Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease

INTRODUCTION — Precipitation of crystals of calcium pyrophosphate (CPP) in connective tissues may be associated with several clinical syndromes, but is sometimes asymptomatic. The consequences of CPP deposition include acute inflammatory arthritis, inflammatory and degenerative chronic arthropathies, and radiographic cartilage calcification and constitute the spectrum of calcium pyrophosphate crystal deposition (CPPD) disease [1-3].

The clinical manifestations and diagnosis of CPPD disease are discussed here. The pathogenesis and etiology of this disorder and the treatment of CPPD diseases are discussed separately. (See "Pathogenesis and etiology of calcium pyrophosphate crystal deposition (CPPD) disease" and "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease".)

TERMINOLOGY — The term calcium pyrophosphate crystal deposition (CPPD) refers to the presence of calcium pyrophosphate (CPP) crystals as detected by microscopy or imaging. The term "CPPD disease" indicates the presence of symptomatic arthritis. Chondrocalcinosis refers to radiographic calcification in hyaline and/or fibrocartilage (image 1). It is commonly present in patients with CPPD disease but is neither absolutely specific for CPPD nor universal among affected patients.

The names used in the past to describe CPPD disease included terms such as pseudogout, chondrocalcinosis, and pyrophosphate arthropathy. Adding the prefix "pseudo" was intended to highlight similarities between various manifestations of CPPD disease and other common rheumatic diseases [1-3]. The European Alliance of Associations for Rheumatology (EULAR) consensus panel suggested alternative terminology that has been widely adopted in the subsequent literature. We will place primary emphasis here on the use of EULAR task force terminology [4]. Traditional older names (in parentheses below) relate to the nomenclature proposed by the EULAR task force [4] as follows:

●Asymptomatic CPPD disease ("asymptomatic CPPD") (see 'Asymptomatic CPPD disease' below)

●Acute CPP crystal arthritis ("pseudogout") (see 'Acute CPP crystal arthritis' below)

●Chronic CPP crystal inflammatory arthritis ("pseudo-rheumatoid arthritis [RA]") (see 'Chronic CPP crystal inflammatory arthritis' below)

●Osteoarthritis (OA) with CPPD, with or without superimposed acute attacks ("pseudo-OA") (see 'Osteoarthritis with CPPD' below)

●Severe joint degeneration (pseudo-neuropathic joint disease) (see 'Severe joint degeneration' below)

●Spinal involvement

EPIDEMIOLOGY — Calcium pyrophosphate crystal deposition (CPPD) disease has been estimated to affect 4 to 7 percent of the adult populations of Europe and the United States [5,6], especially among persons of advanced age. However, an estimate of the prevalence of clinically significant CPPD disease has been more difficult to attain, in large part because the available prevalence estimates have relied primarily upon radiographically detected cartilage calcification rather than clinical evaluation.

The average age at diagnosis of CPPD disease in one study was 72 years [3]. Radiographic surveys have demonstrated an age-related increase in the prevalence of cartilage calcification [7,8]. This was illustrated in a report that supplemented radiographs of the knees with radiographs of the hands, wrists, and pelvis [8]. The prevalence of radiographic CPPD according to age, among 100 consecutive patients admitted to an acute geriatric unit, was:

●65 to 74 years – 15 percent

●75 to 84 years – 36 percent

●>84 years – Almost 50 percent

The sex distribution of CPPD disease has differed among large series [3,9,10], but no major sex predominance appears likely.

CLINICAL MANIFESTATIONS — There is considerable diversity in the patterns of joint disease among patients with symptoms related to calcium pyrophosphate deposition (CPPD) disease. Older nomenclature and the newer terms proposed by the European Alliance of Associations for Rheumatology (EULAR) consensus panel are described above. (See 'Terminology' above.)

Asymptomatic CPPD disease — Many patients who have chondrocalcinosis on radiographs are asymptomatic. However, patients with apparent asymptomatic CPPD disease may be found to have manifestations of an arthritic disorder upon close questioning. As an example, in one series of older patients with radiographic but ostensibly asymptomatic CPPD disease, a higher frequency of wrist complaints and knee deformity were reported by questionnaire and detected by examination, respectively, than in a control group of similar age but without radiographic chondrocalcinosis [7].

Acute CPP crystal arthritis — Acute calcium pyrophosphate (CPP) crystal arthritis is characterized by self-limited acute or subacute attacks of arthritis involving only one or several extremity joints [10]. The traditional term "pseudogout" underlines the usually close resemblance of these attacks to those of urate gout in the accompanying symptoms and signs of severe acute inflammation (intense pain, redness, warmth, swelling, and joint disability) and in the occasional occurrence of synchronous inflammation of several adjacent joints (cluster attacks) or, conversely, petite attacks (which are minimally painful episodes of joint warmth and swelling).

