Target Serum Uric Acid Levels Research Articles

Efficacy and safety of lesinurad for the treatment of hyperuricemia in gout.

The aim of this review is to present current evidence about the efficacy and safety of lesinurad in combination with xanthine oxidase inhibitors (XOIs) in the treatment of hyperuricemia in patients with gout. Gout is the most common inflammatory form of arthritis. It is caused by an elevated concentration of serum uric acid (UA) that leads to the formation of monosodium urate crystals in joints and different tissues. The goal of therapy is to maintain serum UA levels at <6 mg/dL (0.36 mmol/L), to prevent the formation and deposition of monosodium urate crystals, and to dissolve existing crystals. Lesinurad, a new uricosuric, increases renal urate excretion by selectively inhibiting the renal uric acid transporter 1 (URAT1). Lesinurad is indicated in adults, in combination with a XOI, for the adjunctive treatment of hyperuricemia in patients with gout (with or without tophi) who have not achieved target serum UA levels with an adequate dose of a XOI alone. With the combination strategy, serum UA targets could be reached with the consequence of inhibiting formation of new crystals and promoting dissolution of existing crystals and, therefore, inducing improvement of outcomes such as flares and tophi. The approval of lesinurad was based on data from three pivotal phase III studies (CLEAR 1, CLEAR 2, and CRYSTAL). These clinical studies assessed lesinurad 200 and 400 mg doses. As only lesinurad 200 mg/day dose was finally approved and commercialized, it will be the focus of this paper. In the pivotal clinical trials, the target serum UA level was achieved by significantly more patients in lesinurad 200 mg plus allopurinol group (CLEAR 1 and CLEAR 2 trials) or lesinurad 200 mg plus febuxostat group (CRYSTAL study) compared with patients who received either XOI alone. In these trials, the safety profile of lesinurad 200 mg plus a XOI was comparable to allopurinol or febuxostat alone. Lesinurad, in combination with a XOI, is an effective and safe treatment that covers unmet needs in adults with gout who have not achieved target serum UA levels with a XOI alone.

Comorbidity in gout and hyperuricemia: prevalence, causes, prospects of urate lowering therapy

Nowadays, there is increased interest in the connection of gout and asymptomatic hyperuricemia with comorbid conditions such as diabetes mellitus, cardiovascular diseases, hypertension, chronic kidney disease and other. Studies conducted over the past few decades suggest that not only gout, but also asymptomatic hyperuricemia can significantly worsen the prognosis in patients with cardiovascular diseases, as the deposition of urate crystals can be both an immediate cause and a factor in the progression of renal failure. In that way, the timely appointment of urate - lowering therapy and achieving the target serum uric acid level can not only affect joint damage, but also can significantly slow the progression of life - threatening comorbid conditions.

Ultra-performance hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma: Application to pharmacokinetic study in rats.

A fixed dose combination of lesinurad and allopurinol has been recently approved by USFDA and EMA for treatment of gout-associated hyperuricemia in patients who have not achieved target serum uric acid levels with allopurinol alone. In this study, an ultra-performance hydrophilic interaction liquid chromatography (UPHILIC) coupled with tandem mass spectrometry method was developed and validated for simultaneous determination of allopurinol, oxypurinol and lesinurad in rat plasma. Liquid liquid extraction using ethyl acetate as extracting agent was used for samples extraction procedure. Acquity UPLC HILIC column (100 mm x 2.1, 1.7μm) was used for separation of allopurinol, oxypurinol, lesinurad and internal standard (5-Florouracil). The mobile phase consisting of acetonitrile, water and formic acid (95:5:0.1, v/v/v), were eluted at 0.3 mL/min flow rate having total chromatographic run time of 3 min per sample. The analytes were detected on Acquity triple quadrupole mass spectrometer equipped with a Z-Spray electrospray ionization (ESI). The ESI source was operated in negative mode and multiple reaction monitoring was used for ion transition for all compounds. The precursor to product ion transition of m/z 134.94 > 64.07 for allopurinol, 150.89 > 41.91 for oxypurinol, 401.90 > 176.79 for lesinurad and 128.85 >41.92 for internal standard were used for identification and quantification. The calibration curves for all analytes were found to be linear with weighing factor of 1/x2 using regression analysis. The developed assay was successfully applied in an oral pharmacokinetic study of allopurinol, oxypurinol and lesinurad in rats.

Achievement of Target Serum Uric Acid Levels and Factors Associated with Therapeutic Failure among Japanese Men Treated for Hyperuricemia/Gout.

