Health disparities in gout.

PURPOSE OF REVIEW: Gout, the most common type of inflammatory arthritis in the world, is characterized by painful episodes of arthritis linked by asymptomatic intercritical periods of hyperuricemia. Once characterized as a disease of wealthy white men, contemporary evidence demonstrates gout disproportionately afflicts racial/ethnic minorities, Indigenous populations and other underrepresented groups leading to significant health disparities. RECENT FINDINGS: Herein, we review the current literature reporting a higher incidence and prevalence of gout in racial/ethnic minorities and Indigenous populations, in addition to a growing gout burden reported in females. We also examine how these population are more likely to receive suboptimal treatment for flares and chronic phases of gout. Additionally, we examine biologic and social health determinants that may be contributing to these findings. SUMMARY: Racial/ethnic minorities, Indigenous populations, and females have experienced a disproportionate rise in the prevalence and incidence of gout in recent years, are more likely to seek acute medical care and are less likely to receive optimal long-term care for gout with urate lowering therapy. Mechanisms underpinning these findings appear to be multifactorial and include differences in social determinants of care and in some cases may be due to population differences in select biologic factors such as differences in age, sex, genetics.

Efficacy and Safety of Allopurinol and Febuxostat in Patients With Gout and CKD: Subgroup Analysis of the STOP Gout Trial.

RATIONALE & OBJECTIVE: We conducted a prespecified examination of the efficacy and safety of allopurinol and febuxostat administered using a treat-to-target strategy in trial participants with chronic kidney disease (CKD). STUDY DESIGN: Prespecified subcohort analysis of a randomized controlled trial. SETTING & PARTICIPANTS: A substudy of the STOP Gout Trial in participants with CKD. CKD was defined as an estimated glomerular filtration rate (eGFR) 30-59mL/min/1.73m2 at baseline. EXPOSURE: Trial participants with CKD and gout and serum urate (SUA) concentration of≥6.8mg/dL were randomized 1:1 to receive allopurinol or febuxostat. Urate-lowering therapy (ULT) was titrated during weeks 0-24 to achieve a goal SUA of<6.0mg/dL (<5.0mg/dL with tophi) (phase 1) and maintained during weeks 25-48 (phase 2). Gout flare was assessed between weeks 49-72 (phase 3). OUTCOME: Gout flare between weeks 49-72 (phase 3) was the primary outcome. Secondary outcomes included SUA goal achievement and ULT dosing at end of phase 2, and serious adverse events. ANALYTICAL APPROACH: Outcomes between treatment groups were compared using logistic regression models for binary outcomes, and Poisson regression for flare rates. Multivariable models were subsequently used, adjusting for factors identified to be imbalanced by treatment arm. RESULTS: CKD was present in 351 of 940 participants; 277 were assessed for the primary outcome. Fewer patients randomized to allopurinol had a flare during phase 3 (32% vs 45%; P=0.02) despite similar attainment of the SUA goal (79% vs 81%; P=0.6) by the end of phase 2. Acute kidney injury was more common in participants with stage 3 CKD randomized to allopurinol compared with febuxostat. LIMITATIONS: Limited power to assess infrequent safety events, largely male, older population. CONCLUSIONS: Allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen with lower incidence of gout flares in participants randomized to allopurinol. PLAIN-LANGUAGE SUMMARY: The STOP Gout Trial was a multicenter, randomized, double-blind, noninferiority, comparative effectiveness trial, which found that allopurinol was noninferior to febuxostat in gout flare prevention and that both medications were similarly efficacious in reaching a serum urate goal when used as part of a treat-to-target approach. A significant proportion of patients with chronic kidney disease (CKD) are afflicted by gout, yet there is a lack of high-quality comparative effectiveness data comparing allopurinol and febuxostat in these patients. We evaluated the efficacy and safety of allopurinol and febuxostat in the subgroup of STOP Gout Trial participants with stage 3 CKD and found that allopurinol and febuxostat are similarly efficacious and well-tolerated in the treatment of gout in people with CKD when used in a treat-to-target regimen, with lower incidence of gout flares in participants randomized to allopurinol.

Determinants of Achieving Serum Urate Goal with Treat-to-Target Urate-Lowering Therapy in Gout.

