Urate lowering therapy in patients starting hemodialysis limit gout flares occurrence: ten years retrospective study.

BACKGROUND: Uncontrolled gout can cause articular impairment but is also associated with a global and cardiovascular excess mortality, especially in dialysis population. Data documented within existing research is not conclusive regarding gout flares evolution during hemodialysis and their control by urate lowering therapy (ULT). Without clear guidelines concerning hemodialysis patients management with chronic gout, this study proposes to investigate whether gout flare incidence reduction could be observed on this population treated by urate lowering therapy versus patients without treatment. METHODS: We performed a retrospective cohort study in two hemodialysis centers in France. Were selected patients over 18 years old with a gout history who started hemodialysis between January 2005 and September 2015. Demographics and clinicals data were recorded at hemodialysis start and throughout 5 years of follow up. Gout flare was defined as presence of uric acid crystal in joint punction or clinically diagnosed as such with a colchicine prescription. All statistical analysis were performed in SAS® version 9.4 (SAS Institute Inc., Cary, NC). RESULTS: One hundred eighty-one patients have been included, mean age at dialysis initiation was 68.6 years (± 12.4) with 72% of men, 54% were treated by ULT: 89.7% by allopurinol and 9.3% by febuxostat. One patient received both treatments successively. After hemodialysis initiation, 35.36% patients had experienced at least one gout flare. The appearance of at least one gout flare concerned 50% of patients in no ULT group and 22.68% patients in ULT group (p = 0.0002). Dialysis efficiency was measured at regular interval during follow-up and was similar in both groups. To study the association strength between clinical factors and gout flares occurrences, a Cox model was performed; ULT is a protector factor of gout flare (HR:0,42, CI 95: 0,25-0,71). The proportion of serum urate values within the target (median 53% vs 29.3%, p < 0.0001) was significantly higher in ULT group versus no ULT group (median 53% vs 29.3%, p < 0.0001). CONCLUSION: Urate lowering therapy limit new gout flares occurrence in hemodialysis patients with gout historyCollaboration between rheumatologists and nephrologists may help to update guidelines for urate-lowering therapies in patients on dialysis.

Ultrasonography in the prediction of gout flares: a 12-month prospective observational study.

OBJECTIVES: To evaluate whether US findings indicating MSU deposits and US-detected inflammation (i.e. power Doppler signal) predict gout flares over 12 months. METHODS: Gout patients on urate-lowering therapy for at least the preceding 6 months were enrolled consecutively in this 12-month prospective, observational, single-centre study. A nested case-control analysis was performed. Cases were participants with at least one flare in the follow-up period, while controls did not self-report any gout flare. The US assessment included elbows, wrists, second MCP joints, knees, ankles, and first MTP joints. The US findings indicating MSU deposits [i.e. aggregates, double contour (DC) sign and tophi] were identified as present/absent according to the Outcome Measure in Rheumatology definitions. Power Doppler signal was scored semiquantitatively. Summated scores were calculated for each US finding. RESULTS: Eighty-one gout participants were enrolled, and 71 completed the study. Thirty (42.3%) of 71 participants experienced at least one flare over 12 months, with a median of 2.0 flares. Cases had a greater US burden of MSU deposits (6.7 ± 4.7 vs 2.9 ± 2.6, P = 0.01) and power Doppler signal (3.73 ± 3.53 vs 0.82 ± 1.44, P < 0.01) than controls, at baseline. The baseline US scores indicating MSU deposits and US-detected inflammation were significantly associated with the occurrence (total MSU score, adjusted odds ratio:1.75, 95% CI: 1.26, 2.43; power Doppler score, adjusted odds ratio: 1.63, 95% CI: 1.12, 2.40) and the number (total MSU score, adjusted incidence risk ratio: 1.17, 95% CI: 1.08, 1.26; power Doppler score, adjusted incidence risk ratio: 1.29, 95% CI: 1.19, 1.40) of flares over 12 months in multivariate analyses. CONCLUSIONS: Baseline US findings indicating MSU deposits and US-detected inflammation are independent predictors of gout flares over 12 months.

Association between the initial dose urate-lowering drugs and gout flares in adult males with gout.

