Calcium Pyrophosphate Deposition Disease (CPPD) Imaging and Diagnosis

Calcium pyrophosphate deposition disease (CPPD) is a type of arthritis caused by the deposition of calcium pyrophosphate crystals. CPPD is divided into several varieties, primarily pseudogout and chondrocalcinosis. Synovial calcium pyrophosphate crystals, seen on polarizing microscopy, characterize pseudogout, an acute goutlike arthritis.  Flares can be characterized by acute joint pain, swelling, tenderness, and warmth. ^{[1, 2, 3, 4]}  CPPD has been reported to affect 4-7% of the adult population and is rare in persons younger than 60 years. In studies of radiographs of the knee, pelvis, and wrist, chondrocalcinosis has been identified in 44% of patients older than 84 years; with prevalence doubling with each decade after 60 years of age. ^{[5, 6, 7]}

Phosphate-to-pyrophosphate ratios less than 3 result in CPPD formation. When the ratio is greater than 100, hydroxyapatite crystals form. ^[8] This ratio is controlled by a balance between ank/ANKH, interference with ectonucleotide pyrophosphatase/phosdiesterase activity, a protein referred to as PiT-1, and tissue-nonspecific alkaline phosphatase. Formation of CPPD crystals requires pyrophosphate levels that are 10-40 times the normal serum levels.

Pseudogout is the most common form of CPPD disease, with patients typically presenting with the acute onset of monoarticular or oligoarticular arthritis. Most patients with chronic CPPD have polyarticular arthritis that resembles osteoarthritis. The crowned dens syndrome occurs around the C2 vertebra, and patients have acute severe neck pain, fever, and high levels of inflammatory markers. The crowned dens syndrome can be  confused with meningitis or sepsis. ^{[7, 5, 9, 10, 11, 12, 13]}

CPPD can be associated with metabolic disorders that increase the risk of calcium pyrophosphate deposition, such as hemochromatosis, hyperparathyroidism, hypophosphatemia, hypomagnesaemia, and hypothyroidism. Synovial fluid analysis is the gold standard for diagnosis, especially in the acute phase. Although there are no specific imaging  signs in the acute phase, imaging can still be important in the detection and differential diagnosis of chronic crystal arthropathies. ^{[14, 15, 16]}

Imaging modalities

Routine radiographs usually reveal the pathology of CPPD. Calcium pyrophosphate deposition disease is strongly suggested when findings indicative of degenerative osteoarthritis are observed in unusual locations, such as in the shoulder and elbow, which are non–weight-bearing joints that seldom manifest degenerative osteoarthritis. Radiologic examination confirms the presence of calcific shelves and concretions. Also noted are sharply defined cysts that communicate with the articular surface. The cysts have characteristic sclerotic margins.

Calcifications of chondrocalcinosis present on MRI as a signal void or decreased signal intensity, although increased T1-weighted signal intensity is rarely noted. ^{[17, 18]} High-field MRI is especially effective for visualization of CPPD deposits. ^[19]

Synovitis and calcific deposits may be noted on ultrasonography. A hypoechoic area may be found in the cartilage. ^{[20, 21, 22, 23, 24, 25, 26]}

Chondrocalcinosis is recognized as calcification within fibrous or hyaline cartilage structures. Radiologically, a dense line within the hyaline cartilage parallels the articular surface, often resulting in a calcified hyaline cartilage surface (see the images below). This can be recognized grossly as a calcified sheet reflecting over the articular surface and as concretions of calcium pyrophosphate exuded beyond the subchondral articular surface. Pseudogout and chondrocalcinosis may overlap with each other and with other varieties. ^[7]

Ultrasound (US) and CT have played an increasing role in the detection and differential diagnosis of crystal arthropathies. CT can identify the location, density, and morphology of the crystal deposits by means of volumetric reconstruction. ^{[14, 15, 16, 27, 28, 26]}

Other varieties appear ill defined and include a subgroup referred to as pseudorheumatoid. Periarticular metacarpophalangeal and interphalangeal joint calcification may be a component of that form of calcium pyrophosphate deposition disease (CPPD). Radiocarpal articular surface indentation (an unusual joint to be affected in osteoarthritis [OA]) is also considered evidence of CPPD, as are large subchondral cysts (ie, geodes), which rarely occur (see the images below).

