Calcium Pyrophosphate Deposition Disease

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Diagnosis and reasoning

This elderly gentleman has presented with an alarming constellation of findings - longstanding pain and swelling of the right knee associated with a progressively enlarging mass. Examination of the affected joint reveals a hard, mobile mass in the para-patellar region; this is most worrisome of a tumor. Other differentials include cartilaginous degeneration of, or crystal deposition in the joint. If this were indeed a tumor, the possibilities include malignant lesions such as synovial sarcoma, leiomiosarcoma or osteosarcoma, as well as benign lesions such as myositis ossificans or a calcified lipoma. Further imaging of the mass is a good next step; plain radiography of the knee is a simple and cheap first-line investigation in this respect. Unfortunately, the meniscal calcifications seen here while abnormal, are too nonspecific to further narrow down the differentials. Magnetic resonance imaging (MRI) of the knee is a good follow up investigation; this reveals a 4 x 4 x 1.5cm mass in the medial parapatellar joint space, with irregular marginal calcifications. Note that soft tissue calcifications are almost due to dystrophic calcification (95-98%); the few rare exceptions are tumoral calcinosis (which is commonly observed in proximity of a joint); metastatic calcification, metastatic osteosarcoma, primary soft tissue osteosarcoma and chondrocalcinosis. Arthrocentesis should be the next step; unfortunately, this persistently results in a dry tap, necessitating more invasive procedures. As the nature of the mass is still unclear, and particularly given that a malignancy needs to be excluded, an excisional biopsy is probably justifiable. This reveals the mass to have a whitish glossy surface (suggestive of fibrous or articular cartilage), in apposition to the synovium; interestingly, histology subsequently reveals large calcified deposits, with no evidence of tumoral cells, i.e. this seems to be chondrocalcinosis. The positive birefringence test in turn confirms this, and reveals the diagnosis to be calcium pyrophosphate dihydrate crystal deposition disease (CPPD). The management of CPPD is based on prevention of crystal formation, dissolution of crystals and decreasing biological consequences of crystal-cell interactions. Colchicine has been found to prevent recurrence of the condition, and should be considered in this patient. Note that surgical excision of joint masses associated with CPPD results in improvement of mobility and abatement of inflammation in the affected joint; this is further improved by temporary joint immobilisation. Therefore, physiotherapy is best avoided early after surgery; nor will intra-articular steroids be required after excision. Allopurinol is a xanthine oxidase inhibitor which reduces production of uric acid; while helpful in the management of gout, it is of little use in this patient.


Discussion

Calcium pyrophosphate dihydrate crystal deposition disease (CPPD, also known as chondrocalcinosis or pseudogout) is a metabolic condition associated with periarticular and intra-articular calcification. CPPD is a disease of aging; in the United States, approximately half of all individuals above 85 years of age are believed to be affected, with a similar prevalence across all ethnic groups; a slight female preponderance of 1.4:1 is present. The pathophysiology of the condition is unclear, although several hypotheses exist; one of these is that increased catabolism of adenosine triphosphate (ATP) results in deposition of calcium pyrophosphate crystals in the joints; another is that crystal development occurs secondary to trauma or chronic inflammation. Regardless of the mechanism of formation, there is evidence that the crystals amplify joint degeneration by forcing increased phagocytosis of the joint space; these patients are thus at risk of developing rapidly progressive osteoarthritis. Note also that CPPD is known to be associated with hypomagnesemia, hypophosphatemia, hyperparathyroidism, hypothyroidism, hemochromatosis, acromegaly, renal osteodystrophy, osteoarthritis and Wilson's disease. The majority of patients with CPPD are asymptomatic, and only identified incidentally following plain radiography for other indications. Note also that these patients can present with acute attacks (which are usually self-limiting), or with a more indolent chronic form of the disease; note that the former can be provoked by intercurrent illness or surgery. The knees are the joints most frequently affected, followed by the symphysis pubis, small joints of the hand (including the metacarpophalangeal and carpal joints), wrist, hip, shoulder and spine; the involved joints may show features of inflammation such as restricted movement, morning stiffness, as well as contracture formation. Less often, a progressively enlarging mass may be seen in association with the affected joints; in such patients, the diagnosis may be challenging, as the mass may mimic the clinical and imaging characteristics of chondrosarcoma and chondroblastoma. A combination of joint imaging and arthrocentesis is key towards diagnosing CPPD. Plain radiography is usually nonspecific; this may reveal cloudlike synovial calcifications, fine irregular joint calcifications, and linear calcifications. Ultrasonography of the affected joints may reveal echogenic foci with no acoustic shadow within the hyaline cartilage. Computerized tomography (CT), magnetic resonance imaging (MRI) and nuclear imaging may visualize calcific masses within the ligamentum flavum and joint capsule. Arthrocentesis may reveal rhomboid shaped calcium pyrophosphate crystals in the synovial fluid; these are weakly positive birefringent, and appears basophilic on a hematoxylin and eosin stain. At the time of writing, there is no treatment to completely remove, or prevent formation of calcium pyrophosphate crystals. Thus, the management of CPPD mainly aims to achieve three key goals - relief of symptoms, restoration of normal joint function, and prevention or slowing of further joint degeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and naproxen relieve joint inflammation and thus reduce pain; in high doses, they are of use in terminating acute attacks, and in continuous low doses are of use in preventing recurrences. Joint aspiration can also provide relief by reducing fluid pressure; this can be combined with intra-articular corticosteroid injection. Systemic corticosteroids can also be used to relieve the inflammation associated with acute attacks. Colchicine (which is best known as a treatment of gout) has also shown the ability to prevent recurrences but this should be administered on a per-patient basis, following assessment of associated risks and benefits. Hydroxychloroquine and methotrexate are reported to provide relief in non responders to the above treatments; however, these too should only be prescribed on a patient-by-patient basis, with regular monitoring being mandatory. Note that joint immobilisation results in reduction of symptoms during acute attacks, as well as early recovery and achievement of joint mobility. However, muscle strengthening exercises and range of motion exercises are helpful later on, so as to maintain the function of the affected joints. Surgical removal is a novel treatment modality, and is indicated in patients with large space occupying calcified lesions. However, further research regarding the efficacy and post-procedure impact on recurrences is still underway. Last but not least, it is essential to appreciate that if CPPD is secondary to another condition, treatment of that condition itself may be sufficient for symptomatic relief.


Take home messages

  1. Calcium pyrophosphate dihydrate crystal deposition disease (CPPD) is a metabolic disease of aging.
  2. The knees are the joints most frequently affected, followed by the symphysis pubis and small joints of the hands.
  3. Imaging and arthrocentesis are key to establishing the diagnosis of CPPD.
  4. There is no definitive treatment for the condition; currently, provision of symptomatic relief, and prevention of further deposition of crystals are the key goals of management.

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