Objective To assess the rate of successfully achieving treatment goals among Japanese men with hyperuricemia/gout and identify factors influencing the success rate. Methods This cross-sectional study, conducted from January to December 2012, examined the serum uric acid (SUA) levels and clinical characteristics of 2,103 men with hyperuricemia/gout selected from an initial population of 136,770 individuals who participated in a workplace health checkup. The success rates (defined as SUA ≤6.0 mg/dL) were calculated, and a multivariate analysis was used to identify factors associated with “therapeutic failure” to achieve target SUA levels. Results The rate of successfully achieving the target SUA level was 37.5%. The body mass index (BMI) was significantly associated with therapeutic failure [25.0≤ Category (C)2<27.5, adjusted odds ratio (AOR) =1.35; 27.5≤C3<30.0, AOR=1.69; C4 ≥ 30.0, AOR=1.94; relative to C1<25.0]. A significant positive association was also observed between waist circumference (WC) and therapeutic failure (85≤C2<90, OR=1.29; 90≤C3<95, OR=1.41; 95≤C4, OR=2.28; relative to C1<85.0 cm). Those with higher BMI/WC measurements were significantly more likely to have higher SUA levels than those with lower such measurements. The ongoing intake of dyslipidemia medication was identified as a protective factor against therapeutic failure. Discussion Our findings suggest a possible association between obesity and therapeutic failure, underscoring the importance of maintaining lipid profiles as part of managing SUA levels. Better management of both obesity and dyslipidemia may prevent future cardiovascular disorders by ensuring healthier SUA levels.

Preparation, Pharmaceutical Properties and Stability of Lesinurad Co-crystals and Solvate

Lesinurad is a BCS class 2, low solubility drug, indicated for hyperglycemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. Co-crystallization and solvate formation with pharmaceutically acceptable coformers and solvents are one of the best ways to improve solubility of BCS class 2 drugs. Lesinurad DMSO (dimethyl sulphoxide) solvate (1:1 mole ratio), urea and 4-Hydroxy benzoic acid co-crystals (1:1 mole ratio) prepared and scaled up to 100g and characterized using PXRD, FTIR, DSC, TGA, solid state 13C NMR and H1 NMR. Unique PXRD pattern, red shift in acid carbonyl stretching of Lesinurad in DMSO solvent, Urea co-crystal and parahydroxybenzoic acid co-crystals are the evidence of solvate and co-crystal formation. Urea co-crystal is further characterized using 13C solid state NMR. Deshielding of acid carbonyl carbon from δppm of 168.98 to 173.12 and shielding of urea carbonyl carbon from δppm of 169 to 164.56 indicates co-crystal formation between lesinurad and urea. DMSO solvate has shown 1.26 fold increase in Intrinsic dissolution rate measurement (IDR) over marketed Form-II and urea co-crystal. DMSO solvate, urea and 4-Hydroxy benzoic acid cocrystals of lesinurad are stable for six months at 40 °C and 75%RH.

The Experience of Using a Combination of Febuxostat and Canakinumab in Tophaceous Gout Complicated by Chronic Kidney Disease in a Teenage Patient: A Case Study

Background . Gout is extremely rare in childhood and is genetically determined in almost all cases. Late initiation of urate-lowering therapy in children with gout increases the risk of severe disability due to the state of the musculoskeletal system and kidney function. Description of a Clinical Case . At the age of 13 years and 9 months, the boy first experienced acute pain, hyperthermia, and restriction of movement in the right elbow joint. Acute haematogenous osteomyelitis was excluded. Further, repeated recurrences of arthritis of the 1st metatarsophalangeal joint of the left foot, distal interphalangeal joints of the 3rd and 5th fingers of the right hand were noted. After 8 months, a diagnosis of 'Rheumatoid arthritis, polyarticular type' was established at his place of residence. Hyperuricemia (0.99 μ mol/L), high serum levels of creatinine (127 μ mol/L) and urea (7.2 μ mol/L), hypoisostenuria (1,008–1,009) were detected for the first time. Nephrological examinations were not conducted. He received non-steroidal anti-inflammatory drugs and sulfasalazine without effect, with increasing deformity in the affected joints. At the age of 15 years and 7 months, gout was diagnosed with damage to the joints and kidneys, allopurinol therapy was initiated. Normalization of serum uric acid levels was not reached, repeated attacks of gouty arthritis were noted. Direct automated sequencing of the coding sequence of the HPRT1 gene, including exon-intron regions, revealed a mutation of c.481G&gt; А (p.Aia161Thr)CM088136 NM 000194.1 in the hemizygous state. Genetically determined tophaceous gout, stage 2–3 chronic kidney disease were diagnosed. The patient was administered the interleukin-1 inhibitor canakinumab (single injection), urate-lowering therapy with a non-purine inhibitor of xanthine oxidase febuxostat was prescribed. As a result, the target serum uric acid level was reached a week later. Over the next 7 months, there were no repeated gouty attacks. Conclusion . Late initiation of treatment for tophaceous gout in the teenage patient caused chronic kidney disease. The successful experience of using a combination of canakinumab and febuxostat in a patient under 18 years old has been described for the first time.

