Methotrexate in Rheumatoid Arthritis (Adverse effects)

Methotrexate is a structural analog of folic acid widely used in the treatment of some types of cancer and rheumatic diseases, such as rheumatoid arthritis. The presence of adverse effects is relatively common, with the MTHFR gene being one of the most studied, directly involved in the metabolism of methotrexate and folic acid.

Methotrexate is a drug pertaining to the antimetabolites family of drugs that presents several indications. It is used to treat rheumatoid arthritis, severe psoriasis, certain types of cancer (lymphomas, leukemias, uterus, breast, lung, head and neck) and is also used as an immunosuppressant in organ transplants to prevent rejection. Methotrexate can treat rheumatoid arthritis by decreasing the activity of the immune system. Methotrexate treats cancer by slowing the growth of cancer cells. Methotrexate treats psoriasis by slowing the growth of skin cells to interrupt desquamation. Methotrexate is used to prevent rejection of the graft in transplants since it decreases the activity of the immune system.

Methotrexate is also sometimes used to treat Crohn's disease, multiple sclerosis, autoimmune diseases, and other conditions that develop when the immune system attacks healthy cells in the body by mistake.

If you wish to know all the substances that we analyze in our DNA test, please consult the pharmacological compatibility or pharmacogenetic section.


Antineoplastic and immunosuppressant antagonist of folic acid. Methotrexate interferes in processes of DNA synthesis, repair and cellular replication; It can decrease the development of malignant tissues without irreversible damage in normal tissues.


Pregnancy, breastfeeding, existing or recent chickenpox, herpes zoster. Should be evaluated the risk-benefit ratio in patients suffering ascites, gastrointestinal obstruction, peritoneal or pleural effusion, renal dysfunction, depression of the bone marrow, history of gout, kidney stones, liver dysfunction, infection, peptic ulcer and ulcerative colitis. Caution should also be exercised in patients undergoing treatment with cytotoxic drugs or radiation therapy.


Many adverse reactions are unavoidable and represent the pharmacological action of methotrexate; for example, leucopenia and thrombocytopenia, which are used as indicators of the effectiveness of the medication and facilitate the adjustment of the individual dosage. The development of side effects require medical attention only if they persist or are annoying: anorexia, nausea and vomiting. The side effects that are more frequent and require medical attention are: hematemesis, diarrhea, hematuria, arthralgia and edema. With intrathecal administration may appear: blurred vision, confusion, dizziness, drowsiness, headaches, seizures or unusual fatigue. Alopecia does not require medical attention. The development of certain side effects can indicate possible toxicity of the central nervous system: blurred vision, confusion, dizziness and headaches. Side effects are more likely to occur in very young or elderly patients.

When used as an antineoplastic the side effects that can be developed are the following: Leukocytopenia, thrombocytopenia, anemia; headache, fatigue, drowsiness, paresthesia; pulmonary complications due to interstitial alveolitis/pneumonitis (typical symptoms: malaise, irritating and dry cough, respiratory distress that progresses to dyspnea at rest, chest pain, fever); loss of appetite, nausea, vomiting, abdominal pain, inflammation and ulceration of the mucous membrane of the mouth and throat, stomatitis, dyspepsia, diarrhea; rash, erythema, pruritus; increase in liver enzymes (ALAT, ASAT, alkaline phosphatase and bilirubin).

If an overdose of methotrexate occurs, it should be rescued with folinic acid by intravenous infusion in doses of up to 75 mg in the first 12 hours followed by folinic acid 15 mg oral or intravenous every 6 hours at least 4 doses, until the serum levels of methotrexate are less than 5x10-7 M. A treatment with intravenous and intrathecal carboxypeptidase G2 has been published to accelerate the clearance of methotrexate.


The simultaneous administration of intrathecal methotrexate with acyclovir can produce neurological abnormalities. Methotrexate increases the risk of hepatotoxicity with alcohol or hepatotoxic medications. Methotrexate increases the concentration of uric acid in the blood, so it is necessary to readjust the dosage of allopurinol, colchicine or probenecid. Methotrexate increases the anticoagulant activity and the risk of hemorrhages by reducing the hepatic synthesis of the coagulation factors, for this reason the dose of anticoagulants derived from coumarin needs to be regulated. The use of NSAIDs increases the risk of agranulocytosis (phenylbutazone). Asparaginase can block the effects of methotrexate by inhibiting cell replication. The administration of cytarabine after initiation of therapy with methotrexate may produce a synergistic cytotoxic effect. Folic acid can interfere with the antifolate effects of methotrexate. Oral kanamycin increases the absorption of oral methotrexate. Oral neomycin decreases the absorption of oral methotrexate. Probenecid and salicylates can inhibit renal excretion of methotrexate. Pyrimethamine, triamterene or trimethoprim may increase the toxic effects of methotrexate due to their similar actions as folic acid antagonists.


  • Rheumatrex®
  • Trexall®
  • Bertanel®
  • Metoject®
  • Emthexate®

Genes analyzed



Chen Y, Zou K, Sun J, Yang Y, Liu G. Are gene polymorphisms related to treatment outcomes of methotrexate in patients with rheumatoid arthritis? A systematic review and meta-analysis. Pharmacogenomics, 2017; 18(2):175–95.

van Ede AE, Laan RF, Blom HJ, Huizinga TW, Haagsma CJ, Giesendorf BA, et al. The C677T mutation in the methylenetetrahydrofolate reductase gene: a genetic risk factor for methotrexate-related elevation of liver enzymes in rheumatoid arthritis patients. Arthritis Rheum, 2001; 44(11):2525–30.

Shao W, Yuan Y, Li Y. Association Between MTHFR C677T Polymorphism and Methotrexate Treatment Outcome in Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis. Genet Test Mol Biomarkers, 2017; 21(5):275–85.

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