Search Results (50)

Gout is a chronic inflammatory disease characterized by the deposition of monosodium urate (MSU) crystals within joints, leading to recurrent acute flares and long-term tissue damage. While various hypotheses have been proposed to explain the self-limiting nature of acute gout attacks, we posit that aggregated neutrophil extracellular traps (aggNETs) play a central role in this process. This review focuses on the mechanisms underlying MSU crystal-induced formation of neutrophil extracellular traps (NETs) and explores their dual role in the clinical progression of gout. During the initial phase of acute flares, massive NET formation is accompanied by the release of preformed inflammatory mediators, which is a condition that amplifies inflammatory cascades. As neutrophil recruitment reaches a critical threshold, the NETs tend to form high-order aggregates (aggNETs). The latter encapsulate MSU crystals and further pro-inflammatory mediators within their three-dimensional scaffold. High concentrations of neutrophil serine proteases (NSPs) within the aggNETs facilitate the degradation of soluble inflammatory mediators and eventually promote the resolution of inflammation in a kind of negative inflammatory feedback loop. In advanced stages of gout, MSU crystal deposits are often visible via dual-energy computed tomography (DECT), and the formation of palpable tophi is frequently observed. Based on the mechanisms of resolution of inflammation and the clinical course of the disease, building on the traditional static model of “central crystal–peripheral fibrous encapsulation,” we have expanded the NETs component and refined the overall concept, proposing a more dynamic, multilayered, multicentric, and heterogeneous model of tophus maturation. Notably, in patients with late-stage gout, tophi exist in a stable state, referred to as “silent” tophi. However, during clinical tophus removal, the disruption of the structural or functional stability of “silent” tophi often leads to the explosive reactivation of inflammation. Considering these findings, we propose that future therapeutic strategies should focus on the precise modulation of NET dynamics, aiming to maintain immune equilibrium and prevent the recurrence of gout flares. Full article

Objectives: Identification of monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in synovial fluid should ideally be performed within 24 h to ensure optimal diagnostic accuracy for gout and CPP arthritis. However, crystal identification is often delayed in community-based healthcare facilities due to limited access to specialists or necessary equipment. This study aimed to determine whether MSU and CPP crystals remain detectable in synovial fluid after two weeks of storage at 4 °C and −20 °C. Methods: Anonymized synovial fluid samples were obtained from Thammasat University Hospital between February and March 2024. All samples underwent an initial round of crystal identification using compensated polarized light microscopy, conducted by two experienced examiners blinded to the clinical diagnosis. Following the initial analysis, each sample was divided into two equal portions and placed in ethylenediaminetetraacetic acid (EDTA)-coated tubes. One portion was stored at 4 °C, while the other was frozen at −20 °C. After two weeks, all samples underwent a second round of crystal identification. Results: Forty-nine samples were included for the first evaluation; MSU and CPP crystals were identified in 14 and 6 samples, respectively. On the second examination, MSU crystals were detectable in 13/14 (92.8%) samples stored at 4 °C and 12/14 (85.7%) samples stored at −20 °C. However, CPP crystals were detectable in 2/6 (33.3%) samples stored at both temperatures. No new crystal formation in initially negative samples was observed. Conclusion: MSU crystals remain detectable in synovial fluid for up to two weeks when stored in a standard refrigerator or freezer. However, the identification rate of CPP crystals tends to decline over this period. These findings may help inform best practices for handling synovial fluid samples in cases where immediate access to a specialist or necessary equipment is unavailable. Full article