OBJECTIVE: Using trial data comparing treat-to-target allopurinol and febuxostat in gout, we examined participant characteristics associated with serum urate (SU) goal achievement. METHODS: Participants with gout and SU ≥6.8 mg/dL were randomized to allopurinol or febuxostat, titrated during weeks 0 to 24, and maintained weeks 25 to 48. Participants were considered to achieve SU goal if the mean SU from weeks 36, 42, and 48 was <6.0 mg/dL or <5 mg/dL if tophi were present. Possible determinants of treatment response were preselected and included sociodemographics, comorbidities, diuretic use, health-related quality of life (HRQoL), body mass index, and gout measures. Determinants of SU response were assessed using multivariable logistic regression with additional analyses to account for treatment adherence. RESULTS: Of 764 study participants completing week 48, 618 (81%) achieved SU goal. After multivariable adjustment, factors associated with a greater likelihood of SU goal achievement included older age (adjusted odds ratio [aOR] 1.40 per 10 years), higher education (aOR 2.02), and better HRQoL (aOR 1.17 per 0.1 unit). Factors associated with a lower odds of SU goal achievement included non-White race (aORs 0.32-0.47), higher baseline SU (aOR 0.83 per 1 mg/dL), presence of tophi (aOR 0.29), and the use of diuretics (aOR 0.52). Comorbidities including chronic kidney disease, hypertension, diabetes, and cardiovascular disease were not associated with SU goal achievement. Results were not meaningfully changed in analyses accounting for adherence. CONCLUSIONS: Several patient-level factors were predictive of SU goal achievement among patients with gout who received treat-to-target urate-lowering therapy (ULT). Approaches that accurately predict individual responses to treat-to-target ULT hold promise in facilitating personalized management and improving outcomes in patients with gout.

Comparison of Gout Flares With the Initiation of Treat-to-Target Allopurinol and Febuxostat: A Post-Hoc Analysis of a Randomized Multicenter Trial.

OBJECTIVE: Initiating urate-lowering therapy (ULT) in gout can precipitate arthritis flares. There have been limited comparisons of flare risk during the initiation and escalation of allopurinol and febuxostat, administered as a treat-to-target strategy with optimal anti-inflammatory prophylaxis. METHODS: This was a post-hoc analysis of a 72-week randomized, double-blind, placebo-controlled, noninferiority trial comparing the efficacy of allopurinol and febuxostat. For this analysis, the occurrence of flares was examined during weeks 0 to 24 when ULT was initiated and titrated to a serum urate (sUA) goal of less than 6 mg/dl (<5 mg/dl if tophi). Flares were assessed at regular intervals through structured participant interviews. Predictors of flare, including treatment assignment, were examined using multivariable Cox proportional hazards regression. RESULTS: Study participants (n = 940) were predominantly male (98.4%) and had a mean age of 62.1 years with approximately equal proportions receiving allopurinol or febuxostat. Mean baseline sUA was 8.5 mg/dl and all participants received anti-inflammatory prophylaxis (90% colchicine). In a multivariable model, there were no significant associations of ULT treatment (hazard ratio [HR] 1.17; febuxostat vs allopurinol), ULT-dose escalation (HR 1.18 vs no escalation), prophylaxis type, or individual comorbidity with flare and no evidence of ULT-dose escalation interaction. Factors independently associated with flare risk during ULT initiation/escalation included younger age, higher baseline sUA, and absence of tophi. CONCLUSION: These results demonstrate that gout flare risk during the initiation and titration of allopurinol is similar to febuxostat when these agents are administered according to a treat-to-target strategy using gradual ULT-dose titration and best practice gout flare prophylaxis.

Cause-Specific Mortality in Patients With Gout in the US Veterans Health Administration: A Matched Cohort Study.

