Urate-lowering Therapy Research Articles

Should all people starting urate-lowering therapy for gout receive anti-inflammatory prophylaxis?

Co-prescription of anti-inflammatory prophylaxis with colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroids when initiating urate-lowering therapy (ULT) for gout is recommended in clinical guidelines to prevent ULT-induced flares and optimise adherence to ULT. Colchicine prophylaxis is highly clinically and cost-effective and there has been great interest recently in its cardioprotective effects. However, one in four people initiating ULT without prophylaxis in randomised trials do not have a gout flare within six months of initiation, raising the question of whether all people initiating ULT for gout should receive prophylaxis. Uptake of prophylaxis varies and appears to be common in secondary care settings but less commonly used in primary care, where most people with gout are managed and gout may be less severe. Recent clinical guidelines have highlighted that the patient’s perspective is important and that the pros and cons of prophylaxis should be discussed with people with gout initiating ULT. Uptake of prophylaxis seems likely to be influenced by perception of an individual’s risk of ULT-induced flares, as well as concerns about adverse events, polypharmacy, drug interactions, and cost. We advocate a personalised approach between people with gout and clinicians to reach shared treatment decisions when considering co-prescription of prophylaxis when initiating ULT, empowering people with gout to make decisions about their care.

Recent Progress and Future Perspectives on Anti-Hyperuricemic Agents.

Increased biosynthesis or underexcretion of uric acid (UA or urate) in the body ultimately leads to the development of hyperuricemia. Epidemiological studies indicate that hyperuricemia is closely associated with the occurrence of various diseases such as gout and cardiovascular diseases. Currently, the first-line therapeutic medications used to reduce UA levels primarily include xanthine oxidase (XO) inhibitors, which limit UA production, and urate transporter 1 (URAT1) inhibitors, which decrease urate reabsorption and enhance urate excretion. Despite significant progress in urate-lowering therapies, long-term use of these drugs can cause hepatorenal toxicity as well as cardiovascular complications. Therefore, there is an urgent need for novel anti-hyperuricemic agents with better efficacy and lower toxicity. This perspective mainly focuses on the current research progress and design strategy of anti-hyperuricemic agents, particularly those targeting XO and URAT1. It is our hope that this perspective will provide insights into the challenges and opportunities for anti-hyperuricemic drug discovery.

An Artificial Intelligence-Based Gout Management System Reduced Chronic Kidney Disease Incident and Improved Target Serum Urate Achievement

Abstract Objectives Stage ≥ 3 chronic kidney disease (CKD) affects ∼25% of people with gout. The effects of urate-lowering therapy (ULT) on CKD incidence and progression have remained inconclusive. Here, we assessed the impact of a gout urate-lowering therapy (ULT) clinic intervention using artificial intelligence (AI) on CKD incidence and achievement of serum urate target. Methods An observational study compared propensity score-matched gout cohorts from an AI-based Gout Intelligent Management System (GIMS) and a standard Electronic Medical Records system (EMRS) clinic database. The GIMS included a mobile application, data fusion interface, and modules for expert consultation and laboratory results management. All patients had gout and a starting eGFR > 60 ml/min. Using a 1:2 propensity score (PS)-matched cohort study design we assessed the impact of the AI-based system on CKD outcomes and ULT effectiveness over 4 years of follow-up. Results Compared with EMRS, GIMS was associated with reduced incidence of CKD stage ≥ 3. Specifically, 169/4117 new onset CKD stage ≥ 3 (incidence 4.1 per 100 person-years) with GIMS compared with 164/2128 with EMRS (incidence 7.7 per 100 person-years) during follow-up. More participants achieved serum urate <6.0 mg/dl with GIMS vs EMRS during follow-up (49.8% vs 25.9%, p < 0.001). Conclusion Application of the AI-based GIMS was associated with lower incidence of CKD stage ≥ 3 and superior target serum urate achievement in people with gout. The AI-based GIMS represents a novel approach to improve real-world renal outcomes and ULT success in gout.