Objectives: (1) To compare cytokine levels in participants with serum urate (SU) < 360 µmol/L, SU ≥ 360 µmol/L with and without monosodium urate (MSU) crystal deposition, respectively, and inter-critical gout. (2) To explore the association of IL-1β, IL-6 and high-sensitivity (hs) CRP with disease duration and the frequency of self-reported gout flares. Methods: Samples and data from 184 participants from studies conducted at Academic Rheumatology, Nottingham City Hospital, were included. Serum high-sensitivity CRP and cytokines involved in the pathogenesis of gouty inflammation were measured. MANCOVA and multivariate linear regression were used, as appropriate, and were adjusted for age, sex, body mass index and self-reported comorbidities. p values were adjusted for multiple testing using a 5% false-discovery rate. Results: Participants with inter-critical gout had greater levels of IL-1β (p_corr = 0.009), IL-18 (p_corr = 0.02), IL-6 (p_corr < 0.0001), IP-10 (p_corr < 0.0001), TNF-α (p_corr < 0.0001), GRO-α (p_corr = 0.0006) and hsCRP (p_corr = 0.009) compared to other groups in multivariate analyses and after correcting for multiple testing. There were no differences in cytokine and hsCRP levels in participants with SU < 360 µmol/L and in participants with SU ≥ 360 µmol/L with or without MSU crystal deposition. There was a statistically non-significant trend for association between IL-6 levels and number of self-reported gout flares. Conclusions: Our findings suggest that gout is a chronic inflammatory condition. The pre-clinical phases of gout were not associated with systemic inflammation, potentially due to the modest sample size. Further research is required to understand whether treating gout by targeting the complete dissolution of MSU crystals would reduce systemic inflammation in inter-critical gout. Full article

Gout, a metabolic and autoinflammatory disease, is the most common form of inflammatory arthritis worldwide. Hyperuricemia may result in monosodium urate (MSU) crystals forming and depositing in joints and surrounding tissues, triggering an autoinflammatory response. Effective urate-lowering therapies, as well as anti-inflammatory medications, are used to treat gout. Over the past few decades, new antihyperglycemic drug classes with different modes of action have been added to treat hyperglycemia in type 2 diabetes mellitus (T2DM). Two of these drug classes, sodium–glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), have reduced cardiovascular and renal events and mortality. Several clinical studies have demonstrated that SGLT2 inhibitors possess urate-lowering properties, which may be beneficial for treating gout patients, particularly those with comorbid T2DM. Regarding SGLT2 inhibitors, some researchers have suggested that their benefits are partly explained by their ability to reduce serum urate (SU) levels, probably through increased urinary uric acid excretion. The effect of GLP-1 RA on SU levels and urinary excretion of uric acid in humans is unclear. This paper reviews the mechanisms of action of SGLT2 inhibitors and GLP-1RA, both approved and in development. Additionally, it examines what is known about their structure–activity relationships, uricosuric effects, pharmacokinetic profiles, and adverse effects. Full article

Background/Objectives: 7-Methylxanthine (7-MX) is a naturally occurring metabolite of caffeine and theobromine that can inhibit the crystallization of monosodium urate (MSU) and may be useful for the prevention or treatment of gout. However, the pharmacokinetics and ex vivo activity of 7-MX remain poorly characterized. Methods: The present study assessed the pharmacokinetics of 7-MX in Sprague Dawley rats following a single oral dose (30 mg/kg), and the ex vivo inhibition of MSU crystallization by 7-MX in rat plasma after the repeated administration of oral 7-MX. Results: The pharmacokinetic analysis showed that 7-MX reached peak plasma concentration (C_max ≈ 30 µM) at 30 min after administration (t_max), the terminal half-life was approximately 1.4 h, and there was no evidence of accumulation after repeated daily dosing. After repeated administration, the relationship between dose (30 or 60 mg/kg) and plasma concentration was proportional. In vitro and ex vivo crystallization assays demonstrated that 7-MX inhibited MSU crystallization in a concentration-dependent manner. The in vitro studies showed that 100 µM 7-MX inhibited up to 74% of MSU crystallization under supersaturated conditions (400 mg/L urate). The ex vivo experiments indicated that plasma from rats that received 30 or 60 mg/kg of 7-MX had 41.4% and 52.6% inhibition of crystallization, consistent with the measured plasma concentrations. Conclusions: These findings confirm that oral administration of 7-MX to rats led to a plasma level that was sufficient to decrease MSU crystallization in plasma, and there were no observable toxicities. These results support the potential of 7-MX as a safe oral treatment for gout, especially in combination with urate-lowering therapies, such as allopurinol. Further clinical investigations are warranted to confirm the therapeutic potential of 7-MX in humans. Full article

