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

From the Guidelines

Methotrexate should be initiated at a dose of 15mg once weekly for most autoimmune conditions, with gradual titration based on clinical response and tolerability, as recommended by the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis 1. When starting methotrexate, it is essential to consider the following:

• Obtain baseline labs including complete blood count, liver function tests, renal function, and consider hepatitis B/C and tuberculosis screening.
• Folic acid supplementation (1mg daily or 5mg weekly, taken 24-48 hours after methotrexate) is crucial to reduce side effects, as supported by a Cochrane systematic review 1.
• Patients should avoid alcohol, limit sun exposure, use reliable contraception, and be counseled about potential side effects including nausea, fatigue, mouth sores, and rare but serious complications like hepatotoxicity, bone marrow suppression, and pneumonitis.
• Regular monitoring includes CBC and liver enzymes every 2-4 weeks initially, then every 1-3 months once stable.
• Methotrexate works by inhibiting dihydrofolate reductase and promoting adenosine release, which reduces inflammation and modulates immune function.
• The medication may take 4-8 weeks to show full therapeutic benefit, so patience is needed when evaluating efficacy. Some key points to consider when prescribing methotrexate include:
• Oral methotrexate is conditionally recommended over subcutaneous methotrexate for patients initiating methotrexate, due to ease of administration and similar bioavailability at typical starting doses 1.
• Initiation/titration of methotrexate to a weekly dose of at least 15mg within 4 to 6 weeks is conditionally recommended over initiation/titration to a weekly dose of <15mg 1.
• A split dose of oral methotrexate over 24 hours or subcutaneous injections, and/or an increased dose of folic/folinic acid, is conditionally recommended over switching to alternative DMARD(s) for patients not tolerating oral weekly methotrexate 1.

From the FDA Drug Label

Patients should be informed of the early signs and symptoms of toxicity, of the need to see their physician promptly if they occur, and the need for close follow-up, including periodic laboratory tests to monitor toxicity Baseline assessment should include a complete blood count with differential and platelet counts, hepatic enzymes, renal function tests and a chest X-ray During therapy of rheumatoid arthritis and psoriasis, monitoring of these parameters is recommended: hematology at least monthly, renal function and liver function every 1 to 2 months.

When starting methotrexate, it is essential to:

• Inform patients of the potential toxicity and the need for close follow-up
• Conduct baseline assessments, including complete blood count, hepatic enzymes, renal function tests, and chest X-ray
• Monitor patients closely, with periodic laboratory tests, especially during the initial stages of therapy 2
• Be aware of the potential drug interactions, such as with nonsteroidal anti-inflammatory drugs (NSAIDs) and salicylates 2
• Consider the increased risk of toxicity in older individuals due to diminished hepatic and renal function 2

From the Research

Starting Methotrexate: Key Considerations

• Methotrexate is eliminated almost entirely by the kidneys, and the risk of toxicity is increased in patients with poor renal function 3.
• Before starting low-dose methotrexate therapy, a full blood count, liver function tests, renal function tests, and chest radiography should be performed 3.
• Blood counts and liver function tests should be repeated at regular intervals to monitor for potential toxicity 3.
• Therapeutic drug monitoring of methotrexate has also been suggested as a means of limiting toxicity 3.

Dosing Regimens and Toxicity

• The dose of methotrexate used in oncology is several-fold higher compared to the dose used in systemic immunoinflammatory rheumatological diseases 4.
• Low-dose methotrexate (LD-MTX) and high-dose methotrexate (HD-MTX) have different therapeutic actions, clinical indications, adverse effects, and mechanisms of action 4.
• LD-MTX is contraindicated in advanced chronic kidney disease (CKD), but kidney safety in normal kidney function or mild-to-moderate CKD is less clear 5.
• A study found that LD-MTX had less decline in estimated glomerular filtration rate (eGFR) than placebo, and a lower incidence of kidney adverse events 5.

Folic Acid Supplementation and Monitoring

• Concomitant use of low doses of folic acid has been recommended as an approach to limiting toxicity 3.
• Folic acid supplementation is commonly used in methotrexate treatment, with most guidelines recommending its use 6.
• Monitoring of kidney function, blood counts, and liver function is essential to minimize the risk of toxicity and ensure safe use of methotrexate 3, 7.