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Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease
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Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2016. | This topic last updated: Jul 14, 2015.

INTRODUCTION — Precipitation of crystals of calcium pyrophosphate dihydrate (CPP) in connective tissues may be associated with several clinical syndromes, but is sometimes asymptomatic. The consequences of CPP deposition include an acute and chronic inflammatory arthropathy and radiographic 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 names traditionally used for calcium pyrophosphate dihydrate (CPP) crystal deposition (CPPD) diseases include pseudogout, chondrocalcinosis, and pyrophosphate arthropathy. Based upon a review of the relevant literature, a European League Against Rheumatism (EULAR) consensus panel suggested alternative terminology and reviewed diagnostic approaches to these conditions and the evidence supporting these approaches [4]. The term “calcium pyrophosphate crystal deposition”, which is abbreviated as ‘CPPD, is proposed by the EULAR task force as the umbrella term for all instances of calcium pyrophosphate crystal occurrence. The clinical syndromes and findings implied by the traditional terms and their limitations, together with the nomenclature proposed by EULAR, include:

Pseudogout – Pseudogout accurately describes acute attacks of CPPD-induced synovitis, which clinically resemble acute attacks of urate gout. However, the majority of individuals with CPPD never experience such episodes, and the range of clinical events characterizing gout and CPPD disease extend well beyond those that characterize acute gouty arthritis. The EULAR consensus panel thus prefers the term “acute calcium pyrophosphate (CPP) crystal arthritis” instead of pseudogout.

Notably, however, the use of the term “pseudogout” has also been used more broadly to direct attention to the shared clinical features of the two major crystal-induced arthritides (gout and pseudogout) that are seen much less commonly in other joint diseases, such as rheumatoid arthritis (RA) or spondyloarthritis; these features include recurrent, usually monoarticular, flares of inflammatory arthritis that are self-limited in duration and most often resolve completely. Thus, retention of the diagnostically useful concept of a shared clinical profile of crystal-induced arthritis has merit, as does the mandate to distinguish gout from pseudogout with respect to therapeutic approaches, and it is likely that the term “pseudogout” will persist.

Chondrocalcinosis – Chondrocalcinosis refers to radiographic calcification in hyaline and/or fibrocartilage (image 1). It is commonly present in patients with CPP crystal deposition disease but is neither absolutely specific for CPPD nor universal among affected patients. The EULAR group designates this finding as “cartilage calcification (CC).”

Pyrophosphate arthropathy – Pyrophosphate arthropathy is the term sometimes used for the joint diseases or radiographic abnormalities accompanying CPP crystal deposition. Although this name has little justification in terms of the pathologic anatomy of the disorder, evidence of aberrant inorganic pyrophosphate metabolism in the pathogenesis of CPPD disease (see "Pathogenesis and etiology of calcium pyrophosphate crystal deposition (CPPD) disease") may legitimize use of this term.

A commentary has been published concerning the EULAR committee recommendations, which is coauthored by one of the authors of this topic review and generally supports use of the 2011 EULAR terms [5]. However, these terms are not yet widely accepted, and we have therefore retained use of the traditional terminology while also noting the alternative terms for these conditions.

EPIDEMIOLOGY — Calcium pyrophosphate crystal deposition (CPPD) disease is a disease of older adults, and increasingly common in both men and women with advancing age. The average age at diagnosis in one study was 72 years [6]. Radiographic surveys also demonstrate an age-related increase in the prevalence of articular chondrocalcinosis [7-9]. This was illustrated in a report that supplemented radiographs of the knees with radiographs of the hands, wrists, and pelvis [9]. The prevalence of radiographic calcium pyrophosphate deposition according to age, among 100 consecutive admissions to an acute geriatric unit, was:

65 to 74 years – 15 percent

75 to 84 years – 36 percent

>84 years – Almost 50 percent

Precise prevalence data concerning younger patients are not available.

