Calcium Pyrophosphate Deposition Disease (CPPD)

History and Epidemiology

Calcium pyrophosphate deposition disease (CPPD) is a crystal deposition arthropathy that involves the synovial and periarticular tissues,¹ often characterized by painful swelling in one or more joints.² Other names that have been traditionally used for CPPD are chondrocalcinosis, pyrophosphate arthropathy, and most especially, pseudogout.³ It is commonly known as pseudogout due to its similarity to gout, another arthropathy that involves crystalline deposits within a joint.

The specific crystals involved in CPPD are calcium pyrophosphate dihydrate, and commonly affect larger, weight-bearing joints, such as the hips, knees, and shoulders.¹ Most patients affected by acute CPPD are over the age of 65, and 30 to 50 percent of patients present over after 85 years of age. CPPD rarely presents in people under the age of 60.¹ According to the American College of Rheumatology, CPPD affects roughly three percent of people in their 60s and as many as 50 percent in their 90s.⁴

CPPD Diagnosis and Presentation

Patients who present with acute CPPD have manifestations similar to acute urate arthropathy (gout), including joint edema, erythema, and tenderness.¹ A low-grade fever may also be present in up to 50 percent of these patients.¹
Symptoms are:⁵

• Sudden, intense joint pain
• Red skin involving the affected joint
• Swollen joint that is warm and tender to touch
• Less often, there may be persistent swelling, warmth, and pain in several joints that can mimic rheumatoid arthritis

The most commonly affected joint is the knee, but calcium pyrophosphate deposition disease can also affect hips,¹ shoulders, wrists, ankles, elbows, hands, or other joints.⁴ Some patients may have chronic CPPD that resembles rheumatoid arthritis, often presenting with non-synchronous, inflammatory arthritis symptoms that come and go and affect multiple non-weight-bearing joints.¹ CPPD should always be suspected in elderly patients who present with acute degenerative arthritis in weight-bearing joints. Acute flares may also be present in some patients after traumatic injuries.

Several risk factors have been linked to the development of CPPD. These risk factors include:

• Older age²
• Previous joint trauma²
• Genetic disorders that can lead to the development of CPPD at younger ages²
• Disorders that affect calcium, phosphate, or iron metabolism (such as hemochromatosis)²
• A thyroid condition⁵
• Kidney failure⁵
• Parathyroid disease⁵
• Low magnesium levels⁵
• Osteoarthritis/degenerative joint disease⁵

Diagnostic Workup

Arthrocentesis

Once the clinician has completed an appropriate physical examination, patients suspected to have CPPD should undergo arthrocentesis for synovial fluid analysis. The presence of rhomboid-shaped calcium pyrophosphate dihydrate crystals in the synovial fluid analysis confirms the diagnosis of CPPD.

Imaging

Imaging findings can support the diagnosis of CPPD, but an absence of evidence in imaging studies does not rule out the disease. Imaging tests that include:

X-Rays. Radiography should be taken of any symptomatic joints, which may provide further evidence by showing joint cartilage calcification (chondrocalcinosis).

Ultrasound. Ultrasound imaging can detect early signs of the disease as cartilage abnormalities.

MRI. Magnetic resonance imaging, particularly gradient-echo sequences, has shown to be useful in the evaluation of calcium pyrophosphate crystal deposition burden in joint cartilage.

Differential Diagnosis

As CPPD has clinical manifestations similar to other joint diseases, there are multiple differential diagnoses. These include:¹

• Gout
• Rheumatoid arthritis
• Ankylosing spondylitis
• Erosive osteoarthritis
• Diffuse idiopathic skeletal hyperostosis (DISH)

Management of CPPD

There is no cure for CPPD, as no therapy is available that can dissolve the crystal deposits within the joint.⁴ As such, treatment options revolve around managing symptoms. The first goal of treatment is to decrease inflammation and stabilize any underlying metabolic disease that may predispose patients to CPPD.¹ For patients suffering acute flares that involve one or two joints, the treatment of choice is joint aspiration and intra-articular glucocorticoid administration unless these options are contraindicated. If the patients present with acute flares involving three or more joints, the treatment should be more systemic, utilizing anti-inflammatory drugs. A list of common medications used for the management of systemic inflammation in CPPD patients include:¹

