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Gout and crystal deposition-associated disorders are among the leading causes of inflammation and arthritis throughout the world [...]

The predominant mechanism driving hyperuricemia in gout is renal uric acid underexcretion; however, the standard urate-lowering therapy (ULT) recommendation is first-line xanthine oxidase inhibitor (XOI), irrespective of the cause of hyperuricemia. This comparative effectiveness clinical trial was undertaken to compare first-line nontitrated low-dose benzbromarone (LDBen) uricosuric therapy to XOI ULT with low-dose febuxostat (LDFeb) in gout patients with renal uric acid underexcretion.We conducted a prospective, randomized, single-center, open-label trial in men with gout and renal uric acid underexcretion (defined as fractional excretion of urate5.5% and uric acid excretion ≤600 mg/day/1.73 mMore participants in the LDBen group achieved the serum urate target than those in the LDFeb group (61% compared to 32%, P 0.001). Rates of adverse events, including gout flares and urolithiasis, did not differ between groups, with the exception of greater transaminase elevation in the LDFeb group (4% for LDBen compared to 15% for LDFeb, P = 0.008).Compared to LDFeb, LDBen has superior urate-lowering efficacy and similar safety in treating relatively young and healthy patients with renal uric acid underexcretion-type gout.

Background Verinurad is a human uric acid (UA) transporter (URAT1) inhibitor known to decrease serum UA (sUA) levels and that may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval 4–62%) among patients with Type 2 diabetes mellitus, hyperuricaemia and albuminuria. The Phase 2b, randomized, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicaEmia (SAPPHIRE; NCT03990363) will examine the effect of verinurad + allopurinol on albuminuria and estimated glomerular filtration rate (eGFR) slope among patients with chronic kidney disease (CKD) and hyperuricaemia. Methods Adults (≥18 years of age) with CKD, eGFR ≥25 mL/min/1.73 m2, UACR 30–5000 mg/g and sUA ≥6.0 mg/dL will be enrolled. Approximately 725 patients will be randomized 1:1:1:1:1 to 12, 7.5 or 3 mg verinurad + allopurinol, allopurinol or placebo. An 8-week dose-titration period will precede a 12-month treatment period; verinurad dose will be increased to 24 mg at Month 9 in a subset of patients in the 3 mg verinurad + allopurinol arm. The primary efficacy endpoint the is change from baseline in UACR at 6 months. Secondary efficacy endpoints include changes in UACR, eGFR and sUA from baseline at 6 and 12 months. Conclusions This study will assess the combined clinical effect of verinurad + allopurinol on kidney function in patients with CKD, hyperuricaemia and albuminuria, and whether this combination confers renoprotection beyond standard-of-care.

Human untargeted metabolomics studies annotate only ~10% of molecular features. We introduce reference-data-driven analysis to match metabolomics tandem mass spectrometry (MS/MS) data against metadata-annotated source data as a pseudo-MS/MS reference library. Applying this approach to food source data, we show that it increases MS/MS spectral usage 5.1-fold over conventional structural MS/MS library matches and allows empirical assessment of dietary patterns from untargeted data.

OBJECTIVE: Classification criteria for calcium pyrophosphate deposition disease (CPPD) will facilitate clinical research on this common crystalline arthritis. We report on the first two phases of a four-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member Steering Committee. Item generation (Phase I) included a scoping literature review of five literature databases and contributions from a 35-member Combined Expert Committee and two Patient Research Partners. Item reduction and refinement (Phase II) involved a Combined Expert Committee meeting, discussions among Clinical, Imaging, and Laboratory Advisory Groups, and an item rating exercise to assess the influence of individual items toward classification. The Steering Committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The Advisory Groups eliminated items they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the Steering Committee recommended focusing on imaging of the knee, wrist, and one additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

