Search Results (50)

Genetic association studies in gout have identified genetic variants in or near genes involved in the biosynthesis and transport of urate and in immunological pathways. However, the causal role of the remaining genetic variants, genes, and pathways in gout is not clear. Here, we present the results from a genetic colocalization analysis of gout-associated signals with metabolite quantitative trait loci (mQTL), shedding light on the metabolites that are likely directly affected by genetic variants associated with gout. We identified 141 candidate metabolites with evidence of colocalization with at least one gout-associated genetic signal, of which 29 showed evidence of a causal relationship with gout by Mendelian randomization. Among the 29 metabolites were lysophosphatidylcholines, which may affect the inflammatory response by binding to the TLR-2/4 receptors, providing plausible candidate metabolites for future studies that link metabolites with inflammatory processes in gout. Full article

Calcium pyrophosphate deposition disease (CPPD) has been shown to be associated with inflammatory arthritis such as rheumatoid arthritis. However, few studies have investigated the correlation between CPPD and psoriatic arthritis (PsA). Our study aimed to determine whether there were higher rates of PsA in patients with CPPD than controls. A retrospective cohort study was conducted using the Veterans Affairs’ Corporate Data Warehouse. Individuals with a CPPD ICD code were matched with controls and diagnoses of PsA and psoriasis were collected. A total of 41,084 CPPD patients were matched with 119,192 controls. The proportion of CPPD patients with PsA diagnosis was more than double that of controls (1.07% vs. 0.37%; p < 0.0001), and more CPPD patients were diagnosed with psoriasis (3.05% vs. 2.52%; p < 0.0001). Those with CPPD had higher odds of a PsA diagnosis (OR 3.550, 95% CI 2.602–4.844). A total of 61.59% of PsA diagnoses preceded the CPPD diagnoses by at least one year. This is the first case–control study demonstrating an association between CPPD and PsA, potentially related to the fact that both PsA and CPPD could be triggered by trauma, and are closely associated with osteoarthritis. It also is possible that inflammatory pathways contribute to CPP crystal deposition in joints. Full article

This review examines the concept of “psout”, an overlap syndrome of hyperuricemic psoriatic arthritis (HU-PsA) and co-existing gout and PsA. The manuscript explores its epidemiology, pathophysiology, clinical implications, and treatment strategies, focusing on emerging data since its first description in 2020. The psout concept is sustained by shared inflammatory and metabolic pathways between gout and PsA, contributing to a broad spectrum of phenotypes and moderate-to-severe clinical manifestations. Monosodium urate crystals and hyperuricemia are central to this overlap, influencing cytokine production, keratinocyte activation, and immune responses, being able to activate both innate and acquired immunity. Clinical management is complex due to diagnostic challenges and therapeutic considerations not yet implemented in international recommendations. Emerging data from clinical trials underscore the significance of hyperuricemia in worsening PsA outcomes while highlighting the potential of personalized treatments. Future research into shared pathophysiological mechanisms, the accurate description of the diversity of phenotypes, innovative imaging assessments, and therapeutic strategies could provide insights into the interplay of these two conditions and enhance patient outcomes. Full article

Gout management strategies remain a topic of debate, particularly regarding the efficacy of treat-to-target (T2T) and treat-to-avoid-symptoms (T2S) approaches. T2T, endorsed by major rheumatology societies, involves systematic serum urate (sUA) monitoring and urate-lowering therapy (ULT) dose escalation to maintain sUA below a predefined threshold. In contrast, T2S, which focuses on symptom relief rather than routine sUA monitoring, is supported by alternative guidelines. Despite the widespread adoption of T2T in other chronic diseases, its clinical benefits beyond biochemical parameters, such as serum urate reduction, remain uncertain in gout. This study evaluates current evidence on T2T and T2S, analyzing data from a pragmatic multicenter trial comparing both strategies. Findings suggest that while T2T is effective in reducing sUA levels, its superiority in preventing flares and improving patient-reported outcomes remains inconclusive. Some studies report reduced tophus burden and better adherence with T2T, whereas others find negligible differences in pain relief and functional improvement between the two strategies. The lack of high-quality comparative trials underscores the need for further investigation. Future research should prioritize long-term, patient-centered outcomes and pragmatic implementation strategies. Full article

