A female patient with a longstanding history of erosive polyarthritis and frequent episode… — USMLE Step 2 CK

A female patient with a longstanding history of erosive polyarthritis and frequent episodes of podagra is brought to the emergency department by her family due to mucosal bleeding, diffuse bruising, and profound weakness. Three weeks prior, her rheumatologist discontinued her tumor necrosis factor inhibitor due to loss of efficacy and initiated a new oral disease-modifying antirheumatic drug. Her home medications also include a daily prophylactic agent to prevent her foot flares. Vital signs are within normal limits, though she appears pale and fatigued. Laboratory analysis reveals:

Laboratory Test	Result	Reference Range
Hemoglobin	$6.5\text{ g/dL}$	$12.0-16.0\text{ g/dL}$
Leukocyte count	$1,100/\mu L$	$4,500-11,000/\mu L$
Absolute neutrophil count	$300/\mu L$	$1,500-8,000/\mu L$
Platelet count	$15,000/\mu L$	$150,000-400,000/\mu L$

Pharmacologic inhibition of which of the following enzymes most directly caused this patient's hematologic abnormalities?

A
Dihydrofolate reductase
B
Thiopurine methyltransferase
Xanthine oxidaseAnswer
D
Inosine monophosphate dehydrogenase
E
Cyclooxygenase-2

Answer

Xanthine oxidase

The correct answer is xanthine oxidase. This patient's presentation of profound pancytopenia (anemia, neutropenia, and thrombocytopenia) shortly after starting a new oral disease-modifying antirheumatic drug (DMARD) while taking a gout prophylactic agent is classic for azathioprine toxicity induced by an interaction with allopurinol or febuxostat. Azathioprine is metabolized into 6-mercaptopurine (6-MP), which exerts its immunosuppressive effects. 6-MP is inactivated through two primary pathways: thiopurine methyltransferase (TPMT) and xanthine oxidase. Because the patient is taking a xanthine oxidase inhibitor for recurrent gout flares, the primary degradation pathway of 6-MP is blocked. This causes a massive intracellular accumulation of active 6-MP metabolites (thioguanine nucleotides), which halt DNA synthesis in rapidly dividing cells, most notably leading to severe, life-threatening bone marrow suppression.

Step-by-Step Solution

Analyze the patient's medical history and current presentation.

The patient has rheumatoid arthritis (erosive polyarthritis) and gout (podagra) presenting with severe pancytopenia after starting a new oral DMARD.

Identifying the baseline diseases helps determine which medications the patient is taking.

Identify the likely home medications based on the history.

The daily prophylactic agent for podagra is a xanthine oxidase inhibitor (allopurinol or febuxostat).

Urate-lowering therapy is standard prophylaxis for frequent gout flares.

Determine the cause of the severe bone marrow suppression.

The pancytopenia is a consequence of a dangerous drug-drug interaction between the xanthine oxidase inhibitor and the new oral DMARD, azathioprine.

Azathioprine is a purine analog whose active metabolite (6-mercaptopurine) relies heavily on xanthine oxidase for degradation into inactive metabolites.

Link the mechanism to the correct enzyme.

The inhibition of xanthine oxidase by the gout medication directly blocked the metabolism of the azathioprine, causing fatal levels of active drug to accumulate.

This confirms the target enzyme asked for in the question.

Key Concept

Drug-drug interaction between azathioprine (a purine analog DMARD) and xanthine oxidase inhibitors (allopurinol or febuxostat), which prevents the degradation of 6-mercaptopurine and leads to life-threatening myelosuppression.

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