The knee is affected in over 50 percent of all acute attacks of acute CPP crystal arthritis, while the first metatarsophalangeal joint is the most frequently affected in urate gout. Other joints typically affected in acute CPP crystal arthritis include wrists, shoulders, ankles, feet, and elbows. Initial episodes of acute CPP crystal arthritis may persist longer before remitting than the one or two weeks commonly encountered in urate gout, and an upper-extremity site of inflammation (wrist, elbow, shoulder) for a first attack should raise suspicion for acute CPP crystal arthritis [11]. These episodes are typically self limited, and they usually last days to weeks.

A review of 50 cases of acute CPP crystal arthritis, many of which were polyarticular attacks, described low-grade fevers in 50 percent and frequently elevated sedimentation rates [11]. In some cases, systemic features accompanying polyarticular acute CPP crystal arthritis are quite prominent and may suggest pyogenic arthritis, osteomyelitis, and/or systemic sepsis. (See 'Chronic CPP crystal inflammatory arthritis' below.)

Rarely, and usually after several acute arthritic flares, palpable and visible masses of CPP crystals, resembling gouty tophi, accumulate in synovium and adjacent joint structures and may lead to locally destructive and compressive symptoms.

Chronic CPP crystal arthritis

Chronic CPP crystal inflammatory arthritis — The term "pseudo-rheumatoid arthritis" (pseudo-RA) was applied to a nonerosive, inflammatory arthritis in which CPP crystals were demonstrable in joint fluid [2]. This presentation of CPPD disease resembles RA in several respects, including the presence of significant morning stiffness, fatigue, synovial thickening, localized edema, and restricted joint motion due either to active inflammation or to flexion contracture. The relative frequency of chronic CPP crystal inflammatory arthritis is not known.

Typically, the chronic inflammatory arthritis of CPPD disease involves multiple joints, frequently involving peripheral joints of the upper and lower extremities, including the wrists and metacarpophalangeal (MCP) joints, as well as the knees and elbows, in a symmetric or nearly symmetric pattern. Articular inflammation may last up to several months, and inflammation in affected joints tends to wax and wane independently of one another, in distinction to RA, where synchronous flare and remission are more typical. These episodes are typically self-limited, usually lasting from days to weeks.

Older patients may have prominent systemic features during an acute polyarticular attack, such as leukocytosis, fever, and mental confusion, closely mimicking systemic sepsis [12]. In such patients, the delirium is reported to resolve with resolution of the acute flare.

Osteoarthritis with CPPD — Osteoarthritis (OA) with CPPD is a more common and often unrecognized form of symptomatic CPPD disease; for example, 20 percent of unselected patients examined at total knee joint replacement for OA showed CPP crystals in synovial fluid samples [13]. Approximately 50 percent of patients with symptomatic CPPD disease show progressive joint degeneration, usually involving multiple joints. This pattern of disease has historically been referred to as "pseudo-OA" because of its resemblance to OA occurring in the absence of CPPD. In approximately one-half of such patients, episodes of acute inflammatory arthritis typical of pseudogout punctuate the course. In the remainder, joint degeneration proceeds by a process more typical of classical OA. (See "Clinical manifestations and diagnosis of osteoarthritis".)

The most commonly affected joints in this form of CPPD disease are the knees, followed by the wrists, MCP joints, hips, shoulders, elbows, and spine. Although a symmetric pattern of joint involvement is frequent, unilateral or more severe degenerative change on one side is not unusual. Findings on clinical examination of individual joints do not typically differ from those observed in OA, which include asymmetric bony enlargement, tenderness, effusions, crepitus, and restricted joint motion. Patients with OA with CPPD may also exhibit contractures of involved joints.

The arthritic process of CPPD may occur in joints typically involved in OA, such as the interphalangeal joints of the hands, the first carpometacarpal joints, the knees, or the first metatarsophalangeal joints. An etiologic or accelerating role for CPPD in joint degeneration seems likely when radiographic calcification is present early in the course of degeneration, particularly if the degenerative changes also involve joints atypical for OA (wrists, MCP joints, elbows, and shoulders) in the absence of a preceding history of joint trauma or of vocational or avocational stress.

As cartilage is lost during the course of progressive joint degeneration, previously apparent cartilage calcification may become increasingly difficult or impossible to detect radiographically, thereby obscuring the diagnosis. (See 'Imaging findings' below.)

