Are patients with gout with negative dual-energy computed tomography for monosodium urate crystal deposition easy-to-treat?

OBJECTIVES: To determine the clinical associations and predictive value of two thresholds of negative dual-energy CT (DECT) for MSU crystal deposition in gout patients initiating urate lowering therapy (ULT), and identify which threshold is more clinically relevant. METHODS: Patients from the CRYSTALILLE cohort with a diagnosis of gout naive to ULT with baseline DECT scans of knees and feet were selected. Two thresholds of positivity for DECT detection of MSU crystal deposition were considered (<0.01 cm3 and <0.1 cm3). Baseline characteristics and the prediction of key outcomes after ULT initiation including reaching serum urate (SU) levels <6.0 and 5.0 mg/dl and occurrence of flares at 6, 12 and 24 months, associated with both thresholds of negative DECTs were compared with those of. PATIENT: s having positive DECT scans. RESULTS: 211 patients aged 66.2 years [57; 75.8] with a symptom duration of 3 years [0; 7.8] were included. 38/211 (18%) and 90/211 (43%) had negative DECT scans for the 0.01 and 0.1 cm3 thresholds, respectively. Factors associated with negative DECT scans were younger age, shorter symptom duration, and absence of cardiovascular disease for both volume thresholds. 9/39 (23.1%), 3/26 (11.5%), and 1/18 (5.6%) of patients with <0.1 cm3 MSU crystals had flares at 6, 12 and 24 months, respectively, compared with 18/45 (40.0%), 9/36 (25.0%) and 2/18 (11.1%) patients with ≥0.1 cm3 (p> 0.05).Overall, 95 patients (68.3%) reached SU levels <6.0 mg/dl and 68 (48.9%) <5.0 mg/dl, without any difference between positive and negative DECTs, with ULT dosages which tended to be lower in patients with negative DECT. CONCLUSION: The 0.1 cm3 threshold was better correlated to clinical presentation and evolution than 0.01 cm3. Patients with gout with negative DECTs exhibit milder disease and a lower comorbidity burden. They do not exhibit particularly easy-to-treat hyperuricemia, but may have a lower risk of flares.

The COMPARE head-to-head, randomized controlled trial of SEL-212 (pegadricase plus rapamycin-containing nanoparticle, ImmTOR™) versus pegloticase for refractory gout.

OBJECTIVES: Serum urate (SU) lowering with PEGylated uricases in gout can reduce flares and tophi. However, treatment-emergent anti-drug antibodies adversely affect safety and efficacy and the currently approved PEGylated uricase pegloticase requires twice-monthly infusions. Investigational SEL-212 therapy aims to promote uricase-specific tolerance via monthly sequential infusions of a proprietary rapamycin-containing nanoparticle (ImmTOR) and pegadricase. METHODS: COMPARE was a randomized, phase 2, open-label trial of SEL-212 vs pegloticase in adults with refractory gout. SEL-212 [ImmTOR (0.15 mg/kg) and pegadricase (0.2 mg/kg)] was infused monthly or pegloticase (8 mg) twice monthly for 6 months. The primary endpoint was the proportion of participants with SU <6 mg/dl for ≥80% of the time during 3 and 6 months. Secondary outcomes were mean SU, gout flares, number of tender and/or swollen joints and safety. RESULTS: During months 3 and 6 combined, numerically more participants achieved and maintained a SU <6 mg/dl for ≥80% of the time with SEL-212 vs pegloticase (53.0% vs 46.0%, P = 0.181). The percentage reductions in SU levels were statistically greater during months 3 and 6 with SEL-212 vs pegloticase (-73.79% and -47.96%, P = 0.0161). Reductions in gout flare incidence and number of tender and/or swollen joints were comparable between treatments. There were numerical differences between the most common treatment-related adverse events of interest with SEL-212 and pegloticase: gout flares (60.2% vs 50.6%), infections (25.3% vs 18.4%) and infusion-related reactions (15.7% vs 11.5%), respectively. Stomatitis (and related terms) was experienced by eight participants (9.6%) with SEL-212 and none with pegloticase. Stomatitis, a known event for rapamycin, was associated with ImmTOR only. CONCLUSIONS: SEL-212 efficacy and tolerability were comparable to pegloticase in refractory gout. This was associated with a substantial reduction in treatment burden with SEL-212 due to decreased infusion frequency vs pegloticase. CLINICAL TRIAL REGISTRATION: NCT03905512.

