Editing Methotrexate

{{Short description|Chemotherapy and immunosuppressant medication}}
{{Redirect-distinguish|Amethopterin|Aminopterin}}
{{Use dmy dates|date=February 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields      = changed
| verifiedrevid      = 464193974
| image              = Methotrexate skeletal.svg
| image_class        = skin-invert-image
| width              = 300
| alt                =
| image2             = Methotrexate-from-xtal-3D-bs-17.png
| image_class2       = bg-transparent
| width2             = 300
| alt2               = 

<!-- Clinical data -->
| pronounce          = {{IPAc-en|audio=En-us-Methotrexate.ogg|ˌ|m|ɛ|θ|ə|ˈ|t|r|ɛ|k|ˌ|s|eɪ|t|,_|ˌ|m|iː|-|,_|-|θ|oʊ|-}}{{refn|{{cite web |url=https://www.oxforddictionaries.com/definition/english/methotrexate |archive-url=https://web.archive.org/web/20121022071848/http://oxforddictionaries.com/definition/english/methotrexate |url-status=dead |archive-date=22 October 2012 |title=methotrexate – definition of methotrexate in English from the Oxford dictionary |publisher=[[OxfordDictionaries.com]] |access-date=20 January 2016 }} }}{{refn|{{MerriamWebsterDictionary|methotrexate}}}}{{refn|{{Dictionary.com|methotrexate}}}}
| tradename          = Trexall, Rheumatrex, Otrexup, others<ref name=AHFS2016/>
| Drugs.com          = {{drugs.com|monograph|methotrexate}}
| MedlinePlus        = a682019
| DailyMedID         = Methotrexate
| pregnancy_AU       = D
| routes_of_administration = [[Oral administration|By mouth]], [[intravenous]], [[intramuscular]], [[subcutaneous injection|subcutaneous]], [[intrathecal]]
| ATC_prefix         = L01
| ATC_suffix         = BA01
| ATC_supplemental   = {{ATC|L04|AX03}}

| legal_AU           = S4
| legal_CA           = Rx-only
| legal_UK           = POM
| legal_US           = Rx-only
| legal_EU           = Rx-only
| legal_EU_comment   = <ref>{{cite web | title=Jylamvo EPAR | website=European Medicines Agency | date=29 March 2017 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/jylamvo | access-date=25 June 2024}}</ref>
| legal_status       = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability    = 60% at lower doses, less at higher doses.<ref name=MSR>{{cite web|title=Trexall, Rheumatrex (methotrexate) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=12 April 2014|url=http://reference.medscape.com/drug/trexall-methotrexate-343201#showall|url-status=live|archive-url=https://web.archive.org/web/20140208210608/http://reference.medscape.com/drug/trexall-methotrexate-343201#showall|archive-date=8 February 2014}}</ref>
| protein_bound      = 35–50% (parent drug),<ref name = MSR/> 91–93% (7-hydroxymethotrexate)<ref name = drugs94>{{cite journal | vauthors = Bannwarth B, Labat L, Moride Y, Schaeverbeke T | title = Methotrexate in rheumatoid arthritis. An update | journal = Drugs | volume = 47 | issue = 1 | pages = 25–50 | date = January 1994 | pmid = 7510620 | doi = 10.2165/00003495-199447010-00003 | s2cid = 46974070 }}</ref>
| metabolism         = [[Hepatic]] and intracellular<ref name = MSR/>
| elimination_half-life = 3–10 hours (lower doses), 8–15 hours (higher doses)<ref name = MSR/>
| excretion          = Urine (80–100%), feces (small amounts)<ref name = MSR/><ref name = drugs94/>

<!-- Identifiers -->
| IUPHAR_ligand      = 4815
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 59-05-2
| PubChem            = 126941
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB00563
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 112728
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = YL5FZ2Y5U1
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D00142
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 44185
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 34259
| PDB_ligand         = MTX
| synonyms           = MTX, amethopterin

