Synovial fluid crystal analysis with compensated polarization using a gout analyser in clinical practice.

OBJECTIVE: To validate the gout analyzer as a clinical method of synovial fluid crystal analysis. METHODS: Thirty knee synovial fluid samples with suspected calcium pyrophosphate (CPP) crystals were analyzed. Within 48 hours after collection, each non-centrifuged sample was examined blindly and independently by one or more rheumatologists in the following order: 1) with an optical microscope under ordinary light, 2) with the same microscope under compensated polarization provided by a gout analyzer, and 3) with a fully equipped compensated polarized microscope with a rotating stage as the gold standard. As a reference, laboratory technicians analyzed fresh, centrifuged synovial fluid using a gout analyzer. RESULTS: Of the 30 samples analyzed, CPP and monosodium urate (MSU) crystals were detected in 11 and four, non-centrifuged samples, respectively, using a fully equipped compensated polarized microscope. The rheumatologists' detection rate of crystals in the non-centrifuged synovial fluid under ordinary light and with a gout analyzer was 73.3% and 80%, respectively. The laboratory technicians' detection rate in fresh centrifuged synovial fluid using a gout analyzer was 100%. CONCLUSION: A gout analyzer may be used to diagnose gout and calcium pyrophosphate deposition disease definitively if a fully equipped compensated polarized microscope is unavailable.

Synovial fluid analysis: Relevance for daily clinical practice.

Synovial fluid analysis can provide a prompt and definite diagnosis of crystal-induced arthritis, the most common acute inflammatory arthritis and a cause of chronic arthritis that may mimic rheumatoid, psoriatic, or peripheral spondyloarthritis. In many patients the diagnosis of gout or calcium pyrophosphate arthritis cannot be made with certainty without synovial fluid analysis. Additional information from fluid analysis can assist the clinician in honing the differential diagnosis of non-crystalline arthritis.

[Acute monoarthritis in a third level hospital]. / Estudio de los pacientes con monoartritis aguda en un hospital de tercer nivel.

INTRODUCTION: Acute monoarthritis (AM) represents a relevant cause of morbidity that requires prompt medical care. The study of synovial fluid becomes relevant to allow a rapid diagnostic approach. The main objective of the study was to determine the frequency and clinical-analytical characteristics of episodes of AM and acute bursitis evaluated in a hospital during a period of 6 years. METHODS: Cross-sectional retrospective analytical study in a hospital at Córdoba, Argentina. All episodes of acute monoarthritis and bursitis that occurred in patients aged 18 years or older between 2012 and 2017 were included. AM in pregnant women and chronic monoarthritis were excluded. RESULTS: One hundred and eighty episodes of AM and 12 of acute bursitis were included. Among the AM, 120 (66.7%) occurred in male patients and the average age was 62.1±16.9 years. The main cause of AM was septic, identifying 70 (36%) cases, followed by microcrystalline AM identify 54 (28%) cases, which corresponded to gout and calcium pyrophosphate dihydrate (CPPD) with 27 (14%) cases each one. Monosodium urate crystals were identified in 26 (14.3%) patients, CPPD in 28 (15.6%) and cholesterol in 1 (0.6%). DISCUSSION: The main cause of AM was septic arthritis, followed by microcrystalline AM (gout and secondary to CPPD). The main affected joint was the knee, followed by the shoulder. Synovial fluid analysis was a key element when making the differential diagnosis between the different causes of acute monoarthritis and bursitis.

Introducción: La monoartritis aguda (MA) representa una causa relevante de morbilidad que requiere de atención médica oportuna: El estudio del líquido sinovial constituye un elemento clave para su diagnóstico. El objetivo del estudio fue determinar la frecuencia y características clínicas-analíticas de los episodios de MA y bursitis agudas valoradas en un hospital durante un período de 6 años. Métodos: Estudio analítico retrospectivo de corte transversal en un hospital de Córdoba, Argentina. Se identificaron todos los episodios de monoartritis y bursitis agudas que ocurrieron en pacientes de =18 años entre 2012 y 2017. Se excluyeron los cuadros de MA en embarazadas y las monoartritis crónicas. Resultados: Se incluyeron 180 episodios de MA y 12 de bursitis aguda. Entre las MA, 120 (66.7%) ocurrieron en hombres, la edad promedio fue 62.1±16.9 años. La principal causa de MA fue séptica, identificándose 70 (36%) casos, seguida la secundaria a microcristales con 54 episodios (28%) que correspondieron 27 (14%) a MA por gota y 27 (14%) a MA por depósitos de pirofosfato de calcio dihidratado (CPPD). Se identificaron cristales de urato monosódico en 26 (14.3%) pacientes, CPPD en 28 (15.6%) y de colesterol en 1 (0.6%). Discusión: La principal causa de MA fue séptica, seguida de la secundaria a microcristales (gota y secundaria a CPPD). La principal articulación afectada fue la rodilla, seguida del hombro. El análisis del líquido sinovial fue un elemento clave a la hora de poder realizar el diagnóstico diferencial entre las distintas causas de monoartritis aguda y bursitis.

