What is the drug of choice for rheumatoid arthritis?

Methotrexate is the Drug of Choice for Rheumatoid Arthritis

Methotrexate (MTX) should be part of the first treatment strategy for rheumatoid arthritis, starting at 15 mg/week orally and escalating to 25-30 mg/week or the highest tolerable dose, with subsequent switch to subcutaneous administration if response is insufficient. 1

Initial Treatment Approach

• MTX is the anchor drug and gold standard for RA treatment due to its established efficacy, acceptable safety profile, and low cost 1, 2
• Start with oral MTX at 15 mg/week, with dose escalation by 5 mg/month to a target of 25-30 mg/week (or highest tolerable dose) 1
• Folate supplementation is essential to reduce adverse effects and should be prescribed alongside MTX 1
• MTX reaches maximum efficacy after 4-6 months of treatment, so maintain the optimal dose for at least 3 months before concluding efficacy 1

Dose Optimization and Administration Route

• For patients with inadequate response to oral MTX, switching to subcutaneous administration improves bioavailability, especially at doses >15 mg/week 1, 3
• Subcutaneous MTX has higher clinical efficacy and less variable bioavailability compared to oral MTX at equivalent doses 3
• The optimal evidence-based approach is starting with oral MTX 15 mg/week, escalating to 25-30 mg/week, then switching to subcutaneous administration if response is insufficient 1
• In Asian populations, lower maximum doses (around 16 mg/week) may be appropriate due to lower body weight and potential pharmacogenetic differences 1

Alternative First-Line Options

• In cases of MTX contraindications (hepatic or renal disease) or early intolerance, leflunomide (20 mg/day) or sulfasalazine (3-4 g/day) should be considered as alternative first-line DMARDs 1
• Both leflunomide and sulfasalazine have shown efficacies similar to MTX in clinical trials 1
• Sulfasalazine is considered safe during pregnancy, which may be an important consideration for women of childbearing potential 1

Treatment Escalation for Inadequate Response

• If MTX monotherapy fails to achieve low disease activity or remission after 6 months of optimal dosing, consider these options:
  • Add sulfasalazine and hydroxychloroquine to MTX (triple DMARD therapy) 1, 4
  • Add a biologic agent such as TNF inhibitor (adalimumab, etanercept), abatacept, or tocilizumab 1, 5, 6
• When using biologics, continuing MTX co-therapy often improves efficacy 5, 6

Common Pitfalls and Considerations

• Inadequate MTX dosing or premature switching to biologics before reaching optimal MTX dose and duration (at least 3-6 months) 1
• Failure to switch from oral to subcutaneous MTX before declaring MTX failure 1, 3
• Discontinuing MTX due to minor side effects that could be managed with folate supplementation or anti-emetics 1
• Nausea is more common with higher starting doses (15 mg vs 7.5 mg), but fast dose escalation in both regimens may ultimately yield similar efficacy 7
• Regular monitoring for adverse effects is essential, particularly for gastrointestinal, hematologic, hepatic, and pulmonary toxicities 2

MTX remains the cornerstone of RA therapy and should be optimized before considering more expensive treatment options. The evidence strongly supports its use as first-line therapy, with appropriate dose escalation and potential route changes to maximize efficacy before adding or switching to other agents 1, 8.