Calcium pyrophosphate deposition disease

Calcium pyrophosphate deposition (CPPD) disease is a crystalline inflammatory arthritis seen primarily in individuals over age 60. It results from the deposition of calcium pyrophosphate dihydrate (CPP) crystals within articular cartilage. While it is typically idiopathic, it may also be caused by joint damage, various metabolic abnormalities, or a genetic predisposition. CPPD disease can be asymptomatic or manifest with acute or chronic symptoms. Pseudogout refers to acute CPP crystal arthritis, which typically presents as sporadic flares of monoarticular synovitis affecting a large joint and can last for much longer than a typical gout flare. Chronic CPP crystal arthritis has many clinical phenotypes, the most common of which resembles severe osteoarthritis. Identification of CPP crystals on synovial fluid analysis or on imaging in a patient with typical symptoms confirms the diagnosis. Treatment is primarily symptomatic and consists of antiinflammatory medications (including intraarticular and systemic glucocorticoids, colchicine, and NSAIDs). There is currently no specific treatment targeted at CPP crystals.

• Sex: ♂ = ♀ ^[1]
• Age of onset: adults > 60 years ^[1]
• Prevalence: 8–10 million adults in the US ^[1][2]

Epidemiological data refers to the US, unless otherwise specified.

• The primary (idiopathic) form is most common, with age as a major risk factor. ^[3]
• Secondary forms ^[3][4]
  • Joint trauma/damage: including joint surgery, previous juvenile idiopathic arthritis, and osteoarthritis ^[1]
  • Metabolic disorders: including hyperparathyroidism, hemochromatosis,; hypomagnesemia, hypophosphatasia, and possibly gout
  • Familial chondrocalcinosis: due to mutations in the CCAL1 or CCAL2 genes

Deposition of calcium pyrophosphate dihydrate (CPP or CPPD) crystals in articular cartilage → paroxysmal joint inflammation and cartilage destruction → inflammatory arthritis (crystalline arthritis)

There are several distinct clinical phenotypes of CPPD disease. CPPD may also remain asymptomatic and be identified incidentally on imaging (asymptomatic chondrocalcinosis). ^[1][2][4]

Acute CPP crystal arthritis (pseudogout)

• Clinical features
  • Acute attack of pain and swelling in the affected joint(s)
  • Monoarthritis (occasionally oligoarthritis)
  • Most commonly affects the knee and wrist; can also affect other large joints (e.g., hips, ankles)
  • Typically self-limited
• Features that differ from acute gout
  • Longer duration of acute attacks
  • Possible systemic symptoms ^[5]
• Triggers: can occur spontaneously or be triggered by joint trauma/surgery or acute illness ^[4]

Pseudogout refers to the acute, not chronic, form of CPPD disease.

Chronic CPP crystal arthritis

• Osteoarthritis-like presentation (osteoarthritis with CPPD; pseudo-osteoarthritis) ; ^[3]
  • Most common form of CPPD disease
  • Characterized by progressive joint degeneration
    • Usually polyarticular; can occur in joints not typically affected by OA
    • More severe than typical OA
    • Often associated with pseudogout-like flares of acute inflammatory arthritis
• Rheumatoid arthritis-like presentation (chronic CPP crystal inflammatory arthritis)
  • Manifests similarly to rheumatoid arthritis (RA), with polyarticular distribution associated with morning stiffness
  • In contrast to typical RA, joint involvement may be asymmetric and sequential. ^[4]
• Less common phenotypes
  • Pseudoneuropathic arthropathy: manifests with destructive monoarthritis similar to neuropathic arthropathy, but sensation and proprioception are preserved ^[6]
  • Crowned dens syndrome: CPP inflammatory arthritis of the C2 vertebra; causes acute neck pain resembling meningitis or vertebral osteomyelitis ^[4][7]

There are currently no validated diagnostic criteria for CPPD disease. Diagnosis is based on the identification of CPP crystals on synovial fluid analysis and/or the presence of cartilage calcification on imaging in a patient with suggestive symptoms. ^[2][6]

Arthrocentesis and synovial fluid analysis (SFA) ^[4]

• The most accurate diagnostic method, but crystals can often be difficult to identify. ^[2]
• Expected findings
  • Polarized light microscopy (with a red filter) appearance of CPP crystals
    • Rhomboid-shaped crystals that are weakly positively birefringent
    • Crystals appear blue when their optical axis is oriented parallel to the polarizer.
    • Crystals appear yellow when their axis is perpendicular to the polarizer.
  • Cell count: WBC > 2,000/μL with > 50% neutrophils ^[4]
  • See also “Interpretation of synovial fluid analysis.”

SFA can be falsely negative, as CPPD crystals are small and weakly birefringent. A negative SFA does not rule out CPPD disease. ^[1][6]

Imaging ^[1][4][8]

• X-ray of the affected joint(s)
  • Chondrocalcinosis: calcification of cartilage in the affected joints ^[2]
  • Appears as radiodense shadows within the cartilage
  • Types of cartilage involved:
    • Fibrocartilage (meniscus, annulus fibrosus of intervertebral disk)
    • Articular hyaline cartilage
  • Sensitivity: ∼ 40% (i.e., x-ray may appear normal) ^[8]
• Ultrasound of the affected joint(s)
  • Hyperechoic deposits within cartilage ^[1]
  • Operator-dependent; good sensitivity and specificity if performed by experienced sonographers ^[8]
• Other modalities ^[8]
  • CT: can be used to identify chondrocalcinosis; not typically used to evaluate joint pain
  • MRI: not a sensitive/specific modality for diagnosing CPPD
  • Dual-energy CT shows promise, but is not yet widely in use.

Laboratory studies

• Serum uric acid
  • Obtain in patients with acute CPP crystal arthritis to differentiate it from gout.
  • Typically normal in CPPD
• Tests to rule out differential diagnoses of inflammatory arthritis: e.g., CBC, rheumatoid factor, anti-CCP antibodies
• Evaluate for underlying metabolic disorders if appropriate : e.g., obtain serum levels of iron, transferrin, ferritin, calcium, magnesium, PTH, and alkaline phosphatase ^[4]

• Other inflammatory arthritides, e.g.:
  • Gout and other crystalline arthropathies (e.g., basic calcium phosphate crystal deposition disease)
  • Rheumatoid arthritis
  • Seronegative spondyloarthropathies (e.g., psoriatic arthritis, reactive arthritis)
  • See also “Differential diagnoses of inflammatory arthritis.”
• Septic arthritis (in patients with acute CPPD): See “Interpretation of synovial fluid analysis.”
• Osteoarthritis and erosive osteoarthritis

The differential diagnoses listed here are not exhaustive.

Management of CPPD is primarily symptomatic, as there is currently no therapy that can prevent or treat CPP crystal deposition in cartilage. ^[1]

• All patients: Treat any underlying condition (e.g., hyperparathyroidism, hemochromatosis).
• Asymptomatic patients: no further treatment required
• Acute CPP crystal arthritis (pseudogout): Symptomatic therapeutic options in order of preference include the following. ^[4]
  1. Intraarticular injection of glucocorticoid, with or without prior joint aspiration ^[1]
  2. Colchicine (off-label)
  3. NSAIDs, e.g., naproxen (prescribe with a proton pump inhibitor)
  4. Systemic glucocorticoids (oral or parenteral), e.g., prednisone
• Chronic CPP crystal arthritis ^[4]
  • Same antiinflammatory therapies as above
  • Sometimes in combination
• Prophylaxis: Consider low-dose colchicine to decrease the frequency of acute attacks. ^[4]