GPR105-Targeted Therapy Promotes Gout Resolution as a Switch Between NETosis and Apoptosis of Neutrophils.

The fate of infiltrating neutrophils in inflamed joints determines the development of acute gouty arthritis (AGA). GPR105 highly expressed in human neutrophils is sensitive to monosodium urate crystals (MSU); nevertheless, the roles of GPR105 in AGA remain unclear. Here, we show that GPR105 is significantly upregulated in peripheral polymorphonuclear neutrophils of AGA patients. GPR105 knockout (GPR105-/-) prevented NETosis and induced apoptosis of neutrophils under MSU exposure, as well as attenuating inflammatory cascades in AGA. Mechanistically, GPR105 deletion activated cAMP-PKA signals, thereby disrupting Raf-Mek1/2-Erk1/2 pathway-mediated NADPH oxidase activation, contributing to inhibition of NETosis. Whereas, cAMP-PKA activation resulting in GPR105 deficiency modulated PI3K-Akt pathway to regulate apoptosis. More importantly, suppression of cAMP-PKA pathway by SQ22536 and H-89 restored NETosis instead of apoptosis in GPR105-/- neutrophils, promoting MSU-induced gout flares. Interestingly, lobetyolin was screened out as a potent GPR105 antagonist using molecular docking-based virtual screening and in vitro activity test, which efficiently attenuated MSU-induced inflammatory response interacting with GPR105. Taken together, our study implicated that modulating cell death patterns between NETosis and apoptosis through targeting GPR105 could be a potential therapeutic strategy for the treatment of AGA.

Purinergic Signaling in the Regulation of Gout Flare and Resolution.

Gout flares require monosodium urate (MSU) to activate the NLRP3 inflammasome and secrete sufficient IL-1ß. However, MSU alone is not sufficient to cause a flare. This is supported by the evidence that most patients with hyperuricemia do not develop gout throughout their lives. Recent studies have shown that, besides MSU, various purine metabolites, including adenosine triphosphate, adenosine diphosphate, and adenosine bind to different purine receptors for regulating IL-1ß secretion implicated in the pathogenesis of gout flares. Purine metabolites such as adenosine triphosphate mainly activate the NLRP3 inflammasome through P2X ion channel receptors, which stimulates IL-1ß secretion and induces gout flares, while some purine metabolites such as adenosine diphosphate and adenosine mainly act on the G protein-coupled receptors exerting pro-inflammatory or anti-inflammatory effects to regulate the onset and resolution of a gout flare. Given that the purine signaling pathway exerts different regulatory effects on inflammation and that, during the inflammatory process of a gout flare, an altered expression of purine metabolites and their receptors was observed in response to the changes in the internal environment. Thus, the purine signaling pathway is involved in regulating gout flare and resolution. This study was conducted to review and elucidate the role of various purine metabolites and purinergic receptors during the process.

Pleiotropic Effects of Functional MUC1 Variants on Cardiometabolic, Renal, and Hematological Traits in the Taiwanese Population.

MUC1 is a transmembrane mucin involved in carcinogenesis and cell signaling. Functional MUC1 variants are associated with multiple metabolic and biochemical traits. This study investigated the association of functional MUC1 variants with MUC1 DNA methylation and various metabolic, biochemical, and hematological parameters. In total, 80,728 participants from the Taiwan Biobank were enrolled for association analysis using functional MUC1 variants and a nearby gene regional plot association study. A subgroup of 1686 participants was recruited for MUC1 DNA methylation analysis. After Bonferroni correction, we found that two MUC1 variants, rs4072037 and rs12411216, were significantly associated with waist circumference, systolic blood pressure, hemoglobin A1C, renal functional parameters (blood urea nitrogen, serum creatinine levels, and estimated glomerular filtration rate), albuminuria, hematocrit, hemoglobin, red blood cell count, serum uric acid level, and gout risk, with both favorable and unfavorable effects. Causal inference analysis revealed that the association between the variants and gout was partially dependent on the serum uric acid level. Both gene variants showed genome-wide significant associations with MUC1 gene-body methylation. Regional plot association analysis further revealed lead single-nucleotide polymorphisms situated at the nearby TRIM46-MUC1-THBS3-MTX1 gene region for the studied phenotypes. In conclusion, our data demonstrated the pleiotropic effects of MUC1 variants with novel associations for gout, red blood cell parameters, and MUC1 DNA methylation. These results provide further evidence in understanding the critical role of TRIM46-MUC1-THBS3-MTX1 gene region variants in the pathogenesis of cardiometabolic, renal, and hematological disorders.