Assessing the causal relationships of gut microbial genera with hyperuricemia and gout using two-sample Mendelian randomization.

BACKGROUND AND AIMS: The causal relationship between gut microbiota and gout and hyperuricemia (HUA) has not been clarified. The objective of this research was to evaluate the potential causal effects of gut microbiota on HUA and gout using a two-sample Mendelian randomization (MR) approach. METHODS AND RESULTS: Genetic instruments were selected using summary statistics from genome-wide association studies (GWASs) comprising a substantial number of individuals, including 18,473 participants for gut microbiome, 288,649 for serum urate (SU), and 763,813 for gout. Two-sample MR analyses were performed to determine the possible causal associations of gut microbial genera with the risk of HUA and gout using the inverse-variance weighted (IVW) method, and robustness of the results was confirmed by several sensitivity analyses. A reverse MR analysis was conducted on the bacterial taxa that were identified in forward MR analysis. Based on the results of MR analyses, Escherichia-Shigella (OR = 1.05; 95% CI, 1.01-1.08; P = 0.009) exhibited a positive association with SU levels, while Lachnospiraceae NC2004 group (OR = 0.95; 95% CI, 0.92-0.98; P = 0.001) and Family XIII AD3011 group (OR = 0.94; 95% CI, 0.90-0.99; P = 0.015) were associated with a reduced HUA risk. Moreover, Coprococcus 3 (OR = 1.17, 95% CI: 1.01-1.34, P = 0.031) was causally associated with a higher gout risk. In reverse MR analysis, no causal relationships were identified between these bacterial genera and HUA or gout. CONCLUSION: This study provides evidence for a causal association between gut microbial genera and HUA or gout, and further investigations of the underlying mechanism are warranted.

Patient factors and health outcomes associated with illness perceptions in people with gout.

OBJECTIVE: Illness perceptions are views and beliefs formed in response to a health threat which may influence self-management behaviours and chronic disease outcomes. Despite effective medication, sub-optimal outcomes in gout are common. This study aimed to quantitatively investigate illness perceptions in gout to examine how illness perceptions relate to health outcomes. METHODS: Data were obtained from a randomised-controlled trial where people with gout (n = 493) completed surveys measuring illness perceptions (Brief Illness Perception Questionnaire (B-IPQ)), gout flares, medication adherence, health-related quality of life, healthcare utilisation and productivity, alongside serum urate blood tests at baseline, 6- and 12-month follow-ups. Multivariable linear regression identified patient factors independently associated with each B-IPQ item score. Logistic and linear regression, adjusted for age and sex, determined whether baseline B-IPQ items could predict current and future health outcomes. RESULTS: Younger individuals and those with severe gout were more likely to experience pessimistic illness perceptions at baseline. Optimistic illness perceptions were associated with lower odds of having at least one flare in the preceding 6 months. Every 1-point increase in B-IPQ treatment control, indicating the optimistic view that gout is treatable, decreased the odds of a recent flare prior to baseline by 33% (OR : 0.67; 95%CI : 0.53,0.85; p< 0.001) and prior to 12-month follow-up by 15% (OR : 0.85; 95%CI : 0.76,0.96; p= 0.01). Pessimistic illness perceptions also predicted poorer medication adherence, health-related quality of life and productivity but not serum urate levels. CONCLUSION: Modifying pessimistic illness perceptions, including, but not limited to, patient education, may promote prudent self-management behaviours and better outcomes in gout. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; https://www.anzctr.org.au/; ACTRN12616000455460.