<!-- Chemical data -->
| IUPAC_name         = (2''S'')-2-[(4-<nowiki/>{[(2,4-Diaminopteridin-6-yl)methyl](methyl)amino}benzoyl)amino]pentanedioic acid
| C                  = 20
| H                  = 22
| N                  = 8
| O                  = 5
| smiles             = O=C([C@H](CCC(O)=O)NC(C1=CC=C(N(CC2=CN=C(N=C(N)N=C3N)C3=N2)C)C=C1)=O)O
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C20H22N8O5/c1-28(9-11-8-23-17-15(24-11)16(21)26-20(22)27-17)12-4-2-10(3-5-12)18(31)25-13(19(32)33)6-7-14(29)30/h2-5,8,13H,6-7,9H2,1H3,(H,25,31)(H,29,30)(H,32,33)(H4,21,22,23,26,27)/t13-/m0/s1
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = FBOZXECLQNJBKD-ZDUSSCGKSA-N
}}

<!-- Definition and medical uses -->
'''Methotrexate''', formerly known as '''amethopterin''', is a [[chemotherapy agent]] and [[immunosuppressive drug|immune-system suppressant]].<ref name=AHFS2016>{{cite web|title=Methotrexate|url=https://www.drugs.com/monograph/methotrexate.html|work=The American Society of Health-System Pharmacists|access-date=22 August 2016|url-status=live|archive-url=https://web.archive.org/web/20161008130258/https://www.drugs.com/monograph/methotrexate.html|archive-date=8 October 2016}}</ref> It is used to treat [[cancer]], [[autoimmune disease]]s, and [[ectopic pregnancy|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 [[Oral administration|by mouth]] or by injection.<ref name=AHFS2016/>

<!-- Side effects and mechanism -->
Common side effects include nausea, feeling tired, fever, increased risk of infection, [[leukopenia|low white blood cell counts]], and [[ulcerative stomatitis|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 problem]]s, lower doses may be needed.<ref name=AHFS2016/> It acts by blocking the body's use of [[folic acid]].<ref name=AHFS2016/>

<!-- History society and culture -->
Methotrexate was first made in 1947 and initially was used to treat cancer, as it was less toxic than the then-current treatments.<ref>{{cite book| vauthors = Sneader W |title=Drug Discovery: A History |date=2005 |publisher=John Wiley & Sons |isbn=9780470015520 |page=251 |url=https://books.google.com/books?id=jglFsz5EJR8C&pg=PA251 |url-status=live|archive-url=https://web.archive.org/web/20170216080949/https://books.google.com/books?id=jglFsz5EJR8C&pg=PA251|archive-date=16 February 2017}}</ref> In 1956 it provided the first cures of a metastatic cancer.<ref>{{cite news|title=Today's anti-cancer tools are ever better wielded|url=https://www.economist.com/news/technology-quarterly/21728780-they-are-sharper-too-todays-anti-cancer-tools-are-ever-better-wielded|access-date=16 September 2017 |newspaper=[[The Economist]]|date=14 September 2017}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> Methotrexate is available as a [[generic medication]].<ref name=AHFS2016/> In 2022, it was the 132nd most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Methotrexate Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Methotrexate | access-date = 30 August 2024 }}</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 lymphoblastic leukemia|acute lymphocytic leukemias]], non-Hodgkin's lymphoma, osteosarcoma, and [[choriocarcinoma]] and other [[trophoblastic neoplasm]]s. It is also used in the treatment of [[aggressive fibromatosis]] (desmoid tumor).<ref name=AHFS2016/><ref name="medicines.org.uk" /><ref>{{cite journal | vauthors = Lee YS, Joo MW, Shin SH, Hong S, Chung YG | title = Current Treatment Concepts for Extra-Abdominal Desmoid-Type Fibromatosis: A Narrative Review | journal = Cancers | volume = 16 | issue = 2 | pages = 273 | date = January 2024 | pmid = 38254764 | pmc = 10813957 | doi = 10.3390/cancers16020273 | doi-access = free }}</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 antirheumatic drug|disease-modifying]] treatment for several autoimmune diseases in adults, including rheumatoid arthritis,<ref name="Donahue_2018" />  [[psoriasis]] and [[psoriatic arthritis]], [[reactive arthritis]], [[Enteropathic arthropathy|enteropathic arthritis]], [[myositis]], [[Systemic scleroderma|systemic sclerosis]],  [[lupus]], [[sarcoidosis]], [[Crohn's disease]],<ref>{{cite journal | vauthors = Herfarth HH, Long MD, Isaacs KL | title = Methotrexate: underused and ignored? | journal = Digestive Diseases | volume = 30 | issue = Suppl 3 | pages = 112–8 | year = 2012 | pmid = 23295701 | pmc = 4629813 | doi = 10.1159/000342735 }}</ref><ref name="pmid9782534">{{cite journal |vauthors=Boehm IB, Boehm GA, Bauer R |title=Management of cutaneous lupus erythematosus with low-dose methotrexate: indication for modulation of inflammatory mechanisms |journal=Rheumatol Int |volume=18 |issue=2 |pages=59–62 |year=1998 |pmid=9782534 |doi=10.1515/cclm.1993.31.10.667|s2cid=25311594 |url=http://edoc.hu-berlin.de/18452/13106 }}</ref> and many forms of [[vasculitis]]. In children, it can be used for [[juvenile dermatomyositis]], [[juvenile idiopathic arthritis]], [[uveitis]] and [[Morphea|localised scleroderma]].<ref name="AMH" /><ref name="BNF">{{cite book | vauthors = ((Joint Formulary Committee)) | title = British National Formulary (BNF) | year = 2013 | url = https://archive.org/details/bnf65britishnati0000unse | isbn = 978-0-85711-084-8 | edition = 65 | location = London, UK  | publisher = Pharmaceutical Press | url-access = registration }}</ref><ref name="Versus_Arthritis" />

