Calcium Pyrophoshate Dihydrate Crystal Deposition Disease (CPPD)Dz

Synonyms: Pseudogout, chondrocalcinosis, pyrophosphate arthropathy.

ICD-9 Codes: Pseudogout, 712.2; CPPD crystal deposition disease, 712.2; chondrocalcinosis, 712.3.

Definition: CPPD crystal deposition disease includes arthritic syndromes associated with CPPD crystal deposition disease in articular tissues. The following definitions are used here:

—Chondrocalcinosis: Calcification of articular cartilage (identified by x-ray).

—Chronic CPPD crystal deposition disease: Structural bone and cartilage abnormalities associated with intraarticular deposition of CPPD crystals.

—Pseudogout: Clinical syndrome of acute synovitis caused by intraarticular CPPD crystal deposition, the most common form of CPPD crystal deposition disease.

Etiology: The cause of CPPD crystal deposition disease is unknown. Formation of CPPD crystals in cartilage may be related to matrix changes or result from elevated levels of calcium or inorganic pyrophosphate. Some cases appear to be hereditary, whereas others are idiopathic.

Pathology: CPPD crystals are found in joint capsules and fibrocartilaginous structures. The earliest deposition is seen at the lacunar margin of chondrocytes. Neutrophils can be seen invading matrix structures, with erosion of cartilage and degradation of collagen fibrils. Synovial proliferation can resemble rheumatoid pannus.

Demographics: Data on CPPD crystal deposition disease are largely derived from radiographic surveys of chondrocalcinosis of the knee. Predominantly a condition of the elderly, it has a peak age of 65 to 75 years and female predominance (F:M ratio, 2–7:1). The prevalence of chondrocalcinosis in the general population is 5% to 8% and increases to >15% by the ninth decade. It is ubiquitous in geographic distribution. Familial predisposition has been reported in several groups, some of whom have early-onset, severe, polyarticular disease (third to fourth decades).

Disease Associations: Several conditions are associated with CPPD crystal deposition disease: hyperparathyroidism, hypocalciuria, hypercalcemia, hemochromatosis, hemosiderosis, hypophosphatasia, hypomagnesemia, hypothyroidism, gout, neuropathic joints, amyloidosis, trauma, OA, and aging.

Cardinal Findings: Findings vary according to the type of disease.

—Pseudogout: Pseudogout often begins as self-limited acute arthritic attacks lasting from 1 day to 4 weeks and may be as severe as and resemble acute gout. Attacks are often provoked by concurrent medical illnesses or surgery. The knee joint is involved in 50% of cases, followed by the wrist, shoulder, ankle, and elbow. Podagra (first metatarsophalangeal arthritis) has been reported. Patients are asymptomatic between attacks. Men are predominantly affected. As many 20% have concurrent hyperuricemia, and 5% have monosodium urate crystals in synovial fluid as well. The diagnosis is suggested by the clinical presentation and confirmed by synovial fluid analysis (CPPD crystals) or radiography (chondrocalcinosis).

—Chronic CPPD crystal deposition disease: Chronic CPPD crystal deposition disease predominantly affects women as a chronic, progressive, often symmetric polyarthritis affecting the knees (most common) but also the wrists, metacarpophalangeal (especially second and third) joints, hips, spine, shoulder, elbows, and ankles. Some patients have episodic pseudogout. Patients typically have chronic pain, morning and inactivity stiffness, limitation of movement, and functional impairment. Symptoms may be restricted to a few joints. Affected joints reveal signs of OA with varying degrees of synovitis. Variations in compartmental knee involvement may cause valgus or varus deformities. Chronic CPPD crystal deposition disease differs from pseudogout in its chronicity, tendency to affect the metacarpophalangeal joints and spine, and the pattern of progressive OA with intermittent inflammation/synovitis.

—Chondrocalcinosis: Generally an incidental radiographic finding, chondrocalcinosis is usually seen in asymptomatic individuals, typically in the elderly.

Uncommon Findings: Severe synovitis in chronic CPPD crystal deposition disease may produce a pseudorheumatoid pattern. Charcot-like arthropathy of the knee has been ascribed to CPPD crystal deposition disease in some patients. Rarely, a predominantly axial pattern is seen, simulating AS. Tendinitis, tenosynovitis, bursitis, and tophaceous CPPD crystal deposition may occur.