Relationship between rs4349859 and rs116488202 polymorphisms close to MHC-I region and serum urate levels in patients with gout.

BACKGROUND: Gout is the most common inflammatory rheumatic disease and elevated levels of serum urate (SU) are the main cause for its development. Major histocompatibility complex class 1 (MHC-1) plays an important role in the development of multiple inflammatory diseases; however, there is little evidence of its involvement in gout. The present study focused on evaluating the association of the rs4349859 and rs116488202 single nucleotide polymorphisms (SNPs) close to the MHC-1 region in patients with gout. METHODS AND RESULTS: One hundred and seventy-six individuals of Mexican origin were included, of which 81 were patients with primary gout and 95 were healthy controls. The rs4349859 and rs116488202 SNPs were genotyped using TaqMan probes by allelic discrimination by real-time PCR. Serum concentrations of biochemical parameters were measured with enzymatic methods. Descriptive statistics were applied and P-values < 0.05 were considered significant. It was observed that the rs4349859 and rs116488202 SNPs showed significant association with the risk of gout (OR = 146, 95%CI = 44.8-480.2, P < 0.01; OR = 2885, 95%CI = 265-31398, P < 0.01, respectively). Our results also showed significantly higher serum SU levels in gout patients with respect to controls (P < 0.01) in the carriers of the GA genotype compared with the GG genotype of the rs4349859 variant, and in the carriers of the CT genotype compared with the CC genotype of the rs116488202 variant. CONCLUSION: The study revealed that rs4349859 and rs116488202 SNPs close to MHC-I region confers strong susceptibility to gout in Mexican population, and the heterozygous genotypes of both were associated with higher levels of SU.

Initiation Dose of Allopurinol and the Risk of Severe Cutaneous Reactions in Older Adults With CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Allopurinol should be started at lower doses in patients with chronic kidney disease (CKD) to avoid adverse effects. We examined the risk of severe cutaneous reactions in older adults with CKD who were newly prescribed allopurinol at varied doses. STUDY DESIGN: Population-based cohort study using linked health care databases. SETTING & PARTICIPANTS: Patients in Ontario, Canada (2008-2019) aged ≥66 years, with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, and who were new users of allopurinol. EXPOSURE: A new prescription for allopurinol >100 mg/d versus a dose ≤100 mg/d. OUTCOME: The primary outcome was a hospital visit with a severe cutaneous reaction within 180 days of starting allopurinol. Secondary outcomes included all-cause hospitalization and all-cause mortality. ANALYTICAL APPROACH: The exposure and referent groups were balanced on indicators of baseline health using inverse probability of treatment weighting on the propensity score. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. RESULTS: Of 47,315 patients (median age, 76 years; median eGFR, 45 mL/min/1.73 m2), 55% started allopurinol at >100 mg/d. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of a severe cutaneous reaction: number of events (weighted), 103 of 25,802 (0.40%) versus 46 of 25,816 (0.18%), respectively (weighted RR, 2.25 [95% CI, 1.50-3.37]; weighted RD, 0.22% [95% CI, 0.12%-0.32%]. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of all-cause hospitalization but not with all-cause mortality. LIMITATIONS: This study was underpowered to detect risk differences in the association of allopurinol dose with outcomes across eGFR categories (ie, 45-59, 30-44, and <30 mL/min/1.73 m2). CONCLUSIONS: Older patients with CKD who started allopurinol at >100 mg/d versus ≤100 mg/d were twice as likely to visit a hospital with a severe cutaneous reaction in the next 180 days.