Pseudorheumatoid CPPD has a polyarticular character. One variety of idiopathic CPPD with destructive peripheral arthritis has been reported. Bony fragmentation or a crumbling appearance, which may simulate a neuropathic joint, characterizes this variety (see the following image).

The skeletal and clinical distribution pattern of nonerosive components of primary calcium pyrophosphate deposition disease (CPPD) are shown in the table below.

Table 1. Distribution Pattern (%) of Nonerosive Component of Primary CPPD in Skeletal and Clinical Populations (Open Table in a new window)

Secondary calcium pyrophosphate deposition disease

The variety of CPPD is associated with rheumatoid arthritis or spondyloarthropathy. The distribution of CPPD in individuals with secondary CPPD (eg, rheumatoid arthritis, spondyloarthropathy) is identical to that noted in those with primary CPPD and is shown in the table below. Craniometaphyseal dysplasia is related to ANKH (a transmembrane protein) mutations. ^[8]

Table 2. Joint Distribution Pattern (%) of CPPD in Familial, Idiopathic, and Metabolic (eg, hemochromatosis [hemo] and ochronosis [ochro]) Varieties (Open Table in a new window)

Differentials and other problems to be considered

The differential diagnosis includes ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, gout, meniscal tears, neuropathic arthropathy (Charcot joint), Osgood-Schlatter disease, primary osteoarthritis, osteochondritis dissecans, osteochondroma and osteochondromatosis, classic and variant osteosarcomas, rheumatoid arthritis of the hands and spine, septic arthritis, spinal stenosis, and synovial osteochondromatosis.

Other conditions that should be considered are basic calcium phosphate crystal deposition, calcinosis, calcium oxalate arthritis, chondrosarcoma, erosive osteoarthritis, hydroxyapatite arthritis, joint replacement failure, juxtacortical chondroma, neoplasm, osteonecrosis, prosthetic joint breakdown, secondary osteoarthritis, spondyloarthropathy, and tumoral calcinosis.

Failure to differentiate CPPD from rheumatoid arthritis may expose the patient to the potential toxicity of cytotoxic drugs (eg, methotrexate) with no proven efficacy in treating CPPD.

Crowned dens syndrome (calcific deposits in the cruciform and alar ligaments surrounding the odontoid process of the second cervical vertebra [the dens], which appear as a 'crown' surrounding the top of the dens on imaging studies) may complicate CPPD. ^[13]  Haikal et al reported that cervical computed tomography (CT) scans revealed crowned dens syndrome in 34 of 57 patients with CPPD, and they recommended considering cervical CT in elderly patients with neck pain in the setting of CPPD. ^[29]

Routine radiographs usually reveal the pathology of calcium pyrophosphate deposition disease (CPPD). Recommendations from the European League Against Rheumatism suggest that radiographic chondrocalcinosis supports the diagnosis of CPPD, but its absence does not exclude it. ^[30] Chondrocalcinosis is recognized by calcification within fibrous or hyaline cartilage structures (as shown in the images below), which appears on radiographs as a dense line within the hyaline cartilage that parallels the articular surface. Grossly, this is recognized as a calcified sheet reflecting over the articular surface and as white, hard, 3- to 4-mm concretions of calcium pyrophosphate or hydroxyapatite exuded beyond the subchondral articular surface. A third variety presents with periarticular metacarpophalangeal and interphalangeal joint calcification.

Just as the CPPD pattern can mimic rheumatoid arthritis, it can also mimic osteoarthritis. Whereas the radiocarpal and metacarpophalangeal joints are usually not affected in osteoarthritis, osteoarthritis-like changes in these locations are highly suggestive of CPPD (as shown in the images below).

Large subchondral cysts (ie, geodes; see the image below) are also rarely noted in CPPD. The pseudorheumatoid variety of CPPD is an erosive disease. Another variety of CPPD is described as a destructive peripheral arthritis associated with bony fragmentation.

