Objectives Calcium pyrophosphate deposition (CPPD) disease is a common form of arthritis affecting older individuals. This disease is characterised by high levels of pyrophosphate in articular cartilage, resulting in calcium pyrophosphate crystal formation in humans and inflammatory and degenerative arthritis. A loss-of-function mutation in the TNFRSF11B locus (also known as CCAL1), which encodes osteoprotegerin (OPG) causes familial CPPD. OPG acts as a decoy receptor for RANKL, thereby inhibiting osteoclast differentiation and activity. CPPD currently lacks any animal models. The goal of this study was to develop a murine model of early CPPD by incorporating the TNFRSF11B gene mutation in mice and determining its effects on bones, joints and CPPD biomarkers. Methods We used CRISPR/Cas9 editing to generate mice carrying the TNFRSF11B mutation (Opgmt). Joint and bone phenotypes, bone remodelling biomarkers and key CPPD biomarkers were assessed in wild type (WT; Opgwt/wt), Opgwt/mt and Opgmt/mt mice at 6 and 12 months of age. Results Male and female mice carrying Opgmt displayed osteopenia and high bone remodelling markers at 6 and 12 months of age. This phenotype was concurrent with increased osteoclast numbers and activity. Female Opgmt/mt mice also displayed significant osteoarthritis features by 12 months of age, including articular cartilage loss in the lateral compartment of the knee based on Mankin structural damage scores. Additionally, biomarkers pathognomonic of CPPD disease, such as pyrophosphate, transforming growth factor (TGF)-β1 levels and ENPP1 activity, were significantly elevated in the joints of both 6- and 12-month-old female mice with OPGmt. Conclusions Mice carrying Opgmt display bone and joint phenotypes characteristic of early-stage CPPD disease in humans. Opgmt mice represent a novel preclinical model of early CPPD, ideal for exploring potential therapies targeting the disease prior to the development of major joint damage.

Calcium pyrophosphate deposition disease (CPPD) has been shown to be associated with inflammatory arthritis such as rheumatoid arthritis. However, few studies have investigated the correlation between CPPD and psoriatic arthritis (PsA). Our study aimed to determine whether there were higher rates of PsA in patients with CPPD than controls. A retrospective cohort study was conducted using the Veterans Affairs’ Corporate Data Warehouse. Individuals with a CPPD ICD code were matched with controls and diagnoses of PsA and psoriasis were collected. A total of 41,084 CPPD patients were matched with 119,192 controls. The proportion of CPPD patients with PsA diagnosis was more than double that of controls (1.07% vs. 0.37%; p < 0.0001), and more CPPD patients were diagnosed with psoriasis (3.05% vs. 2.52%; p < 0.0001). Those with CPPD had higher odds of a PsA diagnosis (OR 3.550, 95% CI 2.602–4.844). A total of 61.59% of PsA diagnoses preceded the CPPD diagnoses by at least one year. This is the first case–control study demonstrating an association between CPPD and PsA, potentially related to the fact that both PsA and CPPD could be triggered by trauma, and are closely associated with osteoarthritis. It also is possible that inflammatory pathways contribute to CPP crystal deposition in joints.

Background/Objective Calcium pyrophosphate deposition disease (CPPD) is a type of arthritis affecting aging adults that presents with chronic and acute inflammatory and non-inflammatory joint disease. While the etiology of CPPD is not fully understood, recent work suggests that it may be associated with other mineralization disorders. In this retrospective cohort study, we investigated the hypothesis that the prevalence of nephrolithiasis is increased in patients with CPPD. Methods We used the National VA Corporate Data Warehouse to identify CPPD patients with at least one inpatient or outpatient ICD9 code for CPPD between January 1, 2010 and December 31, 2014. This disease cohort was age-, sex-, and date-matched to up to four controls. The presence of independent risk factors for nephrolithiasis was noted for both cohorts, including hyperparathyroidism, renal tubular acidosis, inflammatory bowel disease, short gut syndrome, and obesity (BMI>30). Results A total of 18,761 CPPD patients were identified who were matched by age and sex to 75,043 controls, for a total sample size of 93,804 individuals. The average age of the cohorts was 68.5 years, with a predominant male demographic (94.3%). The prevalence of nephrolithiasis was significantly higher in the CPPD cohort (8.6%) compared to controls (5.1%, P<.0001). Adjusted analyses revealed an odds ratio of 1.659 (95% CI 1.560, 1.764) for nephrolithiasis in CPPD patients which remained significant after removal of patients with hyperparathyroidism. Conclusions These data suggest that CPPD is an independent risk factor for kidney stone formation and provide further support for the hypothesis that CPPD is a systemic disorder of mineralization with extra-articular implications.

