Musculoskeletal System ORGAN SYSTEMS

Calcium pyrophosphate deposition (CPPD) disease

Crystal arthritis caused by calcium pyrophosphate (CPP) crystals.


Crystal arthritis caused by calcium pyrophosphate (CPP) crystals.


Common risk factors:

  • Hyperparathyroidism (strongest association)
  • Age
  • Gout/hyperuricemia
  • Osteoarthritis (OA)
  • Rheumatoid arthritis (RA) (inverse association)
  • Diuretics
  • Hemochromatosis

Other risk factors:

  • Osteoporosis
  • Hypomagnesemia, hypophosphatemia
  • Chronic kidney disease
  • Calcium supplementation

Deposition of calcium pyrophosphate is believed to cause activation of the immune system producing inflammation and further soft tissue injury.


Formation of CPP crystals in the pericellular matrix of cartilage is the essential first step in the disease process. CPP crystals rarely form in noncartilaginous tissues. Thus, the cells and highly specialized extra-cellular matrix of cartilage are clearly conducive to CPPD. For example, chondrocytes constitutively generate pericellular exosome-sized vesicles, termed “articular cartilage vesicles,” which serve as important sites of crystal formation in cartilage. Chondrocytes also produce high levels of extracellular inorganic pyrophosphate, which is critical to the formation of CPP crystals.

Schematic diagram of calcium crystal formation [calcium pyrophosphate dihydrate (CPPD) versus basic calcium phosphate (BCP)], with subsequent inflammasome activation via CPPD and synovial inflammation via BCP, and how both can contribute to the vicious cycle of joint degeneration in calcium crystal-related arthropathies. | ePPi, extracellular inorganic phosphate; HA, hydroxyapatite; IL-1β, interleukin 1β; MMP, matrix metalloproteinase; MV, matrix vesicle; NALP 3, NACHT, LRR and PYD domains-containing protein 3; NTPPPH, nucleoside triphosphatase pyrophosphohydrolase; PPi, inorganic phosphate. | MacMullan, P., & McCarthy, G. (2012). Treatment and management of pseudogout: insights for the clinician. Therapeutic Advances in Musculoskeletal Disease, 121–131.

Clinical features

Acute CPP crystal arthritis “pseudogout” (25% cases):

Represent a dose-related auto-inflammatory response to CPPD crystals shed from cartilaginous tissues into the synovial cavity. Acute calcium pyrophosphate arthritis is generally self-limited, and the inflammation usually resolves within days to weeks of treatment.
  • Typically present with the acute onset of monoarticular or oligoarticular arthritis
  • Warmth, erythema, and swelling in and around the affected joint (due to vigorous inflammatory response to CPP crystals); indistinguishable from acute gouty arthritis or septic arthritis
  • Involved joints: Knee > wrist; acute podagra in the first MTP joint is rare.
  • Systemic symptoms: Fevers, chills, and constitutional symptoms

Chronic CPP crystal arthritis (50% cases): Chronic degenerative polyarticular arthritis

Chronic CPP inflammatory arthritis may present overlapping manifestations with rheumatoid arthritis, such as morning stiffness, localized edema, and decreased range of motion. Some patients also present tenosynovitis with carpal or cubital tunnel syndrome. Multiple joints are commonly involved, and the episodes of inflammation may present in a nonsynchronous, waxing, and waning clinical course lasting several months
  • CPPD resembling osteoarthritis (common): Distinguishable from typical osteoarthritis by flares of inflammatory signs and symptoms and by unusually severe articular damage
    • Joints such as the glenohumeral joint, the wrist, and the metacarpophalangeal joints, which are not often affected by typical osteoarthritis, should lead one to suspect the presence of CPPD disease
  • CPPD resembling rheumatoid arthritis (rare): Persistent inflammatory arthritis affecting large and small joints. Flares often involve joints sequentially, and involvement is less symmetric than that seen with rheumatoid arthritis

Other clinical forms:

