Basic calcium phosphate and pyrophosphate calcium crystals are the 2 main calcium-containing crystals that can deposit in all skeletal tissues. These calcium crystals give rise to numerous manifestations, including acute inflammatory attacks that can mimic alarming and threatening differential diagnoses, osteoarthritis-like lesions, destructive arthropathies, and calcific tendinitis. Awareness of uncommon localizations and manifestations such as intraspinal deposition (eg, crowned dens syndrome, tendinitis of longus colli muscle, massive cervical myelopathy compression) prevents inappropriate procedures and cares. Coupling plain radiography, ultrasonography, computed tomography, and synovial fluid analysis allow accurate diagnosis by directly or indirectly identifying the GRAAL of microcrystal-related symptoms.
Key points
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Calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals are the 2 main families of calcium-containing crystals that can form simultaneously in all joint structures, ligament, tendon, muscle, and soft tissue.
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BCP and CPP crystal deposition are 2 common multifaceted diseases that can mimic alarming clinical manifestations.
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Ultrasonography seems to be an excellent imaging technique for CPP crystal detection but lacks efficacy for deep locations.
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Computed tomography remains the gold standard imaging modality for detection of calcification in the axial skeleton, especially at the cervical level.
Introduction
Calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals are the 2 main families of calcium-containing crystals that can form simultaneously in all joint structures, ligament, tendon, muscle, and soft tissue. Although these calcium crystal depositions are mostly asymptomatic, they can give rise to a wide range of clinical manifestations and syndromes, including acute inflammatory articular or periarticular attacks, chronic tendinitis, rapidly destructive arthropathies, or osteoarthritis (OA)-like lesions, as well as nervous compressions ( Table 1 ). Some of these clinical symptoms have been referred to by a variety of names and confusing terms. Recently, a group of experts from the European League Against Rheumatism (EULAR) have elaborated 2 sets of recommendations for the terminology and diagnosis of CPP and its management. Similar efforts should be made for BCP crystals.
| CPP Crystals | BCP Crystals | |
|---|---|---|
| Chemical composition | Ca 2 P 2 O 7 ·2H 2 O | Ca 10−x (HPO 4 ) x (PO 4 ) 6−x (OH) 2−x |
| Ca 2+ /P ratio | 1.67 | 1.3 |
| Members identified in human samples | Monoclinic Triclinic | Carbonated-apatite Octacalcium phosphate Whitlockite Tricalcium phosphate (?) |
| Intra-articular deposition | +++ | + |
| Extra-articular deposition | + | +++ |
| Clinical Manifestations | ||
| Asymptomatic | ++ | ++ |
| Acute joint flare | ++ | ? |
| Acute tendinitis | + | ++ |
| Acute bone erosion | + | + |
| Acute neck pain | ++ | + |
| Acute spinal pain | ++ | + |
| Chronic arthritis | ++ | +/− |
| OA associated | ++ | +++ |
| Calcific tendinitis | + | +++ |
| Milwaukee shoulder | ? | ++ |
| Destructive arthropathies | + | + |
| Crowned dens syndrome | ++ | + |
| Spinal cord compression | + | + |
| Tumoral deposition | + | ++ |
| Synovial fluid detection | +++ | +/− |
| Alizarin red staining | + | + |
| Radiographic pattern | Dense, linear | Dense, homogeneous without bone trabeculation |
| Ultrasonography | Hyperechoic deposits without posterior shadow | Hyperechoic with posterior acoustic shadowing |
| CT scan | +++ | +++ |
| Associated clinical conditions | Aging, OA, trauma Hemochromatosis hyperparathyroidism Hypomagnesemia Hypophosphatasia Wilson disease? Ochronosis? | Aging, OA Diabetes mellitus Chronic kidney disease Connective diseases Trauma, infection |
Introduction
Calcium pyrophosphate (CPP) and basic calcium phosphate (BCP) crystals are the 2 main families of calcium-containing crystals that can form simultaneously in all joint structures, ligament, tendon, muscle, and soft tissue. Although these calcium crystal depositions are mostly asymptomatic, they can give rise to a wide range of clinical manifestations and syndromes, including acute inflammatory articular or periarticular attacks, chronic tendinitis, rapidly destructive arthropathies, or osteoarthritis (OA)-like lesions, as well as nervous compressions ( Table 1 ). Some of these clinical symptoms have been referred to by a variety of names and confusing terms. Recently, a group of experts from the European League Against Rheumatism (EULAR) have elaborated 2 sets of recommendations for the terminology and diagnosis of CPP and its management. Similar efforts should be made for BCP crystals.