Diagnostic Tests: Synovial fluid usually shows a mean leukocyte count of 20,000/mm3 with >90% neutrophils, and blood-tinged effusions may be seen. Compensated polarized light microscopy reveals rhomboidal or rod-like intracellular crystals with weakly positive birefringence. In pseudogout, joint fluid should always be sent for Gram and culture to exclude a septic process.

An increase in acute-phase reactants (ESR or CRP) can be seen along with an elevated leukocyte count, but these are not diagnostic. In chronic arthropathy, an elevated serum ferritin level and a mild anemia are not uncommon. Routine screening for metabolic causes of CPPD crystal deposition disease should be reserved for those with early-onset arthritis (age <55 years), florid polyarticular disease, or recurrent acute attacks out of proportion to the degree of chronic arthropathy. In such patients, the following screening tests are suggested: serum calcium, serum alkaline phosphatase, serum magnesium, and serum ferritin levels and tests of liver function.

Imaging: Calcification of articular fibrocartilage may be visible as punctate and linear densities, most frequently seen in the fibrocartilaginous menisci of the knee. Other sites of calcification include the articular discs of the distal radioulnar joint (triangular fibrocartilage), the symphysis pubis, the glenoid and acetabular labra, and the annulus fibrosus of the intervertebral discs. Calcification of hyaline cartilage occurs in the midzonal layer, appearing as a radiopaque line that runs parallel to the cortex of the underlying bone. Typically, the larger joints are involved. Degenerative arthropathy is similar to that observed in OA, with visible subchondral cysts, sclerosis, osteophytes, and joint space narrowing, all of which are often pronounced.

Keys to Diagnosis

—Pseudogout: The presence of an acute synovitis in one or a few joints, with radiographic chondrocalcinosis and/or synovial CPPD crystals strongly suggests pseudogout. Synovial fluid may be purulent, mandating exclusion of sepsis (which may coexist).

—Chronic CPPD crystal deposition disease: In most cases, a characteristic joint pattern, radiographic findings, and CPPD crystals in joint fluid easily establish a diagnosis. Polyarticular involvement with modestly elevated ESR and RF may cause confusion with RA. The infrequency of systemic features, lack of radiographic erosions, and periarticular osteopenia often permit differentiation from RA. Differentiation from OA is possible by involvement of metacarpophalangeal joints, radiographic findings, and the presence of superimposed acute attacks.

Diagnostic Criteria: See Table 7.

Differential Diagnosis: Pseudogout and CPPD crystal deposition disease may be misdiagnosed as gout, pseudogout, OA, septic arthritis, inflammatory OA, neuropathic arthritis, or hypertrophic osteoarthropathy.

Therapy

—Pseudogout: General principles of management include relief of symptoms, identification and treatment of triggering illnesses, and rapid mobilization. Although aspiration alone can relieve symptoms, intraarticular steroid injection is appropriate, either concurrently with the first aspiration or after Gram staining and culture results are negative. Acetaminophen or NSAIDs can be of additional benefit. Colchicine (see p. 437) may be used as acute therapy for pseudogout but is rarely necessary. Colchicine may also be useful as prophylaxis in those with recurrent attacks of pseudogout. Systemic corticosteroids can be used if other treatments are contraindicated, although their efficacy remains untested in controlled trials.

—Chronic CPPD crystal deposition disease: No specific therapy exists for chronic CPPD crystal deposition disease, and treatment of any underlying metabolic abnormalities usually does not reverse joint damage. The aims of management are to relieve symptoms and improve function. Chronic NSAID or colchicine therapy may be effective. Troublesome individual joints can be managed with injection of intraarticular steroids. Joint arthroplasty may eventually be needed.

Prognosis: Although pseudogout usually responds well to therapy, chronic CPPD crystal deposition disease is often progressive and in some may lead to significant disability and deformity.

BIBLIOGRAPHY

Agudelo CA, Wise CM. Crystal-associated arthritis in the elderly. Rheum Dis Clin North Am 2000;26:527–546.PMID:10989511

Doherty M. Calcium pyrophosphate dihydrate crystal-associated arthropathy. In: Hochberg MC, Silman AJ, Smolen JS, et al., eds. Rheumatology, 3rd ed. Edinburgh: Mosby, 2003:1937–1050.