Febuxostat Therapy Research Articles

Effects of Febuxostat Therapy on Circulating Adipokine Profiles in Patients with Overweight or Obesity and Asymptomatic Hyperuricemia: A Randomized Controlled Study

Introduction: Elevated levels of serum uric acid (SUA) are strongly associated with several components of the metabolic syndrome, particularly obesity. Previous studies have reported the correlation between SUA levels, xanthine oxidoreductase (XOR) activity, and the imbalanced adipokine levels that are characteristic of obesity. In this study, we explored the effect of febuxostat on circulating adipokine profiles in patients with overweight or obesity and asymptomatic hyperuricemia. Methods: This study was a single-center, randomized, and controlled clinical trial that enrolled 130 participants with asymptomatic hyperuricemia and obesity. One hundred seventeen participants were included in the final analysis, with 60 participants in the febuxostat group and 57 in the control group. We compared the circulating adipokine levels at 3 and 6 months, including high molecular weight (HMW) adiponectin, chemerin, omentin, monocyte chemotactic protein-1, asprosin, fibroblast growth factor 21, neuregulin-4, leptin, resistin, vaspin, visfatin, adipsin, and assessed the correlation between changes in adipokine levels (Δadipokines) and changes in XOR activity (ΔXOR) after febuxostat treatment. Results: The results showed that an increase in HMW adiponectin and omentin levels and a decrease in chemerin and asprosin levels at 3 or 6 months compared to the control group. Additionally, a positive correlation was observed between ΔXOR activity and Δasprosin. Furthermore, after adjusting for triglyceride (ΔTG) and serum uric acid (ΔSUA) in multiple linear regression analyses, we found that ΔXOR activity was independently correlated with Δasprosin. Conclusion: This study may provide important evidence that febuxostat could alleviate the imbalance in circulating adipokine levels in patients with overweight or obesity and asymptomatic hyperuricemia. Furthermore, we observed a positive correlation between changes in asprosin levels and changes in XOR activity after febuxostat treatment.

Effect of the Xanthine Oxidase Inhibitor, Febuxostat, on WBC Count in Asymptomatic Hyperuricemia: Subanalysis of the Randomized PRIZE Study.

The anti-inflammatory effects of the xanthine oxidase inhibitor, febuxostat, a urate-lowering agent, have been reported in animal studies. However, the anti-inflammatory effects of urate-lowering therapy and its associated cardiovascular protective effects have not been fully determined in actual clinical practice. This study aimed to investigate the effect of febuxostat on white blood cell (WBC) count in patients with asymptomatic hyperuricemia and to assess for potential correlations between changes in WBC count and inflammatory biomarkers and atherosclerosis in this patient population. This was a post hoc subanalysis of the PRIZE study, a multicenter, prospective, randomized, open-label clinical trial. In the PRIZE study, asymptomatic hyperuricemia patients were randomized to febuxostat group or control group with non-pharmacological therapy and evaluated the effect on vascular. The primary endpoints of this study were the assessment of the time course of WBC count over 24 months and its changes from baseline. Correlations of WBC count with high-sensitivity C-reactive protein (hs-CRP) and mean common carotid artery (CCA)-IMT were also exploratorily examined in the febuxostat group. A total of 444 patients (febuxostat group, n=223; control group, n=221) with WBC measurements available at baseline and at least one of the follow-up time points of 12 or 24 months, were enrolled. Febuxostat modestly, but significantly, reduced WBC counts at 12 and 24 months compared with the baseline levels (P=0.002 and P=0.026, respectively). Notably, the WBC count in the febuxostat group at 12 and 24 months was significantly lower than that in the control group (P=0.007 and P=0.023, respectively). The changes in WBC count were associated with those of hs-CRP (P=0.038), but not with CCA-IMT (P=0.727). Febuxostat therapy for 24 months modestly, but significantly, decreased WBC count in patients with asymptomatic hyperuricemia. This might potentially reflect a modest anti-inflammatory action of febuxostat in clinical settings.

Febuxostat Therapy for Patients with Gout and Stage 2-4 CKD: a Retrospective Study.

