Is methotrexate (disease-modifying antirheumatic drug (DMARD)) used in the treatment of rheumatoid arthritis?

Methotrexate in Rheumatoid Arthritis

Methotrexate is the first-line disease-modifying antirheumatic drug (DMARD) of choice for rheumatoid arthritis and serves as the anchor drug for all treatment strategies. 1, 2, 3

Evidence-Based Rationale for Methotrexate as First-Line Therapy

The American College of Rheumatology strongly recommends methotrexate monotherapy over all other options for DMARD-naive patients with moderate-to-high disease activity, including hydroxychloroquine, sulfasalazine, leflunomide, biologic DMARDs, and targeted synthetic DMARDs. 1 This recommendation is based on:

• Superior disease-modifying properties with proven efficacy on both clinical symptoms and radiographic progression 1
• Optimal safety profile for long-term use compared to alternative DMARDs 1
• Cost-effectiveness and widespread availability 1
• Versatility as an anchor drug that can be combined with biologics or other DMARDs when monotherapy is insufficient 1

The FDA has approved methotrexate specifically for management of severe, active rheumatoid arthritis in patients who have had insufficient response to or are intolerant of first-line therapy including NSAIDs. 3

Optimal Dosing Strategy

Start oral methotrexate at 10-15 mg weekly and rapidly escalate by 5 mg every 2-4 weeks to reach 20-30 mg weekly within 4-6 weeks. 1, 2 This aggressive escalation strategy is critical:

• The 2021 ACR guideline emphasizes rapid dose escalation to at least 15 mg within 4-6 weeks, with a target of 20-25 mg weekly for optimal disease control 2
• Evidence shows that starting doses of 25 mg/week or fast escalation to 25-30 mg/week are associated with higher clinical effect sizes, though also more gastrointestinal adverse events 1
• Switch to subcutaneous administration if inadequate response occurs at the highest tolerable oral dose, as parenteral methotrexate demonstrates superior bioavailability at higher doses and improved ACR20 response rates (85% vs 77% oral) 2, 4

Essential Concurrent Therapy

Prescribe at least 5 mg folic acid weekly with all methotrexate therapy. 1, 2 This is strongly recommended based on meta-analysis evidence showing significant reduction in gastrointestinal and liver toxicity without compromising efficacy. 1

Consider short-term glucocorticoids (≤10 mg/day prednisone equivalent) for up to 6 months as bridging therapy while awaiting DMARD effect, then taper as rapidly as clinically feasible. 2, 5 However, long-term glucocorticoid use (≥3 months) is not recommended. 2

Monitoring Requirements

When starting methotrexate or increasing the dose, monitor ALT/AST, creatinine, and complete blood count every 1-1.5 months until a stable dose is reached, then every 1-3 months thereafter. 1 Clinical assessment for side effects and risk factors should occur at each visit. 1

Stop methotrexate if confirmed ALT/AST elevation exceeds three times the upper limit of normal, but may reinstitute at lower dose following normalization. 1

Treatment Escalation Algorithm

Monitor disease activity every 1-3 months using validated instruments (SDAI, CDAI, or DAS28). 2 The target is low disease activity (SDAI ≤11 or CDAI ≤10) or remission (SDAI ≤3.3 or CDAI ≤2.8). 2

If no improvement by 3 months or target not reached by 6 months on maximally tolerated methotrexate monotherapy:

• Add a biologic DMARD (preferably TNF inhibitor) or targeted synthetic DMARD for patients with poor prognostic factors 2, 5
• The combination of methotrexate with biologics has proven superior to either agent alone in all aspects, including structural damage inhibition 6
• Alternatively, consider triple therapy (methotrexate + sulfasalazine + hydroxychloroquine) for patients without poor prognostic factors 2, 5

Critical Safety Considerations

The FDA warns that methotrexate should only be used in patients with severe, recalcitrant, disabling rheumatoid arthritis not adequately responsive to other forms of therapy, as deaths have been reported. 3 Key contraindications and precautions include:

• Absolute contraindication in pregnancy - methotrexate causes fetal death and congenital anomalies; discontinue at least 3 months before planned pregnancy for both men and women 1, 3
• Avoid in patients with impaired renal function, ascites, or pleural effusions due to reduced elimination and increased toxicity risk 3
• Screen for tuberculosis before initiating combination therapy with TNF inhibitors 5
• Provide prophylactic antiviral therapy for hepatitis B core antibody positive patients when initiating rituximab or other biologics 2

Special Population Modifications

For patients with heart failure (NYHA class III or IV), use non-TNF inhibitor biologics or targeted synthetic DMARDs instead of TNF inhibitors if escalation beyond methotrexate is needed. 2

For patients with nontuberculous mycobacterial lung disease requiring biologic therapy, abatacept is conditionally recommended over other options. 2

Common Pitfalls to Avoid

• Inadequate dose escalation - many practitioners fail to rapidly escalate to 20-30 mg weekly, resulting in suboptimal disease control 1, 7
• Premature discontinuation - methotrexate reaches maximal benefit at approximately 30 months, and practitioners often discontinue too early during the therapeutic response curve 7
• Neglecting subcutaneous route - failing to switch to parenteral administration when oral therapy at maximum tolerated dose is insufficient 4
• Omitting folic acid supplementation - this leads to unnecessary gastrointestinal and hepatic adverse effects 1