What are the considerations for initiating methotrexate (MTX) therapy?

From the Guidelines

Before starting methotrexate, it is recommended to initiate treatment with a weekly dose of at least 15 mg, with escalation to this dose within 4 to 6 weeks, as conditionally recommended by the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis 1. When considering the initiation of methotrexate, several key factors should be taken into account to ensure safe and effective treatment.

• Baseline laboratory tests should be obtained, including complete blood count, liver function tests, renal function tests, and hepatitis B and C screening.
• Pregnancy must be excluded in women of childbearing potential, as methotrexate is teratogenic; effective contraception is required during treatment and for at least 3-6 months after discontinuation.
• Patients should be assessed for pulmonary disease, as methotrexate can cause pneumonitis.
• Alcohol consumption should be limited or avoided due to increased risk of hepatotoxicity.
• Folic acid supplementation (1-5 mg daily) is typically prescribed to reduce side effects, as supported by the multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders 1. The starting dose varies by indication but is often 7.5-15 mg weekly for rheumatoid arthritis, with potential gradual increases based on response and tolerability, aiming for a dose of about 20-25 mg per week as the optimal therapeutic dose in the Western hemisphere, as suggested by the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis 1. Methotrexate can be administered orally or subcutaneously, with the latter route offering better bioavailability and potentially fewer gastrointestinal side effects, although oral methotrexate is conditionally recommended over subcutaneous methotrexate for patients initiating methotrexate, due to the ease of oral administration and similar bioavailability at typical starting doses 1. Regular monitoring during treatment includes complete blood count, liver enzymes, and renal function every 4-12 weeks. Patients should be educated about potential side effects including nausea, fatigue, mouth sores, and the importance of promptly reporting fever, unusual bleeding, or respiratory symptoms. Drug interactions must be considered, particularly with NSAIDs, trimethoprim, and proton pump inhibitors which can increase methotrexate toxicity.

From the FDA Drug Label

Patients undergoing methotrexate therapy should be closely monitored so that toxic effects are detected promptly. Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray The risk of effects on reproduction should be discussed with both male and female patients taking methotrexate. Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate

• Key considerations for starting methotrexate include:
  • Closely monitoring patients for toxic effects
  • Discussing the risk of effects on reproduction with patients
  • Avoiding concomitant use of NSAIDs with high-dose methotrexate
  • Using caution when administering NSAIDs with lower doses of methotrexate
  • Conducting baseline assessments, including complete blood counts and renal function tests
• Precautions to take when starting methotrexate include:
  • Carefully evaluating patients before each course of the drug
  • Monitoring patients regularly for signs of toxicity
  • Adjusting the dose or discontinuing the drug if necessary
  • Considering the potential for increased toxicity with concomitant use of certain medications 2

From the Research

Considerations for Starting Methotrexate

• The starting dosage for methotrexate in patients with rheumatoid arthritis (RA) should not be less than 10 mg/week and should be determined based on disease severity and patient-related factors 3
• When starting methotrexate treatment in a patient with RA, preference should be given to the oral route, with a switch to the intramuscular or subcutaneous route considered in patients with poor compliance, inadequate effectiveness, or gastrointestinal side effects 3
• Investigations that are mandatory before starting methotrexate therapy in a patient with RA consist of a full blood cell count, serum transaminase levels, serum creatinine with computation of creatinine clearance, and a chest radiograph, as well as serological tests for the hepatitis viruses B and C and a serum albumin assay 3
• Folate supplementation can be given routinely to patients treated with methotrexate for RA, with a minimal dosage of 5 mg of folic acid once a week, at a distance from the methotrexate dose 3

Dosing Regimens

• Methotrexate dosing regimens for psoriasis vary, with start-doses ranging from 5 to 25 mg/week, and dosing schemes including single dose or Weinstein schedule 4
• For rheumatoid arthritis, methotrexate was optimally effective when started in a high dosage (more than 10mg/week orally) that was subsequently increased by 5mg/month up to 25-30mg/week, with appropriate adjustments based on clinical disease activity and tolerance of each patient 5
• Parenteral administration of methotrexate was more effective and produced fewer gastrointestinal adverse effects than oral administration 6, 5

Monitoring and Adjustments

• Investigations that are mandatory for monitoring methotrexate therapy in patients with RA consist of full blood cell counts and serum transaminase and creatinine assays, which should be obtained at least once a month for the first 3 months then every 4-12 weeks 3
• Dosage adjustments should be made based on clinical disease activity and tolerance of each patient, with increases in dosage considered at intervals of 6 weeks, up to 20 mg/week, according to tolerance and patient-related factors 3