Risk Factors

CPPD is idiopathic in most cases, with no apparent underlying condition. However, several factors have been associated with an increased risk for crystal deposition. CPPD risk tends to increase with age, being most common among individuals over 80 years old [18]. Hyperparathyroidism raises the risk of CPPD approximately threefold above that of the general population [19]. Other conditions associated with increased CPPD risk include gout (~2.5 times more likely), osteoarthritis (~2 times more likely), rheumatoid arthritis (~2 times more likely), hemochromatosis (~2 times more likely), hypomagnesemia (~1.25 times more likely), and osteoporosis (~1.25 times more likely) [19]. In contrast, certain medications, including proton pump inhibitors, thiazide diuretics, and loop diuretics, have been associated with a decreased risk of CPPD. Other conditions that have been inversely associated with CPPD include alcohol and tobacco abuse disorders, coronary artery disease, congestive heart failure, diabetes, and hypertension [19].

Pathophysiology

CPP crystals are formed within the cartilage, as a result of the interaction of inorganic pyrophosphate with calcium ions. Inorganic pyrophosphate is a breakdown product of extracellular ATP. Although most ATP is generated within chondrocytes, it may be transported out into cartilage where ectonucleotidases enzymatically liberate pyrophosphate. Additionally, a membrane transport protein termed ANKH may directly secrete pyrophosphate from the chondrocytes into the extracellular milieu. Gain-of-function mutations of the ANKH protein have been seen in familial cases of CPPD, but ANKH up-regulation may also occur secondarily in the setting of cartilage damage [20]. Although CPPD crystals are formed from a combination of inorganic phosphate and calcium, the exact mechanism of crystal formation is not well understood.

Once CPPD crystals are liberated from the cartilage into the synovial fluid, they drive acute inflammation in a manner similar to that of MSU crystals. In vitro, CPPD and MSU crystals can be shown to have many similar effects, including activation of the NLRP3 inflammasome in macrophages [21].

Clinical Presentation

Most cases of CPPD are asymptomatic and are discovered incidentally when a radiograph of a joint shows CPPD deposition within the cartilage, the condition known as chondrocalcinosis. As noted earlier, however, CPPD may also present as an acute inflammatory arthritis, or as a chronic arthritis similar to osteoarthritis or rheumatoid arthritis.

Acute CPPD arthritis (colloquially known as pseudogout) usually presents as a rapid onset of mono- or oligoarticular pain but may rarely present with polyarticular involvement. The most common joint involved is the knee, followed by the wrist and the metacarpophalangeal joints [22]. In contrast to gout, bursal involvement is uncommon. Symptoms during an acute episode include pain, erythema, and swelling of the joint that occasionally spreads to the surrounding soft tissues [21]. Due to the inflammatory nature of the pain, patients may develop fevers, chills, and other constitutional symptoms. Occasionally, CPP crystals may deposit in the ligaments at the superior aspect of the dens in the cervical spine, which may intermittently cause acute pain (presumably relating to inflammatory flares) and may be seen on cervical computed tomography scans (crowned dens syndrome).

Symptoms of acute CPPD arthritis are similar to those of an acute gout attack. However, there are several notable features that may distinguish CPPD arthritis from a gout flare, including the fact that CPPD less commonly involves the first metatarsophalangeal joint. Acute CPPD arthritis is typically less severe than gout. On the other hand, whereas gout attacks usually resolve after a few days, acute CPPD arthritis may smolder for weeks to months if not adequately treated [21].

In contrast to acute CPPD arthritis, chronic CPPD arthritis may mimic osteoarthritis, with a mono- or polyarticular presentation. However, chronic CPPD arthritis generally affects different joints than those commonly affected in primary osteoarthritis, namely, the wrists, glenohumeral joints, metacarpophalangeal joints, the midfoot, or the hindfoot [21–23]. In these cases, the presumption is that cartilage damage from CPPD leads to osteoarthritis in atypical locations [22]. On the other hand, the presence of established osteoarthritis appears to promote the risk for CPPD, including up-regulation of the ANKH protein in chondrocytes, suggesting that CPPD and OA can be reiterative processes. Patients with osteoarthritis as a phenotype of chronic CPPD arthritis may also develop acute flares, as well as severe articular destruction, out of proportion to that seen primary osteoarthritis. As noted above, in some cases, CPPD deposition may result in a smoldering polyarthritis similar to rheumatoid arthritis (pseudo-RA).

Diagnosis

As with gout, the gold standard for diagnosis of CPPD is identification of calcium pyrophosphate crystals within the synovial fluid of an affected joint. CPPD crystals are classically rhomboid-shaped, smaller than MSU crystals, and are weakly positively birefringent on polarized light microscopy [23]. They are often pale and may be missed without vigorous and persistent examination. As with gout, the presence of CPPD crystals does not preclude the simultaneous presence of other inflammatory arthritis, most commonly gout or joint infection [13].

