Clinical Presentation and Epidemiology

CPPD comprises a clinically heterogeneous group of arthritides caused by the presence of calcium pyrophosphate (CPP) crystals in articular tissues ( Fig. 1 ). CPP crystals produce a vigorous inflammatory response under certain conditions but are also present in noninflammatory settings. For example, CPP crystals were seen in 20% of unselected samples of cartilage and synovium examined at the time of knee replacement for osteoarthritis (OA). The presence of CPP crystals is often suggested by the finding of chondrocalcinosis on radiographs of affected joints. Chondrocalcinosis typically appears as finely stippled lines of calcification in fibrocartilages such as menisci ( Fig. 2 ), or outlines the bony contours in hyaline articular cartilage ( Fig. 3 ).

CPPD crystals seen under polarizing light microscopy. These crystals appear as weakly positive birefringent rhomboidal crystals.

Radiographic chondrocalcinosis. Dense deposits of CPPD are seen in this knee radiograph in the fibrocartilage of the meniscus.

Radiographic chondrocalcinosis. Dense deposits of CPPD are seen outlining the contours of the articular cartilage in this knee radiograph.

The most commonly recognized clinical manifestation of CPPD is an acute inflammatory monoarthritis or oligoarthritis resembling gout. In acute CPPD (formerly known as pseudogout), the affected joint is erythematous and swollen, and synovial fluids can be inflammatory. The knee is the most commonly affected joint in acute CPPD. CPPD also presents as a chronic noninflammatory arthritis similar to OA, although it often affects joints rarely affected in typical OA, such as shoulders, wrists, metacarpophalangeal joints, and ankles. Patients with CPPD may or may not have intermittent episodes of inflammation in these areas. Polyarticular chronic inflammatory involvement in CPPD may resemble rheumatoid arthritis. Unusual presentations of CPPD similar to those of neuropathic arthropathy have also been described. Although tophaceous deposits of CPPD are unusual, they can be particularly symptomatic in the axial skeleton.

Advanced age is the major risk factor for CPPD, and idiopathic CPPD is unusual in patients younger than 60 years of age. Familial forms of CPPD are well-described. CPPD also occurs in association with a small number of metabolic diseases, including hyperparathyroidism, hemochromatosis, hypomagnesemia, and hypophosphatasia. The association between CPPD and other common comorbidities such as diabetes, renal disease, and hypothyroidism, require further study for confirmation.

Diagnostic Modalities

Because the clinical picture of CPPD may resemble other forms of arthritis, much of the challenge in management of CPPD lies in making an accurate diagnosis. The radiographic finding of chondrocalcinosis is suggestive but not diagnostic of the disease. Isolated chondrocalcinosis developing after meniscal tears in the knee is well-described and is of uncertain clinical significance. In addition, CPP crystals are often seen in synovial fluids of joints without radiographically apparent chondrocalcinosis. Indeed, in histopathologic studies, chondrocalcinosis was present in only about 37% of subjects with articular CPP crystals.

Diagnostic criteria for CPPD were proposed by Ryan and McCarty. Although the presence of rhomboidal, positively-birefringent crystals in synovial fluid (see Fig. 1 ) is relied on to confirm this diagnosis, the presence of severe OA with an unusual distribution in addition to key radiographic findings may strongly suggest CPPD. CPP crystals in synovial fluids can be difficult to identify because they are often quite small and only weakly birefringent. Accurate and reproducible identification of CPP crystals in synovial fluid samples requires some expertise and careful thorough examinations of the samples.

Studies including plain radiography, ultrasonography, and advanced imaging techniques such as CT and MRI scans can be suggestive of CPPD. In addition to chondrocalcinosis (see Figs. 2 and 3 ), CPPD is suggested by radiocarpal or patellofemoral predominant joint space narrowing, large or numerous subchondral cysts, severe progressive joint degeneration with bony collapse and fragmentation, variable osteophyte formation, tendon calcification, and unusual axial skeleton involvement. The increasing use of musculoskeletal ultrasound as a readily available bedside technique provides an additional diagnostic tool for crystal arthritis. The double contour sign may correlate with radiographic chondrocalcinosis and small bright objects in synovial fluid may reflect clusters of CPP crystals. Ultrasound may be a useful screening tool to prompt studies that are more specific and may assist in more accurate and successful arthrocentesis. MRI is relatively insensitive to CPP deposits and presents particular difficulties in distinguishing tears and calcium deposits in menisci. CT scanning more effectively identifies calcified deposits but is not commonly used to image painful joints.

Causal Influences in Therapy

Although there is still much to learn about the pathogenesis of CPPD, it can be conceptualized in three stages. In the first stage, CPP crystals develop in the pericellular matrix of articular cartilage. It is known that overproduction of the anionic component of the crystal, pyrophosphate (PPi), is required for CPP crystals to be generated and that PPi in CPPD is analogous to the urate anion in gout. Less is known about the influence of calcium levels and the extracellular matrix changes that are necessary for the generation of CPP crystals. Probenecid may block PPi production by chondrocytes through its actions on the progressive ankylosis gene product commonly known as ANK. ANK is a putative PPi transporter. Magnesium is a cofactor for PPi degrading enzymes and correction of low levels may increase PPi hydrolysis and reduce levels of PPi available for crystal formation. Drugs that increase alkaline phosphatase may also reduce PPi levels. Ongoing work to understand PPi transport and the role of ANK in CPPD will ultimately result in novel therapies that block PPi production; however, at present, no therapies are available that clearly interfere with this stage of the disease. The presence of mineralized matrix likely alters cartilage biomechanics and may initiate or accelerate articular damage during this early phase.

