When to discontinue methotrexate (MTX) therapy?

From the Guidelines

Methotrexate should be stopped when patients have achieved low disease activity or remission for at least 6 months, and then only through gradual discontinuation, as abrupt discontinuation is associated with a higher risk of flare and irreversible long-term damage. This approach is supported by the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis 1. The guideline conditionally recommends continuation of all DMARDs at their current dose over a dose reduction of a DMARD, and dose reduction is conditionally recommended over gradual discontinuation of a DMARD.

When considering stopping methotrexate, it is essential to weigh the risks and benefits, as the majority of patients who stop their biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) will experience a flare, as seen in studies such as the AVERT trial and the ENCOURAGE study 1. However, some patients may be able to maintain low disease activity or remission after stopping their bDMARD or tsDMARD, particularly if they continue taking methotrexate.

Key considerations for stopping methotrexate include:

• Patients should be at target (low disease activity or remission) for at least 6 months prior to tapering 1
• Gradual discontinuation is conditionally recommended over abrupt discontinuation of a DMARD 1
• Methotrexate should be stopped temporarily before surgery, during active infections, when liver function tests are significantly elevated, with severe kidney dysfunction, or when severe cytopenias develop
• Women should discontinue methotrexate at least 3-6 months before attempting conception, and men should stop at least 3 months before trying to father a child due to potential teratogenic effects
• Methotrexate should also be stopped immediately if pulmonary symptoms develop, particularly unexplained cough or shortness of breath which could indicate methotrexate-induced pneumonitis.

Ultimately, the decision to stop methotrexate should be made on a case-by-case basis, taking into account the individual patient's disease activity, medical history, and potential risks and benefits.

From the FDA Drug Label

Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes (Roenigk grade IIIb or IV) Discontinue methotrexate first and, if the lymphoma does not regress, appropriate treatment should be instituted Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur

• Liver toxicity: Methotrexate should be discontinued if liver biopsy shows moderate to severe changes or if patient refuses liver biopsy and has persistently abnormal liver function tests.
• Lymphoma: Discontinue methotrexate if lymphoma occurs, and if it does not regress, appropriate treatment should be instituted.
• Gastrointestinal toxicity: Methotrexate should be discontinued if diarrhea or ulcerative stomatitis occur.
• Pulmonary toxicity: Methotrexate should be interrupted if pulmonary symptoms occur, and careful investigation is required. Methotrexate should be discontinued in cases of severe toxicity, such as bone marrow suppression, severe infections, or tumor lysis syndrome 2, 2.

From the Research

Deciding When to Stop Methotrexate

• The decision to stop methotrexate in patients with rheumatoid arthritis (RA) depends on various factors, including disease activity, patient response to treatment, and potential side effects 3.
• Studies have shown that tapering or discontinuing methotrexate in patients with RA treated with tumor necrosis factor inhibitors (TNFi) does not seem to influence the average disease activity score over time or the long-term drug survival of TNFi 4.
• However, increasing age has been associated with a greater risk of methotrexate discontinuation in patients with newly diagnosed RA 5.
• The effectiveness of methotrexate in achieving remission in RA patients can be measured using the disease activity score 28 (DAS28), but there is no significant correlation between DAS score and cumulative dose, average dose, maximum dose, or length of therapy 6.

Considerations for Stopping Methotrexate

• Patients who taper or discontinue methotrexate have a similar disease activity score over time as patients who continue methotrexate 4.
• The risk of disease flare after stopping methotrexate is unclear, but it may be minimized by gradual dose reduction (tapering) 3.
• The use of biologic or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) may be considered as an alternative to methotrexate, especially in patients who do not respond to methotrexate or experience adverse effects 7.

Factors Influencing the Decision to Stop Methotrexate

• Disease activity and patient response to treatment are important factors in deciding when to stop methotrexate 3, 4.
• Patient age and comorbidities may also influence the decision to stop methotrexate, as older patients may be more likely to discontinue methotrexate due to adverse effects or comorbidities 5.
• The presence of other health conditions, such as inflammatory bowel disease, cancer, or systemic lupus erythematosus, may also affect the decision to stop methotrexate 6.