A 52-year-old man with a 10-year history of rheumatoid arthritis presents with progressive joint pain, swelling, and morning stiffness lasting 2 hours. Inflammatory markers (ESR 68 mm/h, CRP 12 mg/dL) are elevated. He has failed NSAIDs and low-dose prednisolone monotherapy. Which is the drug of choice for disease-modifying therapy in this patient?

Explanation

## Rationale for Drug of Choice in RA **Key Point:** Methotrexate (MTX) is the anchor DMARD (disease-modifying antirheumatic drug) and first-line disease-modifying therapy for rheumatoid arthritis, especially when NSAIDs and corticosteroids have failed. ### Why Methotrexate is First-Line 1. **Efficacy**: Produces remission or low disease activity in 40–60% of patients when used as monotherapy 2. **Onset**: Clinical benefit appears within 6–12 weeks (faster than alternatives) 3. **Safety profile**: Well-tolerated with predictable, manageable toxicity (hepatotoxicity, myelosuppression monitored by regular LFTs and CBC) 4. **Cost-effectiveness**: Inexpensive and widely available 5. **Synergy**: Forms the backbone of combination DMARD therapy and biologic combinations **High-Yield:** MTX is given weekly (not daily) at doses of 10–25 mg/week, with folic acid supplementation to reduce toxicity. ### Comparison of DMARDs | Drug | Onset | Efficacy | Toxicity | Role | |------|-------|----------|----------|------| | **Methotrexate** | 6–12 weeks | Excellent | Hepatotoxicity, myelosuppression | First-line anchor | | Sulfasalazine | 8–12 weeks | Moderate | GI upset, rash, agranulocytosis | Second-line or combination | | Gold salts | 8–12 weeks | Moderate | Nephrotoxicity, dermatitis, blood dyscrasias | Rarely used now | | Leflunomide | 4–8 weeks | Good | Hepatotoxicity, teratogenicity | Alternative if MTX contraindicated | **Clinical Pearl:** In this patient, MTX monotherapy should be initiated at 7.5–10 mg/week, increased to 15–25 mg/week based on response. If inadequate response after 12 weeks, a biologic (TNF inhibitor, IL-6 inhibitor) should be added to MTX rather than switching to another DMARD alone. **Mnemonic — DMARDs in RA (in order of preference):** **M-S-L-G** = Methotrexate, Sulfasalazine, Leflunomide, Gold (historical). ### Monitoring Requirements for Methotrexate - Baseline: LFTs, CBC, renal function, chest X-ray (TB screening) - Every 8–12 weeks: LFTs and CBC - Folic acid 5 mg daily (or folinic acid 5 mg on non-MTX days) to reduce toxicity - Contraindicated in pregnancy (teratogenic) and severe renal/hepatic impairment