Effect of Clinical Typing on Serum Urate Targets of Benzbromarone in Chinese Gout Patients: A Prospective Cohort Study
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ABSTRACT: Introduction
Achieving a goal of serum urate levels in patients with gout is an important way to prevent gout and its complications while it remains difficult with a low targeting rate worldwidely. Currently, hyperuricemia classification has not been widely applied to the management of gout owing to insufficient clinical evidences. This study aimed to evaluate the effectiveness of achieving target urate based on hyperuricemia classification in Chinese patients with gout. Methods
In this prospective study, patients with gout receiving urate lowering therapy with benzbromarone were assigned to two groups, a renal underexcretion and an unclassified type. The primary endpoint was the proportion of patients achieving the serum urate target (<360 μmol/L) during the 12-week study. The frequency of acute gout attacks as well as physical and chemical indicators were secondary endpoints. Results
Target serum urate level was achieved in 60.5% of underexcretors compared with 39.0% of patients of the unclassified type at week 12 (P = 0.002). Blood glucose and cholesterol levels were lower in the underexcretor group compared with the unclassified type group at the end of the trial, without significant different frequencies in gout flare during the study. In subgroup analysis, stratified by body mass index and estimated glomerular filtration rate, the proportion of patients with serum urate <360 μmol/L was greater in the underexcretion compared with the unclassified type group. Conclusions
The increased achievement of target serum urate in the underexcretion group supports the use of a clinical hyperuricemia typing treatment strategy for gout.
SUBMITTER: Xue X
PROVIDER: S-EPMC8801777 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:The ABCG2 Q141K (rs2231142) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~?60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls. METHODS:We analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables. RESULTS:In Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR?=?1.85, P?=?3.8E-?21 and ORmeta?=?1.85, P?=?1.3E-?03, respectively). There was evidence for an effect of 141K in determining HU in European (OR?=?1.56, P?=?1.7E-?18) but not in Polynesian (ORmeta?=?1.49, P?=?0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR?=?1.37, P?=?4.7E-?06), however significantly weaker than ABCG2 rs2231142 141K (PHet?=?0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P?=?0.009) and 2.6-fold in European (P?=?9.9E-?06). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (Pmeta = 2.5E-?03). CONCLUSION:These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.
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Project description:Gout is a painful inflammatory arthritis affecting more than 8 million Americans. Identifying high-risk patients in early life could potentially encourage people to adopt lifestyle changes to prevent gout. Polygenic risk score (PRS) provides an overall estimate of an individual's genetic liability to develop a disease and can be used for early identification of high-risk individuals. In this study, we validated a previously reported PRS in an independent cohort. The urate-PRS was constructed from 110 significant urate-associated variants identified in Europeans. Phenome-wide and PRS-wide association study showed the urate-PRS is highly specifically associated with gout (phecode: 274.10; beta = 1.495 [1.372, 1.619], p = 4.37e-124). Urate-PRS alone did not performed in the gout prediction (area under the receiver operating characteristic curve, AUROC = 0.640); however, the addition of PRS upon demographics significantly improved the model performance, yielding an AUROC of 0.804 from 0.777 (DeLong test p = 3.66e-9). Trans-ethnic PRS and European-specific PRS showed similar prediction performance. We observed increasing gout prevalence and odds ratio (OR) across the PRS quintiles. Our study showed 8.2% of the cohort had more than 2.5 odds for gout than remainders, indicating that urate-PRS may be a better marker than age and sex to stratify patient risk. With the rapid growth of large biorepositories, such as All of Us, urate-PRS can be applied quickly and widely in population to estimate individual's risk, providing a powerful tool for gout preventive purpose in population health.
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Project description:BackgroundPrevious studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA.MethodsData was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2-4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA > 6.8 mg/dL).ResultsMean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1 to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic. Among those initially normouricemic (n = 72), 21% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA < 6.0 (n = 54) was much less likely to have future values in the range of hyperuricemia compared to the group with screening sUA values between 6.0-6.8 (n = 18) (7% vs 39%, p = 0.0037). Of the participants initially hyperuricemic (n = 13), 46% were later normouricemic during at least one measurement.ConclusionSingle sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Knowing this, if a single measurement must be used in classification, it is worth noting that those with an sUA of < 6.0 mg/dL were less likely to demonstrate future hyperuricemic measurements and this could be considered a safer threshold to rule out intermittent hyperuricemia based on a single measurement point.Trial registrationData from parent study ClinicalTrials.gov Identifier: NCT02038179 .
