In a 64-year-old woman with Lambert-Eaton myasthenic syndrome who was recently started on azathioprine (Imuran) and now has a progressively worsening painful swollen right knee that forces her to drag the leg when getting out of a car, what differential diagnoses should be considered and what laboratory studies are indicated?

Immediate Concern: Septic Arthritis Until Proven Otherwise

This patient requires urgent evaluation for septic arthritis of the right knee, given her immunosuppression from newly started azathioprine combined with her underlying autoimmune condition. The inability to move her right leg (having to drag it) suggests severe functional impairment beyond typical joint pain, raising concern for either severe infection, profound weakness, or both.

Critical Differential Diagnoses

1. Septic Arthritis (HIGHEST PRIORITY)

• Azathioprine causes dose-dependent myelosuppression and increases infection susceptibility 1, 2
• Patients on immunosuppressants are at increased risk for bacterial, viral, fungal, and opportunistic infections that may lead to serious, including fatal outcomes 2
• The monoarticular presentation with progressive worsening is classic for septic joint
• This is a medical emergency requiring immediate arthrocentesis

2. Azathioprine Hypersensitivity Reaction

• Can present with fever, myalgias, arthralgia, malaise, and rash 3
• Typically develops within the first several weeks of therapy 2
• Important caveat: Symptoms may initially be mistaken for "flu" 3
• If hypersensitivity is confirmed, the drug must be discontinued immediately as rechallenge can be life-threatening 3

3. Worsening Lambert-Eaton Syndrome

• The inability to lift her right leg could represent asymmetric progression of LEMS
• However, LEMS typically causes bilateral proximal weakness, not monoarticular joint swelling 4, 5
• The combination of pain, swelling, AND weakness is atypical for LEMS alone

4. Azathioprine-Induced Myelosuppression with Secondary Infection

• Neutropenia occurs in 5-30% of patients on azathioprine 1
• Patients with low/absent TPMT activity are at increased risk of severe, life-threatening myelotoxicity 2
• Bone marrow suppression manifests as unexplained infection, bruising, bleeding 3

5. Paraneoplastic Complication

• 50-60% of LEMS cases are associated with small cell lung cancer 5, 6
• Must consider metastatic disease or new malignancy (azathioprine increases malignancy risk, particularly lymphoma) 2

Essential Laboratory Studies

Immediate (Stat) Labs:

1. Arthrocentesis of right knee - MOST CRITICAL

   • Cell count with differential (>50,000 WBC suggests septic arthritis)
   • Gram stain and culture (aerobic, anaerobic, fungal, mycobacterial)
   • Crystal analysis (to rule out gout/pseudogout)

2. Complete Blood Count with differential

   • Check for neutropenia (neutrophils <1.0 × 10⁹/L requires immediate azathioprine withdrawal) 3
   • Platelet count (<50 × 10⁹/L requires hematology consultation) 3
   • Look for pancytopenia

3. Blood cultures (before antibiotics if septic arthritis suspected)

4. Inflammatory markers

   • ESR and CRP (elevated in infection and hypersensitivity)

Urgent Labs (Same Day):

1. Liver function tests

   • Azathioprine can cause hepatotoxicity 3
   • Elevated transaminases may indicate hypersensitivity reaction 2

2. TPMT activity testing (if not done prior to starting azathioprine)

   • Patients with low/absent TPMT are at high risk for severe myelotoxicity 2
   • Cannot be accurately performed if recent blood transfusion 2

3. Comprehensive metabolic panel

   • Renal function (azathioprine dose adjustment needed in renal impairment) 2

Additional Considerations:

1. Imaging of right knee (X-ray, consider MRI if osteomyelitis suspected)

2. Chest imaging (CT chest if not recently done)

   • Screen for small cell lung cancer given LEMS diagnosis 5, 6
   • Initial and periodic screening for malignancy is essential in LEMS 7

Critical Management Pitfalls

Common Mistake #1: Attributing all symptoms to LEMS progression

• LEMS causes bilateral proximal weakness, not monoarticular joint swelling 4
• The joint swelling points to a separate pathology

Common Mistake #2: Delaying arthrocentesis

• In immunosuppressed patients, septic arthritis can rapidly destroy the joint
• Do not wait for fever or systemic symptoms - they may be blunted by immunosuppression

Common Mistake #3: Missing azathioprine hypersensitivity

• If fever, myalgias, and arthralgia occur together with nausea in first weeks of therapy, this is hypersensitivity, not simple GI side effects 3
• Requires immediate drug discontinuation, not dose adjustment

Common Mistake #4: Inadequate monitoring

• Guidelines recommend weekly CBC during first month, twice monthly for months 2-3, then monthly 2
• Many practitioners fail to follow this schedule

Immediate Action Algorithm

1. Perform arthrocentesis immediately - do not delay for imaging
2. Draw blood cultures and CBC before any antibiotics
3. If WBC >50,000 or Gram stain positive: Start empiric IV antibiotics (vancomycin + 3rd generation cephalosporin)
4. If neutrophils <1.0 × 10⁹/L: Stop azathioprine immediately 3
5. If fever + myalgias + arthralgia present: Consider azathioprine hypersensitivity, discontinue drug 3
6. Consult orthopedics for possible surgical washout if septic arthritis confirmed

The combination of new immunosuppression, monoarticular joint pathology, and functional impairment demands aggressive evaluation for infection as the primary concern, while simultaneously assessing for drug toxicity and disease progression.