Should I start with methotrexate (Disease-Modifying Antirheumatic Drug) as the first treatment option?

Should You Start Methotrexate First?

Yes, methotrexate should be part of your first treatment strategy for rheumatoid arthritis, starting at 15 mg/week orally with escalation to 25-30 mg/week (or highest tolerable dose) over 4-6 weeks, then switching to subcutaneous administration if response is insufficient. 1

Evidence-Based Starting Strategy

Initial Dosing Approach

• Start with oral methotrexate at 15 mg/week and escalate by 5 mg every 2-4 weeks to reach 25-30 mg/week within 4-6 weeks 1
• The American College of Rheumatology conditionally recommends initiating/titrating methotrexate to at least 15 mg weekly within 4-6 weeks over lower starting doses 1
• Starting doses of 25 mg/week or fast escalation to 25-30 mg/week are associated with higher clinical efficacy but also more gastrointestinal adverse events compared to slower escalation 1

Route of Administration

• Begin with oral administration for ease of use and patient acceptance 1
• Oral methotrexate is conditionally recommended over subcutaneous for initial therapy due to similar bioavailability at typical starting doses and better patient acceptance 1
• Switch to subcutaneous administration (15 mg/week with subsequent escalation) if there is insufficient response to oral methotrexate at 15-20 mg/week 1
• Starting with 15 mg/week subcutaneous versus oral methotrexate in early RA was associated with higher clinical efficacy but more withdrawal due to toxicity 1

Why Methotrexate First?

Guideline Consensus

• EULAR 2020 states methotrexate should be part of the first treatment strategy 1
• ACR 2021 strongly recommends methotrexate monotherapy over methotrexate plus biologics or targeted synthetic DMARDs for DMARD-naive patients with moderate-to-high disease activity 1
• The optimal therapeutic dose is approximately 0.3 mg/kg per week (typically 20-25 mg/week in Western populations) 1

Efficacy Profile

• Methotrexate is among the most efficacious slow-acting antirheumatic agents, with efficacy comparable to parenteral gold, penicillamine, and sulfasalazine 2
• At 1 year, one-third of patients on methotrexate have no radiographic progression 3
• Methotrexate has one of the best efficacy/toxicity ratios in the short-term context of clinical trials 2

Adjunctive Therapy Considerations

Glucocorticoid Bridge Therapy

• Short-term glucocorticoids (<3 months) are conditionally recommended as bridging therapy while methotrexate takes effect, but should be tapered as rapidly as clinically feasible 1
• Low-dose glucocorticoids (equivalent to prednisone 7.5-10 mg daily or dexamethasone 1.5-2 mg) should be considered as part of initial treatment strategy for up to 6 months maximum 1
• The ACR 2021 strongly recommends against longer-term (≥3 months) glucocorticoid therapy due to significant toxicity 1

Folic Acid Supplementation

• Folic acid supplementation is essential and should be prescribed with methotrexate 1
• This reduces gastrointestinal and other adverse effects without compromising efficacy 1

Monitoring and Treatment Targets

Frequency of Assessment

• Monitor disease activity every 1-3 months during active disease until remission or low disease activity is achieved 1
• If no improvement occurs by 3 months or target is not reached by 6 months, therapy should be adjusted 1

Safety Monitoring

• Regular monitoring should include complete blood count, liver function tests, and renal function 4
• Methotrexate is contraindicated if estimated glomerular filtration rate is <30 mL/minute 4
• Lower initial doses should be considered with eGFR between 30-59 mL/minute 4

When NOT to Use Methotrexate First

Alternative First-Line Options

• If methotrexate is contraindicated or there is early intolerance, leflunomide or sulfasalazine should be considered as first-line alternatives 1, 5
• Leflunomide has similar clinical efficacy to methotrexate in established and recent rheumatoid arthritis with high-quality evidence 5
• For patients with low disease activity (rather than moderate-to-high), hydroxychloroquine is conditionally recommended as first choice over other conventional synthetic DMARDs 1

Special Populations

• Methotrexate is contraindicated in pregnant women or women of childbearing potential without adequate contraception 6
• For patients with clinically significant preexisting lung disease, methotrexate is conditionally recommended but requires careful monitoring as it may cause methotrexate-induced pneumonitis 1, 6
• In patients with NYHA class III or IV heart failure, non-TNF biologics are preferred if biologics are needed 1

Common Pitfalls to Avoid

• Do not start at doses lower than 15 mg/week or escalate too slowly - this reduces efficacy without improving tolerability 1
• Do not add biologics or targeted synthetic DMARDs to methotrexate as initial therapy in DMARD-naive patients - there is very low-certainty evidence of benefit and this adds unnecessary cost and risk 1
• Do not continue methotrexate beyond 3-6 months without reassessment if there is no improvement - early switching to alternative strategies is crucial 1
• Do not forget folic acid supplementation - this is essential to reduce toxicity 1
• Do not use methotrexate in patients with severe renal impairment (eGFR <30 mL/minute) - this significantly increases toxicity risk 4