Lifelong urate-lowering therapy (ULT) is recommended for gout to prevent flares and urate deposition. However, concerns about its adherence, long-term side effects, and the necessity of continuous treatment after achieving remission raise critical questions. Two randomised controlled trials (RCTs), GO TEST Finale and STING, aim to evaluate the safety and feasibility of ULT discontinuation in gout patients in remission. The GO TEST Finale is a superiority trial involving 310 patients in the Netherlands, comparing a treat-to-target (T2T) ULT continuation strategy with ULT discontinuation. Patients in the discontinuation arm resume ULT only after flare recurrence or tophi development. The primary outcomes focus on remission criteria failure over 24 months, while the secondary outcomes explore predictors of successful discontinuation and cost-effectiveness. The STING study, a non-inferiority trial in France, includes 450 patients without ultrasound (US) evidence of urate deposits. Patients in the discontinuation group resume ULT if a US detects urate deposition during follow-up, minimising flare risk. The primary outcomes measure the proportion of patients experiencing flares at two years, with the secondary outcomes examining the long-term health impacts and cost-effectiveness. These trials provide an opportunity for translational research into the immunological and epigenetic effects of rising serum urate levels. The results could inform personalised strategies for a drug-free period and address the critical question of whether lifelong ULT is necessary for gout management. The complementary findings from both trials are expected to contribute significantly to resolving this ongoing clinical debate. Full article

Gout is a common inflammatory joint disease in China. In recent years, the prevalence of gout in China has been increasing and the onset age of gout has been trending younger. The common risk factors for gout in China include hyperuricemia, age, sex, obesity, hypertension, metabolic syndrome, use of drugs (e.g., diuretics), dietary factors, chronic kidney disease (CKD), ethnicity, and income. Chinese clinical guidelines recommend the diagnosis of subclinical gout, refractory gout, and clinical classification of hyperuricemia in gout patients with early-onset or family history. Maintaining a consistently low level of serum urate is crucial for the effective long-term treatment of gout. However, the Chinese guidelines recommend paying special attention to allopurinol hypersensitivity when considering urate-lowering drugs. The adherence rate to urate-lowering therapy (ULT) in Chinese patients with gout ranges from 9.6% to 40.7%. Patient education and reducing drug side effects are effective approaches to improve the adherence to ULT and the rate of achieving the target urate level. The development of new treatment principles based on clinical trials, such as ULT based on the classification of hyperuricemia and urine alkalization, is recommended to improve patient outcomes and reduce potential side effects. The study of genetics, metabolites, and intestinal microbiota has yielded new findings that may aid in the diagnosis, classification, and pathogenesis of gout in China. Full article

Gout is the most common inflammatory arthritis, with a growing global disease burden. This conference report summarizes nine impactful publications dating from 11/2022 to 10/2023 to inform and improve clinical care in gout. The articles we present here collectively address diverse facets of gout research, including gout epidemiology, predictive biomarkers, the occurrence of complications relating to gout flares, and gout management strategies. Full article

We assessed changes in vascular inflammation and monosodium urate (MSU)-coded deposits after administration of Pegloticase in the vasculature of tophaceous gout patients using ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) Positron emission tomography/computed tomography (PET/CT) and dual-energy CT (DECT). Ten patients with tophaceous gout, intolerant or refractory to urate-lowering therapy (ULT), were treated with Pegloticase every two weeks for six months. ¹⁸F-FDG PET/CT and DECT were performed at baseline and after Pegloticase therapy to detect vessel wall inflammation (Standard uptake value, SUVmean, and SUVmax) and vascular MSU-coded deposition (MSU volume). Data were summarized using means and standard deviations. Baseline and follow-up values were compared for each variable using mixed-effect models. Significant decreases in SUVmean (p = 0.0003) and SUVmax (p = 0.009) were found with a trend towards a decrease in vessel wall MSU volume after treatment. There was a significant decrease in serum urate, correlating with reduction in SUVmean (R² = 0.65), with a trend towards a decrease in CRP and blood pressure in all patients. Despite the small sample size, we were able to demonstrate a decrease in vessel wall inflammation and a trend towards a decrease in MSU volume by intensively lowering serum urate. These findings suggest that MSU-coded deposits and hyperuricemia may play a role in vascular wall inflammation. It remains to be seen whether this correlates with a decrease in adverse cardiovascular outcomes. 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