Sex-specific effect of serum urate levels on coronary heart disease and myocardial infarction prevention: A Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have examined serum urate levels in relation to coronary heart disease (CHD) and myocardial infarction (MI). Whether these associations are causal remains controversial, due to confounding factors and reverse causality. We aim to investigate the causality of these associations using Mendelian randomization method. METHODS AND RESULTS: Instrumental variables were obtained from the largest genome-wide association studies of serum urate (457,690 individuals) to date. Summary statistics were from CARDIoGRAMplusC4D consortium (60,801 CHD cases; 43,676 MI cases), FinnGen (21,012 CHD cases; 12,801 MI cases), UK Biobank (10,157 CHD cases; 7018 MI cases), and Biobank Japan (29,319 CHD cases). Inverse-variance weighted method was applied as the main results. Other statistical methods and reverse MR analysis were conducted in the supplementary analyses. Elevated genetically determined serum urate levels were associated with increased risks of CHD and MI. The association pattern remained for the datasets in FinnGen, the combined results of three independent data sources (CHD: odds ratio (OR), 1.10; 95%CI, 1.06-1.15; p = 4.2 × 10-6; MI: OR, 1.12; 95%CI, 1.07-1.18; p = 2.7 × 10-6), and East Asian population. Interestingly, sex-specific subgroup analyses revealed that these associations kept in men only, but not among women in individuals of European ancestry. No consistent evidence was found for the causal effect of CHD or MI on serum urate levels. CONCLUSION: We provide consistent evidence for the causal effect of genetically predicted serum urate levels on CHD and MI, but not the reverse effect. Urate-lowering therapy may be of cardiovascular benefit in the prevention of CHD and MI, especially for men.

Association of urate deposition shown by ultrasound and frequent gout attacks.

BACKGROUND: There are few data demonstrating the association between urate burden assessed by ultrasound (US) and gout flares. The aim of this study was to determine the association of urate deposition shown by US and frequent gout attacks. MATERIALS AND METHODS: Patients with gout were divided into two groups according to the frequency of gout attacks in the previous 12 months: frequent (>2 attacks) and infrequent (0-2 attacks). Urate deposition in the hands, knees, and feet was assessed by US. RESULTS: Overall, 106 patients were enrolled in this study, of whom 32 (30.1%) had had frequent gout attacks (>2 attacks) in the previous 12 months (the average number of gout attacks was 4.7, range 3-12). Those with frequent gout attacks had significantly longer gout duration, a higher serum urate level, and more urate deposition shown by US than those with infrequent gout attacks (P < 0.05). In both univariate and logistic regression analyses, frequent gout attacks were correlated with gout duration, serum urate level, and urate deposition as shown by US (P < 0.05). CONCLUSION: These findings indicate that urate deposition shown by US is independently associated with frequent gout attacks. Special attention should be given to the prevention of flares in patients with an initially high urate burden as assessed by US.

Lack of effect of tart cherry concentrate dose on serum urate in people with gout.

OBJECTIVES: Cherry concentrate has been suggested to reduce serum urate (SU) and gout flares. The aims of this study were to determine the magnitude of the effect of tart cherry concentrate on SU in people with gout, the most effective dose of tart cherry concentrate for lowering SU, and adverse effects. METHODS: Fifty people with gout and SU > 0.36 mmol/l were recruited. Half were on allopurinol and half were on no urate-lowering therapy. Participants were randomized to receive tart cherry juice concentrate: placebo, 7.5 ml, 15 ml, 22.5 ml or 30 ml twice daily for 28 days. Blood samples were taken at baseline, then at 1, 3 and 5 h post cherry and then on days 1, 3, 7, 14, 21 and 28. The area under the curve for SU was calculated over the 28-day study period. RESULTS: Cherry concentrate dose had no significant effect on reduction in SU area under the curve, urine urate excretion, change in urinary anthocyanin between day 0 and day 28, or frequency of gout flares over the 28-day study period (P = 0.76). There were 24 reported adverse events, with only one (hyperglycaemia) considered possibly to be related to cherry concentrate. Allopurinol use did not modify the effect of cherry on SU or urine urate excretion. CONCLUSION: Tart cherry concentrate had no effect on SU or urine urate excretion. If there is an effect of cherry concentrate on gout flares over a longer time period, it is not likely to be mediated by reduction in SU. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR), https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368887, ANZCTR 12615000741583).

