Use Of Urate-lowering Therapy Research Articles

P085 Implementing treat-to-target urate-lowering therapy during hospitalisations for gout flares: a prospective cohort study

Abstract Background/Aims Hospitalisations for gout flares have doubled in England during the last 15 years. Despite this, no studies have evaluated strategies designed to increase the uptake of urate-lowering therapy (ULT) in people hospitalised for gout flares. Methods We conducted a prospective cohort study in people hospitalised for gout flares. We designed and evaluated an intervention package that consisted of an optimal, in-hospital management pathway based upon BSR, EULAR and ACR guidelines, which encouraged ULT initiation prior to discharge, followed by a nurse-led, post-discharge review. Outcomes including: i) ULT initiation; ii) serum urate target attainment, and iii) re-hospitalisation rates were compared between patients hospitalised for flares in the 12 months post-implementation vs. a retrospective cohort of hospitalised patients from 12 months pre-implementation. Results 119 and 108 patients, respectively, were hospitalised for gout flares in the 12 months before and after the intervention was launched. For patients with six-month follow-up data available (n = 94 and n = 97, respectively), the proportion of patients who were newly initiated on ULT increased to 92% post-implementation, from 49% pre-implementation (age and sex-adjusted odds ratio (aOR) 11.5; 95% CI 4.36-30.5; p < 0.001). More patients achieved a serum urate ≤360 micromol/L within six months of discharge (27% post-implementation vs. 11% pre-implementation; aOR 3.04; 95% CI 1.36-6.78; p = 0.007). The proportion of patients who were re-hospitalised for flares was 9% post-implementation vs. 15% pre-implementation (aOR 0.53, 95% CI 0.22 to 1.32; p = 0.18). Conclusion Following implementation of a strategy designed to optimise care during gout hospitalisations, more than 90% of ULT-naïve patients were initiated on ULT - nearly double the pre-implementation baseline. Despite greater initiation of ULT in the acute flare setting, recurrent hospitalisations did not increase following implementation; supporting the use of ULT in this setting. Improvements were seen in urate target attainment post-discharge; however, focused approaches to optimise ULT dose escalation to achieve target urate levels are required. Disclosure M.D. Russell: Honoraria; AbbVie, Biogen, Eli Lilly, Galapagos, Menarini. Grants/research support; Eli Lilly, Janssen, Pfizer, UCB. L. Ameyaw-Kyeremeh: None. F. Dell'Accio: None. H. Lapham: None. N. Head: None. C. Stovin: None. V. Patel: None. B. Clarke: None. D. Nagra: None. E. Alveyn: None. M.A. Adas: None. K. Bechman: Grants/research support; Versus Arthritis/Pfizer. M.A. de la Puente: None. B. Ellis: None. C. Byrne: None. R. Patel: None. A.I. Rutherford: Other; Educational support from Eli Lilly, UCB. F. Cantle: None. S. Norton: None. E. Roddy: None. J. Hudson: None. A.P. Cope: Honoraria; BMS, AbbVie, GSK/Galvini. Grants/research support; BMS. J.B. Galloway: Honoraria; Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, UCB.

Estimation of adherence to urate-lowering therapy in people living with gout using Australia's Pharmaceutical Benefits Scheme and patient-reported dosing.

The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.

Adherence to the Dietary Approaches to Stop Hypertension (DASH) and Serum Urate Concentrations: A Longitudinal Analysis from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

BackgroundIncreased serum urate (SU) and hyperuricemia (HU) are associated with chronic noncommunicable diseases and mortality. SU concentrations are affected by several factors, including diet, and are expected to rise with age. We investigated whether the Dietary Approaches to Stop Hypertension (DASH) diet alter this trend. ObjectiveThe objective was to assess whether adherence to the DASH diet predicts a longitudinal change in SU concentrations and risk of HU in 8 y of follow-up. MethodsLongitudinal analyses using baseline (2008–2010, aged 35–74 y), second (2012–2014), and third (2016–2018) visits data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). The inclusion criteria were having complete food frequency questionnaire (FFQ) and urinary sodium measurement, in addition to having SU measurement at the 1st visit and at least 1 of the 2 follow-up visits. For the HU incidence analyses, participants had also to be free from HU at baseline. The final samples included 12575 individuals for the SU change analyses and 10549 for the HU incidence analyses. Adherence to DASH diet was assessed as continuous value. HU was defined as SU>6.8 mg/dL and/or urate-lowering therapy use. Mixed-effect linear and Poisson regressions (incidence rate ratio [IRR] and 95% confidence interval [CI]) were used in the analyses, adjusted for confounders. ResultsThe mean age was 51.4 (8.7) y, and 55.4% were females. SU means (standard deviation) were 5.4 (1.4) at 1st visit, 5.2 (1.4) at 2nd visit, and 5.1(1.3) mg/dL at 3rd visit. The HU incidence rate was 8.87 per 1000 person-y. Each additional point in adherence to the DASH diet accelerated SU decline (P< 0.01) and lowered the incidence of HU by 4.3% (IRR: 0.957; 95% CI: 0.938,0.977) in adjusted model. ConclusionThe present study findings reinforce the importance of encouraging the DASH diet as a healthy dietary pattern to control and reduce the SU concentrations and risk of HU.