OBJECTIVES: Frequent gout attacks in the initial introduction of urate-lowering therapy (ULT) are significant causes of poor drug adherence and ULT discontinuation. Initial low-dose urate-lowering drugs may be effective in reducing gout flares, however, robust evidence is sparse. The aim of this study was therefore to assess the association of initial dose urate-lowering drugs with gout flares in adult males with gout during the initial introduction of ULT. METHODS: This cohort study obtained data on consecutive gout patients from a single-center gout cohort study from August 2017 to October 2020. A standard questionnaire was applied to collect demographic and clinical information, and biochemical parameters were tested on the same day. The primary end point was to estimate the association of initial dose febuxostat with gout flares, using cox hazard models with inverse probability of treatment weighting (IPTW). RESULTS: A total of 582 gout patients were included in this study. During 6-week follow-up, 71 (12.2%) patients suffered gout flares. In the main analysis using cox hazard models with IPTW, compared with colchicine prophylaxis, initial low-dose febuxostat alone had no statistical significance with the increased risk of gout flares [hazard ratio (HR), 1.26; 95% CI, 0.58-2.72], while initial high-dose febuxostat was associated with an increased risk of gout flares (HR, 3.08; 95% CI, 1.34-7.07). CONCLUSIONS: This observational study demonstrated that initial low-dose febuxostat was equally effective in preventing gout flares as colchicine prophylaxis, while initial high-dose febuxostat alone was associated with an increased risk of gout flares.

Onset of comorbidities and flare patterns within pre-existing morbidity clusters in people with gout: 5-year primary care cohort study.

OBJECTIVE: To investigate the onset of comorbidities and pattern of flares over 5 years according to baseline comorbidity clusters in people with gout. METHODS: In a prospective primary care-based cohort study, adults aged ≥18 years with gout were identified from primary care medical records in 20 general practices across the West Midlands, UK and followed up over 5 years. Four clusters of participants have been defined previously according to baseline comorbidity status. The associations of (i) incident comorbidities and (ii) gout flares with baseline cluster membership were estimated using age and sex-adjusted Poisson regression and mixed effects ordinal logistic regression, respectively. RESULTS: The comorbidity with the highest incidence was coronary artery disease (39.2%), followed by hypertension (36.7%), chronic kidney disease stage ≥3 (18.1%), obesity (16.0%), hyperlipidaemia (11.7%), diabetes (8.8%) and cancer (8.4%). There were statistically significant associations observed between cluster membership and incidence of coronary artery disease, hyperlipidaemia, heart failure and hypertension. In each cluster, nearly one-third of participants reported two or more gout flares at each time-point. History of oligo/polyarticular flares (odds ratio [OR]= 2.16, 95% confidence interval [CI]: 1.73, 2.70) and obesity (1.66, 95% CI: 1.21, 2.25) were associated with increasing flares whereas current use of allopurinol was associated with lower risk (0.42, 95% CI: 0.34-0.53). Cluster membership was not associated with flares. CONCLUSION: Substantial numbers of people in each cluster developed new comorbidities that varies by cluster membership. People also experienced multiple flares over time, but these did not differ between clusters. Clinicians should be vigilant for the development of new comorbidities in people with gout.

IL-33 enhances macrophage release of IL-1ß and promotes pain and inflammation in gouty arthritis.

OBJECTIVE: To investigate the role of IL-33 in gouty arthritis. MATERIAL: 174 Balb/c (wild-type) and 54 ST2-/- mice were used in this study. In vitro experiments were conducted in bone marrow-derived macrophages (BMDMs). Synovial fluid samples from gouty arthritis (n = 7) and osteoarthritis (n = 8) hospital patients were used to measure IL-33 and sST2 levels. METHODS: Gout was induced by injection of monosodium urate (MSU) crystals in the knee joint of mice. Pain was determined using the electronic von Frey and static weight bearing. Neutrophil recruitment was determined by H&E staining, Rosenfeld staining slides, and MPO activity. ELISA was used for cytokine and sST2 measurement. The priming effect of IL-33 was determined in BMDM. RESULTS: Synovial fluid of gout patients showed higher IL-33 levels and neutrophil counts than osteoarthritis patients. In mice, the absence of ST2 prevented mechanical pain, knee joint edema, neutrophil recruitment to the knee joint, and lowered IL-1ß and superoxide anion levels. In macrophages, IL-33 enhanced the release of IL-1ß and TNF-α, and BMDMs from ST2-/- showed reduced levels of these cytokines after stimulus with MSU crystals. CONCLUSION: IL-33 mediates gout pain and inflammation by boosting macrophages production of cytokines upon MSU crystals stimulus.