Epistatic interaction between PKD2 and ABCG2 influences the pathogenesis of hyperuricemia and gout.

BACKGROUND: Genetic background affects serum urate concentration and gout risk, especially regarding these variants in the urate-transporter gene ABCG2. However, the role of epistasis between PKD2 and ABCG2 on the pathogenesis of gout is poorly understood. Here we assess this epistatic interaction in the progression from elevated serum urate to gout. RESULTS: We identified two epistatic interaction pairs (rs2728121: rs1481012 and rs2728121: rs2231137) were associated with urate levels in 4914 Chinese individuals (Pint = 0.018 and 0.004, respectively). Using subgroup analysis for gender and BMI, we found the degree of associations was varied by gender and BMI. The SNP pair rs2728121:rs1481012 influenced urate levels in females and overweight subjects (Pint = 0.006 and 0.022, respectively), but rs2728121:rs2231137 did in males, overweight and normal-weight subjects (Pint = 0.017, 0.047 and 0.013, respectively). Consistent results were also observed in associations between these epistatic interactions with hyperuricemia. Next, the SNP pair rs2728121:rs2231137 was identified to influence the development of gout from both hyperuricemia and healthy (Pint = 0.035 and 0.001, respectively), especially in males (Pint = 0.030 and 0.001, respectively). Furthermore, we demonstrated that interacting regions were enriched by regulatory elements. Finally, we observed a strong gene co-expression pattern between PKD2 and ABCG2 (r = 0.743, P = 5.83E-06). CONCLUSION: Our findings indicate epistasis between PKD2 and ABCG2 influence serum urate concentrations, hyperuricemia and gout risk, thus providing insight into the pathogenesis of gout.

Sex Differences in Urate Handling.

Hyperuricemia, or elevated serum urate, causes urate kidney stones and gout and also increases the incidence of many other conditions including renal disease, cardiovascular disease, and metabolic syndrome. As we gain mechanistic insight into how urate contributes to human disease, a clear sex difference has emerged in the physiological regulation of urate homeostasis. This review summarizes our current understanding of urate as a disease risk factor and how being of the female sex appears protective. Further, we review the mechanisms of renal handling of urate and the significant contributions from powerful genome-wide association studies of serum urate. We also explore the role of sex in the regulation of specific renal urate transporters and the power of new animal models of hyperuricemia to inform on the role of sex and hyperuricemia in disease pathogenesis. Finally, we advocate the use of sex differences in urate handling as a potent tool in gaining a further understanding of physiological regulation of urate homeostasis and for presenting new avenues for treating the constellation of urate related pathologies.

Characterization of patients with chronic refractory gout who do and do not have clinically apparent tophi and their response to pegloticase.

OBJECTIVES: To determine the characteristics and response to pegloticase of patients with chronic refractory gout with and without clinically apparent tophi. METHODS: Results from two randomized controlled trials of pegloticase in patients with chronic refractory gout with clinically apparent tophi or without tophi were used to assess baseline and on-treatment between-group differences. RESULTS: Patients with tophi were significantly older than those without tophi, had a significantly longer duration of disease, higher numbers of tender and swollen joints, higher Patient Global Assessment scores and Health Assessment Questionnaire-Disability Index scores, and lower Arthritis-Specific Health Index scores. Patients with tophaceous gout also had significantly lower scores for physical functioning, role physical, social functioning, and the physical component summary scores of the Short Form 36 vs patients without tophi. In addition, subjects with clinically apparent tophi had a significantly lower mean estimated glomerular filtration rate. Pegloticase treatment of tophaceous patients caused significant reductions in serum urate, flares, Patient Global Assessment, tender joints, swollen joints, Health Assessment Questionnaire-Disability Index, visual analogue scale pain and Short Form 36 Bodily Pain, whereas patients without tophi had significant improvement in serum urate, flares, Patient Global Assessment, tender joints, and Short Form 36 Bodily Pain, but not swollen joints, Health Assessment Questionnaire-Disability Index functional score or pain visual analogue scale. Treatment with pegloticase had no effect on estimated glomerular filtration rate despite significant lowering of the urinary uric acid: creatinine ratio. CONCLUSION: Patients with chronic refractory gout and clinically apparent tophi have more severe disease as well as reduced renal function. Both groups experienced significant clinical benefit with pegloticase treatment, although no change in renal function was noted.

