Which disease-modifying antirheumatic drug (DMARD) acts primarily by inhibiting dihydrofolate reductase and disrupting purine synthesis?

Explanation

## Mechanism of Methotrexate in Rheumatoid Arthritis **Key Point:** Methotrexate is a folate antagonist that inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate. This disrupts one-carbon transfer reactions essential for purine and pyrimidine synthesis, leading to suppression of T-cell proliferation and reduced inflammatory cytokine production. ### Mechanism of Action 1. Inhibits DHFR enzyme 2. Depletes tetrahydrofolate cofactors 3. Impairs nucleotide synthesis (purines and pyrimidines) 4. Reduces T-cell and B-cell proliferation 5. Decreases TNF-α and IL-1 production **High-Yield:** Methotrexate is the anchor DMARD for RA — used as monotherapy or in combination regimens. Onset of action is 6–12 weeks. ### Toxicity Profile - **Hepatotoxicity:** Cirrhosis with chronic use; monitor LFTs - **Myelosuppression:** Dose-dependent; reversible - **Teratogenicity:** Absolute contraindication in pregnancy (Category X) - **Folate deficiency:** Managed with folic acid supplementation (1 mg daily or 5 mg on non-MTX days) **Clinical Pearl:** Folic acid supplementation reduces toxicity without compromising efficacy. NSAIDs may increase MTX levels by reducing renal clearance. **Mnemonic:** **DHFR** = Dihydrofolate Reductase inhibition → Disrupts nucleotide synthesis → Dampens immune response.