Calcium Pyrophosphate Deposition (CPPD) Disease 

Updated: Apr 03, 2021
Author: Constantine K Saadeh, MD; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Calcium pyrophosphate deposition (CPPD) disease 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] (See Etiology, Presentation, and Workup.)

 

Calcium pyrophosphate deposition disease. Radiogra Calcium pyrophosphate deposition disease. Radiograph of the wrist and hand showing chondrocalcinosis of the articular disc of the wrist and atypical osteoarthritis involving the metacarpophalangeal joints in a patient with underlying hemochromatosis.

Almost any joint may be involved by CPPD, 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 CPPD are as follows[2] :

  • Asymptomatic (lanthanic) CPPD
  • Acute pseudogout
  • Pseudo-osteoarthritis
  • Pseudorheumatoid arthritis
  • Pseudoneuropathic joints

Patients with CPPD can experience significant morbidity due to the pain of an acute attack of pseudogout or to symptoms of chronic arthropathy. Treatment of symptomatic CPPD is important to prevent further end-organ damage, but it cannot reverse the joint disease. (See Treatment and Medication).

For patient education information, see Arthritis and Pseudogout.

Etiology

Although the exact mechanism for the development of CPPD 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 CPPD 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 CPPD disease. Therefore, inorganic pyrophosphate can bind calcium, leading to CPPD deposition in the cartilage and synovium.[3, 4] Hyaline cartilage is affected most commonly, but fibrocartilage, such as the meniscal cartilage of the knee, can also be involved.[5]

Hypotheses based on in vitro studies propose that pyrophosphohydrolase activity and inorganic phosphate content, as noted above, are generalized phenomena that occur in fibroblasts.[6] Although these phenomena are generalized, the reason they occur only in joints remains unknown.

Genetics

Genetic defects have been identified as specific gene mutations in a few kindred families.[7, 8] 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.[9]

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.[10]

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.[10]

Epidemiology

Occurrence in the United States

CPPD 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%.[11] Nearly 50% of people older than 85 years have radiologic evidence of chondrocalcinosis.

Sex- and age-related demographics

CPPD is slightly more common in women than in men. The exact female-to-male ratio is unknown but is probably 1.4:1.

CPPD 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.

Comorbidities

In a cross-sectional study in the national Veterans Affairs (VA) population that included 25,157 patients with CPPD, the strongest positive associations with CPPD were as follows[12] :

  • Hyperparathyroidism (odds ratio [OR] 3.35)
  • Gout (OR 2.82)
  • Osteoarthritis (OR 2.26)
  • Rheumatoid arthritis (OR 1.88)
  • Hemochromatosis (OR 1.87)

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.[12]

 

Presentation

History

Presentations of calcium pyrophosphate deposition (CPPD) disease include the following[2] :

  • Asymptomatic CPPD, as an incidental radiographic finding
  • Acute pseudogout
  • Pseudo-osteoarthritis
  • Pseudo–rheumatoid arthritis
  • Pseudo–neuropathic joints

Asymptomatic (lanthanic) CPPD

This is usually associated with radiographic findings of chondrocalcinosis in the absence of clinical manifestations and may be the most common form of CPPD.

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

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 CPPD 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

Pseudo-osteoarthritis often involves the metacarpophalangeal (MCP) joints, wrists, elbows, and shoulders—joints unlikely to be involved in primary osteoarthritis. Most commonly, however, it affects the knees, and it can involve the proximal interphalangeal (PIP) joints and spine, as occurs in patients with primary osteoarthritis. Pseudo-osteoarthritis accounts for 50% of all CPPD cases. Approximately half of these patients also have associated pseudogout.

Pseudorheumatoid arthritis

Pseudorheumatoid arthritis in patients with CPPD involves symmetrical inflammation of the PIP and MCP joints. Clinically, these patients complain of morning stiffness and joint swelling. In a study from Finland, the prevalence of CPPD in 435 patients with early seronegative rheumatoid arthritis was 3.9% overall, but the percentage was 7.0% in patients age 60 years or older at baseline.[13]

Pseudoneuropathic joints

Neuropathic-like arthropathy, which is observed in fewer than 5% of patients with CPPD, 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.

