Basic Calcium Phosphate Deposition – Introduction
- Calcium pyrophosphate dihydrate crystal deposition (CPPD) disease refers to the precipitation of calcium pyrophosphate dihydrate (CPP) in connective tissues that may be asymptomatic or may be associated with several clinical syndromes, including acute and chronic arthritis.
- CPP was formerly abbreviated and commonly referred to as “CPPD,” but the abbreviation is now reserved for “CPP deposition.” Alternative names ( Table E1 ) representing specific clinical or radiographic features of CPPD disease include pseudogout, chondrocalcinosis, and pyrophosphate arthropathy.
TABLE E1
Nomenclature of Calcium Pyrophosphate and Associated Syndromes
From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
| Definition | Old Terms | EULAR Recommendations | Preferred Term (Abbreviation) |
|---|---|---|---|
| Radiographic correlate of CPPD | Chondrocalcinosis, chondrocalcinosis articularis | Chondrocalcinosis | Chondrocalcinosis (CC) |
| Acute inflammatory arthritis caused by CPP crystals | Pseudogout | Acute CPP crystal arthritis | Acute CPP crystal arthritis |
| Calcium pyrophosphate dihydrate crystals | Calcium pyrophosphate dehydrate; calcium pyrophosphate dihydrate | Calcium pyrophosphate crystals | Calcium pyrophosphate crystals (CPP crystals) |
| All clinical syndromes associated with CPP crystals | Calcium pyrophosphate dihydrate deposition disease | None | Calcium pyrophosphate deposition disease (CPPD) |
| Chronic arthritis caused by CPP crystals ± inflammation | Calcium pyrophosphate dihydrate deposition disease: Pyrophosphate arthropathy; pseudorheumatoid arthritis; pseudo-osteoarthritis | Chronic CPP crystal arthritis, OA with CPPD | Chronic CPP crystal arthritis, OA with CPPD |
| Deposition of calcium pyrophosphate crystals in joints or tissue with or without clinical symptoms | Calcium pyrophosphate dihydrate deposition | CPPD | Calcium pyrophosphate deposition (CPPD) |
CPP, Calcium pyrophosphate; CPPD, calcium pyrophosphate dihydrate crystal deposition disease; EULAR, European League Against Rheumatism; OA, osteoarthritis.
Pseudogout/acute CPP crystal arthritis is used to describe acute attacks of CPP crystal-induced arthritis that clinically resembles the arthritis that is commonly encountered in gout. The term acute CPP crystal arthritis is now preferred in place of pseudogout .
Chondrocalcinosis (CC) refers to radiographic calcification in hyaline cartilage and/or fibrocartilage and does not confirm the diagnosis of CPP-related arthritis as it can be present in other types of crystal deposition diseases or be asymptomatic.
Pyrophosphate arthropathy is the term used for a chronic structural arthropathy related to CPP deposition.
Synonyms
- CPPD
- Calcium pyrophosphate dihydrate crystal deposition disease
- CPP crystal deposition disease
- Chondrocalcinosis (CC)
- Pseudogout
- Pyrophosphate arthropathy
| ICD-10CM CODES | |
| M11.2 | Other chondrocalcinosis |
| M11.9 | Crystal arthropathy, unspecified |
| M11.8 | Other specified crystal arthropathies |
| M11.1 | Familial chondrocalcinosis |
Epidemiology & Demographics
Prevalence
- •The epidemiology of CPPD crystal deposition is described in Table E2 .
TABLE E2
Epidemiology of Calcium Pyrophosphate Dihydrate Crystal Deposition
From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.
| Age Association | Rises With Age |
|---|---|
| Sex distribution | (F:M) 1:1 |
| Chondrocalcinosis prevalence | 8.1% (age range 63-93) |
| Pyrophosphate arthropathy prevalence | 3.4% (age range 40-89) |
| Geography | Appears ubiquitous |
| Genetic associations | Mutations of ANKH gene on chromosome 5p (CCAL2) and unknown genes on chromosome 8q (CCAL1) |
- Most linked with advancing age (average age of 72).
Genetics
Familial forms
Associated with ANKH (ankylosis human) gene, which transports inorganic pyrophosphate (PPi) out of cells, or the osteoprotegerin gene (TNFRSF11B).
