A 52-year-old woman presents with a 6-month history of symmetrical polyarthritis affecting her hands, wrists, and knees. Laboratory investigations reveal elevated ESR (68 mm/hr), CRP 12 mg/dL, and positive rheumatoid factor (1:640) with anti-CCP antibodies. X-rays show early erosive changes. What is the drug of choice for initiating disease-modifying antirheumatic therapy (DMARD) in this patient?

## First-Line DMARD in Rheumatoid Arthritis **Key Point:** Methotrexate is the gold-standard first-line DMARD for RA and remains the anchor drug in combination DMARD therapy. ### Rationale for Methotrexate 1. **Efficacy**: Achieves remission or low disease activity in 40–50% of patients as monotherapy; higher rates in combination regimens. 2. **Rapid onset**: Clinical improvement typically seen within 6–12 weeks (faster than sulfasalazine or leflunomide). 3. **Cost-effectiveness**: Inexpensive, well-tolerated at low doses (15–25 mg/week), and extensive safety data. 4. **Synergy with biologics**: Backbone drug in TNF inhibitor and other biologic combinations; reduces immunogenicity. 5. **Evidence base**: Supported by ACR, EULAR, and Indian guidelines as first-line monotherapy or combination anchor. ### Mechanism in RA **High-Yield:** Methotrexate inhibits dihydrofolate reductase, reducing purine and pyrimidine synthesis. At low doses used in RA, it also: - Increases adenosine release → anti-inflammatory effect - Reduces IL-6 and TNF-α production - Suppresses T-cell proliferation - Decreases synovial inflammation and slows radiological progression ### Monitoring Requirements | Parameter | Baseline | Frequency | |-----------|----------|----------| | CBC, LFTs, Creatinine | Before start | Every 8–12 weeks | | Chest X-ray | Before start | Once (TB screening) | | Pregnancy test | Women of childbearing age | Before each cycle | | Folic acid supplementation | — | 5 mg daily (except MTX day) | **Clinical Pearl:** Folic acid (5 mg) is given on alternate days or daily except on MTX day to reduce toxicity without compromising efficacy. ### Contraindications & Precautions - Pregnancy and lactation (teratogenic) - Active infection or uncontrolled TB - Severe renal impairment (CrCl < 30 mL/min) - Hepatic cirrhosis - Bone marrow suppression **Warning:** Do NOT use methotrexate in patients with undiagnosed or active TB; always screen with chest X-ray and tuberculin test before initiation.