Serum urate levels and therapy in adults treated with long-term dialysis: a retrospective cross-sectional study.

BACKGROUND: The management of gout in chronic kidney disease and end-stage renal disease is challenging and remains controversial. There are limited data on the use of urate-lowering therapy in people receiving dialysis. AIM: To estimate the point prevalence of gout, gout treatment and achievement of target serum urate (SU) among adults treated with long-term dialysis. METHODS: Three secular cohorts of adults receiving dialysis for at least 90 days on 1 February 2017, 1 January 2016 and 1 January 2015 were identified. Medical records were reviewed for SU concentrations. Results were compared between haemodialysis (HD) and peritoneal dialysis (PD), and participants prescribed and not prescribed urate-lowering therapy. The percentage reduction in SU 24- and 48-h post-HD was estimated based on data from a previous study. SU concentrations were then used to estimate the percentage time the SU was <0.36 mmol/L using linear interpolation. RESULTS: Of 216 dialysis patients, 61 (point prevalence 28.2%, 95% confidence interval 22.35-34.8%) had a diagnosis of gout. The mean (SD) age among those with gout was 61 years (14.4), 46 (75.4%) were men and 18 (31.1%) identified as Maori or Pacific Island. Forty-two (68.9%) were prescribed allopurinol (mean (SD) dose 116.0 ± 66.9 mg/day). 46% had a predialysis SU ≤0.36 mmol/L on less than 25% of occasions and 23% were below target on 76-100% of occasions. SU was below target 41% of time, with no statistically significant difference in those on HD or PD (P = 0.39), and those prescribed or not prescribed allopurinol (P = 0.55). CONCLUSIONS: Gout is experienced by approximately one in four adults treated with dialysis and two-thirds are prescribed allopurinol. A minority have SU at a target sufficient to prevent gout despite allopurinol and HD. A treat to target SU should be considered in those with SU above target.

Safety and efficacy of verinurad, a selective URAT1 inhibitor, for the treatment of patients with gout and/or asymptomatic hyperuricemia in the United States and Japan: Findings from two phase II trials.

Objective: Evaluate efficacy/safety of verinurad monotherapy in patients with gout (Japan/US) or asymptomatic hyperuricemia (Japan).Methods: Two randomized, placebo-controlled, phase II studies were conducted (NCT01927198/NCT02078219). Patients were randomized to once-daily doses of placebo or escalating doses of verinurad (study 1: 5-12.5 mg; study 2: 2.5-15 mg). Primary endpoint was percentage change from baseline in serum urate (sUA) at week 12 (study 1)/week 16 (study 2). Safety was also assessed.Results: Most patients in study 1 (n = 171) were white (74.9%); all patients were Japanese in study 2 (n = 204). Least squares means (±SE) estimate of percentage change in sUA levels from baseline in study 1 was 1.2 ± 2.9 for placebo, and -17.5 ± 2.8, -29.1 ± 2.8, -34.4 ± 2.9 for verinurad 5, 10, 12.5 mg, respectively. In study 2, results were -2.4 ± 2.5 and -31.7 ± 2.5, -51.7 ± 2.6,-55.8 ± 2.5, respectively. Difference from placebo was significant for each verinurad dose (p<.0001). The proportion of patients with treatment-emergent adverse events (TEAEs) was similar across all groups. Renal-related TEAEs were more common with verinurad than placebo.Conclusion: Verinurad monotherapy resulted in sustained reductions in sUA in Japanese/US patients but renal AEs occurred, so verinurad alone is not recommended for treatment of hyperuricemia or gout. The renal consequences of excessive uric acid excretion deserve study.

