Search Results (15)

Calcium pyrophosphate deposition disease (CPPD) is a common crystal arthropathy characterized by the deposition of calcium pyrophosphate crystals in joints and soft tissues. Ultrasonography (US) has emerged as a valuable imaging modality for diagnosing CPPD, offering real-time visualization of crystal deposits and joint inflammation. In the context of personalized medicine, US plays a critical role in enabling individualized patient assessment, facilitating early and accurate diagnosis, and supporting tailored therapeutic decisions based on specific imaging findings. This article reviews the ultrasonographic features of CPPD, their diagnostic utility, and clinical applications, emphasizing the relevance of US in stratifying patients and guiding personalized management approaches. Full article

Background: Polymyalgia rheumatica (PMR) has a multifaceted onset and course, and making a distinction between true PMR and so-called “polymyalgic syndrome” (that is, similar manifestations caused by different conditions) is far from easy in clinical practice. The existence of subsets within true PMR may further complicate the diagnostic question. Distinguishing PMR subsets from PMR-mimicking conditions does not just carry nomenclature value and speculative significance. Indeed, the correct diagnosis influences treatment, prognosis, epidemiological assessments, and health policies. Objectives: We aimed to (1) ascertain the presence of a definite and peculiar subset/subgroup/cluster of PMR in the scientific literature; (2) describe any possible subset/cluster/subgroup of PMR identified in at least two different studies. Methods: We performed a non-systematic (PRISMA protocol not followed) literature search on Embase and Medline (OVID interface). The following search terms were used: polymyalgia rheumatica, subset, cluster, subgroup, subclinical giant cell arteritis, mimicking conditions, polymyalgia rheumatica-like conditions, immunotherapy, checkpoint inhibitor, acute-phase reactants or acute-phase proteins, vaccination, infection, and calcium pyrophosphate deposition disease or chondrocalcinosis. Each paper’s reference list was scanned for additional publications meeting this study’s aim. Abstracts submitted at conferences or from non-peer-reviewed sources were not included. Results: The initial search yielded 2492 papers, of which 2389 articles were excluded based on title and abstract screening. A total of 103 articles underwent a full-length review, and 84 of them were finally assessed for eligibility. A total of seven large subsets of PMR could be identified: (1) PMR with normal acute-phase reactants; (2) PMR with an infection trigger; (3) PMR with a vaccination trigger; (4) PMR with subclinical giant cell arteritis (GCA); (5) PMR and calcium pyrophosphate deposition disease (CPPD); (6) PMR following immune checkpoint inhibitor (ICI) therapy; (7) PMR with peculiar clinical clusters (based on clinical or statistic clustering methods). Conclusions: PMR with normal baseline acute-phase reactants and PMR with an infection or a vaccination trigger could be categorized as subsets of disease. PMR with subclinical GCA and most cases of PMR/CPPD should be categorized as mimickers. Finally, further studies are required to better categorize some peculiar clinical subsets emerging from cluster analyses, and ICI-induced PMR. Full article

