Calcium Pyrophosphate Deposition Disease

Etiology

CPPD is believed to result from pathological formation and deposition of CPP crystals, which subsequently trigger an immune response.[1] CPP crystals are rod- or rhomboid-shaped, measure 1 to 22 μm in size, and display birefringence under polarized light.[4] The deposition of CPP crystals in hyaline or fibrocartilage is referred to as chondrocalcinosis, the precursor of CPPD.[5]

The mechanisms that lead to crystal deposition in cartilage and joints are yet to be clearly defined. Mutations of the ANKH and ENPP1 genes—both involved in cartilaginous phosphate metabolism—along with other genetic conditions, such as hypophosphatasia, or metabolic factors, including hypomagnesemia and hyperferritinemia, which lead to reduced alkaline phosphatase activity, are proposed underlying mechanisms.[1][5] CPPD is also commonly associated with age and osteoarthritis.[6] Other recognized risk factors include hemochromatosis, hyperparathyroidism, hypophosphatasia (a rare inherited bone disease), and hypomagnesemia.[2][7] Patients with Gitelman syndrome are also frequently affected, likely related to underlying hypomagnesemia.

Epidemiology

Approximately 30% to 50% of patients with CPPD are older than 85.[8] Men and women appear to be equally affected.[2][7][6]

Chondrocalcinosis has been frequently used as a surrogate for CPPD. The prevalence of chondrocalcinosis varies depending on the location of the joint, the imaging modality used, and the individual's ethnicity.[6][9][10] On plain radiographs, chondrocalcinosis is observed in 7.0% to 8.1% of knees, and in 10.0% to 10.4% of cases when the knees plus either the hand/wrist or the hip/symphysis pubis are involved.[11] An ultrasound study of patients with knee pain found that CPPD was present in 22% and 10% of patients in fibrocartilage and hyaline cartilage, respectively.[6]

A study found that the presence of cartilage calcification—another possible marker for CCPD—is 4% to 7% in the United States and Europe.[12] The low sensitivity of conventional radiography likely leads to an underestimation of CPPD prevalence.[1]

Pathophysiology

The pathophysiology of CPP disease is linked to an imbalance of inorganic pyrophosphate in the cartilage's extracellular matrix, which promotes its interaction with calcium and leads to the formation of calcium pyrophosphate crystals.[13] CPP crystals are commonly deposited in cartilaginous structures but can also be found in the fibrocartilaginous layers at the insertion sites of tendons and ligaments. The deposition of CPP crystals triggers an inflammatory cascade, activating the immune system and leading to synovitis and progressive joint damage. Tissue nonspecific alkaline phosphatase may contribute to the increased risk of osteoporotic fractures and cardiovascular events observed after acute episodes of CPP arthritis.[14] In severe cases associated with Gitelman disease, involvement of the axial skeleton may also occur.[15]

Histopathology

Histologically, the presence of weakly birefringent, double-refracting crystals on polarized light microscopy is diagnostic of CPPD disease. These crystals are rhomboid or parallelepipedal, as opposed to the strongly negatively birefringent, needle-shaped urate crystals of gout.[12][16]

History and Physical

Acute CPPD crystal arthritis typically presents as either acute monoarticular or oligoarticular arthritis. This condition is often characterized by the sudden onset of pain, warmth, swelling, and, in some cases, periarticular erythema. When a large joint is involved, systemic symptoms such as fever, chills, and malaise may also occur.[17] Although the knees are the most commonly affected joints, studies have shown that radiographic chondrocalcinosis is common in the wrists and hips, even in the absence of knee involvement.[18] 

CPPD of the atlanto-occipital joint, also known as crowned dens syndrome, can cause periodic acute cervico-occipital pain accompanied by fever, neck stiffness, and laboratory evidence of inflammation.[19] Chronic CPPD crystal arthritis can present as persistent inflammatory polyarthritis or recurrent acute flares. The persistent inflammatory polyarthritis subtype often resembles rheumatoid arthritis or polymyalgia rheumatica. Some subtypes of CPPD, particularly the pseudo-neuropathic type, can lead to structural damage, particularly in the wrist and metacarpophalangeal joints, with clinical presentation often characterized by mechanical pain in the affected joint.[1] Clinical manifestations of CPPD disease may be atypical in the older population due to cognitive impairment and inflammation-induced delirium, which can make diagnosis more challenging.[1]

Compared to CPPD, primary osteoarthritis is more likely to affect the medial knee compartment, resulting in a varus deformity.[3] CPPD can also have overlapping symptoms with gout, which also affects the large joints; however, gout is much more likely to affect the first metatarsal joint (podagra) and other small joints of the metatarsals.

The first validated classification criteria for symptomatic CPPD were recently developed by the American College of Rheumatology and the EULAR in 2023 (see Table. Calcium Pyrophosphate Deposition Disease, Classification Criteria).[20] EULAR 2023 CPPD Guidelines. A patient is classified as having CPPD under the following conditions:

• They meet the entry criterion of having a history of at least 1 episode of joint pain, swelling, or tenderness.
• They do not meet any exclusion criteria (ie, symptoms are better explained by another diagnosis)
• They fulfill at least 1 sufficient criterion, such as clinical and radiographic evidence of crowned dens syndrome or the presence of CPP crystals in a patient with inflammatory arthritis

If these criteria are not met, CPPD can be defined based on a cumulative point system, with a total score greater than 56 indicating the diagnosis (see Table. CPPD Cumulative Point-Based Criteria).

