Calcium pyrophosphate deposition disease: A common, under-diagnosed condition
Prevalence of calcium pyrophosphate deposition disease
Calcium pyrophosphate deposition (CPPD) disease is a common condition that affects between 4% and 7% of adults in the USA and Europe. It was the fourth most prevalent musculoskeletal condition in an Italian population survey, with a prevalence of 0.42%. However, these figures underestimate the true prevalence of CPPD disease as they are derived from community surveys using plain radiography, which has a low sensitivity for detecting CPPD compared with other imaging modalities such as ultrasonography.
Pathogenesis of calcium pyrophosphate deposition disease
CPPD disease is caused by the deposition of calcium pyrophosphate dihydrate crystals. Research studies suggest that CPPD disease is a systemic articular disease, and that the underlying abnormality is a combination of elevated intraarticular pyrophosphate levels and a cartilage matrix that allows crystal nucleation and growth. Unlike monosodium urate (MSU) crystals, calcium pyrophosphate crystals deposit only in the cartilage, with a predilection for fibrocartilaginous involvement over hyaline cartilage, and synovial CPPD occurs in areas of chondrometaplasia. However, once shed from these deposits, calcium pyrophosphate crystals can be seen in the aspirated synovial fluid under polarised light microscopy. Just like MSU crystals, they induce inflammation by activating the NALP-3 inflammasome.
Risk factors for calcium pyrophosphate deposition disease
The association between CPPD, ageing, and osteoarthritis (OA) is so well recognized, that CPPD is generally considered to be a sole consequence of these two factors. However, CPPD disease can present with symptomatic arthritis even at a young age, eg, younger than 40 years. In this age group, the risk factors for CPPD include: joint injury, eg, previous meniscectomy at the knee; metabolic disorders such as hemochromatosis, hyperparathyroidism, hypomagnesemia, and hypophosphatasia; and genetic variations in the ANKH or TNFRSF11B genes coding for osteoprotegerin. In addition, some young people with severe dysplastic OA may have concurrent CPPD. It is also reasonable to screen for underlying metabolic disorders in people older than 60 years in age with florid polyarticular CPPD. The prevalence of hyperparathyroidism increases with age, and it should be screened for in older people with florid polyarticular CPPD. Similarly, people with hemochromatosis may go undiagnosed, and present after the age of 60 years.
Clinical features of calcium pyrophosphate deposition disease
CPPD is frequently asymptomatic, and is detected as an incidental radiographic finding, eg, articular chondrocalcinosis in many instances (see figure 1). However, these crystalline deposits can induce a myriad of inflammatory clinical presentations, such as acute calcium pyrophosphate crystal inflammatory arthritis (previously termed “pseudogout”) that can be recurrent, chronic calcium pyrophosphate crystal inflammatory arthritis, and CPPD with OA.
Figure 1: (A) Knee radiograph showing linear calcification in the knee fibrocartilage, lateral and medial meniscus; (B) Left hip radiograph showing arcuate-linear calcification in the hip hyaline cartilage; (C) Left wrist and hand radiograph showing calcification in the triangular fibrocartilage and in the third metacarpophalangeal joint.
Radiologic studies suggest that CPPD most commonly occurs at the knees and wrists, and these joints are frequently symptomatic. Hips, shoulders, elbows and spine may be involved, but this is less frequent.
The underlying metabolic and genetic abnormalities outlined above should be suspected in people with atypical clinical presentations, eg, either young onset CPPD, recurrent flares of acute crystal synovitis, or florid polyarticular CPPD. As metabolic disorders and mutations in the ANKH gene cause recurrent acute calcium pyrophosphate crystal arthritis, it is even more important to screen for these disorders in people with recurrent acute calcium pyrophosphate crystal arthritis. However, it is important to bear in mind that hemochromatosis causes structural arthropathy and chronic joint symptoms.
Diagnosis of calcium pyrophosphate deposition disease
The diagnosis of CPPD can be difficult due to a high false-negative rate of detecting calcium pyrophosphate crystals by polarized light microscopy of the aspirated synovial fluid, and the low sensitivity of conventional radiography in detecting articular chondrocalcinosis. It is possible that the increasing use of ultrasonography and increased availability of dual energy computed tomography (CT) will make a reliable diagnosis of CPPD easier. In the absence of a sensitive and specific diagnostic test, CPPD is frequently undiagnosed.
