Treatment of hyperuricemia, gout and other crystalline arthritidies

Gout is a very common joint disease which is due to chronic hyperuricemia and its related articular involvements. Yet it can be cured when appropriately managed. Comprehensive management of gout involves correct identification and addressing all causes of hyperuricemia, treating and preventing attacks of gouty inflammation (using colchicine NSAIDs, and/or steroids), and lowering serum urate (SUA) to an appropriate target level indefinitely. The ideal SUA target is, at a minimum, less than 6 mg/dL (60 mg/L or 360 μmol/L), or even less than 5 mg/dL in patients with tophi. The SUA target should remain at less than 6 mg/dL for long in all gout patients, especially until tophi have resolved. Patient education and adherence to therapy are key point to the optimal management of gout, aspects which are often neglected. Adherence can be monitored in part by continuing, regular assessment of the SUA level. More difficult cases of gout often need a combination of urate lowering therapy (ULT) for both refractory hyperuricemia and chronic tophaceous arthritis. Chronic tophaceous gouty arthropathy which do not respond adequately to optimized oral ULT might benefit from the use of pegloticase, when this is available in, for example, Italy and other European countries. By contrast, in calcium pyrophosphate (CPP) crystal deposition disease (CPPD), as evidenced by pseudo gout attacks or chronic polyarthritis, similar anti-inflammatory strategies have been recommended, but there have as yet been no controlled trials. Of note, there is no treatment for the underlying metabolic disorders able to control the CPPD. Management of crystal-induced arthropathies (CIA) depends not only on clinical expression, namely acute attacks or chronic arthropathy, but also on the underlying metabolic disorder. We will mainly focus on gout as an archetype of CIA.     

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。     

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.     

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.     

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.     

Management of gout and hyperuricemia: Multidisciplinary consensus in Taiwan

Gout is an inflammatory disease manifested by the deposition of monosodium urate (MSU) crystals in joints, cartilage, synovial bursa, tendons or soft tissues. Gout is not a new disease, which was first documented nearly 5,000 years ago. The prevalence of gout has increased globally in recent years, imposing great disease burden worldwide. Moreover, gout or hyperuricemia is clearly associated with a variety of comorbidities, including cardiovascular diseases, chronic kidney disease, urolithiasis, metabolic syndrome, diabetes mellitus, thyroid dysfunction, and psoriasis. To prevent acute arthritis attacks and complications, earlier use of pharmacotherapeutic treatment should be considered, and patients with hyperuricemia and previous episodes of acute gouty arthritis should receive long‐term urate‐lowering treatment. Urate‐lowering drugs should be used during the inter‐critical and chronic stages to prevent recurrent gout attacks, which may elicit gradual resolution of tophi. The goal of urate‐lowering therapy should aim to maintain serum uric acid (sUA) level <6.0 mg/dL. For patients with tophi, the initial goal can be set at lowering sUA to <5.0 mg/dL to promote tophi dissolution. The goal of this consensus paper was to improve gout and hyperuricemia management at a more comprehensive level. The content of this consensus paper was developed based on local epidemiology and current clinical practice, as well as consensuses from two multidisciplinary meetings and recommendations from Taiwan Guideline for the Management of Gout and Hyperuricemia.     

Hyperuricemia, gout, and autosomal dominant polycystic kidney disease

The relationship between hyperuricemia, gout, and autosomal dominant polycystic kidney disease (ADPKD) is not widely recognized. In an attempt to further clarify this relationship, the authors have studied 17 patients with ADPKD, 9 controls, 9 patients with proven gout and chronic renal failure, 11 patients with gout and normal renal function, and 11 patients with chronic renal failure. The mean serum uric acid concentration was higher in patients with ADPKD as a group than in controls (8.0 +/- 1.7 mg/dl vs. 6.4 +/- 1.6 mg/dl, p less than .02). Clinical gout was identified in 24% of patients with ADPKD; none of the patients with chronic renal failure of other etiologies had gout. Fractional excretion of uric acid and the activity of the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT) were not different among the groups studied. From this study the authors conclude that ADPKD should be included among those diseases associated with hyperuricemia and gout. A partial deficiency in HGPRT or abnormal renal handling of uric acid do not appear to be responsible for the increased incidence of gout in patients with ADPKD.     