CPPD can present as spondylodiscitis. This was shown in 2 case reports, one in a 75-year-old woman who presented with neck pain and in whom magnetic resonance imaging showed spondylodiscitis based on contrast enhancement of C5-C6 vertebrae corpus, and the other in a 61-year-old woman with spondylodiscitis at the C5-C6 intervertebral disc.[14]

Physical Examination

The physical examination findings vary depending on the form of CPPD in a given patient, who may present with an acute arthritis or different patterns of chronic arthritis.

Acute pseudogout

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.

Pseudo-osteoarthritis

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 CPPD associated with an underlying metabolic disease.

Pseudorheumatoid arthritis

Physical examination findings show a picture similar to rheumatoid arthritis, with synovitis in a symmetrical, polyarticular pattern, especially involving the wrists and MCP joints.

Complications

Common complications from CPPD 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) CPPD 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.[15] Tumoral pseudogout of a PIP (proximal interphalangeal joint) with an enlarging calcified mass and secondary bony erosion was reported by Park et al.[16]  

Coexistent infection with CPPD is a possible complication but the occurrence 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.[17]  

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. Patients with crowned dens syndrome typically present with localized pain at the base of skull/back of the neck, neck stiffness, and systemic evidence of inflammation (eg, fever and elevated levels of inflammatory markers).[18] Haikal et al reported that cervical computed tomography (CT) scans revealed crowned dens syndrome in 34 of 57 patients with CPPD,  and recommended considering cervical CT in elderly patients with neck pain in the setting of CPPD.[19]

Odontoid fracture with nonunion rates are significantly higher in CPPD patients.  This illustrates the importance of making the appropriate diagnosis and deciding on treatment.[20]

 

DDx

Diagnostic Considerations

Gitelman syndrome

Gitelman syndrome is associated with hypokalemic metabolic acidosis and hypomagnesemia. Patients with Gitelman syndrome may have renal tubular acidosis and a history of pseudogout. Consequently, this diagnosis should be considered in patients with such findings.

Gitelman syndrome has been shown to be associated with a mutation in the gene solute carrier family 12, member 3 (SLC12A3). The cause may be related to the thiazide-sensitive sodium chloride cotransporter, which is found in a variant form in most patients with the syndrome.

Gitelman syndrome can mimic several other manifestations of calcium pyrophosphate deposition (CPPD) disease , including osteoarthritis, carpal tunnel syndrome, and tenosynovitis with calcifications along the tendon sheath itself.[21]

Septic arthritis

Septic arthritis can present as monoarticular arthritis and, therefore, can mimic acute pseudogout. Therefore, a Gram stain of the fluid should be performed. The results of the Gram stain will be negative unless a concomitant infection is present.

If septic arthritis is suggested clinically, even if crystals are seen on compensated polarized microscopy, it must be evaluated and, possibly, treated.

Other differentials

The differential diagnosis for pseudo-osteoarthritis includes hemochromatosis, hyperparathyroidism, hypothyroidism, and traumatic arthritis (as occurs in heavy-equipment machinery operators).

Basic calcium phosphate deposition disease and Lyme arthritis are also included in the differential diagnosis of CPPD.

See also The Approach to the Painful Joint.