Hyperuricemia, induced by monosodium urate (MSU) crystals that accumulate in articular joints and periarticular soft tissues, can impair macrophages. Possible causes of macrophage injury include uric acid-induced oxidative stress or inflammation. This study examined the dried fruits of guava (DFG) as a complementary medicine with urate-lowering properties, utilizing THP-1 macrophages to determine if high uric acid-induced cellular damage could be mitigated through the reduction of oxidative stress and inflammation via treatment with a phytochemical extract. The active extract was prescreened using a xanthine oxidase (XO) inhibition assay coupled with fractionation and component analysis. The DFG extracts were used to identify, through an in vitro study of THP-1 cells. The results indicated that the DFG extracts with the highest total flavonoids (12.08 ± 0.81 mg/g DW) exhibited the XO inhibition activity. High-performance liquid chromatography–tandem mass spectrometry analysis showed that DFG extract contained 85.32% flavonoids, including quercetin and kaempferol derivatives. Furthermore, fractionation results of DFG extracts indicated a significant reduction in MSU-induced cytotoxicity in THP-1 cells obtained from the 75% ethanol-eluted fraction (Fr-75). Additionally, kaempferol, an active compound in Fr-75, effectively mitigated MSU-induced NF-κB and NLRP3 gene overexpression. These findings suggest that the prepared Fr-75 is a promising hyperuricemia therapeutic candidate. Full article

Background: Crystal arthritides represent the most common inflammatory rheumatologic condition. While the prevalence of gouty arthritis by monosodium urate (MSU) is well established, the prevalences of calciumpyrophosphat (CPP) and basic calcium pyrophosphate (ARP) arthritis are less clear. We herein sought to assess the prevalence and inflammatory characteristics of crystal arthritides at our institution, the biggest tertiary center in Switzerland. Methods: A total of 5036 synovial fluid (SF) samples were analyzed with regard to crystal positivity as well as joint, age, and sex distribution in affected patients. We furthermore compared inflammatory and non-inflammatory SF samples for yields of their Polymorphonuclear (PMN) fractions. Results: About half of all samples were derived from knee joints, a male/female ratio up to 10.1:1 among the MSU-positive, and a clear shift towards elder patients with CPP–arthritis was seen. These findings were in line with previous studies and suggest good comparability of our cohort. Of note, 21.9% of all samples were CPP positive, whereas 15.3% and 9.5% were positive for MSU and ARP/alizarin-red positive, respectively. Importantly, CPP crystals were predominant in inflammatory (58.9%) and non-inflammatory (65.7%) samples. By contrast, MSU crystals were significantly more often associated with synovitis (p < 0.001). Interestingly, higher PMN fractions were found in non-inflammatory MSU-positive samples (p < 0.01), whereas a similar trend was seen in CPP-positive samples. Conclusions: CPP arthritis represented the most frequent crystal arthritis form at our center. Higher PMN fractions in non-inflammatory samples with CPP and MSU crystals suggest subclinical inflammation and provide further arguments for earlier anti-inflammatory and uric acid-lowering therapies in patients with crystal deposits. Full article

Background/Objectives: The accumulation of uric acid in arteriosclerotic plaques has recently attracted attention. Because the interaction between hyperuricemia and atherosclerosis is complex, the details remain obscure. We aimed to elucidate the clinical effect of monosodium urate monohydrate (MSU) deposition on carotid plaques. Methods: This study enrolled 89 patients with carotid plaques. MSU deposits were confirmed using Gomori’s methenamine silver staining of carotid endarterectomy (CEA) specimens. To evaluate the macrophage and microvessel marker counts, we used CD68 and CD31. Plaque composition was investigated in carotid plaques with MSU deposition and inflammation. We also examined the use of dual-energy computed tomography (DECT) and compensated for pathological findings to detect MSU crystal deposition in carotid plaques. Results: Of the 89 patients who underwent CEA, 31 (34.8%) had hyperuricemia. Overall, 22 (24.7%) participants had MSU deposits and 67 (75.3%) did not. MSU deposits, CD31-positive microvessels, and CD68-positive cells were observed in shoulder lesions. The number of CD31-positive microvessels and CD68-positive cells was higher in patients with MSU deposits than in those without MSU deposits. Most plaques expressing MSU were plaques with intraplaque hemorrhage. The consistency in MSU deposit identification between histopathology and DECT was poor (kappa = 0.34). Conclusions: MSU deposition may be related to the inflammation of carotid plaques. Full article

