Which of the following terms best describes methotrexate?

Methotrexate may cause very serious, life-threatening side effects. You should only take methotrexate to treat cancer or certain other conditions that are very severe and that cannot be treated with other medications. Talk to your doctor about the risks of taking methotrexate for your condition.

Tell your doctor if you have or have ever had excess fluid in your stomach area or in the space around your lungs and if you have or have ever had kidney disease. Also tell your doctor if you are taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, choline magnesium trisalicylate (Tricosal, Trilisate), ibuprofen (Advil, Motrin), magnesium salicylate (Doan's), naproxen (Aleve, Naprosyn), or salsalate. These conditions and medications may increase the risk that you will develop serious side effects of methotrexate. Your doctor will monitor you more carefully and may need to give you a lower dose of methotrexate or stop your treatment with methotrexate.

Methotrexate may cause a decrease in the number of blood cells made by your bone marrow. Tell your doctor if you have or have ever had a low number of any type of blood cells or any other problem with your blood cells. Call your doctor immediately if you experience any of the following symptoms: sore throat, chills, fever, or other signs of infection; unusual bruising or bleeding; excessive tiredness; pale skin; or shortness of breath.

Methotrexate may cause liver damage, especially when it is taken for a long period of time. If you drink or have ever drunk large amounts of alcohol or if you have or have ever had liver disease, your doctor may tell you not to take methotrexate unless you have a life-threatening form of cancer because there is a higher risk that you will develop liver damage. The risk that you will develop liver damage may also be higher if you are elderly, obese, or have diabetes. Tell your doctor if you are taking any of the following medications: acitretin (Soriatane), azathioprine (Imuran), isotretinoin (Accutane), sulfasalazine (Azulfidine), or tretinoin (Vesanoid). Ask your doctor about the safe use of alcoholic beverages while you are taking methotrexate. Call your doctor immediately if you experience any of the following symptoms: nausea, extreme tiredness, lack of energy, loss of appetite, pain in the upper right part of the stomach, yellowing of the skin or eyes, or flu-like symptoms. Your doctor may order liver biopsies (removal of a small piece of liver tissue to be examined in a laboratory) before and during your treatment with methotrexate.

Methotrexate may cause lung damage. Tell your doctor if you have or have ever had lung disease. Call your doctor immediately if you experience any of the following symptoms: dry cough, fever, or shortness of breath.

Methotrexate may cause damage to the lining of your mouth, stomach, or intestines. Tell your doctor if you have or have ever had stomach ulcers or ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum). If you experience any of the following symptoms, stop taking methotrexate and call your doctor right away: mouth sores, diarrhea, black, tarry, or bloody stools, or vomit that is bloody or looks like coffee grounds.

Taking methotrexate may increase the risk that you will develop lymphoma (cancer that begins in the cells of the immune system). If you do develop lymphoma, it might go away without treatment when you stop taking methotrexate, or it might need to be treated with chemotherapy.

If you are taking methotrexate to treat cancer, you may develop certain complications as methotrexate works to destroy the cancer cells. Your doctor will monitor you carefully and treat these complications if they occur.

Methotrexate may cause serious or life-threatening skin reactions. If you experience any of the following symptoms, call your doctor immediately: fever, rash, blisters, or peeling skin.

Methotrexate may decrease the activity of your immune system, and you may develop serious infections. Tell your doctor if you have any type of infection and if you have or have ever had any condition that affects your immune system. Your doctor may tell you that you should not take methotrexate unless you have life-threatening cancer. If you experience signs of infection such as a sore throat, cough, fever, or chills, call your doctor immediately.

If you take methotrexate while you are being treated with radiation therapy for cancer, methotrexate may increase the risk that the radiation therapy will cause damage to your skin, bones, or other parts of your body.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests before, during, and after your treatment to check your body's response to methotrexate and to treat side effects before they become severe.

Tell your doctor if you or your partner is pregnant or plan to become pregnant. If you are female, you will need to take a pregnancy test before you begin taking methotrexate. Use a reliable method of birth control so that you or your partner will not become pregnant during or shortly after your treatment. If you are male, you and your female partner should continue to use birth control for 3 months after you stop taking methotrexate. If you are female, you should continue to use birth control until you have had one menstrual period that began after you stopped taking methotrexate. If you or your partner become pregnant, call your doctor immediately. Methotrexate may cause harm or death to the fetus.

