Calcium pyrophosphate deposition disease (CPDD) is a metabolic arthropathy caused by the deposition of calcium pyrophosphate dihydrate in and around joints, especially in articular cartilage and fibrocartilage (see the images below).[1] Although CPDD is often asymptomatic, with only radiographic changes seen (ie, chondrocalcinosis), various clinical manifestations may occur, including acute (pseudogout) and chronic arthritis. (See Etiology, Presentation, and Workup.)
View Image | Calcium pyrophosphate deposition disease. Radiograph of the knee showing chondrocalcinosis involving the meniscal cartilage, as well as evidence of os.... |
View Image | Calcium pyrophosphate deposition disease. Radiograph of the wrist and hand showing chondrocalcinosis of the articular disc of the wrist and atypical o.... |
Almost any joint may be involved by CPDD, although the knees, wrists, and hips are most often affected. This condition is the most common cause of secondary metabolic osteoarthritis. (See Presentation.)
According to McCarty, the five most common presentations of CPDD are as follows:
Patients with CPDD can experience significant morbidity due to the pain of an acute attack of pseudogout or to symptoms of chronic arthropathy. Treatment of symptomatic CPDD is important to prevent further end-organ damage, but it cannot reverse the joint disease.
For patient education information, see the Arthritis Center, as well as Knee Pain.
Although the exact mechanism for the development of CPDD remains unknown, increased adenosine triphosphate breakdown with resultant increased inorganic pyrophosphate in the joints results from aging, genetic factors, or both. Changes in the cartilage matrix may play an important role in promoting CPPD deposition. Rare hereditary forms of CPDD occur, generally inherited in an autosomal dominant mode.
Overactivity of enzymes that break down triphosphates, such as nucleoside triphosphate pyrophosphohydrolase, has been observed in the cartilage of patients with CPDD. Therefore, inorganic pyrophosphate can bind calcium, leading to CPPD deposition in the cartilage and synovium.[2, 3] Hyaline cartilage is affected most commonly, but fibrocartilage, such as the meniscal cartilage of the knee, can also be involved.[4]
Hypotheses based on in vitro studies propose that pyrophosphohydrolase activity and inorganic phosphate content, as noted above, are generalized phenomena that occur in fibroblasts.[5] Although these phenomena are generalized, the reason they occur only in joints remains unknown.
Genetic defects have been identified as specific gene mutations in a few kindred families.[6, 7] The mutations were in the genes ANKH and COL, which may be involved in crystal-induced inflammation. This is related to synovial tissue and direct cartilage activation, leading to the arthritis caused by CPPD. The ANKH protein is involved in transport of inorganic pyrophosphate (PPi), which regulates calcification, bone mineralization, and bone resorption.[8]
The gene TNFRSF11B encodes osteoprotegerin, which has a critical role in regulating osteoclast development. In a study of patients with familial osteoarthritis with chondrocalcinosis, Ramos et al identified a mutation in TNFRSF11B that results in a form of osteoprotegerin with enhanced capacity to inhibit osteoclastogenesis and bone resorption.[9]
Subsequent messenger RNA expression analysis of the relevant genes in this pathway, in articular cartilage of independent patients undergoing joint replacement surgery for osteoarthritis, showed that upregulation of TNFRSF11B is a general phenomenon in the pathophysiological process of osteoarthritis.[9]
CPDD is a common condition that occurs with aging in all races. In a retrospective study of 1070 consecutive computed tomographic scans of the abdomen and pelvis in patients over 65 years of age, the prevalence of symphysis pubis chondrocalcinosis was 21.1%.[10] Nearly 50% of people older than 85 years have radiologic evidence of chondrocalcinosis.
CPDD is slightly more common in women than in men. The exact female-to-male ratio is unknown but is probably 1.4:1.
CPDD usually occurs in individuals who are in the fifth decade of life or older, with increasing prevalence as age increases. When it occurs early, before the fourth decade of life, it is usually associated with a secondary cause, such as an underlying metabolic disease, or with a familial cause.
In a cross-sectional study in the national Veterans Affairs (VA) population that included 25,157 patients with CPDD, the strongest positive associations with CPDD were as follows[11] :
In addition, positive associations were seen with osteoporosis (OR 1.26), hypomagnesemia (OR 1.23), chronic kidney disease (OR 1.12), and calcium supplementation (OR 1.15). Negative associations were seen with use of proton-pump inhibitors or loop diuretics.[11]
Presentations of calcium pyrophosphate deposition disease (CPDD) include the following:
This is usually associated with radiographic findings of chondrocalcinosis in the absence of clinical manifestations and may be the most common form of CPDD.
