CPPD Arthropathy

Does this patient have calcium pyrophosphate dihydrate crystal deposition disease?


Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is an umbrella term encompassing all instances of calcium pyrophosphate dihydrate (CPP) crystal precipitation in connective tissues seen in asymptomatic patients or associated with several clinical syndromes. The names traditionally used to describe CPPD crystal deposition disease include: pseudogout, chondrocalcinosis, and pyrophosphate arthropathy. The European League Against Rheumatism (EULAR) has suggested alternative terminology:

Pseudogout-Pseudogout accurately describes acute attacks of CPPD crystal-induced arthritis which clinically resembles gout. However, the majority of patients with CPPD crystal deposition never experience such episodes. The EULAR consensus panel refers the term "acute clacium pyrophosphate (CPP) crystal arthritis" instead of pseudogout.

Chondrocalcinosis- Chondrocalcinosis pertains to calcific deposits in hyaline and/or fibrocartilage identified by imaging or histology. It is commonly present in patients with CPPD crystal deposition disease but is neither absolutely specific for CPP nor universal among affected patients. Chondrocalcinosis is seen by CPP depositis or basic calcium phosphate crystals, or both, or calcium oxalate (CaOx). The EULAR group designates this finding as "cartilage calcification (CC)".

Pyrophosphate arthropathy-Pyrophosphate arthropathy is the term used for the joint disease or radiographic abnormality accompanying CPPD crystal deposition. Calcium pyrophosphate crystal-associated arthropathy consists of articular structural abnormality of cartilage and other periarticular tissues that are related to CPP-crystal deposition diseases.

Acute CPP crystal arthritis, previously termed acute pseudogout, is the clinical syndrome of acute arthritis associated with intra-articular CPP-crystal deposition. Most individuals with CPP-crystal deposition disease have a primary/idiopathic form that most often appears with increasing age with an average age of 72 years of age in one study. The prevalence of radiographic calcium pyrophosphate deposition increases with age: 65 to 74 years (15%); 75-84 (36%) and >84 years (about 50%).

Two common presentations of CPPD are "acute or chronic calcium pyrophosphate (CPP)-crystal arthritis".

Acute CPP arthritis

Acute CPP-crystal arthritis classically presents as a monoarthritis, with rapid development of severe pain, swelling, and stiffness, maximal within 6-24 hours of onset. The patient may describe gout-like symptoms, with the pain being the “worst ever” experienced and being unable to tolerate even light pressure from clothing or bedding (hence, the term “pseudogout”).

Any joint can be involved, but the most common site of acute attacks is the knee, followed by the wrist, shoulder, ankle, and elbow. The first metatarsophalangeal (MTP) joint can be involved, which may simulate gout (“pseudopodagra”). Polyarticular attacks are unusual, but may occur.

On examination, there are signs of marked synovitis: erythema, warmth, tenderness of the joint, usually with a large effusion and limited range of motion. Fever is common, and may be high. Elderly patients may appear unwell and have mild confusion.

Acute attacks are self-limiting, usually resolving within 1-3 weeks. Compared with gout, pseudogout attacks may take longer to reach peak intensity. Symptoms are often considerably longer lasting than gout attacks, as symptoms can persist 3-120 days despite therapy.

Most episodes of acute arthritis develop spontaneously, but certain triggers may precede the attack by a few days. The most common predisposing factor is the stress of intercurrent medical illness or surgery (especially post-parathyroidectomy).

Pseudogout of the knee may be precipitated by arthroscopy, intra-articular hyaluronan injection, or by the use of bisphosphonates. Only isolated case reports are found: one case with weekly alendronate, and a few with pamidronate or etidronate. This effect was speculated to be due to the structural similarity between bisphosphonates and pyrophosphate. It is speculated that the phosphate present in the hyaluronate preparation may lower intraarticular calcium concentration and lead to calcium shedding.

Isolated chondrocalcinosis is a common age-associated phenomenon, often seen as an incidental radiographic finding in the elderly. Mostly these cases are asymptomatic or may manifest as acute attacks of CPP-crystal arthritis. Acute attacks may superimpose on chronic symptomatic arthropathy.