| CPP Crystals | BCP Crystals | |
|---|---|---|
| Chemical composition | Ca 2 P 2 O 7 ·2H 2 O | Ca 10−x (HPO 4 ) x (PO 4 ) 6−x (OH) 2−x |
| Ca 2+ /P ratio | 1.67 | 1.3 |
| Members identified in human samples | Monoclinic Triclinic | Carbonated-apatite Octacalcium phosphate Whitlockite Tricalcium phosphate (?) |
| Intra-articular deposition | +++ | + |
| Extra-articular deposition | + | +++ |
| Clinical Manifestations | ||
| Asymptomatic | ++ | ++ |
| Acute joint flare | ++ | ? |
| Acute tendinitis | + | ++ |
| Acute bone erosion | + | + |
| Acute neck pain | ++ | + |
| Acute spinal pain | ++ | + |
| Chronic arthritis | ++ | +/− |
| OA associated | ++ | +++ |
| Calcific tendinitis | + | +++ |
| Milwaukee shoulder | ? | ++ |
| Destructive arthropathies | + | + |
| Crowned dens syndrome | ++ | + |
| Spinal cord compression | + | + |
| Tumoral deposition | + | ++ |
| Synovial fluid detection | +++ | +/− |
| Alizarin red staining | + | + |
| Radiographic pattern | Dense, linear | Dense, homogeneous without bone trabeculation |
| Ultrasonography | Hyperechoic deposits without posterior shadow | Hyperechoic with posterior acoustic shadowing |
| CT scan | +++ | +++ |
| Associated clinical conditions | Aging, OA, trauma Hemochromatosis hyperparathyroidism Hypomagnesemia Hypophosphatasia Wilson disease? Ochronosis? | Aging, OA Diabetes mellitus Chronic kidney disease Connective diseases Trauma, infection |
Calcification formation
Mechanisms of ectopic calcifications remain unresolved and have been reviewed recently. Multiple factors contribute to this cellular driven process, including genetics, aging, imbalance between inhibitors and stimulators of calcification, alteration of calcium, phosphate and pyrophosphate metabolisms, extracellular matrix lesions, cellular differentiation state, and cell death.
Two types of CPP crystals have been identified in synovial fluid, hyaline cartilage, and fibrocartilage: monoclinic and triclinic CPP crystals. BCP crystals encompass several types of crystals, including carbonated-apatite, octacalcium phosphate, and apatite-containing magnesium (whitlockite) crystals.
The type of calcium-containing crystal depends on the levels of extracellular inorganic pyrophosphate (ePPi) and extracellular inorganic phosphate (ePi). High ePPi levels promote CPP crystal formation and inhibit BCP crystal nucleation. In contrast, high ePi concentration and low ePPi favor BCP crystal formation. Several proteins regulate inorganic pyrophosphate (PPi) and inorganic phosphate (Pi) concentrations, including ANKH (ankylosis human), ENPP-1 (ectonucleotide pyrophosphate phosphodiesterase 1), or PC-1 (plasma-cell membrane glycoprotein 1), TNAP (tissue nonspecific alkaline phosphatase), PiT-1 (sodium-dependent phosphate transport protein 1), and CD73. ANKH is a transmembrane protein that transports intracellular PPi across the cell membrane. PC-1 converts extracellular nucleotide triphosphate into PPi and adenosine monophosphate (AMP). TNAP transforms PPi into orthophosphate. Pit-1 transports extracellular Pi into cell cytoplasm. CD73 converts AMP into adenosine and Pi. Adenosine inhibits TNAP activity ( Fig. 1 ). Thus, ANKH, PC-1, and CD73 increase extracellular PPi concentration, which is decreased by TNAP. Mutations of these proteins have been associated with pathologic calcifications: gain-of-function mutations of ANKH or loss-of-function mutations of TNAP genes increase PPi concentration and lead to CPP crystal deposition (CPPD) disease ; loss-of-function mutations of PC-1 and NT5E (gene encoding CD73 protein) genes decrease ePPi level and are associated with diffuse vascular calcifications and periarticular BCP crystal deposition. Mutations of many other genes have been associated with vascular and joint calcification and are detailed in several reviews.
