Review: Unmet Needs and the Path Forward in Joint Disease Associated With Calcium Pyrophosphate Crystal Deposition

Abstract

Calcium pyrophosphate (CPP) crystal deposition (CPPD) is prevalent and can be associated with synovitis and joint damage. The population of elderly persons predominantly affected by CPPD is growing rapidly. Since shortfalls exist in many aspects of CPPD, we conducted an anonymous survey of CPPD unmet needs, prioritized by experts from the Gout, Hyperuricemia and Crystal-Associated Disease Network. We provide our perspectives on the survey results, and we propose several CPPD basic and clinical translational research pathways. Chondrocyte and cartilage culture systems for generating CPP crystals in vitro and transgenic small animal CPPD models are needed to better define CPPD mechanism paradigms and help guide new therapies. CPPD recognition, clinical research, and care would be improved by international consensus on CPPD nomenclature and disease phenotype classification, better exploitation of advanced imaging, and pragmatic new point-of-care crystal analytic approaches for detecting CPP crystals. Clinical impacts of CPP crystals in osteoarthritis and in asymptomatic joints in elderly persons remain major unanswered questions that are rendered more difficult by current inability to therapeutically limit or dissolve the crystal deposits and assess the consequent clinical outcome. Going forward, CPPD clinical research studies should define clinical settings in which articular CPPD does substantial harm and should include analyses of diverse clinical phenotypes and populations. Clinical trials should identify the best therapeutic targets to limit CPP crystal deposition and associated inflammation and should include assessment of intraarticular agents. Our perspective is that such advances in basic and clinical science in CPPD are now within reach and can lead to better treatments for this disorder.

Dual-energy computed tomography in calcium pyrophosphate deposition: initial clinical experience

“…Calcifications comprised BCP crystals at all times, which coexisted with CPP crystals in approximately 40% of cases. Utilizing the potential of DECT to non-invasively discriminate CPP from BCP crystal deposits in vivo would be a major advance in this field of research and could enable the development of targeted therapies that are currently lacking 1,4 .…”

“…The reference standard for the diagnosis of CPP arthritis remains crystal identification in synovial fluid aspirates using compensated polarized light microscopy 3 . The sensitivity of CPP crystal identification is however lower than in gout, and calcium pyrophosphate deposition (CPPD) diagnosis without crystal confirmation remains challenging 3,4 . Radiographic chondrocalcinosis and clinical assessment may be sufficient to retain a probable diagnosis of CPP crystal arthritis 3 .…”

Cartilage icing and chondrocalcinosis on knee radiographs in the differentiation between gout and calcium pyrophosphate deposition

“…BCP, cannot be excluded due to their lack of visibility in light microscopy. Additionally, diagnosis of CPPD using synovial fluid analysis has limitations [38,39], which could have an influence on our study population. Although the diagnosis of gout or CPPD was proven by synovial fluid analysis, pathologic proof of icing, chondrocalcinosis, tophus, or gastrocnemius calcification was not possible.…”

Association between serum zinc and copper concentrations and copper/zinc ratio with the prevalence of knee chondrocalcinosis: a cross-sectional study

“…Chondrocalcinosis is a disease characterized by the formation of calcium pyrophosphate and basic calcium phosphate crystals in the pericellular matrix of cartilage, and by the calcification of articular fibrocartilage and hyaline cartilage [1][2][3]. Patients with chondrocalcinosis may suffer from fever, joint pain and a series of other clinical symptoms that are similar to acute gouty arthritis or septic arthritis and chronic symptoms resembling osteoarthritis, which all contributes to a compromised quality of life and a worsened comorbidity [4][5][6][7][8]. As for asymptomatic patients, though no clinical symptoms manifested, the crystals deposited on the cartilage surface may cause or accelerate joint damage by activating inflammatory response, altering the mechanical stress distribution on the cartilage surface and acting as wear particles, which was postulated as a condition representing a presymptomatic phase of clinical arthritis [9,10].…”