Differences in the Optical Response of MSU and CPP Crystals During Magnetic Orientation: Possibility of Diagnosing Gout and Pseudogout.

Pseudogout is crystalline arthritis. It has a similar clinical picture to that of gout, and it is difficult to distinguish the two diseases using conventional analysis methods. However, it is important to identify the different crystals responsible for these two cases because the treatment strategies are different. In a previous study, we reported magnetic orientation of monosodium urate (MSU) crystals, which are the causative agent of gout, at the permanent magnet level. In this study, we investigated the effect of an applied magnetic field on calcium pyrophosphate (CPP) crystals, which are the causative agent of pseudogout, and the difference in the magnetic responses of CPP and MSU crystals. We found that the CPP crystals were oriented in a magnetic field on milli-Tesla order because of the anisotropy of the diamagnetic susceptibility. In addition, the CPP crystals exhibited different anisotropic magnetic properties from those of MSU crystals, which led to a characteristic difference between the orientations of the two crystals. That is, we found that the causative agents of gout and pseudogout responded differently to a magnetic field. This report suggests that the discrimination between CPP and MSU by optical measurements is possible by application of magnetic fields appropriately. © 2023 Bioelectromagnetics Society.

Calcium pyrophosphate deposition (CPPD) in a liver transplant patient: are hypomagnesemia, tacrolimus or both guilty? A case-based literature review.

Calcium pyrophosphate deposition (CPPD) can be induced by a persistent hypomagnesemia. Tacrolimus is an immunosuppressive treatment especially used in organ transplant, potentially inducer of hypomagnesemia by renal loss. A 53-year-old man, liver transplant 10 months earlier, developed an acute peripheral oligoarthritis of wrist, hip and elbow with fever, associated with acute low back pain. Synovial fluid was sterile, and revealed calcium pyrophosphate crystals. Spinal imaging showed inflammatory changes. Magnesium blood level was low at 0.51 mmol/l, with high fractional excretion in favor of renal loss. Tacrolimus was changed for everolimus, proton pump inhibitor was stopped, and magnesium oral supplementation was started. After 8 months follow-up and slow prednisone tapering, he did not relapse pain. Persistent hypomagnesemia is a rare secondary cause of CPPD. In this entity, drug liability should be investigated such as tacrolimus in organ transplant patient.

Dinosaur senescence: a hadrosauroid with age-related diseases brings a new perspective of "old" dinosaurs.

Senile vertebrates are extremely rare in the fossil record, making their recognition difficult. Here we present the largest known representative of the Late Cretaceous hadrosauriform Gobihadros mongoliensis showing features of cessation of growth indicating attainment of the terminal size. Moreover, this is the first non-avian dinosaur with an age-related pathology recognized as primary calcium pyrophosphate deposition disease indicating its advanced age. Because senile dinosaurs are so rare and thus "senescence" in dinosaurs is unclear, we also propose a new unified definition of a senile dinosaur: an individual which achieved the terminal size as revealed by the presence of the external fundamental system and closed transcortical channels, has completely secondary remodeled weight-bearing bones and possesses non-traumatic, non-contagious bone pathologies correlated with advanced age.

The diagnostic value of conventional radiography and musculoskeletal ultrasonography in calcium pyrophosphate deposition disease: a systematic literature review and meta-analysis.