Differential Diagnoses

 

Workup

Approach Considerations

Revised diagnostic criteria for calcium pyrophosphate deposition (CPPD) disease are from the Primer on Rheumatic Diseases (1997) and are used with permission from the Arthritis Foundation. The criteria are as follows[22] :

  • Criterion I - Demonstration of calcium pyrophosphate crystal deposition in tissue or synovial fluid by definitive means (eg, characteristic radiographs, diffraction analysis, or chemical analysis)

  • Criterion IIa - Identification of monoclinic or triclinic crystals showing no or weakly positive birefringence by compensated polarized light microscopy

  • Criterion IIb - Presence of typical radiographic calcifications

  • Criterion IIIa - Acute arthritis, especially of knees or other large joints

  • Criterion IIIb - Chronic arthritis, especially of knee, hip, wrist, carpus, elbow, shoulder, or metacarpophalangeal (MCP) joint, particularly if accompanied by acute exacerbation

In criterion IIIb, chronic arthritis shows the following features, which are helpful in differentiating it from osteoarthritis:

  • Uncommon sites - Wrist, MCP joint, elbow, shoulder

  • Radiographic appearance - Radiocarpal or patellofemoral joint-space narrowing, especially if isolated (eg, patella wrapped around the femur)

  • Subchondral cyst formation

  • Severity of degeneration - Progressive, with subchondral bony collapse and fragmentation with formation of intra-articular, radiodense bodies

  • Osteophyte formation - Variable and inconsistent

  • Tendon calcifications - Especially triceps, Achilles, obturators

Criteria-based categories include the following:

  • Definite disease - Criterion I or IIa plus IIb must be fulfilled
  • Probable disease - Criterion IIa or IIb must be fulfilled
  • Possible disease - Criterion IIIa or IIIb should alert the clinician to the possibility of underlying calcium pyrophosphate deposition

Arthrocentesis

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 Findings

Histologic changes associated with CPPD 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.

Associated conditions

A number of conditions have been associated with CPPD. When CPPD is diagnosed, especially in a patient younger than 60 years, a metabolic workup should be performed. The following metabolic conditions have definite associations with CPPD[12] :

  • Hemochromatosis
  • Hyperparathyroidism
  • Hypophosphatasia [12]  

Hypothyroidism has a probable association with CPPD, so thyroid function testing should be included in the metabolic workup.[23]

Lab Studies

General laboratory studies usually are not helpful in calcium pyrophosphate deposition (CPPD) disease. 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.[24] Laboratory tests can include the following:

  • Serum calcium, phosphorus, magnesium, and alkaline phosphatase levels
  • Iron level, total iron-binding capacity, transferrin saturation, and ferritin level
  • Thyroid-stimulating hormone and free thyroxine levels

Pseudogout

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.[25]

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.)

Calcium pyrophosphate deposition disease. Appearan 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-pow 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-pow 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.

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.)

Calcium pyrophosphate deposition disease. Ultrason Calcium pyrophosphate deposition disease. Ultrasonography of the wrist demonstrates chondrocalcinosis.

Pseudorheumatoid arthritis

The erythrocyte sedimentation rate (ESR) is usually elevated in pseudorheumatoid arthritis. The older age at onset for this condition, the absence 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.

Imaging Studies

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).[26] For complete discussion of imaging techniques, see Imaging in Calcium Pyrophosphate Deposition Disease.

Radiography

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.

Calcium pyrophosphate deposition disease. Radiogra Calcium pyrophosphate deposition disease. Radiograph of the knee showing chondrocalcinosis involving the meniscal cartilage, as well as evidence of osteoarthritis.
Calcium pyrophosphate deposition disease. Radiogra Calcium pyrophosphate deposition disease. Radiograph of the wrist and hand showing chondrocalcinosis of the articular disc of the wrist and atypical osteoarthritis involving the metacarpophalangeal joints in a patient with underlying hemochromatosis.

CPPD may involve hyaline cartilages, fibrocartilages, or tendons.[27] 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.[27] 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.[28]

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 CPPD 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.

MRI and ultrasonography

Routine magnetic resonance imaging (MRI) has not been shown to be as sensitive as radiography in detecting the presence of CPPD. However, 4T MRI holds better promise in detecting these crystals.

