57 (2):163–72.doi:10.1124/pr.57.2.3.PMID15914465.S2CID1643606.
^American Rheumatoid Arthritis Guidelines (February 2002). "Guidelines for the management of rheumatoid arthritis: 2002 Update".Arthritis and Rheumatism.46 (2):328–46.doi:10.1002/art.10148.PMID11840435.
^Colebatch AN, Marks JL, Edwards CJ (November 2011). "Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis)".The Cochrane Database of Systematic Reviews (11) CD008872.doi:10.1002/14651858.CD008872.pub2.PMID22071858.
^Tsang-A-Sjoe MW, Bultink IE (2015). "Systemic lupus erythematosus: review of synthetic drugs".Expert Opinion on Pharmacotherapy.16 (18):2793–806.doi:10.1517/14656566.2015.1101448.PMID26479437.S2CID36049926.] To date, three small [86–88] RCTs in SLE patients have been published, including in total 76 patients in the active arm
^Oliff A, Bleyer WA, Poplack DG (1 September 1979). "Methotrexate-induced oral mucositis and salivary methotrexate concentrations".Cancer Chemotherapy and Pharmacology.2 (3):225–226.doi:10.1007/BF00258300.PMID313282.S2CID6273303.
^Gromnica-Ihle E, Krüger K (1 September 2010). "Use of methotrexate in young patients with respect to the reproductive system".Clinical and Experimental Rheumatology.28 (5 Suppl 61): S80-4.PMID21044438.
^Scheinfeld N (December 2006). "Three cases of toxic skin eruptions associated with methotrexate and a compilation of methotrexate-induced skin eruptions".Dermatology Online Journal.12 (7): 15.doi:10.5070/D30NQ2C0BX.PMID17459301.
^Imran M, Ali S, Ibrahim AA, Amjad A, Tanveer A, Khalil S, et al. (July 2024). "Effect of methotrexate hold on COVID-19 vaccine response in the patients with autoimmune inflammatory disorders: a systematic review and meta-analysis".Clinical Rheumatology.43 (7):2203–2214.doi:10.1007/s10067-024-07013-3.PMID38802670.
^Abhishek A, Peckham N, Pade C, Gibbons JM, Cureton L, Francis A, et al. (February 2024). "Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial".The Lancet. Rheumatology.6 (2):e92 –e104.doi:10.1016/S2665-9913(23)00298-9.PMID38267107.
^Böhm I (June 2004). "Increased peripheral blood B-cells expressing the CD5 molecules in association to autoantibodies in patients with lupus erythematosus and evidence to selectively down-modulate them".Biomedicine & Pharmacotherapy.58 (5):338–43.doi:10.1016/j.biopha.2004.04.010.PMID15194170.
^Brody M, Böhm I, Bauer R (October 1993). "Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells".European Journal of Clinical Chemistry and Clinical Biochemistry.31 (10):667–74.CiteSeerX10.1.1.633.8921.doi:10.1515/cclm.1993.31.10.667.PMID8292668.S2CID25311594.
^Hertz R, Li MC, Spencer DB (November 1956). "Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma".Proceedings of the Society for Experimental Biology and Medicine.93 (2):361–6.doi:10.3181/00379727-93-22757.PMID13379512.S2CID22939197.
^Wright JC, Gumport SL, Golomb FM (November 1960). "Remissions produced with the use of Methotrexate in patients with mycosis fungoides".Cancer Chemotherapy Reports.9:11–20.PMID13786791.