According to EULAR recommendations, diagnosis of CPPD disease in young patients needs to be accompanied by ruling out of diseases such as hemochromatosis, primary hyperparathyroidism, chronic hypomagnesemia, and hypophosphatasemia. There may also be an association between Wilson disease and CPPD (Marson L, Quemeneur AS, Trocello JM, et al, personal communication, 2013). A family history of CPPD disease suggests genetic disorder, especially a gain-of-function mutation of ANKH gene. This gene has been implicated in Spanish, Argentinean, and French families with CPPD disease. Similarly, several clinical conditions favor BCP crystal deposition: chronic renal disease, diabetes mellitus, hyperparathyroidism, autoimmune diseases such as dermatomyositis, scleroderma, CREST syndrome, systemic lupus, trauma, and infection. Aging and OA are associated with CPPD and BCP crystal deposition in articular hyaline cartilages and fibocartilages. BCP crystals are identified in 80% to 100% of OA cartilage according to different studies, and CPPD prevalence is greater than 20% in people older than 80 years. In the skeletal system, CPP crystals occur preferentially in articular tissues (synovial fluid, hyaline cartilage, fibrocartilage, intervertebral disk, ligament, joint synovium, and capsule), whereas BCP crystals are frequent in articular and extra-articular tissues involving especially tendons and soft tissue.
Clinical manifestations related to BCP and CPPD
CPPD and BCP crystal deposition are often asymptomatic and identified as an incidental radiographic finding. However, both calcium crystals may be associated with several manifestations. Intra-articular CPP crystals may cause acute and relapsing CPP crystal arthritis attacks, chronic CPP crystal inflammatory arthritis, and OA with CPP crystal. Extra-articular CPP and BCP crystals can cause tenosynovitis, peripheral nerve and spinal cord compression, and pseudotumoral deposition. Both CPPD and BCP crystal deposition around the odontoid process cause the crowned dens syndrome (CDS). Periarticular BCP crystal deposition may cause calcifying tendinitis, acute periarthritis, bursitis, and bone pain secondary to bone erosion. Similarly, BCP crystals deposited in soft tissues may cause an acute inflammatory reaction, which is frequently associated with their resorption. Intra-articular BCP crystals may be responsible for severe destructive arthropathies known as the Milwaukee shoulder syndrome (MSS), as an example.
Clinical Symptoms Related to BCP Crystals
Calcific periarthritis
Calcific tendinitis or calcific periarthritis most commonly involves the rotator cuff tendons of the shoulder joint and the medius gluteus tendon, but can occur at any tendon ( Fig. 2 ). Multiple localizations are common, occurring in 33%; bilateral calcification occurs in about half of shoulder cases, and deposits can be identified in other sites. Calcium crystals are composed mainly of carbonated-apatite crystals. Pathogenesis of periarticular calcification remains unresolved and involves systemic and local factors. Calcific periarthritis of the shoulder affects women more frequently in middle age and the dominant side (60%). Boswoth found a prevalence of 2.7% in 6061 asymptomatic office workers, with about 30% to 45% of individuals becoming symptomatic in a period of 3 years. In a prospective study, the prevalence of rotator cuff calcification was 7.3% in 1276 asymptomatic patients seen in the emergency department. Calcifications occurred in 44% of patients between 40 and 50 years old. In painful shoulders, the prevalence was higher and varied between 7% and 50%. The supraspinatus tendon (78%) is the most frequently involved tendon, followed by the infraspinatus (16%), the subscapularis (6%), and the long biceps tendons. Calcific periarthritis may be associated with chronic pain and self-limited episodes of acute periarticular inflammation, which corresponds to the resorption phase of the crystals with migration in the subacromial bursae and acute bursitis. Persistent calcification can lead to local complications with joint tenderness, tendon tears, or adhesive capsulitis.
Cortical bone erosions
Cortical bone erosion and great tuberosity lysis are lesser known complications. Flemming and colleagues described in a retrospective series 50 cases of calcific tendinitis with bone involvement. The humerus and femur were the 2 most frequent sites, with each representing 40% of cases (20 of 50 patients). Femoral involvement was posterior and subtrochanteric along the linea aspera in 95% of cases. Humeral involvement was located in the diaphysis at or near the insertion of the pectoralis major tendon (n = 9), in the lesser tuberosity (n = 6), and in the greater tuberosity (n = 5). The other sites included hand and wrist (n = 3), foot (n = 3), and cervical spine (n = 1). Calcification appeared solid in 50% of patients, stippled in 25%, and amorphous in 20%. Cortical erosion was evident in 78% of patients, periosteal reaction in 32%, and bone marrow involvement in 36%. Computed tomography (CT) is the key imaging tool, with a limitation between calcifications and the cortex of bone, whereas magnetic resonance imaging (MRI) can provide inflammatory figures and can mimic tumoral process.