Assessing Changes in Vascular Inflammation and Urate Deposition in the Vasculature of Gout Patients After Administration of Pegloticase Using Positron Emission Tomography and Dual-Energy Computed Tomography—A Pilot Study

We assessed changes in vascular inflammation and monosodium urate (MSU)-coded deposits after administration of Pegloticase in the vasculature of tophaceous gout patients using 18F-fluorodeoxyglucose (18F-FDG) Positron emission tomography/computed tomography (PET/CT) and dual-energy CT (DECT). Ten patients with tophaceous gout, intolerant or refractory to urate-lowering therapy (ULT), were treated with Pegloticase every two weeks for six months. 18F-FDG PET/CT and DECT were performed at baseline and after Pegloticase therapy to detect vessel wall inflammation (Standard uptake value, SUVmean, and SUVmax) and vascular MSU-coded deposition (MSU volume). Data were summarized using means and standard deviations. Baseline and follow-up values were compared for each variable using mixed-effect models. Significant decreases in SUVmean (p = 0.0003) and SUVmax (p = 0.009) were found with a trend towards a decrease in vessel wall MSU volume after treatment. There was a significant decrease in serum urate, correlating with reduction in SUVmean (R2 = 0.65), with a trend towards a decrease in CRP and blood pressure in all patients. Despite the small sample size, we were able to demonstrate a decrease in vessel wall inflammation and a trend towards a decrease in MSU volume by intensively lowering serum urate. These findings suggest that MSU-coded deposits and hyperuricemia may play a role in vascular wall inflammation. It remains to be seen whether this correlates with a decrease in adverse cardiovascular outcomes.

Gout Flare Burden in the United States: A Multiyear Cross-Sectional Survey Study.

The objective of this study was to assess the burden of gout flares and examine associated patient characteristics and outcomes in a sample of US adults. Data were collected via an online survey of US adults ≥18 years using a random stratified sampling framework. Participants with gout completed questions about treatments, serum urate (SU) levels, severity, satisfaction with control, and gout flares. All participants completed the Veterans RAND 12-Item Health Survey, the Generalized Anxiety Disorder 7-Item Scale, and the Patient Health Questionnaire 9-Item Scale. Data were summarized using descriptive statistics. Multivariable-adjusted logistic regression analyses examined factors predictive of reporting gout flares to a physician. A total of 933 participants met the study criteria for having gout. Those with gout tended to be older (58.3 [SD 13.3] years vs 45.4 [SD 16.1] years; P < 0.001), male (76.3% vs 46.9%; P < 0.001), White (80.5% vs 76.8%; P = 0.01), and married or living with their partner (58.9% vs 52.8%; P < 0.001) compared with those without gout (n = 30,146). The total gout flare burden for those with gout was 6.6 gout flares per year. Nearly 72% of gout flares were either not reported to physicians or pretreated or prevented. Characteristics of those who were less likely to report gout flares included being younger, being less educated, having a lower Charlson Comorbidity Index score, not being diagnosed with gout by their doctor, and not taking a urate-lowering therapy. This study confirmed that gout flares are common in US adults with gout and found that gout flares are underreported. Reliance on clinical documentation of physician-reported gout flares is insufficient to assess the true patient burden of gout.

Post-hoc analysis of the CARES trial suggests delayed progression of chronic kidney disease in patients with gout during urate-lowering therapy.

Post-hoc analysis of the CARES trial suggests delayed progression of chronic kidney disease in patients with gout during urate-lowering therapy.

Bridging the evidence-practice gap for people with gout

Gout is a common and disabling form of arthritis. Despite widely available, highly effective, urate-lowering therapies, such as allopurinol, studies continue to demonstrate poor care for individuals with gout in healthcare systems worldwide. In this commentary, we highlight strategies that can be utilised to overcome real-world barriers to optimal gout care, including allied health professional input, patient and clinician education, self-management strategies, and electronic health record solutions.

Febuxostat in patients with hyperuricemia and gout: is the nephroprotective effect real?