Methotrexate is one of the first-line therapies for the treatment of rheumatoid arthritis. Weekly doses of 5 to 25mg 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>{{cite journal | vauthors = Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME | title = Methotrexate for treating rheumatoid arthritis | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD000957 | date = June 2014 | volume = 2014 | pmid = 24916606 | pmc = 7047041 | doi = 10.1002/14651858.CD000957.pub2 }}</ref><ref name="AMH">{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | edition = 2013 | place = Adelaide | veditors = Rossi S }}</ref><ref>{{cite journal | vauthors = Cronstein BN | title = Low-dose methotrexate: a mainstay in the treatment of rheumatoid arthritis | journal = Pharmacological Reviews | volume = 57 | issue = 2 | pages = 163–72 | date = June 2005 | pmid = 15914465 | doi = 10.1124/pr.57.2.3 | s2cid = 1643606 }}</ref><ref>{{cite journal | author = American Rheumatoid Arthritis Guidelines | title = Guidelines for the management of rheumatoid arthritis: 2002 Update | journal = Arthritis and Rheumatism | volume = 46 | issue = 2 | pages = 328–46 | date = February 2002 | pmid = 11840435 | doi = 10.1002/art.10148 | doi-access =  }}</ref>

Use of low doses of methotrexate together with [[Nonsteroidal anti-inflammatory drug|NSAIDs]] such as [[aspirin]] or analgesics such as [[paracetamol]] is relatively safe in people being treated for rheumatoid arthritis, with appropriate monitoring.<ref>{{cite journal | vauthors = Colebatch AN, Marks JL, Edwards CJ | title = 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) | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD008872 | date = November 2011 | pmid = 22071858 | doi = 10.1002/14651858.CD008872.pub2 }}</ref> Methotrexate is also sometimes used in combination with other conventional [[Disease-modifying antirheumatic drug|DMARDs]], such as sulfasalazine and hydroxychloroquine.<ref>{{Cite web |title=Methotrexate and its use in rheumatoid arthritis (RA) |url=https://nras.org.uk/resource/methotrexate/ |access-date=19 February 2023 |website=NRAS |language=en-GB}}</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.{{Citation needed|date=August 2023}} 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>{{cite journal | vauthors = Weinblatt ME | title = Methotrexate in rheumatoid arthritis: a quarter century of development | journal = Transactions of the American Clinical and Climatological Association | volume = 124 | pages = 16–25 | year = 2013 | pmid = 23874006 | pmc = 3715949 }}</ref> Those individuals with rheumatoid arthritis treated with methotrexate have been found to have a lower risk of cardiovascular events such as [[myocardial infarction]]s and [[stroke]]s.<ref>{{cite journal | vauthors = Marks JL, Edwards CJ | title = Protective effect of methotrexate in patients with rheumatoid arthritis and cardiovascular comorbidity | journal = Therapeutic Advances in Musculoskeletal Disease | volume = 4 | issue = 3 | pages = 149–57 | date = June 2012 | pmid = 22850632 | pmc = 3400102 | doi = 10.1177/1759720X11436239 }}</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 [[TNF inhibitor|anti-TNF]] or other [[Biopharmaceutical|biologic medications]], compared with methotrexate monotherapy.