Calcification may disappear spontaneously without symptom. Bosworth found that radiographic resolution of calcification was around 6% per year, whereas Wölk and Wittenberg reported an ultrasonographic (US) resolution rate of 82% within 8.6 years.
Acute calcific tendinitis and acute inflammatory reaction
BCP crystals like CPP crystals and urate crystals may induce self-limiting acute inflammatory attacks. Clinical symptoms may be impressive, with rapid onset of pain, important soft tissue swelling, and joint mobility reduction, inducing total or partial impotence. Fever may be present, and laboratory analysis may show increased inflammatory parameters and neutrophil count. Acute inflammatory attack related to uncommon BCP crystal localizations can be challenging and misdiagnosed with alarming conditions such as cellulitis, pyogenic arthritis, retropharyngeal abscess, infectious spondylitis, meningitides, or sarcoma. This situation can lead to inappropriate management with invasive diagnostic procedures and therapies, including surgery and amputation. Diagnostic clues rely on awareness of this disease, history of a similar self-limiting flare, evidence of BCP crystal deposition by simple imaging procedures such as radiography, US, and mostly, CT scan examination.
Acute inflammatory flares may involve any tendons and commonly affects shoulder and hip joints followed by fingers, elbows, wrists, knees, ankles, and feet. Acute attack of the longus colli muscle is rare but not infrequently reported. The longus colli muscle is a weak flexor of the neck, composed of 3 portions with superior, central, and inferior fibers. It extends from the level of the anterior tubercle of the atlas into the superior mediastinum to the level of the T3 vertebral body. Calcification involves mainly the superior fibers, which attach the tubercle of the atlas to the transverse processes of the C3-C5 vertebrae. Acute calcific tendinitis of the longus colli muscle was first described in 1964. It usually affects patients who are between 30 and 60 years old, without gender predilection. Ring and colleagues showed that this condition was caused by BCP crystal deposition with a foreign-body inflammatory response. The most frequent presentation is neck pain with rapid onset, and stiffness, dysphagia, odynophagia, and headache. In some cases, there may be fever, with increased inflammatory markers. Clinical presentation can be confused with retropharyngeal abscess, infectious spondylitis, or meningitis pain and stiffness associated with odynophagia. The pathognomonic radiographic findings are prevertebral soft tissue swelling typically extending from C1 to C4 and the presence of amorphous calcification anterior to C2 at the insertion of the superior tendon of the muscle. However, these signs may be difficult to see on plain radiographs. CT is more sensitive than radiography for the detection of calcification and prevertebral soft tissue swelling ( Fig. 3 ). It represents the method of choice, also allowing bone destruction or fracture to be ruled out. Retropharyngeal soft tissue edema and muscle inflammation can be better visualized by MRI, which eliminates retropharyngeal abscess and cervical spondylitis. Thus, a correct diagnosis can be easily made by combining CT and MRI. Treatment relies on a short course of antiinflammatory drugs and neck immobilization. Like other acute attacks secondary to BCP crystal deposition, symptoms usually spontaneously resolve within 1 to 2 weeks followed by calcification disappearence.