Severe joint degeneration — A number of reports have documented CPPD in association with severe joint degeneration which closely resembles neuropathic arthropathy [14-16]. Neuropathic arthropathy is characterized by severe joint degeneration and disruption occurring in the course of neurologic disorders leading to joint denervation; the affected joint is often called a Charcot joint. Underlying disorders associated with Charcot joints include diabetes mellitus (most common), tabes dorsalis, and syringomyelia. (See "Diabetic neuroarthropathy".)

In contrast to neuropathic arthropathy, neurologic function is typically normal in severe joint degeneration associated with CPPD, prompting use of the term "pseudo-neuropathic joint disease" for this relationship, although an underlying neurologic impairment (typically tabes dorsalis) has, in some instances, been demonstrated [15,16].

Spinal involvement (including crowned dens syndrome) — CPPD in and about the spine has been associated with a number of clinical manifestations, including spine stiffness, sometimes associated with bony ankylosis, which can resemble the spinal changes of ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis (DISH). Such symptoms have been most commonly encountered in familial CPPD disease [17]. In addition, crystal deposition in the ligamentum flavum at the cervical spine level or in the posterior longitudinal ligament at lower levels of the spine may lead to spinal cord compression syndromes or to symptoms either of acute nerve compression or of chronic spinal stenosis [18-20].

The crowned dens syndrome (CDS) is a rare, but important to recognize, syndrome characterized by severe acute or recurrent axial neck pain, neck and shoulder girdle stiffness, and associated fever; elevated inflammatory markers (C-reactive protein, erythrocyte sedimentation rate), and CPPD demonstrable on computed tomography (CT) in and around the atlanto-axial articulation) (image 2) [21,22]. The importance of identification of the crystal deposition basis of CDS lies both in the resemblance of its symptoms and signs to those of polymyalgia rheumatica, giant cell arteritis, or, less frequently, meningitis, cervical discitis, or inflammatory spondyloarthritis; and in the usually favorable response of CDS clinical features to treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or colchicine. The diagnosis of CDS is made based on clinical presentation and imaging alone. (See 'Diagnostic imaging' below and 'Classification criteria' below.)

Other manifestations — CPPD in bursae, ligaments, and tendons may be sufficient to cause local nerve compression, as in the carpal tunnel [23], as well as tissue damage.

SYNOVIAL FLUID FINDINGS — The total synovial fluid leukocyte concentration during an episode of acute calcium pyrophosphate (CPP) crystal arthritis can vary between 10,000 and 150,000 cells/mm³, with a neutrophilic predominance, based on the author's experience.

The most helpful finding on synovial fluid analysis in calcium pyrophosphate crystal deposition (CPPD) disease is the presence of positively birefringent CPP crystals by compensated polarized light microscopy. In inflamed joints during an attack of acute CPP crystal arthritis, phagocytosed crystals within polymorphonuclear leukocytes are virtually always present (picture 1), but extracellular CPP crystals are equally important for diagnosis.

CPP crystals differ from the needle-shaped, strongly and negatively birefringent monosodium urate crystals in acute gouty arthritis (picture 2); CPP crystals are more difficult to detect than monosodium urate crystals because they are:

●Smaller (0.5 to 10 microns)

●Weakly positively birefringent or not birefringent at all

●More polymorphic with rod-shaped and rhomboidal forms

Patients with CPP crystals in a synovial fluid sample may also have the simultaneous presence of monosodium urate crystals. The coexistence of urate and CPP crystals in a single effusion is neither uncommon nor unexpected, given the observed frequencies of hyperuricemia (20 percent) and gout (approximately 5 percent) among patients with CPPD disease [2].

IMAGING FINDINGS — Imaging evidence for calcium pyrophosphate crystal deposition (CPPD) has traditionally relied upon conventional radiography, which reveals findings of cartilage calcification (see 'Cartilage calcification (chondrocalcinosis)' below). Degenerative changes in the joint are also frequently present, and certain radiographic findings in particular joints are characteristic of CPPD disease in those locations (see 'Degenerative changes' below and 'Other radiographic features in specific joints' below). Ultrasonographic findings that correlate with radiographic features of CPPD disease have also been described (see 'Ultrasonographic findings' below). Magnetic resonance imaging (MRI) is a less sensitive imaging modality for documenting CPPD than conventional radiography, ultrasonography, or CT. Dual-energy CT (DECT) is very effective at identifying gout crystal deposits, but the literature still lacks strong evidence for its ability to conclusively identify calcium pyrophosphate (CPP) crystals [24,25].