SummaryBackgroundGout is a polygenetic inflammatory disease. Although hundreds of genetic variants associated with gout and serum urate levels have been identified in studies of adults, the pathogenesis of adolescent-onset gout remains unclear. To better characterize the genetic landscape of adolescent-onset gout, a whole genome sequencing study was done in a large Chinese adolescent-onset gout cohort.MethodsWe conducted whole genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12-19 years) to discover common SNVs, uncommon SNVs, and indels associated with gout. Candidate common SNVs were replicated in an early-onset gout cohort of 2834 individuals (gout onset ≤ 30 years old). Loci associated with early-onset gout (P< 5.0 × 10−8) were identified after meta-analysis with the discovery and replication cohorts. Transcriptome and epigenomic analyses, RT-qPCR and RNA-seq in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated regulation and functions of candidate geneRCOR1.FindingsIn addition toABCG2, a urate transporter previously linked to pediatric-onset and early-onset gout, we identified four novel loci:VPRBP(rs868933181,Pmeta= 6.27 × 10−9; ORmeta= 1.66),NKILA-MIR4532(rs72626599,Pmeta= 6.48 × 10−9; ORmeta= 1.58),RCOR1(rs12887440,Pmeta= 3.37 × 10−8; ORmeta= 1.48), andFSTL5-MIR4454(rs35213808,Pmeta= 4.02 × 10−8; ORmeta= 1.49). Additionally, we found association atABCG2andSLC22A12that was driven by low frequency SNVs. Furthermore, eight uncommon SNVs and three indels in the exome were predicted to be harmful. SNVs inRCOR1were linked to heightened blood leukocyte mRNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation.InterpretationPerforming the first comprehensive characterization of adolescent-onset gout genomes identified risk loci of early-onset gout. Loci mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout.FundingThe National Natural Science Foundation of China and the National Key R&D Program of China.Research in contextEvidence before this studyGout is a polygenic disease and can present in adolescents and young adults. We searched PubMed for studies published as of Dec 31, 2021, without starting date or language restrictions and with the terms “adolescent-onset gout”, “early-onset gout”, “whole genome sequencing”, and “GWAS”, and no reports were found. Although GWAS have identified hundreds of genetic variants associated with gout and serum urate levels, they are all identified in adults (mean age 37.6-76.4 years old). The mechanism of early-onset gout is still unclear. The variants previously associated with early-onset gout are only inABCG2. Due to the lack of large-scale genetic studies of the adolescent gout population, the mechanism of the early-onset gout is unknown.Added value of this studyTo the best of our knowledge, this is the first report of the comprehensive characterization of adolescent gout genomes. We identified common and uncommon risk loci of early-onset gout, most of which implicated in inflammation response, includingRCOR1. SNVs in candidate risk geneRCOR1displayed expression regulation function. Knockdown of RCOR1 decreased IL-1β levels in THP-1 cells after MSU treatment. These immune-related genetic variants leading to heightened inflammatory responses to monosodium urate (MSU) crystals may contribute to early onset of gout in adolescents.Implications of all the available evidenceThis is the first report of the genetic landscape of adolescent-onset gout and increases our knowledge of the biological mechanisms underlying early-onset gout. The immune-related loci associated with early-onset gout discovered in this study are potential drug targets. Reducing inflammatory MSU crystal inflammatory responses to MSU crystals is a central objective in the prevention and treatment of adolescent-onset gout.

ObjectivesCOVID-19 vaccination often triggers a constellation of transitory inflammatory symptoms. Gout is associated with several comorbidities linked to poor outcomes in COVID-19, and gout flares can be triggered by some vaccinations. We analysed the risk of gout flares in the first 3 months after COVID-19 vaccination with inactivated virus, and whether colchicine can prevent gout flares following post-COVID-19 vaccination.MethodsA clinical delivery population-based cross-sectional study was conducted in the Gout Clinic at the Affiliated Hospital of Qingdao University between February and October 2021. Study participants were selected using a systematic random sampling technique among follow-up patients with gout. We collected data, including vaccinations and potential risk factors, using a combination of interviews, health QR codes and medical records. Logistic regression was used to adjust for covariates.ResultsWe enrolled 549 gout participants (median age 39 years, 84.2% vaccinated). For the 462 patients who received COVID-19 vaccine, 203 (43.9%) developed at least one gout flare in the 3 months after vaccination. Most of these flares were experienced within 1 month after the first (99/119 (83.2%)) or second (70/115 (60.9%)) dose of vaccine. Compared with unvaccinated participants, COVID-19 vaccination was associated with higher odds of gout flare within 3 months (adjusted OR 6.02; 95% CI 3.00 to 12.08). Colchicine use was associated with 47% less likelihood of postvaccine gout flare.ConclusionCOVID-19 vaccination was associated with increased odds of gout flare, which developed mainly in month 1 after each vaccine dose, and was negatively associated with colchicine prophylaxis.