MSS, hemorrhagic shoulder of the elderly
MSS was described for the first time by McCarty and colleagues in 1981. It has received several names, including hemorrhagic shoulder of the elderly, rapid destructive arthritis of the shoulder, and apatite-associated destructive arthritis. MSS is the prototypical BCP crystal–associated joint destructive arthropathy. It affects mainly elderly women (ratio of 4:1) and both shoulders in 60% to 80%. The dominant side is involved in unilateral disease, and the disease is most severe in the dominant shoulder. It is associated with rotator cuff defects and numerous aggregates of BCP crystals in the fluids of affected joints. Characteristically, shoulder pain is mild and intermittent and is exacerbated by motion and at night when lying in bed. Joint mobility is restricted or excessively mobile and instable (when the joint is completely destroyed). Large joint blood-stained effusions are common, with a low leukocyte count. Collagenase activity is increased in synovial fluids. Usually, joint destruction occurs within months. Radiographs show initially superior subluxation of the humeral head from the glenoid fossa, secondary to widespread tear of the rotator cuff. Calcifications of periarticular soft tissues are frequent and noted in about 60% of affected shoulders. Bony sclerosis and cyst formation in the humeral head are common, as well as erosions of the greater tuberosity at the site of insertion of the rotator cuff. Later, the glenohumeral joint is destroyed, with commonly, a large destruction of the humeral head and glenoid cavity. Diagnosis is helped by the identification of BCP crystals in synovial fluid using alizarin red staining. MSS can also affect the knee joint, involving more frequently the patellofemoral and lateral tibiofemoral compartments. Recently, Ornetti and colleagues described a woman with MSS involving shoulder and elbow joints. The natural history of the disease is unclear, but many cases seem to stabilize after a year or 2, with reduction of symptoms, joint effusions, and no further radiographic changes. MSS is also associated with OA in other joints. In their first description, MSS was associated with knee OA in more than 60% of cases. Pons-Estel and colleagues had reported kindred in which multiple members spanning several generations had features of MSS and OA in other joints. Genetic linkage was not identified.
Clinical Symptoms Related to CPPD
According to EULAR recommendations for terminology and diagnosis, 4 different clinical settings are associated with CPPD diseases:
- 1.
Asymptomatic CPPD with no apparent clinical consequence
- 2.
OA with CPPD
- 3.
Acute CPP crystal arthritis (replacing the term pseudogout)
- 4.
Chronic CPP crystal inflammatory arthritis
Less commonly, atypical or periarticular CPP crystals may associate with tendinitis, bursitis, tumoral CPPD (especially in the temporomandibular joint and the foramen magnum), and acute spinal pain related to spine involvement.
Asymptomatic CPPD
Asymptomatic CPPD is CPPD with no apparent clinical consequence. It may consist of isolated cartilage or fibrocartilage calcifications detected by plain radiographs (chondrocalcinosis [CC]), or OA with CPP crystals. Radiologic CC is not always caused by CPPD and is often an incidental finding. We and other investigators have shown that CPP and BCP crystals coexist in 20% of OA articular tibia cartilages harvested at the time of total joint arthroplasty. The prevalence of CC varies from 3.7% in patients aged 55 to 59 years to 17.5% in patients aged 80 to 84 years.
Acute CPP crystal arthritis
An acute joint attack caused by CPP crystals might mimic a gout flare and was formerly named pseudogout, which could give rise to confusion regarding the nature of the guilty crystals. The attack can be monoarticular, oligoarticular, or polyarticular. It is a common cause of monoarticular inflammation in elderly women. In a hospital series, CPP crystal inflammation was related to monoarthritis/oligoarthritis in 89% and to polyarthritis in 11%. Knee, wrist, and metacarpophalangeal (MCP) joints are the most affected sites, but any joint can be involved, including uncommon ones such as acromion-clavicular, temporomandibular, sacroiliac, symphysis pubis, and spinal facet joints. Characteristics of CPP crystal arthritis were highlighted by EULAR experts in 2 of 11 EULAR propositions :
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EULAR proposition 2: “the rapid development of severe joint pain, swelling and tenderness that reaches its maximum within 6–24 h, especially with overlying erythema, is highly suggestive of acute crystal inflammation though not specific for acute CPP crystal arthritis.”
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EULAR proposition 3: “presentation with features suggesting crystal inflammation involving the knee, wrist or shoulder of a patient over age 65 years is likely to be acute CPP crystal arthritis. The presence of radiographic CC and advanced age increases this likelihood, but definitive diagnosis needs to be crystal proven.”
Thus, a rapid onset of acute synovitis with pain and marked soft tissue and joint swelling is highly characteristic of crystal inflammation without specificity for the type of crystal. Like microcrystal inflammation, CPP crystal attack is self-limited and lasts for 7 to 10 days. In a geriatric hospital series, acute CPP crystal arthritis resolved within 3 to 4 days. Thus, a history of self-resolving flares is helpful for the diagnosis. However, because acute CPP crystal arthritis and infection may coexist, microbiological investigation should be performed even if CPP crystals are identified (EULAR proposition 10). Laboratory tests show unspecific increase of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Acute CPP crystal inflammation, as observed in gout flares, can be favored by several stresses, including infection, surgery, cardiovascular events such as myocardial infarction or stroke, joint trauma, or surgery. Joint lavage and meniscectomy are 2 classic factors inducing CPP crystal inflammation. The incidence of acute CPP crystal arthritis after arthroscopic lavage for knee OA with preexisting CC is estimated to be 26%. A case-control study showed that patients with knee CC had 5 times more risk of acute CPP arthritis after meniscectomy than those without knee CC. Other uncommon factors have been associated with acute CPP crystal arthritis: bisphosphonates, granulocyte colony-stimulating factor, and intra-articular injection of hyaluronan.
