New developments in clinically relevant mechanisms and treatment of hyperuricemia

The prevalence of gout has increased markedly in the United States in the past two decades, and new treatments for hyperuricemia are being developed. Recent molecular identification of urate transporter-1 (URAT1) as the central mediator of renal urate reabsorption has provided novel understanding of the pathogenesis of hyperuricemia, and the target site for current and possibly future primary uricosuric agents. Recent studies have also highlighted uricosuric effects of several drugs (losartan, atorvastatin, fenofibrate) that are prescribed for primary indications other than hyperuricemia. The niche of these agents in current management of hyperuricemia is discussed. We also review the ongoing development of recombinant uricase preparations and of novel xanthine oxidase inhibitors exemplified by febuxostat. These agents should provide novel options for patients with chronic, refractory gout and hyperuricemia, particularly in association with allopurinol hypersensitivity and renal insufficiency.     

New developments in clinically relevant mechanisms and treatment of hyperuricemia

The prevalence of gout has increased markedly in the United States in the past two decades, and new treatments for hyperuricemia are being developed. Recent molecular identification of urate transporter-1 (URAT1) as the central mediator of renal urate reabsorption has provided novel understanding of the pathogenesis of hyperuricemia, and the target site for current and possibly future primary uricosuric agents. Recent studies have also highlighted uricosuric effects of several drugs (losartan, atorvastatin, fenofibrate) that are prescribed for primary indications other than hyperuricemia. The niche of these agents in current management of hyperuricemia is discussed. We also review the ongoing development of recombinant uricase preparations and of novel xanthine oxidase inhibitors exemplified by febuxostat. These agents should provide novel options for patients with chronic, refractory gout and hyperuricemia, particularly in association with allopurinol hypersensitivity and renal insufficiency.     

Gout and other crystal-associated arthropathies.

Intra-articular crystals (monosodium urate monohydrate, calcium pyrophosphate dihydrate, basic calcium phosphates) can cause acute and chronic inflammation and joint damage. Identification of the crystals by polarized microscopy is the key step in diagnosis but improved reliability of synovial examination is required. Treatment of disorders associated with gout or calcium pyrophosphate deposition may reduce non-joint morbidity and assist treatment of the arthritis. Various forms of anti-inflammatory therapy work for acute crystal-induced arthritis; prompt commencement is usually more important than which option is used. In gout, recurrent attacks are usual, but hypouricaemic therapy is almost never urgent, is life-long, and is too often negated by poor compliance. In most patients, allopurinol or any of the potent uricosuric drugs will allow maintenance of normouricaemia but renal failure, renal calculi, transplantation, and allopurinol allergy narrow the options and complicate management.     

痛风合并慢性肾脏疾病的药物治疗

慢性肾脏疾病(CKD)正困扰越来越多的痛风患者,是痛风最常见的合并症.然而,目前痛风和CKD的随机对照试验比较有限,并且指南并没有明确的痛风合并CKD患者的用药指导.痛风的治疗主要是控制痛风发作以及降尿酸治疗.非甾体类抗炎药物和秋水仙碱是急性痛风发作的一线治疗药物.然而,对于CKD患者,非甾体类抗炎药物因肾损伤并不被推荐.同样,秋水仙碱的毒性在CKD患者中是加剧的,其剂量应根据肾功能情况酌减.类固醇激素的使用也需要权衡利弊,因此免疫治疗可能成为未来治疗手段的重要方面.别嘌呤醇、非布司他、促尿酸排泄药物及聚乙二醇重组尿酸酶用于控制急性发作后的高尿酸血症.然而,因CKD患者需要限制别嘌呤醇剂量,从而影响了其疗效.聚乙二醇重组尿酸酶有待进一步研究,非布司他未曾在肌酐清除率＜ 30 ml/min的患者中研究.     

Hyperuricemia and associated diseases

After introduction of urate-lowering therapy, asympotomatic hyperuricemia was treated with allopurinol or uricosuric agents in the belief that hyperuricemia and/or gout caused chronic kidney disease. Epidemiologic studies in the 1970s, however, failed to confirm the view that hyperuricemia and gout were independent risk factors for chronic kidney disease. As a result, urate-lowering pharmacotherapy is generally not recommended at the present time in the management of asymptomatic hyperuricemia even though recent epidemiological, experimental, and clinical studies have prompted reexamination of a causal role for hyperuricemia (with or without gout) in chronic kidney disease as well as other important disorders including cardiovascular disease, hypertension, and metabolic syndrome. The issue of such a role remains unresolved and this article reviews the current status of the relationship between hyperuricemia and associated disorders.     