KindProteinOrganismHumansPharmacological action

Unknown

Substrate

General FunctionXenobiotic-transporting atpase activitySpecific FunctionHigh-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...Gene NameABCG2Uniprot IDQ9UNQ0Uniprot NameATP-binding cassette sub-family G member 2Molecular Weight72313.47 Da

1. Suzuki M, Suzuki H, Sugimoto Y, Sugiyama Y: ABCG2 transports sulfated conjugates of steroids and xenobiotics. J Biol Chem. 2003 Jun 20;278(25):22644-9. Epub 2003 Apr 7. [Article]
2. Breedveld P, Zelcer N, Pluim D, Sonmezer O, Tibben MM, Beijnen JH, Schinkel AH, van Tellingen O, Borst P, Schellens JH: Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles: potential role for breast cancer resistance protein in clinical drug-drug interactions. Cancer Res. 2004 Aug 15;64(16):5804-11. [Article]
3. Mitomo H, Kato R, Ito A, Kasamatsu S, Ikegami Y, Kii I, Kudo A, Kobatake E, Sumino Y, Ishikawa T: A functional study on polymorphism of the ATP-binding cassette transporter ABCG2: critical role of arginine-482 in methotrexate transport. Biochem J. 2003 Aug 1;373(Pt 3):767-74. [Article]
4. Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD: Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54. [Article]
5. Volk EL, Schneider E: Wild-type breast cancer resistance protein (BCRP/ABCG2) is a methotrexate polyglutamate transporter. Cancer Res. 2003 Sep 1;63(17):5538-43. [Article]
6. Suzuki K, Doki K, Homma M, Tamaki H, Hori S, Ohtani H, Sawada Y, Kohda Y: Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol. 2009 Jan;67(1):44-9. doi: 10.1111/j.1365-2125.2008.03303.x. Epub 2008 Nov 17. [Article]
7. Hou YX, Li CZ, Palaniyandi K, Magtibay PM, Homolya L, Sarkadi B, Chang XB: Effects of putative catalytic base mutation E211Q on ABCG2-mediated methotrexate transport. Biochemistry. 2009 Sep 29;48(38):9122-31. doi: 10.1021/bi900675v. [Article]
8. Tiwari AK, Sodani K, Wang SR, Kuang YH, Ashby CR Jr, Chen X, Chen ZS: Nilotinib (AMN107, Tasigna) reverses multidrug resistance by inhibiting the activity of the ABCB1/Pgp and ABCG2/BCRP/MXR transporters. Biochem Pharmacol. 2009 Jul 15;78(2):153-61. doi: 10.1016/j.bcp.2009.04.002. Epub 2009 Apr 11. [Article]
9. Dai CL, Liang YJ, Wang YS, Tiwari AK, Yan YY, Wang F, Chen ZS, Tong XZ, Fu LW: Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2. Cancer Lett. 2009 Jun 28;279(1):74-83. doi: 10.1016/j.canlet.2009.01.027. Epub 2009 Feb 18. [Article]

Methotrexate (MTX) is an anti-metabolite most commonly used in chemotherapy and immunosuppressant in auto-immune diseases. This activity describes the indications, action, and contraindications for Methotrexate as a valuable agent in treating a wide variety of neoplastic diseases. This activity will highlight the mechanism of action, adverse event profile, and other key factors (uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional healthcare team in managing patients with cancer and auto-immune conditions.

Objectives:

• Describe the mechanism of action of methotrexate in chemotherapy as well as in autoimmune diseases.

• Identify the common and rare but serious adverse events associated with methotrexate use.

• Outline the typical presentations of methotrexate toxicity and how to manage it.

• Review the importance of patient education before starting treatment with methotrexate in any disease to sustain continuity of treatment and prevent morbidity to a greater extent and increase life expectancy in cancer patients.

Methotrexate is an FDA-approved folic acid antagonist indicated for the treatment of rheumatoid arthritis because of its high potency and efficacy in such patients; it can also be useful in patients with juvenile idiopathic arthritis.[1] Gubner first suggested methotrexate use in rheumatoid arthritis after performing a double blinded-placebo controlled clinical trial of methotrexate in patients with rheumatoid arthritis.[2] Aminopterin was originally considered the parent compound for the methotrexate was first used successfully to treat childhood leukemia.[3] 

In today's world, methotrexate is one of the major chemotherapeutic choices for various types of cancers. The medication is also safe and effective for patients with psoriasis, systemic lupus erythematosus, inflammatory bowel disease, vasculitis, and many other connective tissue diseases.[4] However, drug safety and efficacy have not been established in patients with blood dyscrasia, and it is not recommended in pregnant women. The medication is also effective in patients with organ transplantation because of its anti-inflammatory and immunomodulatory activity.[5] Also, methotrexate can be combined with anti-TNF agents and has shown effective in managing patients with ulcerative colitis, lymphoma (non-Hodgkin's type), carcinoma of the breast, small-cell carcinoma of the lung, epidermal tumors of the head and neck, and carcinoma of the ovary.[6] The medication has the same effects as cyclosporin for patients with graft-versus-host disease. Methotrexate is used in off-lain cases of mycosis fungoides, dermatomyositis, pityriasis rubra pilaris, eczema, sarcoidosis, Non- Hodgkin's lymphoma (advanced stage), and non-metastatic osteosarcoma.

