Search Results (16)

Gout is strongly associated with atherosclerosis and other cardiovascular comorbidities. Furthermore, sites of extra-articular monosodium urate (MSU) crystal deposits in gout can include heart valves and atherosclerotic artery plaques, but with unclear effects therein. Hence, we seminally explored cultured vascular smooth muscle cell (VSMC) responsiveness to MSU crystals. To limit confounding effects, we cultured human aortic VSMCs under serum-free conditions to assess MSU crystal effects on VSMC differentiation and function, differentially expressed genes (DEGs) via RNA sequencing, and selected atherogenic changes in cytokines and the lipidome. MSU crystals induced p38 phosphorylation, IL-6, and VSMC vacuolization with dysregulated autophagy. MSU-crystal-induced DEGs included decreased late-stage autophagosome maturation mediator GABARAPL1, decreased physiologic VSMC differentiation regulators (LMOD1 and SYNPO2), increased ATF4, CHOP, and the intrinsic apoptosis signaling pathway in response to ER stress, and neointimal atherogenic nuclear receptors (NR4A1 and NR4A3). MSU crystals alone increased the levels of cholesterol biosynthetic intermediates 14-demethyl-lanosterol (14-DML), desmosterol, and zymosterol. Adding MSU crystals increased oxidized LDL’s capacity to increase intracellular 27-OH cholesterol, and MSU crystals and oxidized LDL synergistically induced a marked release of arachidonate. In conclusion, MSU crystals deposited in arterial media and neointima have the potential to dysregulate VSMC differentiation and proteostasis, and to induce further atherogenic effects, which include enhanced VSMC loading of oxidized cholesterol intermediates and release of IL-6 and arachidonic acid (AA). Full article

The eighth annual international G-CAN research symposium was held in Alexandria, VA on 21st and 22nd October 2022. This hybrid meeting, live face-to-face and virtual live symposium, was attended by over 150 participants. Over 20 research abstract submissions were received from early-career investigators, for plenary oral and poster presentations. Here, we present the accepted, lightly-edited abstracts from the presenters consenting to have their materials published. We thank and congratulate the presenters for their work and contributions to the meeting. Full article

Gout is intimately associated with cardiovascular disease—especially in cases of an atherosclerosis origin, but also with others such as heart failure, atrial fibrillation, or aortic valve stenosis. Besides the common presence of vascular comorbidities in gout sufferers, the disease is—in itself—an independent cardiovascular risk factor, with disease events and mortality attributable to having this condition. This review aims to update the current knowledge regarding several grey areas of the gout–cardiovascular disease spectrum—particularly in terms of risk variations across sex or ancestries, potential monosodium urate crystal deposition in the artery tree as a pathogenic pathway, the efforts undertaken to assess risk estimations in the gout population, and recent controversies surrounding the effects of gout therapies on cardiovascular disease. Full article

The analysis of metabolite mediators has allowed a broader understanding of disease mechanisms. Experimental evidence indicates that metabolic rewiring is a key feature of inflammatory cells to restore tissue homeostasis upon damage. Over the last two decades, next-generation sequencing techniques have offered the possibility of looking at the genome-wide effect of the exposure of inflammatory cells to external stimuli. During gout flares, monosodium urate crystals activate a distinct metabolic profile and inflammatory transcriptional program in inflammatory cells. The extracellular signals are transduced through distinct signalling pathways, which are regulated by non-coding RNA and DNA sequences, and modification of histones. During response to inflammatory stimuli, changes in the abundance of metabolic mediators can regulate the activation of histones and of chromatin remodellers. The interplay between metabolic changes by MSUc, the regulation of epigenetic changes and the activation of transcription factor networks in inflammatory cells remains unknown. A better understanding of the interplay between metabolites and how it alters inflammatory response may provide novel insights into disease mechanisms during gout. In this review, we aim to provide a deeper understanding of the current view of how metabolic deregulation could alter the epigenetic landscape of inflammatory cells during gout. Full article

Proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes, released into synovial fluid, and adsorbed on cartilage and synovial surfaces. PRG4′s roles include cartilage boundary lubrication, synovial homeostasis, immunomodulation, and suppression of inflammation. Gouty arthritis is mediated by monosodium urate (MSU) crystal phagocytosis by synovial macrophages, with NLRP3 inflammasome activation and IL-1β release. The phagocytic receptor CD44 mediates MSU crystal uptake by macrophages. By binding CD44, PRG4 limits MSU crystal uptake and downstream inflammation. PRG4/CD44 signaling is transduced by protein phosphatase 2A, which inhibits NF-κB, decreases xanthine oxidoreductase (XOR), urate production, and ROS-mediated IL-1β secretion. PRG4 also suppresses MSU crystal deposition in vitro. In contrast to PRG4, collagen type II (CII) alters MSU crystal morphology and promotes the macrophage uptake of MSU crystals. PRG4 deficiency, mediated by imbalance in PRG4-degrading phagocyte proteases and their inhibitors, was recently implicated in erosive gout, independent of hyperuricemia. Thus, dysregulated extracellular matrix homeostasis, including deficient PRG4 and increased CII release, may promote incident gout and progression to erosive tophaceous joint disease. PRG4 supplementation may offer a new therapeutic option for gout. Full article

The past year generated significant change and advancement of the urate field with novel insights regarding the role of uric acid (UA) in multiple pathophysiologic processes from gout to COVID-19. While these contributions continue to move the field forward, the basic biochemistry and biology of UA is often overlooked, being lost in the shadow of clinical associations and omics. However, the seminal impact of UA begins with biochemistry and the associated interplay with cell biology. In these basic reactions and resultant impacts on physiology, UA mediates its influence on clinical outcomes. As such, this review focuses on published advances in UA biochemistry and biology in 2022 and associates these advances with downstream consequences. Full article

Together with the substantial role of genetic factors, serum urate levels and the occurrence of gout are also heavily driven by environmental and clinical factors, including adiposity, dietary patterns, alcohol, kidney function, and diuretic medication use. These are, in turn, greatly influenced by the social determinants of health, which encompass access to health care, availability of healthy foods, and opportunities for physical activity but also education, income, social norms, and racism, among other forces. Gout-related health disparities have been described for Māori and Pacific people in New Zealand, but racial disparities in gout prevalence and outcomes between Black and White Americans have been under-recognised, and particularly, sex-specific data are scarce. In this article we review evidence from prior cohort studies and contemporary national-level data which show the incidence and prevalence of gout and hyperuricemia in Black adults in the US have come to exceed that in White adults and are disproportionately greater in Black women. Importantly, this emerging disparity can be attributed entirely to social determinants of health, including higher levels of adiposity and poverty in Black women compared to White women and lower kidney function and poorer quality diet among Black men compared to White men. Furthermore, Black patients with gout have received poorer quality gout-related care and experienced higher levels of healthcare use, especially Black women. While identifying targets for culturally safe interventions for addressing risk factor disparities is essential, evidence gaps remain about potential disparities in longer-term outcomes of gout, including cardio-metabolic-kidney endpoints and premature mortality. Sociodemographically diverse, population-based longitudinal cohort studies, research on implementation strategies for improved gout care delivery models for underserved groups, and efforts to minimise structural racism and its effects are key to achieving health equity in gout. Full article

(1) The Multi-Ethnic Study of Atherosclerosis (MESA) is a multi-center longitudinal cohort study designed to investigate the risk factors associated with the incidence of CVD. The purpose of this study is to examine the impact of gout on incident CVD. (2) Participants reporting the use of gout-specific medications (urate lowering drugs or colchicine) were compared with non-users. Kaplan–Meier survival curves and multivariable models to control for known CV risk factors evaluated hazard ratios (HR) between participants taking gout medications versus those not taking gout medications. (3) For the 6734 participants, analyses were stratified by gender owing to a gout-gender interaction. For the 164 male and 59 female participants taking gout medications, Kaplan–Meier (unadjusted) survival curves demonstrate that participants taking gout medications have higher rates of CVD than participants not taking gout medications, particularly for women. After controlling for known CV risk factors, the adjusted HR for female participants taking gout medications was 1.79 (0.99, 3.23), p = 0.05; the adjusted HR for male participants on gout medications was 1.20 (0.81, 1.77), p = 0.36; (4) Participants treated for gout in this study have many comorbid conditions with known CVD risk factors, making it difficult to confirm the independent effect of gout on CVD. There are a paucity of data on women with gout. These findings suggest that there is a clinically meaningful and potentially greater risk of CVD among women with gout as compared to men. Full article