Gout in the heart transplant recipient: physiologic puzzle and therapeutic challenge

PURPOSE: Hyperuricemia and gouty arthritis have been associated with cyclosporine use in renal transplant recipients. Patients requiring heart or heart-lung transplantation may have additional risk factors for the development of gout, yet it has not previously been described in this population. We share herein our clinical experience with gouty arthritis in six heart transplant recipients. PATIENTS AND METHODS: During a one-year period, six hospitalized male heart transplant patients were seen in consultation for gouty arthritis. Five were subsequently followed for gout as outpatients; the sixth died within six months. Management included trials of nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, allopurinol, and intra-articular steroid injections, as well as attempts to minimize cyclosporine nephrotoxicity. RESULTS: Three patients had gout in remission at time of transplant surgery, and three others developed gout for the first time two to 45 months after transplantation. Following transplant surgery, both pre-existing and new-onset gout appeared to exhibit an accelerated course, with unusually rapid development of chronic polyarticular disease and tophi in four of the five patients followed for more than six months. Peak serum uric acid levels ranged from 11.0 mg/dL to 16.5 mg/dL. NSAIDs produced reversible renal insufficiency in four patients. Gout-related infections occurred in three patients, one of whom died. CONCLUSION: Acute gouty arthritis may occur in the heart transplant recipient despite concomitant use of immunosuppressive drugs. Cyclosporine, with its attendant hypertension and nephrotoxicity, appears to be the major risk factor for hyperuricemia in this setting, leading to the accelerated development of tophi and chronic polyarthritis. Management is complicated by the patients' renal insufficiency and propensity to infection, as well as by interaction with transplant-related medications. Prevention of hyperuricemia by minimizing cyclosporine nephrotoxicity appears to be the best management strategy, with judicious use of allopurinol for those patients in whom this preventive approach fails.     

A SHORT TRIAL ASSESSMENT OF URICOSURIC THERAPY IN GOUT

A study has been made of the short-term effects of two uricosuric drugs (sulphinpyrazone and probenecid) in 12 gouty patients. The changes induced by these drugs on serum uric acid levels, 24-hour urate excretion rates and urate clearance values have been related to glomerular function. Since allopurinol is now available for the therapy of gout, and as uricosuric agents may fail to resolve tophaceous deposits, it is held that long-term uricosuric therapy should not be undertaken unless the efficacy of the chosen drug has been established. Therapeutic criteria have been proposed as a result of this trial. The magnitude of the urate diuresis induced by these drugs was found in general to be dependent on glomerular function; but even in the presence of a normal glomerular filtration rate a particular uricosuric drug could be ineffective. A glomerular filtration rate of less than 80 ml. per minute was associated with a relative failure of the drugs under trial, and it is considered that this level of renal impairment is an indication for the use of allopurinol. In the type of assessment described it is important that both the fall in the serum uric acid level and the rise in urate excretion should be estimated, for these changes do not under all circumstances bear a constant inverse relationship to one another.     

Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout

OBJECTIVE: Published guidelines state that allopurinol doses should be adjusted according to creatinine clearance. We investigated whether such dosing provides adequate control of hyperuricemia. METHODS: We studied 250 patients with gout attending rheumatology clinics in South Auckland from 2001 to 2004. Allopurinol dose, creatinine clearance, and serum uric acid (SUA) level were recorded. We analyzed the relationship between recommended allopurinol dose and SUA lowering to 相似文献   

Risk factors associated with renal lithiasis during uricosuric treatment of hyperuricemia in patients with Gout

Objective

To find factors associated with the development of renal colic during uricosuric therapy.

Methods

We performed a prospective cohort followup study of patients with gout and no previous history of kidney stones who had been treated with uricosurics. Clearance of creatinine and urate, 24‐hour urinary uric acid (UA), undissociated urinary UA concentration, 24‐hour undissociated urinary UA, and pH and urine sediment were obtained. Cox proportional hazards regression analysis was used to identify variables associated with renal colic as the outcome. The rate of renal colic was compared with that of control patients receiving allopurinol who had no previous history of renal stones.

Results

We analyzed a 784 patient‐year exposure from 216 patients: 206 with renal underexcretion of UA and 10 with normal excretion. There were 21 clinical events. Two variables showed increased risk hazard for developing lithiasis: clearance of UA at baseline and undissociated urinary UA concentration during followup. When only patients with underexcretion of UA were included in the analysis, undissociated urinary UA during followup remained the only statistically significant variable. Patients who showed an undissociated UA concentration <20 mg/dl did not show an increase in the rate of lithiasis or events compared with patients receiving allopurinol.

