Systemic Inflammation In Asymptomatic Hyperuricemia With Sonographic Crystal Deposits, Including A Comparison With Normouricemia And Gout.

OBJECTIVE: To describe the inflammatory profile of asymptomatic hyperuricemia (AH) with ultrasound evidence of monosodium urate (MSU) crystals (AH-MSUpos), vs AH without deposits (AH-MSUneg), intercritical gout, and normouricemia. METHODS: Based on serum urate levels, musculoskeletal ultrasound, and history of flares, we divided 122 participants into four groups: normouricemia, AH-MSUneg, AH-MSUpos, and intercritical gout. We tested four ultrasound definitions for MSU deposition in AH: grade 2-3 (G2-3) double contour and/or tophi, G1-3 double contour and/or tophi, G1-3 Stewart scheme (double contour sign in knee cartilage and/or first metatarsophalangeal joint and/or tophi in first metatarsophalangeal joint), and G2-3 Stewart scheme. Serum acute phase reactants, cytokines, pyroptosis derivates, and neutrophil-related proteins were measured and compared between groups. A linear regression model was fitted to correlate crystal and inflammatory burden (measured by ultrasound) with inflammatory markers in hyperuricemics. RESULTS: Rates of MSU deposition in AH ranged from 26.0% to 68.8%, depending on the definition used. Levels of CRP, leukocytes, IL-1RA, IL-6, sIL-6R, IL-18, TNF-α, TGF-ß, and galectin-3 were higher in hyperuricemics vs normouricemics. Sex, obesity, and comorbidity scores influenced some comparisons. We saw no differences comparing AH-MSUpos  vs AH-MSUneg groups, except for higher calprotectin using G1-3 sonographic definitions and higher CRP and TGF-ß when restricted to women and obese participants. CONCLUSIONS: Hyperuricemia is associated with substantial inflammation and some degree of active pyroptosis. Four different ultrasound definitions for AH with MSU deposits yielded similar findings, although we noted some differences in calprotectin, CRP, and TGF-ß. Sex, obesity, and comorbidities influenced some inflammatory responses.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

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.

Serum Urate Levels of Hemodialyzed Renal Patients Revisited.

OBJECTIVES: The need of maintaining serum urate (SU)-lowering agents in hemodialysis (HD) patients is an understudied area that requires a review, as it is a common practice. The aims were to assess the SU reduction achieved under HD and to analyze the kinetics of SU in a week of intermittent HD. METHODS: The serum urate levels were determined before and after HD sessions in 96 consecutive patients with end-stage renal disease, and the average SU reduction was assessed. Variables related to HD were analyzed whether they were associated with SU reductions of 80% greater. In addition, a kinetics study was performed on 10 selected patients with hyperuricemia (SU before HD >6.8 mg/dL) throughout intermittent HD sessions in a 1-week period. RESULTS: The mean ± SD age of the patients was 66.5 ± 13.8 years, and 62 of them were male (64.6%). The mean ± SD time on HD replacement was 7.1 ± 7.2 years, and 16 (16.4%) continued with urate-lowering agents. The mean SU reduction immediately after HD was 80.2% (95% confidence interval, 78.4-82.0); 51 patients (56.7%) showed SU reduction of 80% or greater. In the SU kinetics study, SU levels significantly reduced all over the period and persisted below hyperuricemia threshold (p = 0.015). Noteworthy, 6 patients (60%) were hyperuricemic before session 1, but only 1 (10%) before session 2 and none before session 3. CONCLUSIONS: Under HD replacement therapy, the SU levels effectively reduced and persisted below saturation point, suggesting that the SU-lowering therapy would be unnecessary for patients on HD, but necessary in selected cases. The definition of hyperuricemia under HD needs to be revised.

Progresses in the imaging of calcium pyrophosphate crystal disease.