The classic radiologic findings include chondrocalcinosis of the hyaline cartilage and fibrocartilage of the knees, the fibrocartilage of the triangular ligament of the wrist, the fibrocartilage of the symphysis pubis, and the acetabulum labrum of the hips.
Acute pseudogout is characterized by acute monoarticular or oligoarticular arthritis. Pseudogout usually involves the knee or the wrist, although almost any joint can be involved, including the first metatarsophalangeal (MTP) joint, as occurs in patients with gout. This form of CPDD accounts for 25% of cases. Glucose levels are usually normal.
Clinical manifestations are similar to those of acute gouty arthritis—typically an acute monoarthritis with pain and swelling—although generally not as intense. Polyarticular attacks may occur on occasion. Pseudogout may be precipitated by medical illness such as myocardial infarction, congestive heart failure, or stroke or may occur after surgery. Trauma may also be a precipitating factor. Events that affect serum calcium levels also may precipitate attacks of pseudogout.
Occasionally, pseudogout may present as a pseudoseptic syndrome with acute arthritis, fever, and leukocytosis with a left shift.
Pseudo-osteoarthritis often involves the metacarpophalangeal (MCP) joints, wrists, elbows, and shoulders, joints unlikely to be involved in primary osteoarthritis. It affects the knees most commonly and can involve the proximal interphalangeal (PIP) joints and spine, as occurs in patients with primary osteoarthritis. This form of CPDD accounts for 50% of all cases. Approximately half of these patients also have associated pseudogout.
This pattern is found in approximately 5% of patients with CPDD and is associated with symmetrical inflammation of the PIP and MCP joints. Clinically, these patients complain of morning stiffness and joint swelling.
Neuropathic-like arthropathy, which is observed in fewer than 5% of patients with CPDD, most commonly involves the knee. This is a severe, destructive arthropathy. Unlike true neuropathic arthropathy, no clear underlying neurologic disorder is present. The presence of chondrocalcinosis can aid in making the diagnosis.
The physical examination findings vary depending on the form of CPDD in a given patient, who may present with an acute arthritis or different patterns of chronic arthritis.
Physical examination findings show an acutely inflamed joint with swelling, effusion, warmth, tenderness, and pain on range of motion similar to acute gouty arthritis. This typically occurs in the knee but may be present in the wrists, shoulders, ankles, hands, and feet.
Physical examination findings show a picture similar to osteoarthritis, sometimes with an unusual joint predilection. If a patient has osteoarthritis involving the MCP joints and wrists, consider CPDD associated with an underlying metabolic disease.
Physical examination findings show a picture similar to rheumatoid arthritis with synovitis in a symmetrical, polyarticular pattern, especially involving the wrists and MCP joints.
Common complications from CPDD include acute synovitis and chronic degenerative arthritis, which is expected from the various phenotypes (ie, pseudogout, pseudo-osteoarthritis, pseudorheumatoid arthritis). Joint destruction from a neuropathic-like arthropathy is very rare. In addition, case reports of invasive (tumoral or tophaceous) CPDD have been reported. Kudoh et al reported a case of tophaceous pseudogout of the temporomandibular joint extending to the base of the skull in a 38-year-old man.[12] Tumoral pseudogout of a PIP (proximal interphalangeal joint) with an enlarging calcified mass and secondary bony erosion was reported by Park et al.[13]
Coexistent infection with CPDD is a complication but the occurence rate for this is not established. However, evaluation for coexistent infection should be performed when clinically indicated. Tuberculosis of the wrist accompanied by calcium pyrophosphate deposition was reported by Watanabe et al.[14]
Crowned dens syndrome (calcific deposits around the dens in the transverse ligament of the atlas and alar ligaments) is a rare complication of CPDD. Tedeschi et al reported a case of crowned dens syndrome with myelodysplastic syndrome (MDS) in a 75-year-old man; the authors hypothesize that this was paraneoplastic pseudogout secondary to MDS.[15]
Revised diagnostic criteria for calcium pyrophosphate deposition disease (CPDD) are from the Primer on Rheumatic Diseases (1997) and are used with permission from the Arthritis Foundation. The criteria are as follows[16] :
In criterion IIIb, chronic arthritis shows the following features, which are helpful in differentiating it from osteoarthritis:
Criteria-based categories include the following:
Arthrocentesis is the most important procedure to perform, especially in patients with acute pseudogout. The acquired fluid can be examined using compensated polarized microscopy, and fluid cultures can be performed.