Patient and clinical characteristics associated with gout flares in an integrated healthcare system.

Gout flares have been challenging to identify in retrospective databases due to gout flares not being well documented by diagnosis codes, making it difficult to conduct accurate database studies. Previous studies have used different algorithms, and in this study, we used a computer-based method to identify gout flares. The objectives of this study were to identify gout flares in gout patients newly initiated on urate-lowering therapy and evaluate factors associated with a patient experiencing gout flares after starting drug treatment. This was a retrospective cohort study identifying gout patients newly initiated on a urate-lowering therapy (ULT) during the study time period of January 1, 2007-December 31, 2010. The index date was the first dispensed ULT prescription during the study time period. Patients had to be ≥18 years of age on index date, have no history of prior ULT prescription during 12 months before index date, and were required to have 12 months of continuous membership with drug benefit during pre-/post-index. Electronic chart notes were reviewed to identify gout flares; these reviews helped create a validated computer-based method to further identify patients with gout flares and were categorized into 0 gout flares, 1-2 gout flares, and ≥3 gout flares during the 12 months post-index period. Multivariable logistic regression was used to examine patient and clinical factors associated with gout flares during the 12-month follow-up period. There were 8905 patients identified as the final cohort and 68 % of these patients had one or more gout flares during the 12-month follow-up: 2797 patients (31 %) had 0 gout flares, 4836 (54 %) had 1-2 gout flares, and 1272 patients (14 %) had ≥3 gout flares. Using a multivariate regression analyses, factors independently associated with 1-2 gout flares and ≥3 gout flares versus no gout flares were similar, however, with slight differences, such as younger patients were more likely to have 1-2 gout flares and patients ≥65 years of age had ≥3 gout flares. Factors such as male gender, not attaining sUA goal, having ≥3 comorbidities, diuretics use, no changes in initial ULT dose, and not adhering to ULT all were associated with gout flares versus no gout flares. Using a new method to identify gout flares, we had the opportunity to compare our findings with the previous studies. Our study findings echo other previous studies where older patients, male, diuretics, having a greater number of comorbidities, and non-adherence are more likely to have more gout flares during the first year of newly initiating ULT. There is an unmet need for patients with gout to be educated and managed more closely, especially during the first year.

The association between gout flares and monosodium urate burden assessed using musculoskeletal ultrasound in patients with gout.

Background: Ultrasound (US) has a high sensitivity in detecting monosodium urate (MSU) deposition in gout patients. However, the value of US in predicting gout flares has been reported only in a few monocentric studies. Objective: To investigate the association between gout flares in the previous year and US-detected MSU burden using two different US scores. Design: A retrospective study. Methods: Patients with gout were consecutively recruited to undergo musculoskeletal US examinations of their knees, ankles, and feet. The score derived from Outcome Measure in Rheumatology (hereinafter referred to as MSU score) and musculoskeletal US features-based (hereinafter referred to as MSKF score) were used to quantify the MSU burden of gout. Odds ratios for frequent gout flares were calculated. Results: We enrolled 1894 patients with gout (mean age: 45 years; gout duration: 5 years; males: 96.1%), experiencing a median of three flares over the past year. Of these, 428 (22.6%) patients reported frequent (⩾7) gout flares. The MSU and MSKF median scores were 6 and 9, respectively. For each five-point increase in MSU and MSKF score, the odds ratio of frequent gout flares increased 1.13-fold and 1.24-fold, respectively. The area under the curve (AUC) for the MSU and MSKF score was 0.635 [95% confidence interval (CI): 0.604-0.665] and 0.688 (95% CI: 0.659-0.718), respectively, (AUC difference 0.054, p value for AUC difference < 0.001). Conclusion: The MSU and MSKF scores were significantly associated with the number of gout flares in the previous year. The MSKF score outperformed the MSU score in terms of frequent gout flare discrimination.