Chronic CPP crystal arthritis
EULAR proposition 5 stipulated that “chronic CPP crystal inflammatory arthritis presents as chronic oligoarthritis or polyarthritis with inflammatory symptoms and signs and occasional systemic upset (with elevation of CRP and ESR); superimposed flares with characteristics of crystal inflammation support this diagnosis. It should be considered in the differential diagnosis of rheumatoid arthritis (RA) and other chronic inflammatory joint diseases in older adults. Radiographs may assist diagnosis, but the diagnosis should be ‘crystal proven’.” However, physicians should pay attention to the addition of monoarthritis leading with time to bilateral asymmetrical polyarthritis involving both hands and wrists.
Chronic CPP crystal arthritis is not rare, occurring in 11% of CPP crystal inflammation. It may be misdiagnosed as RA, or even as polymyalgia rheumatica when shoulders are affected. However, some clinicoradiologic features strongly suggest metabolic arthropathy and encourage searching for the GRAAL , which is the identification of CPP crystals; negativity of immunologic tests; involvement of the second and third MCP joints; presence of both spinal and peripheral articular symptoms; plain radiographs and US depicting characteristic abnormalities, including CC and the presence of hyperechoic deposits without posterior shadow within the cartilage (see diagnosis section).
OA with CPP and BCP crystals
The role of calcium-containing crystals in OA pathogenesis continues to be under debate. Some investigators consider calcium crystals as bystanders of cartilage destruction, releasing bone mineral (eg, apatite crystals) into the joint cavity. However, recent clinical and research data strongly suggest that calcium-containing crystals may induce a real crystal stress and contribute to cartilage destruction in OA. Crystal-associated OA is more severe and affects joints usually spared in primary OA. These features are highlighted by EULAR proposition 4: “OA with CPPD may associate with more inflammatory symptoms and signs, an atypical distribution (eg, radiocarpal or midcarpal, glenohumeral, hindfoot or midfoot involvement)….”
BCP and CPP crystals are found frequently in OA femoral condyle, tibial, and femoral head cartilage, as well as OA knee joint fluid. Their presence is correlated with more severe radiographic scores. Furthermore, BCP crystals appear with joint degeneration. Calcium-containing crystal formation is a cell-driven process involving several factors, including aging, chondrocyte hypertrophy, apoptosis, and cartilage extracellular matrix alteration. In vitro studies have shown that both BCP and CPP crystals induce inflammatory, catabolic, and apoptotic responses. In vivo, intra-articular injection of CPP crystals worsens OA lesions induced by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments in a rabbit model. Similarly, intra-articular injection of BCP crystals into mouse knees induces synovial inflammation and cartilage degradation.
The knee is a common target site for OA and the most common site for CPPD. BCP crystals are identified in 100% of femoral condyle and tibia plateau cartilages harvested at the time of joint replacement. A strong association between OA and CPPD was noted in analysis conducted as part of the EULAR recommendations. The pooled odds ratio (OR) is 2.66 (95% confidence interval [CI] 2.00–3.54) and is consistent between cross-sectional (2.52, 95% CI 1.86–3.44) and case-control (2.80, 95% CI 1.44–5.47) studies, suggesting that people with OA are more than twice as likely to have CPPD than not. Compared with isolated OA, OA with CPPD may occur in less typical locations (eg, radiocarpal joints, elbows, shoulders, ankles) and have more patellofemoral and lateral tibiofemoral compartment involvement. In hip OA, the presence of CPP crystals is associated with rapidly destructive OA. A prospective observational study noted that the presence of CPP crystals in synovial fluids or CC is associated with radiographic progression, with an OR of 3.44 (95% CI 1.97–6.02). However, in 2 longitudinal studies, the presence of knee CC at baseline was negatively associated with cartilage loss assessed by MRI. These contradictory results keep the debate active. However, studies are heterogeneous, involving different joints and different populations. Calcium-containing crystals may have different properties according to the site where they deposit. In vitro, they induce different cellular responses according to cell type.