Histologic changes associated with CPDD correspond to calcium deposits and to inflammation due to cartilage fragments. These changes are nonspecific, but calcium deposits inside the chondrocartilage are perhaps the most typical finding in patients with this condition. The pathognomonic finding with compensated polarized microscopy is the presence of weakly positively birefringent crystals, typically intracellular, that are usually rhomboid in shape.
A number of conditions have been associated with CPDD. When CPDD is diagnosed, especially in a patient younger than 60 years, a metabolic workup should be performed. The following metabolic conditions have definite associations with CPDD[11] :
Hypothyroidism has a probable association with CPDD, so thyroid function testing should be included in the metabolic workup.[17]
General laboratory studies usually are not helpful in calcium pyrophosphate deposition disease (CPDD). The white blood cell (WBC) count and erythrocyte sedimentation rate (ESR) may be elevated.
Evaluating for an underlying metabolic disease (eg, hemochromatosis, hyperparathyroidism, hypothyroidism) is reasonable, especially in younger patients. Hypomagnesemia—and even low-normal serum magnesium levels—has been associated with a higher prevalence of knee chondrocalcinosis.[18] Laboratory tests can include the following:
Occasionally, pseudogout may present as a pseudoseptic syndrome with acute arthritis, fever, and leukocytosis with a left shift.
The diagnosis of acute pseudogout is made by performing compensated polarized microscopy after aspiration of fluid from the involved joint. The most commonly involved joint is the knee, followed by the wrist, the MCP joints, the elbows, and the MTP joints. Centrifugation of the synovial fluid sample may improve identification of calcium pyrophosphate crystals.[19]
The crystals are rhomboid-shaped, weakly positively birefringent, and difficult to see. If intracellular, an acute attack of pseudogout is strongly suggested. Aspiration of the fluid from affected joints during an acute attack usually yields mildly to moderately inflammatory fluid, with 10,000-50,000 WBCs/µL, more than 90% of which are neutrophils. (See the images below.)
View Image | Calcium pyrophosphate deposition disease. Appearance of calcium pyrophosphate dihydrate crystals obtained from the knee of a patient with pseudogout. .... |
View Image | Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The bla.... |
View Image | Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The cry.... |
Gout and pseudogout can coexist, even in the same joint; therefore, the presence of gout does not rule out the possibility of pseudogout and vice versa. Ultrasonography may be helpful in diagnosing pseudogout. (See the image below.)
View Image | Wrist chondrocalcinosis. |
The ESR is usually elevated in pseudorheumatoid arthritis. The older age at onset for this condition, the lack of rheumatoid factor, and the presence of chondrocalcinosis help to differentiate it from true rheumatoid arthritis. However, rheumatoid arthritis can occur in older individuals. In addition, older individuals may have low-titer–positive rheumatoid factor. Thus, the diagnosis must be made with care.
Radiography is the criterion diagnostic standard for imaging of CPPD. However, ultrasonography appears more useful for detection of chondrocalcinosis (cartilage calcification, most commonly due to CPPD).[20] For complete discussion of imaging techniques, see Imaging in Calcium Pyrophosphate Deposition Disease.
Radiologic studies usually include the hands, wrists, pelvis, and knees (see the images below). The pelvic radiograph should include an anteroposterior view that shows the symphysis pubis and hips.
View Image | Calcium pyrophosphate deposition disease. Radiograph of the knee showing chondrocalcinosis involving the meniscal cartilage, as well as evidence of os.... |
View Image | Calcium pyrophosphate deposition disease. Radiograph of the wrist and hand showing chondrocalcinosis of the articular disc of the wrist and atypical o.... |
CPPD may involve hyaline cartilages, fibrocartilages, or tendons.[21] Chondrocalcinosis is usually found in the articular cartilage or meniscal cartilage of the knee, the triangular ligament of the wrist, the symphysis pubis, or the glenoid or acetabulum labra.[21] Chondrocalcinosis has also been noted in other areas of the wrist (aside from the fibrocartilage), such as the distal radioulnar joint and the midcarpal joint, as well as in the pisotriquetral joint. In addition, it has been reported in the spine as calcification of the ligamentum flavum.[22]
In some situations, hemochromatosis can produce specific radiographic findings, such as large, hooklike osteophytes, especially around the second to fifth MCP joints. However, these findings also can occur in patients with CPDD alone.
Hooklike osteophytes are a common radiologic finding in patients with a pseudo-osteoarthritis condition and are usually present along the second and third metacarpal heads.
Radiologically, erosions can be observed in pseudorheumatoid arthritis but are usually associated with chondrocalcinosis.
Routine magnetic resonance imaging (MRI) has not been shown to be as sensitive as radiography in detecting the presence of CPPD deposits. However, 4T MRI holds better promise in detecting these crystals.