The deposition of monosodium urate (MSU) crystals within joint spaces produces a painful inflammatory condition known as gout, a specific form of arthritis. The condition calls for a combined curative and preventive management model. A new development in the approach to gout is that of NLRP3-targeted biologic agents, such as monoclonal therapies, to provide more accurate treatment by blocking specific pro-inflammatory cytokines. Nanoparticle drug delivery enhances biological availability and delivery to targets, which may increase therapeutic efficacy and decrease general toxicity. The preventive approach again cannot be ignored, mainly keeping up certain modifications in diet and weight, along with pharmacological therapies to reduce uric acid (UA) levels and to decrease the frequency of acute attacks. The advancement of genetic profiling of patients and biomarker discoveries drives the trend towards building individualized medicine and care, quickly gaining ground as the most effective method of delivering treatments to individual patients, moving away from one-size-fits-all treatments. The following paper aims to provide an updated account of the management of gout with a focus on recent developments, in order to enhance these approaches, the quality of life for patients with gout, and the standard of gout treatment. Full article

Background: Monosodium urate crystal accumulation in the joints is the cause of gout, an inflammatory arthritis that is initiated by elevated serum uric acid levels. It is the most prevalent form of inflammatory arthritis, affecting millions worldwide, and requires effective treatments. The necessity for alternatives with fewer side effects is underscored by the frequent adverse effects of conventional therapies, such as urate-lowering drugs. IL-1β is a potential therapeutic target due to its significant role in the inflammatory response induced by MSU. Zanthoxylum piperitum Benn. (ZP), a shrub that possesses antibacterial, antioxidant, and anti-inflammatory properties, has demonstrated potential in the treatment of inflammatory conditions. Methods: For anti-inflammatory properties of ZP, Raw264.7 cell stimulated LPS were treated ZP and using RNA-seq with Bone marrow derived macrophage, we observed to change inflammatory gene. Pharmacological networks were conducted to select target gene associated with ZP. For in vivo, mice were injected MSU in footpad for induce gouty arthritis model. The components of ZP were analyzed using GC-MS, and distilled extracts of ZP (deZP) were prepared. Results: In vitro, deZP decreased inflammatory cytokines. However, in vivo, it also decreased paw thickness and IL-1β levels. The anti-inflammatory effects of deZP are believed to be mediated through the NLRP3 inflammasome pathway, as indicated by RNA sequencing and network pharmacology analyses. Conclusions: ZP has an anti-inflammatory effect and regulation of the NLRP3 inflammasome in vitro and in vivo. Further research, including clinical trials, is required to confirm the safety of deZP, determine the optimal dosing, and evaluate its long-term effects. Full article

Neutrophil extracellular traps (NETs) formation is a key process in inflammatory diseases like gout, but the underlying molecular mechanisms remain incompletely understood. This study aimed to establish a model to examine the formation of NETs induced by monosodium urate (MSU) and phorbol 12-myristate 13-acetate (PMA) and to elucidate their molecular pathways. Laser confocal microscopy was used to visualize NET formation, while flow cytometry was employed to detect reactive oxygen species (ROS) production. The microstructure of neutrophils was observed by transmission electron microscopy, and the expression of key proteins was determined by Western blotting. Additionally, the effect of various inhibitors targeting the MAPK signaling pathway on NET formation was evaluated. They include the Ras inhibitor Salirasib, Raf inhibitor Vemurafenib, ERK inhibitor PD98059, and p38 MAPK inhibitor SB203580, as well as NADPH oxidase inhibitor DPI and neutrophil elastase inhibitor Alvelestat. The results showed that MSU and PMA triggered significant NET formation, which was accompanied by increased ROS levels, lactate dehydrogenase release, dsDNA, and IL-8. Notably, selective MAPK pathway inhibitors and DPI and Alvelestat, except for SB203580, effectively down-regulated these indicators. These data indicated that the activation of a signaling pathway involving Ras-Raf-ERK, which is dependent on ROS, is crucial for the induction of NET formation by MSU and PMA. Given the involvement of NETs in multiple pathologies, our findings could potentially serve as molecular targets for the intervention and treatment of crystal-related diseases, especially for gout. Full article