OBJECTIVES:The genetic basis of calcium pyrophosphate deposition (CPPD) disease is unknown. This limits the development of therapeutic strategies. We aimed to analyse a genome-wide association study (GWAS) on a large administrative database to identify new candidate causal genes for CPPD disease. METHODS:We used publicly available GWAS summary statistics for Phecode-defined chondrocalcinosis and crystal arthropathy from the Veterans Affairs Million Veteran Program in people of African (AFR) and European (EUR) ancestry. Included were 3004 (536 AFR and 2468 EUR) cases for chondrocalcinosis and 3766 (700 AFR and 3066 EUR) cases for crystal arthropathy (operationally interpreted as calcium crystal arthropathy). Our primary analysis was in chondrocalcinosis, with secondary analysis in crystal arthropathy. We tested for colocalisation of chondrocalcinosis genetic association signals with genetic control of gene expression. RESULTS:There were 2 genome-wide significant loci for chondrocalcinosis in both AFR and EUR cases, both on chromosome 6 (signals within the ENPP1 and RNF144B genes). Findings were supported by analysis of the crystal arthropathy cohort. Colocalisation analysis of chondrocalcinosis genetic association signals with genetic control of gene expression and alternative splicing further supported ENPP1 and RNF144B as candidate casual genes. At ENPP1, the allele that increases the risk for chondrocalcinosis was associated with increased ENPP1 expression. CONCLUSIONS:ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (NPP1) that produces adenosine monophosphate (AMP) and inorganic pyrophosphate which, together with calcium ions, leads to the formation of calcium pyrophosphate crystals. Selective NPP1 inhibitors developed for infectious disease and cancer could be tested as treatment for CPPD disease.

There is no doubt that Dr Daniel J McCarty warrants inclusion among the giants of rheumatology. He has made major contributions to both clinical and scientific knowledge in our field, and his impact has been long-lasting and paradigm shifting. He is perhaps best known for his pioneering work in crystal arthritis, but as an astute clinician, he is also responsible for describing several other novel rheumatic conditions and developing innovative treatment protocols.

Pathologic calcification is a frequent occurrence in osteoarthritis, and both initiates and augments tissue damage in affected joints. Articular cartilage vesicles (ACVs) are exosome-sized extracellular vesicles found in the pericellular matrix of normal cartilage. ACVs concentrate enzymes, substrates, and transporters necessary for calcium crystal formation. In vitro, ACVs produce both calcium phosphate and calcium pyrophosphate crystals. ACV production by chondrocytes is regulated in concert with autophagy and involves membrane blebbing. However, characterization of processes governing ACV-mediated mineralization in vivo remains poorly studied. This chapter will focus on our current understanding of ACVs and their role in biomineralization in osteoarthritis.

Background: The gold standard for crystal arthritis diagnosis relies on the identification of either monosodium urate (MSU) or calcium pyrophosphate (CPP) crystals in synovial fluid. With the goal of enhanced crystal detection, we adapted a standard compensated polarized light microscope (CPLM) with a polarized digital camera and multi-focal depth imaging capabilities to create digital images from synovial fluid mounted on microscope slides. Using this single-shot computational polarized light microscopy (SCPLM) method, we compared rates of crystal detection and raters’ preference for image. Methods: Microscope slides from patients with either CPP, MSU, or no crystals in synovial fluid were acquired using CPLM and SCPLM methodologies. Detection rate, sensitivity, and specificity were evaluated by presenting expert crystal raters with (randomly sorted) CPLM and SCPLM digital images, from FOV above clinical samples. For each FOV and each method, each rater was asked to identify crystal suspects and their level of certainty for each crystal suspect and crystal type (MSU vs. CPP). Results: For the 283 crystal suspects evaluated, SCPLM resulted in higher crystal detection rates than did CPLM, for both CPP (51%. vs. 28%) and MSU (78% vs. 46%) crystals. Similarly, sensitivity was greater for SCPLM for CPP (0.63 vs. 0.35) and MSU (0.88 vs. 0.52) without giving up much specificity resulting in higher AUC. Conclusions: Subjective and objective measures of greater detection and higher certainty were observed for SCPLM over CPLM, particularly for CPP crystals. The digital data associated with these images can ultimately be incorporated into an automated crystal detection system that provides a quantitative report on crystal count, size, and morphology.