Aggregates are one of the elementary lesions seen on musculoskeletal ultrasound (US) in gout patients as defined by Outcome Measures in Rheumatology (OMERACT). The aim of this study was to evaluate the threshold of detection of aggregate findings on ultrasound and to analyze these findings with corresponding compensated light microscope (CPLM) images in vitro. Patient derived monosodium urate (MSU) crystals were obtained from two separate patients with gout during routine clinical care. In addition, fabricated in-house synthetic MSU crystals were used for comparison. Each sample was scanned using a GE Logic ultrasound machine and corresponding CPLM images obtained. As the aggregates became imperceptible by ultrasound, MSU clumping by CPLM examination was no longer detectable and crystal density per high power field fell markedly. Aggregates on US images are present only from patient-derived samples likely representing MSU crystal clustering or packing. Thus, when synovial aspiration is considered, a joint with aggregates on US would be a more suitable target with a higher likelihood of noting MSU crystals. Full article

The detection and differentiation of BCP and CPP crystals in calcified tissue is an important factor in the context of research and potential future treatment of osteoarthritis and chondrocalcinosis. Current standard methods originate from clinical practice and often lack precision in the correct identification of the calcium crystal type. In this work, a step-by-step guide for the use of the high-resolution imaging methods of tissue sections, Raman spectroscopy and scanning electron microscopy (SEM) in combination with energy-dispersive X-ray spectroscopy (EDS), for calcium crystal identification is presented. Sample preparation including Von Kossa staining, measurement and measurement parameters, data processing and data analysis methods are discussed and described. Furthermore, the different methods are compared to show advantages and disadvantages. Overall, Raman spectroscopy is a reasonable method from an economic point of view and regarding the time/effort required for acquiring highly reliable data in calcium crystal identification. Potentially, semi-quantitative results can be obtained with little effort and without the destruction of the respective test sample. The analysis/penetration depth during the Raman measurements, which is not precisely defined, poses a potential problem for accuracy. SEM can also be used for this task but requires more time, advanced technical knowledge and a pre-treatment of the samples using, e.g., gold sputtering, which may distort further analysis on the specific specimen. Therefore, this technique yields additional value compared to Raman spectroscopy only with additional research questions needed to be answered in the same sample, such as analysis of the sample topography or analysis of other unknown particles/deposits using EDS. The methods described in this manuscript are helpful for retrospective analyses in the context of research, but can also be used for potential future treatment strategies to discriminate between osteoarthritis and chondrocalcinosis patients. Full article

Urate is one of the key metabolites of purine metabolism, and the overproduction of urate in the liver or decreased excretion in the kidney in humans may lead to elevated levels of urate in the circulation, termed hyperuricemia (HU). The formation of monosodium urate (MSU) crystals in the joint or surrounding tissues may trigger inflammatory responses and gout attacks, which is the most common inflammatory arthritis. In addition to gout, HU has also been associated with many other metabolic diseases, such as cardiovascular disease, obesity, diabetes, fatty liver diseases, kidney diseases, hypertension, and various cancers. Overwhelming evidence indicates that HU and gout lead to systematic metabolic alterations underlying these metabolic disorders. As one of the most powerful omics techniques, metabolomics systematically analyzes all small-molecule metabolites in a biological system that directly reflect the physiological and pathological conditions. In recent years, metabolomics has been increasingly employed in clinical and experimental research in HU and gout. Emerging studies have developed predictive models to differentiate HU from gout based on metabolomics and machine-learning algorithms. In this review, we systematically summarize recent advances in metabolomic research in gout and HU in animal and human clinical studies. A comprehensive understanding of systemic metabolic changes caused by HU and gout may provide unprecedented insights into the pathological mechanisms in HU, gout, and related metabolic diseases, which may have a profound impact on the prevention, diagnosis, and treatment of HU and gout. Full article