Aim: To identify ultrasound (US) predictors of persistence or change in the diagnosis of rheumatoid arthritis (RA) after five years in a cohort of patients with early RA. Patients and Methods: One hundred and twenty patients with early arthritis who met the 2010 ACR/EULAR classification criteria for RA were followed for a period of five years. The US assessment at baseline included a bilateral evaluation of the wrists, second to fifth metacarpophalangeal (MCP) joints, second to fifth proximal interphalangeal (PIP) joints, the IV and VI extensor compartments of the wrists, and the flexor tendons of the second to fifth fingers. This evaluation was conducted using both grayscale ultrasound (GSUS) and power Doppler ultrasound (PDUS). The following scores were recorded for each patient: synovitis score, mini-enthesitis score (including paratenonitis of the finger extensor tendon at the MCP joint, central slip enthesitis at the PIP joint, pseudotenosynovitis, and the A1 pulley of the second finger), finger flexor tenosynovitis score, and tenosynovitis score for the IV and VI wrist extensor compartments. The receiver operating characteristic (ROC) curve was utilized to identify the ultrasound predictors for either maintaining or revising an initial diagnosis of RA. Results: At month 6, 82 (68%) patients were classified as having RA according to 1987 ACR RA criteria, 23 (19.2%) were diagnosed with psoriatic arthritis (PsA), 10 (8.3%) with systemic connective tissue disease (SCTD)–8 (6.7%) patients with Sjogren Syndrome and 2 (1.7%) patients with systemic lupus erythematosus (SLE)–and 5 (4.2%) patients with calcium pyrophosphate deposition disease (CPPD). The most significant predictor of RA in the fifth year was the VI extensor compartment tenosynovitis score, with an AUC of 0.915 and a criterion value > 0, associated with a sensitivity of 82.93% and a specificity of 100% (p < 0.001). The PDUS synovitis score demonstrated the second-best prognostic ability with an AUC of 0.823, a criterion value > 2, a sensitivity of 82.93%, and a specificity of 73.68% (p < 0.001). The mini-enthesitis score showed the best prognostic ability of a PsA diagnosis with an AUC of 0.998, a criterion value > 1, a sensitivity of 95.65%, and a specificity of 100% (p < 0.001). The paratenonitis score, pseudotenosynovitis score, and thickened A1 pulley were also predictive of PsA diagnosis with AUCs of 0.977, 0.955, and 0.919, respectively (p < 0.001 for all). Conclusions: Nearly one-third of the patients who were initially classified as having RA had their diagnosis revised at the end of the fifth year. Ultrasound of joints, tendons, and mini-entheses at baseline may serve as potential imaging predictive biomarkers for persistence or change in diagnosis after 5 years. Full article

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. Full article

Calcium pyrophosphate dehydrate (CPPD) crystals are found in the synovial fluid of patients with articular chondrocalcinosis or sometimes with osteoarthritis. In inflammatory conditions, the synovial membrane (SM) is subjected to transient hypoxia, especially during movement. CPPD formation is supported by an increase in extracellular inorganic pyrophosphate (ePPi) levels, which are mainly controlled by the transporter Ank and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We demonstrated previously that transforming growth factor (TGF)-β1 increased ePPi production by inducing Ank and Enpp1 expression in chondrocytes. As the TGF-β1 level raises in synovial fluid under hypoxic conditions, we investigated whether hypoxia may transform SM as a major source of ePPi production. Synovial fibroblasts and SM explants were exposed to 10 ng/mL of TGF-β1 in normoxic or hypoxic (5% O₂) culture conditions. Ank and Enpp1 expression were assessed by quantitative PCR, Western blot and immunohistochemistry. ePPi was quantified in culture supernatants. RNA silencing was used to define the respective roles of Ank and Enpp1 in TGF-β1-induced ePPi generation. The molecular mechanisms involved in hypoxia were investigated using an Ank promoter reporter plasmid for transactivation studies, as well as gene overexpression and RNA silencing, the respective role of hypoxia-induced factor (HIF)-1 and HIF-2. Our results showed that TGF-β1 increased Ank, Enpp1, and therefore ePPi production in synovial fibroblasts and SM explants. Ank was the major contributor in ePPi production compared to ENPP1. Hypoxia increased ePPi levels on its own and enhanced the stimulating effect of TGF-β1. Hypoxic conditions enhanced Ank promoter transactivation in an HIF-1-dependent/HIF-2-independent fashion. We demonstrated that under hypoxia, SM is an important contributor to ePPi production in the joint through the induction of Enpp1 and Ank. These findings are of interest as a rationale for the beneficial effect of anti-inflammatory drugs on SM in crystal depositions. Full article