PURPOSE OF REVIEW: Calcium pyrophosphate crystal disease (CPPD) may be considered a neglected disorder, common in clinics and wards, but not receiving enough attention since the time it was recognized as a disease entity. This review aims to highlight the advances occurred in recent years in terms of imaging of CPPD, and their potential aid in diagnosing CPPD. RECENT FINDINGS: The main advances in CPPD imaging have occurred with ultrasound and computed tomography. Ultrasound has been shown as more sensitive than conventional radiography in detecting chondrocalcinosis. OMERACT definitions of ultrasound signs of CPPD have been provided; validations process is still ongoing. Computed tomography has been used to assess CPPD at the spine. Some studies suggest that dual-energy scans could accurately detect chondrocalcinosis and discriminate from other calcified structures. SUMMARY: Ultrasound and computed tomography may have a role in CPPD detection, though the specifics are still unclear. It remains necessary to have studies comparing them with synovial fluid analysis for crystals in a clinical scenario.

2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout.

Although gout is the most common inflammatory arthritis, it is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since the first EULAR recommendations for the diagnosis of gout in 2006. This prompted a systematic review and update of the 2006 recommendations. A systematic review of the literature concerning all aspects of gout diagnosis was performed. Recommendations were formulated using a Delphi consensus approach. Eight key recommendations were generated. A search for crystals in synovial fluid or tophus aspirates is recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definite diagnosis of gout. There was consensus that a number of suggestive clinical features support a clinical diagnosis of gout. These are monoarticular involvement of a foot or ankle joint (especially the first metatarsophalangeal joint); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling; erythema; male gender and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it is recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of MSU crystal deposition (double contour sign and tophi). There was consensus that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all people with gout should be systematically assessed for presence of associated comorbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed.

Gout: Where Is the Weak Link?

In the field of rheumatic and musculoskeletal diseases, no other condition has evolved so significantly since the mid-1950s as gout. In this period, the cause of gout has been firmly established; the close relationship with other conditions clarified; a rapid, unequivocal diagnostic test established; and agents effective in dissolving monosodium urate crystals and controlling inflammation made widely available. All these insights have ultimately led to deem gout as curable, an end point formerly considered out of reach. Unfortunately, diagnosis and management of gout in clinical practice have not paralleled the scientific advances and remain far from established quality standards. This paradox is the topic of the present review article, intending to increase the widespread interest of clinicians in gout.

Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions of disease states of gout.

OBJECTIVE: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. METHODS: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. RESULTS: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). CONCLUSION: Consensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

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.

Therapy for CPPD: Options and Evidence.

PURPOSE OF REVIEW: Current evidence and accumulated experience for the management of calcium pyrophosphate deposition disease (CPPD) are presented. RECENT FINDINGS: Contrary to other rheumatic inflammatory conditions that account for high interest and growing research, advances in treating CPPD are still very limited and mostly derive from those achieved in gout. Once formed, calcium pyrophosphate crystals cannot be dissolved; therefore, management relies on the control of crystal-derived inflammation. Besides classical agents-such as colchicine, glucocorticoids, or NSAIDs-the use of targeted therapies, mostly against interleukin-1, has provided a relevant relief for refractory CPPD patients in recent years. Meanwhile, former enthusiasm about conventional disease-modifying agents such as methotrexate is currently controversial.

Cardiovascular risk of patients with gout seen at rheumatology clinics following a structured assessment.

