What is pseudogout (calcium pyrophosphate deposition disease, CPPD)?

Pseudogout (Calcium Pyrophosphate Deposition Disease)

Pseudogout is an inflammatory arthropathy caused by calcium pyrophosphate dihydrate (CPP) crystal deposits in articular tissues, primarily affecting fibrocartilage and hyaline cartilage, and is characterized by both acute and chronic inflammatory manifestations. 1, 2

Clinical Presentations

According to the European League Against Rheumatism, CPPD presents in four distinct clinical patterns:

1. Asymptomatic CPPD - Incidental finding of chondrocalcinosis on imaging
2. Osteoarthritis with CPPD - Joint degeneration with crystal deposits
3. Acute CPP crystal arthritis - Sudden inflammatory attacks (classic pseudogout)
4. Chronic CPP inflammatory crystal arthritis - Persistent inflammatory arthritis 2

Acute Attacks

• Characterized by sudden onset of pain, swelling, tenderness, and erythema
• Most commonly affects large joints: knee, wrist, shoulder, and hip
• Can mimic gout but typically less severe 2
• May present with fever and elevated inflammatory markers 1

Special Presentations

• Crowned Dens Syndrome: CPPD affecting the atlanto-occipital joint causing acute cervico-occipital pain, fever, neck stiffness, and inflammatory laboratory findings 2
• Spinal CPPD: Rare but can cause myelopathy or radiculopathy due to ligamentum flavum involvement 3, 4

Diagnosis

Imaging

• Radiography should be the initial imaging method for suspected CPPD, showing:

  • Chondrocalcinosis (calcification of cartilage)
  • Tendon, ligament, and capsular calcification
  • Target sites: triangular fibrocartilage (wrist), knee menisci, symphysis pubis, and labrum at the pelvis 5
  • Characteristic arthropathy affecting radiocarpal, metacarpophalangeal, and patellofemoral joints 5

• Ultrasound complements radiography by showing:

  • Intra-articular microtophi
  • Echogenic synovial hypertrophy
  • "Icing" of cartilage (double contour sign) with 83% sensitivity and 76% specificity 5

• CT can identify:

  • Chondrocalcinosis and soft tissue calcifications
  • Useful for axial joints, particularly in crowned dens syndrome 6

Definitive Diagnosis

• Synovial fluid analysis is the gold standard:
  • Identification of weakly positive birefringent rhomboid-shaped crystals under compensated polarized light microscopy
  • Initial screening with non-polarized light microscopy based on crystal morphology 1, 2

Associated Conditions

Patients with CPPD should be evaluated for underlying metabolic disorders:

• Primary hyperparathyroidism (3x higher risk)
• Hemochromatosis
• Hypomagnesemia
• Hypophosphatasia 1

Treatment

Acute Attacks

1. First-line: Joint aspiration with intra-articular glucocorticoid injection for monoarticular/oligoarticular attacks 1

2. If joint aspiration not feasible:

   • NSAIDs (if no contraindications)
   • Colchicine (if NSAIDs contraindicated)
   • Systemic glucocorticoids (if both contraindicated) 1

3. For severe cases:

   • IV methylprednisolone (125 mg) provides rapid relief (NNT of 3 compared to oral NSAIDs)
   • IM betamethasone (7 mg) is an alternative injectable option 1

Chronic Management

1. First-line options:

   • NSAIDs with gastroprotection
   • Low-dose colchicine (0.5-1.0 mg daily) - NNT of 2 at 4 months for >30% pain reduction 1

2. Second-line options:

   • Low-dose corticosteroids 1

3. Third-line options:

   • Methotrexate (5-10 mg/week)
   • Hydroxychloroquine - NNT for clinical response of 2 (95% CI 1 to 7) 1

4. Refractory cases:

   • IL-1 inhibitors
   • Biologics targeting IL-6 may have a role 1, 6

Special Considerations

• Elderly patients: Higher risk of toxicity with NSAIDs and colchicine; require careful monitoring 1
• Renal impairment: Increases risk of adverse effects; requires dose adjustment 1
• Early-onset disease (before age 60): Requires thorough metabolic workup, particularly for hemochromatosis 1

Adverse Effects to Monitor

• NSAIDs: Gastrointestinal bleeding, cardiovascular events, renal impairment
• Colchicine: Diarrhea and other gastrointestinal side effects (high-dose regimens should be avoided)
• Parenteral glucocorticoids: Mild hypokalemia, hyperglycemia, fluid retention 1

Prognosis

• Currently, no treatment effectively dissolves CPP crystals, making control of inflammation the main therapeutic goal 6
• The relationship between CPPD and osteoarthritis remains unclear - whether crystals cause joint degeneration or result from it 2
• Regular follow-up is necessary to assess treatment response and monitor disease progression 1