Familial mutations can increase extracellular Ppi levels and lead to onset of CPPD disease in the third or fourth decade of life.
Physical Findings and Clinical Presentation
- •Acute CPP crystal arthritis/pseudogout: Monoarticular attacks most commonly involve the knee and wrist but can be polyarticular ( Fig. E1 ). Patients, especially the elderly, can have systemic manifestations such as fever and altered mental status, and therefore diagnostic aspiration is essential to rule out septic arthritis. Situations that may trigger acute CPPD crystal arthritis are described in Box E1
FIG. E1Distribution of joint involvement with calcium pyrophosphate dihydrate crystal deposition (CPPD) disease.CPPD often involves joints not typically involved in osteoarthritis.From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
- BOX E1
- Situations That May Trigger Acute Calcium Pyrophosphate Dihydrate Crystal Arthritis
- From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.
- Definite
- •Direct trauma to joint•
- Intercurrent medical illness (e.g., chest infection, myocardial infarction)
- •Surgery (especially parathyroidectomy)
- •Blood transfusion, parenteral fluid administration
- •Joint lavage
- •Institution of thyroxin replacement therapy
- •Intraarticular injection of hyaluronan
- •Bisphosphonate treatment
- •Note: Most cases of pseudogout develop spontaneously
- •Asymptomatic disease (“asymptomatic CPPD”)
- •Pseudogout (acute CPP crystal arthritis)
- •Pseudo–rheumatoid arthritis (RA) (chronic CPP crystal inflammatory arthritis): Symmetric polyarthritis
- •Pseudo-osteoarthritis (OA) with or without superimposed acute attacks (OA with CPPD)
- •Pseudo-neuropathic joint disease
- •Crowned-dens syndrome caused by crystal deposition in the ligamentum flavum of the cervical spine, either asymptomatic or causing acute neck pain
- •Pseudo-polymyalgia rheumatica (pseudo-PMR): Pain and stiffness in the neck and shoulder girdle mimicking PMR
Etiology
- •Idiopathic
- •Familial
- •Trauma
- •Metabolic and endocrine disorders ( Table E3 ): Hyperparathyroidism, hypophosphatasia, hemochromatosis, hypomagnesemia, Gitelman syndrome, Bartter syndrome, gout, ochronosis, acromegaly, Wilson disease, familial hypocalciuric hypercalcemia, X-linked hypophosphatemic rickets
TABLE E3
Diseases Associated With Calcium Pyrophosphate Dihydrate Crystal Deposition Disease
From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
| Disease | Strength of Evidence for a Link With CPPD | Recommended Testing |
|---|---|---|
| Hyperparathyroidism | Strong | Calcium, parathyroid hormone level |
| Hemochromatosis | Strong | Fe, TIBC, ferritin, C282Y |
| Hypophosphatasia | Strong | Alkaline phosphatase |
| Hypomagnesemia | Strong | Magnesium |
| Gout | Strong | Synovianalysis |
| Rheumatoid arthritis | Moderate | Clinical judgement |
| Osteoporosis | Moderate | Bone density if warranted |
CPPD, Calcium pyrophosphate dihydrate crystal deposition disease; TIBC, total iron-binding capacity.
Differential Diagnosis
- •Gouty arthritis ( Table E4 )
TABLE E4
Differences Between Acute Gouty Arthritis and Acute Calcium Pyrophosphate Crystal Arthritis
From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
| Symptom or Sign | Acute Gout | Acute CPP Crystal Arthritis |
|---|---|---|
| Pattern of joint involvement | First MCP joint, other lower extremity joints | Knee, wrist, ankle, spine |
| Response to colchicine | Excellent in early attack | Variable |
| Blood in joint fluid | Unusual | Not unusual |
| Duration of attack | 7-10 days | Days to weeks |
CPP, Calcium pyrophosphate dihydrate; MCP, metacarpophalangeal.
- Septic arthritis
- •RA
- •Spondyloarthritis (ReA, psoriatic arthritis [PsA])
- •PMR
Table E5 describes metabolic diseases predisposing to CPPD disposition. Section II describes the differential diagnosis of acute monoarticular and oligoarticular arthritis and crystal-induced arthritides. An algorithm for evaluation and treatment of CPPD is shown in Fig. E2 .
