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Calcium Pyrophosphate Deposition Disease
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 representing specific clinical or radiographic features of CPPD disease include pseudogout, chondrocalcinosis, and pyrophosphate arthropathy.
Nomenclature of Calcium Pyrophosphate and Associated Syndromes
5 Interesting Facts of Calcium Pyrophosphate Deposition Disease
1. Calcium pyrophosphate deposition disease (CPPD) is a disease of the elderly, with onset and increasing frequency after the age of 50 years.
2. Patients younger than 55 years with chondrocalcinosis (CC) should be evaluated for a familial form or metabolic disease associated with CPPD.
3. Chronic CPPD should be considered in any elderly patient with symptoms suggesting seronegative rheumatoid arthritis (RA) or polymyalgia rheumatica.
4. Chronic CPPD should be considered in any patient with diffuse osteoarthritis (OA) in atypical joints such as the metacarpophalangeal joints (MCPs), wrists, elbows, and shoulders.
5. The mnemonic ABC ( A lignment B lue C alcium) is useful for remembering the color of a CPPD crystal parallel to the first-order red compensator when viewing synovial fluid by polarized light microscopy.
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; pseudoosteoarthritis | 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
- Calcium pyrophosphate dihydrate crystal deposition disease
- CPP crystal deposition disease
- CPPD
- Chondrocalcinosis (CC)
- Pseudogout
- Pyrophosphate arthropathy
Epidemiology & Demographics
Prevalence
- •The epidemiology of CPPD crystal deposition is described in the below table.
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 functions to transport 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 & Clinical Presentation
- •Acute CPP crystal arthritis/pseudogout: Monoarticular attacks most commonly involve the knee and wrist but can be polyarticular. Patients, especially the elderly, can have systemic manifestations such as fever and altered mental status. Situations that may trigger acute CPPD crystal arthritis are described below
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
Possible
- 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-RA (chronic CPP crystal inflammatory arthritis): Symmetric polyarthritis
- •Pseudo-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: Hyperparathyroidism, hypophosphatasia, hemochromatosis, hypomagnesemia, Gitelman syndrome, Bartter syndrome, gout, ochronosis, acromegaly, Wilson disease, familial hypocalciuric hypercalcemia, X-linked hypophosphatemic rickets
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
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, PsA)
- •PMR
The below table describes metabolic diseases predisposing to CPPD disposition. Section II describes the differential diagnosis of acute monoarticular and oligoarticular arthritis and crystal-induced arthritides.
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 with 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 co-exist.
- •Evaluate for possible metabolic causes, especially in younger patients aged <55 yr or patients with florid polyarticular disease.
- Screening Blood Tests for Metabolic Diseases Associated with Calcium Pyrophosphate Dihydrate Crystal DepositionFrom Hochberg MC et al: Rheumatology, ed 5, St Louis, 2011, Mosby.
- Calcium
- Alkaline phosphatase
- Magnesium
- Ferritin, iron, transferrin
- Liver function
- Thyroid-stimulating hormone
Imaging Studies
- •Plain radiographs often reveal CC located parallel to subchondral bone.
Musculoskeletal ultrasound can detect deposition of CPP crystals within the hyalinecartilage 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 CT scan can differentiate mineral deposits through color-coded images and may aid in the diagnosis of CPPD from other crystal arthropathies.
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 General Treatment
Prophylaxis: Colchicine 0.6 mg twice daily or once daily 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 below
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
Hydroxychloroquine
Methotrexate
Interleukin-1β antagonists
Combinations of drugs listed above
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
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.
Seek Additional Information
- Abhishek A., Doherty M.: Update on calcium pyrophosphate deposition. Clin Exp Rheumatol 2016; 34 (4 Suppl 98): pp. 32-38.
- Andres M: Methotrexate is an option for patients with refractory calcium pyrophosphate crystal arthritis. J Clin Rheumatol 2012; 18 (5): pp. 234-236.
- Liew J.W., Gardner G.C.: Use of anakinra in hospitalized patients with crystal-associated arthritis. J Rheumatol 2019; 46 (10): pp. 1345-1349.
- MacMullan P., McCarthy G.: Treatment and management of pseudogout: insights for the clinician. Ther Adv Musculoskelet Dis 2012; 4 (2): pp. 121-131.
- McCarthy G.M., Dunne A.: Calcium crystal deposition disease: beyond gout. Nat Rev Rheumatol 2018; 14 (10): pp. 592-602.
- Mulay S.R., Anders H.J.: 2016; 374: pp. 2465-2476.
- Rosenthal A.K., Ryan L.M.: Calcium pyrophosphate deposition disease. N Engl J Med 2016; 374: pp. 2575-2584.
- Tedeschi S.K., et al.: Calcium pyrophosphate crystal inflammatory arthritis (pseudogout) with myelodysplastic syndrome: a new paraneoplastic syndrome? J Rheumatol 2017; 44 (7): pp. 1101-1102.
- Zhang W.: European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis 2011; 70: pp. 563-570.
