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Pronunciation | /ˌmɛθəˈtrɛkˌseɪt,ˌmiː-,-θoʊ-/ [1] [2] [3] |
Trade names | Trexall, Rheumatrex, Otrexup, others [4] |
Other names | MTX, amethopterin |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682019 |
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Routes of administration | By mouth, intravenous, intramuscular, subcutaneous, intrathecal |
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Bioavailability | 60% at lower doses, less at higher doses. [7] |
Protein binding | 35–50% (parent drug), [7] 91–93% (7-hydroxymethotrexate) [8] |
Metabolism | Hepatic and intracellular [7] |
Elimination half-life | 3–10 hours (lower doses), 8–15 hours (higher doses) [7] |
Excretion | Urine (80–100%), feces (small amounts) [7] [8] |
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ECHA InfoCard | 100.000.376 |
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Formula | C20H22N8O5 |
Molar mass | 454.447 g·mol−1 |
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Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. [4] It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. [4] Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. [4] Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. [4] It can be given by mouth or by injection. [4]
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. [4] Other side effects may include liver disease, lung disease, lymphoma, and severe skin rashes. [4] People on long-term treatment should be regularly checked for side effects. [4] It is not safe during breastfeeding. [4] In those with kidney problems, lower doses may be needed. [4] It acts by blocking the body's use of folic acid. [4]
Methotrexate was first made in 1947 and initially was used to treat cancer, as it was less toxic than the then-current treatments. [9] In 1956 it provided the first cures of a metastatic cancer. [10] It is on the World Health Organization's List of Essential Medicines. [11] [12] Methotrexate is available as a generic medication. [4] In 2021, it was the 132nd most commonly prescribed medication in the United States, with more than 4 million prescriptions. [13] [14]
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 a number of 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). [4] [15] [16]
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 a number of autoimmune diseases in adults, including rheumatoid arthritis, [17] psoriasis and psoriatic arthritis, reactive arthritis, enteropathic arthritis, myositis, systemic sclerosis, lupus, sarcoidosis, Crohn's disease, [18] [19] and many forms of vasculitis. In children, it can be used for juvenile dermatomyositis, juvenile idiopathic arthritis, uveitis and localised scleroderma. [20] [21] [22]
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. [23] [20] [24] [25]
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. [26] Methotrexate is also sometimes used in combination with other conventional DMARDs, such as sulfasalazine and hydroxychloroquine. [27]
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. [28] 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. [29]
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. [17] [30]
Likewise, a 2016 study found the use of methotrexate, in combination with anti-TNF agents, has been shown to be effective for the treatment of ulcerative colitis. [31]
Methotrexate has also been used for multiple sclerosis [4] and is used occasionally in systemic lupus erythematosus, with tentative evidence to support such use. [32]
Along with other immunosuppressants, methotrexate is used to treat severe atopic dermatitis (eczema). [33] [34] [35]
Methotrexate is an abortifacient and is used to treat ectopic pregnancies, provided the fallopian tube has not ruptured. [4] [36] Methotrexate with dilation and curettage is used to treat molar pregnancy. Rarely, it is used in combination with misoprostol to abort intrauterine pregnancies. [37]
Methotrexate can be given by mouth or by injection (intramuscular, intravenous, subcutaneous, or intrathecal). [4] Doses are usually taken weekly, not daily, to limit toxicity. [4] Routine monitoring of the complete blood count, liver function tests, and creatinine are recommended. [4] Measurements of creatinine are recommended at least every two months. [4]
Folic acid is commonly co-prescribed with methotrexate to minimise the risk of adverse effects. [22]
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. [4] [20] [38] [15] Methotrexate can also cause mucositis. [39]
Methotrexate pneumonitis is a rare complication of therapy, and appears to be reducing in frequency in most recent rheumatoid arthritis treatment trials. [40] In the context of rheumatoid arthritis interstitial lung disease, methotrexate treatment may be associated with a lower incidence of ILD over time.[ citation needed ]
Methotrexate is teratogenic and it is advised stop taking it at least 4 weeks before becoming pregnant and it should be avoided during pregnancy (pregnancy category X) and while breastfeeding. [41] Guidelines have been updated to state that it is safe for a male partner to take at any point while trying to conceive. [42]
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. [43]
Another little-understood but serious possible adverse effect of methotrexate is neurological damage and memory loss. [44] 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". [44]
Penicillins may decrease the elimination of methotrexate, so increase the risk of toxicity. [4] While they may be used together, increased monitoring is recommended. [4] The aminoglycosides neomycin and paromomycin have been found to reduce gastrointestinal (GI) absorption of methotrexate. [45] Probenecid inhibits methotrexate excretion, which increases the risk of methotrexate toxicity. [45] Likewise, retinoids and trimethoprim have been known to interact with methotrexate to produce additive hepatotoxicity and haematotoxicity, respectively. [45]
Other immunosuppressants like cyclosporins may potentiate methotrexate's haematologic effects, hence potentially leading to toxicity. [45] NSAIDs have also been found to fatally interact with methotrexate in numerous case reports. [45] Nitrous oxide potentiating the haematological toxicity of methotrexate has also been documented. [45]
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. [45]
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. [46] [47] The affinity of methotrexate for DHFR is about 1000-fold that of dihydrofolate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. [46] Tetrahydrofolate is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. [46] Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins. [46]
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. [48] [49] Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor. [50] Thereby, it acts as anticytokine.