Hyperuricemia (HU) and gout are independent risk factors for chronic kidney disease (CKD). Worldwide, the increasing prevalence of CKD leads to a deterioration in the quality and duration of life of patients and an increase in mortality. If HU plays a significant role in the development of renal failure, then lowering high uric acid (UA) levels should theoretically contribute to the improvement of kidney function. The main method of lowering UA levels is administration of a urate-lowering therapy – xanthine oxidase (XO) inhibitors. The nephroprotective effect of one of the XO inhibitors, febuxostat has been demonstrated in animal models.The article analyzes the currently available data on the use of febuxostat in patients with HU and gout and different levels of renal function impairment and discusses the possible mechanisms of the drug's nephroprotective effect.

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement and inflammation modulators

Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined in association with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Sera demonstrated altered complement activation and regulatory gene ontology biologic processes. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat treatment decreased complement activation biologic process proteins in cultured BMDMs. Reduced gout flares are linked with a XOI treatment-emergent serum protein interactome that includes inflammation regulators, associated with altered complement activation and regulatory biologic processes. Serum and leukocyte proteomics could help identify when gouty inflammatory processes begin to subside in response to ULT.Trial Registration: ClinicalTrials.gov Identifier NCT02579096, posted October 19, 2015.

From Patents to Progress: Unraveling Gout's Journey Through Clinical Trials and Advancements.

Gout, an inflammatory arthritis form, is renowned for its historical association with affluence. This review delves into its pathophysiology, exploring hyperuricemia, urate crystal formation, and the ensuing inflammatory response. The epidemiology of gout is examined, focusing on its rising prevalence and impact on public health. In this study, progress in gout management is discussed, involving pharmacological interventions, dietary changes, and emerging therapies. Genetic predisposition and triggers like alcohol, temperature, and diet are highlighted in this study. Prevention strategies, including serum urate-lowering therapy and lifestyle modifications, aim to reduce recurrent flares and complications. The inflammatory response in acute gout attacks is elucidated, involving immune cells, cytokines, and the NLRP3 inflammasome. Chronic gout manifestations, such as gouty tophus formation, are explored for their destructive impact on surrounding tissues. Recent advancements in gout treatment, including nanotherapies and novel compounds, are discussed, along with promising urate-lowering drugs. Cutting-edge research on zinc ferrite nanoparticles, dimethyl fumarate, and myricetin/nobiletin hybrids addresses oxidative stress and inflammation in gout. Additionally, the potential therapeutic role of methanolic leaf extract of Euphorbia milii and tip-loaded CLC-Soluplus® MAPs is explored as natural and transdermal alternatives for gout management. The review also covers the development status of new urate-lowering drugs, providing insights into promising candidates and their mechanisms. Patents on gout and recent diagnostic advancements using techniques like laser confocal micro Raman spectrometer, FTIR, and THz-TDS offer a more accurate approach for gout stone analysis, enabling early detection and targeted treatment.

6741 Serum Urate-Lowering Effects Of Sodium-Glucose Transport Protein 2 Inhibitors Compared To Dipeptidyl Peptidase-4 Inhibitors In Gout Patients With Type 2 Diabetes Mellitus: A Population-Based Cohort Study