Chronic pyrophosphate arthropathy

This mainly affects elderly females, who may present with chronic pain, morning and inactivity stiffness, restricted joint movement, and functional limitation. Acute attacks of CPP-crystal arthritis may be superimposed on this chronic condition. It most commonly and most severely affects the knees, then the wrists, shoulders, elbows, hips, and midtarsal joints. In the hands, the metacarpophalangeal (MCP) joints are the most severely affected sites, particularly the second and third MCPs and resemble rheumatoid arthritis with the term “pseudo-rheumatoid arthritis”. Joint involvement is usually only of a few joints, although mono- and polyarticular involvement may also occurs.

On examination, the affected joints display the typical signs of osteoarthritis (OA): bony swelling, crepitus, limited motion, and with varying degrees of synovitis. Synovitis is usually most marked in the knee, wrist, or shoulder joints. There may be a more widespread but asymptomatic arthropathy on examination, particularly in elderly females, such as accompanying findings of generalized OA with Heberden’s and Bouchard’s nodes.

Clinical patterns of CPP-crystal arthropathy can be summarized into five groups:

  1. Pseudogout/acute CPP-crystal arthritis: acute, gout-like attacks of inflammation. About 25% of patients with CPP deposition disease exhibit this pattern.

  2. Pseudo-osteoarthritis: Patients with pyrophosphate arthropathy may have an unusually severe and oddly-distributed degenerative arthritis resembling OA. This pattern of presentation can be difficult to differentiate from OA and thus may be significantly under-recognized. Distinguishing features in comparison with primary OA are listed below (see differential diagnosis). In one series, 30% of patients diagnosed with OA had CPP crystals in their affected joints at the time of total knee replacement.

  3. Pseudo-rheumatoid arthritis: About 5% of patients with CPP crystal deposition disease may manifest with polyarticular, symmetric joint distribution with accompanying morning stiffness, fatigue, synovial thickening, and elevated erythrocyte sedimentation rate (ESR) that often lead to a misdiagnosis of rheumatoid arthritis (RA). Around 10% of those with CPPD disease have low titers of rheumatoid factor (RF), adding to the diagnostic confusion. Factors that should favor a diagnosis of RA include: presence of high titer RF, anti-cyclic citrullinated peptide (CCP) antibodies, along with radiographic evidence of juxta-articular osteopenia and typical rheumatoid bony erosions.

  4. Pseudo-neuropathic arthropathy: Some patients with CPPD disease have a dramatic destructive monoarthritis similar to that seen in neuropathic joints. Despite having no neurologic abnormalities, these patients present with painful monoarthritis associated with severe destructive radiographic changes.

  5. Lanthanic or idiopathic: Some individuals with chondrocalcinosis have no clinically apparent arthritis, and it is of unclear clinical significance.

Deposition of CPP crystals is not limited to articular cartilage. Uncommonly, these can deposit in synovial lining, ligaments, tendons, periarticular soft tissues, and in the spine. Atypical presentations result from CPP-crystal deposition at these unusual locations.

Self-limiting spinal syndromes have been described in relation to the periodontoid process (Crowned dens syndrome), cervical and lumbar regions and may reflect acute CPP-crystal attacks. Spinal ligaments seem prone to CPP crystal deposition. Affected patients may present with a myelopathy. Preferential deposition of CPP crystals in ligamentum flavum at C3-C6 remains unexplained, but corresponds to the level of greatest mobility. Severe spinal stiffness, particularly in certain familial forms, may present as pseudoankylosing spondylitis.

Tendinitis and tenosynovitis relating to CPP crystals have been described for triceps, hand flexors and extensors, and Achilles tendons. Flexor tendon involvement may be associated with carpal tunnel syndrome.

Bursitis (olecranon, infrapatellar, retrocalcaneal) is a rare manifestation, predominating in those with widespread pyrophosphate arthropathy. Tophaceous or tumoral CPP is rare, but well-described to occur in intra-articular or periarticular sites and can cause nerve compression syndromes.

