Methotrexate, commonly used as first-line therapy in rheumatoid arthritis, belongs to which class and mechanism?

• A. A folate antagonist
• B. A COX-2 inhibitor
• C. A TNF-alpha inhibitor
• D. A PDE inhibitor

Answer: (A)

Methotrexate works primarily as a folate antagonist. It inhibits dihydrofolate reductase, lowering tetrahydrofolate availability and reducing synthesis of thymidine and purines, which dampens DNA replication in rapidly dividing cells. In rheumatoid arthritis, at low doses, it also boosts extracellular adenosine, a potent anti-inflammatory mediator, contributing to its effectiveness as a disease-modifying treatment. This combination is what makes it a foundational DMARD. It is not a COX-2 inhibitor (which blocks prostaglandin synthesis), nor a TNF-α inhibitor (which neutralizes TNF-α), nor a PDE inhibitor (which affects cyclic nucleotide breakdown).