Management of gout by UK rheumatologists: a British Society for Rheumatology national audit.

To assess the concordance of gout management by UK rheumatologists with evidence-based best-practice recommendations. Data were collected on patients newly referred to UK rheumatology out-patient departments over an 8-week period. Baseline data included demographics, method of diagnosis, clinical features, comorbidities, urate-lowering therapy (ULT), prophylaxis and blood tests. Twelve months later, the most recent serum uric acid level was collected. Management was compared with audit standards derived from the 2006 EULAR recommendations, 2007 British Society for Rheumatology/British Health Professionals in Rheumatology guideline and the National Institute for Health and Care Excellence febuxostat technology appraisal. Data were collected for 434 patients from 91 rheumatology departments (mean age 59.8 years, 82% male). Diagnosis was crystal-proven in 13%. Of 106 taking a diuretic, this was reduced/stopped in 29%. ULT was continued/initiated in 76% of those with one or more indication for ULT. One hundred and fifty-eight patients started allopurinol: the starting dose was most commonly 100 mg daily (82%); in those with estimated glomerular filtration rate <60 ml/min the highest starting dose was 100 mg daily. Of 199 who started ULT, prophylaxis was co-prescribed for 94%. Fifty patients started a uricosuric or febuxostat: 84% had taken allopurinol previously. Of 44 commenced on febuxostat, 18% had a history of heart disease. By 12 months, serum uric acid levels ⩽360 and <300 μmol/l were achieved by 45 and 25%, respectively. Gout management by UK rheumatologists concords well with guidelines for most audit standards. However, fewer than half of patients achieved a target serum uric level over 12 months. Rheumatologists should help ensure that ULT is optimized to achieve target serum uric acid levels to benefit patients.

Lesinurad: what the nephrologist should know.

Lesinurad is an oral inhibitor of the monocarboxylic/urate transporter URAT1 encoded by the SLC22A12 gene. Market authorization was granted in February 2016 in Europe and December 2015 in the USA. As a potentially nephrotoxic uricosuric drug acting on the kidney, nephrologists should become familiar with its indications and safety profile. The approved indication is treatment of gout in combination with a xanthine oxidase (XO) inhibitor in adult patients who have not achieved target serum uric acid levels with an XO inhibitor alone. It is not indicated for asymptomatic hyperuricaemia or for patients with estimated creatinine clearance <45 mL/min. The only authorized daily dose is 200 mg and cannot be exceeded because of the nephrotoxicity risk. Nephrotoxicity is thought to be related to uricosuria. At the 200 mg/day dose, serum creatinine more than doubled in 1.8% of lesinurad patients (versus 0% in placebo) and in 11% of these it was not reversible. In addition, it is subject to a risk management plan given the potential association with cardiovascular events. In randomized clinical trials, the association of lesinurad with either allopurinol or febuxostat achieved a greater reduction in serum uric acid (∼1 mg/dL lower) than the XO inhibitors alone, and this allowed the serum uric acid target to be met in a higher proportion of patients, which was the primary endpoint. However, no clinical differences were observed in gout flares or tophi, although these were not the primary endpoints.

Novel medication approved for gout

Novel medication approved for gout

A Real-World Study of Switching From Allopurinol to Febuxostat in a Health Plan Database.