Untangling the relationship between bempedoic acid and gout: results from a systematic literature review.

Bempedoic acid (BA) is a small-molecule first-in-class of inhibitor of ATP citrate lyase that significantly lowers low-density lipoproteins cholesterol (LDL-c) in statin-intolerant and inadequate responders. Increased serum uric acid (SUA) levels and gout incidence have been described in BA-treated patients. The aim of this systematic review was to investigate the safety of BA regarding SUA levels and gout in randomised controlled trials (RCTs). A search on 7 databases was performed from inception to May 4, 2023. RCTs of BA monotherapy or combination with other lipid-lowering treatment (LLT) in patients with increased LDL-c were included. Dual data extraction was performed with disagreements resolved through consensus. Due to the methodological purpose of this review risk-of-bias assessment of studies was not performed. 6 Phase 3 RCTs (N = 17,975 patients of which 9,635 received BA) 9 Phase 2 RCTs (N = 362 patients of which 170 received BA) and an open-label extension of a Phase 3 RCT were included. Gout and/or hyperuricemia were not mentioned as exclusion criteria, previous/current use of urate-lowering therapies (ULT) and/or colchicine and/or dietary patterns were not reported. Phase 3 RCTs: 2 studies specified the number of patients experiencing hyperuricemia over the study period (BA: 4.9%-11%; placebo: 1.9%-5.6%) and the effect size was significant only in 1 study (OR = 2.0, 95% CI 1.8-2.3). Four RCTs reported a higher incidence of gout in the BA arm however, when we calculated the effect size, it was small and often not significant. Two studies reported 0 cases of gout. The paucity of information about SUA levels at baseline and/or at the end of follow-up do not allow us to quantify the effect sizes for BA-induced SUA elevation. Data on gout from Phase 2 RCTs is scant. Data from phase 2 and 3 RCTs do not allow for confirming a clear association between BA and gout. It is conceivable that a careful assessment of SUA levels/history of gout at baseline and the concomitant use of urate-lowering agents may be instrumental to minimise the risk of new-onset gout/gout flares in patients treated with BA.

Sex and country differences in gout: cross-country comparison between Sweden and the UK

Objective Compare characteristics, sex differences, and management of gout in Sweden and the UK. Method The results from two separate primary care gout surveys from Sweden and the UK were compared. Participants aged ≥18 years with gout were sent a questionnaire asking about lifestyle, gout characteristics, uratelowering therapy (ULT), comorbidities, disability, and disease impact. For sex comparison, participants were pooled across countries. Results In total, 784 (80% male) participants from Sweden and 500 (87% male) from the UK were included. Swedish patients were significantly older at gout onset, mean (SD) age 72 (12) versus 63 (13) years, (p<0.0001), with more comorbidities, and more frequent use of ULT (48% vs 35%, p=0.0005, age-adjusted). Use of alcohol and diuretics was significantly more common among UK patients, who also reported a higher number of gout flares, mean (SD) 2.2 (1.7) versus 1.6 (3.6), (p=0.003) age-adjusted. Females with gout were older at gout onset, mean (SD) age 67 (13) versus 56 (15), (p<0.0001), more often obese, and reported higher use of diuretics. Furthermore, females reported greater impact of gout, more pain and physical limitations, whereas no sex differences were seen in ULT or flares. Conclusions In the UK, gout was more frequently associated with modifiable risk factors. People with gout in Sweden were more commonly taking ULT and had lower frequency of gout flares and impact of gout. Females with gout more commonly took diuretics, had higher body mass index, and reported greater physical disability, which should be considered when managing gout in women.