Ultrasonography (US) has been significantly beneficial in the visualization of CPPD crystals.[29] In addition, Gutierrez et al reported that US is accurate and reliable for detecting articular cartilage calcification at the knee level in patients with CPPD. In their study, US detected hyaline cartilage spots in at least one knee in 44 of 74 patients with CPPD (59.5%), whereas radiography detected hyaline cartilage spots in 34 of those patients (45.9%) (P < 0.001).[30]

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.[31] These findings were also reported in the American College of Radiology Appropriateness Criteria for evaluation of suspected inflammatory arthritis.[32]

Further evidence supporting the use of US in the detection of CPPD comes from a study by Forein et al that compared US and radiography of the wrist for diagnosis of CPPD disease. In their study of 32 patients with CPPD disease 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.[33]

Filippou et al demonstrated that US was as accurate as synovial fluid analysis for the diagnosis of CPPD disease 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, while synovial fluid analysis had 77% sensitivity and 100% specificity.[34]

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); comparable figures for conventional radiography were 72 (0.59-0.83), 1.0 (0.91-1.0), and 0.83 (0.74-0.90), respectively.[35]

Further US data show that scanning a higher number of sites with demonstration of hyperechoic spots that do not generate acoustic shadowing in the hyaline and fibrocartilage can increase the specificity for CPPD. Real-time images can be reviewed during office visits to help illustrate CPPD, which may facilitate patient education.[36]

Diagnosing CPPD with US typically requires scanning multiple joints to localize the crystals. The 2 most commonly affected sites where these crystals can be seen are the triangular fibrocartilage complex (TFCC) of the wrist and the knee. US at these sites show thin hyperechoic bands parallel to the surface of the hyaline cartilage. Other findings include a punctate pattern consisting of several hyperechoic spots and homogeneous hyperechoic nodular or oval deposits in the articular surface. (See the image below.) These homogeneous structures are referred to as double contour. Double contour is also noted in gout, but in CPPD disease the crystal is more moveable with dynamic imaging than it is in gout.[37]

Calcium pyrophosphate deposition disease. Ultrasou Calcium pyrophosphate deposition disease. Ultrasound scan of the triangular fibrocartilage complex (TFCC) of the wrist shows thin hyperechoic bands parallel to the surface of the hyaline cartilage. Other findings include a punctate pattern consisting of several hyperechoic spots and homogeneous hyperechoic nodular or oval deposits in the articular surface.
 

Treatment

Approach Considerations

Management of calcium pyrophosphate deposition (CPPD) disease depends on the clinical manifestations.

Asymptomatic (lanthanic) CPPD should not be treated. However, if CPPD is a possible manifestation of other syndromes, such as hyperparathyroidism or hemochromatosis, treatment of the underlying condition is important to prevent further end-organ damage, although it cannot reverse the joint disease.

Acute pseudogout may be treated with joint aspiration and intra-articular corticosteroid injection; systemic corticosteroids; nonsteroidal anti-inflammatory drugs (NSAIDs); or, occasionally, high-dose colchicine. Sodium hyaluronate, which is injected intra-articularly to increase joint mobility and improve function when conventional drugs have failed, is approved for treatment of osteoarthritis and has been shown to be effective in CPPD disease as well (note that osteoarthritis can result from CPPD).[38, 39, 40]

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 5 mg daily.

Hydroxychloroquine can be used as adjuvant therapy to prevent flareups. It reduces the release of cytokines such as interleukin-1 (IL-1) and IL-6 and tumor necrosis factor alpha by macrophages. In an animal model of CPPD, it inhibited the activity of matrix metalloprotease.[41]  A double-blind prospective 6-month trial found hydroxychloroquine to be beneficial for chronic CPPD-related arthropathy.[38, 39, 40]

Methotrexate has proved effective in small numbers of patients with severe disease, especially those with joint destruction. However, this treatment has been described only in patients with the pseudorheumatoid presentation.[42]  Methotrexate does help reduce joint pain and swelling, and it decreases serum levels of inflammatory biomarkers. In one study of 10 patients with acute inflammation resistant to conventional therapies, methotrexate seemed to be partially effective.[38, 39, 40]