The gender distribution of CPPD disease has differed among large series [6,10-12], but no major sex predominance appears likely. Attacks of acute arthritis may occur more frequently in men, while typical osteoarthritis (OA) with calcium pyrophosphate dihydrate (CPP) or the atypical pattern of OA characteristic of CPPD are more common in women.

CLINICAL MANIFESTATIONS — The majority of individuals with calcium pyrophosphate dihydrate (CPP) crystal deposition (CPPD) disease are asymptomatic with respect to joint involvement, and there is considerable diversity in the patterns of joint disease among those who develop symptoms. A clinical classification of CPPD disease emerged from the studies of McCarty [1] and colleagues [2,3], which drew particular attention to the capacity for the clinical manifestations of this disorder to mimic virtually any type of arthritis, including gout, rheumatoid arthritis (RA), osteoarthritis (OA), and neuropathic joint disease. This clinical classification relates to the nomenclature (in parentheses) proposed by the European League Against Rheumatism (EULAR) as follows:

Asymptomatic disease (“asymptomatic CPPD”) (see 'Asymptomatic CPPD' below)

Pseudogout (“acute CPP crystal arthritis”) (see 'Acute arthritis/Pseudogout' below)

Pseudo-RA (“chronic CPP crystal inflammatory arthritis”) (see 'Chronic CPP crystal inflammatory arthritis/Pseudo-rheumatoid arthritis' below)

Pseudo-OA, with or without superimposed acute attacks (“OA with CPPD”) (see 'Osteoarthritis with CPPD' below)

Pseudo-neuropathic joint disease (see 'Severe joint degeneration/Pseudo-neuropathic joint disease' below)

Asymptomatic CPPD — Most joints in which CPP crystal deposition is readily apparent on radiographs are asymptomatic, even among patients in whom acute or chronic clinical manifestations of CPPD disease in one or several other joints have occurred. However, patients with apparent asymptomatic CPPD 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 CPP crystal deposition, a higher frequency of wrist complaints and genu varus deformity was reported by questionnaire and detected by examination, respectively, than in a control group of similar age but without radiographic chondrocalcinosis [7].

Acute arthritis/Pseudogout — Pseudogout (“acute CPP crystal arthritis”) is characterized by self-limited acute or subacute attacks of arthritis involving only one or several extremity joints [11]. The use of the 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 (MTP) 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.

Trauma, surgery, or severe medical illness may frequently provoke acute attacks. In particular, flares of pseudogout after parathyroidectomy have been observed [13]; these episodes may be related to abrupt reduction in serum calcium and magnesium levels during postoperative hypoparathyroidism (see "Hungry bone syndrome following parathyroidectomy"). Such reduction may cause partial dissolution of crystals with subsequent release from the cartilage matrix into the joint fluid, allowing phagocytosis and the phlogistic response of inflammatory cells.

Intraarticular hyaluronate injection and treatment with pamidronate or granulocyte-macrophage colony-stimulating factor (GM-CSF) [14-16] have also been reported to precipitate acute attacks of pseudogout. However, most patients affected with CPPD who experience acute joint inflammation following hyaluronate injection do not demonstrate crystals in their joint fluids [17].

In our experience, systemic findings and laboratory abnormalities, such as fever, leukocytosis with a left shift in the differential count, and an elevated sedimentation rate and serum C-reactive protein (CRP), occur during attacks of acute CPP crystal arthritis in a small minority of affected patients, but the frequency of each is probably less than in acute gouty arthritis. A review of 50 cases of pseudogout, many of which were polyarticular attacks, described low-grade fevers in 50 percent and frequently elevated sedimentation rates [18]. In some cases, the systemic features are quite prominent and may suggest pyogenic arthritis, osteomyelitis, and/or systemic sepsis.

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 inflammatory arthritis/Pseudo-rheumatoid arthritis — The term pseudo-rheumatoid arthritis (pseudo-RA) applies to a nonerosive, inflammatory arthritis in which CPP crystals are demonstrable in joint fluid [2]. The alternative name proposed for this condition is “chronic CPP crystal inflammatory arthritis.” Pseudo-RA has been used traditionally as the label for this presentation of CPPD because the clinical picture may closely resemble 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.