Urate-Lowering Therapy Use among US Adults with Gout and the Relationship between Patients’ Gout Treatment Status and Associated Comorbidities

Gout is one of the most common inflammatory conditions with a growing global prevalence. Individuals with gout are at higher risk of developing chronic conditions, such as diabetes, chronic kidney disease (CKD), and cardiovascular diseases. In this study, the association between urate-lowering therapy (ULT) use and the prevalence of these conditions was evaluated. This observational cross-sectional pharmacoepidemiologic study used the 2013–2018 biannual cycles of the National Health and Nutrition Examination Survey. The inclusion criteria were adults that were 30 years of age or older that had a diagnosis of gout. The association between patients’ ULT treatment status and dyslipidemia, coronary heart disease, heart failure, hypertension, and chronic kidney disease was evaluated as well as its association with select clinical laboratory biomarkers. The prevalence of ULT use was 28.9% (95% CI 24.3–33.9%). Those receiving ULT had a higher prevalence of CKD diagnoses, of a college graduate or higher and of health insurance coverage, and they were older obese males. There was no significant association between ULT use and the prevalence of heart failure, coronary heart disease, hypertension, or dyslipidemia (p &gt; 0.05). Those receiving ULT had lower high-sensitivity c-reactive protein levels compared to those who were not on treatment (4.74 versus 7.21 mg/L, p = 0.044). LDL and total cholesterol were significantly lower among those receiving ULT treatment (p &lt; 0.05). ULT use continues to be low among US individuals diagnosed with gout. Socioeconomic factors may influence patients’ ULT treatment status. Also, gout risk factors, including obesity, male sex, and CKD, are associated with receiving ULT. While our findings may have reflected the guideline recommendations for ULT use in CKD patients, worsening kidney functions while receiving ULT is unlikely. Gout patients receiving ULT may garner added health benefits beyond lower urate levels. Further research is necessary to determine the long-term impact of ULTs on lipid fractions, kidney functions, and other cardiovascular biomarkers.

Monitoring and Achievement of Target Serum Urate Among Gout Patients Receiving Long-Term Urate-Lowering Therapy in the American College of Rheumatology RISE Registry.

The American College of Rheumatology's (ACR) 2020 guidelines for the management of gout recommend using a treat-to-target approach to lower serum urate (SU). Using the ACR's Rheumatology Informatics System for Effectiveness registry, we examined the use of a treat-to-target approach among gout patients receiving long-term urate-lowering therapy (ULT) and followed longitudinally by rheumatologists. Included patients had one or more diagnoses for gout in 2018-2019 and continuous use of ULT for ≥12 months. We assessed the proportions of patients with SU monitoring and, among those tested, who achieved SU <6.0 mg/dl during the measurement year. Multilevel logistic regression adjusting for sociodemographics, comorbidities, region, and health care utilization was used to determine factors associated with SU monitoring and achievement of target SU. A total of 9,560 were included. The mean ± SD age was 67.2 ± 12.7 years, 73.5% of patients were male, and 32.3% were non-White. Fifty-six percent of patients had at least 1 SU recorded during the measurement year; among patients with at least 1 SU recorded, 74% achieved the SU target. In multivariate analyses, non-White patients were slightly less likely to be tested or achieve a target SU. Among gout patients receiving long-term ULT followed longitudinally by rheumatologists, more than half had a documented SU, and among those tested, three-quarters achieved the recommended SU target. Routine monitoring of SU is a first step toward improving quality of care for patients with gout.

Achievement of serum uric acid target by rheumatology clinic pharmacists compared with primary care providers in patients with gout

BackgroundThe American College of Rheumatology strongly recommends a treat-to-target management strategy to achieve and maintain serum uric acid (sUA) less than 6 mg/dL to decrease risk of gouty flare recurrence and permanent joint damage. ObjectiveTo compare the effectiveness of rheumatology clinic pharmacists and primary care providers (PCPs) in achieving a target sUA goal in patients with gout. MethodsThis retrospective chart review included patients aged 18 years and older starting urate-lowering therapy (ULT) (allopurinol, febuxostat, or probenecid) for gout between January 1, 2015, and December 31, 2019. Exclusion criteria were ULT use within the previous 6 months, baseline sUA less than 6 mg/dL, and death within 12 months of starting ULT. From ULT initiation, data were collected until sUA less than 6 mg/dL was achieved or a maximum of 12 months. The primary outcome was the percentage of patients who achieved sUA less than 6 mg/dL. Key secondary outcomes were percent reduction in sUA and time to sUA target achievement. ResultsOf 62 patients included in each group, 75.8% of patients in the pharmacist cohort versus 30.6% of patients in the PCP cohort achieved target sUA less than 6 mg/dL (odds ratio 7.09, 95% confidence interval 3.28–16.11, P < 0.001). Patients in the pharmacist-managed group also achieved a greater reduction in mean sUA (−36.7% vs. −26.9% respectively, P = 0.001). Among patients achieving target sUA, median time to target was similar at 92 and 86 days, respectively, despite significantly lower initial mean allopurinol doses in the pharmacist-managed group (102 mg/d vs. 145 mg/d, P < 0.001). ConclusionThe odds of achieving target sUA within 12 months were 7 times higher if gout was managed by a rheumatology clinic pharmacist as compared with a PCP. This study suggests the need for prescriber education and supports expansion of pharmacist-led gout management to primary care settings.