<ref name="Donahue_2018">{{Cite book | vauthors = Donahue KE, Gartlehner G, Schulman ER, Jonas B, Coker-Schwimmer E, Patel SV, Weber RP, Lohr KN, Bann C, Viswanathan M |url=http://www.ncbi.nlm.nih.gov/books/NBK524950/ |title=Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update |date=2018 |publisher=Agency for Healthcare Research and Quality (US) |series=AHRQ Comparative Effectiveness Reviews |location=Rockville (MD) |pmid=30199187}}</ref><ref>{{cite journal | vauthors = Donahue KE, Schulman ER, Gartlehner G, Jonas BL, Coker-Schwimmer E, Patel SV, Weber RP, Bann CM, Viswanathan M | title = Comparative Effectiveness of Combining MTX with Biologic Drug Therapy Versus Either MTX or Biologics Alone for Early Rheumatoid Arthritis in Adults: a Systematic Review and Network Meta-analysis | journal = Journal of General Internal Medicine | volume = 34 | issue = 10 | pages = 2232–2245 | date = October 2019 | pmid = 31388915 | pmc = 6816735 | doi = 10.1007/s11606-019-05230-0 }}</ref>

Likewise, a 2016 study found the use of methotrexate, in combination with [[TNF inhibitor|anti-TNF agents]], is effective for the treatment of [[ulcerative colitis]].<ref>{{cite journal | vauthors = Herfarth HH | title = Methotrexate for Inflammatory Bowel Diseases - New Developments | journal = Digestive Diseases | volume = 34 | issue = 1–2 | pages = 140–6 | date = 1 January 2016 | pmid = 26981630 | pmc = 4820247 | doi = 10.1159/000443129 }}</ref>

Methotrexate has also been used for [[multiple sclerosis]]<ref name="AHFS2016" /> and is used occasionally in [[lupus|systemic lupus erythematosus]], with tentative evidence to support such use.<ref>{{cite journal | vauthors = Tsang-A-Sjoe MW, Bultink IE | title = Systemic lupus erythematosus: review of synthetic drugs | journal = Expert Opinion on Pharmacotherapy | volume = 16 | issue = 18 | pages = 2793–806 | date = 2015 | pmid = 26479437 | doi = 10.1517/14656566.2015.1101448 | s2cid = 36049926 | quote = ] To date, three small [86–88] RCTs in SLE patients have been published, including in total 76 patients in the active arm }}</ref>

=== Atopic dermatitis ===
Along with other immunosuppressants, methotrexate is used to treat severe [[atopic dermatitis]] (eczema).<ref>{{cite journal |vauthors=Paolino A, Alexander H, Broderick C, Flohr C |date=May 2023 |title=Non-biologic systemic treatments for atopic dermatitis: Current state of the art and future directions |journal=Clinical and Experimental Allergy |volume=53 |issue=5 |pages=495–510 |doi=10.1111/cea.14301 |pmid=36949024 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Flohr C, Rosala-Hallas A, Jones AP, Beattie P, Baron S, Browne F, Brown SJ, Gach JE, Greenblatt D, Hearn R, Hilger E, Esdaile B, Cork MJ, Howard E, Lovgren ML, August S, Ashoor F, Williamson PR, McPherson T, O'Kane D, Ravenscroft J, Shaw L, Sinha MD, Spowart C, Taams LS, Thomas BR, Wan M, Sach TH, Irvine AD |date=November 2023 |title=Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel group assessor-blinded clinical trial |journal=The British Journal of Dermatology |volume=189 |issue=6 |pages=674–684 |doi=10.1093/bjd/ljad281 |pmid=37722926}}</ref><ref name="NIHR Evidence-2024">{{Cite report |url=https://evidence.nihr.ac.uk/collection/eczema-in-children-uncertainties-addressed/ |title=Eczema in children: uncertainties addressed |date=2024-03-19 |publisher=NIHR Evidence |doi=10.3310/nihrevidence_62438 |language=en|url-access=subscription }}</ref>