Hyperuricemia, Acute and Chronic Kidney Disease, Hypertension, and Cardiovascular Disease: Report of a Scientific Workshop Organized by the National Kidney Foundation.

Urate is a cause of gout, kidney stones, and acute kidney injury from tumor lysis syndrome, but its relationship to kidney disease, cardiovascular disease, and diabetes remains controversial. A scientific workshop organized by the National Kidney Foundation was held in September 2016 to review current evidence. Cell culture studies and animal models suggest that elevated serum urate concentrations can contribute to kidney disease, hypertension, and metabolic syndrome. Epidemiologic evidence also supports elevated serum urate concentrations as a risk factor for the development of kidney disease, hypertension, and diabetes, but differences in methodologies and inpacts on serum urate concentrations by even subtle changes in kidney function render conclusions uncertain. Mendelian randomization studies generally do not support a causal role of serum urate in kidney disease, hypertension, or diabetes, although interpretation is complicated by nonhomogeneous populations, a failure to consider environmental interactions, and a lack of understanding of how the genetic polymorphisms affect biological mechanisms related to urate. Although several small clinical trials suggest benefits of urate-lowering therapies on kidney function, blood pressure, and insulin resistance, others have been negative, with many trials having design limitations and insufficient power. Thus, whether uric acid has a causal role in kidney and cardiovascular diseases requires further study.

Predicting Response or Non-response to Urate-Lowering Therapy in Patients with Gout.

PURPOSE OF REVIEW: To review the extent of treatment success or failure with the xanthine oxidoreductase inhibitors allopurinol and febuxostat and indicate how the dosage of urate-lowering therapy (ULT) may be modified to increase the response in the majority of patients with gout. RECENT FINDINGS: Gout flares are associated with serum concentrations of urate above 0.42 mmol/L (7 mg/dL). Achieving and maintaining serum urate below 0.36 mmol/L is considered an effective response to ULT. On an intention to treat basis, clinical trials indicate that allopurinol at daily doses of 100 to 300 mg decreases serum urate adequately in only about 40% of gout patients while febuxostat 80 mg daily reduces serum urate adequately in approximately 70% of gout patients. Higher doses of ULT may be required in patients receiving concomitant diuretics. The addition of a uricosuric agent to allopurinol and febuxostat therapy significantly increases the proportion of patients achieving adequate lowering of serum urate. Finally, carriers of a genetic variant of the transporter, ABCG2 (BCRP), have a decreased response to allopurinol. Careful examination of medication adherence, titration of doses, and the addition of uricosuric agents increase the percentage of patients responding to allopurinol and febuxostat.

Allopurinol dose escalation to achieve serum urate below 6 mg/dL: an open-label extension study.

OBJECTIVES: To determine the long-term safety and efficacy of allopurinol dose escalation (DE) to achieve target serum urate (SU) in gout. METHODS: People, including those with chronic kidney disease, who completed the first 12 months of a randomised controlled trial continued into a 12-month extension study. Participants randomised to continue current dose for the first 12 months began allopurinol DE at month 12 if SU was ≥6 mg/dL (control/DE). Immediate DE participants who achieved target SU maintained allopurinol dose (DE/DE). The primary endpoints were reduction in SU and adverse events (AEs) at month 24. RESULTS: The mean (SE) change in SU from month 12 to 24 was -1.1 (0.2) mg/dL in control/DE and 0.1 (0.2) mg/dL in DE/DE group (p<0.001). There was a significant reduction in the percentage of individuals having a gout flare in the month prior to months 12 and 24 compared with baseline in both groups and in mean tophus size over 24 months, but no difference between randomised groups. There were similar numbers of AEs and serious adverse events between groups. CONCLUSIONS: The majority of people with gout tolerate higher than creatinine clearance-based allopurinol dose and achieve and maintain target SU. Slow allopurinol DE may be appropriate in clinical practice even in those with kidney impairment. TRIAL REGISTRATION NUMBER: ACTRN12611000845932.