IntroductionThe aim of this study is to explore the efficacy and renal safety of febuxostat in gout and stage 2–4 chronic kidney disease (CKD) and factors that correlated with target serum urate (SU).MethodsA single-center retrospective study including male patients with gout and CKD was conducted. SU, the rate of SU < 360 µmol/L (RAT), and renal safety were analyzed in subjects who received febuxostat over 44 weeks. Factors that correlated with target SU were also explored.ResultsBetween January 2017 and March 2021, 102 patients (stage 2 CKD: n = 27; stage 3 CKD: n = 70; stage 4 CKD: n = 5) were enrolled. The SU level reduced significantly over 44 weeks (600.76 ± 95.42 versus 405.52 ± 111.93 µmol/L; P < 0.05), and RAT increased to 39.20%. The overall estimated glomerular filtration rate (eGFR) level improved over 44 weeks (52.05 ± 11.68 versus 55.46 ± 14.49 mL/min/1.73 cm2, P < 0.05). An obvious improvement of eGFR was observed in stage 3 CKD, in patients with ≤ 1 risk factor (hypertension, diabetic mellitus, hyperlipidemia, or usage of non-steroidal anti-inflammatory drugs), and in patients with terminal SU < 360 µmol/L (P < 0.05). Logistic regression analysis indicated that baseline SU level and body weight were correlated with RAT. Further analysis revealed that patients with SU < 600 μmol/L and body weight ≤ 70 kg reached higher RAT (56.7%).ConclusionsFebuxostat demonstrated efficacy and renal safety in patients with gout and CKD in clinical practice. Achieving the target SU could obviously improve renal function. Baseline SU level and body weight could affect the achievement of target SU.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00480-7.

Risk factors for type 2 diabetes mellitus in patients with gout: results from a prospective study

The development of type 2 diabetes mellitus (DM) (DM2) in patients with gout can be influenced by both conventional and directly linked to gout risk factors (RFs).Objective: to identify RFs for the development of DM2 in patients with gout, including those directly associated with gout, based on long-term prospective follow-up data.Patients and methods. The study included 444 patients with gout older than 18 years (49 women, 395 men) who did not have DM. The followup period ranged from 2 to 8 years. The studied RFs for DM2 were: gender, age, family history of DM2, obesity, alcohol consumption &gt;20 units per week, insufficient physical activity, unbalanced nutrition, history of hyperglycemia, coronary heart disease (CHD), arterial hypertension (AH), chronic heart failure, antihypertensive drugs, diuretics, glucocorticoids (GCs), urate-lowering therapy, serum levels of cholesterol, triglycerides, CRP, uric acid (UA), glucose, creatinine, glomerular filtration rate &lt;60 ml/min/1.73 m2, the presence of tophi, &gt;4 attacks of gout per year, ≥5 affected joints during the disease.Results and discussion. DM2 developed in 108 (24.3%) patients. These patients were older, had a family history of DM, more often received antihypertensive therapy, diuretics, and glucocorticoids (49.1; 73.1; 27.8 and 47.2%, respectively) than patients who did not develop DM2 (25.6; 50.5; 14.8 and 36.4%, respectively; p&lt;0.05 for all cases). In addition, patients with DM2 were more likely to have subcutaneous tophi (59.3% versus 30.0%; p=0.001), among them there were more individuals (67.6% versus 31.6%; p=0.001) with frequent attacks of arthritis (&gt;4 attacks per year). UA levels &gt;480 and 600 μmol/l were also significantly more frequent (p=0.0002) in patients with DM2 (71.3 and 34.3%, respectively).According to logistic regression data, factors that increase the risk of developing DM2 were: family history of DM, a history of hyperglycemia, CHD, AH, intake of GCs, antihypertensive drugs, the presence of tophi, &gt;4 exacerbations of gout per year. Febuxostat use and UA &lt;300 μmol/L were associated with a lower risk of DM2.Conclusion. The occurrence of DM2 in gout is associated not only with well-known risk factors, but also with hyperuricemia and microcrystalline inflammation. Febuxostat therapy is associated with a lower risk of developing DM2.