Evaluation

Basic bloodwork should include a basic metabolic panel (including calcium, magnesium, and phosphate), parathyroid hormone level, iron studies, thyroid-stimulating hormone level, and uric acid level.[1]

Crystal identification in synovial fluid aspirates by compensated polarized light microscopy remains the gold standard for diagnosing CPP arthritis.[21] Given the invasive nature of synovial fluid analysis, the role of imaging continues to evolve in clinical practice. Commonly used imaging modalities for diagnosing CPPD include plain x-ray, computed tomography (CT), dual-energy computed tomography (DECT), and ultrasound.[22]

CCP deposits are found more commonly in fibrocartilage, such as in weight-supporting structures like the spine, pubic symphysis, and menisci, than in hyaline cartilage, such as in articular joints. Conventional radiography is the first-line imaging modality for identifying CPP calcification.[23] The classic findings on x-ray are linear and punctate densities in the hyaline/fibrous cartilage, synovial membranes, or tendons.[23] However, some studies have found that conventional radiography has a sensitivity of only about 40% for detecting clinically significant CPPD.[24]

Over the last decade, the ultrasound has been extensively used as a diagnostic modality for crystal arthropathies. This modality is more sensitive but less specific than conventional radiography.[22] Ultrasound findings are hyperechoic deposits of variable shape and size, localized within the fibrous/hyaline cartilage, that remain fixed or move along with the fibrous/hyaline cartilage during dynamic assessment and do not create posterior shadowing.[23]

Conventional computed tomography generally shows well-defined punctate or linear calcifications, less dense than cortical bone, within the fibrous/hyaline cartilage, synovial membranes, or tendons.[23]

DECT is considered the most sensitive imaging modality for detecting crystals based on their characteristic attenuation, described by its material-specific dual-energy gradient.[25] DECT has the potential to differentiate between different crystal deposits.[21] Findings indicating CPPD are punctate or linear calcifications less dense than cortical bone in the fibrous/hyaline cartilage, synovial membranes, or tendons with a dual-energy index between 0.016 and 0.036.[23]

Treatment / Management

Despite ongoing progress in clinical research on CPPD, no disease-modifying therapies have been approved to reduce the deposition of CPP crystals. The goal of treatment is largely based on decreasing inflammation, reducing the frequency and severity of symptoms, and stabilizing any underlying metabolic disease that may predispose patients to CPP deposition.[22]

The treatment of acute CPP arthritis has mostly been guided by the treatment of acute gout flares. In 2011, the EULAR recommended the use of nonsteroidal anti-inflammatory drugs, colchicine, and systemic or intra-articular corticosteroids depending on the patient's age and other comorbidities.[26] In 2023, the COLCHICORT trial recommended initiating treatment of acute CPP crystal arthritis with a daily dose of 30 mg prednisone as first-line therapy.[27] When colchicine is used, early administration (within 12 hours of arthritis onset) is crucial. For chronic CPP crystal inflammatory arthritis, daily colchicine is the preferred first-line treatment, whereas methotrexate and tocilizumab are considered second-line options.[28](A1)

Differential Diagnosis

The manifestations of CPPD can mimic several other rheumatological conditions and have different phenotypes. About one-fourth of patients experience acute CPP arthritis, often called pseudogout, whereas chronic CPP arthritis, previously referred to as pseudo-rheumatoid arthritis, affects approximately another 25% of patients. Asymptomatic CPPD may present as chondrocalcinosis on plain radiographs without apparent clinical consequences. A significant portion of patients with CPPD have associated degenerative arthritis, most commonly osteoarthritis. A key distinguishing feature in knee involvement is that primary osteoarthritis predominantly affects the medial compartment, whereas the lateral compartment is more frequently involved in CPPD-related osteoarthritis. Pseudo-polymyalgia rheumatica is a term used for the atypical presentation of CPPD in older adults with early morning stiffness and bilateral shoulder pain. Pseudo-neuropathic arthropathy and tumoral CPPD are some other rare presentations of CPPD.[3] 

Pertinent Studies and Ongoing Trials

To date, there are no specific outcomes agreed on for the assessment of CPPD disease.[1] A scoping review by the OMERACT CPPD working group identified imaging manifestations, joint pain, and response to treatment domains as the most commonly reported outcomes.[29]

The field of CPPD disease is rapidly evolving. Future research should focus on the genetics and metabolomics of sporadic CPPD disease, as well as the incidence and prevalence of CPPD disease and its various phenotypes. The imaging field is evolving, underscoring the need for continued efforts to standardize imaging protocols. Therapeutic studies are needed to explore the efficacy of existing IL-1 and IL-6 inhibitors, as well as novel agents, including inflammasome inhibitors and other new targets, in reducing CPP crystal-induced inflammation.[1]

Prognosis

Acute attacks of CPP crystal arthritis are generally self-limiting, typically lasting 7 to 10 days. Patients with chronic CPP inflammatory arthritis experience recurrent flare-ups, with symptoms that frequently overlap those of rheumatoid arthritis.[17] Some patients may develop tenosynovitis leading to carpal or cubital tunnel syndrome.[12][17]

Acute CPP crystal arthritis causes severe joint pain that temporarily restricts movements and can lead to significant disability, often requiring bed rest or limiting daily activities. This condition may also negatively affect mental health. Chronic CPPD disease leads to reduced mobility, frequently necessitating walking aids and increasing care needs. Pain often disrupts sleep and limits exercise, social interactions, leisure activities, and work.[1]

Complications

The presence of CPP crystals triggers an inflammatory response, which can lead to atypical presentations and complications. In a rare scenario, biopsy of tophi-like nodules, typically found only in urate-related gout, revealed CPPD.[30] Tumoral CPPD, a rare clinical phenotype of CPPD, may present as CPP crystals in the spine, leading to ossification of the ligamentum flavum.[31]