Abstract Disclosure: R.K. Shariff: None. C. Chung: None. P. Huang: None. S. Mon: None. K. Ma: None. Background/Purpose: Effective management of gout in patients requiring long-term urate-lowering therapy involves maintaining serum rate levels within specific ranges. Hyperuricemia and gout have been associated with an increased risk of Type 2 Diabetes Mellitus (T2DM), with a reported prevalence of 16% in gout patients. Pharmacological approaches to glycemic control, including Sodium-glucose Transport Protein 2 Inhibitors inhibitor (SGLT2i) and Dipeptidyl Peptidase-4 Inhibitors (DPP-4i), have showed potential serum urate lowering effects. However, a direct comparison of these effects in patients with gout and concomitant T2DM is lacking. This study aims to evaluate the serum urate-lowering effects of SGLT2i compared to DPP-4i in this patient population. Methods: This was a population-based cohort study of patients with gout diagnosed following the 2015 Gout classification criteria in the American College of Rheumatology/European League Against Rheumatism collaborative initiative and T2DM diagnosed following the American Diabetes Association criteria, respectively. Subjects treated between 2008 and 2023 at 92 United States hospitals were screened. Propensity score matching was used to balance the baseline differences in age of gout onset, sex, comorbidities, and past medical history between the two groups. The primary predictor variable was the use of therapies of SGLT2i and DPP-4i. The primary outcome of interest was the serum urate more than 6 mg/dL during the follow-up period. Kaplan-Meier analysis and log-rank tests were utilized to compare if the numbers of serum urate were higher than 6 mg/dL in both arms. A Cox proportional hazards model was utilized to estimate the association between the use of SGLT2i versus DPP-4i and the numbers of serum urate higher than 6 mg/dL. Inclusion criteria include patients with gout and concomitant T2DM, age over 18, and must have serum uric acid level data available. Results: Of the 11,495 gout patients, including 3,593 users of SGLT2i users, were propensity score-matched to 3593 DPP-4i users. Among gout patients with T2DM on SGLT2i, 598 experienced serum urate levels exceeding than 6 mg/dL, while in the DPP-4i group, 920 patients had serum urate higher than 6 mg/dL. The use of SGLT2i was associated with significantly lower odds of serum uric acid exceeding 6 mg/dl compared to DPP-4i. (OR: 0.580 [0.517-0.651]). Conclusion: Our study suggests that SGLT2i may offer a more effective means of managing serum uric acid levels in gout patients with concomitant T2DM compared to DPP-4i. Clinical trials are required to validate the findings. For clinical practice, the dosage for SGLT2i to cause the urate-lowering effect needs to be investigated. With further studies and clinical trials, the rationale of choosing SGLT2i over DPP-4i may be incorporated into the management of T2DM in gout patients with T2DM. Presentation: 6/1/2024

Pediatrics hyperuricemia in clinical practice: A retrospective analysis in 1753 children and adolescents with hyperuricemia

ObjectivesSerum levels of uric acid (S-UA) are influenced by the interaction of genetic and environmental factors; detailed studies of hyperuricemia in children are rare. This retrospective study aimed to analyze the causes, risk factors, and therapeutic approaches associated with the development of hyperuricemia in childhood. MethodsIn a single-center study, serum uric acid levels were analyzed in 33,900 samples from 13,890 children and adolescents˂19 years (6760 girls and 7130 boys) obtained between 2013 and 2023. Hyperuricemia was defined as S-UA>370μmol/L (6.22mg/dL) in girls and>420μmol/L (7.06mg/dL) in boys; mild hyperuricemia was defined as 370–420μmol/L in boys˂13 years. ResultsIn the analyzed group, hyperuricemia was found in 1753 patients (12.6%), including 586 girls and 864 boys; mild hyperuricemia was found in 303 boys˂13 years. The most common associated conditions were obesity with body mass index>95th percentile (27.8% of girls, 26.3% of boys) and chronic kidney disease (18.6% of boys, 11.4% of girls). Hyperuricemia was also relatively common in children with connective tissue disorders (10.6%) or different inherited metabolic disorders (10.7%). Transitory hyperuricemia was found in 19.1% of girls and 10.1% of boys with acute gastroenteritis. Urate-lowering therapy was used in 73 children and adolescents with severe hyperuricemia (S-UA 556±107μmol/L, fraction excretion of UA 3.27±1.98%). Eight treated children had chronic kidney disease, nine were extremely obese, one had combined antiepileptic therapy, and 55 had inherited metabolic diseases, including 26 children with disorders of purine metabolism. The initial daily dose of allopurinol (50–100mg) normalized the S-UA (350±80μmol/L) in a majority of children, except for extremely obese adolescents (weight 98–149kg) where the dose had to be increased to 200–300mg. ConclusionsAsymptomatic hyperuricemia is a relatively common biochemical finding in pediatric clinical practice. The etiology of hyperuricemia should be carefully analyzed, and the value of individualized hyperuricemia management and the eventual benefits of urate-lowering therapy in children must be carefully considered.