Differential diagnosis

Acute CPP crystal arthritis

Acute synovitis in one or a few joints, with overlying erythema, fever, leukocytosis, particularly after surgery, trauma, or infective systemic illness, should always lead to consideration of septic arthritis.

Septic arthritis can coexist with CPP-crystal deposition disease, thus gram stain and culture of synovial fluid should always be undertaken especially in a hospitalized patient, even once CPP crystals or chondrocalcinosis are identified.

Gout and/or BCP crystals are other crystal-induced arthritis that can co-exist with pseudogout which requires evaluation of synovial fluid analysis under compensated polarized light microscopy or specialized staoining such as alizarin red.

Chronic pyrophosphate arthropathy

In the majority of cases, the characteristic distribution of joint involvement, radiographic features, and synovial fluid findings permit a ready diagnosis of CPP-crystal arthropathy. Occasionally, diagnostic confusion may arise.

Chronic CPP crystal disease may present with a pseudo-RA pattern of symmetric polyarthritis, however certain features of pyrophosphate arthropathy may permit distinction from RA:

  • MTPs and tenosynovium are infrequently involved.

  • Absence of extra-articular features.

  • Lack of juxta-articular osteopenia and marginal erosion.

  • Lack of strong positivity for RF, and absence of anti-CCP antibodies.

Chronic pyrophosphate arthropathy may be clinically distinguished from primary, uncomplicated OA by the following features:

  • Pattern of joint involvement: pyrophosphate arthropathy affects joints that are not typically affected by OA such as the wrists, shoulder, ankles, elbows, and the knee involvement predominates in the medial compartment (valgus knee deformities are especially suggestive of CPPD crystal deposition).

  • There is often a marked inflammatory component.

  • Presence of superimposed, recurrent acute attacks.

Destructive pyrophosphate arthropathy may resemble a neuropathic joint radiographically, however joints with CPPD crystals may be severely symptomatic (in contrast to the insensate neuropathic joint), and occur despite the absence of overt neurologic abnormality.

Atypically, patients with CPPD disease may have marked proximal stiffness along with glenohumeral and polyarticular involvement, and with elevated ESR that may suggest a clinical picture of polymyalgia rheumatica (PMR). Oral steroids often improve symptoms but rarely give the dramatic improvement as seen in PMR.

CPP-crystal can commonly coexist, rather than closely mimic, other recognizable joint disorders. The most common associated condition is OA. Coexistent gout, sepsis, RA, apatite-associated destructive arthropathy, and Charcot arthropathy may all occur. Thus, concurrent disorders must be distinctly recognized and the diagnoses should reflect both conditions.

Tophaceous CPP should be distinguished from malignancy and from chronic tophaceous gout.

What tests to perform?

Diagnosis of CPPD deposition disease relies on the identification of CPP crystals in the synovial fluid from affected joints by compensated polarized light microscopy in the synovial fluid of affected joints (Figure 1), or on histologic examination of cartilage or synovial biopsies. This is complemented by typical chondrocalcinosis on radiographic findings.

Figure 1.

Morphology under compensated polarized light microscopy of CPP crystal. A.Rectangular, rhomboid shaped CPP crystal with weakly positive birefringence: when the crystal is parallel to the axis of compensator (arrow), crystal adopts a blue color under compensated polarized light microscopy; 400 x. B. If CPP crystal is rotated perpendicular to the axis of the compensator, it adopts a yellow color under compensated polarized light microscopy; 400 x. Definitions: Negative birefringence- crystal is yellow when parallel to direction of the light (arrow), and blue when it is perpendicular. Positive birefringence- crystal is blue when parallel to direction of the light (arrow), and yellow when it is perpendicular.

Synovial fluid analysis should always be performed to confirm the diagnosis and to exclude other conditions, particularly septic arthritis or gout. Synovial fluid evaluation should always include cell count, crystals evaluation under compensated polarized microscopy, gram stain and culture. Aspirated fluid in acute CPP crystal arthritis is often turbid with diminished viscosity. Synovial fluid cell count is usually greatly elevated with >90% neutrophils.