Objective To examine the disease, demographic, and imaging features associated with different inflammatory phenotypes of calcium pyrophosphate deposition (CPPD) disease i.e., recurrent acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and crowned dens syndrome (CDS). Methods Data from an international cohort assembled from 25 sites in 7 countries for the development and validation of the 2023 ACR/EULAR CPPD classification criteria, that met the criteria were included. Three cross‐sectional studies were conducted to determine the phenotypic characteristics of recurrent acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and CDS. Multivariable logistic regression analysis was used to calculate the adjusted odds ratios (aOR) and 95% confidence intervals (CIs) to examine the association between potential risk factors and the inflammatory phenotype. Results Among the 618 people included ((56% female), mean age (standard deviation (S.D.)) 74.0 (11.9) years), 602 (97.4%) had experienced acute CPP crystal arthritis, 332 (53.7%) had recurrent acute arthritis, 158 (25.6%) had persistent inflammatory arthritis, and 45 (7.3%), had had CDS. Recurrent acute CPP crystal arthritis associated with longer disease duration (aOR 2.88 (95%CI 2.00;4.14)). Chronic CPP crystal inflammatory arthritis was associated with ). acute wrist arthritis (aOR(95%CI) 2.92(1.81‐4.73)), metacarpophalangeal (aOR(95% CI) 1.87(1.17‐2.97)) and scapho‐trapezio‐trapezoid (STT) joint osteoarthritis (aOR(95% CI) 1.83(1.15‐2.91)), and negatively associated with either metabolic or familial risk for CPPD (aOR(95% CI) 0.60(0.37‐0.96). CDS was associated with male sex (aOR(95% CI) 2.35(1.21‐4.59)), STT joint osteoarthritis (aOR(95% CI) 2.71(1.22‐6.05)), and more joints affected with chondrocalcinosis (aOR(95% CI) 1.46(1.15‐1.85)). Conclusions CPPD disease encompasses acute and chronic inflammatory phenotypes, each with specific clinical and imaging features which need to be considered in the diagnostic workup.

Objective Calcium pyrophosphate deposition (CPPD) disease was associated with osteopenia in two cross‐sectional studies. We compared fracture risks in patients with acute calcium pyrophosphate (CPP) crystal arthritis versus matched comparators. Methods We performed a longitudinal cohort study using electronic health record data from a single large academic health system, with data from 1991 to 2023. Patients with one or more episodes of acute CPP crystal arthritis were matched to comparators on the index date (first documentation of “pseudogout” or synovial fluid CPP crystals or matched encounter) and first encounter in the health system. The primary outcome was first fracture at the humerus, wrist, hip, or pelvis. We excluded patients with fracture before the index date. Covariates included demographics, body mass index, smoking, comorbidities, health care use, glucocorticoids, and osteoporosis treatments. We estimated incidence rates and adjusted hazard ratios for fracture. Sensitivity analyses excluded patients prescribed glucocorticoids, patients prescribed osteoporosis treatments, or patients with rheumatoid arthritis and additionally adjusted for chronic kidney disease. Results We identified 1,148 patients with acute CPP crystal arthritis matched to 3,730 comparators, with a mean age of 73 years. Glucocorticoids and osteoporosis treatments were more frequent in the acute CPP crystal arthritis cohort. Fracture incidence rates were twice as high in the acute CPP crystal arthritis cohort (11.7 per 1,000 person‐years) versus comparators (5.5 per 1,000 person‐years). After multivariable adjustment, fracture relative risk was twice as high in the acute CPP crystal arthritis cohort (hazard ratio 1.8 [95% confidence interval 1.3–2.3]); results were similar in sensitivity analyses. Conclusion In this first published study of fractures and CPPD, fracture risk was nearly doubled in patients with acute CPP crystal arthritis.

