What is CPPD (Calcium Pyrophosphate Deposition Disease)?

Calcium Pyrophosphate Deposition Disease (CPPD)

CPPD is a common inflammatory arthritis caused by calcium pyrophosphate dihydrate crystal deposits in articular tissues, primarily affecting fibrocartilage and hyaline cartilage, with no current disease-modifying treatments available to dissolve these crystals. 1

Clinical Presentations

CPPD can manifest in four distinct clinical forms:

• Asymptomatic CPPD: Crystal deposits visible on imaging without symptoms 2
• Osteoarthritis with CPPD: Joint degeneration with crystal deposits, though the causal relationship remains unclear 2, 1
• Acute CPP crystal arthritis (pseudogout): Characterized by sudden onset of pain, swelling, tenderness, and erythema, typically in large joints like knees, wrists, shoulders, and hips 2
• Chronic CPP inflammatory crystal arthritis: Presents with persistent joint swelling, morning stiffness, pain, and elevated inflammatory markers 2

Epidemiology and Risk Factors

• Prevalence increases significantly with age, affecting 10-15% of people aged 65-75 years and over 40% of those above 80 years 3
• Common risk factors include:
  • Advanced age 1
  • Previous joint injury 1
  • Metabolic conditions (hyperparathyroidism, hemochromatosis, hypomagnesemia, hypophosphatasia) 3, 1
  • Genetic variants (ANKH and osteoprotegerin genes) 1

Diagnosis

Diagnosis relies on a combination of:

• Synovial fluid analysis: The reference standard for diagnosis is identification of CPP crystals in synovial fluid 4
  • Non-polarized light microscopy for initial screening based on crystal morphology 2
  • Compensated polarized light microscopy showing weakly positive birefringent crystals (definitive identification, though only visible in about 20% of samples) 2
• Imaging:
  • Conventional radiography: Shows punctate and linear radiodense areas in fibrocartilage and hyaline cartilage 3
  • Ultrasonography: Increasingly used for detection 1
  • CT: Useful for axial joints, particularly in crowned dens syndrome 1

Management

Acute CPP Crystal Arthritis

• First-line options:
  • Prednisone: Offers the best benefit-risk ratio for acute attacks 1
  • NSAIDs: Effective for symptom control 3, 5
  • Colchicine: Effective for acute attacks, though may cause mild diarrhea 1
  • Intra-articular corticosteroids: Useful for monoarticular presentations 3

Chronic CPP Inflammatory Arthritis

• Treatment options (limited evidence base):
  • Colchicine: May be effective for prophylaxis of recurrent flares 5, 1
  • Low-dose methotrexate: Showed promise in small uncontrolled studies for refractory cases 3, 1
  • Hydroxychloroquine: May help manage persistent inflammation 5, 1
  • Biologics: IL-1 inhibitors (anakinra) and IL-6 inhibitors (tocilizumab) for refractory cases 5, 1

Special Considerations

• Early-onset disease (before age 60): Requires evaluation for underlying metabolic conditions, particularly hemochromatosis 3
• Comorbidity management: Treatment of associated conditions is required, though impact on CPPD outcomes remains unclear 6
• Asymptomatic CPPD: No treatment currently recommended 6

Treatment Limitations

• No disease-modifying therapies: Currently no treatments can reduce articular calcification or dissolve CPP crystals 5, 1
• Limited evidence base: Few randomized controlled trials exist, making it difficult to establish evidence-based treatment protocols 5
• Magnesium supplementation: Despite theoretical benefits and in vitro evidence of crystal solubilization, clinical trials have shown symptom improvement but no reduction in radiographic calcification 6

Research Priorities

Future research should focus on:

• Basic studies to better understand CPPD mechanisms and crystal effects on joint tissues 6
• Evaluation of biological agents, particularly IL-1 inhibitors, for both acute and chronic CPP crystal arthritis 6
• Further investigation of methotrexate for chronic CPP inflammatory arthritis 6