Five decades after its characterization, “pseudogout” and associated calcium pyrophosphate crystal deposition (CPPD)-related arthropathies still lack a clearly defined diagnostic and treatment strategy. One of the key challenges of treatment is that the clinical features of CPPD are often confused with those of other inflammatory joint diseases, including osteoarthritis (OA), rheumatoid arthritis (RA), and gout.1 A study of 25,157 veterans with CPPD found a positive association of CPPD with RA, hypomagnesemia, and osteoporosis.2 

Positively correlated with aging, CPPD is conservatively estimated to affect approximately 3% of American adults between 60 and 69 years and as many as 50% of those older than 90 years.3,4 Between 8 and 10 million people in the United States are currently reported to be affected by CPPD,5 but the prevalence of CPPD and the associated CPPD-related arthropathies are projected to increase significantly in the coming decades in correlation with the aging US population.

Although the pathophysiology and clinical features of CPPD have been well defined,6 several aspects of the disease diagnosis and treatment are nonspecific and ill defined. For example, chondrocalcinosis on radiographic imaging of joint aspirate is often used as a surrogate indicator for CPPD, but the accuracy of this assessment is poor because of the low specificity and accuracy of the imaging. In addition, between 25% and 50% of the knee joint synovial aspirate with CPP crystals lack radiographically detectable chondrocalcinosis. There is also considerable individual and institutional variation among imaging observations, which calls into question the accuracy of CPPD diagnostic evaluation.7 Furthermore, no specific treatment is currently available to eliminate CPP crystals, and therefore the current treatment approach is primarily directed toward symptom management, including rest, ice, joint aspiration, colchicine, and intraarticular corticosteroids.6 Disease-modifying agents such as methotrexate have not shown efficacy in CPPD, and despite interest in the use of interleukin-1 inhibitor agents, their efficacy has not been demonstrated for this disease state.6 In the absence of a clearly defined management strategy, CPPD and its associated diseases will continue to present significant challenges in the future.

Addressing the challenges associated with clinical management of CPPD must start with understanding the unmet needs of associated joint damage and establishing a clearly defined strategy to address these needs. Recent progress has been made by an international group of experts from the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) to advance clinical understanding of CPPD and improve its diagnosis and treatment.7 Survey questions were developed by G-CAN members, which were comprised of rheumatologists, nephrologists, and nonclinical scientists. The questions focused on key unmet needs that were broadly categorized into 6 research domains: clinical phenotyping, diagnostic modalities, pathogenesis, disease stratification, outcomes, and treatment.

A total of 140 attendees of the 2015 or 2016 G-CAN annual symposia were invited to participate in the survey. The attendees anonymously categorized the CPPD research domains according to their perceived priority. Responses were categorized as highest priority (as rated by >80% of respondents), medium priority (rated by 66.7% to 80% of respondents), and lower priority (<66.7% of respondents). A total of 26 surveys were completed; responders were residents of 10 countries across 4 continents. Highest research priorities included the need for new approaches to limit or prevent CPPD, methods to improve detection of CPP crystals in tissues and intraarticular CPPD, strategies to improve understanding of the mechanisms of disease pathogenesis, and clinical phenotyping and patient stratification.7 Based on the priorities identified, the experts provided recommendations for future basic, clinical, and translational research in CPPD.

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To improve the understanding of CPPD pathogenesis and its association with OA, the expert panel recommends the development of better, unifying disease models. Such models may include chondrocyte and cartilage organ culture systems, a transgenic animal model of CPPD, and gene mutational analysis to identify phenotypic heterogeneity to provide insight into idiopathic and OA-associated CPPD pathogenesis.7

“Crystal identification is paramount and does not have to be confined to joint fluid crystal analysis,” stated Robert Terkeltaub, MD, professor and chief of rheumatology at the VA Medical Center in San Diego, California, and a lead author on the study. “Specifically, urate and CPPD crystal deposits can be detected via advanced imaging by ultrasound, which appears more sensitive than plain radiography for CPPD and is certainly more sensitive than plain radiographic changes with early disease in gout. There also is a role for dual-energy [computed tomography] (DECT) in gout, although DECT has not been adequately investigated for CPPD to this point.”

Given the several different tools for assessing CPPD and to improve detection and diagnostic classification of CPPD, the panel suggests the development of internationally standardized classification criteria and consensus agreement for highly specific imaging modalities for the detection of tissue CPPD deposits. Such modalities may require improvements of high-resolution ultrasound, DECT, and magnetic resonance imaging to integrate these diverse modalities and generate a uniform CPPD diagnostic criteria.7 “Unlike the case for gout, there is not enough evidence from randomized controlled trials in acute and chronic CPPD inflammatory arthritis to craft treatment recommendations based on published, high-quality evidence” stated Dr Terkeltaub.

Consequently, to improve treatment, the panel recommends designing high-quality clinical trials of existing and emerging anti-inflammatory drugs to explore new targets and determine their safety and efficacy to treat CPP crystal arthritis. A better understanding of CPPD phenotype, and in particular, the differences between CPPD and OA and the relationship between CPPD, chondrocalcinosis, and OA can result in the improved assessment of the clinical course. The panel recognizes the need for genomic and molecular approaches in combination with well-designed prospective longitudinal studies. Implementing these research recommendations may lead to improved understanding and treatment of CPPD.


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  2. Kleiber Balderrama C, Rosenthal AK, Lans D, Singh JA, Bartels CM. Calcium pyrophosphate deposition disease and associated medical comorbidities: a national cross-sectional study of US veterans. Arthritis Care Res (Hoboken). 2017;69(9):1400-1406.
  3. Abhishek A. Calcium pyrophosphate deposition disease: a review of epidemiologic findings. Curr Opin Rheumatol. 2016;28(2):133-139. 
  4. The American College of Rheumatology. Calcium Pyrophosphate Deposition (CPPD). Updated March 2017. Accessed April 18, 2018.
  5. Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl J Med. 2016;374(26):2575-2584.
  6. Abhishek A, Doherty M. Update on calcium pyrophosphate deposition. Clin Exp Rheumatol. 2016;34(4 Suppl 98):32-38.
  7. Abhishek A, Neogi T, Choi H, Doherty M, Rosenthal AK, Terkeltaub R. Unmet needs and the path forward in joint disease associated with calcium pyrophosphate crystal deposition [published online April 2, 2018]. Arthritis Rheumatol. doi: 10.1002/art.40517