Plain film radiography

Cartilage calcification (chondrocalcinosis) — Radiographic evidence of CPPD is the defining feature of this finding. CPPD typically appears as punctate and linear radiodensities in articular cartilage (fibrocartilage and/or hyaline cartilage) (image 1) and, with lesser frequency, in ligaments, tendons, synovia, bursae, and joint capsules. Although deposits of basic calcium phosphate crystals may occasionally cause confusion, such deposits are usually faint and are irregularly contoured.

●Cartilage – Among affected fibrocartilages in CPPD disease are the menisci of the knee (usually bilaterally), the symphysis pubis, the triangular fibrocartilage of the wrist joints, and the glenoid and acetabular labra. CPP deposits in hyaline cartilage frequently appear as radiopaque lines paralleling the surface of the underlying bone.

●Joints – Larger joints, such as the knee, wrist, elbow, shoulder, and hip, are most frequently involved in CPPD disease, but almost any diarthrodial joint may be affected radiographically. Articular capsule or synovial calcification is often fainter and more diffuse than cartilage calcification.

Linear calcifications involving the Achilles tendon or plantar fascia are often seen in CPPD disease [26].

Degenerative changes — CPPD is often associated with degenerative changes in joints, even in the absence of radiographic cartilage calcification. Characteristic degenerative changes in CPPD disease include typical features of osteoarthritis (OA), including subchondral cysts, osteophyte formation, and bone and cartilage fragmentation.

CPPD disease may also underlie the occurrence of radiographic features of OA in joints not commonly affected by primary OA. (See 'Classification criteria' below and 'Differential diagnosis' below.)

Other radiographic features in specific joints — A variety of radiographic signs restricted to joints or regions are more or less characteristic of CPPD disease, sometimes in addition to cartilage calcification (see 'Cartilage calcification (chondrocalcinosis)' above). The affected joints and findings include:

●Metacarpophalangeal (MCP) joints – Squared-off bone ends and hook-like osteophytes in the MCP joints, particularly if these changes are located in the second and third MCP joints. Such changes are especially common in hemochromatosis [27] and hemochromatosis-associated CPPD disease [28]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

●Wrist – Isolated or unusually extensive radiocarpal joint narrowing and/or navicular-lunate dissociation [29].

●Patellofemoral joints – Severe patellofemoral joint space degeneration, especially with a wraparound deformity of the patella on the femur. This finding is seen in hyperparathyroidism with or without CPPD. Notching or erosion of the distal femoral cortex superior to the patella may also occur [30].

●Spine and pelvis – Axial skeleton changes, such as subchondral cysts in the small joints of the spine and in the sacroiliac joints, calcification of multiple intervertebral discs, and sacroiliac joint vacuum phenomena [31].

Crowned dens syndrome (CDS) can be identified by use of CT (image 2), which is the preferred modality to demonstrate its presence. Findings may include CPP crystal masses at the atlanto-axial articulation and/or in the transverse ligament of the atlas and/or in the ligamentum flavum [32]. (See 'Spinal involvement (including crowned dens syndrome)' above.)

Ultrasonographic findings — The following findings on ultrasonography of articular and fibrocartilage may be indicative of the presence of deposits of CPP crystals [33,34]:

●A thin hyperechoic band paralleling the bone cortex and separated from it by a hypoechoic region representing cartilage. The resulting ultrasonographic appearance resembles the double contour sign (DCS) initially described in gout [35], but it often exhibits a thin, stippled appearance rather than the smooth pattern characteristic of gout.

●Small hyperechoic rounded amorphous shaped regions, often with acoustic shadowing, which are most often found in images of fibrocartilage of the wrist (image 3) and menisci of the knee as well as in tendons.

●Nodular hyperechoic deposits in bursae and articular recesses.

●Hyperechoic lines of calcification running parallel to tendon fibers.

In contrast to urate crystal deposits in gout, CPP crystals often deposit within the substance of hyaline cartilage, providing a potentially attractive means to distinguish between these crystal deposition arthropathies.

Ultrasonography is increasingly commonly used clinically and has utility for the diagnosis of CPPD disease in experienced hands [36,37] and for tracking the efficacy of CPPD disease therapies. Based upon the limited data available, ultrasonography appears to have sensitivity for aspiration-confirmed CPPD disease better than that of conventional radiography when employed by experts in joint imaging [38].

Dual-energy computed tomography — There has been significant interest in the use of DECT in crystal arthritis. Unlike traditional CT scanning, DECT can identify the chemical composition of crystal deposits. It has been highly successful in detecting gout crystals, and some small studies have supported its potential use in identifying CPPD [39,40]. Subsequent work suggested that it may not be as useful as ultrasonography in detecting CPP crystal deposits [24] and that when used alone it has difficulty differentiating CPP crystals from basic calcium phosphate crystals [25]. DECT is not yet widely available and will require further validation before recommending routine clinical use for diagnosing CPPD.