CPP crystals are commonly seen in spinal tissues, including inter-vertebral disks and spinal ligaments
  • Crowned dens syndrome: Deposition of CPP crystals around the C2 vertebra and manifests as acute severe neck pain, fever, and high levels of inflammatory markers. This syndrome is often confused with meningitis or sepsis.
  • Severely destructive arthritis similar to neurotrophic (Char-cot’s) arthropathy.
  • Tumoral deposits of CPP crystals in soft tissues (rare): Can cause considerable tissue damage and may be mistaken for cancers
  • Chondrocalcinosis is present without clinical arthritis: Presymptomatic phase of clinical arthritis, similar to that of hyperuricemia in gout


CPPD disease is underdiagnosed. 20% unselected patients examined at the time of total joint replacement for osteoarthritis of the knee have CPP crystals in their synovial fluid.

Arthrocentesis (synovial fluid analysis):

definitive diagnosis made by identifying CPPD crystals, by compensated polarized light microscopy, in the SF of affected joints
  • Rectangular/rhomboid shaped, positively birefringent crysals
Calcium Pyrophosphate Deposition (CPPD): Rhomboid, birefringent calcium pyrophosphate (CPP) crystals are seen under polarizing light microscopy in this sample of synovial fluid that was obtained from a patient with acute CPP crystal arthritis of the wrist (Panel A). The hands of an elderly patient with CPPD disease show swelling in the left wrist and the third proximal interphalangeal joint of the left hand (Panel B). | Rosenthal, A. K., & Ryan, L. M. (2016). Calcium Pyrophosphate Deposition Disease. The New England journal of medicine, 374(26), 2575–2584.


Characteristic intra-articular radiological calcification seen
  • Chondrocalcinosis (CHARACTERISTIC): Calcification in hyaline and/or fibrocartilage
Imaging of Chondrocalcinosis in Patients with CPPD Disease: Panel A shows a radiograph of a knee with meniscal chondrocalcinosis (arrow). Panel B shows a radiograph of a wrist with chondrocalcinosis of the triangular cartilage (arrow). Panel C shows a radiograph of a hand with hooklike osteophytes (arrows). Panel D shows an ultrasonographic image of a right knee, which was obtained with the transducer in the anatomical axial plane, with the knee flexed 90 degrees. The probe was pointed at the femoral cartilage on the “V” of the patellar groove. Chondrocalcinosis is seen in the substance of the cartilage; the arrow indicates the direction of the probe. | Rosenthal, A. K., & Ryan, L. M. (2016). Calcium Pyrophosphate Deposition Disease. The New England journal of medicine, 374(26), 2575–2584.

Differential diagnosis:

  • Gout: In contrast to the brief attacks of acute gouty arthritis that typically last for several days to 1 week, acute attacks of CPPD disease may last for weeks to months.
  • Osteoarthritis
  • Rheumatoid arthritis


Strategies that are currently employed in ameliorating CPPD-related joint disease are broadly limited to the following; those directed against correcting underlying metabolic abnormalities and treating associated conditions, general treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids (either by local intra-articular injection or systemic therapy), and finally, low-dose oral colchicine

Acute CPP arthritis:

Acute CPP crystal arthritis is managed with strategies that are aimed at reducing inflammation and that are borrowed from therapies used for acute gouty arthritis
Management Strategy for Acute CPP Crystal Arthritis: Treatment is considered to be feasible if it is not associated with unacceptable side effects. | NSAID: Nonsteroidal anti-inflammatory drug. | Rosenthal, A. K., & Ryan, L. M. (2016). Calcium Pyrophosphate Deposition Disease. The New England journal of medicine, 374(26), 2575–2584.

Chronic CPP arthritis:

All strategies are aimed at reducing inflammation. Unlike the case with gout, in which long-term therapies reduce the urate burden, no current disease-modulating treatments are available for CPPD disease.
Management Strategy for Chronic CPP Crystal Arthritis: Combination therapy may include various combinations of colchicine, prednisone, methotrexate, and hydroxychloroquine. | Rosenthal, A. K., & Ryan, L. M. (2016). Calcium Pyrophosphate Deposition Disease. The New England journal of medicine, 374(26), 2575–2584.


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