Gout:A clinical overview and its association with cardiovascular diseases

Gout is a common disease caused by the deposition of monosodium urate(MSU) crystals in patients with hyperuricemia, and characterized by very painful recurrent acute attacks of arthritis. The gold standard for diagnosing gout is the identification of MSU crystals in synovial fluid by polarization light microscopy. Arthritis attacks can be treated with anti-inflammatory medications, such as non-steroidal anti-inflammatory drugs, colchicine, oral prednisone, or intra-articular or intramuscular glucocorticoids. To prevent gout uric acid lowering therapy with for example allopurinol can be prescribed. When gout is adequately treated, the prognosis is good. Unfortunately, the management of gout patients is often insufficient. Gout is associated with dietary factors, the use of diuretics, and several genetic factors. Comorbidities as hypertension, chronic kidney disease, cardiovascular diseases, the metabolic syndrome, diabetes, obesity, hyperlipidemia, and early menopause are associated with a higher prevalence of gout. Xanthine oxidase and chronic systemic inflammation seem to play an important role in the pathophysiology of the association between gout and cardiovascular diseases. To prevent cardiovascular diseases goutpatients must be early screened for cardiovascular risk factors.     

Pathogenesis, diagnostics and therapy of gout

Gout refers to heterogeneous group of metabolic diseases characterized by production of deposits of sodium urate crystals in tissues. Gout manifests as acute gouty arthritis with classic clinical picture, or as chronic gouty arthropathy with periarticular and subcutaneous deposits of sodium urate crystals, i.e. tophi. As for kidney, gout is manifested as acute or chronic gouty nephropathy and urolithiasis. These manifestations occur separately or they are combined. Hyperuricemia of primary gout is caused rather by impaired renal secretion than overproduction of uric acid. Secondary hyperuricemia is associated with many pathological conditions; it is also connected with the use of various medicaments. Pathogenesis of gouty arthritis is critically influenced by sodium urate crystals and inflammatory processes they induce. Hyperuricemia is part of metabolic syndrome X which is associated with unanswered question of the relationship between uric acid and atherosclerosis. Although gouty arthritis is the most frequent inflammatory disease of joints in men over 50 years of age, it is often diagnosed and treated inadequately. On that account, the indication of long-term hypouricemic therapy should be always based on the following criteria: secondary causes of hyperuricemia have to be excluded first; frequency of gout attacks and the risk of their recurrence should be taken into consideration; then it is necessary to search for renal manifestations of gout; and last but not least, we should check whether there are any associated diseases classified in metabolic syndrome X.     

Concordance of the management of chronic gout in a UK primary-care population with the EULAR gout recommendations

OBJECTIVES: To assess concordance of the management of chronic gout in UK primary care with the European League Against Rheumatism (EULAR) gout recommendations. METHODS: A postal questionnaire was sent to all adults aged >30 years registered with two general practices. Patients with possible gout attended for clinical assessment, at which the diagnosis was verified clinically. Aspects of chronic gout management, including provision of lifestyle modification advice, use of urate-lowering therapies (ULT) including dose titration to serum urate (SUA) level, prophylaxis against acute attacks, and diuretic cessation were assessed in accordance with the EULAR recommendations. RESULTS: Of 4249 (32%) completed questionnaires returned, 488 reported gout or acute attacks and were invited for clinical assessment. Of 359 attendees, 164 clinically confirmed cases of gout were identified. Advice regarding alcohol consumption was recalled by 59 (41%), weight loss by 36 (25%) and diet by 42 (29%). Allopurinol was the only ULT used and was taken by 44 (30%); 31 (70%) were taking 300 mg daily. Mean SUA was lower in allopurinol users than non-users (318 vs 434 micromol/l) and was less often >360 micromol/l in allopurinol users (23% vs 75%). Eight patients had recently commenced allopurinol; two of these also were taking prophylactic colchicine or non-steroidal anti-inflammatory drugs. Of 25 patients with diuretic-induced gout, 16 (64%) were still taking a diuretic. CONCLUSION: Treatment of chronic gout is often suboptimal and poorly concordant with EULAR recommendations. Lifestyle advice is infrequently offered, and allopurinol is restricted to a minority. Persistent hyperuricaemia was often seen in allopurinol non-users, but was also in allopurinol users, suggesting that doses >300 mg are often necessary.     

Characteristics of chronic gout in Northern Sulawesi, Indonesia

OBJECTIVE: To identify associations and possible risk factors for gout that may contribute to chronic tophaceous gout in rural and urban districts of North Sulawesi, Indonesia. METHODS: A total of 190 patients with chronic gout and 190 age and sex matched controls were selected from 28 community health centers. Potential risk factors including alcohol consumption, food habits, family history, body weight, related medical conditions, drug use, and laboratory investigations were sought. RESULTS: Alcohol consumption and certain food habits were associated with gout. A positive family history of gout and overweight were also significant risk factors. Renal impairment was found in 86.3% of patients and hyperuricemia in 92.1%. In controls, renal impairment and hyperuricemia were 7.4% and 32.6%, respectively. Patients with hypertension and nephrolithiasis were more at risk of having associated gout. There was a significant association between gout, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, and higher levels of creatinine and urea. There was also a significantly lower level of urine uric acid in gout cases compared with controls. Gouty tophi were found in 91% of these cases with chronic gout. The use of diuretics for treating hypertension, continuing excessive alcohol consumption and purine-rich food habits in untreated gout, and hyperuricemia were associated with chronic and tophaceous gout. Urate-lowering drugs were not available in the community health centers. CONCLUSION: Severe tophaceous gout with deformities and disability is found in North Sulawesi. Prominent risk factors include alcohol, obesity, renal impairment, diet, hypertension, and family history. Improved education about gout seems needed. Urate-lowering drugs are not available in community health centers but are needed, especially in rural areas, as studied here.     