OBJECTIVE: To examine and compare the accuracy of conventional radiography (CR) and musculoskeletal ultrasonography (US) in the diagnosis of calcium pyrophosphate (CPP) crystals deposition disease (CPPD). DESIGN: A systematic search of electronic databases (PubMed, Embase, and Cochrane), conference abstracts and reference lists was undertaken. Studies which evaluated the accuracy of CR and/or US in the diagnosis of CPPD, using synovial fluid analysis (SFA), histology or classification criteria as reference tests were included. Subgroup analyses by anatomic site and by reference test were performed. RESULTS: Twenty-six studies were included. Using SFA/histology as reference test, CR and US showed an excellent (CR AUC = 0.889, 95%CI = 0.811-0.967) and an outstanding (US AUC = 0.954, 95%CI = 0.907-1.0) diagnostic accuracy (p < 0.01), respectively. Furthermore, US showed a higher sensitivity (0.85, 95%CI = 0.79-0.90 vs 0.47, 95%CI = 0.40-0.55) and only a little lower specificity (0.87, 95%CI = 0.83-0.91 vs 0.95, 95%CI = 0.92-0.97) than CR. A considerable heterogeneity between the studies was found, with adopted reference test being the main source of heterogeneity. In fact, subgroup analysis showed a significant change in the diagnostic accuracy of CR, but not of US, using Ryan and McCarty criteria or SFA/histology as reference test (CR: AUC = 0.956, 95%CI = 0.925-1.0 vs AUC = 0.889, 95%CI = 0.828-0.950, respectively, p < 0.01) (US: AUC = 0.922, 95%CI = 0.842-1.0 vs AUC = 0.957, 95%CI = 0.865-1.0, respectively, p = 0.08) CONCLUSIONS: Although US is more sensitive and a little less specific than CR for identifying CPP crystals, both these two techniques showed a great diagnostic accuracy and should be regarded as complementary to each other in the diagnostic work-up of patients with CPPD.

Calcium Pyrophosphate Dihydrate Crystal Deposition in Gouty Tophi.

OBJECTIVE: The coexistence of calcium pyrophosphate dihydrate (CPPD) and monosodium urate monohydrate crystals in gouty tophi has rarely been reported. We undertook this study to investigate CPPD crystal deposits in a series of surgically removed gouty tophi and to identify factors associated with these deposits. METHODS: Twenty-five tophi from 22 gout patients were analyzed using polarized light microscopy, field emission scanning electron microscopy (FESEM), and µ Fourier transform infrared (µFTIR) spectroscopy. RESULTS: Tophi consisted of multiple lobules separated by fibrous septa and surrounded by a foreign-body giant cell reaction. CPPD crystal aggregates were identified in 9 of 25 tophi from 6 patients. CPPD crystals were dispersed or highly compacted, localized at the edge or inside the tophus lobules, with some lobules completely filled with crystals. Both monoclinic and triclinic CPPD crystal phases were identified using FESEM and µFTIR. Compared to patients without CPPD, those with CPPD-containing tophi were older (mean 60.5 years versus 47.2 years; P = 0.009), and had longer-term gout duration (mean 17.0 years versus mean 9.0 years; P < 0.05) and tophi duration (mean 10.0 years versus mean 4.6 years; P < 0.01). None of the patients had radiographic chondrocalcinosis of the knee or wrist. CONCLUSION: CPPD crystal formation seems to be a late and frequent event of tophus maturation, occurring more frequently with aging, and could contribute to the speed of tophus dissolution and the apparent persistence of tophus sometimes observed even after effective, long-lasting urate-lowering therapy.

Criterion validity of ultrasound in the identification of calcium pyrophosphate crystal deposits at the knee: an OMERACT ultrasound study.

OBJECTIVE: To evaluate the discriminatory ability of ultrasound in calcium pyrophosphate deposition disease (CPPD), using microscopic analysis of menisci and knee hyaline cartilage (HC) as reference standard. METHODS: Consecutive patients scheduled for knee replacement surgery, due to osteoarthritis (OA), were enrolled. Each patient underwent ultrasound examination of the menisci and HC of the knee, scoring each site for presence/absence of CPPD. Ultrasound signs of inflammation (effusion, synovial proliferation and power Doppler) were assessed semiquantitatively (0-3). The menisci and condyles, retrieved during surgery, were examined microscopically by optical light microscopy and by compensated polarised microscopy. CPPs were scored as present/absent in six different samples from the surface and from the internal part of menisci and cartilage. Ultrasound and microscopic analysis were performed by different operators, blinded to each other's findings. RESULTS: 11 researchers from seven countries participated in the study. Of 101 enrolled patients, 68 were included in the analysis. In 38 patients, the surgical specimens were insufficient. The overall diagnostic accuracy of ultrasound for CPPD was of 75%-sensitivity of 91% (range 71%-87% in single sites) and specificity of 59% (range 68%-92%). The best sensitivity and specificity were obtained by assessing in combination by ultrasound the medial meniscus and the medial condyle HC (88% and 76%, respectively). No differences were found between patients with and without CPPD regarding ultrasound signs of inflammation. CONCLUSION: Ultrasound demonstrated to be an accurate tool for discriminating CPPD. No differences were found between patents with OA alone and CPPD plus OA regarding inflammation.

Clinical implications of synovial fluid specimen handling for crystal associated arthritides: A systematic review.