In chronic pyrophosphate arthropathy, synovial fluid findings are more variable, and range from inflammatory to non-inflammatory. CPP crystals are identified under compensated polarized light microscopy as rhomboids or rods with weak positive birefringence (Figure 1).

Crystals of CPP are more difficult to discern and often less numerous than monosodium urate (MSU) crystals, thus can be missed frequently.

Acute CPP crystal arthritis triggers an acute phase response with often impressive elevation of ESR, C-reactive protein, and peripheral white blood cell count. In chronic pyrophosphate arthropathy, mild anemia and modest elevations of acute phase reactants can occur.

Metabolic predisposition to CPPD disease is rare; these include hemochromatosis, hyperparathyroidism, and hypomagnesemia, and hypophosphatasia (rare). Gitelman's syndrome, an inherited renal tubular disorder resulting in hypokalemia and hypomagnesemia, has been associated with both chondrocalcinosis and pseudogout. Gout, hypothyroidism, X-linked hypophosphatemic rickets, and familial hypocalciuric hypocalcemia are probably associated with CPPD crystal deposition disease, but the relationship less clearly demonstrated. Routine screening for metabolic diseases is unrewarding, but may be warranted in certain situations because chondrocalcinosis and pseudogout may be presenting manifestations of such diseases. These situations should include early-onset arthritis <55 years, and florid polyarticular chondrocalcinosis (as opposed to oligoarticular).

If indicated, check to evaluate for metabolic disorders: serum calcium, phosphate, alkaline phosphatase, magnesium, iron panel, ferritin, kidney and liver function, and PTH levels.


Plain radiography reveals chondrocalcinosis, appearing as typical punctate and linear densities in fibrocartilage (particularly knee menisci, wrist triangular cartilage, symphysis pubis, annulus fibrosus of intervertebral discs), and hyaline cartilage (knee, glenohumeral, hip joint).

Chondrocalcinosis usually affects several joints. If x-rays of the knees, wrists, symphysis pubis show no evidence of crystal deposits, it is unlikely to be present elsewhere. Calcifications may also be seen in articular capsule, ligaments and tendons (particularly favoring the Achilles, triceps, and obturator tendons). Capsular and synovial calcification is less common than chondrocalcinosis and is usually most apparent in the MCPs and knee.

In the MCPs, changes such as squaring of the bone ends, subchondral cysts, and “hook-like osteophytes” are characteristic features of hemochromatosis-related arthritis, but are also found with CPPD alone or in combination with hemochromatosis.

Chondrocalcinosis and calcifications are dynamic and may change in size over time. Chondrocalcinosis may become less evident during acute attacks, as they are thought to shed from the cartilage into the joint space or synovium.

The changes of chronic pyrophosphate arthropathy are of cartilage loss, sclerosis, cysts, and osteophytes, similar to OA.

Radiographic characteristics of CPPD that aid in distinction from OA are: occurrence of changes in joints atypically affected by OA, the often exuberant osteophyte and cyst formation at the knee and wrist, and the isolated patellofemoral joint space narrowing, or isolated wrist degeneration with CPPD.

The destructive form of pyrophosphate arthropathy shows marked attrition of cartilage and bone, loose bodies, and disorganization that may resemble a neuropathic joint.

Other imaging modalities

CT and MRI are relatively insensitive in detecting CPPD crystal deposits compared with plain radiographs, but may have certain roles. CT is useful in the evaluation of the spine, and may particularly show periodontoid calcification at the cervico-occipital region in cases with Crowned dens syndrome. MRI may be useful in those with neurologic symptoms.

High-resolution ultrasound can demonstrate CPP deposition in cartilage, tendons, ligaments, and synovium, and meniscus (Figure 2, Figure 3, Figure 4). Chondrocalcinosis appear as linear or punctate hyperechoic densities within the substance of hyaline cartilage (intermediate layer of articular cartilage), usually parallel to subchondral bone (Figure 2). This is in contrast to gout, where MSU-crystals deposit on the surface of the superficial layer of the articular cartilage.