Calcium-containing crystal deposition diseases are extremely common in rheumatology. However, they are under-explored compared to gout or other inflammatory rheumatic diseases. Major advances have been made in 2023 that will undoubtedly stimulate and facilitate research in the field of calcium pyrophosphate (CPP) deposition disease (CPPD): the ACR/EULAR classification criteria for CPPD and a semi-quantitative OMERACT score for ultrasound assessment of the extent of CPP deposition have been validated and published. A large randomized controlled trial compared the efficacy and safety of colchicine and prednisone in acute CPP arthritis. Preclinical studies have elucidated the pro-inflammatory and anti-catabolic effects of basic calcium phosphate (BCP) crystals on mononuclear cells and chondrocytes. The association between osteoarthritis (OA) and IA calcifications has been the subject of several epidemiological publications, suggesting that calcium crystals are associated with a greater risk of progression of knee OA. Research in the field of calcium crystal deposition diseases is active: the areas of investigation for the coming years are broad and promising. Full article

Calcium pyrophosphate deposition (CPPD) disease is a crystalline arthritis that was described more than 60 years ago, yet our knowledge about this condition greatly lags behind other forms of arthritis. This is an exciting era for CPPD disease as a robust framework for CPPD clinical research has been established. The American College of Rheumatology (ACR) and EULAR co-sponsored the development of the first-ever classification criteria for CPPD. The Outcomes Measures in Rheumatology (OMERACT) CPPD Ultrasound Subtask Force developed and validated definitions for ultrasonographic findings of CPPD, and the OMERACT CPPD Working Group is establishing a core outcome domain set for this crystalline arthritis. This review focuses on key elements of the 2023 ACR/EULAR CPPD disease classification criteria and considerations for measuring outcomes in CPPD disease. Full article

Ultrasound is a pivotal exam in calcium pyrophosphate deposition (CPPD) identification. It has been demonstrated to be feasible, accurate, and reliable for CPPD diagnosis. Even if standardized definitions and a scoring system for CPPD have been established by the OMERACT ultrasound working group, ultrasound is still considered one of the most operator-dependent techniques. This is because in ultrasound, both the acquisition and the interpretation phases of the diagnostic process are in the hands of one operator and are performed simultaneously, in contrast to what happens with other imaging exams, where the acquisition process is standardized and independent from the interpretation process. Therefore, the scanning technique and machine setting acquire a central role, almost as important as the interpretation of the images, as erroneous scanning may lead to interpretative mistakes. In this review, we will delve into the appearance of CPPD on ultrasound, based on the latest research findings, passing through its pathogenesis, and focusing on machine settings and ultrasound scanning techniques, providing some tips and tricks to facilitate accurate CPPD recognition in the most frequently affected sites. Full article

Calcium-containing crystal deposition diseases are a common cause of pain and disability but remain relatively under-investigated. No drug has been identified that can prevent deposition or effect dissolution of either calcium pyrophosphate (CPP) or basic calcium phosphate (BCP) crystals. In comparison to the field of gout and urate biology, published research in relation to calcium crystal deposition diseases in 2022 was relatively modest in quantity. In CPP deposition (CPPD) disease, progress was made mainly in epidemiology, imaging, surgical management and Gitelman’s syndrome. In relation to BCP crystals, the effect on tenocytes in vitro was explored and results indicate that BCP crystals likely reduce tendon matrix integrity via their interaction with tenocytes. The involvement of calcification in the progression of osteoarthritis (OA) was elegantly demonstrated contributing to further discovery of the process of OA progression. There was a paucity of mechanistic and genetic studies in calcium crystal deposition diseases published in 2022, nor any breakthrough in therapy, showing that there is abundant scope for investigation under these themes in the future. Full article