Contains fulltext : 249973.pdf (Publisher’s version ) (Closed access) Over the last decade, evidence has demonstrated that long-term, low-dose colchicine (0.5 mg daily) is effective for preventing gout flare and cardiovascular (CV) events in a wide range of patients. Given the potentially expanding use of colchicine in CV disease, we here review and update the biologic effects and safety of colchicine based on recent data gathered from bench and pharmacodynamic studies, clinical reports, controlled clinical trials, and meta-analyses, integrated with important studies over the last 50 years, to offer a consensus perspective by experts from multiple specialties familiar with colchicine's long-term use. We conclude that the clinical benefits of colchicine in gout and CV disease achieved at low dose do not sustain serum levels above the upper limit of safety when used in patients without advanced renal or liver disease or when used concomitantly with most medications. Further, data accrued over the last 50 years strongly suggest that the biologic effects of long-term colchicine do not increase the risk of cancer, sepsis, cytopenia, or myotoxicity.

Objective Gout flares during urate-lowering therapy (ULT) initiation are common, but predictors of these flares are poorly understood. The aim of this study was to determine whether serum CA72-4 is an independent predictor for gout flares during ULT initiation. Methods A prospective cohort study was conducted between March 2021 and January 2022. Men with gout, at least one gout flare in the past year, and at least three serum CA72-4 measurements in the previous six months were enrolled. Participants were grouped according to their highest recorded serum CA72-4 levels (above or within the normal range). All participants took oral febuxostat 20 mg daily without flare prophylaxis therapy, and attended face-to-face visits every four weeks until 24 weeks. The incidence of gout flare was compared between the two groups. Backward stepwise logistic regression analyses were used to identify risk factors associated with flares. Receiver operating characteristic curve analysis was used to evaluate prediction efficacy. Results A total of 193 completed the study (79 with high CA72-4; 114 with normal CA72-4). The cumulative incidence of at least one gout flare was 48.1% (62.1% in the high CA72-4 group, 38.4% in the normal CA72-4 group, P = 0.001), and recurrent (≥2) flares was 33.0% (47.1% in the high CA72-4 group, 23.2% in the normal CA72-4, P Conclusion High serum CA72-4 predicts the risk of gout flares during ULT initiation. Trial registration ChiCTR; https://www.chictr.org.cn/; ChiCTR2100043573.

In gout, hyperuricemia promotes urate crystal deposition that stimulates the NLRP3 inflammasome and IL-1β-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis meeting ACR/EULAR gout classification criteria in a normouricemic young adult female.Whole genome sequencing, quantitative proteomics, whole blood RNA-seq, and IL-1β-induced murine knee synovitis characterized proband candidate genes, biomarkers, and pathogenic mechanisms.Lubricin was attenuated in proband serum, associated with elevated acute phase reactants and inflammatory whole blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of Inter-Alpha-Trypsin Inhibitor Heavy Chain 3, an inhibitor of lubricin-degrading Cathepsin G. Proband serum protein interactome network changes supported enhanced lubricin degradation, with Cathepsin G activity increased relative to its inhibitors SERPINB6 and Thrombospondin1. TLR2 activation suppressed cultured human synovial fibroblast lubricin mRNA and release (p0.01). Lubricin blunted urate crystal precipitation, and IL-1β induction of xanthine oxidase and urate in cultured macrophages (p0.001). In lubricin-deficient mice, IL-1β knee injection increased xanthine oxidase positive synovial resident M1 macrophages (p0.05).We linked normouricemic erosive gout to attenuated lubricin, with impaired control of Cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization, and blunted IL-1β-induced increases in macrophage xanthine oxidase and urate. Collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated Cathepsin G, and synovial fibroblast TLR2 signaling. This article is protected by copyright. All rights reserved.

Gout and chronic kidney disease (CKD) frequently coexist, but quality evidence to guide gout management in people with CKD is lacking. Use of urate-lowering therapy (ULT) in the context of advanced CKD varies greatly, and professional bodies have issued conflicting recommendations regarding the treatment of gout in people with concomitant CKD. As a result, confusion exists among medical professionals about the appropriate management of people with gout and CKD. This Consensus Statement from the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) discusses the evidence and/or lack thereof for the management of gout in people with CKD and identifies key areas for research to address the challenges faced in the management of gout and CKD. These discussions, which address areas for research both in general as well as related to specific medications used to treat gout flares or as ULT, are supported by separately published G-CAN systematic literature reviews. This Consensus Statement is not intended as a guideline for the management of gout in CKD; rather, it analyses the available literature on the safety and efficacy of drugs used in gout management to identify important gaps in knowledge and associated areas for research., In this Consensus Statement, members of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) highlight gaps in knowledge about the management of gout in people with chronic kidney disease, and identify important areas for future research to address challenges in the treatment of this patient population.