OBJECTIVES: Gout-associated cardiovascular (CV) risk relates to comorbidities and crystal-led inflammation. The aim was to estimate the CV risk by prediction tools in new patients with gout and to assess whether ultrasonographic carotid changes are present in patients without high CV risk. METHODS: Cross-sectional study. Consecutive new patients with crystal-proven gout underwent a structured CV consultation, including CV events, risk factors and two risk prediction tools-the Systematic COronary Evaluation (SCORE) and the Framingham Heart Study (FHS). CV risk was stratified according to current European guidelines. Carotid ultrasound (cUS) was performed in patients with less than very high CV risk. The presence of carotid plaques was studied depending on the SCORE and FHS by the area under the curve (AUC) of receiver operating curves. RESULTS: 237 new patients with gout were recruited. CV stratification by scores showed a predominance of very high (95 patients, 40.1%) and moderate (72 patients, 30.5%) risk levels. cUS was performed in 142 patients, finding atheroma plaques in 66 (46.5%, 95% CI 37.8 to 54.2). Following cUS findings, patients classified as very high risk increased from 40.1% up to 67.9% (161/237 patients). SCORE and FHS predicted moderately (AUC 0.711 and 0.683, respectively) the presence of atheroma plaques at cUS. CONCLUSIONS: The majority of patients presenting with gout may be at very high CV risk, indicating the need for initiating optimal prevention strategies at this stage. Risk prediction tools appear to underestimate the presence of carotid plaque in patients with gout.

Inflammatory status and uricaemia determine HDL-cholesterol levels in hypertensive adults over 65: an analysis of the FAPRES register.

In inflammatory disease, the levels of high-density lipoprotein cholesterol (HDL-C) decrease, and the composition of HLD-C changes. Data from the "non-inflammatory" general population indicate the presence of the same phenomenon, albeit to a smaller extent. Levels of uricaemia contribute to the overall inflammatory state of patients. The aim of this study was to analyse the association between inflammatory state, levels of uricaemia, and levels of HLD-C in a hypertensive Spanish population aged 65 or older. This was a retrospective analysis of the FAPRES database. We compared lipid levels [HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides] in terciles of patients according to their leukocyte counts and uricaemia. When we observed statistically significant differences at a 95% confidence level, we constructed a multivariable linear regression model to adjust for possible confounders. We analysed 860 patients (52.7% women) with a mean age of 72.9 years (±5.8). Participants in the highest tercile for leukocytes or uricaemia presented with significantly lower levels of HDL-C and higher levels of triglycerides, but there was no difference in total cholesterol or LDL-C. The multivariable analysis confirmed an independent and inverse association between HDL-C and both leukocytes (ß = -0.001, p = 0.025) and uricaemia (ß = -1.054, p = 0037) as well as an independent, direct association between triglycerides and both leukocytes (ß = 0.004, p = 0.049), and uricaemia (ß = 8.411, p = 0.003). In hypertensive adults aged 65 or older, inflammatory state, and uricaemia independently operate to decrease HDL-C-these findings confirm those described in studies in people with inflammatory disease. This phenomenon could help to define a proatherogenic profile in people without inflammatory disease.

Current advances in therapies for calcium pyrophosphate crystal arthritis.

PURPOSE OF REVIEW: Calcium pyrophosphate (CPP) crystal disease is a common rheumatologic disorder that has received limited attention from the scientific community. This review is aimed at summarizing current evidence for managing CPP disease (CPPD), focusing on recently reported advances. RECENT FINDINGS: New data from case series indicate that interleukin-1ß inhibitors can help patients with refractory forms of CPPD. Methotrexate, formerly a promising agent, failed to demonstrate benefits in a recent trial, but still merits consideration for some patients. No significant advances on crystal dissolution have been achieved to date. Proper characterization of the CPP crystal disease picture is needed, ruling out the possible coexistence of another persistent arthritis unrelated to the CPP deposition. SUMMARY: Advances on CPP crystal dissolution and establishing definitions of the clinical spectrum of CPPD remain the main challenges for CPP crystal disease management.

Ultrasound-detected musculoskeletal urate crystal deposition: which joints and what findings should be assessed for diagnosing gout?

