What is Calcium Pyrophosphate Deposition Disease (CPPD)?
Calcium pyrophosphate deposition disease is a crystal-induced arthropathy caused by the pathological accumulation of calcium pyrophosphate dihydrate (CPP) crystals in articular tissues—primarily fibrocartilage and hyaline cartilage—triggering an immune response that results in acute or chronic inflammatory arthritis. 1, 2
Pathophysiology
CPPD develops when elevated inorganic pyrophosphate levels in cartilage lead to CPP crystal formation and deposition 3. Unlike urate crystals in gout, there is currently no treatment to prevent CPP crystal formation or enhance their dissolution, which fundamentally limits management to symptomatic control rather than disease modification 4, 3.
The inflammatory cascade is driven by:
- NLRP3 inflammasome activation when CPP crystals are present in joints 2
- Interleukin-1 (IL-1) playing a central role in the inflammatory response 3
- Magnesium deficiency promoting crystal formation, as magnesium normally solubilizes CPP crystals and inhibits their nucleation 3
Clinical Presentations
The European League Against Rheumatism recognizes four distinct clinical patterns 1:
1. Asymptomatic CPPD (Chondrocalcinosis)
- Radiographic calcium deposits in cartilage without symptoms 5
- Common in elderly patients and requires no treatment 5
- Prevalence increases dramatically with age: 10-15% in ages 65-75 years, exceeding 40% in those over 80 5
2. Acute CPP Crystal Arthritis (Pseudogout)
- Sudden onset of severe pain, swelling, tenderness with overlying erythema 1
- Most commonly affects large joints: knee, wrist, shoulder, hip 1
- Can involve ligaments, tendons, bursae, bone, and spine 1
- Crowned dens syndrome (atlanto-occipital joint involvement) presents with acute cervico-occipital pain, fever, neck stiffness, and elevated inflammatory markers 1
3. Chronic CPP Inflammatory Crystal Arthritis
- Joint swelling, morning stiffness, pain, and elevated ESR/CRP 1
- Can mimic rheumatoid arthritis (pseudorheumatoid presentation) 6
4. Osteoarthritis with CPPD
- Degenerative changes with superimposed crystal deposition that may accelerate joint destruction 5
- The causal relationship remains unclear—crystals may drive OA or result from joint degeneration 1
Epidemiology and Risk Factors
CPPD is likely the most common cause of inflammatory arthritis in people over 60 years old, though direct evidence is limited 2.
Common Risk Factors:
Metabolic Associations:
- Primary hyperparathyroidism (3-fold increased risk, OR=3.03) 4, 2
- Hemochromatosis 4, 6
- Hypomagnesemia 4, 3
- Hypophosphatasia 2
Critical caveat: Early-onset disease (before age 60) mandates screening for metabolic conditions, particularly hemochromatosis 6.
Diagnosis
Synovial Fluid Analysis (Gold Standard):
- Non-polarized light microscopy initially screens for characteristic crystal morphology 1
- Compensated polarized light microscopy shows weakly positive birefringent crystals for definitive identification, though this pattern appears in only 20% of samples 1
Imaging:
- Conventional radiography remains the key diagnostic modality, showing punctate and linear radiodense areas in fibrocartilage and hyaline cartilage 1, 6
- Ultrasound and CT can also detect crystal deposits 5
- CT is particularly useful for axial joints (e.g., crowned dens syndrome) 2
Management Principles
The primary goal is symptomatic control of inflammation and prevention of acute attacks, as no disease-modifying treatments exist 4. Treatment of associated metabolic conditions is required but whether this affects CPPD arthritis outcomes remains unclear 4.
Acute CPP Crystal Arthritis:
- Prednisone provides the best benefit-risk ratio 2
- NSAIDs and intra-articular or systemic glucocorticoids are effective 6, 7
- Colchicine is effective with mild diarrhea risk 2, 7
- Anakinra (IL-1 receptor antagonist) for refractory cases 7
Prophylaxis and Chronic Disease:
- Low-dose colchicine prevents recurrent flares 2, 7
- Hydroxychloroquine showed clinical response (NNT=2) in chronic inflammatory arthritis 4
- Low-dose weekly methotrexate may be valuable for severe refractory disease 4, 2
- Tocilizumab for refractory chronic cases 7
Important Limitation:
Magnesium supplementation showed symptom improvement but no reduction in radiographic calcification 8, reinforcing that no current therapy modifies crystal deposition 4.