Gout, Urate, and Crystal Deposition Disease

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

Uric acid is the final purine metabolite in humans. Serum urate levels are regulated by a balance between urate production, mainly in the liver, and its excretion via the kidneys and small intestine. Given that uric acid exists as a urate anion at physiological pH 7.4, membrane transporters are required to regulate urate homeostasis. In the kidney, urate transporter 1, glucose transporter 9, and organic anion transporter 10 contribute to urate reabsorption, whereas sodium-dependent phosphate transport protein 1 would be involved in urate excretion. Other transporters have been suggested to be involved in urate handling in the kidney; however, further evidence is required in humans. ATP-binding cassette transporter G2 (ABCG2) is another urate transporter, and its physiological role as a urate exporter is highly demonstrated in the intestine. In addition to urate, ABCG2 regulates the behavior of endogenous substances and drugs; therefore, the functional inhibition of ABCG2 has physiological and pharmacological effects. Although these transporters explain a large part of the urate regulation system, they are not sufficient for understanding the whole picture of urate homeostasis. Therefore, numerous studies have been conducted to find novel urate transporters. This review provides the latest evidence of urate transporters from pathophysiological and clinical pharmacological perspectives. Full article

The ninth annual international G-CAN research symposium was held in La Jolla, CA on the 7th and 8th of November 2023. This hybrid meeting, a live face-to-face and virtual live symposium, was attended by 191 participants. Over 20 research abstract submissions were received from early-career investigators, for plenary oral and poster presentations. Here, we present the 20 accepted, lightly edited abstracts from the early-career presenters consenting to have their materials published. We thank and congratulate the presenters for their work and contributions to the meeting. Full article

A relationship between metabolic disorders and hyperuricemia is well established. The nature of the relationship—risk factor, causal agent, or byproduct—remains unclear. Recent studies of sodium–glucose transporter 2 inhibitors (SGLT2i’s) have established that this pharmacological intervention is beneficial to patients with hyperglycemia and type 2 diabetes mellitus (T2D) and also against the common cardio and renal comorbidities associated with diabetes. Hyperuricemia, or high plasma uric acid levels, is one of the comorbidities mitigated with SGLT2i treatment, raising the potential for using SGLT2i’s as part of the treatment for gout and hyperuricemia. However, the mechanisms underlying the lower plasma urate levels and increased uricosuria produced with SGLT2i’s remains poorly understood. Here, we review the renal physiology of glucose and uric acid transport, the renal consequences of hyperglycosuria and diabetes, the benefits and physiology of SGLT2i use, and discuss several potential mechanisms that may be responsible for the favorable uricosuric effect observed in those treated with SGLT2i’s. Full article

Population-based databases in Nordic countries offer unique opportunities for large-scale population-based epidemiological studies. The personal identity number enables researchers to link different registers at the individual level, which can be used for large-scale epidemiological population-based studies. This review outlines how these opportunities have been used so far in the field of gout research, as well as the potential challenges and limitations. Their major advantage is that they cover the entire population, minimizing problems such as selection bias and loss to follow-up. This has enabled us to provide information on gout regarding risk factors; occurrence; association with comorbidities in relation to gout onset; treatment patterns; as well as its effect on other outcomes, such as sick leave and mortality. Validity issues, missing data, and legal issues are some of the challenges that researchers need to deal with. Choosing the most appropriate combination of databases to use for a specific question is crucial in order to maximize validity and adjust for confounders. Despite challenges and potential limitations, the Swedish registers have provided valuable epidemiological results and will continue to play an important role in the years to come. Full article

Gout, an inflammatory disease orchestrated by interleukin-1β activation and release, is more prevalent in men. The clinical profiles of patients with gout report differences by sex. This study aims to investigate sex-specific cytokine profiles in circulation and in stimulated peripheral blood mononuclear cells (PBMCs) of patients with gout and controls. Participants included in the gout group met the criteria of the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR). The control group included individuals with varying levels of serum urate and absence of gout. PBMCs were stimulated in vitro for 24 h with various TLR ligands. Cytokines were determined in culture supernatants and plasma. Plasma IL-1Ra and high-sensitivity C-reactive protein (hsCRP) were higher in men with gout compared to men without gout whereas no significant differences in circulating cytokines were observed in women. PBMCs of patients with gout showed higher cytokine production of IL-1β, IL-1Ra, and TNF-α following 24 h stimulation, predominantly observed in women. We identified sex-specific cytokine production in gout in response to in vitro stimulation. While men with gout had higher levels of circulating cytokines, stimulated PBMCs of women with gout show an enhanced capacity for cytokine production. These data may suggest potentially different regulatory mechanisms of inflammation in men and women with gout. Full article