Updates in the management of gout

The majority of patients with gout are cared for by primary care physicians. Although both the physician and patient may easily recognize the acute arthritis of gout, errors in selecting the most appropriate medication and proper dose are common. The clinical stages of gout include asymptomatic hyperuricemia, intermittent gouty arthritis, and chronic tophaceous gout. Treatment of gout is usually considered after the first attack of arthritis, typically podagra. The aims of treatment are to alleviate the pain and inflammation associated with acute attacks, prevent future attacks, and decrease uric acid levels. Confusion frequently arises because certain medications such as colchicine may have dual purposes: to treat an acute attack and to suppress future attacks. The purpose of this management update is to provide practical advice about prescribing the proper medication considering both treatment goals and patient comorbidities.     

《2010年中国痛风临床诊治指南》解读

《2010年中国痛风临床诊治指南》指出,在诊断痛风时要特别注意痛风患者的病程阶段:即无症状高尿酸血症、急性痛风性关节炎或慢性痛风,强调关注患者是否为无症状高尿酸血症或痛风合并其它情况(糖尿病、高血压病,或心脑血管的危险因素)。除了合理应用非甾类抗炎药或糖皮质激素积极治疗急性关节炎急性发作外,痛风患者的综合管理尤为重要,包括对所有患者去除引起高尿酸血症的诱因及给予非药物干预(生活方式和饮食调整、减轻体重、适度饮酒,停用引起尿酸升高的药物等),有效控制合并症。对反复发作的、间歇期或慢性痛风患者给予降尿酸药物治疗以维持血尿酸水平低于327μmol/L,以及为严重的慢性痛风石患者寻找可能的手术治疗机会。     

Asymptomatic hyperuricemia: the case for conservative management

The management of asymptomatic hyperuricemia is controversial. Reported benefits from treatment prevention of acute gouty arthritis, chronic tophaceous gout, urolithiasis, or gouty nephropathy. A review of experimental and clinical data suggests that the risks of asymptomatic hyperuricemia are small or unknown and the efficacy of long-term treatment in preventing gout or renal disease is unproved. The costs and risks of prolonged drug administration and practical considerations such as patient compliance mitigate against long-term therapy in asymptomatic persons. We offer some recommendations for an expectant approach to the management of asymptomatic hyperuricemia.     

高尿酸血症与痛风患者并发肾结石的影响因素

目的收集高尿酸血症及痛风患者的临床资料及生化结果,分析高尿酸血症及痛风患者并发肾结石的危险因素。方法收集安徽省立医院门诊和住院及体检中心的痛风患者82例及高尿酸血症患者178例进行对照研究,所有患者统一问卷调查,收集一般资料及实验室检查数据,均进行双肾、输尿管、膀胱B超;采用组间对照及二元Logistic回归方法进行统计学分析。结果痛风组与高尿酸血症组肾结石发生率分别为36.6%和27.5%,两组比较差异无统计学差异(P>0.05)。痛风并发肾结石组相比痛风无肾结石组身高更高、体质量更重、病程更长、低密度脂蛋白(LDL)较高(P<0.05)。Logistic回归分析显示:病程>9年[OR=23.493,95%CI(2.824~195.421),P=0.003]、LDL≥4.1 mmol/L[OR=10.160,95%CI(1.218~84.747),P=0.032]是痛风患者发生肾结石的危险因素;痛风并发肾结石组相比高尿酸血症并发肾结石组有吸烟史、饮酒史的比例更高(P<0.05);所有高尿酸血症患者并发结石组相比高尿酸血症无肾结石组的体质量更重,BMI更高,舒张压更高(P<0.05)。结论高尿酸血症与痛风患者均有较高的肾结石发生率。病程>9年、LDL≥4.1 mmol/L是痛风患者肾结石发病的独立危险因素。高体质量及高体质量指数的痛风/高尿酸血症患者更应注意进行泌尿系结石的筛查以利于早期发现肾结石并及时治疗。     

高尿酸血症/痛风流行病学特点及危险因素

高尿酸血症/痛风的患病率逐年攀升,呈现高流行、年轻化、男性高于女性、沿海高于内地的流行趋势.肥胖、高血压、高血脂、高血糖等与高尿酸血症/痛风的发生、发展密切相关.小剂量阿司匹林、袢利尿剂和噻嗪类利尿剂等药物亦可促进血清尿酸水平的升高.高尿酸血症是2型糖尿病、高血压、动脉粥样硬化、心血管事件、脑卒中和慢性肾脏病等疾病的独立危险因素,是痛风发作的最主要生化基础和最直接病因.对于高尿酸血症/痛风患者,应强调早期发现和早期治疗.     