Decrease in Serum Urate Level Is Associated With Loss of Visceral Fat in Male Gout Patients.

Objective: To clarify the relationship between serum urate (SU) decrease and visceral fat area (VFA) reduction in patients with gout. Methods: We retrospectively analyzed 237 male gout patients who had two sets of body composition and metabolic measurements within 6 months. Subjects included had all been treated with urate-lowering therapy (ULT) (febuxostat 20-80 mg/day or benzbromarone 25-50 mg/day, validated by the medical record). All patients were from the specialty gout clinic of The Affiliated Hospital of Qingdao University. The multiple linear regression model evaluated the relationship between change in SU [ΔSU, (baseline SU) - (final visit SU)] and change in VFA [ΔVFA, (baseline VFA) - (final visit VFA)]. Results: ULT resulted in a mean (standard deviation) decrease in SU level (464.22 ± 110.21 µmol/L at baseline, 360.93 ± 91.66 µmol/L at the final visit, p <0.001) accompanied by a decrease in median (interquartile range) VFA [97.30 (81.15-118.55) at baseline, 90.90 (75.85-110.05) at the final visit, p < 0.001]. By multiple regression model, ΔSU was identified to be a significant determinant variable of decrease in VFA (beta, 0.302; p = 0.001). Conclusions: The decrease in SU level is positively associated with reduced VFA. This finding provides a rationale for clinical trials to affirm whether ULT promotes loss of visceral fat in patients with gout.

Correlation of Serum Cystatin C with Renal Function in Gout Patients with Renal Injury.

The gout-induced continuous deposition of urate in the kidney tissues is the main cause of renal injury, for which cystatin C (Cys C) is an important indicator. This research analyzed the correlation between general renal injury indicators and serum Cys C level, and further investigated the potential of Cys C in renal injury diagnosis. A total of 140 gout patients with renal injury (GRI) were recruited and grouped by their glomerular filtration rate (GFR). Urea nitrogen, uric acid, creatinine, and Cys C levels in the serum were evaluated. The diagnostic efficacy of serum Cys C was evaluated by the nonparametric receiver operating characteristic analysis. Serum Cys C level was increased with decreased GFR in GRI. Urea nitrogen, uric acid, and creatinine levels in the serum showed positive correlations with Cys C level. The area under the curve for serum Cys C was 0.8589 (P < 0.001). In conclusion, this research demonstrated that the serum Cys C level was a precise diagnostic marker for GFR and renal damage evaluation, and showed a significant diagnostic value for renal injury in patients with gout.

Gout-induced endothelial impairment: The role of SREBP2 transactivation of YAP.

Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA- or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The SREBP2 knockdown by siRNA partially abolished UA- or MSU-induced YAP activity, pro-inflammatory gene expression, and monocytes adhesion. Vascular intima from transgenic mice overexpressing SREBP2 in endothelium or mice with hyperuricemia exhibited activated YAP signaling and increased expression of pro-inflammatory genes. Betulin, an SREBP pharmacological inhibitor, attenuated the UA-, MSU-, or gout serum-induced endothelial cell inflammation and dysfunction. In the human study, endothelial cell function, assessed by EndoPAT, was negatively correlated with serum UA level among gouty patients and healthy controls. Collectively, UA or MSU causes endothelial dysfunction via SREBP2 transactivation of YAP. Betulin inhibition of SREBP2 may restrain gout-induced endothelial dysfunction.

Presence of tophi is associated with a rapid decline in the renal function in patients with gout.

We aimed to compare clinical characteristics of patients with and without tophi at the time of the diagnosis of gout and investigate the association of tophi and renal function in gout patients. The patients who were first diagnosed with gout at the Kangwon National University Hospital were retrospectively studied. Patients were divided into 2 groups according to the presence of tophi at the diagnosis. We compared clinical characteristics and the progression of renal dysfunction between the two groups. Of 276 patients, 66 (25.5%) initially presented with tophi. Tophi group was older, had a longer symptom duration, and a higher prevalence of multiple joint involvement than those without tophi. In multivariate logistic regression analysis, prolonged symptom duration and multiple joint involvement were significantly associated with increased risk of formation of tophi. The decline in the eGFR was more prominent in patients with tophi than in those without (- 4.8 ± 14.5 vs. - 0.7 ± 11.9 ml/min/1.73 m2/year, respectively; P = 0.039). The presence of tophi was significantly associated with a rapid decline in the eGFR (ß = - 0.136; P = 0.042). In conclusion, the presence of tophi was associated with a rapid declining renal function. Therefore, an early diagnosis and closely monitoring of renal function might be important in gout patients with tophi.