Studies have indicated that activation of IL-1 by the inflammasome complex plays a pivotal role in pseudogout attacks, which suggested the IL-1 receptor antagonist anakinra (Kineret) as a potential alternative for treating patients with CPPD.[43, 44, 45] A systematic review found 74 cases of anakinra use in CPPD, in patients with refractory disease (85.1%) or contraindications to standard treatments. Clinical response to anakinra was observed in 80.6% of patients with acute CPPD disease and in 42.9% of those with chronic CPPD disease. Short-term treatment was well tolerated; adverse events were reported in 4.1% of cases.[46]

Finally, a theoretical possibility for pharmacologic treatment of CPPD is the use of anticrystal agents to prevent deposition of calcium pyrophosphate dihydrate. Such agents include probenecid, phosphocitrate, and polyphosphate. The mechanism of action appears to be through inhibition of transforming growth factor beta 1 (TGF-beta 1), which is an important stimulant of nucleoside triphosphate pyrophosphohydrolase (NTPPPH), an enyzme required for pyrophosphate synthesis.[38, 39, 40]

Radiosynovectomy is a minimally invasive technique that involves the intra-articular injection of small radioactive particles to remove inflamed synovium. Patients with CPPD secondary to hemophilia have responded well to radiosynovectomy, particularly those with a history of repeated joint bleeding. This procedure is considered to be safe, cost-effective, and efficient, with low radiation exposure.[40]

Patients with pseudoneuropathic arthropathy that is refractory to medical management may benefit from surgical replacement of the damaged joint with a bioprosthesis.[38, 39, 40]  

Theoretically, surgically removing calcifications from an affected joint could be beneficial. However, this is currently considered an experimental procedure.

Pharmacotherapy for Pseudogout

The use of NSAIDs 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 (eg, celecoxib) may be as effective as traditional NSAIDs but with less toxicity, although this has not been rigorously tested.

Injection of corticosteroids—such as 40-80 mg (depending on the size of the joint) of methylprednisolone or triamcinolone—into the affected joint has the advantage of avoiding the adverse effects of systemic NSAIDs. Short courses of systemic corticosteroids may be used for polyarticular attacks of pseudogout.  

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. Small doses of colchicine (0.6 mg once or twice daily) or NSAIDs have been tried, with variable success.

While anakinra has been used in pseudogout attacks, other biologics have not demonstrated consistent benefit in CPPD disease. Case reports describe treatment with tumor necrosis factor–alpha (TNF-alpha) inhibitors as well as the anti–IL-6 receptor antibody tocilizumab.[47, 48]

 

Medication

Medication Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) or, occasionally, low-dose prednisone may be beneficial for chronic arthropathies due to calcium pyrophosphate deposition (CPPD) disease. Medical therapy for acute pseudogout is similar to that for gout, including the use of NSAIDs; intra-articular 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.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Class Summary

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 CPPD. 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).

Indomethacin (Indocin)

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.

Ibuprofen (Motrin, Advil, Addaprin, Caldolor)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen sodium (Anaprox, Naprelan, Naprosyn, Anaprox)

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.

Diclofenac (Voltaren, Cataflam XR, Zipsor, Cambia)

Diclofenac inhibits prostaglandin synthesis by decreasing COX activity, which, in turn, decreases formation of prostaglandin precursors.

Ketoprofen

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.

Anti-Inflammatory Agents

Class Summary

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.

Colchicine

Colchicine inhibits microtubules and, as a result, may inhibit neutrophil chemotaxis and phagocytosis. It also may inhibit prostaglandin generation.

Corticosteroids

Class Summary

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 calcium pyrophosphate 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.

Prednisone

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.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

 

Questions & Answers

Overview

What is calcium pyrophosphate deposition disease (CPDD)?

What are the common presentations of calcium pyrophosphate deposition disease (CPDD)?

What is the prognosis of calcium pyrophosphate deposition disease (CPDD)?

Where can patient education information about calcium pyrophosphate deposition disease (CPDD) be found?

What causes calcium pyrophosphate deposition disease (CPDD)?

What is the role of genetics in the etiology of calcium pyrophosphate deposition disease (CPDD)?