Efficacy of rasburicase therapy in obstructive renal failure secondary to urolithiasis: a novel therapeutic option

The overall incidence of nephrolithiasis-related acute and chronic renal failure is poorly known and surely underestimated. However, obstructive nephropathy represents a potentially curable form of kidney disease that often requires for managing an instrumentation of urinary tract. Rasburicase is an enzyme that transforms uric acid to allantoin, a compound more water soluble that will be excreted by the kidney more easily. Rasburicase has been proven to be an effective therapy for prevention of tumour lysis syndrome. But it also represents an interesting new option in managing hyperuricemia in patients with severe tophaceous gout. We administered rasburicase intravenously (0.20 mg/kg/day, for 2 days) in 2 adults with acute obstructive nephropathy from renal calculi, which was receiving temporary haemodialysis. Rasburicase produced a sharp polyuria 12-18 hours after its administration accompanied with a fast reduction of serum creatinine levels, that returned to normal range without further dialysis. If we suppose that rasburicase can pass through glomerular filter by its relatively low molecular weight, it could dissolve tubular uric acid crystals in acute renal failure associated to tumour lysis syndrome, providing the restoration of renal function. But we also could postulate that rasburicase can act in urinary tract, fragmentating renal calculi, promoting relief of obstructive uropathy and the resolution of renal failure. We suggest rasburicase should be tried in this new indication to prove its potential efficacy.     

Crystal-induced arthritis--old but important

Gout is the most common inflammatory arthropathy for men. Asymptomatic hyperuricemia, which should lead to diet, but not to medication, is much more common still. Increased uric acid levels mostly result from diminished renal excretion, which is more commonly familiar than secondary (renal failure, diuretics). With the first episode of often typical (red, hot, exquisitely painful first MTP joint) acute arthritis or with urate nephrolithiasis, increased uric acid turns pathological. Attacks are treated with NSAIDs or corticosteroids. More common attacks, chronic gout, or urate nephropathy are definite indications for long-term (at least 5 years) therapy with allopurinol or febuxostat. Additional anti-inflammatory medication will be necessary during the first months. Calcium pyrophosphate deposition arthropathy, the second common crystal-induced arthritis, is diagnosed by synovial fluid analysis or for chondrocalcinosis. Treatment for attacks resembles therapy of acute gout; causal therapy is possible in case of secondary forms (e.g. hypothyroidism. hyperparathyroidism, hemochromatosis).     

The effect of control and self-medication of chronic gout in a developing country. Outcome after 10 years

OBJECTIVE: We describe a 10 year observation of the effect of control of hyperuricemia compared with self-medication alone in patients with chronic gout. METHODS: We studied 299 consecutively self-referred Malayo-Polynesian men with chronic gout, mean age 35 +/- 14.3 SD years. Subjects comprised 228 cases with chronic gout without tophi or urolithiasis (Group 1) and 71 with those complications (Group 2). Attacks of acute gouty arthritis were treated with nonsteroidal antiinflammatory drugs (NSAID) and/or corticosteroids. After acute arthritis had settled, urate-lowering drugs were instituted in both groups combined with low dose colchicine and/or low dose NSAID for at least 0.5-2 years. Urate levels were maintained longterm at a mean of < 5 mg/dl. After 10 years, the dropouts were traced and evaluated for comparison with baseline and those who remained in the study. In Group 2 the urate-lowering drugs were continued. RESULTS: Control of gout and hyperuricemia was achieved in all patients who remained under control: 91.6% of the 299 patients for at least 2 years (short-term), up to 5 years in 87.5% (medium term), and up to 10 years in 79.6% (longterm). In Group 1 (chronic gout without complication) only 36.8% had no attacks during 8 years, after they had tapered urate-lowering drug after the first 2 years of the study. In the 61 dropouts the intermittent symptomatic treatment and/or self-medication without longterm control of hyperuricemia resulted after 1 decade in chronic gout with more complications and associated conditions leading to increased morbidity, disability, and comorbidity, and 3 early mortalities. CONCLUSION: By controlling hyperuricemia, improvement of the prognosis of chronic gout, comorbidity, and early death was achieved compared with self-medication alone. Self-medication in a developing country if continued unchecked may become a public health problem in a population with a high prevalence rate of gout.