OBJECTIVE: To compare all-cause and cause-specific mortality risk between patients with gout and patients without gout in the Veteran's Health Administration (VHA). METHODS: We performed a matched cohort study, identifying patients with gout in the VHA from January 1999 to September 2015 based on the presence of ≥2 International Classification of Diseases, Ninth Revision codes for gout (274.X). Gout patients were matched up to 1:10 on birth year, sex, and year of VHA enrollment with patients without gout and followed until death or end of study (December 2017). Cause of death was obtained from the National Death Index. Associations of gout with all-cause and cause-specific mortality were examined using multivariable Cox regression. RESULTS: Gout (n = 559,243) and matched non-gout controls (n = 5,428,760) had a mean age of 67 years and were 99% male. There were 246,291 deaths over 4,250,371 patient-years in gout patients and 2,000,000 deaths over 40,441,353 patient-years of follow-up in controls. After matching, gout patients had an increased risk of death (hazard ratio [HR] 1.09 [95% confidence interval (95% CI) 1.08-1.09]), which was no longer present after adjusting for comorbidities (HR 0.98 [95% CI 0.97-0.98]). The strongest association of gout with cause-specific mortality was observed with genitourinary conditions (HR 1.50 [95% CI 1.47-1.54]). Gout patients were at lower risk of death related to neurologic (e.g., Alzheimer's disease and Parkinson's disease) (HR 0.63 [95% CI 0.62-0.65]) and mental health (HR 0.66 [95% CI 0.65-0.68]) conditions. CONCLUSION: A higher risk of death among gout patients in the VHA was related to comorbidity burden. While deaths attributable to neurologic and mental health conditions were less frequent among gout patients, genitourinary conditions were the most overrepresented causes of death.

Associations Between Low Serum Urate, Body Composition, and Mortality.

OBJECTIVE: Controversy remains as to whether low serum urate or uric acid (UA) levels contribute to adverse outcomes. We evaluated the relation between low serum UA levels and sarcopenia and assessed whether sarcopenia confounds associations between these low levels and mortality. METHODS: We utilized data from the National Health and Nutrition Examination Survey (1999-2006). Participants with available whole-body dual x-ray absorptiometry body composition measurements and serum UA concentrations were included. Body composition assessments included body mass index (BMI), waist circumference, maximum lifetime BMI, and age-, sex-, and race-specific appendicular lean mass index (ALMI) and fat mass index (FMI) Z scores. We also calculated Z scores for ALMI relative to FMI (ALMIFMI ). We evaluated associations between serum UA levels and body composition using logistic regression and assessed associations between serum UA levels and mortality before and after adjusting for differences in body composition using Cox proportional hazards regression. RESULTS: Among the 13,979 participants, low serum UA concentrations (<2.5 mg/dl in women, <3.5 mg/dl in men) were associated with low lean mass (ALMI and ALMIFMI Z scores), underweight BMI (<18.5 kg/m2 ), and higher rates of weight loss. The proportion of patients with low ALMI Z scores was 29% in the low serum UA group and 16% in the normal serum UA group (P = 0.001). Low serum UA levels were associated with increased mortality before we adjusted for body composition (hazard ratio 1.61 [95% confidence interval 1.14-2.28]; P = 0.008) but was attenuated and not significant after adjustment for body composition and weight loss (hazard ratio 1.30 [95% confidence interval 0.92-1.85], P = 0.13). CONCLUSION: Sarcopenia and weight loss are more common among patients with low serum UA concentrations. Differences in body composition may help to explain associations between low levels of serum UA and higher mortality.

Environmental Triggers of Hyperuricemia and Gout.

Gout is the most prevalent type of inflammatory arthritis worldwide and environmental factors contribute to hyperuricemia and risk for gout flare. Causes of hyperuricemia include increased purine consumption from meat, alcohol, and high fructose corn syrup as well as medications such as cyclosporine, low-dose aspirin, or diuretics. Triggers for gout flares include increased purine consumption and medication use such as urate lowering therapy and diuretics. Environmental exposures including lead exposure, particulate matter exposure, temperature fluctuations, and physiologic stress have been found to trigger flares. In the right clinical scenario, these factors should be considered when treating gout patients.

Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management.