Figure 2.

Musculoskeletal ultrasound of the knee showing CPP-crystal deposition within the intermediate layer of the articular cartilage. Transverse view of the femoral condyles. Normal articular cartilage (a) appears as an anechoic signal on gray scale. The CPP-crystals are deposited within the middle layer (arrows) of the articular cartilage (a).

Figure 3.

Musculoskeletal ultrasound of the knee showing joint effusion and hyperechoic signals consistent with CPP-crystal synovial calcifications (longitudinal view of a knee in extension). This image demonstrates irregular hyperechoic material deposition (solid arrow) consistent with calcifications within hypoechoic synovium (curved arrow), which are found within the anechoic synovial effusion (asterisk) in the suprapatellar pouch of the knee. Synovial lining (open arrow), femur (red arrowhead). This patient's effusion was aspirated; synovial fluid analysis confirmed the presence of CPP crystals.

Figure 4.

Musculoskeletal ultrasound of the knee showing hyperechoic signal consistent with CPP-crystal in the medial meniscus. Longitudinal view of a knee demonstrates irregular hyperechoic material deposition (arrow) consistent with calcification of the displaced medial meniscus in a patient with osteoarthritis. (o) osteophytes.

In fibrocartilage such as the menisci of the knee, chondrocalcinosis appears as rounded or amorphous deposits (Figure 4).

Musculoskeletal ultrasound has a reported specificity of 96.4-97.6%, and sensitivity of 68.7-86.7% for detecting chondrocalcinosis at the knee. It may be more sensitive than plain radiography, although no direct comparison studies have yet been done.

How should patients with calcium pyrophosphate dihydrate crystal deposition disease be managed?

There is no current treatment for CPPD deposition disease. Unlike in gout, there is no practical way to remove or dissolve CPP crystals from the joints articular cartilage or soft tissues. No treatment can modify the progression of structural changes.

Treatment of associated metabolic diseases does not result in resorption of CPP crystal deposits and does not influence the outcome of CPPD deposition disease, except possibly for the correction of hypomagnesemia.

General principles

All patients should receive: education about their arthritis, prescription for local strengthening and aerobic exercise, advice on reduction of adverse mechanical factors (e.g. obesity, inappropriate footwear), and simple analgesia.

Goals of treatment include control of symptoms, early mobilization to avert effects of prolonged immobility, and maintenance or improvement of function. Local therapy is preferred over systemic therapy, if possible.

The treatment of acute attacks of CPP crystal arthritis are predominantly expert opinion-based and modeled on the treatment of acute gout.


Non-pharmacologic treatment with ice and temporary rest are beneficial adjuncts to pharmacologic modalities, which should be tailored to individual patients and their comorbidities.

Aspiration alone may be the only treatment needed, which greatly improves symptoms in majority of cases. However, fluid re-accumulation is common.

Injection of corticosteroids may be warranted, especially for severe attacks. Response to local steroid injection is often superior to systemic therapy in the elderly.

Simple analgesics or NSAIDs are beneficial.

Colchicine, (a microtubule assembly and inflammasome inhibitor), may work to treat acute attacks by preventing crystal induction of inflammation. Its effects are less predictable in pseudogout than in gout, but it may reduce the number and duration of acute attacks when given as prophylaxis.

Systemic corticosteroids are considered for severe, polyarticular attacks.

The successful use of anakinra, an interleukin-1 receptor inhibitor, was described for treatment and prophylaxis of acute CPP arthritis resistant to NSAIDS and prednisolone. Use of methotrexate, hydroxychloroquine, and rilonacept (IL-1 trap) are investigational.

Treatment strategies of chronic pyrophosphate arthropathy are the same as for OA. Stronger analgesics (e.g. opioids, coxibs, tramadol) should be used with caution in the elderly.

Radio-synovectomy may be entertained for recurrent hemarthrosis. Surgery with joint replacement may be required for patients with advanced destructive large joint arthropathy.