Conclusion

Clearance of UA at baseline may be useful for selecting patients suitable for uricosuric treatment. The estimation of the concentration of undissociated urinary UA is useful for evaluating the risk of lithiasis during followup.     

Efficacy and safety of desensitization to allopurinol following cutaneous reactions

OBJECTIVE: To evaluate the long-term efficacy and safety of slow oral desensitization in the management of patients with hyperuricemia and allopurinol-induced maculopapular eruptions. METHODS: A retrospective evaluation of an oral desensitization regimen using gradual dosage-escalation of allopurinol in 32 patients (30 with gout and 2 with chronic lymphocytic leukemia) whose therapy was interrupted because of a pruritic cutaneous reaction to the drug. RESULTS: Twenty-one men and 11 women with a mean age of 63 years (range 17-83 years), a mean serum urate level of 618 micromoles/liter (range 495-750) (or, mean 10.4 mg/dl [range 8.3-12.6]), and a mean serum creatinine level of 249 micromoles/liter (range 75-753) (or, mean 2.8 mg/dl [range 0.8-8.5]) were studied. Desensitization failed in 4 patients because of unmanageable recurrent rash. Twenty-eight patients completed the desensitization procedure to a target allopurinol dosage of 50-100 mg/day, 21 without deviation from the protocol for a mean of 30.5 days (range 21-56 days) and 7 requiring dosage adjustments because of a recurrent rash over 53.8 days (range 40-189 days). Seven of these 28 patients developed late cutaneous reactions 1-20 months postdesensitization, 4 responding to dosage modification and 3 discontinuing the drug. Twenty-five of the 32 patients (78%) continued to take allopurinol; their mean duration of followup was 32.6 months (range 3-92 months) and the mean postdesensitization serum urate level was 318 micromoles/liter (range 187-452) (or, mean 5.3 mg/dl [range 3.0-7.5]). CONCLUSION: The study confirms the long-term efficacy and safety of slow oral desensitization to allopurinol in patients with maculopapular eruptions, particularly in those with gout, who cannot be treated with uricosurics or other urate-lowering drugs. Although pruritic skin eruptions may recur both during and after desensitization, most of these cutaneous reactions can be managed by temporary withdrawal of allopurinol and dosage adjustment.     

慢性心力衰竭高尿酸血症和痛风的处理

痛风是由于尿酸结晶沉积在关节引起炎症、疼痛,甚至造成患者活动障碍的一组临床综合征。慢性心力衰竭患者经常伴随高尿酸血症,在这些患者中,痛风的处理是一个特殊的问题。由于心力衰竭患者对容量状态敏感和经常伴有慢性肾功能不全, 因而其痛风的治疗限制了非甾体类抗炎药和皮质类固醇激素的应用;同时,治疗高尿酸血症和痛风的药物与治疗心力衰竭的药物也存在相互影响。因此,现就慢性心力衰竭患者中高尿酸血症和痛风的处理作一综述。     

Treatment of gout

In France, colchicine remains the standard treatment for the acute flare of gout. The lowest dose currently used decreases digestive toxicity. Doses of colchicine should be adapted to renal function and age, and possible drug interactions should be considered. Non steroidal anti-inflammatory drugs are an alternative to colchicine, but their use is frequently limited by comorbidity. When these treatments are contraindicated, corticosteroid injections can be performed after excluding septic arthritis. Systemic corticosteroids could be used in severe polyarticular flares. Anti-IL1 should provide a therapeutic alternative for severe cortico dependant gout with tophus. To prevent acute flares and reduce tophus volume, uric acid serum level should be reduced and maintained below 60 mg/L (360 μmol/L). To achieve this objective, it is often necessary to increase the daily dose of allopurinol above 300 mgs, but the need to adapt the dose to renal function is a frequent cause of therapeutic failure. In the absence of renal stone or renal colic and hyperuraturia, uricosuric drugs are the second-line treatment. Probenecid is effective when creatinine clearance is superior to 50 mL/min Benzbromarone, which was withdrawn due to hepatotoxicity, can be obtained on an individualized patient basis in the case of failure of allopurinol and probenecid. Febuxostat, which was recently approved, is a therapeutic alternative. Diuretics should be discontinued if possible. Use of fenofibrate should be discussed in the presence of dyslipidemia and losartan in patient with high blood pressure. Uricolytic drugs (pegloticase), which are currently being investigated, may be useful for the treatment of serious gout with tophus, especially in the presence of renal failure. Education of patient, identification and correction of cardiovascular risk factors should not be forgotten.     