Gout in Dalarna, Sweden – a population-based study of gout occurrence and compliance to treatment guidelines

Objective This study aimed to describe the incidence and prevalence of gout, describe the use of allopurinol among prevalent gout cases, and determine persistence with allopurinol and degree of compliance with treat-to-target recommendations before and after the publication of Swedish national guidelines in 2016. Method Prospectively registered data on gout diagnoses and allopurinol prescriptions were used to calculate incidence and prevalence, and the proportion of prevalent patients on allopurinol. Gout patients starting allopurinol during 2013–2015 versus 2016–2018 were compared regarding persistence and compliance with treat-to-target principles. Results The incidence of gout was 221–247 per 100 000 person-years during 2014–2019, prevalence in 2018 was 2.45%. Among prevalent cases, the proportion on allopurinol ranged from 21% to 25%. Allopurinol persistence was better for individuals starting therapy during 2016–2018 compared with 2013–2015 (45% vs 39%, p = 0.031), as were several outcomes related to treat-to-target principles, e.g. measuring baseline serum urate (SU) (84% vs 77%, p < 0.001), follow-up SU (50% vs 36%, p < 0.001), and the proportion of patients reaching an SU level < 360 µmol/L (45% vs 30%, p < 0.001). Conclusion Incidence and prevalence were slightly higher than in previous Swedish reports. Allopurinol use among prevalent gout patients did not increase during 2014–2019. Only a minor improvement in persistence was seen, and a moderate increase in compliance with guidelines, suggesting a need for improved management and extended patient involvement to increase and optimize the use of urate lowering therapy.

Lowering Uric Acid May Improve Prognosis in Patients With Hyperuricemia and Heart Failure With Preserved Ejection Fraction.

Background An association between uric acid (UA) and cardiovascular diseases, including heart failure (HF), has been reported. However, whether UA is a causal risk factor for HF is controversial. In particular, the prognostic value of lowering UA in patients with HF with preserved ejection fraction (HFpEF) is unclear. Methods and Results We enrolled patients with HFpEF from the PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction) registry. We investigated whether UA was correlated with the composite events, including all-cause mortality and HF rehospitalization, in patients with hyperuricemia and HFpEF (UA >7.0 mg/dL). Additionally, we evaluated whether lowering UA for 1 year (≥1.0 mg/dL) in them reduced mortality or HF rehospitalization. We finally analyzed 464 patients with hyperuricemia. In multivariable Cox regression analysis, UA was an independent determinant of composite death and rehospitalization (hazard ratio [HR], 1.15 [95% CI, 1.03-1.27], P=0.015). We divided them into groups with severe and mild hyperuricemia according to median estimated value of serum UA (8.3 mg/dL). Cox proportional hazards models revealed the incidence of all-cause mortality was significantly higher in the group with severe hyperuricemia than in the group with mild hyperuricemia (HR, 1.73 [95% CI, 1.19-2.25], P=0.004). The incidence of all-cause mortality was significantly decreased in the group with lowering UA compared with the group with nonlowering UA (HR, 1.71 [95% CI, 1.02-2.86], P=0.041). The incidence of urate-lowering therapy tended to be higher in the group with lowering UA than in the group with nonlowering UA (34.9% versus 24.6%, P=0.06). Conclusions UA is a predictor for the composite of all-cause death and HF rehospitalization in patients with hyperuricemia and HFpEF. In these patients, lowering UA, including the use of urate-lowering therapy, may improve prognosis.