DIAGNOSIS — The diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease is largely based upon the demonstration of calcium pyrophosphate (CPP) crystals in tissue or synovial fluid and/or upon radiographic evidence of the disease (see 'Diagnostic evaluation' below and 'Classification criteria' below). Generally, differences between the patterns of joint involvement in urate gout and acute CPP crystal arthritis are insufficient to permit definite diagnosis without demonstration of the specific crystal in the inflammatory joint effusion (picture 1).

When to suspect CPPD disease — A diagnosis of CPPD disease should be suspected in adults, especially those over age 55 years old, with any of the following features (see 'Clinical manifestations' above):

●Acute or subacute attacks of arthritis (particularly of the knee)

●Arthritis similar in character to rheumatoid arthritis (RA) or osteoarthritis (OA) but with some unusual features

●Apparent CPPD on radiographs

●Severe acute or recurrent axial neck pain, neck and shoulder girdle stiffness

Diagnostic evaluation — Patients suspected of CPPD disease should undergo arthrocentesis and synovial fluid analysis of the affected joint and conventional radiography of the involved joint(s) (see 'Synovial fluid analysis' below and 'Diagnostic imaging' below). Radiographs of asymptomatic joints are sometimes also helpful.

Synovial fluid analysis — Arthrocentesis of an affected joint with synovial fluid analysis for CPP crystals should be promptly undertaken, if possible, to establish the diagnosis (see 'Synovial fluid findings' above). An exception is in patients with axial neck pain and suspected crowned dens syndrome (CDS), as clinical symptoms and imaging findings are usually sufficient to establish the diagnosis of this type of CPPD disease (see 'Classification criteria' below). Synovial fluid analysis should include a white blood cell count and differential, and if infection is suspected, a Gram stain and culture to exclude alternative or concurrent diagnoses. Joint aspiration technique and synovial fluid analysis are described in detail separately. (See "Joint aspiration or injection in adults: Technique and indications" and "Synovial fluid analysis".)

Certain technical factors are important in the effort to identify CPP crystals in synovial fluid and tissue:

●Synovial fluid – Positively birefringent material other than CPP crystals may be identified in joint fluid samples unless care is taken to clean and remove dust from the microscope slide and cover slip. Lack of attention to these details may contribute to reports of a relatively low specificity and sensitivity in identifying CPP crystals in synovial fluid, particularly when the observers carrying out the analysis are relatively inexperienced [41-43]. The European Alliance of Associations for Rheumatology (EULAR) recommendations for CPPD disease suggest refinement of an optimal protocol (including training) and standards for identification of CPP crystals in joint fluids [4].

●Synovial tissue – CPP crystals may also be present in synovial tissue, although tissue sections stained with hematoxylin and eosin (H&E) are less likely to demonstrate typical birefringent crystals, possibly due to the dissolution of crystalline CPP in the acid reagents. Use of alizarin red has been reported to preserve the crystals and reduces the likelihood of a false negative result, but false-positive or -negative staining may occur [44]. Alizarin red also stains basic calcium phosphate crystals, so cannot distinguish between these two types of calcium-containing crystals. A nonaqueous stain, such as Wright's, is another alternative to routine H&E staining for synovial tissue.

Diagnostic imaging — Conventional radiographs of affected joints should be obtained to identify evidence of cartilage calcification (chondrocalcinosis) or other signs characteristic of CPPD disease. (See 'Plain film radiography' above.)

In patients in whom the diagnosis is suspected, but conventional radiographs of pertinent affected joints have not shown evidence of cartilage calcification screening, radiographs of other frequently involved joints should be obtained. We suggest that such radiographs should include:

●Anteroposterior (AP) view of each knee

●AP view of the symphysis pubis

●Posterior to anterior (PA) views of each wrist

A surprising number of patients demonstrate cartilage calcification on radiographs and CT performed for other than musculoskeletal evaluations at a variety of anatomic sites [45,46]. These deposits are often unrecognized or recognized but not reported by radiologists. Thus, reviewing films and CTs of the chest and pelvis may disclose unreported cartilage calcification.

In patients with neck pain suspected of CDS, the presence of chondrocalcinosis in other joints supports but does not confirm the diagnosis. A cervical spine CT scan is required for definitive diagnosis. (See 'Other radiographic features in specific joints' above.)