Calcium pyrophosphate deposition disease is strongly suggested when findings indicative of degenerative osteoarthritis are observed in unusual locations, such as in the shoulder and elbow, which are non–weight-bearing joints that seldom manifest degenerative osteoarthritis.

Indentation of the radiocarpal joint and joint space narrowing with sclerosis are indicators of CPPD (see the image below). Tendon calcification and fluffy calcification of soft tissue within joints or bursae may also occur. The latter, termed a tophus, is analogous to that occasionally found in gout.

Involvement of the spine in calcium pyrophosphate deposition disease manifests as calcification of the nucleus pulposus or anulus fibrosus (see the image below). The zygapophyseal and costovertebral joints are spared.

Disruption of cortical margins (ie, erosion) is present in approximately one eighth of patients with calcium pyrophosphate deposition disease, usually as an isolated phenomenon (see the image below).

Articular surface localization of erosion is site dependent. Although metacarpophalangeal, proximal interphalangeal, and distal interphalangeal erosions tend to occur subchondrally, involvement of other joints tends to be marginal (eg, bare area) in distribution. Subchondral erosions are not sharply defined; rather, they have a smudged appearance (see the images below).

The nonerosive component of calcium pyrophosphate deposition disease (CPPD) is symmetric in two thirds of patients, although typically pauciarticular (80%). CPPD predominantly affects knee, shoulder, wrist, and metacarpophalangeal joints in patterns reproducible across multiple populations.

The density of bone in the vicinity of joints is unchanged. Radiologic examination confirms the presence of calcific shelves and concretions. Also noted are sharply defined cysts that communicate with the articular surface. The cysts have characteristic sclerotic margins. Demonstrated communication of such lesions with the articular surfaces emphasizes that CPPD may have an erosive component.

Erosions of the pseudorheumatoid variety of calcium pyrophosphate deposition disease (ie, 5% of patients with CPPD) are essentially limited to the small joints of the hands and feet (see the image below). ^[31]

The table below delineates the distribution pattern of erosions in CPPD.

Table 3. Distribution Pattern (%) of Erosions in Patients With Primary CPPD (Open Table in a new window)

 

The crumbling lesions of pseudorheumatoid calcium pyrophosphate deposition disease differ from those of other varieties, which are predominantly marginal in location and affect only 1-2 joints (see the image below).

The joints affected (predominantly shoulder, metacarpophalangeal, proximal interphalangeal, distal interphalangeal) mirror those of the nonerosive component of CPPD. Although the lesions tend to be subchondral in distribution and without new bone formation, 8 joints are typically affected. However, the extent of nonerosive CPPD manifestations is more extensive than that observed in individuals with other CPPD patterns.

What has been previously called erosive osteoarthritis appears to be part of the spectrum of CPPD. The crumbling erosions are characteristic. ^[32]

Imaging pearls

Chondrocalcinosis is the radiographic finding most often associated with CPPD disease. Findings that help differentiate primary osteoarthritis from CPPD include hooklike osteophytes; axial skeletal involvement such as annulus fibrosis calcification, severe disc degeneration with the vacuum phenomenon and subchondral erosions, and the vacuum phenomenon of sacroiliac joints; radiocarpal- or patellofemoral-predominant narrowing of the joint space; subchondral cyst formation; severe articular destruction such as subchondral collapse, bony fragments, and microfractures; and tendon or fascial calcifications such as at the Achilles tendon, plantar fascia, gastrocnemius, quadriceps, rotator cuff, or triceps at the elbow or shoulder. ^{[7, 5, 9, 10, 11, 12]}

Aspiration of joint fluid may be necessary to identify the type of crystals. Radiologic findings may be within reference range in a patient with crystals documented with a polarizing microscopic examination of the joint fluid.

Chondrocalcinosis is pathognomonic for the calcium pyrophosphate deposition disease category. Some authors divide this into calcium pyrophosphate and hydroxyapatite varieties; however, because the crystals often co-occur, the term CPPD may be reasonable. Crumbling erosions and radiocarpal joint indentation are pathognomonic for CPPD.