OBJECTIVE:The study objective was to examine the disease, demographic, and imaging features associated with different inflammatory phenotypes of calcium pyrophosphate deposition (CPPD) disease, ie, recurrent acute calcium pyrophosphate (CPP) crystal arthritis, chronic CPP crystal inflammatory arthritis, and crowned dens syndrome (CDS). METHODS:Data from an international cohort (assembled from 25 sites in 7 countries for the development and validation of the 2023 CPPD classification criteria from the American College of Rheumatology/EULAR) that met the criteria were included. Three cross-sectional studies were conducted to determine the phenotypic characteristics of recurrent acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and CDS. Multivariable logistic regression analysis was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI) to examine the association between potential risk factors and the inflammatory phenotype. RESULTS:Among the 618 people included (56% female; mean age [standard deviation] 74.0 [11.9] years), 602 (97.4%) had experienced acute CPP crystal arthritis, 332 (53.7%) had recurrent acute arthritis, 158 (25.6%) had persistent inflammatory arthritis, and 45 (7.3%) had had CDS. Recurrent acute CPP crystal arthritis associated with longer disease duration (aOR 2.88 [95% CI 2.00-4.14]). Chronic CPP crystal inflammatory arthritis was associated with acute wrist arthritis (aOR 2.92 [95% CI 1.81-4.73]), metacarpophalangeal joint osteoarthritis (aOR 1.87 [95% CI 1.17-2.97]), and scapho-trapezo-trapezoid (STT) joint osteoarthritis (aOR 1.83 [95% CI 1.15-2.91]), and it was negatively associated with either metabolic or familial risk for CPPD (aOR 0.60 [95% CI 0.37-0.96]). CDS was associated with male sex (aOR 2.35 [95% CI 1.21-4.59]), STT joint osteoarthritis (aOR 2.71 [95% CI 1.22-6.05]), and more joints affected with chondrocalcinosis (aOR 1.46 [95% CI 1.15-1.85]). CONCLUSION:CPPD disease encompasses acute and chronic inflammatory phenotypes, each with specific clinical and imaging features that need to be considered in the diagnostic workup.

Objective Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. Methods Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. Results Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). Conclusion The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

ObjectiveCalcium pyrophosphate deposition (CPPD) disease represents a common crystalline arthritis with a range of manifestations. Our goal was to investigate risks for cardiovascular events in patients with CPPD.MethodsWe performed a retrospective matched cohort analysis in the Veterans Health Administration Corporate Data Warehouse, 2010–2014. CPPD was defined by ≥1 International Classification of Diseases, Ninth Revision codes for chondrocalcinosis or calcium metabolism disorder. CPPD patients were age‐ and sex‐matched to approximately 4 patients without codes for CPPD; we excluded patients with a cardiovascular event during the 365 days prior to the index date. Demographic information, traditional cardiovascular risk factors, medications, and health care utilization were assessed at baseline. The primary outcome was a major adverse cardiovascular event (MACE: myocardial infarction, acute coronary syndrome, coronary revascularization, stroke, or death). Secondary outcomes included individual components of MACE. Cox proportional hazards models estimated fully adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs).ResultsWe identified 23,124 CPPD patients matched to 86,629 non‐CPPD patients with >250,000 person‐years of follow‐up. The study population was 96% male, mean age was 78 years, and 75% were White. The frequency of traditional cardiovascular risk factors was similar between the 2 cohorts. CPPD was not significantly associated with risk for MACE (HR 0.98 [95% CI 0.94–1.02]) in fully adjusted models, though risks of myocardial infarction, acute coronary syndrome, and stroke were significantly higher in the CPPD cohort compared to the non‐CPPD cohort.ConclusionCPPD did not confer an increased risk for MACE, a composite end point including all‐cause mortality. Our results propose CPPD as a novel risk factor for MACE components, including myocardial infarction, acute coronary syndrome, and stroke.

Objective Patients identified as black and from disadvantaged backgrounds have a twofold higher hydroxychloroquine (HCQ) non-adherence, which contributes to worse lupus outcomes and disparities. Yet, most adherence interventions lack tailored strategies for racially and socioeconomically diverse patients who face unique challenges with HCQ. We aimed to examine a broadly representative group of patients with SLE and physician perspectives on HCQ adherence and adherence strategies to redesign an adherence intervention. Methods We conducted four virtual focus groups (90 min each) with 11 racially and socioeconomically diverse patients with SLE recruited from two health systems. Additionally, we hosted two focus group meetings with nine healthcare advisors. In focus groups, patients: (1) shared their perspectives on using HCQ; (2) shared concerns leading to non-adherence; (3) discussed strategies to overcome concerns; (4) prioritised strategies from the most to least valuable to inform an adherence intervention. In two separate focus groups, healthcare advisors gave feedback to optimise an adherence intervention. Using content analysis, we analysed transcripts to redesign our adherence intervention. Results Worry about side effects was the most common barrier phrase mentioned by patients. Key themes among patients’ concerns about HCQ included: information gaps, logistical barriers, misbeliefs and medication burden. Finally, patients suggested adherence strategies and ranked those most valuable including co-pay assistance, personal reminders, etc. Patient and healthcare advisors informed designing a laminate version of an adherence intervention to link each barrier category with four to six patient-recommended adherence strategies. Conclusion We developed a patient stakeholder-informed and healthcare stakeholder-informed tailored intervention that will target non-adherence at the individual patient level.