Порівняльна оцінка застосування урикодепресантів алопуринолу та фебуксостату при подагричній нефропатії. Повідомлення 1. Клінічне випробування

Актуальність. Практично постійним проявом подагри є ураження нирок, яке визначає прогноз хвороби. Гіперурикемія при подагричній нефропатії належить до незалежних чинників ризику зниження азото- й електролітовидільної функції нирок. Метою дослідження стала порівняльна оцінка впливу урикодепресантів алопуринолу і фебуксостату на функціональний стан нирок у хворих на подагру. Матеріали та методи. Під наглядом перебували 73 хворі на первинну подагру (чоловіки із середнім віком 49 років та тривалістю захворювання 10 років). Хронічну форму артриту встановлено в 71 % від числа хворих, інтермітовану — в 29 %, периферійні тофуси виявлено в 53 % випадків. Хронічну хворобу нирок I, II, III і IV стадії виявлено у співвідношенні 56 : 12 : 2 : 1, латентний, уролітіазний і протеїнуричний типи подагричної нефропатії — у 53, 37, 10 %, артеріальну гіпертензію — у 47 %. Гіперурикемію на момент обстеження констатовано у 84 % хворих, гіперурикурію — у 52 %, метаболічний, нирковий і змішаний типи гіперурикемії мали місце відповідно в 57, 3 і 40 % випадків. Результати. При порівняльній оцінці інгібіторів ксантиноксидази алопуринолу й ксантиноксиредуктази фебуксостату відносно функції нирок у хворих на подагричну нефропатію перевагу слід віддати другому препарату, хоча гіпоурикемічна дія обох урикодепресантів приблизно однакова, а прогностичними критеріями ефективності алопуринол- та фебуксостат-терапії відповідно є початкові показники в’язкоеластичності сечі і β2-мікроглобулінурії. Висновки. У перспективі буде корисним визначення морфологічних змін з боку нирок при експериментальній подагричній нефропатії під впливом алопуринолу й фебуксостату, а також доцільна оцінка результатів комбінованого застосування урикодепресантів з іншими групами гіпоурикемічних засобів (урикозуриками, ферментом пеглотиказой тощо).

Impact of urate-lowering therapy on quality of life indicators in patients with gout

Gout can have a significant impact on the quality of life (QoL) of patients.Objective: to assess the dynamics of QoL indicators and the possibility of achieving the target level of uric acid (UA) in patients with gout on febuxostat therapy, with ineffectiveness and / or contraindications to the allopurinol administration.Patients and methods. The prospective, single-center study included 80 patients with gout. The follow-up period was at least 6 months of allopurinol or febuxostat (Azurix®) therapy in doses required to achieve the target UA level. When urate-lowering therapy was initiated, allopurinol 100 mg per day was prescribed, followed by dose titration (up to maximum of 900 mg per day) until the target UA level was reached (&lt;360 μmol/L). Patients with ineffectiveness of allopurinol and / or adverse reactions (ADRs) were transferred to febuxostat 80–120 mg per day. To prevent arthritis attacks, all patients received low doses of non-steroidal anti-inflammatory drugs or colchicine 0.5 mg per day or glucocorticoids 7,5 mg per day (in prednisolone equivqlent). At the first and last visits, patients on febuxostat completed the SF-36 questionnaire.Results and discussion. After 6 months of follow-up, 70 (88%) patients received urate-lowering therapy, of whom 51 (73%) reached the target UA level. Allopurinol dosage titration required 26 patients, of whom 14 (54%) achieved the treatment goal. Due to the ineffectiveness of allopurinol, 32 patients were switched to febuxostat, which allowed to achieve normouricemia in 69% of cases. Fifteen (68%) of 22 patients who were initiated with febuxostat due to ADRs to allopurinol also achieved the target UA level. Patients who received febuxostat and reached the target UA level improved QoL indicators: role-physical functioning, bodily pain, general health, vitality and general physical well-being (p&lt;0.05 in all cases). Patients who did not reach the target UA level on febuxostat therapy improved such indicators as physical functioning, role-physical functioning, and bodily pain (p&lt;0.05 in all cases). High compliance was observed in 63% of patients, treated with febuxostat and in 36% of patients, treated with allopurinol.Conclusion. In patients with ineffectiveness or intolerance to allopurinol, in 69% of cases febuxostat allows to achieve the target UA level and improving QoL and complience.

A single-centre experience of febuxostat as a second-line urate-lowering therapy.