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Colchicine. Patients with recurring acute bouts may be prescribed a daily low-dose.¹
• Systemic glucocorticoids

Less commonly used medications include hydroxychloroquine, methotrexate, or an interleukin 1 beta antagonist, such as anakinra. These are typically reserved for more severe attacks of calcium pyrophosphate deposition disease or for patients who experience chronic inflammation rather than acute attacks.⁴ At-home management includes the application of cold therapy via ice packs to affected joints, as well as joint rest with restriction of weight-bearing activity.⁶

Monitoring CPPD

Acute CPPD attacks are self-limited, and inflammation typically resolves within days to weeks of treatment. Patients with chronic CPPD may present with manifestations such as morning stiffness, localized edema, decreased range of motion, and tenosynovitis with carpal or cubital tunnel syndrome. Monitoring entails noting the frequency and severity of attacks and determining if degradation of the joint is increasing with passing time. Rarely, multiple episodes of acute CPPD may lead to the development of palpable nodules or masses resembling gout tophi.

These nodules are calcium pyrophosphate crystal accumulations localized in the periarticular tissue and may lead to further joint degradation. Some patients may also present with spinal involvement that causes clinical manifestations, such as spine stiffness and bony ankylosis, or manifestations similar to diffuse idiopathic skeletal hyperostosis that can lead to spinal cord compression symptoms.¹

The use of medications can lead to side effects in some patients. Colchicine may cause issues within the gastrointestinal tract, including diarrhea, vomiting, and nausea. It should also be used cautiously with drugs known to inhibit CYP3A4 or P-glycoprotein, as this can increase concentrations of colchicine and lead to fatal drug interactions.⁷

Glucocorticoids administered in high doses for prolonged periods of time can have adverse effects such as osteoporosis and fractures, suppression of the hypothalamic-pituitary-adrenal (HPA) axis, Cushingoid features, diabetes and hyperglycemia, myopathy, glaucoma and cataracts, psychiatric disturbances, immunosuppression, gastrointestinal and dermatologic adverse effects, and cardiovascular disease.⁸ NSAIDs may have side effects that affect the gastric mucosa, cardiovascular system, renal system, hepatic system, and hematologic system.⁹

References

1. Zamora EA, Naik R. Calcium Pyrophosphate Deposition Disease (Pseudogout). In: StatPearls. NCBI Bookshelf version. Published 2020. Accessed September 2, 2022.

2. Pseudogout – Symptoms and causes. Mayo Clinic. Published 2018. Accessed September 2, 2022.

3. Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease. UpToDate. Update March 11, 2022. Accessed September 2, 2022.

4. Calcium Pyrophosphate Deposition (CPPD). American College of Rheumatology. Updated December 2021. Accessed September 2, 2022.

5. Pseudogout (CPPD): What Is It, Causes, & Treatment. Cleveland Clinic. Updated October 16, 2020. Accessed September 2, 2022.

6. Pseudogout – Diagnosis and treatment – Mayo Clinic. Mayo Clinic. Updated July 28th, 2022. Accessed September 2, 2022.

7. Sadiq NM, Robinson KJ, Terrell JM. Colchicine. In: StatPearls. NCBI Bookshelf version. Published 2020. Accessed September 2, 2022.

8. Hodgens A, Sharman T. Corticosteroids. In: StatPearls. NCBI Bookshelf version. Published 2020. Accessed September 2, 2022.

9. Ghlichloo I, Gerriets V. Nonsteroidal Anti-inflammatory Drugs (NSAIDs). In: StatPearls. NCBI Bookshelf version. Published 2020. Accessed September 2, 2022.

Author Bio:

Jonathan Poole is a freelance writer and copyeditor with a BSc in Exercise Science living in West Lafayette, IN. When not writing, he owns and operates a fitness training company, Unstoppable Athletes. More information regarding his training business can be found here: https://www.unstoppableathletes.com