The objective of this study was to assess the real-world comparative effectiveness of continuing on allopurinol versus switching to febuxostat. In a retrospective claims data study of enrollees in health plans affiliated with Optum, we evaluated patients from February 1, 2009, to May 31, 2012, with a gout diagnosis, a pharmacy claim for allopurinol or febuxostat, and at least 1 serum uric acid (SUA) result available during the follow-up period. Univariate and multivariable-adjusted analyses (controlling for patient demographics and clinical factors) assessed the likelihood of SUA lowering and achievement of target SUA of less than 6.0 mg/dL or less than 5.0 mg/dL in allopurinol continuers versus febuxostat switchers. The final study population included 748 subjects who switched to febuxostat from allopurinol and 4795 continuing users of allopurinol. The most common doses of allopurinol were 300 mg/d or less in 95% of allopurinol continuers and 93% of febuxostat switchers (prior to switching); the most common dose of febuxostat was 40 mg/d, in 77% of febuxostat switchers (after switching). Compared with allopurinol continuers, febuxostat switchers had greater (1) mean preindex SUA, 8.0 mg/dL versus 6.6 mg/dL (P < 0.001); (2) likelihood of postindex SUA of less than 6.0 mg/dL, 62.2% versus 58.7% (P = 0.072); (3) likelihood of postindex SUA of less than 5.0 mg/dL, 38.9% versus 29.6% (P < 0.001); and (4) decrease in SUA, 1.8 (SD, 2.2) mg/dL versus 0.4 (SD, 1.7) mg/dL (P < 0.001). In multivariable-adjusted analyses, compared with allopurinol continuers, febuxostat switchers had significantly higher likelihood of achieving SUA of less than 6.0 mg/dL (40% higher) and SUA of less than 5.0 mg/dL (83% higher). In this "real-world" setting, many patients with gout not surprisingly were not treated with maximum permitted doses of allopurinol. Patients switched to febuxostat were more likely to achieve target SUA levels than those who continued on generally stable doses of allopurinol.

Adherence to the 2012 American College of Rheumatology (ACR) Guidelines for Management of Gout: A Survey of Brazilian Rheumatologists.

ObjectiveTo describe the current pharmacological approach to gout treatment reported by rheumatologists in Brazil.MethodsWe performed a cross-sectional survey study using an online questionnaire e-mailed to 395 rheumatologists, randomly selected, from among the members of the Brazilian Society of Rheumatology.ResultsThree hundred and nine rheumatologists (78.2%) responded to the survey. For acute gout attacks, combination therapy (NSAIDs or steroid + colchicine) was often used, even in monoarticular involvement, and colchicine was commonly started as monotherapy after 36 hours or more from onset of attack. During an acute attack, urate-lowering therapy (ULT) was withdrawn by approximately a third of rheumatologists. Anti-inflammatory prophylaxis (98% colchicine) was initiated when ULT was started in most cases (92.4%), but its duration was varied. Most (70%) respondents considered the target serum uric acid level to be less than 6 mg/dl. Approximately 50% of rheumatologists reported starting allopurinol at doses of 100 mg daily or less and 42% reported the initial dose to be 300 mg daily in patients with normal renal function. ULT was maintained indefinitely in 76% of gout patients with tophi whereas in gout patients without tophi its use was kept indefinitely in 39.6%.ConclusionThis is the first study evaluating gout treatment in a representative, random sample of Brazilian rheumatologists describing common treatment practices among these specialists. We identified several gaps in reported gout management, mainly concerning the use of colchicine and ULT and the duration of anti-inflammatory prophylaxis and ULT. Since rheumatologists are considered as opinion leaders in this disease, a program for improving quality of care for gout patients should focus on increasing their knowledge in this common disease.

High serum uric acid is associated with increased cardio-ankle vascular index (CAVI) in healthy Japanese subjects: A cross-sectional study

ObjectiveTo investigate the association of serum uric acid (SUA) with arterial stiffness assessed by cardio-ankle vascular index (CAVI). MethodsWe analyzed the cross-sectional data from 27,360 healthy Japanese subjects (12,910 males and 14,450 females) aged between 20 and 74 years without a past history of heart disease, stroke, hypertension, diabetes, nephritis or gout. We investigated whether SUA was independently associated with CAVI in a gender-specific manner. ResultsBMI, CAVI, systolic/diastolic BP, GOT, GPT, γ-GTP, triglyceride (TG), creatinine and SUA were higher and HDL-C was lower in males than in females. Next, they were stratified by SUA into 3 groups: lower tertile (T1), middle tertile (T2) and upper tertile (T3) and by gender. CAVI increased progressive with increasing SUA tertile, after adjusting for age, BMI and systolic BP (sBP) identified in multiple regression analysis for CAVI. Multivariate analysis showed that the odds ratios (95% CI) relative to T1 for high CAVI (≥90th percentile) were 1.233 (0.928–1.638) in T2 and 1.352 (1.031–1.773) in T3 for males, and 1.133 (0.984–1.303) in T2 and 1.361 (1.098–1.687) in T3 for females, after adjusting for confounders. Furthermore, increase in adjusted CAVI was observed in a lower SUA range in females compared to that observed in males. ConclusionWe demonstrated an independent correlation between SUA and CAVI, and observed gender difference in the SUA range for increase in CAVI. These results may suggest the need to set different target SUA levels for men and women in anti-hyperuricemic treatment for atherosclerosis prevention.