AIM: To identify the appropriate methods of synovial fluid (SF) specimen storage, manipulation and handling for crystal associated arthritides (CAA) diagnosis. METHOD: A systematic literature review was conducted using 5 medical databases to identify diagnostic studies assessing SF specimen handling for calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals identification. All included studies were rated for quality using the Quality Assessment of Diagnostic Accuracy Studies 2. RESULTS: Fifteen studies, including 2 non-English language manuscripts, were included. Eight studies examined both types of crystals, while 3 studies examined CPP and 4 studies examined MSU crystals only. Overall, MSU crystals were more stable over time compared to CPP crystals. MSU stability was generally independent of time, preservative and temperature. CPP crystals deteriorated with time and were more stable if refrigerated. Ethylenediaminetetraacetic acid (EDTA) was a suitable preservative. Re-examining an initially negative SF sample at 24 hours facilitated detection of additional cases. Very few studies had an overall low risk of bias and applicability. CONCLUSION: Monosodium urate crystals remain stable over time independent of storage time, temperature and preservative. CPP crystals are mostly stable for 24-48 hours but can deteriorate with time. Overall, SF crystal examination should ideally be done within 24-48 hours. They may be stored at room temperature without any preservative. Otherwise, refrigeration (4°C/39°F) and EDTA preservation is reasonable. Stored SF re-examination, at 24 hours, helps identify a small number of additional MSU and CPP cases. Centrifugation techniques allow better and easier crystal identification, particularly CPP. Most studies were of unclear or low quality.

A case of acute calcium pyrophosphate arthritis in two rare sites of involvement: The cervical facet and atlantoaxial joint.

Calcium pyrophosphate dihydrate deposition (CPPD) disease, also known as pseudogout, in which crystals are deposited in the joints and/or soft tissues, leads to a variety of articular and periarticular disorders. Herein we report a 67-year-old female patient with neck pain who was diagnosed as CPPD disease of both the atlantoaxial joint and right C4-C5 facet joint with radiological findings. The combined use of computed tomography and magnetic resonance imaging can be helpful in establishing a diagnosis and providing the correct treatment.

White blood cell count and total protein concentration to predict the absence of microcrystals in synovial fluid.

BACKGROUND: Synovial fluid analysis is essential for diagnosing crystal-induced arthritis. Monosodium urate monohydrate (MSU) crystals in gout and calcium pyrophosphate dihydrate (CPP) crystals in pseudogout trigger inflammatory reactions that result in white blood cell (WBC) activation. This study aimed to evaluate the predictive value of synovial fluid WBC count and total protein concentration for the absence of microcrystals. MATERIALS AND METHODS: This prospective study analyzed all synovial fluid samples collected at a single center in a 6-month period. The absolute WBC count and total protein concentration were recorded for each sample. A single expert used polarized light microscopy to detect microcrystals. Mann-Whitney U-tests was used to compare mean counts and concentrations in samples with and without crystals. Diagnostic performance was assessed through the area under the receiver-operating characteristic curve (AUC). RESULTS: A total of 205 samples were included. The absolute WBC count was significantly higher in samples with crystals than in those without. No differences were found between MSU and CPP. The ROC curve showed an AUC 0.773, and an absolute WBC count <1650/mm3 yielded 95.7% sensitivity, 53.1% specificity, and 97.7% negative predictive value for predicting the absence of microcrystals. Total protein concentration was not significantly different between samples with and without crystals. CONCLUSION: The WBC count is useful for screening for the absence of microcrystals in synovial fluid; the cutoff <1650 WBC/mm3 accurately predicts the absence of crystals, obviating the need for polarized light microscopy and thus simplifying and shortening laboratory analysis of synovial fluid, leading to a reduction in laboratory turnaround time.

Pseudogout or pseudolymphoma? Calcium pyrophosphate deposition disease of the cervical spine: a rare presentation and literature review.

Calcium pyrophosphate deposition (CPPD) disease is a crystal arthropathy primarily affecting peripheral joints, most commonly the wrist and the knees. However, CPPD in the cervical spine is a rare entity. This report describes a case of CPPD of the cervical spine which presents with symptoms of neck pain and brachalgia. A 62-year-old woman presented with left-sided upper limb and neck pain. MRI scanning revealed a low signal abnormality within the C6 and C7 vertebrae, and the possibility of lymphoma was raised. The patient was recalled for gadolinium-enhanced scans which showed perivertebral and marrow enhancement. Fine-needle aspirate histology initially suggested a spindle cell tumour or lymphoma. However, CT-guided biopsy showed positively birefringent crystals, confirming CPPD. CPPD of the spine is a rare differential of nerve impingement in the cervical spine when MRI scanning perivertebral signal enhancement. Furthermore, CPPD of the spine can mimic malignancy.