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 is the rule.

Pseudo-RA occurs in 5 percent or less of patients with symptomatic CPPD disease. A rare subtype of chronic CPP crystal inflammatory arthritis is characterized by prominent systemic features such as leukocytosis, fever, mental confusion, as well as inflammatory polyarthritis [19]. In older adults, this clinical presentation can closely mimic systemic sepsis.

Osteoarthritis with CPPD — Approximately 50 percent of patients with symptomatic CPP crystal deposition 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. The alternative term for this presentation is “OA with CPPD.” In about 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 pseudo-OA 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 asymmetrical bony enlargement, tenderness, effusions, crepitus, and restricted joint motion. Patients with OA with CPPD may also exhibit contractures of involved joints and valgus deformities of the knees.

When the arthritic process occurs in joints typical for OA (such as the interphalangeal joints of the hands, the first carpometacarpal joints, the knees, or the bunion joints), even radiograph or joint fluid evidence of CPPD does not permit an unequivocal diagnosis. However, an etiologic or accelerating role for CPP crystal deposition 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 chondrocalcinosis may become increasingly difficult or impossible to detect radiographically, thereby obscuring the diagnosis. The radiographic features of CPPD are described. (See 'Imaging findings' below.)

Severe joint degeneration/Pseudo-neuropathic joint disease — A number of reports have documented CPP crystal deposition in association with severe joint degeneration which closely resembles neuropathic arthropathy [20-22]. 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 neuropathic arthropathy".)

In contrast to neuropathic arthropathy, neurologic function is typically normal in severe joint degeneration associated with CPP crystal deposition, although an underlying neurologic impairment (typically tabes) has in some instances been demonstrated [21,22]. The term “pseudo-neuropathic” also implies that, when crystal deposition is associated with certain neurologic deficits, the presence of crystals amplifies the destructive consequences of joint denervation.

Spinal involvement — CPP crystal deposition 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 [23]. 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 [24,25].

The crowned dens syndrome (CDS) is a rare, but important to recognize, syndrome, which is characterized by severe acute or recurrent axial neck pain, neck and shoulder girdle stiffness, and associated fever; elevated inflammatory markers (C-reactive protein [CRP]; erythrocyte sedimentation rate [ESR]); and CPP or calcium hydroxyapatite crystal deposition demonstrable on computed tomography (CT) in and around the atlanto-axial articulation [26]. 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.

Other manifestations — CPP crystal deposition occurring in the wake of trauma or prior surgery may result in localized inflammation or degeneration, most commonly in the knee or in the lower or lumbar spine. In addition, CPP crystal deposition in bursae, ligaments, and tendons may be sufficient to cause local nerve compression, as in the carpal tunnel [27].

SYNOVIAL FLUID FINDINGS

The most salient finding on synovial fluid analysis in calcium pyrophosphate dihydrate (CPP) deposition (CPPD) disease is the presence of positively birefringent CPP crystals by compensated polarized light microscopy. In inflamed joints during an attack of pseudogout, phagocytosed crystals within polymorphonuclear leukocytes are virtually always present (picture 1). However, certain characteristics of CPP crystals and several technical factors may affect detection of the crystals.

Total synovial fluid leukocyte concentration in acute pseudogout is typically 15,000 to 30,000 per mm3, 90 percent of which are neutrophils. The findings are somewhat different in chronically symptomatic joints, in which the crystals are often found extracellularly and cell counts may be lower.

The abundance of CPP crystals in the synovial fluid is generally related to the degree of clinically apparent inflammation [2]; however, large discrepancies between these variables can occur. The proportion of intracellular crystals varies roughly with the level of inflammation (as reflected clinically and by the synovial fluid neutrophil concentration).