15th Anniversary this year: the ECN workshop is set up in Paris, down town. Every year ECN workshop offers a unique opportunity for clinicians and researchers interested in crystals, inflammation, crystal-induced diseases including gout, to present their latest results and discuss novel concepts. Twenty nine out of 52 accepted abstracts are reported here. Full article

Periarticular calcifications are a common condition for rheumatologists. They are characterized by deposition of carbonated apatite in tendons or connective tissues around joints. It most commonly affects patients between 30 and 60, and the main location is the shoulder (rotator cuff tendons), followed by the hip. Although the disease is frequent, factors associated with the appearance of the deposits or their spontaneous resorption remain unclear. In this review, we will summarize the available data about mechanisms underlying the constitution of the deposits and their resorption and describe the various affected sites and the associated symptoms. In the last part, we will discuss current treatment options. Full article

Many preclinical reports have coalesced to identify a strong association between obesity and increased levels of uric acid (UA) in tissues and, importantly, in the circulation (hyperuricemia). Unfortunately, nearly all these studies were conducted with male mice or, in one case, female mice without a side-by-side male cohort. Therefore, the relationship between obesity and hyperuricemia in female mice remains undefined. This lack of clarity in the field has considerable impact as the downstream effects of obesity and allied hyperuricemia are extensive, resulting in many comorbidities including cardiovascular dysfunction, chronic kidney disease, and nonalcoholic fatty liver disease (NAFLD). Herein we begin to address this issue by revealing phenotypic and metabolic responses to diet-induced obesity (DIO) in a side-by-side male vs. female C57BL/6J study. Beginning at 6 weeks of age, mice were exposed to either an obesogenic diet (60% calories from fat) or control diet (10% calories from fat) for 19 weeks. Similar to numerous reported observations with the 60% diet, male mice experienced significant weight gain over time, elevated fasting blood glucose, impaired glucose tolerance and significantly elevated circulating uric acid levels (2.54 ± 0.33 mg/dL) compared to age-matched lean male controls (1.53 ± 0.19 mg/dL). As expected, the female mice experienced a slower rate of weight gain compared to the males; however, they also developed elevated fasting blood glucose and impaired glucose tolerance compared to age-matched lean controls. Countervailing our previous report whereby the control diet for the female-only study was vivarium standard chow (18% calories from fat), the obese female mice did demonstrate significantly elevated circulating UA levels (2.55 ± 0.15 mg/dL) compared to the proper control (1.68 ± 0.12 mg/dL). This affirms that the choice of control diet is crucial for reaching durable conclusions. In toto, these results, for the first time, reveal elevated circulating UA to be a similar long-term response to obesogenic feeding for both males and females and mirrors clinical observations demonstrating hyperuricemia in obesity for both sexes. Full article

Calcification refers to the deposition of calcium-containing crystals either intracellularly or within the extracellular matrix. Physiologic calcification is a normal process occurring during bone and tooth development and growth. In contrast, pathologic calcification occurs in soft tissues that typically do not undergo mineralization, such as blood vessels, cartilage, tendons, and skin. Pathological calcification is significantly associated with tissue impairment and the development of secondary diseases, such as atherosclerosis, osteoarthritis, tendinopathy, and skin ulcers. Aging, a natural process linked to numerous pathologic conditions, is one of the most recognized risk factors for pathological calcification. In this manuscript, we review the current state of knowledge regarding the role of aging in calcification across different tissues. We focus on the mechanisms activated during normal aging, including cellular senescence, decreased pyrophosphate levels, increased secretion of extracellular vesicles, elevated oxidative stress, and higher levels of pro-mineralizing cytokines, all of which can contribute to pathological calcification. Finally, we discuss the available animal models used to study the impact of aging on calcification. Full article

Gout is a prevalent form of inflammatory arthritis caused by the crystallization of uric acid in the joints and soft tissues, leading to acute, painful attacks. Activation of the NLRP3 inflammasome in mononuclear cells, along with inflammasome-independent pathways, is responsible for the inflammatory phenotype in gout. Research into the different aspects of gout pathophysiology and potential treatment options is ongoing. This review highlights some of the basic research published in the 12 months following the 2022 Gout, Hyperuricemia, and Crystal-Associated Disease Network (G-CAN) conference and focuses on mechanisms of inflammation, encompassing pro- and anti-inflammatory pathways, as well as the exploration of various biological systems, such as single-cell transcriptomics, proteomics, metabolomics, and microbiome analyses. Full article