HLA-B58.01 et vascularite rénale d’hypersensibilité à l’allopurinol chez un patient chinois

IntroductionAllopurinol, widely used in the treatment of hyperuricemia and gout, has been shown to cause severe cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as systemic reactions such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). The HLA-B*5801 allele is known to be a risk factor for severe cutaneous manifestations of hypersensitivity to allopurinol, mostly in Asian populations.ObservationWe report the observation of a 47-year-old Chinese patient, with no previous medical history, carrying the HLA-B*5801 allele, who developed an isolated allopurinol hypersensitivity necrotizing renal vasculitis without cutaneous manifestations.Discussion. The identification of this allele should be proposed before prescribing allopurinol in patients originating from certain regions of Asia, and the imputability of allopurinol should be evoked in case of necrotizing renal vasculitis, even without associated cutaneous involvement.     

Platelets and vascular disease in gout

Vascular complications appear to have more than a coincidental occurrence in primary gout. The presence in gout of hypertension, renal disease, diabetes mellitus, and hyperlipidemia (accepted factors of risk for arterial lesions) may influence onset of atheromas. However, additional data are presented from patients with primary gout, and secondary hyperuricemia, to support the thesis that an elevated serum uric acid level is an increased risk for arterial disease. New data are presented that hyperactive platelet populations occur in at least 51 % of the patients with primary gout. The activation status of the platelet population may relate to the serum uric acid level.It is proposed that the platelet may be a prime reactant linking hyperuricemia (a documented thrombotic risk factor) with the greater incidence of arterial disease in primary gout. Uricosuric drugs can be separated into two classes: those which produce only an indirect inhibitory potential on platelet surface activation by lowering the level of serum uric acid and those which, in addition, possess a direct inhibitory action on platelet surface activation. Halofenate and allopurinol were found to be potent direct inhibitors of platelet activation in both ex vivo and in vivo studies.     

An update on gout

Gout is the most common cause of inflammatory arthritis in men aged more than 50, affecting approximately 1–2% of adult men in the Western world. The incidence and prevalence of gout is on the rise. Increasing longevity, dietary trends, obesity, metabolic syndrome, hypertension, increased use of low-dose aspirin, major organ transplantation and increased survival from coronary artery disease and end-stage renal disease have been implicated as the possible contributory factors. By far, the commonest cause of hyperuricaemia (that accounts for 90% of patients with gout) is decreased renal clearance. Patients with gout should avoid excess of alcohol (beer and spirits, particularly), red-meat and sea-food. Vegetarian food and dairy products reduce the risk of gouty arthritis. For the treatment of acute gout, options include non-steroidal antirheumatic drugs (NSAIDs), steroids (systemic or intra-articular) and colchicine. High dose of colchicine often results in diarrhoea and should be best avoided. Most patients respond within 18 hours to a dose of 0.5 mg twice daily. Colchicine is contraindicated if creatinine clearance is lower than 30 ml/min. Optimal treatment of chronic gout requires long-term reduction of serum urate to the lower half of the normal uric acid reference range. Prevention of attacks requires modification of lifestyle factors such as weight loss, moderation in the consumption of alcohol and meat and withdrawal of drugs known to cause elevated uric acid levels. Drugs used for chronic gout can be divided in three categories: (a) Uricostatic (xanthine oxidase inhibitor), e.g. allopurinol, oxipurinol, febuxostat, (b) Uricosuric, e.g. benzbromarone, sulfinpyrazone, probenecid, losartan, fenofibrate and (c) Uricolytic, e.g. uricozyme, rasburicase. Febuxostat is a new oral xanthine oxidase inhibitor, which has been shown to be more powerful in lowering uric acid levels compared to allopurinol. The drug is mainly metabolised by the liver and can be used in renal and hepatic insufficiency with no dose adjustment. Benzbromarone is an excellent uricosuric agent. Pegylated uricase is currently under development.     