Ultrasonography (US) has been significantly beneficial in the visualization of CPDD crystals.[23] (See the image below.) In addition, Gutierrez et al reported that US is accurate and reliable for detecting articular cartilage calcification at the knee level in patients with CPDD. In their study, US detected hyaline cartilage spots in at least one knee in 44 of 74 patients with CPDD (59.5%), whereas radiography detected hyaline cartilage spots in 34 patients (45.9%) (P < 0.001).[24]
A systematic review concluded that US is potentially a useful tool for the diagnosis of CPPD. However, the accuracy of US varied widely, depending on the reference standards used, and these authors suggest that universally accepted definitions are necessary in order to assess the role of US in the diagnostic process.[25] These findings were also reported in the American College of Radiology Appropriateness Criteria for evaluation of suspected inflammatory arthritis .[26]
Further evidence supporting the use of US in the detection of CPDD comes from a study by Forein et al that compared US and radiography of the wrist for diagnosis of CPDD. In their study of 32 patients with CPDD and 26 controls, US had sensitivity of 94% and specificity of 85%, while the sensitivity and specificity of radiography were 53.1% and 100%, respectively.[27]
Filippou et al demonstrated that US was as accurate as synovial fluid analysis for the diagnosis of CPDD in 42 patients with primary knee osteoarthritis waiting to undergo knee replacement surgery. In this study, cartilage histology was used as the reference standard. US had 96% sensitivity and 87% specificity; radiography, 75% sensitivity and 93% specificity; and synovial fluid analysis, 77% sensitivity and 100% specificity.[28]
Management of calcium pyrophosphate deposition disease (CPDD) depends on the clinical manifestations.
Asymptomatic (lanthanic) CPDD should not be treated unless it is a possible manifestation of other syndromes, such as hyperparathyroidism or hemochromatosis (treatment of which is important to prevent further end-organ damage but cannot reverse the joint disease).
Acute pseudogout may be treated by joint aspiration and intra-articular corticosteroid injection, systemic corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or, occasionally, high-dose colchicine.
Treatment for pseudo-osteoarthritis is similar to that for typical osteoarthritis. Patients with a pseudorheumatoid arthritis can be treated with small doses of corticosteroids, such as prednisone at 5mg daily.
Methotrexate was effective in isolated observations in patients who had severe disease with particular emphasis on joint destruction. However, this treatment was attempted only in patients with the pseudorheumatoid presentation.[29]
Studies have suggested that the inflammasome complex plays a pivotal role for interleukin-1 (IL-1) in pseudogout attacks, which means that the IL-1 receptor antagonist anakinra (Kineret) is a potential alternative for treating patients with calcium pyrophosphate disease.[30] This was initially reported in a single individual, a 71-year-old man with recurrent pseudogout attacks in multiple joints that were resistant to therapy with anti-inflammatory drugs, including glucocorticoids. This could also be important in patients with renal insufficiency (such as this patient), in whom nonsteroidal drugs can be problematic.[30]
In a study of anakinra for treatment of CPPD when conventional therapies are contraindicated or ineffective, 14 of 16 patients demonstrated beneficial responses; 10 had good responses and four had partial responses. These researchers concluded that anakinra may have a role in helping to control flares of CPPD in such patients.[31] In a similar study, four of five patients showed rapid clinical and biological responses at a mean of 3 days after treatment with anakinra.[32]
Theoretically, surgically removing calcifications from an affected joint could be beneficial, but this is currently considered an experimental procedure.
Intra-articular corticosteroid injections—such as 40-80 mg (depending on the size of the joint) of methylprednisolone or triamcinolone—into the affected joint have the advantage of avoiding the adverse systemic effects of NSAIDs. Short courses of systemic corticosteroids may be used for polyarticular attacks of pseudogout.
The use of NSAIDs also can be considered, generally in higher doses during the acute attack and in lesser doses for prevention. Be aware of toxicity, which is common in elderly patients, including gastrointestinal and renal toxicities. Cyclooxygenase-2 (COX-2) ̶ selective NSAIDs (ie, COX-2 inhibitors) may be as effective as traditional NSAIDs but with less toxicity, although this has not been rigorously tested.
Oral colchicine, or even intravenous (IV) colchicine, can be considered for the treatment of acute pseudogout. Colchicine should be a treatment of last resort because of its poor therapeutic ratio.
Preventing acute attacks of pseudogout is difficult. The use of small doses of colchicine (0.6mg qd/bid) or NSAIDs have been tried, with variable success.