Calcium pyrophosphate deposition disease is strongly suggested when findings indicative of degenerative osteoarthritis are observed in unusual locations, such as in the shoulder and elbow, which are non–weight-bearing joints that seldom manifest degenerative osteoarthritis. Isolated involvement of the patellofemoral joint is also suggestive.

The breakdown of joint prostheses may produce a radiodense linear pattern that mimics CPPD.

The pattern of calcium pyrophosphate deposition disease (CPPD) on CT scans may show a calcific mass with a lobulated configuration, typically in the ligamentum flavum or within the joint capsule. Within the mass are septumlike low-density areas. In addition, pressure erosions may be noted with disruption of adjacent bony cortex. Fine granular calcifications may also be noted. Subchondral cysts or erosions, as well as fractures (eg, odontoid), may be observed. ^[25]

Routine radiographs usually reveal CPPD more accurately. Also, the breakdown of prosthetic joints may produce linear patterns of radiodensity, mimicking CPPD.

Calcifications of chondrocalcinosis present on MRI as a signal void or decreased signal intensity, although increased T1-weighted signal intensity is rarely noted. ^{[17, 18]} High-field MRI is especially effective for visualization of CPPD deposits. ^[19]

T1-weighted images reveal low-signal intensity with punctate signal void. T2-weighted images vary in signal intensity, depending on crystal concentration and the amount of associated granulation tissue and fibrosis. Rim enhancement is rarely noted. Gadolinium-enhanced images demonstrate peripheral enhancement. An associated fracture produces lines of low signal intensity on both T1-weighted and T2-weighted spin echo, with marrow edema.

Gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. 

MRI has low sensitivity for detecting calcification but can display massive deposition. Because MRI does not visualize calcific structures well, CT scanning or radiographic confirmation is required. In addition, the breakdown of prosthetic joints may produce signal deficits that suggest calcific deposits. MRI findings may also mimic a meniscal tear.

Synovitis and calcific deposits may be noted on ultrasonography. A hypoechoic area may be found in the cartilage. ^{[20, 21, 22, 23, 24, 25]}

The European League Against Rheumatism’s systematic review of research evidence suggests that ultrasonography of the knee is sensitive and specific for detecting CPPD crystals and may be more effective than conventional radiographs. ^[30]

Ultrasound joint surveys reveal that CPPD involves at least 2 sites (mean = 4 sites). ^[33]

A study by Cipolletta et al supports the diagnostic accuracy of US in evaluating wrist involvement in CPPD. Evaluation of 200 wrists, in 61 patients and 39 controls, using both conventional radiography and US, showed that US had sensitivity of 0.95 (0.86-0.99), specificity of 0.85 (0.69-0.94), and diagnostic accuracy of  0.91 (0.84-0.96); figures for conventional radiography were 72 (0.59-0.83), 1.0 (0.91-1.0), and 0.83 (0.74-0.90), respectively. ^[34]  Similar results were reported by Forien and colleagues in a study of 32 CPPD patients and 26 controls. US had a sensitivity of 94% and specificity of 85%, as compared to radiographic sensitivity of 53.1% and specificity of 100%. ^[35]

In anecdotal reports in the literature, amplitude Doppler or power Doppler ultrasonography has been used to evaluate the synovial hyperemia associated with inflammation in calcium pyrophosphate deposition disease arthropathy in the hands. The degree of abnormal blood flow on Doppler ultrasonograms appears to be in proportion to the severity of the clinical manifestations.

Uptake of bone-seeking radiopharmaceuticals (such as technetium-99m [^99mTc]–labeled diphosphonate) is prominent in affected joints. Extraosseous calcific deposits may also take up the radioisotope.

Nuclear imaging procedures are highly sensitive; however, they lack specificity in this setting. In addition, any cause of localized tissue hyperemia results in increased deposition of radiotracer within the bone and joints. Recent joint trauma or surgery or any type of arthritis may produce essentially identical results.