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Project description:Gout is a chronic disease resulting from elevated serum urate (SU). Previous genome-wide association studies (GWAS) have identified dozens of susceptibility loci for SU/gout, but few have been conducted for Chinese descent. Here, we try to extensively investigate whether these loci contribute to gout risk in Han Chinese. A total of 2255 variants in linkage disequilibrium (LD) with GWAS identified SU/gout associated variants were analyzed in a Han Chinese cohort of 1255 gout patients and 1848 controls. Cumulative genetic risk score analysis was performed to assess the cumulative effect of multiple "risk" variants on gout incidence. 23 variants (41%) of LD pruned variants set (n = 56) showed nominal association with gout in our sample (p < 0.05). Some of the previously reported gout associated loci (except ALDH16A1), including ABCG2, SLC2A9, GCKR, ALDH2 and CNIH2, were replicated. Cumulative genetic risk score analyses showed that the risk of gout increased for individuals with the growing number (≥8) of the risk alleles on gout associated loci. Most of the gout associated loci identified in previous GWAS were confirmed in an independent Chinese cohort, and the SU associated loci also confer susceptibility to gout. These findings provide important information of the genetic association of gout.
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Project description:ObjectivesTo compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment.MethodsA prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12).ResultsA total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred.ConclusionThe efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks.Trial registrationRegistered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518.
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Project description:BackgroundMany gout comorbidities (e.g., hypertension) are correlated with serum urate. In this investigation, we identified risk factors (e.g., systolic blood pressure [SBP]), that (1) are associated with incident gout, (2) have effects on gout risk that cannot be fully explained by correlated differences in serum urate, and (3) may modulate the relationship between gout and serum urate.MethodsUsing data from the Atherosclerosis Risk in Communities (ARIC) study, we estimated the unadjusted associations between gout and risk factors by calculating ORs and using chi-square tests. The adjusted associations were analyzed using logistic regression by sequentially adding (1) one risk factor at a time or (2) all risk factors, to a baseline model that includes serum urate only. Stepwise selection was used to select main effects. Two-way interactions of variables from the main effects model were also analyzed.ResultsAverage gout incidence was 2.7 per 1000 people per year. Serum urate was highly associated with incident gout, with odd ratios of 3.16 [95% CI 2.11, 4.76] and 25.9 [95% CI 17.2, 38.4] for moderately high (6-8 mg/dl) and high serum urate (> 8 mg/dl), relative to normal serum urate (< 6 mg/dl), respectively. Ethnicity and SBP were independently and additively associated with gout after accounting for serum urate levels. No significant interactions were found between serum urate and ethnicity or SBP.ConclusionsEthnicity and hypertension are predictive of gout risk, and the associations cannot be fully explained by serum urate. For serum urate levels near the crystallization threshold (6-8 mg/dl) African Americans and people with hypertension are at two to three times greater risk for developing gout. The gout risk for this group appears to increase before the onset of severe hyperuricemia.
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Project description:Gout is a common arthritis resulting from increased serum urate, and many loci have been identified that are associated with serum urate and gout. However, their influence on the progression from elevated serum urate levels to gout is unclear. This study aims to explore systematically the effects of genetic variants on the pathogenesis in approximately 5,000 Chinese individuals. Six genes (PDZK1, GCKR, TRIM46, HNF4G, SLC17A1, LRRC16A) were determined to be associated with serum urate (PFDR < 0.05) in the Chinese population for the first time. ABCG2 and a novel gene, SLC17A4, contributed to the development of gout from hyperuricemia (OR = 1.56, PFDR = 3.68E-09; OR = 1.27, PFDR = 0.013, respectively). Also, HNF4G is a novel gene associated with susceptibility to gout (OR = 1.28, PFDR = 1.08E-03). In addition, A1CF and TRIM46 were identified as associated with gout in the Chinese population for the first time (PFDR < 0.05). The present study systematically determined genetic effects on the progression from elevated serum urate to gout and suggests that urate-associated genes functioning as urate transporters may play a specific role in the pathogenesis of gout. Furthermore, two novel gout-associated genes (HNF4G and SLC17A4) were identified.