The risk of nonalcoholic fatty liver disease in gout patients with frequent flares: a retrospective cohort study.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease that is related to high serum uric acid; however, the association between the frequency of gout flares and NAFLD risk remains unclear. This study aimed to investigate whether frequent gout flares were associated with incident NAFLD and analyze the interaction of frequency of gout flares and Adipo-IR on NAFLD in the gout Chinese population. METHODS: A total of 350 cases of gout patients were enrolled in this retrospective cohort study. Cox proportional hazard regression analyses were performed to determine the association between frequent gout flares and NAFLD during follow-up and analyze the interaction of frequency of gout flares and Adipo-IR on NAFLD. Receiver operating curves (ROC) were plotted to explore the diagnostic value of frequent gout flares and Adipo-IR on the occurrence of NAFLD. RESULTS: NAFLD developed in 78 participants (22.3%) during follow-up. Logistic regression showed that Adipo-IR was an independent factor associated with frequent gout flares risk. The multivariate Cox regression analysis revealed that frequent gout flares and Adipo-IR were associated with NAFLD risk (HR: 7.88, 95% CI: 2.11-29.48, p < 0.01; HR: 1.058, 95% CI: 1.01-1.2, p < 0.05). And ROC showed that both of them had a great discriminant ability to diagnose NAFLD. CONCLUSIONS: Our data showed an independent association between the frequency of gout flares or Adipo-IR and incident NAFLD. Frequent gout flares and elevated Adipo-IR had a good predictive capability towards NAFLD development and played a synergistic role in the development of NAFLD. KEY POINTS: • Frequent gout flares and elevated Adipo-IR had a good diagnostic capability towards NAFLD development. • Frequent gout flares and Adipo-IR played a synergistic role in the development of NAFLD.

The Effect of Decrease in Serum Urate for the Risk of Gout Flares During Urate-Lowering Therapy Initiation Among Chinese Male Gout Patients: A Prospective Cohort Study.

Purpose: Higher baseline serum urate or higher initial urate-lowering medication dose increased risk of gout flares during urate-lowering therapy (ULT) initiation. The decrease in serum urate may play a crucial role in this process. Therefore, we aim to explore the relationship between decrease in serum urate and the risk of gout flares during ULT initiation. Patients and Methods: A 12-week prospective cohort study of Chinese male gout patients was conducted at Shandong Provincial Clinical Research Center for Immune Diseases and Gout in China. Patients were grouped by baseline serum urate (7-7.9 mg/dL, 8-8.9 mg/dL and ≥9 mg/dL). All patients received febuxostat 20 mg daily during weeks 0-4, then escalated to 40mg during weeks 4-12 if serum urate >6mg/dL. The main outcomes were the number of gout flares and the decrease in serum urate. Poisson regression was performed. Results: A total of 282 participants were enrolled, of whom 260 completed (84, 87 and 89 in each group) from March 2021 to December 2021. A 44.2% of all participants experienced at least one gout flare. In the multivariate Poisson regression 1, Δ serum urate 0-12 weeks (IRR 1.184, 95% CI, 1.062-1.320; P=0.002), the number of gout flares before treatment 1 year (1.017, 1.010-1.024; P<0.001) and tophus (1.580, 1.023-2.440; P=0.039) were independently associated with the number of gout flares. While in the multivariate Poisson regression 2, baseline serum urate (1.256, 1.050-1.503; P=0.013) and the number of gout flares before treatment 1 year (1.014, 1.007-1.022; P<0.001) were independently associated with the number of gout flares, Δ serum urate 0-12 weeks (1.055, 0.923-1.207; P=0.433) was no longer a risk factor. Conclusion: ULT-induced gout flares depend on the degree of decrease in serum urate, which is affected by baseline serum urate. Higher baseline serum urate and greater decrease in serum urate lead to higher risk of gout flares.

Physical activity measured using wearable activity tracking devices associated with gout flares.