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 leukemia, 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. [51] Other analogues of folic acid were in development, and by 1950, methotrexate (then known as amethopterin) was being proposed as a treatment for leukemia. [52] 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.[ citation needed ]
In 1951, Jane C. Wright demonstrated the use of methotrexate in solid tumors, showing remission in breast cancer. [53] 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, [54] and in 1960 Wright et al. produced remissions in mycosis fungoides. [55] [56]
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves, and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage. Folate is required for the body to make DNA and RNA and metabolise amino acids necessary for cell division and maturation of blood cells. As the human body cannot make folate, it is required in the diet, making it an essential nutrient. It occurs naturally in many foods. The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.
Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.
Sulfasalazine, sold under the brand name Azulfidine among others, is a medication used to treat rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It is considered by some to be a first-line treatment in rheumatoid arthritis. It is taken by mouth or can be administered rectally.
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion.
Aminopterin, the 4–amino derivative of folic acid, is an antineoplastic drug with immunosuppressive properties often used in chemotherapy. Aminopterin is a synthetic derivative of pterin. Aminopterin works as an enzyme inhibitor by competing for the folate binding site of the enzyme dihydrofolate reductase. Its binding affinity for dihydrofolate reductase effectively blocks tetrahydrofolate synthesis. This results in the depletion of nucleotide precursors and inhibition of DNA, RNA, and protein synthesis.
Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma. As an immune suppressor it is used in nephrotic syndrome, granulomatosis with polyangiitis, and following organ transplant, among other conditions. It is taken by mouth or injection into a vein.
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a slightly modified recombinant version of the human interleukin 1 receptor antagonist protein. It is marketed by Swedish Orphan Biovitrum. Anakinra is administered by subcutaneous injection.
The era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. The targeted therapy revolution has arrived, but many of the principles and limitations of chemotherapy discovered by the early researchers still apply.
4-Aminosalicylic acid, also known as para-aminosalicylic acid (PAS) and sold under the brand name Paser among others, is an antibiotic primarily used to treat tuberculosis. Specifically it is used to treat active drug resistant tuberculosis together with other antituberculosis medications. It has also been used as a second line agent to sulfasalazine in people with inflammatory bowel disease such as ulcerative colitis and Crohn's disease. It is typically taken by mouth.
Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.
Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in megaloblastic anemia in which red blood cells become abnormally large, and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include fatigue, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.
Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.
Antifolates are a class of antimetabolite medications that antagonise (that is, block) the actions of folic acid (vitamin B9). Folic acid's primary function in the body is as a cofactor to various methyltransferases involved in serine, methionine, thymidine and purine biosynthesis. Consequently, antifolates inhibit cell division, DNA/RNA synthesis and repair and protein synthesis. Some such as proguanil, pyrimethamine and trimethoprim selectively inhibit folate's actions in microbial organisms such as bacteria, protozoa and fungi. The majority of antifolates work by inhibiting dihydrofolate reductase (DHFR).
VAMP regimen or VAMP chemotherapy is a four-drug combination chemotherapy regimen, used today in the treatment of Hodgkin lymphoma. It was one of the earliest combination chemotherapy regimens, originally developed as a treatment for childhood leukemia by a group of researchers at the National Cancer Institute led by Emil Frei and Emil Freireich. The first clinical trial of VAMP began in 1961. Because it was the first time that four chemotherapeutic agents were used at once, the trial was highly controversial at its time. Although new combination chemotherapy regimens have replaced the use of VAMP in the treatment of childhood leukemia, VAMP is considered an important precursor to modern treatments, confirming the effectiveness of combination chemotherapy and leading to the use of combination chemotherapy regimens to treat other types of cancer.
Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it received US FDA approval on 22 May 2017 and European Medicines Agency approval on 23 June 2017.
Olokizumab (OKZ) sold under the name Artlegia, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis and COVID-19. It is a humanized monoclonal antibody against the interleukin-6 (IL-6). IL-6 is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases. Olokizumab is the first interleukin-6 (IL-6) inhibitor approved for treatment of rheumatoid arthritis which blocks directly cytokine instead of its receptor. Olokizumab specifically binds to IL-6 at Site 3, blocking IL-6 ability to form hexameric complex. Olokizumab was developed by R-Pharm group, and was launched in 2020.
Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.
Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.
An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.
] To date, three small [86–88] RCTs in SLE patients have been published, including in total 76 patients in the active arm