Association between urate-lowering therapies and cognitive decline in community-dwelling older adults

Long-term use of urate-lowering therapies (ULT) may reduce inflammaging and thus prevent cognitive decline during aging. This article examined the association between long-term use of ULT and cognitive decline among community-dwelling older adults with spontaneous memory complaints. We performed a secondary observational analysis using data of 1673 participants ≥ 70 years old from the Multidomain Alzheimer Preventive Trial (MAPT Study), a randomized controlled trial assessing the effect of a multidomain intervention, the administration of polyunsaturated fatty acids (PUFA), both, or placebo on cognitive decline. We compared cognitive decline during the 5-year follow-up between three groups according to ULT (i.e. allopurinol and febuxostat) use: participants treated with ULT during at least 75% of the study period (PT ≥ 75; n = 51), less than 75% (PT < 75; n = 31), and non-treated participants (PNT; n = 1591). Cognitive function (measured by a composite score) was assessed at baseline, 6 months and every year for 5 years. Linear mixed models were performed and results were adjusted for age, sex, body mass index (BMI), diagnosis of arterial hypertension or diabetes, baseline composite cognitive score, and MAPT intervention groups. After the 5-year follow-up, only non-treated participants presented a significant decline in the cognitive composite score (mean change − 0.173, 95%CI − 0.212 to − 0.135; p < 0.0001). However, there were no differences in change of the composite cognitive score between groups (adjusted between-group difference for PT ≥ 75 vs. PNT: 0.144, 95%CI − 0.075 to 0.363, p = 0.196; PT < 75 vs. PNT: 0.103, 95%CI − 0.148 to 0.353, p = 0.421). Use of ULT was not associated with reduced cognitive decline over a 5-year follow-up among community-dwelling older adults at risk of dementia.

Change in serum urate level with urate-lowering therapy initiation associates in the immediate term with patient-reported outcomes in people with gout

ObjectiveTo examine the associations of changes in serum urate (SU) with health-related quality of life (HRQOL) in gout. MethodsWe used the first 6-months of data from four interventional trials and one observational, open-label study of urate-lowering therapy (ULT) use. HRQOL were assessed at baseline and every 3-months, and SU was measured monthly. Primary outcome measures were Short-form 36 physical and mental component summary scores, Health Assessment Questionnaire Disability Index (HAQ-DI), Sheehan Disability Scale (SDS), Patient Global Assessment, and pain scores in the last week. Linear mixed models for each outcome were adjusted as appropriate for current SU, change in urate in the last month, number of flare-affected days in the last month, baseline BMI, age, comorbidities, sex, ethnicity, trial/study and treatment combination, and tophi status (fixed effects); subject, and the trial/study month were random effects. ResultsHigher current SU correlated with reduced physical and mental HRQOL, and increased SDS and pain but not with HAQ-DI score. In the first 6-months of new/escalating ULT use, absolute change in SU levels associated with poorer outcomes on the HAQ-DI scale (β (95% CI) = 0.013 (0.007–0.019)) and poorer outcomes on SDS, SF-36 MCS, patient global and pain scales. Reduction of SU associated with poorer outcomes in all six measures. ConclusionHigh SU levels were associated with poorer HRQOL, pain and Sheehan disability score. Recent SU level fluctuations are associated with poorer outcomes, primarily driven by a reduction in SU. Clinical emphasis on slow rather than fast SU reduction and the routine use of effective, anti-inflammatory medications at ULT initiation/escalation may avoid short-term poor outcomes.

The use of febuxostat in comorbid patients with gout in real clinical practice: own data

Objective: to evaluate the efficacy and safety of febuxostat (Azuriks®) in the treatment of patients with gout and concomitant diseases.Patients and methods. An observational, open-label, single-centre study of the results of febuxostat use in 85 gout patients with insufficient prior allopurinol efficacy or its intolerance. The median age of patients was 56.2 [49; 59] years, among them 83.5% were men. All patients had comorbid diseases, mainly cardiovascular pathology (76.5%) and chronic kidney disease (60%). The achievement of target values of uric acid (UA) during 4 months of urate-lowering therapy and its safety were assessed.Results and discussion. After 4 months of therapy with febuxostat, 25% of patients reached the target values of UA. Exacerbations at an early stage of the use of urate-lowering therapy were rare and were characterized by a lesser severity of the articular syndrome. Normalization of purine metabolism was accompanied by a decrease in the laboratory activity index (CRP level) to values corresponding to the interictal period of gout. Febuxostat was well tolerated.Conclusion. According to the data obtained, in patients with gout and concomitant diseases, febuxostat allows reaching target UA values in a short time without dose titration, while a high safety profile is noted.

