Calcium pyrophosphate arthritis (CPP arthritis) involves intra-articular and/or extra-articular deposition of calcium pyrophosphate dihydrate (CPPD) crystals. Manifestations are protean and may be minimal or include intermittent flares of acute arthritis, termed pseudogout or acute CPP arthritis, and a degenerative arthropathy that is often severe. Diagnosis requires identification of CPPD crystals in synovial fluid. Treatment of pseudogout flares is with intra-articular corticosteroids or oral glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine.
(See also Overview of Crystal-Induced Arthritides.)
CPPD crystal deposition (chondrocalcinosis, pyrophosphate arthropathy), whether symptomatic and asymptomatic, becomes more common with age.
Asymptomatic chondrocalcinosis is common in the knee, metacarpophalangeal joints, hip, wrist, annulus fibrosus of the intervertebral disks, symphysis pubis, and spine. Men and women are affected about equally. The incidental detection of chondrocalcinosis on plain x-rays or other imaging does not mean that the patient should be treated for CPP arthritis.
Etiology of Calcium Pyrophosphate Arthritis
The cause of CPP arthritis is unknown. CPP arthritis is frequently 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 dihydrate (CPPD) 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 CPPD crystal formation. ANK protein is a transporter of intracellular and microvesicle pyrophosphate to the extracellular location where CPPD crystals form.
Symptoms and Signs of Calcium Pyrophosphate Arthritis
Acute, subacute, or chronic arthritis can occur, usually in the knee, wrist, or other large peripheral joints; thus, calcium pyrophosphate crystal disease can mimic many other forms of arthritis. 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 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.
Diagnosis of Calcium Pyrophosphate Arthritis
Synovial fluid analysis
Identification of crystals microscopically
CPP arthritis should be suspected in older patients with arthritis, particularly those with a history of recurrent inflammatory arthritis.
BIOPHOTO ASSOCIATES/SCIENCE PHOTO LIBRARY
Image courtesy of Brian Mandell, MD.
Diagnosis of CPP 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 ruled out based on Gram stain and culture findings. Gout is best ruled out by the absence of urate crystals in fluid from the inflamed joint. Notably a patient may have both gout and CPP arthritis. X-rays 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.
Prognosis for Calcium Pyrophosphate Arthritis
The prognosis for individual flares of acute CPP arthritis is usually excellent. However, chronic arthritis can occur, and severe destructive arthropathy resembling neurogenic arthropathy (Charcot joints) occasionally occurs. Unlike gout, chronic CPP arthritis is challenging to manage because there is no therapy that effectively eliminates or reduces the burden of CPPD crystals. Patients, especially younger ones, who have frequent CPPD flares should be evaluated for underlying triggers and diseases.
Treatment of Calcium Pyrophosphate Arthritis
Intra-articular corticosteroids
Oral corticosteroids (eg, prednisone, methylprednisolone)
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Colchicine
Interleukin-1 (IL-1) antagonists (eg, anakinra)
Treatment of acute CPP arthritis is similar to that for acute gout. Symptoms of acute synovial effusion abate with synovial fluid drainage and instillation of a microcrystalline corticosteroid ester suspension into the joint space (eg, 40 mg prednisolone acetate or prednisolone tertiary butylacetate into a knee).
Indomethacin, naproxen, or another NSAID given at anti-inflammatory doses often stops acute flares. Colchicine 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 corticosteroids 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.
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Asymptomatic chondrocalcinosis becomes more common with age, particularly in the knee, hip, wrist, annulus fibrosus of the intervertebral disks, and symphysis pubis but does not require treatment.
CPP arthritis can affect the knee and large peripheral joints and mimic other forms of arthritis (eg, gout, rheumatoid arthritis, osteoarthritis).
Examine joint fluid for characteristic rhomboid- or rod-shaped crystals in synovial fluid that are not birefringent or are weakly positively birefringent, and exclude joint infection.
For acute symptoms, treat with an intra-articular corticosteroid, an oral NSAID, colchicine, or oral corticosteroids; anakinra can also be effective.