The purpose of this study was to describe the local experience in terms of drug efficacy and safety using a new xanthine oxidase inhibitor, febuxostat, as a second-line urate-lowering therapy (ULT) in gout patients with normal renal function and chronic kidney disease. This cross-sectional study included all gout patients who attended the rheumatology clinic from January 2013 to June 2018 and had received febuxostat as a second-line ULT. Analysis focused on the proportion of gout patients who achieved target serum urate (sUA) of <360 μmol/L, duration taken to achieve target sUA, and febuxostat dosage at achievement of target sUA. Safety assessments included comparison of serum creatinine, estimated glomerular filtration rate (eGFR), and serum alanine aminotransferase (ALT) at baseline, at achievement of target sUA, and at 12-monthly intervals. Majority (90.9%) of patients achieved target sUA. Median duration required to achieve target sUA was 5.5 months with IQR (interquartile range) of 8.5. Five (22.7%) patients achieved target sUA within one month of therapy with febuxostat 40 mg per day. Eleven (55%) patients achieved target sUA within six months and 16 (80%) by 12 months. Equal proportion of patients achieved target sUA with febuxostat 40 mg per day and 80 mg per day, respectively. There was no significant difference in the changes in serum creatinine level, eGFR and ALT from baseline and at achievement of target sUA, nor at 12-monthly intervals throughout the duration of febuxostat therapy. Apart from three patients who developed hypersensitivity reactions to febuxostat, no other adverse events were reported. A significant proportion of gout patients with CKD managed to achieve target sUA with a lower dose of febuxostat at 40 mg per day and it is reasonable to maintain this dose for up to six months before considering dose escalation.

Increased Efficacy and Tolerability of Pegloticase in Patients With Uncontrolled Gout Co-Treated With Methotrexate: A Retrospective Study.

IntroductionGout is a painful inflammatory condition caused by chronically elevated serum uric acid levels (sUA). When standard urate-lowering therapies fail/are not tolerated, uncontrolled gout (elevated sUA, subcutaneous tophi, chronic gouty arthritis, frequent flares) can occur. Pegloticase, a recombinant uricase, converts uric acid to allantoin, a readily excreted molecule. Responder rate in trials was 42%, limited by anti-drug antibody (ADA) development. Immunomodulators attenuate ADA formation and case reports suggest immunomodulation increases pegloticase responder rates. The current study retrospectively examined responder rate in patients undergoing methotrexate/pegloticase co-therapy.MethodsPatients who underwent methotrexate/pegloticase co-treatment at a single rheumatology practice were included. Demographics, clinical, treatment, and safety parameters were collected. The primary outcome was the proportion of responders (≥ 12 biweekly pegloticase infusions, sUA < 6 mg/dl just prior to infusion 12).ResultsTen patients (nine men, 52.3 ± 13.5 years) with uncontrolled tophaceous gout (erosive damage, ulcerative tophi, frequent flares, gout-related hospitalizations) were included. Patients had failed allopurinol (100–300 mg) or febuxostat (40 mg) therapy (doses not increased because of intolerance, kidney concerns, noncompliance, or rapid tophi resolution requirement). Baseline sUA was 9.42 ± 2.05 mg/dl. Along with standard pre-infusion prophylaxis, nine patients received subcutaneous methotrexate (25 mg/week) initiated 14–35 days before pegloticase and one patient received oral methotrexate (12.5 mg/week) initiated 14 days after pegloticase. Eight patients (80%) were responders, receiving 15.5 ± 3.8 infusions (range, 12–21) over 31.8 ± 9.5 weeks. One patient had efficacy loss with mild infusion reaction during infusion 4 and one patient was lost to follow-up after infusion 5. One patient reported one gout flare. No new safety concerns emerged.ConclusionsMethotrexate/pegloticase co-therapy resulted in a higher responder rate than the established 42% with pegloticase alone. Therefore, methotrexate/pegloticase co-therapy may safely allow more patients to benefit from a full treatment course, likely through ADA attenuation.