Less common CPP crystal-related manifestations
Spine-related CPP crystals
Although CPPD occurs preferentially in target areas such as second and third MCP joints, wrists (triangular ligament), knees (menisci) and symphysis pubis, these crystals have been identified in mostly all ligaments and musculoskeletal tissue. Resnick and Pineda in a radiographic and pathologic analysis of more than 1000 cadaveric spinal specimens reported that CPPD occurs in practically all vertebral structures: intervertebral, apophyseal, and sacroiliac joints; median atlantoaxial articulations; intraspinal and extraspinal ligaments, including interspinous and supraspinous ligaments, ligamentun flavum, periodontoid ligaments, and posterior longitudinal ligament. These CPPDs can give rise to acute attacks and OA-like and destructive lesions. Massive CPPD may induce nervous compression with myelopathy, radicular pain, or cauda equine syndrome.
Numerous vertebral abnormalities have been reported, including degenerative disk disease, vertebral destruction, scoliosis, spondylolisthesis, atlantoaxial subluxation, vertebral ankylosis, occipitoatlantoaxial joint collapse, and thickening of spinal ligaments.
CDS
The CDS is a clinical-radiologic entity, first described by Bouvet and colleagues, characterized by acute neck pain caused by calcium deposition around the odontoid process. The calcium deposits are mostly CPP crystals, although BCP crystals have also been identified. Clinical presentations may be asymptomatic or alarming, with acute febrile neck pain, cervical stiffness, and increased inflammatory markers. CDS, like acute tendinitis of the longus colli, can be misdiagnosed with meningitis, infectious spondylitis, temporal arteritis, polymyalgia rheumatica, metastatic bone disease, and spinal tumor. Diagnosis is made by the identification of calcification deposition around the atlantoaxial joint by CT scan ( Fig. 4 ). A characteristic pattern is the presence of calcification surrounding the top and sides of the odontoid process in a crownlike or horseshoelike deposition. Calcifications involve mainly the transverse ligament of the atlas, and 3 calcification patterns have been described: curvilinear, stippled, or mixed. Calcifications can also occur in the other periodontoid structures, including synovial membrane, the articular capsule, alar ligaments, apical ligament, and longitudinal fiber of cruciate ligament. Recently, Kobayashi and colleagues showed that acute neck pain in patients with transverse ligament calcification could be secondary to acute CPP arthritis of the lateral atlantoaxial joint. CT showed calcification of the transverse ligament in 22 of 27 (81.5%) patients and calcification of the longus colli muscle in 2 of 27 (7.5%) patients. Lateral atlantoaxial joint puncture allowed collecting synovial fluid in 16 patients (59.3%). CPP crystals were identified in 10 of 16 (62.5%) of the synovial fluid. Thus, dramatic improvement was also observed after joint puncture in all patients. Pain decreased from 81.9 ± 16.3 mm before puncture to 35.6 ± 24.4 mm within 30 minutes of the procedure. Whether the improvement persisted was not mentioned. Similarly, how atlantoaxial puncture improved pain secondary to longus colli tendinitis was not discussed. However, this study highlighted a possible association between CDS and acute CPP crystal arthritis of the atlantoaxial joint. Careful attention should be taken in MRI analysis to rule out this setting. Compared with CT, MRI is also more sensitive for soft tissue assessment and spinal cord compression (see Fig. 4 B). Along with crystal deposition, CT can show subchondral cysts and erosion involving the odontoid process and atlantoaxoidal destructive arthropathy. Prevalence of CDS varies from 6% in unselective patients undergoing CT to 71% in patients with articular CC. A case-control study found a prevalence of cervical calcifications in patients with proven articular CPP crystal disease in 24 of 35 patients (69%) compared with 4 of 35 (11%) in control patients. In a recent prospective study including 513 patients, the overall prevalence of atlantoaxial CPPD shown by cervical spine CT was 12.5%. Prevalence increased with age, reaching 34% for patients aged 60 years and older and 49% for patients aged 80 years and older.
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Nonpharmacologic and Pharmacologic Management of CPP Crystal Arthritis and BCP Arthropathy and Periarticular Syndromes
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Emerging Therapies for Gout
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