Calcium Pyrophosphate Deposition Disease

The cause of most CPP crystal arthritis is unknown. CPP crystal arthritis is associated with other conditions, such as trauma (including surgery), hypomagnesemia, hyperparathyroidism, gout, hemochromatosis, hypophosphatasia, Gitelman syndrome, X-linked hypophosphatemic rickets, familial hypocalciuric hypercalcemia, and old age. These associations suggest that calcium pyrophosphate (CPP) crystal deposits may be caused by degenerative or metabolic changes in the affected tissues.

Some cases are familial, usually transmitted in an autosomal dominant pattern, with complete penetration by age 40.

The ankyrin (ANK) protein is a central factor in producing excess extracellular pyrophosphate, which promotes CPP crystal formation (1). ANK protein is a transporter of intracellular and microvesicle pyrophosphate to the extracellular location where CPP crystals form.

Acute, subacute, or chronic arthritis can occur, usually in the knee, wrist, or other large peripheral joints; thus, CPP crystal arthritis can mimic many other forms of arthritis (1). Acute flares are similar to gout but vary more in intensity, tend to be more protracted, and are often more difficult to treat. There may be no symptoms of CPP crystal arthritis between flares or continuous low-grade symptoms in multiple joints, similar to rheumatoid arthritis or osteoarthritis. These patterns tend to persist for life.

Crowned dens syndrome (with a radiographically "crowned" appearance of the odontoid process of the second cervical vertebra) is a presentation of acute CPP axial arthritis in which there can be profound inflammatory neck pain and stiffness. It can be mistaken for polymyalgia rheumatica, giant cell arteritis, seronegative spondyloarthritis, cervical osteomyelitis, or meningitis.

• Synovial fluid analysis

• Identification of crystals microscopically

CPP crystal arthritis should be suspected in older patients with arthritis, particularly those with a history of recurrent inflammatory arthritis.

Radiopaque deposits may sometimes be present in fibrocartilage, hyaline articular cartilage (particularly the knee), or both, but calcinosis can be seen in the absence of acute flares.

Calcium Pyrophosphate Deposition Disease

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BIOPHOTO ASSOCIATES/SCIENCE PHOTO LIBRARY

Calcium Pyrophosphate Crystals

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Image courtesy of Brian Mandell, MD.

Diagnosis of CPP crystal arthritis is established by identifying rhomboid- or rod-shaped crystals in synovial fluid that are not birefringent, or are weakly positively birefringent on polarized light microscopy. Joint fluid in acute flares has findings typical of inflammation; thus, coincident infectious arthritis and gout (other common causes of inflammatory joint fluid) must also be excluded. Infectious arthritis is excluded based on Gram stain and culture findings. Gout is best excluded by the absence of urate crystals in fluid from the inflamed joint. Notably a patient may have both gout and CPP arthritis. Radiographs or ultrasonography are indicated if synovial fluid cannot be obtained for analysis; findings of multiple linear or punctate calcification in articular cartilage, especially fibrocartilage, support the diagnosis, but do not exclude gout or infection.

Patients, especially younger ones, who have frequent CPP crystal flares should be evaluated for underlying triggers and diseases. Post-diagnostic laboratory testing that should be considered includes serum calcium, parathyroid hormone (PTH), serum magnesium, alkaline phosphatase, and iron studies (. Post-diagnostic laboratory testing that should be considered includes serum calcium, parathyroid hormone (PTH), serum magnesium, alkaline phosphatase, and iron studies (1).

• Intra-articular glucocorticoids

• Oral glucocorticoids (eg, prednisone, methylprednisolone)Oral glucocorticoids (eg, prednisone, methylprednisolone)

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Colchicine Colchicine

• Interleukin-1 (IL-1) antagonists (eg, anakinra)Interleukin-1 (IL-1) antagonists (eg, anakinra)

Treatment of acute CPPD disease is similar to that for acute gout (1). Symptoms of acute synovial effusion abate with synovial fluid drainage and intra-articular glucocorticoid injection (eg, 40 mg prednisolone acetate or prednisolone tertiary butylacetate into a knee).). Symptoms of acute synovial effusion abate with synovial fluid drainage and intra-articular glucocorticoid injection (eg, 40 mg prednisolone acetate or prednisolone tertiary butylacetate into a knee).

Indomethacin, naproxen, or another Indomethacin, naproxen, or anotherNSAID given at anti-inflammatory doses often stops acute flares. Colchicine use for treatment of acute flares is identical to that of gout. Colchicine 0.6 mg orally once a day or 2 times a day may decrease the frequency of recurrent acute flares. Oral glucocorticoids are effective at treating acute CPP arthritis flares and are particularly useful for patients in whom oral NSAIDs and colchicine are contraindicated. However, failure to resolve an acute flare may require a higher dose for a longer period of time. Interleukin-1 antagonists such as anakinra can also be effective. is identical to that of gout. Colchicine 0.6 mg orally once a day or 2 times a day may decrease the frequency of recurrent acute flares. Oral glucocorticoids are effective at treating acute CPP arthritis flares and are particularly useful for patients in whom oral NSAIDs and colchicine are contraindicated. However, failure to resolve an acute flare may require a higher dose for a longer period of time. Interleukin-1 antagonists such as anakinra can also be effective.

The prognosis for individual flares of acute CPPD disease is usually excellent. However, chronic arthritis can occur, and severe destructive arthropathy resembling neurogenic arthropathy (Charcot joints) occasionally occurs. Unlike gout, chronic CPP crystal arthritis is challenging to manage because there is no therapy that effectively eliminates or reduces the burden of CPP crystals.