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Calcium Pyrophosphate Deposition Disease (CPPD) (Pseudogout)

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Calcium Pyrophosphate Deposition Disease (CPPD) (Pseudogout)
Kenneth M. Bielak
Benjamin D. England
Basics
Description
  • Calcium pyrophosphate deposition disease (CPPD) is a crystal arthropathy characterized by deposition of calcium pyrophosphate dihydrate crystals in joints.
  • Synonym(s):
    • Pseudogout: Describes an acute attack of CPPD crystal-induced synovitis (similar to gout), but many will not experience such intense symptoms
    • Chondrocalcinosis: As evidenced by radiographic calcification, but is not absolutely specific for CPPD and not universal among all patients with CPPD
    • Pyrophosphate arthropathy: Specifically associated with inorganic pyrophosphate metabolism as the etiology for CPPD
Epidemiology
  • Prevalence of chondrocalcinosis is 5–8% in the general population, but 15% by the 9th decade
  • Female-to-Male ratio: 2–7:1
  • Peak age: 65–75 yrs
Risk Factors
  • Gout (20% may be hyperuricemic)
  • Hemochromatosis
  • Hypothyroidism
  • Trauma
  • Osteoarthritis
  • Hyperparathyroidism
  • Hemosiderosis
  • Hypophosphatasia
  • Hypomagnesemia
  • Aging
  • Amyloidosis
Genetics
<1% of cases may show an autosomal dominant inheritance pattern.
General Prevention
  • There are no absolute prevention measures, but mainstays include adequate hydration (to prevent crystal precipitation) and decreasing purine-rich foods, such as organ meats, mushrooms, legumes, asparagus, and coffee.
  • For individuals who have experienced 3 or more attacks in 1 yr, colchicine has been found to reduce the recurrence rate (1)[B].
Etiology
CPPD crystal formation is initiated in cartilage located near the surface of chondrocytes, which are embedded in and contribute to the collagen- and proteoglycan-containing cartilage matrix of joint surfaces. The CPPD crystal formation may be a combination of elevated levels of either calcium or pyrophosphate and/or matrix changes that enhance local CaPPi (calcium pyrophosphate) supersaturation. Many cases of CPPD deposition are idiopathically sporadic, but more commonly are precipitated by trauma or various metabolic disorders.
Commonly Associated Conditions
  • Pseudorheumatoid arthritis: A nonerosive, inflammatory arthritis with demonstrable CPPD crystals in the joint fluid. The clinical picture resembles rheumatoid arthritis with morning stiffness, fatigue, synovial thickening, edema, and loss of motion. The 2 may coexist and must be differentiated as the treatment options vary.
  • Pseudoarthritis: Progressive joint degeneration involving multiple joints. CPPD crystal deposition can be differentiated by radiographic evidence of calcifications in the absence of a preceding trauma.
  • Case reports of CPPD associated with Charcot joints.
  • CPPD, especially familial patterns, can be found along the spine and resemble ankylosing spondylitis.
Diagnosis
History
  • Acute joint swelling in 1 or more joints with previous episodes involving the same joint (characteristic of crystal arthropathies)
  • The most common joint is the knee, followed by the wrist, shoulder, and hip.
  • May be severe and associated with malaise and fever
  • Period of previous episodes (typically several days to weeks)
  • Patients often are symptom-free between attacks.
Physical Exam
  • Involved joint:
    • Hot
    • Edema, tender
    • Limited range of motion
  • Uncommon presentations include tendinopathy, tenosynovitis, and bursitis.
  • Chronic CPPD: Symmetrical polyarthritis affecting knees, metacarpophalangeal joints, wrists, ankles, and shoulders:
    • May involve the spine
    • Affected joints show signs of osteoarthritis with varying degrees of synovitis.
    • Predominantly affects women
Diagnostic Tests & Interpretation
Lab
  • Any newly diagnosed CPPD should be followed with laboratory evaluations of calcium, magnesium, thyroid-stimulating hormone, ferritin, transferrin, iron, phosphorus, and alkaline phosphatase.
  • Synovial fluid microscopy with compensated polarized light microscopy showing weakly positive birefringent rhomboidal shaped crystals is diagnostic; gram stain and culture should be considered to rule out differential diagnoses.
  • Erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, uric acid, white cell count (leukocytosis), and blood cultures may be considered to rule out differential diagnoses.
  • Leukocyte concentration typically in the range of 15,000–30,000 per cubic millimeter with 90% neutrophils
Imaging
  • Plain radiography has diagnostic utility in the crystal-induced arthropathies, which illustrates calcium crystal deposition (2).
  • X-ray: Calcification of articular fibrocartilage (chondrocalcinosis) in menisci of the knee, triangular fibrocartilage complex in the wrist. Other sites include glenoid and acetabular labra and symphysis pubis.
  • X-ray changes of osteoarthritis often are pronounced.
  • X-ray hands (2nd/3rd metacarpophalangeal chookd osteophytes in hemochromatosis)
  • High-resolution US may improve noninvasive diagnosis of the crystal-induced arthropathies and allow monitoring of intra-articular tophi in clinical trials.