Clinical presentations and diagnostic dilemma
Acute calcium pyrophosphate deposition disease
Acute calcium pyrophosphate crystal arthritis is the most well-recognized manifestation of CPPD. Symptom onset is fairly abrupt. The knee and the wrist are the most frequently affected joint areas. There is overlying erythema of the affected joints, with other cardinal manifestations of inflammation such as swelling, warmth, and tenderness present. Symptoms typically last for 1–2 weeks before resolving. Other joint areas such as the ankles, elbows, and shoulders may be affected. There may be tenosynovitis present.
It is generally easy to diagnose CPPD disease in these clinical scenarios, provided the synovial fluid can be aspirated and demonstrates weakly positively birefringent calcium pyrophosphate crystals. However, if the crystals are not identified in the aspirated synovial fluid, the diagnosis depends on presence of radiographic articular chondrocalcinosis. If available, ultrasonography can be a very handy tool in this scenario as ultrasonography has a substantially higher sensitivity for detecting CPPD than radiography.
When the acute inflammation targets the intervertebral discs, cervical ligaments, or the facet joints, symptoms mimic those of discitis with severe pain, fever, localized stiffness, and high inflammation markers. It is often very difficult to reach a confident diagnosis of spinal CPPD unless a tissue biopsy is obtained.
If calcium pyrophosphate crystals are not demonstrated, it becomes difficult to distinguish an episode from gout or septic arthritis. While a negative synovial fluid culture and Gram stain is able to exclude septic arthritis, gout can be reliably excluded if MSU crystals are present. However, CPPD only very rarely causes podagra, and, a history of podagra with hyperuricaemia may suggest a diagnosis of gout even if synovial fluid aspirate does not demonstrate MSU crystals.
Recurrent acute calcium pyrophosphate crystal arthritis
Recurrent acute calcium pyrophosphate crystal arthritis is easy to diagnose in the presence of a positive synovial fluid examination. However, in many instances, a synovial fluid examination cannot be performed as the inflamed joints are difficult to aspirate, or the aspirated synovial fluid is negative for calcium pyrophosphate crystals. In these situations, the diagnosis relies on demonstration of CPPD on plain radiographs or on ultrasonography. However, if the presence of CPPD is not sought specifically, the patient may be misdiagnosed with palindromic rheumatoid arthritis, gout, or seronegative spondyloarthritis.
Chronic calcium pyrophosphate crystal inflammatory arthritis
Chronic calcium pyrophosphate crystal inflammatory arthritis can be difficult to diagnose. It is possible that a proportion of people with elderly-onset rheumatoid factor and anti-cyclic citrullinated peptide antibody negative inflammatory arthritis have this condition. It should be suspected in people with disease onset after 60 years of age, wrist and knee involvement, and with superimposed flares. However, the prevalence of this phenotype of CPPD is not known.
Spinal calcium pyrophosphate deposition disease
Spinal involvement manifests with crowned dens syndrome in the cervical spine (see figure 2). Intervertebral disc CPPD can be asymptomatic, or manifest with symptoms that mimic discitis and inflammatory meningoradiculopathy. This can be difficult to diagnose, unless there is a high degree of clinical suspicion and a biopsy or CT scan is performed.
Figure 2: Coronal view computed tomography scan of a patient showing calcification around the odontoid peg, consistent with crowned dens syndrome.
Calcium pyrophosphate deposition disease with osteoarthritis
This is the commonest manifestation of CPPD. Currently diagnosis rests on plain radiography and synovial fluid microscopy. People with CPPD with OA have a different distribution of OA, eg, wrist, shoulder, and metacarpophalangeal joint involvement, greater bony attrition at the knee, and milder structural hip arthropathy.
In conclusion, CPPD is a common cause of arthritis and can be difficult to diagnose. This is because synovial fluid polarized light microscopy has a high false negative rate, and plain radiography has low sensitivity. Ultrasonography is an emerging diagnostic tool that has the potential of improving the diagnosis of CPPD disease. Genetic and metabolic predisposition should be suspected in people with young onset or florid polyarticular CPPD.
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