Management and Cure of Gouty Arthritis.

Gout is the most common inflammatory arthritis in the United States. Gouty arthritis is associated with significant morbidity and mortality and is caused by hyperuricemia. Gout is effectively managed and potentially cured by decreasing the overall urate burden with serum urate-lowering therapy. When serum urate is maintained at less than 6.0 mg/dL urate deposition is resolved and gout can be cured. Unfortunately, owing to a lack of physician monitoring and dose escalation the majority of patients do not achieve these urate levels.

Gout: Rapid Evidence Review.

Gout is caused by monosodium urate crystal deposition in joints and tissues. Risk factors include male sex; obesity; hypertension; alcohol intake; diuretic use; a diet rich in meat and seafood; chronic kidney disease; a diet heavy in fructose-rich food and beverages; being a member of certain ethnic groups, including Taiwanese, Pacific Islander, and New Zealand Maori; and living in high-income countries. Gout is characterized by swelling, pain, or tenderness in a peripheral joint or bursa, including the development of a tophus. Diagnosis of gout can be made using several validated clinical prediction rules. Arthrocentesis should be performed when suspicion for an underlying septic joint is present; synovial fluid or tophus analysis should be performed if the diagnosis is uncertain. Colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids relieve pain in adults with acute gout episodes. Indications for long-term urate-lowering therapy include chronic kidney disease, two or more flare-ups per year, urolithiasis, the presence of tophus, chronic gouty arthritis, and joint damage. Allopurinol and febuxostat are used to prevent flare-ups, although febuxostat is associated with an increase in all-cause and cardiovascular mortality and is therefore not routinely recommended.

Uric acid fluctuation had no effect on renal function among gout patients.

BACKGROUND AND AIMS: To investigate the effects of serum uric acid (SUA) level and its fluctuation on renal dysfunction in gout patients. METHODS AND RESULTS: Data on gout patients was collected from Huzhou city electronic medical record system data sharing platform, and information about relevant diagnoses, prescriptions, biochemical indexes and imaging characteristics was extracted. The gout patients with baseline normal renal function were enrolled in this analysis, and the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 was defined as renal dysfunction. The generalized estimating equation and Cox regression analysis were used. A total of 1009 patients with gout were enrolled. Compared with the reference group (normal baseline SUA with endpoint SUA to be < 6 mg/dL), endpoint SUA ≥ 10 mg/dL was associated with an increased risk of renal dysfunction (baseline normal SUA group: HR [95% CI] = 3.28 [1.21, 8.91]; baseline high SUA group: HR [95% CI] = 3.01 [1.43, 6.35]). Subgroup analysis of 771 SUA stable gout patients demonstrated that SUA levels at 8-10 (excluding 10), and ≥10 mg/dL were significantly associated with an increased risk for renal dysfunction, with HR [95%CI] to be 1.99 [1.05, 3.77], and 2.98 [1.38, 6.43], respectively. CONCLUSION: Regardless of the baseline SUA level, SUA >10 mg/dL was a significant risk factor for renal dysfunction. SUA between 6 and 10 mg/dL was a potential risk factor for renal dysfunction. No significant correlation of SUA fluctuation and renal function was found.

The experience of a gout flare: a meta-synthesis of qualitative studies.

AIMS: Gout flares are an important concern for people with gout and an understanding of patients' experiences with gout flares is central in developing meaningful outcome measures for clinical trials. This study aimed to systematically review and thematically synthesize the qualitative literature reporting the patient experience of gout flares, to inform the development of flare-specific outcome measures. METHODS: MEDLINE, EMBASE, CINAHL Plus and PsycINFO electronic databases were searched in October 2019 to identify original qualitative research articles reporting on the patient experience of gout flares. Methodological quality of all included papers was assessed using the Critical Appraisal Skills Program (CASP) tool. Following data extraction, coding and synthesis was undertaken using reflexive thematic analysis. RESULTS: Sixteen papers reporting the patient experience of gout flares were included. The majority of CASP criteria were met by most studies, indicating good methodological quality. Four predominant and overlapping themes were identified from the thematic analysis: gout flare characteristics (pain, swelling, location, duration and frequency); impact on function and activities of daily living (walking, housework and yard work, self-care, exercise and sports, driving, sleep); effects on social and family life (social participation, inability to plan, employment, dependency, relationships, intimacy); and psychological impact (boredom, irritability, fear, shame and embarrassment, isolation, financial worry, depression and anxiety). CONCLUSIONS: Gout flares impact many aspects of patients' lives, including physical and psychological and social and family life. The patient experience of gout flares goes beyond what is routinely measured in research settings. Measurement and reporting methods that capture these aspects of patients' experiences with gout flares would provide more meaningful outcome measures in clinical trials of flare prevention.