OBJECTIVE: The primary objective of this prospective case-control study was to assess the diagnostic value of several intra-articular and periarticular ultrasound (US)-detected abnormalities in the upper and lower limbs in gout. The secondary objective was to test the concurrent validity of US abnormalities using as gold standard the microscopic demonstration of monosodium urate (MSU) crystals. METHODS: Ninety-one men with gout and 42 age-matched controls were prospectively recruited. All patients with gout and controls underwent US assessment of several US abnormalities in 26 joints, six bursae, eight tendons, 20 tendon compartments, four ligaments, and 18 articular cartilages by experts in US blinded to the patients' group. Patients with gout and controls with US abnormalities were asked to undergo US-guided aspiration for microscopic identification of MSU crystals. Interobserver and intraobserver reliability of the US assessment was evaluated in a web-based exercise. RESULTS: The assessment of one joint (ie, radiocarpal joint) for hyperechoic aggregates (HAGs), two tendons (ie, patellar tendon and triceps tendon) for HAGs and three articular cartilages (ie, first metatarsal, talar and second metacarpal/femoral) for double contour sign showed the best balance between sensitivity and specificity (84.6% and 83.3%, respectively). Intraobserver reliability was good (mean κ 0.75) and interobserver reliability was moderate (κ 0.52). The aspirated material from HAGs was positive for MSU crystals in 77.6% of patients with gout and negative in all controls. CONCLUSIONS: Our results suggest that US bilateral assessment of one joint, three articular cartilages and two tendons may be valid for diagnosing gout with acceptable sensitivity and specificity.

Unraveling the pathological biomineralization of monosodium urate crystals in gout patients.

Crystallization of monosodium urate monohydrate (MSU) leads to painful gouty arthritis. Despite extensive research it is still unknown how this pathological biomineralization occurs, which hampers its prevention. Here we show how inflammatory MSU crystals form after a non-inflammatory amorphous precursor (AMSU) that nucleates heterogeneously on collagen fibrils from damaged articular cartilage of gout patients. This non-classical crystallization route imprints a nanogranular structure to biogenic acicular MSU crystals, which have smaller unit cell volume, lower microstrain, and higher crystallinity than synthetic MSU. These distinctive biosignatures are consistent with the template-promoted crystallization of biotic MSU crystals after AMSU at low supersaturation, and their slow growth over long periods of time (possibly years) in hyperuricemic gout patients. Our results help to better understand gout pathophysiology, underline the role of cartilage damage in promoting MSU crystallization, and suggest that there is a time-window to treat potential gouty patients before a critical amount of MSU has slowly formed as to trigger a gout flare.

Prevalence of crystal deposits in asymptomatic hyperuricemia according to different scanning definitions: A comparative study.

BACKGROUND/AIM: The appropriate sonographic protocol for assessing urate crystal deposits in asymptomatic hyperuricemia (AH) is undefined, as well as how the choice would impact on deposit rates and accompanying sonographic, clinical and laboratory features. METHODS: Patients with AH (serum urate ≥7 mg/dL) underwent musculoskeletal ultrasound of 10 locations for OMERACT elementary gout lesions (double contour [DC] signs, tophi, aggregates). Different definitions for AH with deposits were applied, varying according to deposits (any deposits; only DC and/or tophi); gradation (any grade; only grade 2-3 deposits), location (10 locations; 4-joint scheme including knees and 1MTPs; >1 location with deposits), or pre-defined definitions (DC sign in femoral condyles/1MTP and/or tophi in 1MTP). We evaluated crystal deposits rates and compared between other sonographic features, clinical and laboratory variables. RESULTS: Seventy-seven participants with AH showed a median 1 location (IQR 0-2) with tophi, 1 (IQR 1-2) with aggregates, and 0 locations (IQR 0-1) with DC sign. The deposition rate ranged from 23.4% (in >1 location with grade 2-3 DC or tophi) to 87.0% (in any deposit in all 10 locations). Accompanying inflammation - assessed by a positive power-Doppler (PD) signal - and erosions were found in 19.5% and 28.4% of participants, respectively. Positive PD signal was better discriminated by criteria requiring grade 2-3 or >1 location with lesions. Erosions and the different clinical and laboratory variables were similar among protocols. CONCLUSION: Rates of sonographic deposition in AH varied dramatically among studied protocols, while some could discriminate accompanying inflammation, all highlighting the need for a validated, consensus-based definition.