Association between Urate-Lowering Therapy and Kidney Failure in Patients with CKD

Association between Urate-Lowering Therapy and Kidney Failure in Patients with CKD

Self-management behavior preferences and influencing factors in Chinese patients with recurrent gout: A qualitative study

ObjectiveThis study aimed to explore the preferences and influencing factors of self-management behaviors in patients with recurrent gout and provide a theoretical basis for developing targeted strategies to improve self-management preferences. MethodsA total of 10 patients with recurrent gout were recruited from the gout specialist outpatient clinic at a tertiary hospital in Shenyang, Liaoning Province, China. Semi-structured interviews were conducted with these patients, and the Kawakita Jiro (KJ) method was used to analyze the interview data. ResultsAfter four rounds of screening by five researchers, 35 codes were selected from an initial 132. After three rounds of discussion and induction, the KJ method identified seven domains of self-management behavior preferences in patients with recurrent gout: 1) extensive knowledge of gout, yet difficulty in distinguishing between accurate and inaccurate information; 2) a passive attitude of “no pain, no management”; 3) the challenge of changing entrenched daily habits; 4) the optimistic but unrealistic belief of “self-delusion”; 5) a tendency to seek medical attention late due to hopelessness of cure and familiarity with recurrences; 6) preference for analgesics for gout recurrences while neglecting long-term urate-lowering therapy (ULT); and 7) gout-related stigma. ConclusionThe results of this study showed that the self-management behavior of patients with recurrent gout could be improved, especially in the aspects of medical seeking behavior, medication compliance, daily management and emotional management. At the same time, we found that gout stigma, difficulty in distinguishing true and false knowledge of gout and negative attitude of “ignoring pain” were significantly associated with self-management behavior.

Identifying the association between serum urate levels and gout flares in patients taking urate-lowering therapy: a post hoc cohort analysis of the CARES trial with consideration of dropout

ObjectiveTo investigate gout flare rates based on repeated serum urate (SU) measurements in a randomised controlled trial of urate-lowering therapy (ULT), accounting for dropout and death.MethodsWe performed a secondary analysis...

UNFORESEEN BARRIER IN GOUT TREATMENT: A CASE OF COEXISTING LYME DISEASE

Refractory gout and Lyme disease are distinct conditions that, when coexisting, pose significant diagnostic and therapeutic challenges, particularly in regions endemic for Lyme disease. This case report presents a 49-year-old male with a three-year history of gout, presenting with acute arthritis of the first metatarsophalangeal joint, unresponsive to standard urate-lowering therapy. Despite treatment with colchicine and prednisone, the patient’s symptoms persisted, and inflammatory markers remained elevated. Imaging revealed findings consistent with gouty arthritis, but due to the atypical treatment response, further testing was conducted. Serological analysis confirmed infection with Borrelia burgdorferi, establishing the diagnosis of concurrent Lyme disease. The addition of doxycycline to the treatment regimen resulted in significant clinical improvement within days. This case highlights the importance of considering Lyme disease in patients with refractory gout in areas endemic for Lyme disease. While rare cases of Lyme disease mimicking gout have been reported, this is among the first documented instances of their coexistence. Early recognition and appropriate antibiotic treatment are critical in preventing complications and ensuring optimal management of both conditions.

Non-adherence to urate lowering therapy in gout after 5 years is related to poor outcomes-results from the NOR-Gout study.