Ultrasonography can be a useful diagnostic modality in CPPD (see 'Ultrasonographic findings' above). If available, dual-energy CT (DECT) can assist in the diagnosis of crystal arthritis by definitively detecting the presence of gout crystals.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of each of the presentations of calcium pyrophosphate crystal deposition (CPPD) disease (see 'Clinical manifestations' above) is addressed separately below:

●Asymptomatic cartilage calcification – CPPD without symptoms ("asymptomatic CPPD") is typically discovered when chondrocalcinosis is incidentally noted on radiographs (see 'Cartilage calcification (chondrocalcinosis)' above). Widespread or premature articular or fibrocartilage calcification may be an indication of an underlying, potentially treatable disorder for which screening tests may be valuable. (See 'Post-diagnostic evaluation for associated diseases' below.)

●Acute CPP crystal arthritis – Acute calcium pyrophosphate (CPP) crystal arthritis closely resembles gout in its clinical features (hence the term "pseudogout"), including acute or subacute attacks in a single or only a few joints, with prominent signs of local inflammation and sometimes systemic signs such as leukocytosis and elevated acute phase reactants. In addition, trauma, surgery, or severe medical illness may provoke acute attacks in both of these crystal-induced disorders. Despite these similarities, the joints most commonly involved in an acute episode differ between gout and acute CPP crystal arthritis. The knee is affected in over 50 percent of all acute attacks of pseudogout, whereas the first metatarsophalangeal joint is more frequently involved in gout. The distinction between these conditions is made based upon identification of crystals under polarizing light microscopy that are characteristic of one or the other condition. (See "Clinical manifestations and diagnosis of gout".)

The broader differential diagnosis of an acute monoarthritis is discussed in detail separately; however, infection, trauma, bleeding, and other crystal-associated diseases (eg, gout) are among the important disorders to consider. These conditions can usually be distinguished from acute CPP crystal arthritis by synovial fluid analysis and joint radiography, although the presence of CPP crystals in joint fluid does not exclude infection. Thus, Gram stain, as well as joint fluid and blood cultures, is generally necessary to exclude an infectious etiology. (See "Monoarthritis in adults: Etiology and evaluation" and "Septic arthritis in adults" and "Synovial fluid analysis".)

●Chronic CPP crystal inflammatory arthritis – Chronic CPP crystal inflammatory arthritis ("pseudo-rheumatoid arthritis [RA]") may present in a similar fashion to other forms of chronic inflammatory arthritis, particularly RA, and must be distinguished from RA and other causes of polyarthralgia or polyarthritis. In chronic CPP crystal inflammatory arthritis, the multiple inflamed joints typically flare independently of one another, unlike in RA, where multiple joints usually flare and improve in parallel. Radiographic changes in chronic CPP crystal inflammatory arthritis are more typical of osteoarthritis (OA) than RA, despite the pattern of clinical joint involvement suggestive of the latter disorder (see 'Imaging findings' above). The diagnostic approach to adults with polyarticular joint pain is presented in detail elsewhere. (See "Evaluation of the adult with polyarticular pain".)

Diagnostic confusion between pseudo-RA and RA may arise when inflammation is more or less symmetrical and, particularly, when rheumatoid factor is detectable (as is the case in a substantial proportion of normal older individuals). Generally, the identification of CPP crystals and radiographic changes typical of CPPD disease will help distinguish the disorders. However, to further complicate the picture, symptomatic CPPD disease has been noted to occur as a late complication in patients with RA [47], and RA was noted to be more common in patients with CPPD disease than in age-matched controls without CPPD disease in one retrospective study [48]. It is important to distinguish between the coexistence of RA and CPPD disease and the expression of one masquerading as the other because of the substantial difference in management between these conditions. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

Other forms of subacute and chronic inflammatory arthritis, such as peripheral spondyloarthritis, including reactive arthritis and arthritis associated with inflammatory bowel disease, as well as psoriatic arthritis, can generally be distinguished from CPPD arthropathy by the presence of other clinical features typical of these disorders and the absence of CPP crystals from synovial fluid and of radiographic findings of cartilage calcification. (See "Reactive arthritis" and "Clinical manifestations and diagnosis of psoriatic arthritis" and "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)

●OA with CPPD – In OA with CPPD (pseudo-OA), the findings on clinical examination of individual joints do not typically differ from those observed in OA, and the symptoms and radiographic features include those of OA. However, patients with OA with CPPD often exhibit changes in joints not typically affected in patients with OA alone, and findings of cartilage calcification are often present before there is significant degenerative joint disease, although patients may not have been evaluated at this stage of illness. In addition to the atypical distribution, other features on examination that should alert the clinician to possible CPPD disease include contractures of involved joints and valgus deformities of the knees. The clinical manifestations and diagnosis of OA are discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of osteoarthritis".)