OBJECTIVE To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares. METHODS Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient- and physician-assessed global response. RESULTS One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient-assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction. CONCLUSION Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.

Rationale & Objective Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). Study Design Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. Setting & Participants Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. Intervention Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. Outcomes The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. Results 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks: −38.6% (90% CI, −60.9% to−3.6%), −39.4% (90% CI, −61.8% to−3.8%), and−49.3% (90% CI, −68.2% to−19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. Limitations Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. Conclusions Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. Funding This study was supported by AstraZeneca. Trial Registration Registered at ClinicalTrials.gov with study number NCT03118739.

Elevated serum urate (hyperuricemia) promotes crystalline monosodium urate tissue deposits and gout, with associated inflammation and increased mortality. To identify modifiers of uric acid pathologies, we performed a fly Genome-Wide Association Study (GWAS) on purine metabolites using the Drosophila Genetic Reference Panel strains. We tested the candidate genes using the Drosophila melanogaster model of hyperuricemia and uric acid crystallization (“concretion formation”) in the kidney-like Malpighian tubule. Medusa (mda) activity increased urate levels and inflammatory response programming. Conversely, whole-body mda knockdown decreased purine synthesis precursor phosphoribosyl pyrophosphate, uric acid, and guanosine levels; limited formation of aggregated uric acid concretions; and was sufficient to rescue lifespan reduction in the fly hyperuricemia and gout model. Levels of mda homolog FAM214A were elevated in inflammatory M1- and reduced in anti-inflammatory M2-differentiated mouse bone marrow macrophages, and influenced intracellular uric acid levels in human HepG2 transformed hepatocytes. In conclusion, mda/FAM214A acts in a conserved manner to regulate purine metabolism, promotes disease driven by hyperuricemia and associated tissue inflammation, and provides a potential novel target for uric acid–driven pathologies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00557-9.

The US FDA-mandated CARES trial, published in 2018, reported increased all-cause and cardiovascular (CV) death in participants randomized to febuxostat compared with allopurinol. The subsequent FDA Drug Safety Communication and Boxed Warning resulted in substantial reductions in febuxostat use in the US. The EMA-mandated Febuxostat versus Allopurinol Streamlined Trial (FAST), published in 2020, found no increased risk of composite CV events, CV mortality or all-cause mortality for febuxostat, compared with allopurinol. This commentary discusses implications of these new findings for gout management.

Objective The aim was to test the feasibility of a randomized controlled trial exploring whether omega-3 fatty acid supplementation limits gout flares during treat-to-target urate-lowering treatment (T2T-ULT). Methods Adults with at least one gout flare in the past 12 months and serum urate (SU) ≥360 μmol/l were recruited from general practices (primary method) and randomly assigned 1:1 to receive omega-3 fatty acid supplementation (4 g/day) or placebo for 28 weeks. At week 5, participants began T2T-ULT. The primary outcome was drop-out rate. Secondary outcomes were recruitment rate, outcome data completeness, the number, severity and duration of gout flares between weeks 5 and 28, and study drug compliance. Results Ninety-five per cent of randomized participants (n = 60) completed all study visits. The primary method recruitment rate was 2.2%. Fifty and 42 participants achieved SU Conclusion The study demonstrated feasibility and provided useful metrics for conducting a community-based gout flare prophylaxis trial. Study registration ISRCTN; https://www.isrctn.com/; ISRCTN79392964.

BACKGROUND: The relative efficacy and safety of allopurinol and febuxostat when used according to current guidelines for the treatment of hyperuricemia are unknown. This double-blind noninferiority trial examined these issues. METHODS: Participants with gout and hyperuricemia (with at least 33% having stage 3 chronic kidney disease) were randomly assigned to allopurinol or febuxostat in this 72-week trial, with doses titrated to target serum urate. The trial had three phases: titration (weeks 0 to 24), maintenance (weeks 25 to 48), and observation (weeks 49 to 72). Allopurinol and febuxostat were initiated at daily doses of 100 and 40 mg, with maximum titration to 800 and 120 mg, respectively. Antiinflammatory prophylaxis was given during phases 1 and 2. The primary end point was the proportion of patients experiencing one or more flares during phase 3, with a prespecified noninferiority margin of less than 8 percentage points between allopurinol and febuxostat. Secondary end points included efficacy in patients with chronic kidney disease, proportion achieving target serum urate levels, and serious adverse events. RESULTS: This study included 940 participants; 20.1% withdrew, with similar proportions in treatment arms. During phase 3, 36.5% of allopurinol-treated participants had one flare or more compared with 43.5% of febuxostat-treated participants (P