Calcium pyrophosphate dihydrate (CPPD) deposition disease is a benign disorder characterized by acute gouty arthritis-like attacks and first reported by McCarty. CPPD deposition disease rarely occurs in the temporomandibular joint (TMJ), and although confirmation of positive birefringence by polarized light microscopy is important for diagnosis, it is not reliable because other crystals also show birefringence. We reported a case of CPPD deposition disease of the TMJ that was diagnosed by chemical analysis. A 47-year-old man with a chief complaint of persistent pain in the right TMJ and trismus was referred to our department in 2020. Radiographic examination revealed destruction of the head of the mandibular condyle and cranial base with a neoplastic lesion involving calcification tissue. We suspected CPPD deposition disease and performed enucleation of the white, chalky masses. Histopathologically, we confirmed crystal deposition with weak birefringence. SEM/EDS revealed that the light emitting parts of Ca and P corresponded with the bright part of the SEM image. Through X-ray diffraction, almost all peaks were confirmed to be CPPD-derived. Inductively coupled plasma atomic emission spectroscopy revealed a Ca/P ratio of nearly 1. These chemical analyses further support the histological diagnosis of CPPD deposition disease. Full article

Calcium pyrophosphate (CPP) deposition disease (CPPD) is a form of CPP crystal-induced arthritis. A high concentration of extracellular pyrophosphate (ePPi) in synovial fluid is positively correlated with the formation of CPP crystals, and ePPi can be upregulated by ankylosis human (ANKH) and ectonucleotide pyrophosphatase 1 (ENPP1) and downregulated by tissue non-specific alkaline phosphatase (TNAP). However, there is currently no drug that eliminates CPP crystals. We explored the effects of the histone deacetylase (HDAC) inhibitors (HDACis) trichostatin A (TSA) and vorinostat (SAHA) on CPP formation. Transforming growth factor (TGF)-β1-treated human primary cultured articular chondrocytes (HC-a cells) were used to increase ePPi and CPP formation, which were determined by pyrophosphate assay and CPP crystal staining assay, respectively. Artificial substrates thymidine 5′-monophosphate p-nitrophenyl ester (p-NpTMP) and p-nitrophenyl phosphate (p-NPP) were used to estimate ENPP1 and TNAP activities, respectively. The HDACis TSA and SAHA significantly reduced mRNA and protein expressions of ANKH and ENPP1 but increased TNAP expression in a dose-dependent manner in HC-a cells. Further results demonstrated that TSA and SAHA decreased ENPP1 activity, increased TNAP activity, and limited levels of ePPi and CPP. As expected, both TSA and SAHA significantly increased the acetylation of histones 3 and 4 but failed to block Smad-2 phosphorylation induced by TGF-β1. These results suggest that HDACis prevented the formation of CPP by regulating ANKH, ENPP1, and TNAP expressions and can possibly be developed as a potential drug to treat or prevent CPPD. Full article

Clinical differentiation between gout, osteoarthritis (OA), and calcium pyrophosphate deposition disease (CPPD) remains a hurdle in daily practice without imaging or arthrocentesis. We performed a retrospective analysis of consecutive patients with gout, CPPD, and OA at a tertiary rheumatology center. A total of 277 patients were enrolled, with 164 suffering from gout, 76 from CPPD, and 37 from OA. We used ANOVA and conditional inference tree analysis (Ctrees) to find associations between clinical, laboratory, and imaging data and gout, OA, and CPPD. The sonographic double contour sign was unable to differentiate gout from CPPD. Ctrees were able to exclude OA and CPPD as possible differentials based on elevated uric acid, C-reactive protein (CRP), presence of arterial hypertension, and sex, diagnosing gout with a sensitivity and specificity of 95.1% and 41.6%, respectively. Elevated CRP was observed using simple linear regressions in patients with type II diabetes, higher cumulative joint scores, increased number of affected joints, as well as elevated uric acid, erythrocyte sedimentation rate, and leukocyte count. Ctrees were able to differentiate gout, OA, and CPPD based on just four characteristics. Inflammatory response correlated with type II diabetes, more or larger joint involvement, and elevated uric acid levels. Full article

