Why should methotrexate (MTX) not be stopped abruptly?

Why Methotrexate Should Not Be Stopped Abruptly

Methotrexate can be discontinued abruptly without adverse pharmacologic effects, but abrupt discontinuation significantly increases the risk of disease flare, which can lead to irreversible joint damage, disease progression, and worsening quality of life. 1

Primary Reason: Disease Flare Risk

• Abrupt discontinuation of methotrexate carries a 30-50% relapse rate within 12 months, which is substantially higher than gradual tapering approaches 2
• Disease flares can result in irreversible long-term damage to joints and organs, particularly in rheumatoid arthritis and inflammatory bowel disease 1
• The risk of flare is present even in patients who have achieved sustained remission, making abrupt cessation inadvisable from a disease control perspective 1

Pharmacologic Safety of Abrupt Discontinuation

• From a toxicity standpoint, methotrexate can be stopped abruptly without withdrawal symptoms or rebound toxicity 1
• The drug has a relatively short elimination half-life of 3-10 hours for low-dose therapy, with methotrexate polyglutamates cleared from red blood cells within 1.2-4.3 weeks 1, 3
• There are no pharmacologic adverse effects from sudden cessation—the concern is purely related to loss of disease control 1

Recommended Approach Instead of Abrupt Cessation

For Patients in Sustained Remission

• Continue methotrexate at full therapeutic dose for a minimum of 6-12 months after achieving remission before considering any dose reduction 1, 2
• When tapering is appropriate, use gradual dose reduction rather than abrupt discontinuation 1, 2
• Reduce the weekly dose by half initially, then decrease by 2.5 mg increments every 4-8 weeks if disease remains controlled 2
• Alternatively, extend the dosing interval to every 2 weeks while maintaining the same dose 2

Clinical Scenarios Requiring Temporary Discontinuation

Methotrexate should be temporarily stopped (not permanently discontinued) in specific acute situations:

• Severe infection requiring antibiotics: Stop methotrexate until infection clears and antibiotic course is completed 1, 4
• Elevated liver enzymes ≥3× upper limit of normal for 2 consecutive months: Hold methotrexate until normalization 1
• Bone marrow suppression: Discontinue if WBC <3×10⁹/L, absolute neutrophil count <1×10⁹/L, or platelets <100,000/L 1
• Pregnancy: Stop immediately if conception occurs and initiate folic acid supplementation 1
• Acute hospitalization: Temporarily hold during severe illness, then resume after recovery 4

Common Pitfalls to Avoid

• Do not stop methotrexate solely due to minor side effects without first attempting folic acid supplementation (1 mg daily), which mitigates gastrointestinal effects, mucositis, fatigue, and headache 1
• Do not discontinue methotrexate perioperatively for elective orthopedic surgery—continuation is actually associated with decreased infection risk compared to discontinuation 1, 5
• Do not confuse the need for temporary discontinuation during acute illness with permanent cessation—methotrexate should be restarted once the acute issue resolves 1, 4

Monitoring During Planned Tapering

• Schedule follow-up visits every 4-8 weeks during the first year of tapering 2
• Monitor for early signs of disease recurrence at each visit 2
• If disease flares during tapering, restart methotrexate at the previously effective dose 2

Special Consideration: Pregnancy Planning

• For women contemplating pregnancy, methotrexate must be stopped at least 3 months before attempting conception due to teratogenic risk (3.4-fold increased cardiovascular defects, 2.6-fold increased oral clefts) 1
• This is the one scenario where planned discontinuation is mandatory, but it should be done with a 3-month washout period and transition to alternative therapy to maintain disease control 1