Efficacy and Safety of Simiaowan in Prevention of Acute Flares in Chronic Gout Patients Initiating Febuxostat Therapy

Efficacy and Safety of Simiaowan in Prevention of Acute Flares in Chronic Gout Patients Initiating Febuxostat Therapy

Predictors of poor response to urate-lowering therapy in patients with gout and hyperuricemia: a post-hoc analysis of a multicenter randomized trial

Clinical guidelines have recommended a target of serum uric acid (SUA) level below 6.0mg/dL for the urate-lowering therapy (ULT) of gout patients, but there are still a high proportion of patients failing to achieve the therapeutic target above. This study aimed to identify possible predictors of poor response to ULT in gout patients. We performed a post-hoc analysis of a multicenter randomized double-blind trial which assessed the efficacy of febuxostat in patients with hyperuricemia (serum urate level ≥ 8.0mg/dL) and gout. Demographic characters and baseline data including SUA levels were collected. Poor response to ULT was defined as average SUA after ULT was more than 6.0mg/dL. Factors associated with poor response to ULT in gout patients were analyzed, and multivariate logistic regression analysis was also carried out to find out those independent predictors. A total of 370 patients were enrolled in this post-hoc analysis. Compared with those with good response to ULT, patients with poor response to ULT had younger age (P < 0.001), higher proportion of obesity (P = 0.003), higher proportion of statins use (P = 0.019), higher body mass index (BMI) (P < 0.001), higher baseline SUA (P < 0.001), higher proportion of males (P = 0.001), higher alanine transaminase (P < 0.001), higher aspartate transaminase (P = 0.017), higher total cholesterol (P = 0.005), higher triglyceride (P = 0.042), and higher low density lipoprotein (P = 0.037). Multivariate logistic regression analysis showed that younger age (odds ratio (OR) = 0.965, 95% CI 0.943-0.987, P = 0.002), higher BMI (OR = 1.133, 95% CI 1.049-1.224, P = 0.001), higher baseline SUA (OR = 1.006, 95% CI 1.002-1.009, P = 0.001), and no application of febuxostat therapy (OR = 0.41, 95% CI 0.25-0.68, P < 0.001) were independent predictors of poor response to ULT in patients with gout. In patients with gout and hyperuricemia, younger age, higher BMI, and higher baseline SUA are predictors of poor response to ULT. These findings could help physicians better identify patients who may fail in ULT and give individualized treatment precisely. The trial was registered at chinadrugtrials.org.cn in 2012 (CTR20130172).Key Points• A post-hoc analysis of a multicenter randomized double-blind trial which assessed the efficacy of febuxostat in patients with hyperuricemia and gout was performed.• Multivariate logistic regression analysis showed that younger age, higher BMI, and higher baseline SUA are predictors of poor response to urate-lowering therapy.

Hypersensitivity and Cardiovascular Risks Related to Allopurinol and Febuxostat Therapy in Asians: A Population‐Based Cohort Study and Meta‐Analysis

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P<0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P=0.152) and related death (HR, 1.49; P=0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.

Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study

BackgroundIn gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy.MethodsPatients receiving combined lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study (“200CONT”, “400CONT”), whereas those receiving only febuxostat 80 mg were randomized to lesinurad 200 or 400 mg with febuxostat (“200CROSS”, “400CROSS”). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of lesinurad exposure, 800 days).ResultsOf 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT (n = 64), 200CROSS (n = 33), 400CONT (n = 65), and 400CROSS (n = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged lesinurad exposure in the extension study.ConclusionsPatients receiving lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study.Trial registrationClinicalTrials.gov, NCT01510769. Registered on 13 January 2012.

Effects of febuxostat on serum cytokines IL-1, IL-4, IL-6, IL-8, TNF-α and COX-2.

Effects of febuxostat on serum cytokines interleukin (IL)-1, IL-4, IL-6, IL-8, tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) in patients with gout were investigated. A total of 80 patients with gout admitted and treated in the Affiliated Zhongshan Hospital of Dalian University from January 2015 to September 2017 were selected and divided into two groups by virtue of a random number table, with 40 patients in each group. All the enrolled patients received strict gout diet adjustment and took colchicine at the same time. Patients in the control group were additionally treated with allopurinol, while those in the the observation group were administered with febuxostat. The serum uric acid levels were compared between the two groups. The number of gout attacks and adverse reactions were recorded, and the variations in COX-2 positive value integral were clarified. At different time-points of observation, the serum uric acid levels in the observation group were significantly lower than those in the control group (p<0.05). Moreover, at 3 months after treatment, the levels of inflammatory cytokines in the serum in the observation group were decreased compared with those in the control group (p<0.05). The IL-1 and TNF-α levels were lower in the observation group at 1 week, 1 and 3 months after treatment compared with those in the control group (p<0.05). Furthermore, it was discovered that at 3 months after treatment, the COX-2 positive value integral in the observation group was superior to that in the control group (p<0.05). During follow-up, the number of gout attacks that needed medical intervention in the observation group was smaller than that in the control group (p<0.05). Compared with allopurinol therapy, febuxostat therapy can remarkably inhibit inflammatory responses in the body, relieve clinical symptoms and reduce relapse of the patients with gout.