TABLE E5
Metabolic Diseases Predisposing to Calcium Pyrophosphate Dihydrate Crystal Deposition
| CC | Pseudogout | Chronic PA | |
|---|---|---|---|
| Hemochromatosis | Yes | Yes | Yes |
| Hyperparathyroidism | Yes | Yes | No |
| Hypophosphatasia | Yes | Yes | No |
| Hypomagnesemia | Yes | Yes | No |
| Gout | Possibly | Possibly | No |
| Acromegaly | Possibly | No | No |
| Ochronosis | Yes | Yes | No |
| Familial hypocalciuric hypercalcemia | Possibly | No | No |
| X-linked hypophosphatemic rickets | Possibly | Possibly | Possibly |
CC, Chondrocalcinosis; PA, pyrophosphate arthropathy.
LABORATORY TESTS
- •Arthrocentesis will demonstrate the presence of weakly positive birefringent rhomboid-shaped crystals by compensated polarized light microscopy.
- •Synovial fluid should always be analyzed for cell count with differential, crystals, Gram stain, and culture because acute CPP crystal arthritis/pseudogout and septic arthritis can coexist.
- •Evaluate for possible metabolic causes, especially in younger patients aged <55 yr or patients with florid polyarticular disease.
- Box E2 describes screening blood tests for metabolic diseases associated with CPPD crystal deposition.
- BOX E2
- Screening Blood Tests for Metabolic Diseases Associated With Calcium Pyrophosphate Dihydrate Crystal Deposition
- From Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.
- Calcium
- Alkaline phosphatase
- MagnesiumFerritin, iron, transferrin
- Liver function
- Thyroid-stimulating hormone
IMAGING STUDIES
- •Plain x-rays often reveal CC located parallel to subchondral bone.
- 1.Classic locations for CC include knee menisci, wrist triangular fibrocartilage, symphysis pubis, and glenoid and acetabular labra.
- •Musculoskeletal ultrasound can detect deposition of CPP crystals within the hyaline cartilage and/or fibrocartilage. In contrast to urate crystal deposits in gout, CPP crystals often deposit within the substance of the hyaline cartilage and fibrocartilage, providing a means to distinguish CPP from urate deposition that occurs on the surface of the hyaline cartilage as seen in gout.
- •Early studies suggest that dual-energy computed tomography (CT) scan can differentiate mineral deposits through color-coded images and may aid in the diagnosis of CPPD from other crystal arthropathies.
Treatment
NONPHARMACOLOGIC THERAPY
General measures such as immobilization of inflamed joint
Acute General Treatment
- •Monoarticular pseudogout:
- 1.Aspiration followed by intraarticular corticosteroid injection (often superior to systemic treatment in the elderly)
- •Polyarticular pseudogout:
- 1.Oral corticosteroids, colchicine, or NSAIDs, if not contraindicated
Chronic GeneralTreatment
Prophylaxis: Colchicine 0.6 mg once daily or bid as tolerated
- •Pseudo-RA or refractory disease: Hydroxychloroquine or methotrexate
- •Anakinra (interleukin-1 receptor antagonist): Treatment and prophylaxis of polyarticular acute CPP crystal arthritis unresponsive to oral corticosteroids
- •Treat underlying metabolic disease
- •Management options for CPPD are summarized in Boxes E3 and E4
- BOX E3
- Management Options for Chronic Calcium Pyrophosphate Crystal Arthritis With Inflammatory Symptoms
- From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
- Colchicine
- Low-dose prednisone (<10 mg/day)
- Nonsteroidal antiinflammatory drugs (NSAIDs)
- Hydroxychloroquine
- Methotrexate
- Interleukin-1β antagonists
- Combinations of drugs listed above
- BOX E4
- Management Options for Chronic Calcium Pyrophosphate Crystal Arthritis Without Inflammatory Symptoms
- From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
- Colchicine
- Low-dose prednisone
- Nonsteroidal antiinflammatory drugs (NSAIDs)
- Pain medications
- Combinations of drugs listed above
DISPOSITION
Structural joint damage may occasionally occur, requiring arthroplasty in rare cases.
REFERRAL
Rheumatology
PEARLS & CONSIDERATIONS
Acute CPP crystal arthritis/pseudogout attacks have been reported to occur in the setting of surgical procedures, diuresis, bisphosphonate administration, and hyaluronate joint injections.