Lesinurad monotherapy in gout patients intolerant to a xanthine oxidase inhibitor: a 6 month phase 3 clinical trial and extension study.

Objective: To investigate the efficacy and safety of lesinurad, a selective uric acid reabsorption inhibitor, in a 6 month, phase 3 clinical trial and extension study. Methods: Patients with gout who cannot take a xanthine oxidase inhibitor (XOI) and have serum uric acid (sUA) ⩾6.5 mg/dl were randomized to receive oral lesinurad (400 mg daily) or placebo. The primary endpoint was the proportion of patients with sUA <6.0 mg/dl at month 6. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory data. Patients who completed the study were eligible for an open-label, uncontrolled extension study of lesinurad 400 mg monotherapy. Results: Patients (n = 214) were primarily white males (mean age 54.4 years; gout duration 11.2 years). Significantly more patients achieved the primary endpoint with lesinurad than placebo (29.9 vs 1.9%; P < 0.0001). Overall TEAE rates were higher with lesinurad (77.6 vs 65.4%); renal-related TEAEs (17.8%), renal-related serious TEAEs (4.7%) and serum creatinine elevations (1.5 times baseline, 24.3%) occurred only with lesinurad. A total of 143 patients (65 lesinurad, 78 placebo) enrolled in the extension study. Treatment with lesinurad 400 mg resulted in rapid and sustained sUA lowering that persisted for up to 18 months before the study was terminated prematurely. No new safety findings were observed in the extension. Conclusion: In patients with gout and intolerance/contraindication to XOIs, lesinurad 400 mg monotherapy demonstrated superior sUA lowering compared with placebo, with sustained effects for up to 18 months. Due to a high incidence of serum creatinine elevations and renal-related adverse events, including serious adverse events with lesinurad 400 mg, lesinurad should not be used as monotherapy. Trial registration: ClinicalTrials.gov (http://clinincaltrials.gov), NCT01508702.

Quality of care in gout: a clinical audit on treating to the target with urate lowering therapy in real-world gout patients.

The current paper aimed to describe the quality of care for gout patients by showing the clinical outcomes achieved in two patient cohorts in which differing targeted urate lowering therapy (ULT) treatment approaches were employed, both aiming to reach the European League Against Rheumatism recommended serum urate (sUA) targets. A retrospective medical chart review study was conducted. Data from the medical records of gout patients from two clinical centers in The Netherlands, both applying targeted ULT treatments (albeit using different approaches), were reviewed. Patients in cohort A were given a combination of xanthine oxidase inhibitors with uricosurics if treatment with allopurinol monotherapy failed to reach sUA target levels, whereas patients in cohort B were treated with sequential monotherapy. Data on patient characteristics and clinical outcomes were collected. A total of 177 patient dossiers were included: 99 from cohort A and 78 from cohort B. The great majority (n = 146, 82.5%) of the patients in both cohorts had a current sUA level <360 µmol/L. In addition, more than half (n = 104, 58.8%) of the patients met the stringent sUA target level of <300 µmol/L. The largest reductions in mean sUA levels were observed for patients who were treated with combination therapy. This clinical audit of two cohorts of gout patients provides initial-yet promising-results regarding the proportion of real-world gout patients in whom recommended that sUA target levels can be achieved, and demonstrates the added value that a targeted treatment approach may have in reaching these goals.