What happens to patients with calcium pyrophosphate dihydrate crystal deposition disease?

Prevalence of chondrocalcinosis varies from 7-10% in people aged 60 years, and shows equal sex distribution. Chondrocalcinosis is strongly associated with age; the prevalence is low below 50 years old, and increasing from 10%-15% in those aged 65-75, and 30%-60% in those older than 85. Chondrocalcinosis is reported from most countries and racial groups.

Genetic associations include mutations of the ANKH gene on chromosome 5p (CCAL2) and unknown genes on chromosome 8 (CCAL1). The ANKH (ankylosis human) gene functions to transport inorganic pyrophosphate (PPi) out of the cells. Familial mutations result in a gain of function of the ANKH that increases extracellular PPi and leads to onset of CPPD disease in the third or fourth decade of life.

There have been numerous associations suggested with metabolic diseases, but many reflect chance concurrence of common age-related conditions. The strongest evidence for association is with hyperparathyroidism, hemochromatosis, and hypomagnesemia and hypophosphatasia (rare).

There is strong overlap with OA, however its relationship is complex, but with convincing evidence for a strong positive association, at least in the knee.

The natural history of chronic pyrophosphate arthropathy appears to suggest a benign course, in a five year hospital-based study. This study found that even in severely affected knees, 60% showed stabilization or improvement of symptoms. However, in a second hospital-based study of 350 OA knees, the presence of synovial fluid CPP crystals or chondrocalcinosis was associated with radiographic progression; especially bone attrition and clinical deterioration, suggesting that CPP is a marker of poor prognosis in knee OA.

Occasional development of rapidly progressive arthropathy is well recognized, particularly at the knee, shoulder, or hip. This destructive pyrophosphate arthropathy is mainly confined to elderly women, associated with a poor outcome.

How to utilize team care?

Specialty referral to rheumatologists if diagnosis or treatment is difficult.

Orthopedic surgery referral for advanced or destructive pyrophosphate arthropathy.

Physical and occupational therapy for mobilization exercises, therapeutic modalities, and adaptive devices.

Are there clinical practice guidelines to inform decision making?

EULAR Expert Guidelines for Management of Clinical Manifestations of CPPD Crystal Deposition. In: EULAR recommendations for calcium pyrophosphate deposition. Part II: management.

European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis.

What is the evidence?

Zhang, W, Doherty, M, Bardin, T. "European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis". Ann Rheum Dis. vol. 70. 2011 Apr. pp. 563-70.

Zhang, W, Doherty, M, Pascual, E. "EULAR recommendations for calcium pyrophosphate deposition. Part II: management". Ann Rheum Dis. vol. 70. 2011 Apr. pp. 571-5.

Felson, DT, Anderson, JJ, Naimark, A. "The prevalence of chondrocalcinosis in the elderly and its association with knee osteoarthritis: the Framingham Study". J Rheumatol. vol. 16. 1989 Sep. pp. 1241-5.

Doherty, M, Abhishek, A, Hochberg, M, Silman, A, Smolen, J. "Calcium pyrophosphate crystal-associated arthropathy". Rheumatology. Mosby Elsevier. 2011. pp. 1875-1887.

Guerne, P, Terkeltaub, R, Terkeltaub, R. "Calcium Pyrophosphate Dihydrate Crystal Deposition: Epidemiology, Clinical Features, Diagnosis, and Treatment". Gout and Other Crystal Arthropathies. Elsevier Sauders. 2012. pp. 249-265.

Richette, P, Bardin, T, Doherty, M. "An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease". Rheumatology (Oxford). vol. 48. 2009. pp. 711-715.

Zhang, W, Doherty, M, Pascual, E. "EULAR recommendations for calcium pyrophosphate deposition. Part II: management". Ann Rheum Dis. vol. 70. 2011 Apr. pp. 571-5.

Zhang, W, Doherty, M, Bardin, T. "European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis". Ann Rheum Dis. vol. 70. 2011 Apr. pp. 563-70.

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