OP0164 A POPULATION-BASED, PROSPECTIVE METABOLOMICS STUDY IN THE UK BIOBANK IDENTIFIES GLYCOPROTEIN ACETYLS AS A NOVEL BIOMARKER OF INCIDENT GOUT

BackgroundSerum urate (SU) level is the strongest known causal predictor of clinical gout, but only ~20% with prolonged hyperuricemia develop gout, motivating the need for additional biomarkers for risk prediction and stratification. The metabolome represents a compelling intermediate trait between genome and phenome to elucidate disease mechanisms. Multiple cross-sectional studies of prevalent gout from men in Asia have been conducted, but no prospective data for incident gout (prediagnostic metabolome) are available.ObjectivesOur objectives were to (1) conduct a discovery-based metabolome-wide study to identify novel biomarkers of incident gout; and (2) replicate novel metabolomic biomarkers of gout in independent samples.MethodsWe conducted a prospective cohort analysis of 105,703 UK Biobank (UKB) participants (46% males, mean age 57.2 years) with targeted NMR metabolomic profiling (N=168 metabolites, including routine lipids and amino acids) available from baseline samples (2006-10), and no prior diagnosis of gout or urate lowering therapy use. Incident cases of gout were documented from linked medical records until gout diagnosis, death, or end of study period (Dec 31/19). We used Cox proportional hazard models to obtain hazard ratios (HR) and 95% confidence intervals (CIs) per standard deviation (SD) increase in each of the 168 metabolites to determine associations with incident gout.To replicate our findings, we assessed association of metabolome-wide significant metabolites in a replication set, restricted to 4,804 non-overlapping participants who provided blood in the repeat assessment visit (2012-13).ResultsDuring a median 10.4 years follow-up, we documented 1,367 cases of incident gout in the discovery set. After correction for multiple comparisons, glycoprotein acetyls (GlycA) were positively associated with risk of incident gout (multivariable HR per 1SD increase = 1.34 (1.27 to 1.41), P = 9.04x 10-28) after adjusting for age, sex, and lifestyle and clinical covariates (Table 1). This association persisted even after SU adjustment (HR 1.07, P = 0.0091). In the replication set, among 4,804 participants followed for a median of 6.8 years, we documented 22 cases. In this dataset, we replicated GlycA association with incident gout (multivariable HR per 1SD increase =1.56 (1.08 to 2.25), P = 0.017).Table 1.Association of glycoprotein acetyls (GlycA) with risk of incident gout in the UK BiobankModelUnivariable HR, (95% CI)PMultivariable HR, (95% CI)PDiscovery (N= 105,703)Per Standard deviation:GlycA, per SD1.48 (1.41 to 1.60)3.7x10-591.34 (1.27 to 1.41)9.04x 10-28Categorized as quintiles:GlycA, Q11.0 Ref1.0 RefGlycA, Q21.43 (1.13 – 1.80)0.0021.30 (1.03 – 1.64)0.0252GlycA, Q32.06 (1.66 – 2.56)4.88 x 10-111.73 (139 – 2.15)7.64 x 10-07GlycA, Q42.53 (2.05 – 3.12)4.15 x 10-181.98 (1.60 – 2.45)3.96 x 10-10GlycA, Q53.70 (3.02 – 4.52)3.21 x 10-372.63 (2.12 – 3.23)2.01 x 10-19Replication (N= 4804)Per Standard deviation:GlycA, per SD1.65 (1.19 to 2.29)0.00271.56 (1.08 to 2.25)0.01721 Hazard ratios (HR) and 95% confidence intervals (CIs) obtained after adjusting for the first 4 genomic principal components (controlling for population stratification), age, sex, fasting (&lt;4 hrs, 4-8 hrs and ≥8 hrs), smoking (never, former, current), freq of alcohol, BMI, diabetes (yes/no) and hypertension at baseline (yes/ no).ConclusionIn this large-scale, prospective metabolomics study, we identified and independently replicated our findings that plasma levels of GlycA are associated with incident gout in UKB participants. GlycA is novel for gout, though this pro-inflammatory biomarker has predicted risk of other cardiometabolic-inflammatory phenotypes, independent of CRP.1 These findings may provide insight into the metabolic-inflammatory pathogenesis of gout, with implications for risk prediction, even beyond SU, but call for further investigation with more extensive metabolome profiling and external replication.

Urate-lowering therapy for patients with gout on hemodialysis.