●CPPD with severe joint degeneration – CPPD with severe joint degeneration may resemble neuropathic joint destruction radiographically, with severe degenerative changes and disorganization of the bony structures in the joint. Unlike pseudo-neuropathic joint disease, true neuropathic arthropathy is characterized by loss of joint position sensation and sometimes by loss of other sensory function, such as pain and temperature sensation. Disorders associated with neuropathic arthropathy (Charcot joint) include diabetes mellitus (most common), tabes dorsalis, syringomyelia, and spinal cord injuries, and their presence should increase suspicion of this condition. The presence of CPP crystals, by contrast, is consistent with pseudo-neuropathic joint disease instead. (See "Diabetic neuroarthropathy".)

●CPPD with nerve or spinal cord compression – Mass effects from collections of CPPD crystals and associated soft tissue must be distinguished from other calcifying or ossifying mass lesions. An intraspinal mass with punctate soft tissue calcification suggests chondrosarcoma, and histopathologic examination of the resected tissue may be required to exclude a malignant neoplasm [49] (see "Spinal cord tumors", section on 'Sarcomas'). Monosodium urate tophi may rarely cause neurologic compressive syndromes. (See "Clinical manifestations and diagnosis of gout".)

CLASSIFICATION CRITERIA — There are no validated diagnostic criteria for calcium pyrophosphate crystal deposition (CPPD) disease intended for use in clinical practice. However, the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) have issued validated classification criteria for symptomatic CPPD disease that were developed for use in clinical research and are not intended for diagnostic purposes [50].

The criteria are summarized below (figure):

●Entry criteria – Patients must have at least one episode of joint pain, swelling, or tenderness at a peripheral or axial joint to consider CPPD disease.

●Exclusion criteria – If all symptoms are more likely explained by an alternative diagnosis, then the patient does not have CPPD disease.

●Sufficient criteria – Either evidence of CPP crystals on synovial fluid/biopsy or crowned dens syndrome (CDS) is sufficient to diagnose CPPD disease.

The diagnosis of CDS is based on:

•Clinical features – Acute or subacute onset of severe neck pain localized to the upper neck with limited rotation, elevated inflammatory markers, and often fever, in the absence of other diagnoses that can present similarly including polymyalgia rheumatica and meningitis

and

•Imaging features – CT showing calcific deposits, typically linear and less dense than cortical bone, in the transverse retro-odontoid ligament (transverse ligament of the atlas), often with an appearance of two parallel lines in axial views; calcifications at the atlanto-axial joint, alar ligament, and/or in pannus adjacent to the tip of the dens; and/or dual-energy CT (DECT)

●Additional points – If a patient does not have sufficient criteria, they may still have CPPD disease if they score >56 points in other domains (table 1).

Older criteria classified patients as having definite, probable, or possible CPPD disease [2,3].

POST-DIAGNOSTIC EVALUATION FOR ASSOCIATED DISEASES — Patients with a diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease, even if asymptomatic, may also have one of a number of associated disorders, including hemochromatosis, hyperparathyroidism, hypomagnesemia, hypophosphatasia, and familial hypocalciuric hypercalcemia (table 2) [51]. The conditions associated with CPPD disease are reviewed in detail separately. (See "Pathogenesis and etiology of calcium pyrophosphate crystal deposition (CPPD) disease".)

Given these disease associations, we suggest that some patients diagnosed with CPPD disease undergo the following serum screening studies [2]. A search for these associated metabolic conditions is particularly fruitful when CPPD disease is diagnosed at a young age. Familial forms of CPPD disease may also occur early in life.

●Calcium

●Phosphorus

●Magnesium

●Alkaline phosphatase

●Parathyroid hormone (PTH)

●Iron and transferrin

Appropriate further evaluation should be undertaken if one or more of these values is abnormal or there are other clinical clues to one of these diagnoses. For example, if hypophosphatasia is strongly suspected, elevated circulating levels of pyridoxal-5' phosphate (the active form of vitamin B6) may serve to demonstrate functionally deficient alkaline phosphatase [52]. Despite the value of establishing and treating the non-musculoskeletal system organ-specific abnormalities associated with the presence of some of the disorders associated with CPPD disease, the results of specific treatments directed at the respective associated disorders, such as reversal of the iron overload in hemochromatosis or the parathyroid hormone (PTH) excess in hyperparathyroidism, have been ineffective in halting or reversing CPPD.