BACKGROUND: The relative efficacy and safety of allopurinol and febuxostat when used according to current guidelines for the treatment of hyperuricemia are unknown. This double-blind noninferiority trial examined these issues. METHODS: Participants with gout and hyperuricemia (with at least 33% having stage 3 chronic kidney disease) were randomly assigned to allopurinol or febuxostat in this 72-week trial, with doses titrated to target serum urate. The trial had three phases: titration (weeks 0 to 24), maintenance (weeks 25 to 48), and observation (weeks 49 to 72). Allopurinol and febuxostat were initiated at daily doses of 100 and 40 mg, with maximum titration to 800 and 120 mg, respectively. Antiinflammatory prophylaxis was given during phases 1 and 2. The primary end point was the proportion of patients experiencing one or more flares during phase 3, with a prespecified noninferiority margin of less than 8 percentage points between allopurinol and febuxostat. Secondary end points included efficacy in patients with chronic kidney disease, proportion achieving target serum urate levels, and serious adverse events. RESULTS: This study included 940 participants; 20.1% withdrew, with similar proportions in treatment arms. During phase 3, 36.5% of allopurinol-treated participants had one flare or more compared with 43.5% of febuxostat-treated participants (P<0.001 for noninferiority). Overall, 80% of participants achieved mean target urates during phase 2 with no differences by treatment. There were no treatment differences (including cardiovascular events) in serious adverse events. CONCLUSIONS: Allopurinol and febuxostat achieved serum urate goals in patients with gout; allopurinol was noninferior to febuxostat in controlling flares. Similar outcomes were noted in participants with stage 3 chronic kidney disease. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; ClinicalTrials.gov identifier, NCT02579096.).

Incidence, Prevalence, and Burden of Gout in the Veterans Health Administration.

OBJECTIVE: To determine the prevalence, incidence, and burden of gout in the Veterans Health Administration (VHA) from 2005 to 2014. METHODS: We used national VHA data from January 1999 to December 2014 to determine the annual incidence and prevalence of gout in the VHA. Gout burden to the VHA was determined by the proportion of patients with an encounter related to gout. Rates of urate-lowering therapy (ULT) and opiate use were determined annually. Characteristics of those with and without gout were compared using 2014 data. RESULTS: From 2005 to 2014, gout prevalence in the VHA increased from 4.2% to 5.8%, while disease incidence ranged from 5.8 to 7.4 cases per 1,000 patient-years. Gout prevalence was highest among men, older patients, and non-Hispanic black patients. During 2014, 4.0% of all inpatient or outpatient encounters and 1.3% of hospitalizations were gout related. Administration of ULT remained stable over the 10-year period, with 46% of gout patients receiving ULT in 2014. In contrast, 16.4% of prevalent gout patients were receiving a weak opioid in 2014, nearly doubling the prescription rate of weak opioids in 2005, while the use of stronger opioids did not change significantly over this period. Patients with gout had greater comorbidity and health care utilization than patients without gout. CONCLUSION: The burden posed by gout in the VHA is considerable and increased between 2005 and 2014. While the use of ULT has remained stable, the use of opioid therapy has increased among patients with gout.

Development of a lupus nephritis suboptimal response prediction tool using renal histopathological and clinical laboratory variables at the time of diagnosis.

OBJECTIVE: Lupus nephritis (LN) is an immune complex-mediated glomerular and tubulointerstitial disease in patients with SLE. Prediction of outcomes at the onset of LN diagnosis can guide decisions regarding intensity of monitoring and therapy for treatment success. Currently, no machine learning model of outcomes exists. Several outcomes modelling works have used univariate or linear modelling but were limited by the disease heterogeneity. We hypothesised that a combination of renal pathology results and routine clinical laboratory data could be used to develop and to cross-validate a clinically meaningful machine learning early decision support tool that predicts LN outcomes at approximately 1 year. METHODS: To address this hypothesis, patients with LN from a prospective longitudinal registry at the Medical University of South Carolina enrolled between 2003 and 2017 were identified if they had renal biopsies with International Society of Nephrology/Renal Pathology Society pathological classification. Clinical laboratory values at the time of diagnosis and outcome variables at approximately 1 year were recorded. Machine learning models were developed and cross-validated to predict suboptimal response. RESULTS: Five machine learning models predicted suboptimal response status in 10 times cross-validation with receiver operating characteristics area under the curve values >0.78. The most predictive variables were interstitial inflammation, interstitial fibrosis, activity score and chronicity score from renal pathology and urine protein-to-creatinine ratio, white blood cell count and haemoglobin from the clinical laboratories. A web-based tool was created for clinicians to enter these baseline clinical laboratory and histopathology variables to produce a probability score of suboptimal response. CONCLUSION: Given the heterogeneity of disease presentation in LN, it is important that risk prediction models incorporate several data elements. This report provides for the first time a clinical proof-of-concept tool that uses the five most predictive models and simplifies understanding of them through a web-based application.