In the next phase of this disease, CPPD crystals are mined or released from the cartilage surface and may elicit an inflammatory response though innate immune pathways as well as by interacting with other inflammatory cells. Colchicine and antiinflammatory medications, particularly those targeted at interleukin (IL)-1β, may be useful in this phase of the disease. During the third phase of disease, crystals accelerate cartilage degeneration through mechanical strain and wear, and through other actions on articular chondrocytes and synoviocytes. Although no therapies are currently available to affect crystal interactions with cells, work in vitro with phosphocitrate suggests the crystal–articular cell interaction may represent a rich source of potential therapeutic targets.

This section discusses the current recommendations for management of CPPD. An excellent review of CPPD management strategies based on a consensus from experts across Europe was recently published that summarizes the commonly used medications for CPPD and clearly identifies multiple areas needing further study.

Acute CPPD

Acute CPPD is treated in a similar manner to acute gouty arthritis. The mainstays of pharmacologic therapy are intraarticular corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and colchicine. The relative effectiveness of these therapies has not been studied and, typically, therapeutic decisions are based on the safety of these interventions in the context of individual patient comorbidities and preferences of the provider. There is some evidence supporting the effectiveness of intraarticular corticosteroid injections in acute CPPD. Oral colchicine is also commonly used, but has not been well studied. Because the dose recommendations for acute gout have dramatically changed the way colchicine is used, studies of similar low-dose short-term regimens in acute CPPD are warranted. The use of NSAIDs in acute CPPD is extrapolated from the gout literature but advanced patient age and common comorbidities in CPPD patients often increase the risk of these drugs. Oral corticosteroids have seen a resurgence in use for crystal arthropathies in general. The IL-1β inhibitor, anakinra, has been useful in some patients with acute CPPD. A recent case series of 16 subjects who were otherwise refractory and intolerant of other treatments describes anakinra treatment of CPPD. The mean number of injections was 15 (±42.9) and relapse occurred in one-third. Most subjects had a good response, but certainly the cost and side effects of this and similar medications may limit their widespread use. Similarly, canakinumab, an IL-1β inhibitor with a different mechanism of action than anakinra that has been tested in clinical trials for acute gout, may also have some efficacy in CPPD.

Nonpharmacologic therapies are often used adjunctively in CPPD but, again, have not been rigorously compared with other therapies. Arthrocentesis, with or without lavage, may reduce the burden of both crystals and inflammatory mediators and would logically improve symptoms. Heat, ice, and rest may be useful and pain medications including narcotics may be indicated for short-term relief. Complementary or alternative treatments such as green tea polyphenols may eventually be useful based on their antiinflammatory effects in vitro.

Chronic Inflammatory CPPD

The chronic inflammatory form of CPPD with either a polyarticular inflammatory presentation or an OA-like presentation with episodic inflammation can be particularly challenging to treat. These patients often suffer from frequent attacks and may have significant pain between attacks of inflammation. NSAIDs may help in those patients able to tolerate them. Systemic corticosteroids are also used and may be effective, despite serious long-term side effects. There is some weak evidence to support the use of long-term low-dose oral colchicine, although its current cost makes this option more difficult for many patients. Long-term corticosteroids, despite the high risk of side effects, are necessary in some patients. There is some evidence supporting the use of methotrexate in patients with recurrent inflammatory attacks and scattered case reports using IL-1β blockade. Less evidence supports the use of hydroxychloroquine, magnesium, probenecid, or other long-term antiinflammatory strategies.

If a single or a few large joints are involved in chronic CPPD, joint replacement may be helpful. A recent report suggests similar outcomes in unicompartmental knee arthroplasty in those with and without radiographic chondrocalcinosis. Heat, ice, and physical therapy to maintain strength and flexibility in the muscles and soft tissues around the joints may also be useful adjuncts.

Chronic Noninflammatory CPPD

Chronic noninflammatory CPPD is typically managed with similar strategies used for the treatment of OA. The mainstays of pharmacologic therapy for OA include intraarticular corticosteroids, acetaminophen, NSAIDs, and pain medications. Acetaminophen or NSAIDs, as tolerated, are first-line therapies for patients whose joint involvement precludes use of intraarticular corticosteroids. Hyaluronan injections are relatively contraindicated in CPPD because acute crystal arthritis has been associated with their use. Colchicine may be useful in some patients with OA, but has not been well studied in chronic noninflammatory CPPD. Some patients may require more aggressive pain regimens, including narcotics. Whether recently approved therapies for OA such as duloxetine would be helpful in this form of CPPD is not-known. Emerging strategies include drugs that block nerve growth factor, which may soon be available for patients suffering from OA and may have some efficacy in CPPD.

Heat, ice, and physical therapy are useful adjunctive strategies for some patients. Joint replacement surgery can be effective long-term treatment of large joint involvement.

Summary of CPPD

In summary, therapies are borrowed from acute gout, rheumatoid arthritis, and OA to manage various forms of CPPD. This underscores the need for more specific and effective pharmacologic therapies for CPPD. It is hoped that an improved understanding of the cause of CPPD will lead to the development of novel treatments or preventive strategies that interfere with the early stages of this disease before extensive joint damage occurs. Careful attention to diagnosis and large population-based studies of risk factors and current treatment patterns will provide an improved evidence base on which to make treatment decisions.