Gout is a crystal-induced arthropathy in which monosodium urate (MSU) crystals precipitate within joints as a result of persistent hyperuricemia and elicit an inflammatory response. An intriguing aspect is the occurrence of gout in only 10–15% of hyperuricemic individuals, suggesting the presence of additional risk factors. Although MSU crystal deposition is widely recognized as the cause of gout flares, the variability in initiating the inflammatory response to hyperuricemia and MSU deposition is not well understood. Several studies bring up-to-date information about the environmental and genetic influences on the progression towards clinical gout. Elevated urate concentrations and exposure to different external factors precipitate gout flares, highlighting the potential involvement of epigenetic mechanisms in gouty inflammation. A better understanding of the alteration of the epigenetic landscape in gout may provide new perspectives on the dysregulated inflammatory response. In this review, we focus on understanding the current view of the role of epigenomic reprogramming in gout and the mechanistic pathways of action. Full article

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. Full article

Gouty arthritis (GA) is an inflammatory disease caused by monosodium urate (MSU) crystals deposited in the joint tissues causing severe pain. The disease can recur frequently and tends to form tophus in the joints. Current therapeutic drugs for the acute phase of GA have many side effects and limitations, are unable to prevent recurrent GA attacks and tophus formation, and overall efficacy is unsatisfactory. Therefore, we need to advance research on the microscopic mechanism of GA and seek safer and more effective drugs through relevant targets to block the GA disease process. Current research shows that the pathogenesis of GA is closely related to NLRP3 inflammation, oxidative stress, MAPK, NET, autophagy, and Ferroptosis. However, after synthesizing and sorting out the above mechanisms, it is found that the presence of ROS is throughout almost the entire spectrum of micro-mechanisms of the gout disease process, which combines multiple immune responses to form a large network diagram of complex and tight connections involved in the GA disease process. Current studies have shown that inflammation, oxidative stress, cell necrosis, and pathological signs of GA in GA joint tissues can be effectively suppressed by modulating ROS network-related targets. In this article, on the one hand, we investigated the generative mechanism of ROS network generation and its association with GA. On the other hand, we explored the potential of related targets for the treatment of gout and the prevention of tophus formation, which can provide effective reference ideas for the development of highly effective drugs for the treatment of GA. Full article

The accurate diagnosis of gout frequently constitutes a challenge in clinical practice, as it bears a close resemblance to other rheumatologic conditions. An undelayed diagnosis and an early therapeutic intervention using uric acid lowering therapy (ULT) is of the utmost importance for preventing bone destruction, the main point of managing gout patients. Advanced and less invasive imaging techniques are employed to diagnose the pathology and ultrasonography (US) stands out as a non-invasive, widely accessible and easily reproducible method with high patient acceptability, enabling the evaluation of the full clinical spectrum in gout. The 2023 EULAR recommendations for imaging in diagnosis and management of crystal-induced arthropathies in clinical practice state that US is a fundamental imagistic modality. The guidelines underline its effectiveness in detecting crystal deposition, particularly for identifying tophi and the double contour sign (DCS). Its utility also arises in the early stages, consequent to synovitis detection. US measures of monosodium urate (MSU) deposits are valuable indicators, sensitive to change consequent to even short-term administration of ULT treatment, and can be feasibly used both in current daily practice and clinical trials. This paper aimed to provide an overview of the main US features observed in gout patients with reference to standardized imaging guidelines, as well as the clinical applicability both for diagnosis accuracy and treatment follow-up. Our research focused on summarizing the current knowledge on the topic, highlighting key data that emphasize gout as one of the few rheumatological conditions where US is recognized as a fundamental diagnostic and monitoring tool, as reflected in the most recent classification criteria. Full article