Approach Considerations
Disease-modifying agents are not available for treatment of calcium pyrophosphate deposition (CPPD) disease, so therapy focuses on reducing inflammation and alleviating clinical manifestations. Evidence-based treatment guidelines are lacking, and several of the commonly used treatments are extrapolated from use in gout. [3, 42]
Asymptomatic (lanthanic) CPPD should not be treated. However, if CPPD is a possible manifestation of other syndromes, such as hyperparathyroidism or hemochromatosis, treatment of the underlying condition is important to prevent further end-organ damage, although it cannot reverse the joint disease.
Acute CPP crystal arthritis (pseudogout) may be treated with joint aspiration and intra-articular corticosteroid injection; systemic corticosteroids; nonsteroidal anti-inflammatory drugs (NSAIDs); or, occasionally, high-dose colchicine. Sodium hyaluronate, which is injected intra-articularly to increase joint mobility and improve function when conventional drugs have failed, is approved for treatment of osteoarthritis and has been shown to be effective in CPPD disease as well (note that osteoarthritis can result from CPPD). [43, 44, 45]
Treatment for osteoarthritis with CPPD is similar to that for typical osteoarthritis. Patients with chronic CPP inflammatory crystal arthritis (pseudo–rheumatoid arthritis) can be treated with small doses of corticosteroids, such as prednisone 5 mg daily.
Hydroxychloroquine can be used as adjuvant therapy to prevent flareups. It reduces the release of cytokines such as interleukin-1 (IL-1) and IL-6 and tumor necrosis factor alpha by macrophages. In an animal model of CPPD, it inhibited the activity of matrix metalloprotease. [46] A double-blind prospective 6-month trial found hydroxychloroquine to be beneficial for chronic CPPD-related arthropathy. [43, 44, 45]
Methotrexate has proved effective in small numbers of patients with severe disease, especially those with joint destruction. However, this treatment has been described only in patients with the pseudo-rheumatoid presentation. [47] Methotrexate does help reduce joint pain and swelling, and it decreases serum levels of inflammatory biomarkers. In one study of 10 patients with acute inflammation resistant to conventional therapies, methotrexate seemed to be partially effective. [43, 44, 45]
Studies have indicated that activation of IL-1 by the inflammasome complex plays a pivotal role in pseudogout attacks, which suggested the IL-1 receptor antagonist anakinra (Kineret) as a potential alternative for treating patients with CPPD. [48, 49, 50] A systematic review found 74 cases of anakinra use in CPPD, in patients with refractory disease (85.1%) or contraindications to standard treatments. Clinical response to anakinra was observed in 80.6% of patients with acute CPPD disease and in 42.9% of those with chronic CPPD disease. Short-term treatment was well tolerated; adverse events were reported in 4.1% of cases. [51]
Finally, a theoretical possibility for pharmacologic treatment of CPPD is the use of anticrystal agents to prevent deposition of calcium pyrophosphate dihydrate. Such agents include probenecid, phosphocitrate, and polyphosphate. The mechanism of action appears to be through inhibition of transforming growth factor beta 1 (TGF-beta 1), which is an important stimulant of nucleoside triphosphate pyrophosphohydrolase (NTPPPH), an enyzme required for pyrophosphate synthesis. [43, 44, 45]
Radiosynovectomy is a minimally invasive technique that involves the intra-articular injection of small radioactive particles to remove inflamed synovium. Patients with CPPD secondary to hemophilia have responded well to radiosynovectomy, particularly those with a history of repeated joint bleeding. This procedure is considered to be safe, cost-effective, and efficient, with low radiation exposure. [45]
Patients with pseudoneuropathic arthropathy that is refractory to medical management may benefit from surgical replacement of the damaged joint with a bioprosthesis. [43, 44, 45]
Theoretically, surgically removing calcifications from an affected joint could be beneficial. However, this is currently considered an experimental procedure.
Pharmacotherapy for Pseudogout
The use of NSAIDs can be considered, generally in higher doses during the acute attack and in lesser doses for prevention. Be aware of toxicity, which is common in elderly patients, including gastrointestinal and renal toxicities. Cyclooxygenase-2 (COX-2) ̶ selective NSAIDs (eg, celecoxib) may be as effective as traditional NSAIDs but with less toxicity, although this has not been rigorously tested.
Injection of corticosteroids—such as 40-80 mg (depending on the size of the joint) of methylprednisolone or triamcinolone—into the affected joint has the advantage of avoiding the adverse effects of systemic NSAIDs. Short courses of systemic corticosteroids may be used for polyarticular attacks of pseudogout.
Oral colchicine, or even intravenous (IV) colchicine, can be considered for the treatment of acute pseudogout. Colchicine should be a treatment of last resort because of its poor therapeutic ratio.
Preventing acute attacks of pseudogout is difficult. Small doses of colchicine (0.6 mg once or twice daily) or NSAIDs have been tried, with variable success.
Anakinra has demonstrated efficacy in patients with recurrent acute CPP arthritis who have intolerance of, or inadequate response to, standard treatments. [51] There is also evidence supporting use of the anti–IL-6 receptor antibody tocilizumab in such cases. [51, 52, 53]
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Calcium pyrophosphate deposition disease. Radiograph of the knee showing chondrocalcinosis involving the meniscal cartilage, as well as evidence of osteoarthritis.
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Calcium pyrophosphate deposition disease. Radiograph of the wrist and hand showing chondrocalcinosis of the articular disc of the wrist and atypical osteoarthritis involving the metacarpophalangeal joints in a patient with underlying hemochromatosis.
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Calcium pyrophosphate deposition disease. Appearance of calcium pyrophosphate dihydrate crystals obtained from the knee of a patient with pseudogout. The crystals are rhomboid-shaped with weakly positive birefringence, as seen by compensated polarized microscopy. The black arrow indicates the direction of the compensator.
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Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The black arrow indicates the direction of the compensator. Crystals parallel to the compensator are blue, while those perpendicular to the compensator are yellow.
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Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The crystals parallel to the compensator were blue, while those perpendicular to the compensator were yellow. However, the crystals have been rotated 90%, resulting in a color change in both of them. The direction of the compensator was not changed and is indicated by the black arrow.
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Calcium pyrophosphate deposition disease. Ultrasonography of the wrist demonstrates chondrocalcinosis.
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Intraoperative photographs demonstrate extensive precipitate deposition of the calcium pyrophosphate crystals in the articular cartilage, meniscus, and synovium of a knee. Left images depict femoral and tibial surfaces. Right images depict anterior cruciate ligament.
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Intraoperative photographs demonstrate extensive precipitate deposition of the calcium pyrophosphate crystals in the articular cartilage, meniscus, and synovium of a knee. Upper left image depicts anterior horn medial meniscus. Lower left image depicts undersurface of meniscus. Upper right image depicts medial femoral condyle. Lower right image depicts synovium.
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Calcium pyrophosphate deposition disease. Ultrasound scan of the triangular fibrocartilage complex (TFCC) of the wrist shows thin hyperechoic bands parallel to the surface of the hyaline cartilage. Other findings include a punctate pattern consisting of several hyperechoic spots and homogeneous hyperechoic nodular or oval deposits in the articular surface.
