A 45 year old male, Sonu presented to OPD with severe pain in the knee and shoulder joint. On examination and fuher investigations, a diagnosis of rheumatoid ahritis was made and the patient was staed on methotrexate 15mg weekly. However, even after 6 months of using methotrexate, recurrent episodes of ahritis continued. The physician wanted to add another DMARD that inhibit the pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase enzyme. Which of the following drug, physician is thinking about?

**Core Concept**
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammation and degeneration of joints, requiring treatment with disease-modifying antirheumatic drugs (DMARDs). Methotrexate is a commonly used DMARD that inhibits dihydrofolate reductase (DHFR), but it may not be sufficient for all patients. Adding another DMARD that targets a different pathway can help control the disease.

**Why the Correct Answer is Right**
The physician is looking for a DMARD that inhibits pyrimidine synthesis by targeting dihydroorotate dehydrogenase (DHODH) enzyme. This enzyme is involved in the de novo synthesis of pyrimidines, which are essential for DNA replication and cell proliferation. Inhibiting DHODH can help reduce the proliferation of immune cells, such as T and B cells, which are involved in the pathogenesis of RA.

**Why Each Wrong Option is Incorrect**
**Option A:** Leflunomide is a DMARD that inhibits dihydrofolate reductase (DHFR), similar to methotrexate. It is not the correct answer because it targets a different enzyme.
**Option B:** Cyclosporine is an immunosuppressant that inhibits calcineurin, which is involved in the activation of T cells. It is not the correct answer because it targets a different pathway.
**Option C:** Sulfasalazine is a DMARD that inhibits the production of pro-inflammatory cytokines, but it does not inhibit dihydroorotate dehydrogenase (DHODH) enzyme.
**Option D:** Azathioprine is a DMARD that inhibits DNA synthesis, but it does not inhibit dihydroorotate dehydrogenase (DHODH) enzyme.

**Clinical Pearl / High-Yield Fact**
One memorable point to recall is that Leflunomide and Methotrexate both inhibit dihydrofolate reductase (DHFR) enzyme, but Leflunomide has a longer half-life and can cause hepatotoxicity.

**Correct Answer:** C. Leflunomide is not the correct answer here as the question describes a drug that inhibits dihydroorotate dehydrogenase (DHODH) enzyme, however, leflunomide is a drug that inhibits the enzyme dihydroorotate dehydrogenase thereby inhibiting pyrimidine synthesis.

✓ Correct Answer: C. Leflunomide