Methotrexate has a distinct mechanism of action regarding its use in chemotherapy and immunosuppression in autoimmune diseases. In cancer, methotrexate acts as an antifolate antimetabolite. Methotrexate is taken up into the cell by carriers called the human reduced folate carriers (SLC19A1), and it forms methotrexate-polyglutamate. Both the methotrexate and the methotrexate-polyglutamate inhibit the enzyme dihydrofolate reductase, which catalyzes the conversion of dihydrofolate into tetrahydrofolate, the active form of folic acid.[7] Tetrahydrofolate is necessary for the synthesis of the nucleotides of both DNA and RNA. Methotrexate-polyglutamate further inhibits the de novo purine synthesis of both purine and thymidylate synthase, thereby inhibiting DNA synthesis. This mechanism is utilized in the treatment of cancer because of its cytotoxic effect.[8]

In autoimmune diseases, different mechanisms have involvement in choosing methotrexate as a drug of choice. It inhibits enzyme AICAR transformylase, leading to hindrance in Adenosine and Guanine metabolism, Adenosine accumulation; and due to anti-inflammatory action of adenosine, leads to repression of T-cell activation, down-regulation of B-cells, increasing activated CD-95 T cells sensitivity; and repression of methyltransferase activity, inhibition of the binding of beta-1 interleukin to its cell surface receptor.

Drug interactions- As methotrexate is highly plasma protein bound, any drug that displaces methotrexate from proteins can increase its blood levels.

Also, if any drug has effects on the renal clearance of methotrexate, its concentration may rise.

NSAIDs, salicylates, TMP, penicillin, warfarin, valproate, proton pump inhibitors, cyclosporin, cisplatin increases the risk of MTX toxicity in the blood; aminoglycosides, neomycin, probenecid reduces the absorption of MTX.[9][7]

The most significant and serious interactions are with NSAIDs and PPIs since these are very common therapeutic choices.

A pre methotrexate evaluation is necessary before initiating medical therapy with methotrexate; this evaluation involves the blood tests, which include: complete blood count with differential, renal function tests include the serum creatinine, blood urea nitrogen, and urinalysis, and liver function tests include serum bilirubin, AST, ALT,  serum albumin, hepatitis serology.[10] HIV tests are also necessary, and if appropriate, the clinician should obtain a chest radiograph as well.

Methotrexate is administered orally or as injections (intramuscular, intravenous, intrathecal, or subcutaneous) injection.[11]

Orally: Usual dosing is as a weekly "pulse," administered as a single dose or in three divided doses over 8 hourly in 24 hours every week. Folate supplementation with 1 mg per day or 5 to 7 mg once weekly should be considered for all patients to prevent bone marrow suppression. In adults, oral absorption is dependent upon the dose taken. Peak serum levels are achievable within one to two hours.

Injection: Single-dose auto-injector can deliver MTX in certain doses such as: 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, and 30 mg.[12]

After initiation of medical therapy with methotrexate, follow-up tests should include monitoring of CBC, renal function test, and liver function tests are recommended weekly for 4 weeks and then at least bi-monthly.[13]

Even a low dose of methotrexate is not free from side effects. The most common adverse effects are gastrointestinal manifestations such as nausea, vomiting, mucosal ulcers, loss of appetite. These are noted in most of the patients and are easily managed.[6] The major adverse effect of methotrexate is hepatotoxicity. These side effects are similar to folate deficiency and can be prevented by supplementation of methotrexate with folic acid.[14] A small elevation of aminotransferases level is common, but it is uncommon to have liver steatosis, fibrosis, and cirrhosis when taking a low dose of methotrexate. Over a long duration of treatment, ultrasound scanning and liver biopsy are required to ascertain the level of liver damage.