OBJECTIVE: To determine the feasibility and validity of using wearable activity trackers to test associations between gout flares with physical activity and sleep. METHODS: Participants with physician-diagnosed gout, hyperuricemia (≥ 6.8 mg/dl), current smartphone use, and ≥ 2 self-reported flares in the previous 6 months were enrolled. Physical activity, heart rate, and sleep data were obtained from wearable activity trackers (Fitbit Charge HR2). Daily compliance was defined by the availability of sufficiently complete activity data at least 80% of the day. Associations of weekly gout flares with sleep and activity were measured by comparing flare-related values to average sleep and steps per day. We used mixed linear models to account for repeated observations. RESULTS: Forty-four participants enrolled; 33 met the criteria for minimal wear time and flare reporting, with activity tracker data available for 60.5% of all total study days. Mean ± SD age was 48.8 ± 14.9 years; 85% were men; 15% were black; 88% were on allopurinol or febuxostat, and 30% reported ≥ 6 flares in the prior 6 months. Activity trackers captured 204 (38%) person-weeks with flares and 340 (62%) person-weeks without flares. Mean ± SD daily step count was significantly lower (p < 0.0001) during weeks with gout flares (5900 ± 4071) than during non-flare periods (6972 ± 5214); sleep however did not differ. CONCLUSION: The pattern of wear in this study illustrates reasonable feasibility of using such devices in future arthritis research. The use of these devices to passively measure changes in physical activity patterns may provide an estimate of gout flare occurrence and duration. TRIAL REGISTRATION: NCT, NCT02855437 . Registered 4 August 2016.

Comparison of an interactive voice response system and smartphone application in the identification of gout flares.

OBJECTIVE: To examine the feasibility, preference, and satisfaction of an interactive voice response (IVR) system versus a customized smartphone application (StudyBuddy) to capture gout flares METHODS: In this 24-week prospective, randomized, crossover, open-label pilot study, 44 gout patients were randomized to IVR vs. StudyBuddy and were crossed over to the other technology after 12 weeks. Flares were reported via weekly (and later daily) scheduled StudyBuddy or IVR queries. Feasibility was ascertained via response rate to scheduled queries. At 12 and 24 weeks, participants completed preference/satisfaction surveys. Preference and satisfaction were assessed using dichotomous or ordinal questions. Sensitivity was assessed by the frequency of flare reporting with each approach. RESULTS: Thirty-eight of 44 participants completed the study. Among completers, feasibility was similar for IVR (81%) and StudyBuddy (80%). Conversely, most (74%) preferred StudyBuddy. Measures of satisfaction (ease of use, preference over in-person clinic visits, and willingness for future use) were similar between the IVR and StudyBuddy; however, more participants deemed the StudyBuddy as convenient (95% vs. 73%, P = 0.01) and less disruptive (97% vs. 82%, P = 0.03). Although the per patient number of weeks in flare was not significantly different (mean 3.4 vs. 2.6 weeks/patient, P = 0.15), the StudyBuddy captured more of the total flare weeks (35%) than IVR (27%, P = 0.02). CONCLUSION: A smartphone application and IVR demonstrated similar feasibility but overall sensitivity to capture gout flares and participant preference were greater for the smartphone application. Participant preference for the smartphone application appeared to relate to perceptions of greater convenience and lower disruption. TRIAL REGISTRATION: NCT, NCT02855437 . Registered 4 August 2016.

Gout, flares, and allopurinol use: a population-based study.

BACKGROUND: There is a paucity of community-based data regarding the prevalence and impact of gout flares as these may often be self-managed. The aim of this study was to determine the prevalence of self-reported gout and gout flares, the use of urate-lowering therapy (ULT), and the association of gout flares with health-related quality of life (HRQoL) in a large community sample. Covariate associations with flare frequency and allopurinol use were also examined. METHODS: The South Australian Health Omnibus Survey is an annual, face-to-face population-based survey. Data collected in the 2017 survey included self-reported medically diagnosed gout, allopurinol use (first-line ULT in Australia), and gout attacks (flares) in the last 12 months, in addition to sociodemographic variables and health-related quality of life (HRQoL, SF-12). Data were weighted to the Australian Bureau of Statistics 2016 census data to reflect the South Australian population. Participants 25 years and over (n = 2778) were included in the analysis. RESULTS: The prevalence of gout was 6.5% (95%CI 5.5, 7.5). Amongst participants with gout, 37.1% (95%CI 29.6, 45.3) reported currently using allopurinol, while 23.2% (95%CI 16.9, 21.0) reported prior use (38% discontinuation rate). Frequent flares (≥ 2 in the last year) were reported by 25% of participants with gout and were more likely with younger age, higher body mass index, and current allopurinol use (p < 0.05). The frequency of gout flares was associated with a lower physical HRQoL (p = 0.012). Current allopurinol use was reported by 51% of participants with frequent gout flares. CONCLUSION: Flares were frequently reported by people with gout in the community. Gout flares were associated with reduced physical HRQoL. Almost one half of people with frequent gout flares were not receiving allopurinol, and current allopurinol use was associated with frequent gout flares, suggesting undertreated disease and suboptimal use of ULT. Determining covariate associations with flares and ineffective allopurinol use may identify means of improving treatment and reducing flares.