What is the prevalence of calcium pyrophosphate deposition disease (CPDD) in the US?

What are the demographics predilections in the prevalence of calcium pyrophosphate deposition disease (CPDD)?

What comorbidities are associated with calcium pyrophosphate deposition disease (CPDD)?

Presentation

What are presentations of calcium pyrophosphate deposition disease (CPDD)?

What are the radiographic features of asymptomatic (lanthanic) calcium pyrophosphate deposition disease (CPDD)?

Which clinical history findings are characteristic of an acute pseudogout presentation of calcium pyrophosphate deposition disease (CPDD)?

Which clinical history findings are characteristic of a pseudo-osteoarthritis presentation of calcium pyrophosphate deposition disease (CPDD)?

Which clinical history findings are characteristic of a pseudorheumatoid arthritis presentation of calcium pyrophosphate deposition disease (CPDD)?

Which clinical history findings are characteristic of a pseudoneuropathic joint presentation of calcium pyrophosphate deposition disease (CPDD)?

Which physical findings are characteristic of calcium pyrophosphate deposition disease (CPDD)?

Which physical findings are characteristic of acute pseudogout in calcium pyrophosphate deposition disease (CPDD)?

Which physical findings are characteristic of pseudo-osteoarthritis in calcium pyrophosphate deposition disease (CPDD)?

Which physical findings are characteristic of pseudorheumatoid arthritis in calcium pyrophosphate deposition disease (CPDD)?

What are complications of calcium pyrophosphate deposition disease (CPDD)?

DDX

How is septic arthritis differentiated from calcium pyrophosphate deposition disease (CPDD)?

How is Gitelman syndrome differentiated from calcium pyrophosphate deposition disease (CPDD)?

Which conditions should be included in the differential diagnoses for calcium pyrophosphate deposition disease (CPDD)?

What are the differential diagnoses for Calcium Pyrophosphate Deposition (CPPD) Disease?

Workup

What are the diagnostic criteria for calcium pyrophosphate deposition disease (CPDD)?

How is chronic arthritis differentiated from calcium pyrophosphate deposition disease (CPDD)?

What are criteria-based categories of calcium pyrophosphate deposition disease (CPDD)?

What is the role of arthrocentesis in the workup of calcium pyrophosphate deposition disease (CPDD)?

What are the histologic features of calcium pyrophosphate deposition disease (CPDD)?

What is the role of a metabolic evaluation in the diagnosis of calcium pyrophosphate deposition disease (CPDD)?

What is the role of lab studies in the workup of calcium pyrophosphate deposition disease (CPDD)?

Which lab studies are performed in the workup of pseudogout in calcium pyrophosphate deposition disease (CPDD)?

Which lab studies are performed in the workup of pseudorheumatoid arthritis in calcium pyrophosphate deposition disease (CPDD)?

What is the role of imaging studies in the evaluation of calcium pyrophosphate deposition disease (CPDD)?

What is the role of radiography in the workup of calcium pyrophosphate deposition disease (CPDD)?

What is the role of MRI in the workup of calcium pyrophosphate deposition disease (CPDD)?

What is the role of ultrasonography (US) in the workup of calcium pyrophosphate deposition disease (CPDD)?

Treatment

What are the treatment options for calcium pyrophosphate deposition disease (CPDD)?

What is the role of surgery in the treatment of calcium pyrophosphate deposition disease (CPDD)?

What is the role of drug treatment for calcium pyrophosphate deposition disease (CPDD)?

Medications

Which medications are used in the treatment of calcium pyrophosphate deposition disease (CPDD)?

Which medications in the drug class Corticosteroids are used in the treatment of Calcium Pyrophosphate Deposition (CPPD) Disease?

Which medications in the drug class Anti-Inflammatory Agents are used in the treatment of Calcium Pyrophosphate Deposition (CPPD) Disease?

Which medications in the drug class Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are used in the treatment of Calcium Pyrophosphate Deposition (CPPD) Disease?