Gout,allopurinol intake and clinical outcomes in the hospitalized multimorbid elderly

BackgroundIncreased serum uric acid has been considered a cardiovascular risk factor but no study has assessed its relation with hospital mortality or length of stay. On the basis of data obtained from a prospective registry, the prevalence of gout/hyperuricemia and its association with these and other clinical parameters was evaluated in an Italian cohort of elderly patients acutely admitted to internal medicine or geriatric wards.MethodsWhile the prevalence of gout was calculated by counting patients with this diagnosis hyperuricemia was inferred in patients taking allopurinol at hospital admission or discharge, on the assumption that this drug was only prescribed owing to the finding of high serum levels of uric acid. A series of clinical and demographic variables were evaluated for their association with gout/hyperuricemia.ResultsOf 1380 patients, 139 (10%) had a diagnosis of gout or were prescribed allopurinol. They had more co-morbidities (7.0 vs 5.6; P < 0.0001) and consumed more drugs (6.8 vs 5.0; P < 0.0001). The CIRS (co-morbidity index) was worse in these patients (OR 1.28 95% CI 1.15–1.41). Multivariable regression analysis showed that only renal and heart failures were independently associated with gout/allopurinol intake. Moreover, this combined event was associated with an increased risk of adverse events during hospitalization (OR 1.66, 95% CI 1.16–2.36), but not with the risk of re-hospitalization, length of hospital stay or death.ConclusionsGout/allopurinol intake has a high prevalence in elderly patients acutely admitted to hospital and are associated with renal and cardiovascular diseases, an increased rate of adverse events and a high degree of drug consumption. In contrast, this finding did not affect the length of hospitalization nor hospital mortality.     

EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT)

OBJECTIVE: To develop evidence based recommendations for the management of gout. METHODS: The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert representing 13 European countries. Key propositions on management were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Where possible, effect size (ES), number needed to treat, relative risk, odds ratio, and incremental cost-effectiveness ratio were calculated. The quality of evidence was categorised according to the level of evidence. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales. RESULTS: 12 key propositions were generated after three Delphi rounds. Propositions included both non-pharmacological and pharmacological treatments and addressed symptomatic control of acute gout, urate lowering therapy (ULT), and prophylaxis of acute attacks. The importance of patient education, modification of adverse lifestyle (weight loss if obese; reduced alcohol consumption; low animal purine diet) and treatment of associated comorbidity and risk factors were emphasised. Recommended drugs for acute attacks were oral non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine (ES = 0.87 (95% confidence interval, 0.25 to 1.50)), or joint aspiration and injection of corticosteroid. ULT is indicated in patients with recurrent acute attacks, arthropathy, tophi, or radiographic changes of gout. Allopurinol was confirmed as effective long term ULT (ES = 1.39 (0.78 to 2.01)). If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, allopurinol desensitisation, or a uricosuric. The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic. When gout is associated with the use of diuretics, the diuretic should be stopped if possible. For prophylaxis against acute attacks, either colchicine 0.5-1 mg daily or an NSAID (with gastroprotection if indicated) are recommended. CONCLUSIONS: 12 key recommendations for management of gout were developed, using a combination of research based evidence and expert consensus. The evidence was evaluated and the SOR provided for each proposition.     

Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output

OBJECTIVE: To compare renal handling of uric acid in patients with primary gout with that of a control group. METHODS: A case-control study of 100 patients with primary gout and 72 healthy controls was undertaken. Creatinine clearance, uric acid clearance, 24-hour uric acid urinary excretion, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, urinary uric acid to creatinine ratio, and glomerular uric acid filtered load were calculated using 24-hour urine samples. After treatment with allopurinol to achieve similar glomerular filtered load of uric acid, patients were again compared with controls. RESULTS: Patients with gout showed lower uric acid clearance, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, and urinary uric acid to creatinine ratio than controls at baseline, when patients showed hyperuricemia. Although the glomerular uric acid filtered load was much higher in patients with gout than controls, 24-hour uric acid excretion was not statistically different. After treatment with allopurinol, and achieving similar uric acid filtered loads, patients still showed lower figures than controls. When patients with 24-hour urinary uric acids levels >700 mg/day were compared with controls, they had lower uric acid clearance and fractional excretion of uric acid than controls, both at baseline and after achieving similar filtered loads with allopurinol therapy. CONCLUSIONS: Renal underexcretion is the main mechanism for the development of primary hyperuricemia in gout, but even patients showing apparent high 24-hour uric acid output show lower uric acid clearance than controls, indicating that relative, low-grade underexcretion of uric acid is at work.     

Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28‐week,phase III,randomized, double‐blind,parallel‐group trial

Objective

To compare the urate‐lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function.

Methods

Subjects (n = 1,072) with hyperuricemia (serum urate level ≥8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to ≤2.0 mg/dl) renal function were randomized to receive once‐daily febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks.

Results

Significantly (P ≤ 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with febuxostat than with allopurinol.

Conclusion

At all doses studied, febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.