CPP crystals differ from the relatively easily recognized needle-shaped negatively birefringent monosodium urate crystals in acute gouty arthritis (picture 2); CPP crystals are:

More difficult to detect

Smaller (0.5 to 10 microns)

Only weakly positively birefringent or not birefringent

More polymorphic with rod-shaped and cuboid crystals in addition to the usual rhomboidal form

In some instances, CPP crystals are too small to be readily visualized; for example, CPP crystals are sometimes smaller than can be resolved even by 1000-fold magnification with the aid of phase contrast microscopy [28].

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 inflammatory effusion is neither uncommon nor unexpected, given the observed frequencies of hyperuricemia (20 percent) and gout (5 percent) among patients with CPPD disease [2].

IMAGING FINDINGS — Imaging evidence for calcium pyrophosphate dihydrate (CPP) crystal deposition (CPPD) has traditionally relied upon plain film radiography, which reveals findings of cartilage calcification (see 'Chondrocalcinosis ("cartilage calcification")' 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 CPP crystal deposition than plain film radiography, ultrasonography, or computed tomography (CT).

Plain film radiography

Chondrocalcinosis ("cartilage calcification") — Radiographic evidence of calcium crystal deposition is the defining feature of chondrocalcinosis. CPP crystal deposits typically appear as punctate and linear radiodensities in fibrocartilage, in hyaline or articular cartilage (image 1), and, with lesser frequency, in ligaments and joint capsules. Although deposits of carbonate-substituted 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 discs of the distal radioulnar joint, and the glenoid and acetabular labra. CPP crystal deposits in hyaline cartilage frequently appear as a radiopaque line 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 most commonly detected in large joints, often appearing more faint and diffuse than the cartilage calcification (image 1).

Calcification due to CPP crystal deposition can also occur in bursae, ligaments, and tendons. Linear calcifications involving the Achilles tendon or plantar fascia are often seen in CPPD disease [29].

Degenerative changes — CPP crystal deposition is often associated with degenerative radiographic changes in joints, even in the absence of demonstrable chondrocalcinosis. Characteristic degenerative changes in CPPD disease include subchondral cysts, osteophyte formation, and bone and cartilage fragmentation.

CPP crystal disease may also underlie the occurrence of radiographic features of osteoarthritis (OA) in joints not commonly affected by primary OA (see 'Diagnostic criteria' below and 'Differential diagnosis' below). Cartilage calcification that is apparent at the onset of degenerative changes or which occurs earlier in life than usual and without a pertinent vocational or avocational history is also characteristic of CPPD disease, whether in joints typical or atypical for OA.

Stress fractures or osteonecrosis (avascular necrosis), particularly in the structures of the knee, may be consequences of or may be promoted by CPP crystal deposition.

Other radiographic features in specific joints — In several joints or regions a variety of radiographic signs restricted to such joints, are more or less characteristic of CPPD arthropathy, sometimes in addition to chondrocalcinosis (see 'Chondrocalcinosis ("cartilage calcification")' 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 [30] and hemochromatosis-associated CPPD disease [31]. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

Wrist – Isolated or unusually extensive radiocarpal joint narrowing and/or navicular-lunate dissociation [32]

Patellofemoral joints – Severe patellofemoral joint space degeneration, especially with a wrapped-around deformity of the patella on the femur. This finding is seen in hyperparathyroidism with or without CPP crystal deposition. Notching or erosion of the distal femoral cortex superior to the patella may also occur [33].

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 [34].

Crowned dens syndrome (CDS) (see 'Spinal involvement' above) can be identified by use of CT, which is the preferred modality to demonstrate its presence. Findings may include CPP (or hydroxyapatite) crystal masses at the atlanto-axial articulation and/or in the transverse ligament of the atlas and/or in the ligamentum flavum [35].

