What is the differential diagnosis for a patient with Sjögren's syndrome presenting with pleuritic chest pain, anemia, leukocytosis, thrombocytopenia, hyponatremia, elevated troponin, elevated BNP, and hematuria, two weeks after starting leflunomide?

Differential Diagnosis for Sjögren's Syndrome Patient with Pleuritic Chest Pain and Multi-System Abnormalities After Leflunomide Initiation

The most critical immediate consideration is leflunomide-induced interstitial lung disease with concurrent drug-related hematologic toxicity, which can be fatal and requires urgent drug discontinuation and washout procedures. 1

Primary Differential Diagnoses

1. Leflunomide-Induced Toxicity (Most Urgent)

Interstitial Lung Disease/Pneumonitis:

• Leflunomide causes interstitial lung disease that may occur acutely at any time during therapy with variable clinical presentation, including pleuritic chest pain, cough, and dyspnea 1
• This complication has been associated with fatal outcomes, with approximately 1.1% of patients developing interstitial pneumonia in post-market surveillance 2
• Most cases occur within the first 6 months of therapy, fitting this patient's 2-week timeline 1
• The elevated BNP (1264) may reflect right ventricular strain from pulmonary involvement 3, 4

Hematologic Toxicity:

• Pancytopenia, agranulocytosis, and thrombocytopenia are rare but documented complications of leflunomide 5
• The thrombocytopenia (platelets 57) and anemia (Hgb 9.3) with leukocytosis (WBC 12.0) suggest bone marrow suppression 1
• These effects occur most frequently in patients with recent or concurrent immunosuppressive therapy or prior hematologic abnormalities 1

Leflunomide-Induced Pulmonary Arterial Hypertension:

• Rare but documented cause of elevated BNP and right heart strain 3, 4
• Can present with dyspnea and pleuritic chest pain 3

2. Pulmonary Embolism

• Pleuritic chest pain is the classic presentation of PE, usually caused by pleural irritation from distal emboli 5
• The elevated BNP (1264) and troponin (16) are consistent with right ventricular strain from PE 5
• Dyspnea, chest pain, and tachycardia are present in 80-97% of PE cases 5
• Sjögren's syndrome patients have increased thrombotic risk due to autoimmune hypercoagulability 6
• The thrombocytopenia (57) does NOT exclude PE and may represent consumptive coagulopathy or concurrent drug toxicity 5

3. Acute Coronary Syndrome (Less Likely)

• The troponin elevation (16 ng/L) is modest and below the 50-100 ng/L range typically seen with Type 1 MI 5, 7
• Troponin <50 ng/L suggests alternative causes of cardiac injury rather than acute coronary occlusion 8
• The elevated BNP (1264) with modest troponin suggests volume overload or right heart strain rather than left ventricular MI 5
• Pleuritic chest pain is atypical for ACS; anginal pain is typically substernal and pressure-like 5

4. Sjögren's-Related Complications

Autoimmune Cytopenia:

• Primary Sjögren's can present with autoimmune hemolytic anemia and thrombocytopenia 6
• The anemia (Hgb 9.3) and thrombocytopenia (platelets 57) may represent disease activity rather than drug toxicity 6
• However, the acute onset after leflunomide initiation favors drug-related etiology 1

Pleuritis/Serositis:

• Sjögren's can cause pleuritic chest pain from autoimmune pleuritis 5
• This would not explain the elevated troponin or BNP 5

Glomerulonephritis:

• The hematuria (TNTC RBCs) with hyponatremia (Na 134) suggests renal involvement 1
• Sjögren's can cause tubulointerstitial nephritis or glomerulonephritis 6
• Leflunomide has a uricosuric effect on renal tubules but typically does not cause hematuria 1

5. Neurogenic Cardiac Injury (Unlikely Without CNS Event)

• Troponin elevation can occur from catecholamine-mediated myocardial injury in acute neurological events 7, 8
• No mention of neurological symptoms makes this diagnosis unlikely 7

6. Sepsis/Severe Infection

• Leukocytosis (WBC 12.0) with pleuritic chest pain could indicate pneumonia or sepsis 1
• Leflunomide causes immunosuppression, increasing susceptibility to Pneumocystis jiroveci pneumonia, tuberculosis, and aspergillosis 1
• Severe infections including sepsis have been fatal in leflunomide-treated patients 1
• Elevated troponin and BNP can occur with septic cardiomyopathy 5

Critical Immediate Actions

Discontinue leflunomide immediately and initiate drug elimination procedure:

• Administer cholestyramine 8g three times daily or activated charcoal 50g four times daily to rapidly decrease plasma M1 (active metabolite) concentration 1
• This is essential because leflunomide has a long half-life and continued exposure worsens outcomes 1, 9

Obtain urgent diagnostic studies:

• 12-lead ECG to assess for ST-segment elevation, depression, or T-wave inversions suggesting ACS versus right heart strain pattern from PE 5
• CT pulmonary angiography to definitively exclude or confirm PE given the high clinical suspicion 5
• High-resolution chest CT to evaluate for interstitial lung disease, infiltrates, or pneumonia 1, 2
• Echocardiography to assess right ventricular function, wall motion abnormalities, and estimate pulmonary artery pressure 5, 3
• Serial troponins at 3-6 hour intervals to establish rising/falling pattern 5

Laboratory monitoring:

• Repeat CBC with differential to monitor thrombocytopenia and assess for worsening bone marrow suppression 1
• Blood cultures if infection suspected 1
• Urinalysis with microscopy to characterize hematuria (dysmorphic RBCs suggest glomerulonephritis; isomorphic RBCs suggest lower tract source) 1

Common Pitfalls to Avoid

• Do not reflexively treat elevated troponin as ACS without considering alternative causes: The modest troponin elevation (16 ng/L) with pleuritic pain and elevated BNP suggests PE or drug-induced pulmonary disease rather than coronary occlusion 5, 7, 8
• Do not delay leflunomide washout: Waiting to discontinue leflunomide while pursuing diagnostics can be fatal in cases of drug-induced interstitial pneumonitis 2, 9
• Do not assume thrombocytopenia excludes PE: Consumptive coagulopathy or concurrent drug toxicity can coexist with thromboembolism 5, 1
• Do not overlook infection: Immunosuppressed patients on leflunomide are at high risk for opportunistic infections that can present with similar symptoms 1