Variability in the Reporting of Serum Urate and Flares in Gout Clinical Trials: Need for Minimum Reporting Requirements.

OBJECTIVE: To describe the ways in which serum urate (SU) and gout flares are reported in clinical trials, and to propose minimum reporting requirements. METHODS: This analysis was done as part of a systematic review aiming to validate SU as a biomarker for gout. The ways in which SU and flares were reported were extracted from each study by 2 reviewers. RESULTS: A total of 22 studies (10 randomized controlled trials, 3 open-label extension studies, and 9 observational studies) were identified. There were 3 broad categories of SU reporting: percentage at target SU, mean SU, and change in SU. A median of 2 (range 1-3) categories were reported across all studies. The most common method of reporting SU was percentage at target in 17/22 (77.3%) studies, with all studies reporting a target of SU < 6 mg/dl. There were 12/22 (54.5%) studies reporting mean SU at some time after study entry, with 7 (58.3%) of these reporting at more than just the final study visit. Two ways of reporting gout flares were identified: mean flare rate and percentage of participants with flares. There was variability in time periods over which flares rates were reported. CONCLUSION: There is inconsistent reporting of SU and flares in gout studies. Reporting the percentage of participants who achieve a target SU reflects international treatment guidelines. SU should also be reported as a continuous variable with a relevant central and dispersion estimate. Gout flares should be reported as both percentage of participants and mean flare rates at each timepoint.

Serum urate as surrogate endpoint for flares in people with gout: A systematic review and meta-regression analysis.

OBJECTIVES: The primary efficacy outcome in trials of urate lowering therapy (ULT) for gout is serum urate (SU). The aim of this study was to examine the strength of the relationship between SU and patient-important outcomes to determine whether SU is an adequate surrogate endpoint for clinical trials. METHODS: Multiple databases through October 2017 were searched. Randomized controlled trials comparing any ULT in people with gout with any control or placebo, ≥three months duration were included. Open label extension (OLE) trial data were included in secondary analyses. Standardized data elements were extracted independently by two reviewers. RESULTS: Ten RCTs and 3 OLE studies were identified. From the RCTs (maximum duration 24 months) meta-regression did not reveal an association between the relative risk of a gout flare and the difference in proportions of individuals with SU < 6mg/dL (P = 0.47; R2 = 8%). In a post hoc analysis, the ratio of the time in months at which the proportion of individuals having a flare was reported/time in months at which the proportion of individuals with SU < 6mg/dL was reported was calculated and studies where the ratio was <2 were excluded. Using the remaining 6 studies there was an association between proportion of individuals achieving SU < 6mg/dL and gout flares (over patient years). Duration of ULT was inversely associated with the proportion of patients experiencing a flare. Study duration and variability in reporting of outcomes limited the analysis. Observational studies supported the trend of fewer flares in those with lower SU. CONCLUSIONS: Based on aggregate clinical trial-level data an association between SU and gout flare could not be confirmed. However, based on observational ecological study design data-including longer duration extension studies-SU < 6mg/dL was associated with reduced gout flares.

The Role of Colchicine in the Treatment of Autoinflammatory Diseases.

Colchicine has been longstanding and widely used for the treatment of acute gout flares and prevention of gout relapses. Its use has been extended to a series of autoinflammatory diseases, such as familial Mediterranean fever and more recently to periodic fever with aphthous stomatitis, pharyngitis and adenitis, Behcet's disease and idiopathic recurrent acute pericarditis. In this review, we summarize current indications of colchicine use, discuss its pharmacokinetics and mechanism of action and examine its use in the treatment of autoinflammatory diseases. Further understanding of the underlying mechanisms of the latter conditions as well as identification of the therapeutic efficacy and treatment target of colchicine may lead to more effective management of these diseases.