===During pregnancy===
Methotrexate is an [[abortifacient]] and is used to treat [[ectopic pregnancy|ectopic pregnancies]], provided the [[fallopian tube]] has not ruptured.<ref name=AHFS2016/><ref name="pmid18522946">{{cite journal | vauthors = Mol F, Mol BW, Ankum WM, van der Veen F, Hajenius PJ | title = Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis | journal = Human Reproduction Update | volume = 14 | issue = 4 | pages = 309–19 | year = 2008 | pmid = 18522946 | doi = 10.1093/humupd/dmn012 | doi-access = free }}</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>{{Cite web |title=Medical abortion | work = Mayo Clinic |url=https://www.mayoclinic.org/tests-procedures/medical-abortion/about/pac-20394687 |access-date=10 July 2022 |language=en}}</ref>

===Administration===
Methotrexate can be given by mouth or by injection ([[intramuscular]], [[intravenous]], [[subcutaneous injection|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/>

[[Folate|Folic acid]] is commonly co-prescribed with methotrexate to minimise the risk of adverse effects.<ref name="Versus_Arthritis">{{Cite web |title=Methotrexate |url=https://www.versusarthritis.org/about-arthritis/treatments/drugs/methotrexate/ |access-date=19 February 2023 |website=Versus Arthritis |language=en-gb}}</ref>

==Adverse effects==
The most common adverse effects include [[hepatotoxicity]], [[stomatitis]], blood abnormalities ([[leukopenia]], [[Anemia|anaemia]] and [[thrombocytopenia]]), increased risk of infection, hair loss, nausea, reduced appetite, abdominal pain, diarrhea, fatigue, fever, dizziness, drowsiness, headache, acute [[pneumonitis]] and [[Kidney failure|renal impairment]].<ref name=AHFS2016/><ref name = AMH/><ref>{{Cite web |title=BNF is only available in the UK |url=https://www.nice.org.uk/bnf-uk-only |access-date=19 February 2023 |website=NICE}}</ref><ref name="medicines.org.uk">{{Cite web |title=Methotrexate 2.5 mg Tablets - Summary of Product Characteristics (SmPC) - (emc) |url=https://www.medicines.org.uk/emc/product/9945/smpc |access-date=19 February 2023 |website=www.medicines.org.uk}}</ref> Methotrexate can also cause [[mucositis]].<ref>{{cite journal |vauthors=Oliff A, Bleyer WA, Poplack DG |date=1 September 1979 |title=Methotrexate-induced oral mucositis and salivary methotrexate concentrations |journal=Cancer Chemotherapy and Pharmacology |volume=2 |issue=3 |pages=225–226 |doi=10.1007/BF00258300 |pmid=313282 |s2cid=6273303}}</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">{{cite journal | vauthors = Fragoulis GE, Nikiphorou E, Larsen J, Korsten P, Conway R | title = Methotrexate-Associated Pneumonitis and Rheumatoid Arthritis-Interstitial Lung Disease: Current Concepts for the Diagnosis and Treatment | journal = Frontiers in Medicine | volume = 6 | issue = | pages = 238 | date = 2019 | pmid = 31709258 | pmc = 6819370 | doi = 10.3389/fmed.2019.00238 | doi-access = free }}</ref> In the context of rheumatoid arthritis [[interstitial lung disease]], methotrexate treatment may be associated with a lower incidence of ILD over time.{{cn|date=November 2023}}

