Calcium pyrophosphate deposition disease (CPPD), which stems from the deposition of calcium pyrophosphate (CPP) crystals in articular hyaline and fibrocartilage cartilage, is a common cause of both acute and chronic arthritis in elderly patients. It will become increasingly prevalent as the population ages.
Conservative estimates judge that CPPD now affects at least 10 million Americans. However, although it was described in the early 1960s in both Europe and the US,1,2 fifty years later we know remarkably little about the pathogenesis of CPPD, have few randomized trials of therapies, and consequently have no proven management strategies. Fewer than 3000 references pertaining to CPPD appear in Ovid from 1962 through 2015, notably few of them randomized trials. (In contrast rheumatoid arthritis, which is only about 15% as prevalent as CPPD in the US, has over 100,000 citations.)
CPPD can be a challenge to diagnose accurately, and is often overlooked in patients with a chronic polyarticular pattern of arthritis.3 (About 25% of patients thought to have typical osteoarthritis have CPP crystals in their synovial fluid at the time of knee joint replacement.)4 The similar acute mono- or oligoarthritis known as pseudogout, in contrast, is usually not missed.
CPPD is also associated with a unique group of metabolic disorders including hemochromatosis and hyperparathyroidism. It occurs in both sporadic and familial forms.
Why is CPPD so poorly understood?
• Elderly patients often have several reasons for joint pain, and sorting these out can be difficult.
• The lack of effective therapy may discourage a careful clinical diagnosis of CPPD.
• CPP crystals are small, weakly birefringent, and difficult to find under polarizing light microscopy.
• Diagnostic tests are nuanced and easy to misinterpret.
• Perhaps most importantly, the lack of clear well-validated diagnostic criteria has hampered progress in this disease.
How do we differentiate CPPD from other common forms of arthritis? This is a critical issue for those of us caring for patients with CPPD.
• Acute CPPD (also known as pseudogout) often presents very much like acute gouty arthritis. It can be diagnosed by observing CPP crystals in synovial fluid from the affected joint (Figure 1). Suspect acute CPPD when the involved joint is not typical of gout, such as a shoulder or wrist.
• Important: Remember that the presence of synovial fluid crystals does not rule out septic arthritis.
• The chronic polyarticular forms of CPPD are typically more challenging to diagnose. They often mimic osteoarthritis with or without inflammatory “flares” but can also present with a symmetric inflammatory arthritis resembling rheumatoid arthritis.
Like gout, in the absence of the ability to “crystal-prove” a patient, certain patterns of chronic arthritis suggest CPPD:
• a joint distribution different from that of typical OA, such as involvement of the shoulders, wrists and 2nd and 3rd MCPs
• characteristic radiographic features including tendon calcification and severe joint destruction.5
What are the imaging criteria for diagnosing CPPD?
1. Zitnan D and Sit'Aj S. Chondrocalcinosis articularis Section L Clinical and radiological study. Ann Rheum Dis 1963; 22:142-152
2. McCarty D, Kohn N, and Faires J. The significance of calcium pyrophosphate crystals in the synovial fluid of arthritic patients. 1. Clinical aspects. Ann Intern Med 1962; 56:711-737
3. Ryan L and McCarty D. Calcium pyrophosphate crystal deposition disease: pseudogout: articular chondrocalcinosis. in Arthritis and Allied Conditions, 11th Edition (McCarty, D. ed.), Lea & Febiger, Philadelphia. 1989. pp 1711-1736
4. Derfus BA, Kurian JB, Butler JJ, et al. The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol 2002;29:570-574
5. Miksanek J and Rosenthal AK. Imaging of calcium pyrophosphate deposition disease. Curr Rheumatol Rep 2015;17:20
6. Loffler C, Sattler H, Peters L, et al. Distinguishing Gouty Arthritis from Calcium Pyrophosphate Disease and Other Arthritides. J Rheumatol 2015;42:513-20.
7. Rosenthal AK, Gohr CM, Mitton-Fitzgerald E, et al. The progressive ankylosis gene product ANK regulates extracellular ATP levels in primary articular chondrocytes. Arthritis Res Ther 2013; 15:R154
8. McCarthy GM, Mitchell PG and Cheung HS. The mitogenic response to stimulation with basic calcium phosphate crystals is accompanied by induction and secretion of collagenase in human fibroblasts. 1991; Arthritis Rheum 34:1021-1030
9. Martinon F, Petrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006;440:237-241
10. Masuda I and Ishikawa K. Clinical features of pseudogout attack. A survey of 50 cases. Clin Orthop Relat Res 1988;229:173-181
11. Rothschild B and Yakubov LE. Prospective 6-month, double-blind trial of hydroxychloroquine treatment of CPDD. Compr Ther 1997;23:327-331
12. Finckh A, McCarthy GM, Madigan A, et al. Methotrexate in chronic-recurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial. Arthritis Res Ther 2014;16:458
13. Pascual E, Andres M, and Sivera F. Methotrexate: should it still be considered for chronic calcium pyrophosphate crystal disease? Arthritis Res Ther 2015;17:89
14. Macmullan P and McCarthy G. Treatment and management of pseudogout: insights for the clinician. Ther Adv Musculoskelet Dis 2012;4:121-131