Nonsteroidal anti-inflammatory drugs (NSAIDs) or, occasionally, low-dose prednisone may be beneficial for chronic arthropathies due to calcium pyrophosphate deposition disease (CPDD). Medical therapy for acute pseudogout is similar to that for gout, including the use of NSAIDs, intraarticular or, occasionally, systemic corticosteroids, and, rarely, oral or intravenous colchicine.
Variable success in preventing acute attacks of pseudogout has been achieved with small doses of colchicine (0.6 mg once or twice daily) or NSAIDs.
Clinical Context: Indomethacin is a traditional NSAID used to treat acute gouty arthritis and is used in a similar fashion for acute pseudogout. It blocks COX and, as a result, the generation of proinflammatory prostaglandins. Use the maximum dose initially, tapering it over 2 weeks depending on clinical response.
Clinical Context: Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Clinical Context: This agent is used for the relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which results in a decrease in prostaglandin synthesis.
Clinical Context: Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.
Clinical Context: Ketoprofen is used for relief of mild to moderate pain and inflammation. Small dosages are indicated initially in small patients, elderly patients, and patients with renal or liver disease. Doses higher than 75 mg do not increase the therapeutic effects. Administer high doses with caution, and closely observe the patient's response.
NSAIDs are very effective for the treatment of acute pseudogout and may be used for prophylaxis to prevent recurrent attacks of pseudogout. These agents may also be useful for symptomatic treatment of chronic arthropathies associated with CPDD. NSAID use is limited by toxicity (eg, renal, gastrointestinal), which is common in elderly patients. COX-2 ̶ selective NSAIDs may be as effective as traditional NSAIDs but with less gastrointestinal toxicity (although this has not been rigorously tested).
Clinical Context: Colchicine inhibits microtubules and, as a result, may inhibit neutrophil chemotaxis and phagocytosis. It also may inhibit prostaglandin generation.
If given orally or, rarely, intravenously, these agents can be used to treat acute pseudogout. Toxicity is significant; therefore, other therapies should be considered first. Low-dose colchicine may be useful for long-term prophylaxis of pseudogout attacks.
Clinical Context: Prednisone can be given orally to abort an attack of pseudogout. It can be given intravenously if the patient cannot take it by mouth. Intra-articular corticosteroids are the first choice of therapy due to their excellent safety profile.
Clinical Context: Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
These agents are potent anti-inflammatories that are very useful in the treatment of acute pseudogout in patients who are not good candidates for NSAIDs; moreover, they are much less toxic than colchicine. Corticosteroids can be given orally, intravenously, or intra-articularly. Oral prednisone used for an acute attack of pseudogout is generally tapered over a 2-week period. Intra-articular corticosteroids (eg, methylprednisolone) are very effective for the treatment of acute pseudogout. However, intra-articular dexamethasone promotes CPPD crystal formation by chondrocytes.
The general dose for methylprednisone is 20-80mg or its equivalent, depending on the size of the joint. This treatment has minimal toxicity and few contraindications (septic arthritis). Low-dose prednisone may be used for long-term treatment of pseudorheumatoid arthritis.
Calcium pyrophosphate deposition disease. Appearance of calcium pyrophosphate dihydrate crystals obtained from the knee of a patient with pseudogout. The crystals are rhomboid-shaped with weakly positive birefringence, as seen by compensated polarized microscopy. The black arrow indicates the direction of the compensator.
Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The black arrow indicates the direction of the compensator. Crystals parallel to the compensator are blue, while those perpendicular to the compensator are yellow.
Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The crystals parallel to the compensator were blue, while those perpendicular to the compensator were yellow. However, the crystals have been rotated 90%, resulting in a color change in both of them. The direction of the compensator was not changed and is indicated by the black arrow.
Calcium pyrophosphate deposition disease. Appearance of calcium pyrophosphate dihydrate crystals obtained from the knee of a patient with pseudogout. The crystals are rhomboid-shaped with weakly positive birefringence, as seen by compensated polarized microscopy. The black arrow indicates the direction of the compensator.
Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The black arrow indicates the direction of the compensator. Crystals parallel to the compensator are blue, while those perpendicular to the compensator are yellow.
Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The crystals parallel to the compensator were blue, while those perpendicular to the compensator were yellow. However, the crystals have been rotated 90%, resulting in a color change in both of them. The direction of the compensator was not changed and is indicated by the black arrow.
Intraoperative photographs demonstrate extensive precipitate deposition of the calcium pyrophosphate crystals in the articular cartilage, meniscus, and synovium of a knee. Upper left image depicts anterior horn medial meniscus. Lower left image depicts undersurface of meniscus. Upper right image depicts medial femoral condyle. Lower right image depicts synovium.