Methotrexate is [[Teratology|teratogenic]] and it is advised to stop taking it at least 4 weeks before becoming pregnant and it should be avoided during pregnancy ([[Pregnancy category|pregnancy category X]]) and while breastfeeding.<ref>{{cite journal | vauthors = Gromnica-Ihle E, Krüger K | title = Use of methotrexate in young patients with respect to the reproductive system | journal = Clinical and Experimental Rheumatology | volume = 28 | issue = 5 Suppl 61 | pages = S80-4 | date = 1 September 2010 | pmid = 21044438 }}</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">{{cite journal | vauthors = Russell MD, Dey M, Flint J, Davie P, Allen A, Crossley A, Frishman M, Gayed M, Hodson K, Khamashta M, Moore L, Panchal S, Piper M, Reid C, Saxby K, Schreiber K, Senvar N, Tosounidou S, van de Venne M, Warburton L, Williams D, Yee CS, Gordon C, Giles I | collaboration = BSR Standards, Audit and Guidelines Working Group | title = Executive Summary: British Society for Rheumatology guideline on prescribing drugs in pregnancy and breastfeeding: immunomodulatory anti-rheumatic drugs and corticosteroids | journal = Rheumatology | volume =  62| issue =  4| date = November 2022 | pages = 1370–1387 | pmid = 36318965 | doi = 10.1093/rheumatology/keac558 | pmc = 10070067 }}</ref>

Central nervous system reactions to methotrexate have been reported, especially when given via the [[Intrathecal administration|intrathecal route]] (directly into the [[cerebrospinal fluid]]), which include [[Myelopathy|myelopathies]] and [[Leukoencephalopathy|leukoencephalopathies]]. It has a variety of cutaneous side effects, particularly when administered in high doses.<ref>{{cite journal | vauthors = Scheinfeld N | title = Three cases of toxic skin eruptions associated with methotrexate and a compilation of methotrexate-induced skin eruptions | journal = Dermatology Online Journal | volume = 12 | issue = 7 | pages = 15 | date = December 2006 | doi = 10.5070/D30NQ2C0BX | pmid = 17459301 }}</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 "[[Post-chemotherapy cognitive impairment|chemo brain]]" or "chemo fog".<ref name=Haf2009>{{cite journal | vauthors = Hafner DL | title = Lost in the fog: understanding "chemo brain" | journal = Nursing | volume = 39 | issue = 8 | pages = 42–5 | date = August 2009 | pmid = 19633502 | doi = 10.1097/01.nurse.0000358574.56241.2f | s2cid = 9456346 }}</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 [[aminoglycoside]]s [[neomycin]] and [[paromomycin]] have been found to reduce gastrointestinal (GI) absorption of methotrexate.<ref name = MD>{{cite web|title=Methotrexate|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=6 January 2014|access-date=12 April 2014|url=http://www.medicinescomplete.com/mc/martindale/current/ms-9550-n.htm| veditors = Brayfield A }}</ref> [[Probenecid]] inhibits methotrexate excretion, which increases the risk of methotrexate toxicity.<ref name = MD/> Likewise, [[retinoid]]s and [[trimethoprim]] have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively.<ref name = MD/>

Other immunosuppressants like [[Ciclosporin|cyclosporins]] may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity.<ref name = MD/> [[Nonsteroidal anti-inflammatory drug|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/>

=== Vaccine interactions ===
[[File:NIHR-infographic-methotrexate-01.png|thumb|325x325px|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">{{cite journal | vauthors = Wroński J, Ciechomska M, Kuca-Warnawin E | title = Impact of methotrexate treatment on vaccines immunogenicity in adult rheumatological patients - Lessons learned from the COVID-19 pandemic | journal = Biomedicine & Pharmacotherapy | volume = 165 | pages = 115254 | date = September 2023 | pmid = 37542854 | doi = 10.1016/j.biopha.2023.115254 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bass AR, Chakravarty E, Akl EA, Bingham CO, Calabrese L, Cappelli LC, Johnson SR, Imundo LF, Winthrop KL, Arasaratnam RJ, Baden LR, Berard R, Bridges SL, Cheah JT, Curtis JR, Ferguson PJ, Hakkarinen I, Onel KB, Schultz G, Sivaraman V, Smith BJ, Sparks JA, Vogel TP, Williams EA, Calabrese C, Cunha JS, Fontanarosa J, Gillispie-Taylor MC, Gkrouzman E, Iyer P, Lakin KS, Legge A, Lo MS, Lockwood MM, Sadun RE, Singh N, Sullivan N, Tam H, Turgunbaev M, Turner AS, Reston J | title = 2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases | journal = Arthritis Care & Research | volume = 75 | issue = 3 | pages = 449–464 | date = March 2023 | pmid = 36597813 | pmc = 10291822 | doi = 10.1002/acr.25045 }}</ref>