In addition, CPPD may be associated with an increased risk of cardiovascular disease. In a study of 23,124 CPPD patients and 86,629 controls, the frequency of traditional cardiovascular risk factors was similar between the two groups [53]. However, patients in the CPPD cohort had an increased risk of myocardial infarction (hazard ratio [HR] 1.41), acute coronary syndrome (HR 1.27), and stroke (HR 1.30) when compared with patients without CPPD.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gout and other crystal disorders".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Calcium pyrophosphate deposition disease (The Basics)")

●Beyond the Basics topics (see "Patient education: Calcium pyrophosphate crystal deposition (CPPD) disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Terminology – The term calcium pyrophosphate crystal deposition (CPPD) refers to the presence of calcium pyrophosphate (CPP) crystals as detected by microscopy or imaging. The term "CPPD disease" indicates the presence of symptomatic arthritis. Chondrocalcinosis refers to radiographic calcification in hyaline and/or fibrocartilage. (See 'Terminology' above.)

●Epidemiology – CPPD disease primarily affects adults aged 65 years and older, and radiographic surveys demonstrate an age-related increase in the prevalence of articular cartilage calcification. There is no major sex predominance. (See 'Epidemiology' above.)

●Clinical manifestations – The clinical spectrum of CPPD disease is broad. The range of presentations, named as proposed by a European Alliance of Associations for Rheumatology (EULAR) task force (with alternative and traditional terms in parentheses) includes (see 'Clinical manifestations' above and 'Terminology' above):

•Asymptomatic CPPD disease ("asymptomatic CPPD") (see 'Asymptomatic CPPD disease' above)

•Acute CPP crystal arthritis ("pseudogout") (see 'Acute CPP crystal arthritis' above)

•Chronic CPP crystal inflammatory arthritis ("pseudo-rheumatoid arthritis [RA]") (see 'Chronic CPP crystal inflammatory arthritis' above)

•Osteoarthritis (OA) with CPPD, with or without superimposed acute attacks ("pseudo-OA") (see 'Osteoarthritis with CPPD' above)

•Severe joint degeneration (pseudo-neuropathic joint disease) (see 'Severe joint degeneration' above)

•Spinal involvement

●Synovial fluid findings – Synovial fluid analysis in CPPD disease is characterized by the presence of weakly positively birefringent CPP crystals. CPP crystals and polymorphonuclear leukocytes are virtually always present in inflamed joints during an acute attack of CPP crystal arthritis (picture 1). The total synovial fluid leukocyte concentration can vary between 10,000 and 150,000 cells/mm³ with a neutrophilic predominance. (See 'Synovial fluid findings' above and 'Synovial fluid analysis' above.)

●Imaging findings – Cartilage calcification (ie, chondrocalcinosis) refers to evidence of CPPD in hyaline or articular cartilage or fibrocartilage on radiographs, and it is commonly seen both in CPPD disease and asymptomatic individuals. CPP crystal deposits typically appear as punctate and linear radiodensities in cartilage (image 1) and, with lesser frequency, in ligaments, tendons, synovium, and joint capsules. Ultrasonographic findings that correlate with radiographic features of CPPD disease have also been described (image 3). (See 'Imaging findings' above and 'Plain film radiography' above and 'Ultrasonographic findings' above.)

●Diagnosis – A diagnosis of CPPD disease should be suspected in the patient (most often over age 65) with acute or subacute attacks of arthritis (particularly of the knee), arthritis similar in character to RA or OA, apparent CPPD on radiograph, or other less common presentations. Establishing the diagnosis is largely based upon the demonstration of CPP crystals in tissue or synovial fluid and/or upon radiographic evidence of the disease. Screening radiographs of other frequently involved joints should be obtained in all patients in whom the diagnosis is suspected but in whom radiographs of pertinent affected joints have not yielded a definitive diagnosis. (See 'Clinical manifestations' above and 'Diagnosis' above.)

●Post-diagnostic evaluation for associated diseases – Patients with a diagnosis of CPPD disease may also have one of a number of associated disorders, including hemochromatosis, hyperparathyroidism, hypomagnesemia, hypophosphatasia, and familial hypocalciuric hypercalcemia (table 2). Given these disease associations, patients diagnosed with CPPD, even if asymptomatic and especially if less than 50 years of age, should undergo the following serum screening studies: calcium, phosphorus, parathyroid hormone (PTH), magnesium, alkaline phosphatase, iron, and transferrin. (See 'Post-diagnostic evaluation for associated diseases' above.)

●Differential diagnosis – The differential diagnosis of CPPD disease is broad and differs for each of the potential clinical presentations. Major considerations include gout and septic arthritis, RA, and OA. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Lawrence Ryan, MD, and Michael A Becker, MD, who contributed to an earlier version of this topic review.