In a patient with left knee pain and swelling that has persisted despite five days of prednisone, with normal C‑reactive protein, normal erythrocyte sedimentation rate, normal serum uric acid, and a pending knee X‑ray, what is the most appropriate next step in management?

Persistent Knee Pain and Swelling Despite Prednisone: Next Steps

The most appropriate next step is to perform arthrocentesis with synovial fluid analysis including cell count with differential, Gram stain, and aerobic/anaerobic cultures to definitively rule out septic arthritis, which remains a critical diagnostic consideration despite normal inflammatory markers. 1

Why Arthrocentesis is Essential

Normal CRP and ESR do not exclude septic arthritis. While the combination of elevated ESR and CRP provides the best sensitivity and specificity for infectious arthritis, normal values can occur in early infection or in patients with underlying conditions that affect these markers 1, 2. The failure to respond to 5 days of prednisone is particularly concerning because:

• Prednisone can mask inflammatory markers while allowing infection to progress, making clinical assessment more difficult 3
• Septic arthritis requires urgent diagnosis to prevent irreversible joint destruction and systemic complications, directly impacting morbidity and mortality 1
• Synovial fluid analysis is the gold standard for diagnosing infectious arthritis and cannot be replaced by serum markers alone 2

Critical Diagnostic Algorithm

Step 1: Immediate Arthrocentesis

• Perform arthrocentesis before starting any antibiotics if the patient is medically stable, as antimicrobial therapy significantly reduces organism recovery 1, 2
• Synovial fluid must be analyzed for:
  • Total cell count and differential (>50,000 WBC/mm³ with >90% neutrophils suggests septic arthritis) 1
  • Gram stain and aerobic/anaerobic cultures 1, 2
  • Crystal analysis to exclude pseudogout or gout (which can coexist with infection and may explain normal uric acid) 1

Step 2: Review Pending X-ray

• Plain radiographs are essential to evaluate for structural abnormalities, loose bodies, osteochondritis dissecans, or signs of chronic injury 1
• If X-ray shows joint effusion but is otherwise normal, MRI without contrast should be considered next to evaluate for internal derangement, bone marrow edema, or occult pathology 1

Step 3: Consider Alternative Diagnoses

If arthrocentesis is negative for infection:

• Inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, reactive arthritis):

  • Order anti-CCP antibodies (90% specificity for RA) and rheumatoid factor (70% specificity) 4, 5
  • Note that 20-30% of RA cases are seronegative, and inflammatory markers may be normal in active disease 4, 5
  • Perform 28-joint examination for symmetric small joint involvement 4, 5
  • Morning stiffness >30 minutes suggests inflammatory arthritis 4, 5

• Crystal arthropathy despite normal uric acid:

  • Pseudogout (calcium pyrophosphate deposition) can occur with normal uric acid 1
  • Crystal analysis from synovial fluid is diagnostic 1

• Internal derangement (meniscal tear, cartilage injury):

  • MRI without contrast is the next appropriate study if X-ray is normal or shows only effusion 1
  • However, meniscal tears are common incidental findings in patients >45 years and may not explain symptoms 1

Common Pitfalls to Avoid

• Do not delay arthrocentesis based on normal inflammatory markers—septic arthritis can present with normal CRP/ESR, especially early in the course or in immunocompromised patients 2, 5
• Do not start antibiotics before obtaining cultures unless the patient is septic or hemodynamically unstable, as this dramatically reduces diagnostic yield 1, 2
• Do not assume normal uric acid excludes crystal arthropathy—pseudogout and even gout can occur with normal serum uric acid levels 1
• Do not order MRI before obtaining X-ray results—approximately 20% of patients with chronic knee pain undergo unnecessary MRI without recent radiographs 1

Monitoring Strategy After Diagnosis

• If infection is confirmed: Withhold further corticosteroids, initiate appropriate antibiotics based on culture results, and consider orthopedic consultation for possible surgical debridement 1
• If inflammatory arthritis is diagnosed: Refer to rheumatology within 6 weeks, initiate methotrexate 15 mg weekly as first-line DMARD, and monitor CRP/ESR every 4-6 weeks 4, 5
• If mechanical pathology is found: Refer to orthopedics for consideration of arthroscopy or conservative management based on imaging findings 1