PSS2 - Risk of Severe Adverse Reactions Related to Allopurinol and Febuxostat in Asians

Allopurinol, an anti-hyperuricaemic agent, is one of the common causes of life-threatening cutaneous adverse reactions. Febuxostat is a newer urate-lowering drug. The safety of these two drugs remain unclear. This study aimed to compare the incidence and mortality associated with allopurinol or febuxostat related hypersensitivity in Asians. We conducted a cohort study and collected data of patients receiving allopurinol or febuxostat from the electronic medical records from January, 2012, through June, 2015, of the Chang Gung Memorial Hospital Health System in Taiwan. Among 51,505 and 10,034 patients receiving allopurinol and febuxostat prescriptions, 12,007 and 5,680 patients were identified as new users who had not previously exposed to these two drugs The incidence of hypersensitivity reactions, including maculopapular exanthema (MPE), drug reaction with eosinophilia and systemic symptom (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) related to allopurinol or febuxostat were analyzed. Proportion t-test performed, and P < .05 was considered statistically significant. There were 33 patients with allopurinol-induced hypersensitivity reactions (10 SJS/TEN, 8 DRESS, and 15 MPE) and only 1 case of febuxostat-induced MPE were indentified in this study. The overall incidence of hypersensitivity reactions induced by febuxostat was significantly lower than that induced by allopurinol (0.2 v.s. 2.7 per 1000 new users, P< 0.001). There were 4 deceased patients identified in patients with allopurinol-induced SJS/TEN but none in febuxostat users. Fourteen patients with allopurinol-induced hypersensitivity reactionsshifted to further febuxostat therapy were all well tolerant without any adverse reactions, even in patients with chronic kidney diseases or carried the risk HLA-B*58:01 allele. The incidence and severity of hypersensitivity reactions related to febuxostat are less than that of allopurinol in Asians. There was no risk of cross hypersensitivity between allopurinol and febuxostat of patients with allopurinol hypersensitivity.

Febuxostat Therapy for Patients With Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized Trial

Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. Randomized, double-blind, placebo-controlled trial. 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. The primary end point was the slope (in mL/min/1.73m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23±5.26mL/min/1.73m2 per year) and placebo (-0.47±4.48mL/min/1.73m2 per year) groups (difference, 0.70; 95% CI,-0.21 to 1.62; P=0.1). Subgroup analysis demonstrated a significantbenefit from febuxostat in patients without proteinuria (P=0.005) and for whom serum creatinine concentration was lower than the median (P=0.009). The incidence of gouty arthritis was significantly lower (P=0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. Funded by Teijin Pharma Limited. Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

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

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. Gout flares are associated with serum concentrations of urate above 0.42mmol/L (7mg/dL). Achieving and maintaining serum urate below 0.36mmol/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 300mg decreases serum urate adequately in only about 40% of gout patients while febuxostat 80mg 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.

The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia.

Febuxostat is tolerable in chronic kidney disease (CKD) patients with hyperuricemia. However, the long-term effect of lowering uric acid with febuxostat on renal function and blood pressure has not been elucidated. This was a 2years retrospective observational study. 86 CKD patients with hyperuricemia who continued with allopurinol (allopurinol group, n = 30), switched from allopurinol to febuxostat (switched group, n = 25), or were newly prescribed febuxostat (febuxostat group, n = 31) were included in this study. Serum uric acid, estimated glomerular filtration rate (eGFR), blood pressure, and urinary protein were analyzed. Moreover, the impact of serum uric acid reduction on renal function and blood pressure was assessed. Serum uric acid in the switched and febuxostat groups was significantly reduced at 6months (switched group; 8.49 ± 1.32-7.19 ± 1.14mg/dL, p < 0.0001, febuxostat group; 9.43 ± 1.63-6.31 ± 0.90mg/dL, p < 0.0001). In the allopurinol group, serum uric acid was increased (6.86 ± 0.87-7.10 ± 0.85mg/dL, p = 0.0213). eGFR was significantly increased (35.2 ± 12.8-37.3 ± 13.9mL/min/1.73m2, p = 0.0232), while mean arterial pressure (93.1 ± 10.8-88.2 ± 9.5mmHg, p = 0.0039) was significantly decreased at 6months in the febuxostat group, resulting in the retention of eGFR for 2years. The impact of serum uric acid reduction might have beneficial effects on CKD progression and blood pressure. However, a large prospective study is needed to determine the long-term efficacy of febuxostat therapy in CKD patients with hyperuricemia.