Ultrasonographic findings — The following findings on ultrasonography of articular and fibrocartilage may be indicative of the presence of deposits of CPP crystals [36,37]:

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 [38], 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 2) and menisci of the knee, and 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 a promising modality for clinical use in the diagnosis of CPPD disease and tracking the efficacy of CPPD disease therapies; however, further studies are warranted for validation of ultrasound criteria unique to CPP crystal deposition, resolution of differences reported with regard to the sensitivity and specificity of the procedure for the diagnosis of CPPD disease [36,39-42], and comparison of imaging findings with corresponding histopathology as the gold standard.

Based upon the limited data available, ultrasonography appears to have sensitivity for aspiration-confirmed CPPD disease similar to that of plain film radiography when employed by experts in joint imaging [36]. The utility of ultrasonography in diagnosing cartilage calcification outside of research centers, however, remains uncertain. Thus, we do not believe that the results of ultrasonographic study yet qualify as a diagnostic imaging criterion for CPPD disease.

DIAGNOSIS — The diagnosis of calcium pyrophosphate (CPP) deposition (CPPD) disease is largely based upon the demonstration of CPP crystals in tissue or synovial fluid and/or upon radiographic evidence of the disease (see 'Diagnostic evaluation' below and 'Diagnostic criteria' below). Generally, differences in 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).

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 rheumatoid arthritis (RA) or osteoarthritis (OA), apparent CPP crystal deposition on radiograph, and in patients with other selected but less common presentations. (See 'Clinical manifestations' above.)

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

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). Synovial fluid analysis should also include a white blood cell count and differential, 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 Examination of synovial fluid for CPP crystals should be carried out promptly after joint aspiration, because successful identification of the crystals diminishes as the time elapsed between joint aspiration and microscopic examination increases. Another technical source of error is that 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 [43-45]. The European League Against Rheumatism (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 [46]. A nonaqueous stain, such as Wright’s, is another alternative to routine H&E staining for synovial tissue.

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

In patients in whom the diagnosis is suspected, but plain radiographs of pertinent affected joints have not shown evidence of cartilage calcification screening, radiographs of other frequently involved joints should be obtained, since the radiographic features of CPP crystal deposition disease have good specificity and sensitivity. We suggest that such radiographs should include:

Anterior to posterior (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 computed tomography (CT) performed for other than musculoskeletal evaluations at a variety of anatomic sites [47,48]. 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 chondrocalcinosis.

Diagnostic criteria — The following diagnostic criteria and diagnostic classification for CPPD disease are based upon those initially proposed by McCarty and colleagues [2,3].

Definite CPPD crystal deposition disease A definite diagnosis of CPPD disease requires either:

The presence of both positively (but weakly) birefringent crystals by compensated polarized light microscopy and typical cartilage or joint capsule calcification on radiograph examination of any typically involved joint OR

The demonstration of CPP crystals in tissue or synovial fluid by definitive means (eg, radiograph diffraction, etc)

In clinical practice, definitive demonstration of crystals by radiograph diffraction powder pattern, electron microscopy, chemical analysis, or atomic force microscopy is only rarely achieved except in specialized research centers. Thus, the diagnosis is most commonly established by fulfilling the combination of radiographic and synovial fluid analysis criteria.

Probable CPPD disease A probable diagnosis of CPPD crystal disease occurs with either:

The identification of positively (but weakly) birefringent crystals by compensated polarized light microscopy OR

The presence of typical cartilage or joint capsule calcification on radiographic examination of any typically affected joint

The majority of patients thought to have CPPD disease by rheumatologists fall into the “probable disease” category. Given the state of management of this disorder, this fact does not appear to be a serious diagnostic quandary if alternative diagnostic possibilities are carefully considered and are acted upon appropriately.

Possible CPPD disease Fulfillment of either of the following criteria should raise the suspicion of possible CPPD disease and should prompt a direct evaluation aimed at fulfilling specific criteria for the disorder:

Acute arthritis of large joints, especially the knees, OR

Chronic arthritis which resembles OA, particularly if the involved joints are not typical for OA (wrists, metacarpophalangeal [MCP] joints, elbows, and shoulders) and if it is accompanied by acute, self-limited attacks. As previously mentioned, distinction from OA is further suggested by radiographic features typical of CPPD arthropathy in individual joints and the spine (even in the absence of chondrocalcinosis); severe and progressive joint degeneration, especially with prominent subchondral cyst formation; and tendon calcifications apparent on radiographs.

