BOTTOM LINE

CPPD presents in older adults, often >70 years old, and can look present like pseudo-OA, pseudo-gout (most common), pseudo RA, asymptomatic, or other rarer presentations. Imaging can show calcification of the cartilage and synovial fluid may reveal weakly  birefringent rhomboid crystals. Treatment is supportive and symptomatic.
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EPIDEMIOLOGY

• Prevalence:
  • 4-7% (US and Europe)
• Age at onset:
  • Average 70 years-old; increasing prevalence with age
• Sex:
  • No major sex difference
• Risk factors:
  • Age, underlying OA, rarely genetic mutations (in ANKH gene, procollagen type 2, CCAL1, osteoprotegerin genes)
• Associated diseases:
  • Hemochromatosis, hyperparathyroidism, hypomagnesemia, hypophosphatasia

CLINICAL MANIFESTATIONS

• Asymptomatic CPPD “Lanthanic“
  • Radiographic chondrocalcinosis (often incidental on X-ray, often in knee) without clinical manifestations
• Acute CPPD “Pseudo-gout” (89%)
  • Self-limited acute, red/warm/swollen mono-oligoarticular inflammatory arthritis. Knee (50%) and wrist are most commonly involved; also involves shoulders, ankles, feet, and elbows. Looks like gout except flares can last longer and involve upper extremity.
• Chronic CPPD “Pseudo-rheumatoid” (11%)
  • Chronic polyarticular inflammatory arthritis. Consider CPPD in elderly patient presenting with seronegative RA or PMR
• Secondary OA “Pseudo-osteoarthritis”
  • CPPD causing osteoarthritis in joints not usually involved by primary osteoarthritis (ex: MCP, radiocarpal, and elbow joints). May have superimposed pseudogout flares
• Other
  • Pseudo-tophaceus: deposits in Achilles, gastrocnemius, quadriceps tendon
  • Pseudo-neuropathic: resembles Charcot foot but patient has normal pain perception
  • Cervical stenosis: CPPD in ligamentum flavum and/or transverse ligament of atlas
  • Crowned dens: CPPD above odontoid process causing acute neck pain/meningismus
  • Axial: calcification of intervertebral disc and SI joint

CPPD is a great mimicker of disease

INVESTIGATIONS

Bloodwork

• CBC:
  • Neutrophilia or thrombocytosis during acute flare
• ALT:
  • Normal
• Creatinine:
  • Normal
• Serum Calcium:
  • Not elevated, unless underlying associated hyperparathyroidism etc.
• CRP, ESR:
  • Elevated during flare
• Other:
  • ANA negative, RF negative, uric acid not associated with CPPD, but can rise anyway with age

Fluids

• Synovial fluid is inflammatory (usually 15e9 to 30e9/L total neutrophil count)
• CPP crystals can be visualized: Weakly birefringent blue rhomboid crystals; can be rod or cuboid shaped as well

Imaging

• X-ray
  • Chondrocalcinosis: can see in triangular fibrocartilage of wrist, pubis symphysis, knees, and glenoid/acetabular labra,
  • Degeneration: secondary OA is joints atypical for primary OA as discussed above
  • Specific joint findings
    • MCPs: narrowing with hook-like osteophytes
    • Wrists: extensive radiocarpal and/or navicular-lunate dissociation, scaphoid lunate advanced collapse (“SLAC”)
    • Knees: severe patellofemoral degeneration
    • Axial: subchondral cysts in spine and SI joints
    • Crowned-dens: crystal masses at atlanto-axial articulation or in transverse ligament of atlas and/or ligamentum flavum.
• Ultrasound
  • Calcium deposition on cartilage: superficial hyperechoic band on articular cartilage surface (“double contour sign”); thinner and more stippled that what is seen in gout
  • Small hyperechoic rounded amorphous shaped regions usually on wrist, knee menisci, ad tendons
  • Nodular hyperechoic deposits in bursae and articular recesses
  • Hyperechoic lines of calcification parallel to tendon fibers

DIAGNOSIS

• Definitively:
  • Synovial fluid demonstrating intracellular CPP crystals in patient usually presenting with acute mono/oligoarticular inflammatory arthritis
• Clinically, if unable to see crystals:
  • Patient usually >65 years-old with acute/subacute inflammatory arthritis (especially if knee) with CPP deposition on imaging
• Consider screening if unusually young patient presenting with CPPD
  • Calcium, phosphate Magnesium, ALP, PTH, Iron screen
  • For associated disorders of hypercalcemia, hyperparathyroidism, hemochromatosis

CLASSIFICATION CRITERIA

CPPD is a clinical diagnosis. Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease. Classification Criteria described out of interest only.

2023 ACR/EULAR criteria (sensitivity 92%, specificity of 88%)

• Entry criterion: must have ≥1 episode of peripheral joint pain/swelling/ tenderness, and
• Exclusionary criterion: not having an alternative disease, and
• Sufficient criteria: crowned dens (C1/C2) syndrome or calcium pyrophosphate crystals in synovial fluid, or
• >56 points using the weighted criteria below

TREATMENT

Treatment of CPPD is symptomatic and supportive.

• For flares of joint swelling:
  • Intra-articular corticosteroids
  • NSAIDs
  • Oral steroids
  • Colchicine 1.2mg then 0.6 daily until resolution of flare
• Prophylaxis: No prophylaxis treatment exists, but for frequent recurrent symptoms can try
  • Low dose daily oral prednisone
  • NSAIDs
  • Colchicine 0.6mg daily
  • Little evidence, but has been tried: hydroxychloroquine, methotrexate

REFERENCES

Abhishek, A., & Doherty, M. (2016). Update on calcium pyrophosphate deposition. Clinical and experimental rheumatology, 34(4 Suppl 98), 32–38.

Abhishek, A., Tedeschi, S. K., Pascart, T., Latourte, A., Dalbeth, N., Neogi, T., Fuller, A., Rosenthal, A., Becce, F., Bardin, T., Ea, H. K., Filippou, G., Fitzgerald, J., Iagnocco, A., Lioté, F., McCarthy, G. M., Ramonda, R., Richette, P., Sivera, F., Andrés, M., … Choi, H. K. (2023). The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease. Annals of the rheumatic diseases, 82(10), 1248–1257. https://doi.org/10.1136/ard-2023-224575

Rosenthal, A. K., & Ryan, L. M. (2016). Calcium Pyrophosphate Deposition Disease. The New England journal of medicine, 374(26), 2575–2584. https://doi.org/10.1056/NEJMra1511117

Zhang, W., Doherty, M., Bardin, T., Barskova, V., Guerne, P. A., Jansen, T. L., Leeb, B. F., Perez-Ruiz, F., Pimentao, J., Punzi, L., Richette, P., Sivera, F., Uhlig, T., Watt, I., & Pascual, E. (2011). European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Annals of the rheumatic diseases, 70(4), 563–570. https://doi.org/10.1136/ard.2010.139105

Zhang, W., Doherty, M., Pascual, E., Barskova, V., Guerne, P. A., Jansen, T. L., Leeb, B. F., Perez-Ruiz, F., Pimentao, J., Punzi, L., Richette, P., Sivera, F., Uhlig, T., Watt, I., & Bardin, T. (2011). EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Annals of the rheumatic diseases, 70(4), 571–575. https://doi.org/10.1136/ard.2010.139360