Study of therapeutic efficacy of febuxostat in chronic kidney disease stage IIIA to stage VD.

Hyperuricemia [serum uric acid (SUA) >7.0 mg/dL] which is common in chronic renal diseases is associated with augmented vascular events. In addition to nonpharmacological therapy, hypouricosuric drugs reduce UA levels. The current study was a prospective observational study of six months duration November 2016 to April 2017 done to determine the efficacy of febuxostat in patients with hyperuricemia in chronic kidney disease (CKD) stage G3a to G5 and to correlate any association with reduction of hypertension, improvement in glomerular filtration rate (GFR), and reduction in comorbidities. The study was carried out at the Department of Nephrology, Owaisi Hospital and Research Center, Hyderabad. One hundred and ten patients were screened, of which 53 patients wherein stage G3a to G5 were recruited and SUA levels were obtained after inclusion criteria. SUA >6.0 in females and 7.0 in males were recruited. The drug febuxostat 40 mg was given once day to all patients with stage G3a to G5D with elevate uric acid levels >7.0 in males and more than 6.0 in females and three samples of UA were obtained monthly. The mean of GFR, blood pressure (BP), and SUA levels were obtained before and after the therapy. Of the 53 patients, males were 32 (60.3%), and females were 21 (39.6%). Mean age of the patients were 36.5 years. Mean UA levels before the start of febuxostat therapy were 8.6, and after adding febuxostat, it was 5.10 at the end of the third visit. The mean BP drop was 7.2 ± 2.1 mm in systolic BP (from 154-147 mm Hg) and diastolic BP drop was 93 ± 2.5 mm Hg (5.1 mm Hg). The mean GFR improved from 50.3 to 53.3 mL/min after the start of febuxostat. Febuxostat in asymptomatic CKD patients improves UA levels, BP and estimated GFR at low dose without any adverse events and no cardiac-related events.

Comparison of the effect of allopurinol and febuxostat on urinary 2,8-dihydroxyadenine excretion in patients with Adenine phosphoribosyltransferase deficiency (APRTd): A clinical trial

IntroductionAdenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients. Materials and methodsPatients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay. ResultsEight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75–289) mg at baseline, and 45 (13–112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0–13.4) mg at the completion of febuxostat therapy (P=0.036). ConclusionUrinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample.

Identification of chronic kidney disease patient characteristics influencing the renoprotective effects of febuxostat therapy: a retrospective follow-up study

BackgroundThe ability of antihyperuricemic therapy to exert renoprotective effects in patients with chronic kidney disease (CKD) is controversial. In the present study, we studied patient characteristics that may mask favorable impact of antihyperuricemic therapy on the progression of CKD.MethodsThis was a single-center, retrospective, follow-up study. One-hundred and seventy-eight CKD patients with hyperuricemia who received febuxostat therapy were included in this study. Mean serum uric acid (mUA) level after treatment and changes in estimated glomerular filtration rate (ΔeGFR) over 6 months were measured and their correlation was examined. Patients were divided into two groups based on mUA, and their ΔeGFR were compared. These analyses were evaluated in various subgroups.ResultsFebuxostat therapy markedly decreased UA level in any CKD stage patients without resulting in serious adverse events. eGFRs of CKD patients in the mUA < 6.0 mg/dl group were maintained, whereas those in the mUA ≥ 6.0 mg/dl group decreased. A significant inverse correlation was observed between mUA and ΔeGFR (r = −0.16, p = 0.019). The renoprotective effects of febuxostat were significant in the following subgroups: male patients, age < 70 years, systolic blood pressure < 130 mmHg, normal cholesterol levels, and absence of diabetes. Coexisting vascular risk factors appear to exert additive masking effects against febuxostat renoprotection.ConclusionsThe results of this study suggest that various vascular risk factors markedly attenuate the renoprotective effects of febuxostat.