In a 30-year-old man with three months of recurrent joint pain now presenting with isolated right knee pain, afebrile, normal white blood cell count, normal serum uric acid, and elevated blood urea nitrogen, what is the most likely cause: gout, pseudogout, reactive arthritis, or septic arthritis?

Most Likely Diagnosis: Pseudogout (Calcium Pyrophosphate Deposition Disease)

In this 30-year-old man with three months of recurrent joint pain, isolated right knee involvement, absence of fever, normal WBC, normal uric acid, and elevated urea, pseudogout (CPPD) is the most likely diagnosis among the options provided.

Systematic Diagnostic Reasoning

Why Pseudogout is Most Likely

• The normal serum uric acid effectively excludes gout as the primary diagnosis, as the European League Against Rheumatism guidelines emphasize that while uric acid can drop during acute flares, this patient has had three months of recurrent episodes, making persistently normal uric acid inconsistent with gout 1, 2.

• Pseudogout characteristically presents with recurrent oligoarticular attacks affecting large joints, particularly the knee, which is the most commonly affected joint in CPPD disease 3, 4.

• The absence of fever and normal WBC count argue strongly against septic arthritis, as the American College of Radiology states that septic arthritis typically presents with fever >101.3°F, WBC ≥12,000 cells/mm³, and ESR ≥40 mm/hour 5.

• The elevated blood urea nitrogen may reflect the patient's age and metabolic state, and while not diagnostic, does not contradict pseudogout, which can be associated with metabolic abnormalities 3.

Why Other Diagnoses Are Less Likely

Gout (Option A):

• Normal serum uric acid makes gout highly unlikely in a patient with three months of recurrent symptoms 1, 2
• While uric acid can be normal during acute attacks, persistently normal levels over recurrent episodes argue against gout 2
• Gout typically affects the first metatarsophalangeal joint (podagra) initially, not the knee 6

Reactive Arthritis (Option C):

• The American College of Rheumatology notes that reactive arthritis typically presents with oligoarthritis accompanied by extra-articular features such as conjunctivitis, urethritis, or sacroiliitis 1, 5
• The question specifically states "no recent history of illness," which makes reactive arthritis (typically triggered by preceding gastrointestinal or genitourinary infection) unlikely 1
• The three-month duration of recurrent episodes is atypical for reactive arthritis, which usually follows a more acute post-infectious course 5

Septic Arthritis (Option D):

• The absence of fever is a critical distinguishing feature, as the American College of Radiology identifies fever as a key diagnostic criterion for septic arthritis 5
• Normal WBC count strongly argues against bacterial infection 5
• The three-month duration of recurrent episodes is incompatible with untreated septic arthritis, which causes irreversible cartilage damage within hours to days if left untreated 5
• The American College of Radiology states that meeting diagnostic criteria (fever, elevated ESR, elevated WBC, inability to bear weight, elevated CRP) approaches 100% likelihood of septic arthritis—this patient meets none of these 5

Critical Diagnostic Pitfall to Avoid

The most important clinical action is to perform arthrocentesis with synovial fluid analysis to definitively exclude septic arthritis before assuming pseudogout, as the American College of Radiology emphasizes that joint aspiration is the definitive diagnostic procedure 5. Even if calcium pyrophosphate crystals are identified, septic arthritis must still be ruled out with Gram stain and culture, as these conditions can coexist 5, 7.

Recommended Diagnostic Approach

1. Perform arthrocentesis of the right knee immediately to obtain synovial fluid for:

   • Crystal analysis under polarized light microscopy (looking for rhomboid-shaped, weakly positive birefringent CPPD crystals) 3
   • Gram stain and culture to exclude septic arthritis 5
   • Total nucleated cell count and differential 7

2. Obtain plain radiographs of the knee to look for chondrocalcinosis (meniscal calcifications), which is characteristic of pseudogout and would support the diagnosis 1, 3, 8

3. If synovial fluid analysis confirms CPPD crystals and cultures are negative, screen for metabolic associations including primary hyperparathyroidism, hemochromatosis, hypomagnesemia, and hypophosphatasia, particularly given the patient's relatively young age (30 years) for CPPD disease 3

Treatment Implications Once Diagnosis Confirmed

If pseudogout is confirmed, the European League Against Rheumatism recommends intra-articular glucocorticosteroid injection (triamcinolone acetonide 60 mg) combined with joint aspiration as first-line treatment, followed by oral prednisone 0.5 mg/kg/day for 5-10 days if systemic therapy is needed 3. For prophylaxis of recurrent attacks, low-dose colchicine 0.5 mg twice daily can be considered 3, 4.