Gout and the risk of epilepsy: A population-based cohort study.

Gout is a chronic disease related to uric acid metabolism. It involves crystals of uric acid accumulating in the joints, causing joint pain and releasing cytokines that trigger inflammation. Inflammation is a key component in the pathogenesis of epilepsy. Thus, we conducted a cohort study to investigate if epilepsy is associated with gout and determine the risk of epilepsy in patients with gout.The gout cohort was obtained from the Registry of Catastrophic Illnesses Patient Database (RCIPD). We identified 104,238 patients who were aged 20 years or more and newly diagnosed with gout between 2000 and 2011 and 3 outpatient visits or history of gout-specific hospitalization between 2000 and 2011. Patients without gout were frequency matched with the gout cohort at a 2:1 ratio according to age, sex, comorbidities, and year of gout diagnosis.The gout cohort showed a 1.27-fold higher overall crude hazard ratio (HR) for epilepsy compared with the control cohort. After we adjusted the analyses by age, sex, and comorbidities the gout patients displayed an increased risk of epilepsy compared with the control group (adjusted HR = 1.25, 95% confidence interval = 1.15-1.36).This study revealed a significantly higher risk of epilepsy in patients with gout. It provides further evidence for the debate around the effect of gout on brain health.

Synovial Biopsy in the Diagnosis of Crystal-Associated Arthropathies.

BACKGROUND/ OBJECTIVE: This study seeks to assess the utility of synovial biopsy in the diagnosis of crystal-associated arthropathies (CAAs) in a clinical setting. METHODS: In this retrospective study, we reviewed biopsy reports involving synovial tissue between 1988 and 2015. We then reviewed the records of patients where the biopsy was performed for a clinical suspicion of CAA-the clinical group-and calculated the frequency of a positive diagnosis. The t test, Mann-Whitney-Wilcoxon test, and Fisher test were used to compare clinical characteristics of patients with and without a tissue diagnosis of CAA. We also reviewed cases of unexpected detection of crystalline disease involving synovial tissue-the incidental group. RESULTS: Among 2786 biopsies involving the synovium, we identified 65 cases in the clinical group and 33 cases in the incidental group. In the clinical group, a relevant diagnosis was obtained from synovial tissue in 36.9%, and a CAA was diagnosed in 20%. Restricting analysis to clinical biopsies performed for a primary suspicion of CAA, a relevant diagnosis was obtained in 61.3%, and a CAA was diagnosed in 38.7%. The incidental group comprised 1.2% of all synovial biopsies and included 7 mass lesions. Basic calcium phosphate was not reported on any biopsy in the study period. CONCLUSIONS: Synovial biopsy is a diagnostic option when suspected CAA is resistant to conventional modes of diagnosis. Crystalline diseases should be considered in the differential diagnosis of musculoskeletal mass lesions mimicking neoplasms.

Recent approaches to gout drug discovery: an update.

INTRODUCTION: Inflammation induced by urate deposition in joints causes gout. Healthy individuals maintain serum levels of urate by balancing urate production/excretion, whereas a production/excretion imbalance increases urate levels. Hyperuricemia is diagnosed when the serum urate level is continuously above 7 mg/dl as the solubility limit, and urate accumulates in the kidneys and joints. Because hyperuricemia increases the risk of gout, therapies aim to eliminate urate deposition to prevent gouty arthritis and kidney injury. AREAS COVERED: This review discusses the mechanism underlying hyperuricemia with respect to urate production and urate transport, along with urate-lowering therapeutics, including urate synthesis inhibitors, uricolytic enzymes, and uricosuric agents. The authors asses published data on relevant commercial therapy development projects and clinical trials. EXPERT OPINION: Available treatment options for hyperuricemia are limited. Allopurinol, a urate synthesis inhibitor, is generally administered at a reduced dosage to patients with renal impairment. Some URAT1 inhibitors have an unfavorable side effect profile. A promising strategy for treatment is the use of uricosuric agents that inhibit transporters (e.g. URAT1, URATv1/GLUT9, OAT10) which reabsorb urate from the urine.

Better outcomes for patients with gout.