Methotrexate belongs to category X, which means it is absolutely contraindicated for use in pregnancy. When prescribing this treatment to any female of the reproductive age group, the patient must be made aware of its potential for teratogenesis, and double contraception is mandatory. With high doses, Patients may also experience mucosal ulceration. It may also be a sign of impending methotrexate toxicity. Alopecia, fatigue, fever, increased risk of infection, low white cell count, GI bleeding, pancreatitis, bone marrow suppression (aplastic anemia), malignancy (lymphoproliferative disorders), infections, interstitial pneumonitis, and renal failure are other potentially life-threatening side effects.[15][16]

Methotrexate is contraindicated for use in patients with hypersensitivity reactions to this medication. Pregnant or breastfeeding women should avoid using methotrexate due to the elevated risk of teratogenicity and excretion into breast milk. Caution is necessary for using methotrexate for patients who have pre-existing blood disorders, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.[10] In cases of rheumatoid arthritis or psoriasis, it is contraindicated to use methotrexate in patients with chronic liver disease, liver cirrhosis, alcoholic hepatitis, or chronic alcoholism. it is also not recommended to use methotrexate in HIV/AIDS, blood dyscrasias, renal dysfunction, radiotherapy.[16]

Patients taking methotrexate should undergo monitoring of CBC, serum creatinine, transaminases is recommended weekly for the first four weeks and then at least bimonthly. A complete list of the current medications should be revised to avoid any possible drug interactions before prescribing methotrexate. Liver function tests (monitoring serum AST, ALT, serum albumin levels), liver biopsy can also be done in cases of hepatotoxicity.[10] Creatinine clearance requires monitoring (50 ml/min is necessary before prescribing methotrexate) to avoid possible nephrotoxicity.[16] Monitoring for pulmonary toxicity is also required as the patients may have a dry cough, fever, dyspnoea. baseline chest radiographs recommended to detect interstitial, and alveolar infiltrates, hilar adenopathy, pleural effusions, and pulmonary fibrosis.[15] Methotrexate may also cause reactivation of tuberculosis in endemic countries, so tests to eliminate the presence of tuberculosis are required. Also, monitory for Bone marrow toxicity as myelosuppression can occur due to folate deficiency. A sudden dip in blood counts must alert to that possibility. 

High-dose methotrexate (HDMTX) is the term for doses higher than 500 mg/ml. Patients may experience nausea, mucosal ulceration, alopecia, fatigue, fever, increased risk of infection, leukopenia, GI bleeding, pancreatitis, cirrhosis, aplastic anemia, malignancy (lymphoproliferative disorders), infections, interstitial pneumonitis, renal impairment, and teratogenesis.[10] To manage MTX toxicity: immediate leucovorin administration. In the case of renal failure, adequate hydration and urinary alkalinization with sodium bicarbonate are necessary.

The three antidotes used for MTX toxicity are leucovorin, thymidine, and glucarpidase.[12] Leucovorin is the reduced active form of folic acid. It rescues normal cells from the toxic effects caused by MTX’s inhibition of reduced folates.[17] Leucovorin is particularly effective in preventing myelosuppression, gastrointestinal toxicity, and neurotoxicity during methotrexate treatment. Thymidine rescues cells from the cytotoxic effects of MTX; however, its use is still under investigation and is always given together with the other drugs. Glucarpidase converts methotrexate into DAMPA and glutamate, two nontoxic metabolites, thus rapidly removing methotrexate in patients with renal dysfunction. Glucarpidase, in combination with leucovorin, is a common therapy for MTX toxicity. A single dose of glucarpidase reduces plasma methotrexate concentrations by 97% or more within 15 minutes. Hydration and urine alkalinization is also continued in patients requiring glucarpidase. Leucovorin therapy should continue for 48 hours after glucarpidase administration.[17]

Hemodialysis and hemoperfusion can also lower MTX levels. Intrathecal overdoses require CSF drainage and exchange, steroids, antidotes, and suspension of the medications that interfere with methotrexate clearance (e.g., NSAIDs, salicylates, TMP, penicillin, warfarin, valproate, proton pump inhibitors, cyclosporin, cisplatin).

Measures to increase patient-doctor relationships and sustain treatment continuity should be discussed with the patient before starting treatment with methotrexate to prevent morbidity to a greater extent and increase the life expectancy in cancer patients. The risk of potentially life-threatening side effects, hepatotoxicity, pulmonary toxicity, myelosuppression, and nephrotoxicity should be discussed with the patients.[10][15][16]

• Advise the patient to call 911 immediately if they develop any signs of infection (immunosuppression), experience coughing, wheezing, or shortness of breath (pulmonary toxicity), or notice unusual bleeding (liver or bone marrow suppression).