Imaging of joints in CPPD often shows the presence of chondrocalcinosis. This can readily be seen on plain radiographs, computed tomography, and musculoskeletal ultrasound, where it presents as a hyperechoic dotted line within the cartilage, in contrast to the appearance of MSU, which is visible on ultrasound as a hyperechoic line along the surface of the cartilage (“double contour” sign) [21, 24].

Treatment

Acute CPPD arthritis is treated using many of the same anti-inflammatory medications as gout. In patients with mono-arthritis, intra-articular glucocorticoids are often an effective choice. In patients who have oligo- or polyarticular joint involvement, or who are not amenable to injections, treatment with oral colchicine at a daily dose of 0.6–1.2 mg, oral NSAIDs, or systemic glucocorticoids (oral, or intravenous) may be given [21]. As with gout, anti-IL-1β biologic therapy may be considered for refractory cases [25]. In contrast to gout, in which ULT can provide long-term management by preventing the formation of new crystals and promoting the dissolution of established ones, there are currently no medications available to remove or prevent the formation of CPP crystals, except perhaps in the rare cases of underlying metabolic diseases such as hyperparathyroidism. Thus, patients with frequent recurrent attacks may require chronic anti-inflammatory prophylaxis, most commonly with daily colchicine.

Similarly, there are no disease-modifying medications used in the treatment of primary chronic CPPD crystal arthritis. However, several studies report that use of intra-articular steroids, or the oral medications described, may provide pain relief and prevent recurrence [22]. As with acute CPPD arthritis, screening for and correcting underlying causes such as hyperparathyroidism may provide ameliorative opportunities, although such instances are rare.

Risk Factors

BCP crystal disease appears to be more common in women than men [28]. Risk factors that predispose to BCP crystal deposition include metabolic abnormalities, specifically elevated levels of circulating calcium or phosphate, calciphylaxis in end-stage renal disease, and familial hypophosphatasia (genetic deficiency in alkaline phosphatase activity leading to hyperphosphatemia) [29]. BCP crystal disease has also been described in patients with endocrinopathies including adult onset diabetes mellitus, hypothyroidism, and aberrant estrogen metabolism (menstrual disorders such as endometriosis, ovarian cysts, polycystic ovarian syndrome, or those with recurrent miscarriages) [30].

Pathophysiology

The formation of BCP crystals occurs in areas where there are elevated levels of extracellular calcium and phosphate along with conditions favorable to encourage mineralization of the crystals. When present, BCP crystals may promote production of matrix metalloproteinases and other substances associated with joint damage and erosion of connective tissue [31].

Clinical Presentation

BCP crystal deposition is often asymptomatic and discovered incidentally on x-rays. However, when BCP crystals infiltrate the soft tissues around a joint, they may cause calcific periarthritis, most commonly in the shoulder. Periarthritis is more common in women than men and usually occurs around or after age 50. The supraspinatus tendon is most frequently involved, followed by the infraspinatus tendon. The subscapularis and long biceps tendon are less frequently involved [32]. Other common locations for calcific periarthritis include the gluteus medius tendon and the reflected head of the rectus femoris [33]. More than one tendon may be involved. Symptoms included chronic pain along with self-limited flares of acute inflammatory pain. Calcification may cause tendon tears or adhesive capsulitis [32].

BCP-associated arthritis occurs when the crystals deposit within the joint capsule or cartilage [33]. In these cases an acute self-limiting arthritis may ensue, with edema, erythema, and joint tenderness, along with decreased joint motion. BCP infiltration in the joint capsule of the shoulder may rarely be associated with Milwaukee shoulder, a rapidly destructive arthritis most prevalent in elderly women [32]. As with other acute crystal diseases, systemic signs, including fevers and chills, may be present.

Diagnosis

A definitive diagnosis of BCP disease is made by identifying the crystals. However, because of their small size and relatively amorphous structure, BCP crystals are not birefringent and are invisible under polarizing light microscopy. Based on their calcium content, the alizarin red S stain may be used to identify BCP crystals under light microscopy, where they will resemble reddish-orange clumps. Unfortunately, alizarin red S staining is neither sensitive nor specific as a test for BCP crystals, and is uncommonly performed by hospital labs. Other calcium-sensitive dyes have been used along with flow cytometry to identify the crystals but are costlier and less available. Similarly, electron microscopy may be used but is not available at most centers.

Imaging using x-rays may show erosions, severe joint degeneration, and soft tissue calcifications, the presence of which are usually presumed to represent BCP deposition. MRI and ultrasonography may show tissue destruction and ligament damage, but these are not specific for BCP disease.

Treatment

For calcific tendonitis most patients are treated conservatively with oral NSAIDs or acetaminophen, along with physical therapy to improve function. For acute BCP arthritis NSAIDS, oral steroids and/or colchicine may be tried, but data supporting these strategies is limited. In patients with more severe pain, or who fail oral therapy, intra-articular glucocorticoids may be used. If pain is resistant to injections, in cases of severe joint damage from Milwaukee shoulder surgery may be needed, up to and including joint replacement. At present, there are no available pharmacologic options to prevent or resolve BCP crystals, although managing underlying metabolic defects is always recommended.