ObjectiveGout is the most common form of inflammatory arthritis and is caused by deposition of monosodium urate crystals resulting from a high burden of uric acid (UA). High UA burden also has been associated with increased morbidity and mortality in the general population and progression to chronic kidney disease. In persons with gout and end‐stage renal disease (ESRD), prior studies suggest that UA levels decrease after initiation of hemodialysis (HD). We evaluated UA level and the use of urate‐lowering therapies (ULTs) in patients with gout and ESRD on HD.MethodsWe performed a retrospective review of patients with gout and ESRD seen at a large urban public hospital (The MetroHealth System). We extracted data from the medical record (Epic) for patients diagnosed with gout and ESRD on HD. The main outcomes were the UA level and the use of ULTs before and after HD initiation.ResultsWe identified 131 patients with gout on HD. Of these, 21 patients had crystal proven gout diagnosis, 10 of whom had data on UA level pre‐HD and post‐HD and were included in the analysis. For the total sample (N = 21), the mean age was 65 years, 7 were female and 20 were African American. Mean pre‐HD and post‐HD UA levels were 8.4 and 3.98 mg/dL respectively. Twenty‐one patients were receiving ULT pre‐HD, 11 discontinued post‐HD.ConclusionAmong patients with gout and ESRD, we observed a decrease in UA level associated with initiation of HD. For this group, discontinuation of ULTs may be appropriate.

To Treat or Not to Treat? Effect of Urate-Lowering Therapy on Renal Function, Blood Pressure and Safety in Patients with Asymptomatic Hyperuricemia: A Systematic Review and Network Meta-Analysis.

Hyperuricemia is associated with increased cardiovascular risk. Because patients with asymptomatic hyperuricemia (AH) experience no immediate discomfort and there are possible side effects of urate-lowering drugs, treatment for AH is controversial. We aimed to perform a network meta-analysis (NMA) to investigate the effects of different urate-lowering therapies (ULTs) on serum uric acid level, renal function, blood pressure (BP), and safety in AH patients. This NMA focused on AH patients. The intervention group (patients receiving urate-lowering drugs) was compared with others using other types of drugs, placebo, or usual care. We undertook a NMA under the frequentist framework by R. Thirteen eligible trials were identified. The interventions included allopurinol, febuxostat, and benzbromarone, which are not approved in the United States. Benzbromarone and allopurinol had the best efficacy on lowering serum uric acid level in short-term and long-term follow-up (mean difference [MD] = -3.05; 95% CI, -5.19 to -0.91 vs MD = -3.17; 95% CI, -5.19 to -1.15). Patients using allopurinol had significantly higher eGFR than using placebo in both short-term and long-term follow-up (MD = 3.07; 95% CI, 0.18 to 5.95 vs MD = 4.10; 95% CI, 2.66 to 5.54). No difference in BP was found between groups, except for febuxostat to diastolic BP after long-term treatment (MD = -1.47; 95% CI, -2.91 to -0.04). No statistically increased odds of safety events were found with the use of ULT. Our result showed that in AH patients, allopurinol has a renoprotective effect. Febuxostat has a significant impact in lowering diastolic BP. ULT does not result in a higher risk of safety events.

Management of asymptomatic hyperuricemia in chronic kidney disease: A proposed stepwise approach

Serum uric acid levels are frequently elevated in patients with chronic kidney disease (CKD). The relatively modest hyperuricaemia in CKD may reflect the reduced efficiency of renal excretion of urate. In the past two decades, basic research has shown that hyperuricaemia plays a causal role in the progression of CKD through direct renal injury. However, clinical studies have reported conflicting results, hence there is much controversy about the scope of treating asymptomatic hyperuricaemia to prevent or reduce the rate of CKD progression. In this review, we highlight the most recent guidelines and clinical trials that tested the use of urate-lowering therapy in the management of asymptomatic hyperuricaemia in CKD patients. Keywords: uric acid, hyperuricaemia, chronic kidney disease

Generalized pain hypersensitivity and associated factors in gout.