• Inform patients that adverse reactions such as dizziness and fatigue might affect their ability to drive or operate machinery.

• Inform patients of the risks of adverse effects of many-body systems, including gastrointestinal, hematologic, hepatic, infections, neurologic, pulmonary, renal, and skin.

• Advise patients for close follow-up.

• Advise patients to avoid alcohol, including beer, wine, and hard liquor, because of the increased risk of liver disease.

• Advise patients that methotrexate can cause teratogenicity. Inform both female and male patients of reproductive age that they should practice any two forms of birth control- abstinence, oral contraceptives, or condom plus foam.

• Discuss potential drug interactions, particularly salicylates and over-the-counter NSAIDs.

• Warn patients about the possible development of malignancy, specifically lymphoma.

• Discuss the importance of proper dosing and administration and that the recommended dose is once weekly, and that improper daily use of the recommended dose has led to fatal toxicity. Make sure that patients fully understand the necessity for close follow-up and monitoring for toxicity.[12]

• If an accidental overdose occurs, an antidote is available (leucovorin rescue).

Methotrexate can be an effective drug when used appropriately, but given its propensity for drug-drug interactions and adverse effects, the collaborative efforts of the entire interprofessional healthcare team are necessary to bring about optimal therapeutic results. This team includes clinicians (including mid-level practitioners), specialists, nursing staff, and pharmacists, each providing input based on their particular discipline to enhance patient benefit while preventing adverse outcomes from using the drug. [Level 5]

Review Questions

1.

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Mikhaylov D, Hashim PW, Nektalova T, Goldenberg G. Systemic Psoriasis Therapies and Comorbid Disease in Patients with Psoriasis: A Review of Potential Risks and Benefits. J Clin Aesthet Dermatol. 2019 Jun;12(6):46-54. [PMC free article: PMC6624011] [PubMed: 31360288]

Singh RK, van Haandel L, Kiptoo P, Becker ML, Siahaan TJ, Funk RS. Methotrexate disposition, anti-folate activity and efficacy in the collagen-induced arthritis mouse model. Eur J Pharmacol. 2019 Jun 15;853:264-274. [PMC free article: PMC6500488] [PubMed: 30951714]

Tukukino C, Wallerstedt SM. Drug information centre queries and responses about drug interactions over 10 years-A descriptive analysis. Basic Clin Pharmacol Toxicol. 2019 Jul 16; [PMC free article: PMC6972620] [PubMed: 31310705]

Shetty A, Cho W, Alazawi W, Syn WK. Methotrexate Hepatotoxicity and the Impact of Nonalcoholic Fatty Liver Disease. Am J Med Sci. 2017 Aug;354(2):172-181. [PubMed: 28864376]

Cheng L. Precision dosage of methotrexate in psoriasis. Br J Dermatol. 2019 Oct;181(4):660-661. [PubMed: 31353452]

Lucas CJ, Dimmitt SB, Martin JH. Optimising low-dose methotrexate for rheumatoid arthritis-A review. Br J Clin Pharmacol. 2019 Oct;85(10):2228-2234. [PMC free article: PMC6783593] [PubMed: 31276602]

Patel V, Wang Y, MacDonald JK, McDonald JW, Chande N. Methotrexate for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2014 Aug 26;(8):CD006884. [PMC free article: PMC8202560] [PubMed: 25157445]

Bannwarth B, Labat L, Moride Y, Schaeverbeke T. Methotrexate in rheumatoid arthritis. An update. Drugs. 1994 Jan;47(1):25-50. [PubMed: 7510620]

Gohar A. Response to 'Reply to Gohar on "Lungs, methotrexate and psoriasis", a comment on "Fatal, incidental, idiopathic pulmonary fibrosis in a patient receiving long-term low-dose methotrexate for psoriasis"'. Clin Exp Dermatol. 2019 Dec;44(8):948. [PubMed: 31058367]

Kremer JM, Petrillo GF, Hamilton RA. Pharmacokinetics and renal function in patients with rheumatoid arthritis receiving a standard dose of oral weekly methotrexate: association with significant decreases in creatinine clearance and renal clearance of the drug after 6 months of therapy. J Rheumatol. 1995 Jan;22(1):38-40. [PubMed: 7699678]

Van der Beek JN, Oosterom N, Pieters R, de Jonge R, van den Heuvel-Eibrink MM, Heil SG. The effect of leucovorin rescue therapy on methotrexate-induced oral mucositis in the treatment of paediatric ALL: A systematic review. Crit Rev Oncol Hematol. 2019 Oct;142:1-8. [PubMed: 31323533]