Methotrexate also dampens the immune response to [[COVID-19 vaccine|COVID-19 vaccines]], making them less effective.<ref>{{cite journal | vauthors = Al-Haideri MT, Mannani R, Kaboli R, Gharebakhshi F, Darvishzadehdeldari S, Tahmasebi S, Faramarzi F, Cotrina-Aliaga JC, Khorasani S, Alimohammadi M, Darvishi M, Akhavan-Sigari R | title = The effects of methotrexate on the immune responses to the COVID-19 vaccines in the patients with immune-mediated inflammatory disease: A systematic review of clinical evidence | journal = Transplant Immunology | volume = 79 | pages = 101858 | date = August 2023 | pmid = 37236514 | pmc = 10205646 | doi = 10.1016/j.trim.2023.101858 }}</ref><ref>{{Cite journal |date=26 January 2023 |title=A pause in methotrexate treatment boosted the immune response to the COVID-19 vaccine |url=https://evidence.nihr.ac.uk/alert/a-short-pause-methotrexate-treatment-boosted-immune-response-covid-19-vaccine/ |journal=NIHR Evidence |publisher=National Institute for Health and Care Research |doi=10.3310/nihrevidence_56391|url-access=subscription }}</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>{{cite journal | vauthors = Imran M, Ali S, Ibrahim AA, Amjad A, Tanveer A, Khalil S, Ali M, Abuelazm M | title = Effect of methotrexate hold on COVID-19 vaccine response in the patients with autoimmune inflammatory disorders: a systematic review and meta-analysis | journal = Clinical Rheumatology | volume = 43 | issue = 7 | pages = 2203–2214 | date = July 2024 | pmid = 38802670 | doi = 10.1007/s10067-024-07013-3 }}</ref><ref>{{cite journal | vauthors = Abhishek A, Peckham N, Pade C, Gibbons JM, Cureton L, Francis A, Barber V, Williams JA, Appelbe D, Eldridge L, Julier P, Altmann DM, Bluett J, Brooks T, Coates LC, Rombach I, Semper A, Otter A, Valdes AM, Nguyen-Van-Tam JS, Williams HC, Boyton RJ, McKnight Á, Cook JA | title = 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 | journal = The Lancet. Rheumatology | volume = 6 | issue = 2 | pages = e92–e104 | date = February 2024 | pmid = 38267107 | doi = 10.1016/S2665-9913(23)00298-9 }}</ref>

==Mechanism of action==
[[Image:Methotrexate vs folate.svg|class=skin-invert-image|thumb|right|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.|alt=The chemical structures of folic acid and methotrexate highlighting the differences between these two substances ([[amidation]] of [[pyrimidone]] and [[methylation]] of secondary [[amine]])]]

[[File:DHFR methotrexate.jpg|thumb|left|Methotrexate (green) complexed into the active site of DHFR (blue)]]

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">{{cite journal | vauthors = Rajagopalan PT, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG | title = Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 21 | pages = 13481–6 | date = October 2002 | pmid = 12359872 | pmc = 129699 | doi = 10.1073/pnas.172501499 | bibcode = 2002PNAS...9913481R | doi-access = free }}</ref><ref name="Goodsell">{{cite journal | vauthors = Goodsell DS | title = The molecular perspective: methotrexate | journal = The Oncologist | volume = 4 | issue = 4 | pages = 340–1 | date = August 1999 | pmid = 10476546 | doi = 10.1634/theoncologist.4-4-340 | doi-access = free }}</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|''de&nbsp;novo'' synthesis]] of the [[nucleoside]] [[thymidine]], required for [[DNA replication|DNA synthesis]].<ref name = Raja/> Also, folate is essential for de-novo [[purine]] base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of [[DNA]], [[RNA]], [[thymidylate]]s, and [[protein]]s.<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 cell]]s; increasing [[CD95]] sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function.<ref>{{cite journal | vauthors = Wessels JA, Huizinga TW, Guchelaar HJ | title = Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis | journal = Rheumatology | volume = 47 | issue = 3 | pages = 249–55 | date = March 2008 | pmid = 18045808 | doi = 10.1093/rheumatology/kem279 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Böhm I | title = 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 | journal = Biomedicine & Pharmacotherapy | volume = 58 | issue = 5 | pages = 338–43 | date = June 2004 | pmid = 15194170 | doi = 10.1016/j.biopha.2004.04.010 }}</ref> Another mechanism of MTX is the inhibition of the binding of [[IL1B|interleukin 1-beta]] to its cell surface receptor.<ref name="pmid8292668">{{cite journal | vauthors = Brody M, Böhm I, Bauer R | title = Mechanism of action of methotrexate: experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells | journal = European Journal of Clinical Chemistry and Clinical Biochemistry | volume = 31 | issue = 10 | pages = 667–74 | date = October 1993 | pmid = 8292668 | doi = 10.1515/cclm.1993.31.10.667 | citeseerx = 10.1.1.633.8921 | s2cid = 25311594 }}</ref> Thereby, it acts as [[anticytokine]].