ObjectivesPrevious studies have indicated that a sizeable proportion of patients with inflammatory arthritis present with features characteristic of central pain sensitization. However, this has not yet been examined in patients with gout. The objective of this study was to explore the presence of generalized pain hypersensitivity and associated factors in patients with diagnosed gout.MethodsA cross-sectional survey was performed in outpatients with crystal proven gout using the generalized pain questionnaire (GPQ) to screen for the presence of generalized pain hypersensitivity. Additional self-reported socio-demographic and medical information was collected and several patient-reported outcome measures were completed. Univariable logistic regressions and multivariable LASSO regression analysis with 10-fold cross-validation was used to explore relationships with patient characteristics, clinical features and PROMs.ResultsOf the 97 included patients (84.5% male; mean (s.d.) age: 68.9 ± 11.9 years), 20 patients (20.6%, 95% CI: 13.0, 30.0) reported possible generalized pain hypersensitivity defined as a GPQ score ≥11 (range: 0–28; mean (s.d.) GPQ: 6.3 ± 5.3). Lower age, concomitant fibromyalgia and more experienced difficulties in performing their social role were independently associated with generalized pain hypersensitivity. Notably, use of urate lowering therapy was significantly lower in those with generalized pain hypersensitivity.ConclusionsGeneralized pain hypersensitivity appears to be quite common in gout, despite its more intermittent nature compared with other inflammatory arthritides. As this kind of pain does not respond well to regular treatment, screening for non-inflammatory pain may be important for improving pain management in gout.

Design and implementation of a Pacific intervention to increase uptake of urate-lowering therapy for gout: a study protocol

BackgroundGout is a painful chronic disease which disrupts work and family life and can lead to chronic joint damage. Pacific people in Aotearoa/New Zealand experience significant inequities, with over three times the gout prevalence of the non-Pacific non-Māori populations. Pacific people receive less regular urate-lowering drugs to prevent gout flare-ups, and have nine times the hospitalisation from gout compared with non-Pacific non-Māori people. Rates for Indigenous Māori lie between Pacific and non-Pacific non-Māori. A long-established Collective comprising community members from the Pacific People’s Health Advisory Group, clinical staff from the Pacific Practice-Based Research Network, and University of Auckland researchers have identified that improving Pacific urate-lowering therapy use as the research question of prime importance for improved health outcomes of Pacific people in South Auckland. Building on the existing knowledge, this study aims to develop, implement and evaluate a novel innovative intervention to improve the uptake of urate-lowering therapy by Pacific patients with gout.MethodsThree-phase mixed methods co-design study using the Fa’afaletui research framework following the STROBE statement. Phase1 is observational times series of prevalence of patients with gout, proportion with urate blood-level monitoring and use of urate-lowering medication over past 5 years. In Phase 2 the Collective will workshop new interventions to address previous uptake barriers, using culturally-appropriate Talanga communications with results synthesised in line with Kakala principles. The designed intervention will be implemented and process and outcome evaluations conducted. Finally, an implementation framework will be produced to facilitate further roll-out.DiscussionThe study aims to enhance health and reduce inequities for Pacific people, contribute to creation of Pacific health knowledge and translation of research findings into Pacific health gains. Potential longer-term impact is a gout-management pathway for use throughout Aotearoa/New Zealand. Māori have similar issues with high gout prevalence and low urate-lowering therapy use hence the intervention is likely to translate to Māori healthcare. The project will contribute to Pacific research capacity and capability-building as well as general upskilling of community and practice members involved in the co-design processes.Trial registrationThe Australian New Zealand Clinical Trial Registry is in process, request number 38206, 1-09-2021.

Regular pre-admission urate-lowering therapy and serum urate testing are associated with a shorter hospital length of stay in people with gout: A nation-wide population-based cohort study.

This study aims to explore the association between inpatient gout flare-related variables and the length of stay (LOS) in hospitalized people with comorbid gout. Using data from the Aotearoa/New Zealand national data collections, this cohort study included adults with comorbid gout who were admitted to publicly funded hospitals during 2017 for reasons other than gout. The primary outcome was LOS. Association between 20 variables and the LOS was explored using two generalized linear models. Directed acyclic graph (DAG) was constructed to evaluate the causal relationship between pre-admission urate lowering therapy (ULT) and LOS. The cohort included 36 047 admissions. We identified five variables associated with shorter LOS (pre-admission regular urate-lowering therapy (ULT), serum urate testing, male gender, Māori ethnicity and low-dose aspirin) and seven variables associated with longer LOS (M3 multimorbidity index, acute admission, operation, loop diuretics, potassium-sparing diuretics, NSAIDs, and age). Regular ULT had the strongest impact on shorter LOS (10% shorter). The model estimated an additional four days of hospitalization if the patient had multiple variables associated with longer LOS. DAG suggested a causal relationship between regular ULT and LOS under the condition that all unobserved confounders affected only ULT use, with no impact on in-hospital gout flares and/or LOS except through its influence on ULT use or as mediator of confounders that were observed. We have identified a set of gout flare-related variables found to be associated with LOS in hospitalized people with comorbid gout. Pre-admission ULT may help reduce the LOS in such patients.