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Project description:AimsWith the high prevalence of gout and associated cardiovascular (CV) diseases, information on the comparative CV safety of individual urate-lowering drugs becomes increasingly important. However, few studies examined the CV risk of uricosuric agents. We compared CV risk among patients with gout who initiated allopurinol vs. benzbromarone.Methods and resultsUsing the Korean National Health Insurance claims data (2002-17), we conducted a cohort study of 124 434 gout patients who initiated either allopurinol (n = 103 695) or benzbromarone (n = 20 739), matched on propensity score at a 5:1 ratio. The primary outcome was a composite CV endpoint of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. To account for competing risk of death, we used cause-specific hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the outcomes comparing allopurinol initiators with benzbromarone. Over a mean follow-up of 1.16 years, 2258 patients developed a composite CV event. The incidence rate of the composite CV event was higher in allopurinol initiators (1.81 per 100 person-years) than benzbromarone (1.61 per 100 person-years) with a HR of 1.22 (95% CI 1.05-1.41). The HR for all-cause mortality was 1.66 (95% CI 1.43-1.93) among allopurinol initiators compared with benzbromarone.ConclusionIn this large population-based cohort of gout patients, allopurinol was associated with an increased risk of composite CV events and all-cause mortality compared to benzbromarone. Benzbromarone may reduce CV risk and mortality in patients with gout, although more studies are necessary to confirm our findings and to advance our understanding of the underlying mechanisms.
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Project description:The pathogenesis of osteoarthritis (OA) includes both mechanical and inflammatory features. Studies have implicated synovial fluid uric acid (UA) as a potential OA biomarker, possibly reflecting chondrocyte damage. Whether serum UA levels reflect/contribute to OA is unknown. We investigated whether serum UA levels predict OA progression in a non-gout knee OA population.Eighty-eight patients with medial knee OA (body mass index [BMI] <33 kg/m2 ) but without gout were studied. Baseline serum UA levels were measured in previously banked serum samples. At 0 and 24 months, patients underwent standardized weight-bearing fixed-flexion posteroanterior knee radiography to determine joint space width (JSW) and Kellgren/Lawrence grades. Joint space narrowing (JSN) was calculated as the change in JSW from 0 to 24 months. Twenty-seven patients underwent baseline contrast-enhanced 3T knee magnetic resonance imaging for assessment of synovial volume.Serum UA levels correlated with JSN values in both univariate (r?=?0.40, P?<?0.01) and multivariate (r?=?0.28, P?=?0.01) analyses. There was a significant difference in mean JSN after dichotomization at a serum UA cut point of 6.8 mg/dl, the solubility point for serum urate, even after adjustment (JSN of 0.90 mm for a serum UA ?6.8 mg/dl and 0.31 mm for a serum UA <6.8 mg/dl; P?<?0.01). Baseline serum UA levels distinguished progressors (JSN >0.2 mm) and fast progressors (JSN >0.5 mm) from nonprogressors (JSN ?0.0 mm) in multivariate analyses (area under the receiver operating characteristic curve 0.63 [P?=?0.03] and 0.62 [P?=?0.05], respectively). Serum UA levels correlated with the synovial volume (r?=?0.44, P?<?0.01), a possible marker of JSN, although this correlation did not persist after controlling for age, sex, and BMI (r?=?0.13, P?=?0.56).In non-gout patients with knee OA, the serum UA level predicted future JSN and may serve as a biomarker for OA progression.
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Project description:The Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate (SU); however, the impact of the DASH diet has not been previously evaluated among patients with gout. We conducted a randomized, controlled, crossover pilot study to test the effects of ~$105/week ($15/day) of dietitian-directed groceries (DDG), patterned after the DASH diet, on SU, compared with self-directed grocery shopping (SDG). Participants had gout and were not taking urate lowering therapy. Each intervention period lasted 4 weeks; crossover occurred without a washout period. The primary endpoint was SU. Compliance was assessed by end-of-period fasting spot urine potassium and sodium measurements and self-reported consumption of daily servings of fruit and vegetables. We randomized 43 participants (19% women, 49% black, mean age 59 years) with 100% follow-up. Mean baseline SU was 8.1 mg/dL (SD, 0.8). During Period 1, DDG lowered SU by 0.55 mg/dL (95% CI: 0.07, 1.04) compared to SDG by 0.0 mg/dL (95% CI: -0.44, 0.44). However, after crossover (Period 2), the SU difference between groups was the opposite: SDG reduced SU by -0.48 mg/dL (95% CI: -0.98, 0.01) compared to DDG by -0.05 mg/dL (95% CI: -0.48, 0.38; P for interaction by period = 0.11). Nevertheless, DDG improved self-reported intake of fruit and vegetables (3.1 servings/day; 95% CI: 1.5, 4.8) and significantly reduced total spot urine sodium excretion by 22 percentage points (95% CI: -34.0, -8.6). Though relatively small in scale, this pilot study suggests that dietitian-directed, DASH-patterned groceries may lower SU among gout patients not on urate-lowering drugs. However, behavior intervention crossover trials without a washout period are likely vulnerable to strong carryover effects. Definitive evaluation of the DASH diet as a treatment for gout will require a controlled feeding trial, ideally with a parallel-design.
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