    • P.59


  • CT provides excellent definition of tophi and bone erosion, and 3D CT assessment of tophus volume is a promising outcome measure in gout.
  • MRI is also a reliable method for assessment of tophus size in gout, and has an important role in detection of complications of disease in clinical practice.
  • Emerging imaging techniques include 3D US and dual-energy CT. Advanced imaging modalities also offer new insights into the mechanisms of cartilage and bone damage in the crystal-induced arthropathies (3)[B].
Pathological Findings
Tissue sections are best examined with alizarin red, looking for crystals as the hematoxylin and eosin stains may cause dissolution of the crystalline CPPD due to their acidity.
Differential Diagnosis
  • Gout (can coexist)
  • Septic arthritis (can coexist)
  • Rheumatoid arthritis
  • Osteoarthritis
  • Trauma (hemarthrosis)
  • Human leukocyte antigen B27-related peripheral arthritis (psoriatic arthritis, ankylosing spondylitis, reactive arthritis)
  • Hypertrophic osteoarthropathy
  • Pseudorheumatoid arthritis: Severe synovitis in rheumatoid pattern
Treatment
  • Acute treatment (4)[C]:
    • Joint aspiration (often significantly reduces pain) (4)[C]
    • Intra-articular corticosteroid injection can be effective.
    • Joint rest and splinting
    • NSAIDs and oral analgesia
    • Colchicine and systemic corticosteroids can be used if other treatments are contraindicated.
  • Long-term treatment:
    • For patients suffering recurrent attacks of pseudogout, oral daily colchicine may be effective as a prophylactic agent at a usual dosage of 0.6 mg b.i.d. (1)[B].
    • Repeat joint aspiration may be required.
    • Once acute attacks have settled, the aims of treatment are to relieve symptoms and regain function.
    • No specific treatment exists for chronic CPPD, and no treatments are available that reverse joint damage.
Medication
NSAIDs are first-line treatment.
Additional Treatment
Additional Therapies
Antibiotics if septic arthritis is suspected until joint and blood cultures return negative
Complementary and Alternative Medicine
There have been anecdotal reports of cured acute attacks by the consumption of dark cherries or cherry juice or herbs that contain xanthene oxidase inhibitors to decrease urate formation, but none have been well studied.
Surgery/Other Procedures
Joint arthroplasty may be required for severely damaged joints.
Ongoing Care
  • Primary metabolic disorders or familial predisposition are uncommon, but should be considered if CCPD occurs before 55 yrs of age or if there is florid polyarticular CCPD.
  • After the age of 55 yrs, hyperparathyroidism should be considered in all patients.
Complications
Although acute pseudogout usually responds well to therapy, chronic CPPD often is progressive and may cause considerable disability.
References
1. Alvarellos A, Spilberg I. Colchicine prophylaxis in pseudogout. J Rheumatol. 1986;13:804–805.
2. Ciapetti A, Filippucci E, Gutierrez M, et al. Calcium pyrophosphate dihydrate crystal deposition disease: sonographic findings. Clin Rheumatol. 2008.
3. Dalbeth N, McQueen FM. Use of imaging to evaluate gout and other crystal deposition disorders. Curr Opin Rheumatol. 2009;21:124–131.
4. Announ N, Guerne PA. Treating difficult crystal pyrophosphate dihydrate deposition disease. Curr Rheumatol Rep. 2008;10:228–234.
Additional Reading
Couto AR, Brown MA. Genetic factors in the pathogenesis of CPPD crystal deposition disease. Curr Rheumatol Rep. 2007;9:231–236.
Doherty M. Crystal arthropathies: calcium pyrophosphate dihydrate. In: Klippel JH, Dieppe PA, eds. Rheumatology. London: Mosby-Year Book Europe Limited, 1994:7.13.1–7.13.12.
Ea HK, Lioté F. Advances in understanding calcium-containing crystal disease. Curr Opin Rheumatol. 2009;21:150–157.
Fodor D, Albu A, Gherman C. Crystal-associated synovitis-ultrasonographic feature and clinical correlation. Ortop Traumatol Rehabil. 2008;10:90–102.
Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology (Oxford). 2009.
Ryan LM, McCarty DO. Calcium pyrophosphate crystal deposition disease, pseudogout and articular chondrocalcinosis. In: Koopman WJ, ed. Arthritis and allied conditions: a textbook of rheumatology, 13th ed. Baltimore: Williams & Wilkins, 1997:2103–2125.
Shah K, Spear J, Nathanson LA, et al. Does the presence of crystal arthritis rule out septic arthritis? J Emerg Med. 2007;32:23–26.
Codes
ICD9
  • 275.49 Other disorders of calcium metabolism
  • 712.20 Chondrocalcinosis, due to pyrophosphate crystals, involving unspecified site
Clinical Pearls
The cause of CPPD is unknown (unlike gout, in which hyperuricemia leads to precipitation of uric acid crystals into joints). Therefore, there is no preventative treatment for recurrent attacks, although colchicine may be useful as prophylaxis in those with frequent recurrences.


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