When the arthritic process occurs in joints typical for osteoarthritis (such as the interphalangeal joints of the hands, the first carpometacarpal joints, the knees, or the bunion joints), even radiograph or joint fluid evidence of CPP crystal deposition does not permit an unequivocal diagnosis. However, an etiologic or accelerating role for CPP crystal deposition in joint degeneration seems reasonable 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.

The criteria for possible CPPD disease are aimed at calling attention to the possibility of the disorder and at stimulating the search for more definitive criteria. They are not intended to attach a diagnostic label to an individual patient.

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

Asymptomatic cartilage calcification – CPPD deposition without symptoms (“asymptomatic CPPD”) is typically discovered when chondrocalcinosis is incidentally noted on radiographs (see 'Chondrocalcinosis ("cartilage calcification")' above). 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 arthritis – Acute 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 pseudogout. The knee is affected in over 50 percent of all acute attacks of pseudogout, whereas the first metatarsophalangeal (MTP) 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 pseudogout 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 "Overview of monoarthritis in adults" and "Septic arthritis in adults" and "Synovial fluid analysis".)

Chronic inflammatory arthritis Pseudo-rheumatoid arthritis (“chronic CPP inflammatory arthritis [Pseudo-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 pseudo-RA due to CPPD, 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 pseudo-RA 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, unlike gout, which is negatively associated with RA (occurring less often together than would be predicted from the prevalence of each condition in the population), CPPD disease and RA appear to coexist about as frequently as would be expected from the individual prevalence of the two disorders. 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".)

A rare subtype of chronic CPP inflammatory arthritis is characterized by prominent systemic features such as leukocytosis, fever, mental confusion, and inflammatory polyarthritis [19] In older adults, this clinical presentation can closely mimic systemic sepsis, from which it is distinguishable both by the presence of CPP crystals in synovial fluid from affected joints and by reversal of the clinical features during antiinflammatory drug treatment.

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-related arthritis 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 "Arthritis associated with gastrointestinal disease".)

Chronic degenerative arthritis 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 pseudo-OA 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 which 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".)

Severe joint degeneration Pseudo-neuropathic joint disease associated with CPP crystal deposition 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 neuropathic arthropathy".)

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".)

POST-DIAGNOSTIC EVALUATION FOR ASSOCIATED DISEASES — Patients with a diagnosis of calcium pyrophosphate dihydrate (CPP) crystal deposition (CPPD) disease, even if asymptomatic, may also have one of a number of associated disorders, including hemochromatosis, hyperparathyroidism, hypomagnesemia, hypophosphatasia, hypothyroidism, and familial hypocalciuric hypercalcemia (table 1) [50]. 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 patients diagnosed with CPP crystal deposition undergo the following serum screening studies [2]:

Calcium

Phosphorus

Magnesium

Alkaline phosphatase

Ferritin

Iron and transferrin

In addition to ferritin, iron and transferrin studies are also useful, given the limitations of determining the ferritin level alone. In hemochromatosis, the ferritin level may be falsely normal after bleeding, classically in women with heavy menses, anyone after an occult and slow gastrointestinal bleed, or in celiac disease with iron absorption problems. Additionally, when an elevated ferritin level is present as an acute phase reactant or in liver disease, it is helpful to have the iron study results available without having to redraw the patient’s blood.

Thyroid-stimulating hormone

Appropriate further evaluation should be undertaken if one or more of these values are abnormal. In patients over 60 years of age, serum magnesium and alkaline phosphatase determinations may be omitted because chronic hypomagnesemia and hypophosphatasia present earlier in life. Despite the value of establishing the presence of one of these associated disorders in 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 excess in hyperparathyroidism, have been ineffective in halting or reversing the crystal deposition disorder.