Gout is increasing in prevalence despite effective pharmacotherapies. Barriers to effective management are largely educational deficiencies. Sufferers, usually men, need to understand more about gout, especially that maintaining serum urate below 0.36 mmol/L will eliminate recurrent attacks. Also, of great importance is appreciating that sub-optimal adherence to urate-lowering therapy (ULT) will result in a return of attacks. Prescribers also need to understand that acute attacks are likely to occur in the first few months of urate-lowering therapy (ULT), but these can be mitigated by commencing with a dose of ULT reflective of renal function and escalating the dose slowly, every 2-5 weeks until target serum urate is achieved. Prophylaxis against acute attacks over the initial 6 months period of ULT can be enhanced further with concomitant colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs).Gout is largely managed in primary care. Rates of adherence to ULT are 50% or less, worse than most other chronic illnesses. Efforts at educating primary care physicians to, firstly, manage gout effectively and, secondly, to educate their gout patients sufficiently have not been successful. Allied health practitioners, such as nurses, working with prescribers in primary care settings and given the mandate to educate and manage patients with gout, have been spectacularly effective. However, this approach is resource intensive. 'Personalised' eHealth interventions show promise as an alternative strategy, notably in improving adherence to ULT.Numerous applications for smart phones (apps) are now available to assist people with chronic health conditions. Their design needs to accommodate the barriers and enablers perceived by patients to maintaining adherence to prescribed therapies. Personalised feedback of serum urate may represent an important enabler of adherence to ULT in the case of gout.Harnessing mobile apps to support patients managing their chronic illnesses represents an important opportunity to enhance health outcomes. Rigorous, patient-centred and driven development is critical. These tools also require careful evaluation for effectiveness.

At the crossroads of gout and psoriatic arthritis: "psout".

Psoriatic arthritis and gout are frequently encountered conditions sharing a number of common risk factors, which render their independent study difficult. Epidemiological studies have demonstrated a strong link between these diseases, suggesting the presence of underlying, intertwined pathophysiological mechanisms that currently remain unknown. Indeed, sodium urate crystals could play a pathogenic role in psoriasis and psoriatic arthritis. In daily practice, the distinction between psoriatic arthritis associated with hyperuricemia and a gouty arthropathy with psoriasis is complex. Several common pathogenic features suggest a more intricate relationship than their mere coexistence in the same patient. Thus, the concurrence of these two diseases should be seen as a novel overlap syndrome, at the boundary between inflammatory and metabolic rheumatism. The present update aims to clarify the determinants of the link and to define this new nosological entity. Its recognition could have therapeutic implications that appear essential for treatment optimization in a personalized setting.Key Points• What is already known about this subject? Psoriatic arthritis (PsA) and gout have strong interconnections, including comorbidities and pathophysiology. One must note that confounding clinical symptoms and radiological signs of PsA and gout are similar and difficult to differentiate in patients whose radiological lesions become too advanced to be differentiated or with less clearly defined phenotypes.• What does this study add? The pathogenic role of chronic hyperuricemia in the development and maintenance of PsA is based on epidemiological, clinical, and fundamental arguments and hence does not appear fortuitous. These two pathological processes can influence each other.• How might this impact on clinical practice? This new line of thinking regarding the convergence of gout and PsA, involving the role of urate crystals, could prompt a potential new approach to treatment (urate-lowering therapy) among patients with active/refractory PsA.

Pharmacologic Management of Gout in Patients with Cardiovascular Disease and Heart Failure.

Gout is the most common inflammatory arthritis and is often comorbid with cardiovascular disease (CVD). Hyperuricemia and gout are also independent risk factors for cardiovascular events, worsening heart failure (HF), and death. The recommended treatment modalities for gout have important implications for patients with CVD because of varying degrees of cardiovascular and HF benefit and risk. Therefore, it is critical to both manage hyperuricemia with urate-lowering therapy (ULT) and treat acute gout flares while minimizing the risk of adverse cardiovascular events. In this review, the evidence for the safety of pharmacologic treatment of acute and chronic gout in patients with CVD and/or HF is reviewed. In patients with CVD or HF who present with an acute gout flare, colchicine is considered safe and potentially reduces the risk of myocardial infarction. If patients cannot tolerate colchicine, short durations of low-dose glucocorticoids are efficacious and may be safe. Nonsteroidal anti-inflammatory drugs should be avoided in patients with CVD or HF. The use of canakinumab and anakinra for acute gout flares is limited by the high cost, risk of serious infection, and relatively modest clinical benefit. For long-term ULT, allopurinol, and alternatively probenecid, should be considered first-line treatments in patients with CVD or HF given their safety and potential for reducing cardiovascular outcomes. An increased risk of cardiovascular death and HF hospitalization limit the use of febuxostat and pegloticase as ULT in this population. Ultimately, the selection of agents used for acute gout management and long-term ULT should be individualized according to patient and agent cardiovascular risk factors.