Nanostructured TiO2 Materials for Analysis of Gout-Related Crystals Using Laser Desorption/Ionization Time-of-Flight (LDI-ToF) Mass Spectrometry.

Crystals of monosodium urate monohydrate (MSU) and calcium pyrophosphate dihydrate (CPPD) are known to induce arthropathic diseases called gout and pseudogout, respectively. These crystals are deposited in various joints or tissues, causing severe pain. Correct identification of crystals is crucial for the appropriate treatment of gout and pseudogout, which exhibit very similar symptoms. Herein, a novel approach of laser desorption/ionization time-of-flight (LDI-ToF) mass spectrometry (MS) was introduced to analyze MSU and CPPD crystals with three different types of nanostructured TiO2 materials including TiO2 nanoparticles (P25), TiO2 nanowires synthesized from wet-corrosion method, and the mixture of P25 and TiO2 nanowires (P25/TiO2 nanowires) as inorganic solid matrices. Furthermore, the feasibility of LDI-ToF MS based on these TiO2 nanostructures for the analysis of the two arthropathy-related crystals was tested using spiked samples in synovial fluid at known crystal concentrations. The mass analysis results of MSU and CPPD crystals demonstrated that (1) the electrostatic interaction between analytes and solid matrices was key for the analyte ionization and (2) LDI-ToF MS with nanostructured TiO2 materials has the potential to be a practical approach for the diagnosis of gout and pseudogout.

Diagnostic value of ultrasound in calcium pyrophosphate deposition disease of the knee joint.

OBJECTIVE: To assess the diagnostic performance of ultrasound (US) for calcium pyrophosphate deposition (CPPD) at the level of menisci, hyaline cartilage (HC), tendons, and synovial fluid (SF) of the knee, and to examine inter- and intra-observer reliability. DESIGN: We consecutively included patients with knee effusion over a 2-year period (43 patients with CPPD and 131 controls). All patients underwent SF analysis, conventional radiography (CR), and US examination using the Outcome Measures in Rheumatology (OMERACT) definition of the US characteristics of CPPD. Two independent operators performed the US, and inter-observer agreement was calculated. Intra-observer agreement was examined with static images obtained for all enrolled patients. RESULTS: US revealed calcium pyrophosphate (CPP) deposits in menisci, HC, and tendon more frequently in patients with CPPD than in control patients. The presence of US CPP deposits in SF was not significantly different between the two groups. Combined US evaluation of the three components (menisci, HC, and tendon) showed the best diagnostic performance. The sensitivity and specificity for US evaluation of the three components were 74.4% and 77.1%, respectively, while for CR evaluation, the sensitivity and specificity were 44.2% and 96.9%, respectively. Inter- and intra-observer agreement were excellent for medial (κ = 0.930, 0.972) and lateral menisci (κ = 0.905, 0.942), HC (κ = 0.844, 0.957), and SF (κ = 0.817, 0.925). Tendon showed fair inter-observer (κ = 0.532) and good intra-observer reliability (κ = 0.788). CONCLUSIONS: Based on the OMERACT definition, US demonstrated better diagnostic capacity than CR to diagnose CPPD, with excellent reliability. Combined evaluation of menisci, HC, and tendon showed the best diagnostic accuracy.

Most needle-shaped calcium pyrophosphate crystals lack birefringence.

OBJECTIVES: CPP crystals can be polymorphic (rhomboidal, parallelepiped: R/P), but some look like needles and could be taken as MSU under the bright field microscope. Birefringence of CPP crystals is weaker or absent compared with MSU crystals, but we aim to evaluate whether the grade of birefringence varies regarding the shape of the CPP crystal. METHODS: SF samples from patients with demonstrated acute CPP crystal arthritis were analysed by two observers, using a simple polarized light microscope equipped with two viewing stations. The analysis was performed simultaneously but in a blinded manner. Shape (needles or R/P) and the intensity of birefringence (absent, weak, moderate or MSU-like) were registered. χ2 trend test was used to evaluate the distribution of birefringence regarding the crystal shape. RESULTS: Two-hundred and fifty CPP crystals from 25 SF samples were analysed, well balanced between R/P and needles. The intensity of birefringence significantly differs between R/P or needles in the registries of both observers. R/P most often showed any grade of birefringence compared with needles, while no cases of MSU-like birefringence were found in acicular crystals. Both observers showed high agreement both in crystal shape and in intensity of birefringence. CONCLUSION: CPP crystals birefringence varies according to shape. Needle-shaped CPP crystals did not show strong birefringence, thus reinforcing the value of examining the samples with both ordinary and simple polarized light microscopes in differentiating them from MSU.