Gout is a prevalent and burdensome condition despite the advances in our knowledge of its underlying mechanisms, prevention, and treatment. There is still work to be done to elucidate relevant questions that could lead to better patient care. This conference report summarizes eight impactful publications which inform and improve clinical care in gout from October 2021 to October 2022. The articles we present here address innovative management approaches, the use of serum urate as a surrogate marker, the occurrence of complications such as cardiovascular events and lower extremity amputation, the evaluation of mortality in patients with chronic kidney disease and gout, the effect of intensive serum urate control on radiographic outcomes, and the impact of COVID-19 infection in patients with gout. The conclusions reached by these publications are noteworthy. Some of them are potentially practice-changing, and all provide exciting follow-up questions. Full article

This review re-examines the role of crystal deposition in the kidney in view of recent clinical and experimental findings. The involvement of the renal system in gout seems frequent. Indeed, recent studies showed that approximately 25% of patients with gout experience renal failure, defined by estimated glomerular filtration rate <60 mL/min/1.73 m². The pathophysiology is complex and involves several factors, their respective roles being difficult to dissect. The role of crystal deposition in the kidney was the first suspected, and the concept of gouty microcrystalline nephropathy, also called gouty nephropathy, has been popular, supported by early autopsy studies demonstrating uric acid and urate crystal deposition in the renal medulla of patients with gout, together with features of tubulointerstitial nephritis. Crystal deposition was first considered an important source of renal involvement in gout. After the introduction of urate-lowering drugs and the performance of kidney biopsies, which mainly involved the renal cortex and did not reveal much crystal deposition but rather vascular changes, this concept has been criticized and even dismissed. Thereafter, kidney involvement in gout was considered mainly vascular, related to hypertension and associated comorbidities and later to hyperuricemia. The toxic effects of non-steroidal anti-inflammatory drugs is also an important factor. Modern imaging, especially renal ultrasonography, allows for atraumatic exploration of the kidney and has revealed hyperechogenicity of the renal medulla, suggesting crystalline deposits, in approximately one-third of patients with tophaceous gout. Experimental models of gouty nephropathy have recently demonstrated the pathogenic role of microcrystal deposition in the collecting ducts and parenchyma of the renal medulla. Taken together, these recent findings lead to the re-examination of the pathogenic role of crystal deposition in the renal medulla and testing the effect of urate-lowering drugs on renal features of gouty patients with evidence of renal crystal deposition. Full article

Background: Despite colchicine’s proven efficacy in the non-gout population, the effects of colchicine on the risk of major adverse cardiovascular events (MACE) among high-risk patients with gout remain to be determined. The purpose of this study is to evaluate the association between colchicine use and MACE in gout patients with preexisting coronary artery disease (CAD). Methods: This retrospective cohort study followed patients with gout and established CAD within the VA New York Harbor Healthcare System who did or did not use colchicine regularly (>30 continuous days prescription with at least 1 refill). The primary outcome was first MACE, defined as a composite of non-fatal myocardial infarction, coronary artery bypass graft, non-fatal stroke, and all-cause mortality. Part I of the primary analysis compared MACE between colchicine users and nonusers. Part II of the study compared MACE within the colchicine-use group, divided into quartiles based on consistency of colchicine use (i.e., percentage of time on colchicine). Results: Among 1638 patients with gout, 355 had established CAD (239 colchicine users and 116 nonusers). In this cohort, the odds of MACE were similar between any colchicine use compared to nonuse (OR 1.14; 95% CI (0.59–2.20)); however, colchicine users overall had a higher baseline cardiovascular risk profile than nonusers, suggesting that colchicine may have served to equilibrate risk between the two groups. Moreover, patients in the highest continuous colchicine-use quartile (>70% of observation period on colchicine) demonstrated lower odds of MACE compared to those in the lowest three quartiles (OR 0.35; 95% CI (0.13–0.93)), with no difference in baseline risk. Additionally, colchicine users had a numerically lower rate of MACE during periods of active use compared with periods of lapse. Kaplan–Meier analysis revealed a difference in cumulative MACE over time, favoring the subgroup with the most consistent colchicine use (p_log-rank = 0.01). Conclusions: Despite higher CV risk, gout patients with CAD receiving colchicine had no higher rates of MACE than those not receiving colchicine. Among all patients with gout and CAD treated with colchicine, those with the most consistent colchicine use had lower odds of MACE, and event rates were lower during active use. Colchicine protection against cardiovascular events may require maintenance of colchicine bloodstream levels. Full article