{{Clear left}}

==History==
{{See also|History of cancer chemotherapy}}
[[File:Nci-vol-1831-300 Methotrexate.jpg|thumb|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 [[analog (chemistry)|analogue]] of [[folic acid]] developed by [[Yellapragada Subbarao]] of Lederle, could induce [[cure#Remission|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>{{Cite book | vauthors = Bertino JR |chapter=Methotrexate: historical aspects |title=Methotrexate | veditors = Cronstein BN, Bertino JR |year=2000 |location=Basel |publisher=Birkhäuser |isbn=978-3-7643-5959-1 |chapter-url=https://books.google.com/books?id=VCAFHzHAotsC }}{{page needed|date=December 2010}}</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>{{cite journal | vauthors = Meyer LM, Miller FR, Rowen MJ, Bock G, Rutzky J | title = Treatment of acute leukemia with amethopterin (4-amino, 10-methyl pteroyl glutamic acid) | journal = Acta Haematologica | volume = 4 | issue = 3 | pages = 157–67 | date = September 1950 | pmid = 14777272 | doi = 10.1159/000203749 }}</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.{{cn|date=November 2023}}

In 1951, [[Jane C. Wright]] demonstrated the use of methotrexate in [[solid tumor]]s, showing remission in breast cancer.<ref>{{cite journal | vauthors = Wright JC, Prigot A, Wright B, Weintraub S, Wright LT | title = An evaluation of folic acid antagonists in adults with neoplastic diseases: a study of 93 patients with incurable neoplasms | journal = Journal of the National Medical Association | volume = 43 | issue = 4 | pages = 211–40 | date = July 1951 | pmid = 14850976 | pmc = 2616951 }}</ref> Wright's group was the first to demonstrate use of the drug in solid tumors, as opposed to leukemias, which are a [[hematological malignancy|cancer of the marrow]]. [[Min Chiu Li]] and his collaborators then demonstrated complete remission in women with [[choriocarcinoma]] and [[chorioadenoma]] in 1956,<ref>{{cite journal | vauthors = Hertz R, Li MC, Spencer DB | title = Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma | journal = Proceedings of the Society for Experimental Biology and Medicine | volume = 93 | issue = 2 | pages = 361–6 | date = November 1956 | pmid = 13379512 | doi = 10.3181/00379727-93-22757 | s2cid = 22939197 }}</ref> and in 1960 Wright et al. produced remissions in [[mycosis fungoides]].<ref>{{cite journal | vauthors = Wright JC, Gumport SL, Golomb FM | title = Remissions produced with the use of Methotrexate in patients with mycosis fungoides | journal = Cancer Chemotherapy Reports | volume = 9 | pages = 11–20 | date = November 1960 | pmid = 13786791 }}</ref><ref>{{cite journal | vauthors = Wright JC, Lyons MM, Walker DG, Golomb FM, Gumport SL, Medrek TJ | title = Observations on the Use of Cancer Chemotherapeutic Agents in Patients With Mycosis Fungoides | journal = Cancer | volume = 17 | issue = 8 | pages = 1045–62 | date = August 1964 | pmid = 14202592 | doi = 10.1002/1097-0142(196408)17:8<1045::AID-CNCR2820170811>3.0.CO;2-S | doi-access = free }}</ref>

== References ==
{{Reflist}}

== External links ==
* [https://medlineplus.gov/druginfo/meds/a682018.html Methotrexate Injection] MedlinePlus article from NIH

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