Multinational Gout Recommendations Released

Multinational Gout Recommendations Released

A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout

ObjectiveTo evaluate the safety and efficacy of febuxostat compared to allopurinol for the treatment of chronic gout. MethodsWe did a systematic review and meta-analysis of randomized and non-randomized controlled trials that compared oral febuxostat to oral allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios (RR) were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). ResultsFrom 1076 potentially relevant citations, 7 studies and 25 associated publications met inclusion criteria; 5 studies were ultimately included in the analysis. Febuxostat did not reduce the risk of gout flares compared with allopurinol (RR = 1.16, 95% CI = 1.03–1.30, I2 = 44%). Overall, the risk of any adverse event was lower in febuxostat recipients compared to allopurinol (RR = 0.94, 95% CI = 0.90–0.99, I2 = 13%). Patients receiving febuxostat were more likely to achieve a serum uric acid of <6mg/dl than allopurinol recipients (RR = 1.56, 95% CI = 1.22–2.00, I2 = 92%). Subgroup analysis did not indicate any significant difference between high- and low-dose febuxostat on the risk of gout flares. ConclusionAlthough febuxostat was associated with higher likelihood of achieving a target serum uric acid level of <6mg/dl, there was significant heterogeneity in the pooled results. There was no evidence that febuxostat is superior to allopurinol for clinically relevant outcomes. Given its higher cost, febuxostat should not be routinely used for chronic gout.

CaseBook Challenges: Managing Gout, Hyperuricemia and Comorbidities—Dialogue with the Experts

The prevalence of gout and hyperuricemia are on the rise in the United States corresponding with an increase in risk factors for these conditions, such as obesity, metabolic syndrome, and the use of diuretics. A progressive disorder, untreated gout can be debilitating and result in tophi, chronic arthropathy, and recurrent kidney stones. Although joint aspiration is needed for a definitive diagnosis, the majority of patients are diagnosed presumptively based on medical history and presentation with characteristic signs and symptoms. Patients with gout also often have multiple comorbidities, and there is an increasing body of evidence that shows hyperuricemia is associated with incidence hypertension, diabetes, chronic kidney disease, and heart failure. Clinical strategies for the management of gout and hyperuricemia must include considerations for these and other common cardiometabolic and renal conditions. In addition to acute flare therapy and prophylaxis, the treatment of gout involves lowering serum uric acid (SUA) levels with the urate-lowering therapies (ULTs) allopurinol or febuxostat. Once begun, treatment with ULT is lifelong. However, inadequate dosing and patient nonadherence or intolerance to therapy often lead to treatment failure. Recent guidelines from the American College of Rheumatology stress tailoring therapy and target SUA level (traditionally <6 mg/dL, but lower levels may be needed for certain patients) based on gout severity and the presence of comorbid conditions. Because painful acute gout flares may result in trips to the emergency department and because the majority of gout cases are managed in primary care, it is important for clinicians practicing in these settings to be able to diagnose and treat this condition and communicate with patients to improve their understanding of the disease process and adherence to treatment.

CaseBook Consults: Improving Outcomes in Gout (Multimedia Activity)

Gout is a chronic, potentially debilitating condition characterized by an inflammatory process in the joints or periarticular tissues that results from the deposition of monosodium urate crystals. Underdiagnosis and undertreatment can lead to the development of tophi and chronic arthropathy. A presumptive diagnosis of gout can be made on the basis of the clinical presentation as well as risk factors such as metabolic syndrome. Key conditions to rule out in the differential diagnosis are septic arthritis, calcium pyrophosphate deposition disease (pseudogout), fracture, and rheumatoid arthritis. Acute flares of gout should be managed with nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, or corticosteroids. With a diagnosis of gout, if urate-lowering therapy (ULT) is required, prophylaxis should be considered with low-dose colchicine or an NSAID, followed by the addition of ULT. The goal of ULT is to reach a serum uric acid (SUA) level ≤6.0 mg/dL. Measurements of SUA should be obtained after resolution of an acute attack, then periodically to facilitate titration of the ULT dose to achieve the target SUA level. Studies have confirmed significant reductions in gout attacks among patients who have attained SUA levels ≤6.0 mg/dL with ULT. Patient education concerning the disease and its treatment is essential to ensure close adherence with recommended therapies. Patients should also understand that ULT is intended as long-term, and for most patients, lifelong therapy to maximize the prospects for control of the disease. Clinicians should feel confident in making a presumptive diagnosis and choosing a therapeutic regimen for gout while effectively communicating with and educating patients about their disease.