There are no proven effective medical treatments to prevent calcium pyrophosphate crystal deposition (CPPD). Hypomagnesemia is a known CPPD risk factor. The present study was undertaken to carry out a real-world epidemiologic study on proton-pump inhibitor (PPI) use, which can cause hypomagnesemia, and CPPD risk.We conducted a time-stratified, propensity score (PS)-matched cohort study using the UK-based IQVIA Medical Research Data. We compared risk of incident CPPD among PPI users versus HWe identified 81,102 PPI and HIn this study using real-world data, incident use of PPIs was not associated with a higher risk of CPPD compared with incident H

Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown.To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD.Cohort study.The Health Improvement Network U.K. primary care database (2000 to 2019).Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD.The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)-matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators.Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07).Residual confounding cannot be ruled out.In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD.Project Program of National Clinical Research Center for Geriatric Disorders.

Objective In gout, autoinflammatory responses to urate crystals promote acute arthritis flares, but the pathogeneses of tophi, chronic synovitis, and erosion are less well understood. Defining the pathways of epigenomic immunity training can reveal novel pathogenetic factors and biomarkers. The present study was undertaken to seminally probe differential DNA methylation patterns utilizing epigenome-wide analyses in patients with gout. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from a San Diego cohort of patients with gout (n = 16) and individually matched healthy controls (n = 14). PBMC methylome data were processed with ChAMP package in R. ENCODE data and Taiji data analysis software were used to analyze transcription factor (TF)-gene networks. As an independent validation cohort, whole blood DNA samples from New Zealand Māori subjects (n = 13 patients with gout, n = 16 control subjects without gout) were analyzed. Results Differentially methylated loci clearly separated gout patients from controls, as determined by hierarchical clustering and principal components analyses. IL23R, which mediates granuloma formation and cell invasion, was identified as one of the multiple differentially methylated gout risk genes. Epigenome-wide analyses revealed differential methylome pathway enrichment for B and T cell receptor signaling, Th17 cell differentiation and interleukin-17 signaling, convergent longevity regulation, circadian entrainment, and AMP-activated protein kinase signaling, which are pathways that impact inflammation via insulin-like growth factor 1 receptor, phosphatidylinositol 3-kinase/Akt, NF-κB, mechanistic target of rapamycin signaling, and autophagy. The gout cohorts overlapped for 37 (52.9%) of the 70 TFs with hypomethylated sequence enrichment and for 30 (78.9%) of the 38 enriched KEGG pathways identified via TFs. Evidence of shared differentially methylated gout TF-gene networks, including the NF-κB activation-limiting TFs MEF2C and NFATC2, pointed to osteoclast differentiation as the most strongly weighted differentially methylated pathway that overlapped in both gout cohorts. Conclusion These findings of differential DNA methylation of networked signaling, transcriptional, innate and adaptive immunity, and osteoclastogenesis genes and pathways suggest that they could serve as novel therapeutic targets in the management of flares, tophi, chronic synovitis, and bone erosion in patients with gout.

Objective To determine the relationship between omega-3 polyunsaturated fatty acid (n-3 PUFA) consumption (dietary or supplemental) and risk of gout flares. Methods We used data from the Boston University Online Gout Study, an internet-based case-crossover study conducted from February 2003 to January 2012. At the times of gout flares (hazard period) and during gout flare-free periods (control periods), participants completed questionnaires regarding exposures, including supplements and diet, during the preceding 48 hours. We examined the relationship of self-reported n-3 PUFA-rich supplements and fish intake with the risk of recurrent gout flares using conditional logistic regression, adjusting for total purine intake, diuretic use, and other urate-lowering or flare prophylactic medications (allopurinol, nonsteroidal antiinflammatory drugs, or colchicine). Results Of the 724 participants, 85% met the 1977 American College of Rheumatology preliminary criteria for the classification of the acute arthritis of primary gout. Twenty-two percent of the participants reported some form of n-3 PUFA consumption (supplements, 4.6%; dietary fatty fish, 19%) in the 48 hours preceding a gout flare or flare-free period. The adjusted odds ratios were 1.01 (95% confidence interval [95% CI] 0.63-1.60; P = 0.98) for all 3 supplements combined and 0.74 (95% CI 0.54-0.99; P = 0.04) for consumption of ≥2 n-3 PUFA-rich fish servings. Conclusion Dietary n-3 PUFA-rich fish consumption, when adjusted for total purine intake, was associated with lower risk of recurrent gout flares, whereas n-3 PUFA supplementation alone, as taken in a self-directed manner, was not. Consumption of specific sources and adequate doses of n-3 PUFA for gout flare prevention warrants further study in an adequately powered clinical trial.

