Calcium-Containing Crystal-Associated Arthropathies in the Elderly

Calcium pyrophosphate crystal deposition involving the spine has been associated with a number of clinical manifestations. Spine stiffness, sometimes associated with bony ankylosis, can resemble ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Such symptoms are seen more commonly in familial CPPD rather than in the elderly. However, crystal deposition in the ligamentum flavum at the cervical spine levels has been associated with a condition called crowned dens syndrome.⁷ Although mostly asymptomatic, it may be present with acute neck pain, fever, and an increased ESR, sometimes mimicking PMR or giant cell arteritis or neurologic symptoms. Similarly, CPP crystal deposition in the posterior longitudinal ligament at the lower levels of the spine may lead to spinal cord compression syndromes or symptoms of either acute nerve compression or chronic spinal stenosis.^8,9 Calcium pyrophosphate crystal deposition also can occur in other soft tissues, such as bursae, ligaments, and tendons and may be sufficient to cause local nerve compression, such as carpal or cubital tunnel syndrome.

Epidemiology

Radiographic surveys of the knees, hands, wrists, and pelvis and epidemiologic studies have demonstrated an age-related increase in the prevalence of CPPD: 15% prevalence in patients aged 65 to 74 years, 36% prevalence in patients aged 75 to 84 years, and 50% prevalence in patients aged > 84 years.¹⁰ In a recent radiographic study, 40% of patients with CPPD did not present with CC of the knee, and the study’s authors recommended additional radiographs of pelvis, wrists, or hands for accurate diagnosis of radiographic CC.¹¹

Diagnosis

Accurate diagnosis should be achieved on the basis of the clinical picture and demonstration of CPP crystals in synovial fluid or tissue by compensated polarized light microscopy (Figures 1A and 1B).² The sensitivity and specificity for CPP crystal detection has been shown to be 95.9% and 86.5%, respectively.¹² However, the CPP crystal is more readily identified by a rheumatologist rather than in a standard hospital laboratory, which misses 30% of CPP crystals.¹³

Findings of CC on radiograph strengthens a CPPD diagnosis, but its absence does not rule it out (Figure 2A).² More recently, the use of new imaging modalities, such as musculoskeletal ultrasound, provides the capacity to visualize crystal deposits within the joint structures, the hyaline cartilage, and/or fibrocartilage (Figure 2B and 2C).¹⁴ The presence of hyperechoic bands within the intermediate layer hyaline cartilage and hyperechoic spots in fibrocartilage are consistent with CPP crystal deposits.^2,14 The use of computed tomography is the gold standard imaging modality for the identification of CPPD of the spine.¹⁵ There is not enough evidence to support the use of magnetic resonance imaging in CPPD, but it may play a role in rare complications.²

Treatment

The EULAR recently defined new guidelines for the management of CPPD.¹⁶ Asymptomatic CPPD needs no treatment.In other CPPD phenotypes, the goals are to attempt prompt resolution of the acute synovitis, reduction in chronic damage, and management of associated conditions.In acute attacks, treatment modalities used in gout are often required; however, data for CPPD treatment are limited (Table). Treatment relies on the use of colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs), but toxicity and comorbidities in the elderly limit the usage of these drugs.

Given increased renal impairment, the loading dose of colchicine is not recommended.¹⁶ Colchicine has recently been shown to completely block crystal-induced maturation of IL-1β in vitro, indicating that the drug acts upstream of inflammasome activation.¹⁷ This is in addition to the well-known role of colchicine in inhibition of micro-tubule formation, which likely leads to prevention of cell migration, phagocytosis, and activation of inflammasome.^18-20

Intra-articular injection of corticosteroid is an efficient and well-tolerated treatment alternative for monoarticular CPP flares. Oral or parenteral corticosteroids are frequently used for polyarticular flares in particular for those patients in which NSAIDs and colchicine are contraindicated.¹⁶ Parenteral adrenocorticotropic hormone has been used in patients with congestive heart failure, renal insufficiency, gastrointestinal bleeding, or resistance to NSAIDs.²¹ For prophylaxis of acute CPP crystal arthritis, a low dose of oral NSAIDs, oral colchicine, or prednisone may be used with good results.¹⁶ In chronic CPP arthritis, continuous use of colchicine, NSAIDs, or low-dose prednisone is often appropriate. If these interventions are ineffective or contraindicated, using hydroxychloroquine (HCQ) and methotrexate (MTX) have been successfully used to control chronic CPP crystal inflammation.^22,23 Recent trials have raised questions about MTX, and further trials on HCQ usage are underway.²⁴ Biologic agents targeting IL-1 are not currently approved for the treatment of CPPD, but there are suggestions that it may be effective in refractory cases and induce rapid stable remissions after 3 days of therapy.²⁵