When to taper methotrexate (disease-modifying antirheumatic drug) in patients with rheumatoid arthritis?

When to Taper Methotrexate in Rheumatoid Arthritis

Methotrexate tapering should only be considered after patients achieve persistent remission or low disease activity for at least 6 months, and only after first tapering glucocorticoids and biologics if present. 1

Prerequisites Before Considering Methotrexate Tapering

Before any methotrexate dose reduction, the following conditions must be met:

• Disease activity must be in sustained remission (DAS28 <2.6) or low disease activity for a minimum of 6 months 1, 2
• All glucocorticoids must be tapered first and discontinued 1, 2
• Biologic or targeted synthetic DMARDs should be tapered before conventional synthetic DMARDs like methotrexate 1, 2
• Patients must understand and accept the risk of disease flare, which occurs in approximately 38-52% of patients who reduce DMARD therapy 3, 4

Hierarchical Tapering Sequence

The evidence strongly supports a specific order for tapering medications:

1. First: Taper and discontinue glucocorticoids as rapidly as clinically feasible 1
2. Second: Taper biologics or targeted synthetic DMARDs if the patient is on combination therapy 1, 2
3. Third: Only after successful tapering of the above, consider tapering methotrexate 1, 2

This sequence is critical because methotrexate serves as the anchor drug in RA treatment, and maintaining it provides the best protection against disease flare 1, 5

How to Taper Methotrexate

"Tapering" means reducing the dose or dosing frequency gradually—never abrupt discontinuation 1

The recommended approach:

• Dose reduction is preferred over gradual discontinuation, and gradual discontinuation is preferred over abrupt stopping 1
• Reduce methotrexate dose by 50% initially rather than stopping completely 3, 4
• Monitor disease activity every 1-3 months during the tapering process 1
• If disease activity increases, immediately return to the previous effective dose 1

Risk Factors for Flare During Tapering

Certain patients are at higher risk for disease relapse when tapering:

• ACPA (anti-citrullinated protein antibody) positive patients have significantly higher relapse rates (p=0.038) 3
• Patients not on combination therapy with methotrexate plus another DMARD have worse outcomes 6
• Even patients in sustained DAS28 remission can experience radiographic progression despite clinical stability 7

The RETRO trial demonstrated that 81% of patients maintained remission when continuing full-dose DMARDs, compared to only 59% when tapering to 50% dose and 43% when stopping 4

Critical Monitoring Requirements

During any methotrexate tapering attempt:

• Assess disease activity every 1-3 months using validated measures (DAS28, SDAI, or CDAI) 1
• If no improvement or increased disease activity occurs, therapy must be adjusted within 3 months 1
• Monitor for radiographic progression even in patients maintaining clinical remission, as joint damage can occur despite low disease activity 7
• Continue laboratory monitoring (CBC, liver enzymes, creatinine) every 12 weeks for patients on stable methotrexate doses 1

Important Clinical Caveats

The most common pitfall is attempting to taper methotrexate too early or before tapering other medications. The evidence is clear that:

• Approximately 34-52% of patients will experience disease flare when reducing DMARD therapy, even after sustained remission 3, 4
• Most flares occur within the first 6 months after dose reduction 3
• The good news: most patients who flare regain remission after reintroducing full-dose therapy 4
• Patients on combination therapy (methotrexate plus biologic) have better success rates with tapering than those on monotherapy 6

When Tapering Should NOT Be Attempted

Do not consider methotrexate tapering in:

• Patients with remission duration less than 6 months 1, 2
• Patients still requiring glucocorticoids to maintain disease control 1
• Patients with progressive subcutaneous nodules (consider switching away from methotrexate entirely) 1
• Patients with high disease activity or poor prognostic factors 1

The decision to taper must be made through shared decision-making with the patient, clearly explaining that maintaining full-dose therapy provides the lowest risk of flare (approximately 16% vs 39-52% with tapering/stopping) 1, 4