ObjectivesThe recombinant zoster vaccine (RZV) containing a strong non-aluminium adjuvant is associated with increased risk of gout flares, presumably via NLRP3 inflammasome activation. We tested the possibility that other vaccines may also be associated with gout flares.MethodsWe conducted an online case-crossover study of patients with gout to examine the association between vaccination and gout flares. We collected information through the Internet on exposures to potential risk factors, including vaccinations, during 2-day hazard periods prior to gout flare and 2-day control periods without a flare. Conditional logistic regression was used to adjust for covariates.ResultsThere were 517 participants with gout (mean age 55 years, 79% male) who experienced gout flares during follow-up. There were 28 vaccinations during 990 hazard periods and 21 vaccinations during 1407 control periods. Vaccination was associated with twofold higher odds of gout flare (adjusted OR 1.99; 95% CI 1.01 to 3.89).ConclusionOur findings suggest vaccines other than RZV are associated with increased odds of gout flares, potentially through a shared pathogenetic mechanism like NLRP3 inflammasome. However, the absolute magnitude of increased odds of gout flares with vaccinations remains small and must be interpreted within the context of the overwhelming benefits of vaccinations.

Urate-lowering therapy (ULT) nonadherence is common and problematic in gout. Since, sociocultural factors affect adherence, we analyzed a Chinese cohort.We studied 903 Chinese gout patients aged 46.4±14.7 years (mean±SD), uniquely extending to assay of 2-year medication possession ratio (MPR) ≥80% defined as high adherence. Multivariable logistic regression analyses evaluated factors linked with adherence and ULT target attainment.Characterization of ULT outcomes in this cohort revealed that after 2 years ULT, MPR ≥80% patients had better target serum urate (SU) achievement (from 23.3% to 71.0%, P0.001), lower flare frequency and palpable tophi compared to MPR80%. However, only 44.7% of cohort subjects had MPR ≥80%. Male sex (OR 3.68), gout onset age60 years (OR 3.51), disease duration5 years (OR 1.70), more comorbidities (OR 1.74), baseline palpable tophi (OR 1.53), SU6mg/dL (360μmol/L) (OR 1.92) and more frequent follow-up visits (OR 1.98) were significantly associated with high adherence. Nevertheless, significant independent risk factors for failed SU target achievement included male sex (OR 0.36) and more comorbidities (OR 0.85).Despite adherence to ULT linked to better outcomes for flares and tophi, the more adherent Chinese male patients and those with more comorbidities had decreased target SU attainment. Differences in adherence of Chinese gout patients compared to several primarily Western studies emphasize the importance of not stereotyping gout patients for projected nonadherence. Results underline the dual importance of identifying gout patients more likely to be ULT-adherent and leveraging adherence to drive treatment to SU target.

Human untargeted metabolomics studies succeed in annotating only ~10% of molecular features. We, therefore, introduce reference data-driven analysis that uses the source data as a pseudo-MS/MS reference library to match against human metabolomics MS/MS data. We demonstrate this approach with food source data, allowing an empirical assessment of dietary patterns from untargeted data but is broadly applicable and provides an additional layer of interpretability to metabolomics data.

Monosodium urate crystals (MSUc) induce inflammation invivo without prior priming, raising the possibility of an initial cell-autonomous phase. Here, using genome-wide transcriptomic analysis and biochemical assays, we demonstrate that MSUc alone induce a metabolic-inflammatory transcriptional program in non-primed human and murine macrophages that is markedly distinct to that induced by LPS. Genes uniquely upregulated in response to MSUc belong to lipid and amino acid metabolism, glycolysis, and SLC transporters. This upregulation leads to a metabolic rewiring in sera from individuals and mice with acute gouty arthritis. Mechanistically, the initiating inflammatory-metabolic changes in acute gout flares are regulated through a persistent expression and increased binding of JUN to the promoter of target genes through JNK signaling-but not P38-in a process that is different than after LPS stimulation and independent of inflammasome activation. Finally, pharmacological JNK inhibition limits MSUc-induced inflammation in animal models of acute gouty inflammation.