Gout flares more frequently start late at night or in the early morning compared to during the day. The reasons for this are unknown. Activation of the NLRP3 inflammasome in monocytes/macrophages is central to initiation of gout flares. Here, we review the mechanisms by which circadian clocks control the NLRP3 inflammasome and the implications of this for the nighttime pattern of gout flares. Several hormones involved in inflammation regulation, e.g., glucocorticoids, melatonin and melanocortins, are under circadian control, with both circulating hormone levels as well as the expression of their receptors on target tissues showing time-of day differences. In addition, the NLRP3 inflammasome is also under the control of the macrophage circadian clock, leading to time-of-day differences in expression of NLRP3 inflammasome components and susceptibility to inflammasome-activating stimuli. MSU crystal exposure leads to altered expression of circadian clock components in macrophages, leading to time-of-day-specific loss of repression of NLRP3 inflammasome activity. Taken together, there is clear evidence that circadian clocks regulate the NLRP3 inflammasome and that this regulation may be compromised by MSU crystal exposure in gout. Circadian control of the inflammasome may be one of the factors contributing to nighttime susceptibility to gout flares. Full article

Calcium-containing crystal deposition diseases are extremely common in rheumatology. However, they are under-explored compared to gout or other inflammatory rheumatic diseases. Major advances have been made in 2023 that will undoubtedly stimulate and facilitate research in the field of calcium pyrophosphate (CPP) deposition disease (CPPD): the ACR/EULAR classification criteria for CPPD and a semi-quantitative OMERACT score for ultrasound assessment of the extent of CPP deposition have been validated and published. A large randomized controlled trial compared the efficacy and safety of colchicine and prednisone in acute CPP arthritis. Preclinical studies have elucidated the pro-inflammatory and anti-catabolic effects of basic calcium phosphate (BCP) crystals on mononuclear cells and chondrocytes. The association between osteoarthritis (OA) and IA calcifications has been the subject of several epidemiological publications, suggesting that calcium crystals are associated with a greater risk of progression of knee OA. Research in the field of calcium crystal deposition diseases is active: the areas of investigation for the coming years are broad and promising. Full article

The use of ultrasonography (US) has considerable potential for the diagnosis and monitoring of gout due to its capacity to detect monosodium urate deposits. In the last decade, a critical amount of scientific data has become available. Consensus-based definitions for ultrasonographic elementary lesions in gout have been developed, tested, and validated, as well as a semiquantitative scoring system for their quantification. Many scanning protocols have been proposed in different clinical scenarios. In this review, we formulate a set of practical suggestions for the use of the US in daily practice. We discuss the current knowledge to indicate which joints and structures are to be scanned and which elementary findings are to be evaluated according to the clinical scenario. While for some clinical settings, a quite definite scanning protocol can be indicated, others still need to be further investigated, and how to obtain the best out of the US is still entrusted to the individual experience. Full article

Gout patients have higher mortality, heavier comorbidity burden, and lower quality of life than non-gout patients, but information is sparse on how gout affects advanced CKD patients. This study examined the prevalence and potential health impacts in stage 3–5 CKD patients. Gout was defined as being listed as a comorbidity, ULT use, and/or reported gout symptoms (tophi, >1 flare). Uncontrolled gout was defined as hyperuricemia (serum urate >6 mg/dL) with tophi, ≥2 gout flares/year, or ≥1 swollen/tender joint. This study included 746 patients (55% men, age: 56.2 ± 18.3 years, CKD-duration: 4.0 ± 4.8 years, eGFR: 32.2 ± 15.5 mL/min/1.73 m²), of which 23% met the gout criteria. Prevalence was highest in patients with stage 3b and 4 CKD. Gout patients had a significantly higher prevalence of cardiovascular comorbidities, CKD-mineral bone disorder, and back pain than non-gout patients. Uncontrolled gout patients had more hypertension, joint issues, chronic pain, febuxostat use, and colchicine use than controlled patients. Compared to those without gout, gout patients had higher rates of cardiovascular and bone diseases, with uncontrolled patients having an even higher burden. In conclusion, these data suggest that identifying and monitoring gout in CKD patients provides health benefits. However, more than one-third of gout patients did not have a formal gout diagnosis in their medical record. Full article

In gout research, serum urate has been widely accepted as the primary endpoint in clinical trials of urate-lowering therapies by both the FDA and EMA for many years. However, for serum urate to be a meaningful outcome measure, it should reflect at least one important patient-centered clinical outcome, such as gout flares. The relationship between achieving a pre-specified “target” serum urate and a corresponding improvement in patient-centered outcomes has been difficult to show due to variation in reporting of both serum urate and gout flares in clinical trials; a paradoxical rise in gout flares after starting urate-lowering therapy and a delay after achieving the pre-specified target serum urate before gout flares settle coupled with the relatively short duration of the trials. However, recent evidence from individual-level patient data from two, two-year randomized controlled trials clearly shows that achieving target urate is associated with a subsequent reduction and cessation of gout flares. In this review, we examine the evidence supporting serum urate as a surrogate outcome for gout flares, the methods, and the challenges of showing the validity of surrogacy. Full article

The 14th annual international European Crystal Network was held in Paris on 2 and 3 March 2023. This in-person meeting was attended by 93 participants. Over 40 research abstract submissions were received from investigators, ranging from early career investigators to senior researchers, for plenary oral and poster presentations. Here, we present the accepted, lightly edited abstracts from the presenters consenting to have their work published. We thank and congratulate the presenters for their work and contributions to the meeting. Full article