What are the considerations when initiating Methotrexate (MTX) therapy?

From the Guidelines

Before initiating methotrexate, it is essential to consider several crucial factors to minimize risks and maximize benefits, as supported by the most recent and highest quality evidence from the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis 1.

Key Considerations

• Baseline laboratory testing is vital, including complete blood count, liver function tests, renal function tests, hepatitis B and C screening, and tuberculosis screening.
• Pregnancy must be excluded in women of childbearing potential due to methotrexate's teratogenic effects, and effective contraception should be used during treatment and for at least 3-6 months after discontinuation.
• Folic acid supplementation (at least 5 mg weekly) is strongly recommended to reduce side effects, as evidenced by a Cochrane systematic review 1.
• Methotrexate should be started at a low dose (10-15 mg weekly) and gradually increased as needed and tolerated, with a maximum dose usually around 20-25 mg weekly, according to multinational recommendations for the use of methotrexate in rheumatic disorders 1.
• The medication can be administered orally or subcutaneously, with the latter route often providing better bioavailability and fewer gastrointestinal side effects.
• Regular monitoring is crucial, including blood tests every 1-1.5 months initially, then every 1-3 months once stable, to assess for potential side effects such as hepatotoxicity, bone marrow suppression, and pulmonary toxicity.
• Patients should be counseled about these potential side effects and the importance of limiting alcohol consumption and assessing drug interactions, particularly with NSAIDs, certain antibiotics, and proton pump inhibitors, which can increase methotrexate toxicity.

Administration and Monitoring

• Oral methotrexate is conditionally recommended over subcutaneous methotrexate for patients initiating methotrexate, with moderate certainty of evidence 1.
• Initiation/titration of methotrexate to a weekly dose of at least 15 mg within 4 to 6 weeks is conditionally recommended, considering the balance between efficacy and risks of toxicity.
• A split dose of oral methotrexate or subcutaneous injections, along with increased folic/folinic acid, may be considered for patients not tolerating oral weekly methotrexate, although the evidence for this is of very low certainty.
• Switching to subcutaneous methotrexate is conditionally recommended over adding or switching to alternative DMARDs for patients taking oral methotrexate who are not at target, based on very low certainty of evidence.

By carefully considering these factors and following the recommended guidelines, healthcare providers can help ensure the safe and effective use of methotrexate in patients with rheumatoid arthritis and other rheumatic disorders.

From the FDA Drug Label

Methotrexate has the potential for serious toxicity (see Boxed WARNINGS). Toxic effects may be related in frequency and severity to dose or frequency of administration but have been seen at all doses. Because they can occur at any time during therapy, it is necessary to follow patients on methotrexate closely. Most adverse reactions are reversible if detected early When such reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken. 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 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.

Initiating Methotrexate Considerations:

• Monitor patients closely for signs of toxicity, as it can occur at any time during therapy.
• Baseline assessment should include complete blood count, hepatic enzymes, renal function tests, and chest X-ray.
• Monitoring parameters during therapy should include hematology at least monthly, renal function and liver function every 1 to 2 months.
• Reduce dosage or discontinue the drug if adverse reactions occur, and take appropriate corrective measures.
• Use caution when administering methotrexate, especially in older individuals due to diminished hepatic and renal function. 2

From the Research

Initiating Methotrexate Considerations

When initiating methotrexate therapy for rheumatoid arthritis, several considerations must be taken into account.

• The starting dosage for methotrexate should not be less than 10 mg/week and should be determined based on disease severity and patient-related factors 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.
• Supplementation with folic or folinic acid during treatment with methotrexate may ameliorate side effects such as mucosal, gastrointestinal, hepatic, or haematologic side effects 4.
• 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 3.

Folic Acid Supplementation

Folic acid supplementation is an important consideration when initiating methotrexate therapy.

• A 26% relative risk reduction was seen for the incidence of GI side effects such as nausea, vomiting, or abdominal pain with folic acid supplementation 4.
• Folic acid supplementation also appears to be protective against abnormal serum transaminase elevation caused by methotrexate, with a 76.9% relative risk reduction 4.
• A comparison study of 5 mg/week and 30 mg/week folic acid supplementation found similar tolerability of methotrexate in RA patients, with no significant differences in side effects or discontinuation of methotrexate 5.

Monitoring Methotrexate Therapy

Monitoring methotrexate therapy is crucial to minimize side effects and ensure efficacy.

• 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.
• In patients with a history of respiratory disease or current respiratory symptoms, lung function tests with determination of the diffusing capacity for carbon monoxide are recommended 3.