ObjectiveTo develop a Gout, Hyperuricaemia and Crystal-Associated Disease Network (G-CAN) common language definition of gout, with the goal of increasing public understanding and awareness, and ensure consistent and understandable messages about gout.MethodsA G-CAN working group that included patients, physicians and nongovernmental organisation (NGO) representatives was formed to develop a common language definition of gout for use with the public, media, healthcare providers and stakeholders. A literature search and interviews with patients, healthcare workers and stakeholders informed development of the definition. Following consultation with G-CAN members and partners, the definition was endorsed by the G-CAN board.ResultsThe G-CAN common language definition of gout describes the epidemiology, pathophysiology, symptoms and impact, risk factors, comorbidities, management and healthcare and workforce considerations. Detailed information is provided to support the content of the definition. After the publication of the English-language version, the definition will be available for translation into other languages by G-CAN members.ConclusionG-CAN has developed a concise and easily understandable statement describing gout in language that can be used in conversations with the lay public, media, NGOs, funders, healthcare providers and other stakeholders.

The response of macrophages to monosodium urate crystals (MSUc) is incompletely understood partly due to the use of a toll-like receptor (TLR)-induced priming step in cell lines. Yet, MSUc induce inflammation in vivo without prior priming, raising the possibility of an initial cell-autonomous phase that is TLR-independent. Here, using genome wide transcriptomic analysis and biochemical assays we demonstrate that MSUc alone induce a metabolic-inflammatory transcriptional program in non-primed human and murine macrophages that is markedly distinct to that induced by LPS. Genes uniquely upregulated in response to MSUc belonged to lipid and amino acid metabolism, glycolysis, and SLC transporters. This upregulation led to a metabolic rewiring in sera from individuals and mice with acute gouty arthritis. Mechanistically, the initiating inflammatory-metabolic changes in acute gout flares are regulated through a persistent expression and increased binding of JUN to the promoter of target genes through JNK signaling -but not P38- in a process that is different than after LPS stimulation and unexpectedly independent of inflammasome activation. Finally, pharmacological JNK inhibition limited MSUc-induced inflammation in animal models of acute gouty inflammation. MSUc alone induce a unique strong macrophage activation and distinct phenotype that forces a reconsideration of initiating mechanisms in acute gout flares.

Objective To systematically profile metabolic alterations and dysregulated metabolic pathways in hyperuricemia and gout, and to identify potential metabolite biomarkers to discriminate gout from asymptomatic hyperuricemia. Methods Serum samples from 330 participants, including 109 with gout, 102 with asymptomatic hyperuricemia, and 119 normouricemic controls, were analyzed by high-resolution mass spectrometry-based metabolomics. Multivariate principal components analysis and orthogonal partial least squares discriminant analysis were performed to explore differential metabolites and pathways. A multivariate methods with Unbiased Variable selection in R (MUVR) algorithm was performed to identify potential biomarkers and build multivariate diagnostic models using 3 machine learning algorithms: random forest, support vector machine, and logistic regression. Results Univariate analysis demonstrated that there was a greater difference between the metabolic profiles of patients with gout and normouricemic controls than between the metabolic profiles of individuals with hyperuricemia and normouricemic controls, while gout and hyperuricemia showed clear metabolomic differences. Pathway enrichment analysis found diverse significantly dysregulated pathways in individuals with hyperuricemia and patients with gout compared to normouricemic controls, among which arginine metabolism appeared to play a critical role. The multivariate diagnostic model using MUVR found 13 metabolites as potential biomarkers to differentiate hyperuricemia and gout from normouricemia. Two-thirds of the samples were randomly selected as a training set, and the remainder were used as a validation set. Receiver operating characteristic analysis of 7 metabolites yielded an area under the curve of 0.83-0.87 in the training set and 0.78-0.84 in the validation set for distinguishing gout from asymptomatic hyperuricemia by 3 machine learning algorithms. Conclusion Gout and hyperuricemia have distinct serum metabolomic signatures. This diagnostic model has the potential to improve current gout care through early detection or prediction of progression to gout from hyperuricemia.