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SUMMARY AND RECOMMENDATIONS

The names traditionally used for the calcium pyrophosphate crystal-related disorders include: pseudogout, for the acute attacks of inflammatory arthritis caused by calcium pyrophosphate crystal (CPP) deposition; chondrocalcinosis, for the radiographic calcification in hyaline and/or fibrocartilage; and pyrophosphate arthropathy, for the radiographic or joint abnormalities accompanying calcium pyrophosphate dihydrate crystal deposition (CPPD) disease. (See 'Terminology' above.)

CPPD disease is a disease of older adults, and radiographic surveys demonstrate an age-related increase in the prevalence of articular chondrocalcinosis. There is no major sex predominance, although attacks of acute CPP arthritis, which are often termed pseudogout, occur more frequently in men, while osteoarthritis (OA) with CPP deposition is more common in women. (See 'Epidemiology' above.)

The clinical spectrum of CPPD disease is diverse, and the majority of patients are probably asymptomatic. The range of presentations, with alternative terms proposed by the European League Against Rheumatism (EULAR) noted parenthetically, includes (see 'Clinical manifestations' above and 'Terminology' above):

Asymptomatic disease (“asymptomatic CPPD”) (see 'Asymptomatic CPPD' above)

Pseudogout (“acute CPP crystal arthritis”) (see 'Acute arthritis/Pseudogout' above)

Pseudo-rheumatoid arthritis (RA) (“chronic CPP crystal inflammatory arthritis”) (see 'Chronic CPP crystal inflammatory arthritis/Pseudo-rheumatoid arthritis' above)

Pseudo-OA, with or without superimposed acute attacks (“OA with CPPD”) (see 'Osteoarthritis with CPPD' above)

Pseudo-neuropathic joint disease (see 'Severe joint degeneration/Pseudo-neuropathic joint disease' above)

Synovial fluid analysis in CPPD disease is characterized by the presence of weakly positively birefringent CPP crystals that may be detected by compensated polarized light microscopy. Phagocytosed crystals within polymorphonuclear leukocytes are virtually always present in inflamed joints during an acute attack of pseudogout (picture 1). Examination of synovial fluid for CPP crystals should be carried out promptly after joint aspiration, because successful identification of the crystals diminishes as the time elapsed between joint aspiration and microscopic examination increases. The total synovial fluid leukocyte concentration is typically 15,000 to 30,000 per mm3, 90 percent of which are neutrophils. (See 'Synovial fluid findings' above and 'Synovial fluid analysis' above.)

Plain film radiographic evidence of calcium crystal deposition is the defining feature of chondrocalcinosis. CPP crystal deposits typically appear as punctate and linear radiodensities in fibrocartilage, in hyaline or articular cartilage (image 1), and, with lesser frequency, in ligaments and joint capsules. Even in the absence of demonstrable chondrocalcinosis, CPP crystal deposition is often associated with degenerative radiographic changes in joints. Ultrasonographic findings that correlate with radiographic features of CPPD disease have also been described (image 2). (See 'Imaging findings' above and 'Plain film radiography' above and 'Ultrasonographic findings' above.)

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 CPP crystal deposition 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 and 'Diagnostic criteria' above.)

Patients with a diagnosis of CPPD disease may also have one of a number of associated disorders, including hemochromatosis, hyperparathyroidism, hypomagnesemia, hypophosphatasia, hypothyroidism, and familial hypocalciuric hypercalcemia (table 1). Given these disease associations, patients diagnosed with CPP crystal deposition, even if asymptomatic and especially if less than 50 years of age, should undergo the following serum screening studies: calcium, phosphorus, magnesium, alkaline phosphatase, ferritin, iron, transferrin, and thyroid-stimulating hormone. (See 'Post-diagnostic evaluation for associated diseases' above.)

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.)

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