Gitelman syndrome (GS) and Bartter syndrome (BS) type III are both rare, recessively inherited salt-losing tubulopathies caused by SLC12A3 and CLCNKB mutations, respectively. We described a 48-year-old male patient with fatigue, carpopedal spasm, arthralgia, hypokalemic alkalosis, mild renal dysfunction, hypomagnesemia, hypocalciuria, hyperuricemia, normotension, hyperreninemia and chondrocalcinosis in knees and Achilles tendons. His parents are first cousin. Genetic analysis revealed simultaneous homozygous mutations in SLC12A3 gene with c.248G>A, p.Arg83Gln and CLCNKB gene with c.1171T>C, p.Trp391Arg. The second younger brother of the proband harbored the same simultaneous mutations in SLC12A3 and CLCNKB and exhibited similar clinical features except normomagnesemia and bilateral kidney stones. The first younger brother of the proband harbored the same homozygous mutations in CLCNKB and exhibited clinical features of hypokalemia, normomagnesemia, hypercalciuria and hyperuricemia. Potassium chloride, spironolactone and potassium magnesium aspartate were prescribed to the proband to correct electrolytic disturbances. Benzbromarone and febuxostat were prescribed to correct hyperuricemia. The dose of potassium magnesium aspartate was subsequently increased to alleviate arthralgia resulting from calcium pyrophosphate deposition disease (CPPD). To the best of our knowledge, we are the first to report an exceptionally rare case in an inbred Chinese pedigree with simultaneous homozygous mutations in SLC12A3 and CLCNKB. GS and BS type III have significant intrafamilial phenotype heterogeneity. When arthralgia is developed in patients with GS and BS, gout and CPPD should both be considered. Full article

The aim of the study was to determine the time of mineral growth in human spine ligaments using a mathematical model. The study was based on our previous research in which the physicochemical analysis and computed microtomography measurements of deposits in ligamenta flava were performed. Hydroxyapatite-like mineral (HAP) constituted the mineral phase in ligament samples, in two samples calcium pyrophosphate dehydrate (CPPD) was confirmed. The micro-damage of collagen fibrils in the soft tissue is the crystallization center. The growth of the mineral nucleus is a result of the calcium ions deposition on the nucleus surface. Considering the calcium ions, the main component of HAP, it is possible to describe the grain growth using a diffusion model. The model calculations showed that the growth time of CPPD grains was ca. a month to 6 years, and for HAP grains >4 years for the young and >5.5 years for the elderly patients. The growth time of minerals with a radius >400 μm was relatively short and impossible to identify by medical imaging techniques. The change of growth rate was the largest for HAP deposits. The mineral growth time can provide valuable information for understanding the calcification mechanism, may be helpful in future experiments, as well as useful in estimating the time of calcification appearance. Full article

Calcium pyrophosphate deposition disease (CPPD) is a crystal induced inflammation in joints, and causes severe pain in elderly people. The accumulation of pyrophosphate (PPi) in synovial fluid (SF) results from several enzymatic reactions, especially the highly activated e-NPPs, which catalyze the conversion of ATP to PPi. This study demonstrates the detection of relative catalytic activity of 3 enzymes—ecto-nucleotide pyrophosphatase/phosphodiesterases (e-NPPs), tissue nonspecific alkaline phosphatase (TNAP), and ecto-nucleoside triphosphate diphosphohydrolases (e-NTPDases)—using a single molecular sensor called Kyoto Green. Kyoto Green exhibits excellent performance in sensing the catalytic activity of the commercial representatives of the e-NPPs, TNAP, and e-NTPDases, which are ENPP1, PPase, and apyrase, respectively, in both single-enzyme and multi-enzyme assays. Analysis of SF enzymes in 19 SF samples from human and swine revealed moderate activity of e-NPPs, high activity of e-NTPDases, and low activity of TNAP. Our newly developed method for analysis of multiple enzymatic activities using Kyoto Green in biological SF will assist improvement in accuracy of the CPPD prognosis/diagnosis, which will minimize unnecessary medical procedures. Full article