Patients with gout need to adhere to medication over time to achieve good outcomes. We assessed self-reported adherence to medication with urate lowering therapy (ULT) 5 years after a treat-to-target intervention and studied how non-adherence was related to baseline demographic and disease variables. Patients in the NOR-Gout observational study were included after a recent gout flare and serum urate >360 µmol/L. Patients (mean age 56.2 (S.D. 13.6), 94.5% males, 17.2% with tophi) attended tight-control visits over one year with escalating urate lowering therapy using a treat-to-target strategy. Five-year follow-up included the Medication Adherence Report Scale (MARS-5) questionnaire (range 5-25) for adherence. Flares and SUA target achievement were compared for 5-year adherence to medication. At 5-years most of the 163 patients used ULT (95.1%). MARS-5 adherence scores after 5 years were high (median 24, interquartile range 22-25). Patients in the lowest MARS-5 quartile had, compared to the highest quartile, more often a flare during the last year of follow-up (33.3% vs. 9.5%, P=0.004), and reached the 5-yr serum urate treatment target less frequently (45.2% vs. 87.5%, P<0.001). Baseline lower age (OR 0.56, 95%CI 0.39-0.79), non-European origin (OR 0.22, 95%CI 0.06-0.80), lower SF-36 mental health scores (OR 0.94, 95%CI 0.91-0.98) and less joint pain during last flare (OR 0.73, 95%CI 0.58-0.92) were independent risk factors for non-adherence to medication. Patients reported after 5 years high adherence to medication. Non-adherence was related to more flares and less urate target achievement. Younger age and non-European origin were associated with non-adherence.

Support needs of gout patients and suitability of eHealth to address these needs.

To investigate the support needs of patients with gout regarding information, communication, treatment and disease monitoring, and patients' views on and preferences for eHealth applications to address these needs. A focus group study using purposive sampling was conducted. Three focus group sessions with a duration of 2 h per group were held with in total of 23 patients using urate-lowering therapy, recruited from primary and secondary care. Audio recordings were transcribed, and data were analysed using thematic analysis. Eight themes were identified. Five themes addressed support needs of gout patients and suitability of eHealth in addressing those needs: (1) Timely access to healthcare, especially during flares; (2) (personalized) information regarding diagnosis, medication, and diet; (3) insight into uric acid levels and medication side effects through blood monitoring; (4) better coordination across primary and secondary care; and (5) self-management and shared responsibility over care for maintaining health. Three themes addressed eHealth in general: (1) receptive towards eHealth in gout care; (2) the preference for eHealth to have a complementary role (i.e. not replacing face-to-face) contact with healthcare providers; and (3) preferences on eHealth use and functionalities. Patients expressed various needs regarding their disease management and projected a supporting role for eHealth in (self)management of gout. Addressing the needs and preferences of patients could enhance their understanding of the disease and treatment, self-management, and possibly health outcomes.

Baseline Dual-Energy Computed Tomography Urate Volume Predicts Fulfillment of Gout Remission After Two Years of Urate-Lowering Therapy.

This study aimed to identify variables that predict gout remission in people with erosive gout receiving urate-lowering therapy. We analyzed data from a two-year, double-masked randomized-controlled trial of people with erosive gout, randomized to a serum urate target of <0.20 mmol/L or <0.30 mmol/L using oral urate-lowering therapies. All participants had dual-energy computed tomography (DECT) scans of the feet and ankles at baseline. The proportion of participants achieving gout remission according to the 2016 preliminary gout remission criteria and simplified gout remission criteria (without the patient reported outcomes) was analyzed. Logistic regression models were used to evaluate predictors of gout remission in year 2. The preliminary gout remission criteria were fulfilled in 11 of 97 participants (11%) at year 1 and 21 of 92 participants (23%) at year 2. The simplified criteria were fulfilled in 26 of 97 participants (27%) in year 1 and 40 of 92 participants (44%) in year 2. In multivariable regression models, baseline DECT monosodium urate crystal volume was the only significant independent predictor of gout remission at year 2, using either criteria. Each 1-cm3 increase in the baseline DECT monosodium urate crystal volume decreased the odds of fulfilling the 2016 preliminary gout remission criteria (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.46-0.93; P = 0.02) and the simplified gout remission criteria (OR 0.57, 95% CI 0.41-0.78; P < 0.001). In people with erosive gout on urate-lowering therapy, higher baseline DECT monosodium urate crystal volume is associated with lower odds of gout remission after two years of treatment, defined by either the preliminary gout remission criteria or simplified gout remission criteria.

Relationship between serum urate and changes in dual-energy CT monosodium urate crystal volume over 1 year in people with gout: an individual participant data analysis

ObjectivesThe dynamics of monosodium urate (MSU) crystal changes across a range of serum urate concentrations in people with gout are unknown. This study aimed to systematically examine the relationship between...