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Gout is a metabolic disorder characterized by elevated uric acid levels in the body, associated with painful arthritis, tophi and nephropathy. The most frequently used pharmacologic urate lowering strategies involve reducing urate production with a xanthine oxidase inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. Urate lowering agents are limited in number, availability and effectiveness. The emergence of a new medication, febuxostat, to lower serum urate levels is welcome as no new drug have been approved since the introduction of allopurinol, in 1964, and the drugs that are available have limitations owing to inefficacy or toxicity. Febuxostat is a novel, nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout.

Gout is a disorder of purine metabolism, of varied etiology, associated with an increase in serum uric acid and a recurrent arthritis. The defect may be either metabolic or renal, or either unknown etiology or associated with other disease states. The acute arthritis has been shown to be due to a crystal (sodium urate) synovitis. The many chronic complications, arthritic, renal and vascular, necessitate a vigorous and longterm treatment program. With the advent of the xanthine oxidase inhibiter Allopurinol, excellent control of gout and its complications can be achieved in a large number of patients, with good control in the remainder.

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Introduction:

Gout is a common and disabling cause of arthritis in middle-aged and elderly populations, with its main predisposing factor being hyperuricemia (serum urate > 6.8 mg/dL). Options for treatment of chronic gout until 2008 were allopurinol, a xanthine oxidase inhibitor, and the group of drugs known as uricosurics that stimulate the renal excretion of uric acid. A proportion of patients, including some with chronic kidney disease and solid organ transplantations, could not be treated with the those therapies because of intolerance, drug interactions, or adverse events. Febuxostat is a nonpurine xanthine oxidase inhibitor, recently approved in Europe and the United States for the treatment of chronic gout.

Aim:

To review the clinical evidence (phase II and III studies) of the effectiveness and safety of febuxostat for treatment of hyperuricemia and gout.

Evidence review:

Febuxostat, at doses ranging from 40 to 240 mg/day, is efficacious in reducing serum urate in patients with hyperuricemia and gout, comparing favorably with fixed doses of allopurinol in that respect. Early safety signals with respect to liver test abnormalities and cardiovascular outcomes have not been confirmed in recent large prospective trials but need to be further monitored.

Clinical potential:

Given its low cost and extensive clinical experience, allopurinol will likely remain the first-line drug for management of hyperuricemia and gout. Febuxostat may provide an important option in patients unable to use allopurinol, those with very high serum urate levels, or in the presence of refractory tophi.

Hyperuricemia is a feature of several pathologies and requires an appropriate and often early treatment, owing to the severe consequences that it may cause. A rapid and massive raise of uric acid, during tumor lysis syndrome (TLS), and also a lower and chronic hyperuricemia, as in gout, mainly damage the kidney. To prevent or treat these consequences, a new therapeutic option is represented by rasburicase, a recombinant form of an enzyme, urate oxidase. This enzyme converts hypoxanthine and xanthine into allantoin, a more soluble molecule, easily cleared by kidney. The several types of urate oxidase have followed each other, with progressive reduction of adverse reactions. The most important among them are allergenicity and the development of antibodies which compromise their effectiveness. Nevertheless, a limit of rasburicase's use remains its cost, which obliges to a judicious choice to prevent TLS in high risk patients with cancer and in case of allergy or impossibility to take allopurinol orally both in TLS and in gout. A large body of evidence confirms the efficacy and safety of rasburicase, even in comparison to the standard drugs used in the aforementioned pathologies.

Hyperuricemia, an integral component of metabolic syndrome, is a major health problem causing gout and renal damage. Urine alkalizers like citrate preparations facilitate renal excretion of the uric acid, but its supportive effect on xanthine oxidase inhibitors has not been tested as yet. We thus performed a randomized, prospective study, employing patients with elevated serum uric acid levels (≥7.0 mg/dL), or those treated for hyperuricemia. They were randomly enrolled into two study groups: the allopurinol monotherapy (MT) group or combination treatment (CT) group with allopurinol and a citrate preparation. Allopurinol (100 to 200 mg/day) in the absence or presence of a citrate preparation (3 g/day) was administered for 12 weeks and levels of serum uric acid, its urinary clearance (Cua), and the renal glomerular filtration rates assessed with the creatinine clearance (Ccr) were evaluated before and after the treatment. Serum levels of uric acid decreased significantly in both groups, while the change observed was much greater in CT group. Cua was significantly increased in CT group but not in MT group. Ccr was not altered in both groups in general, whereas it was significantly increased in a fraction of CT group with decreased renal function. These results indicate that an additional use of citrate preparations with xanthine oxidase inhibitors is beneficial for patients with hyperuricemia, reducing circulating uric acid and improving their glomerular filtration rates.

A study of renal function of 51 patients with gout and an equal number of normouricaemic controls revealed significant differences. A relative impairment of the glomerular filtration rate and urine concentrating ability in the gouty subjects could not be wholly explained on the basis of aging or hypertension. Renal dysfunction was generally mild and was not associated with specific clinical characteristics higher levels of uric acid excretion, or hypertriglyceridaemia. Gout patients excreted urine with a significantly lower pH. This was associated with a relatively high excretion of titratable acid and a deficit of ammonium excretion, which was accentuated by ingestion of an acid load. Urate clearance was significantly reduced in gout, even when expressed as a fraction of the glomerular filtration rate.

A report of 20 cases of gout considered to be secondary to chronic renal disease is presented. Studies of renal function and of uric acid metabolism were carried out in 16 patients. The daily production of urate remained within normal limits in the face of progressive renal dysfunction. Renal excretion of uric acid was decreased to a mean of 35.5% of the turnover. The cumulative urinary recovery of intravenously injected 14C-uric acid averaged 32.0%. In 3 patients 14C was successively retrieved in urinary allantoinand urea, in carbon dioxide of expired air, and in faeces. As in normal man, carbon dioxide and ammonia were the principal uricolytic products. The extrarenal excretion of uric acid assumes a greater role in chronic renal disease and eventually becomes the major route of elimination of uric acid. The possibility that gout may be secondary to intrinsic renal disease should be entertained when azotaemia is present.

The prevalence of gout is increasing with increased life expectancy. Approximately half of the patients with gout have some degree of renal impairment. If both conditions persistently coexist, and in severe tophaceous gout, in particular, treatment has been difficult. We here report on the case of an 87-year-old woman, who had been suffering from recurrent gouty arthritis over 4 years. Monthly polyarthritis attacks were accompanied by subcutaneous tophi. Serum uric acid levels were constantly above 600 μmol/L (10 mg/dL). Allopurinol was no option because of intolerance, while benzbromarone was ineffective because of renal impairment. Therefore, the novel xanthin oxidase inhibitor febuxostat was started, achieving rapid control of serum urate levels (<360 μmol/L). After initial worsening of inflammation in the first weeks, gouty attacks stopped and all tophi resolved within the following 10 months. Renal function remained stable.

Along with hydration and urinary alkalinization, allopurinol has been the standard agent for the management of hyperuricemia in patients with a high tumor burden at risk of tumor lysis syndrome; however, this agent often fails to prevent and treat this complication effectively. Rasburicase (recombinant urate oxidase) has been shown to be effective in reducing uric acid and preventing uric acid accumulation in patients with hematologic malignancies with hyperuricemia or at high risk of developing it. Rasburicase acts at the end of the purine catabolic pathway and, unlike allopurinol, does not induce accumulation of xanthine or hypoxanthine. Its rapid onset of action and the ability to lower pre-existing elevated uric acid levels are the advantages of rasburicase over allopurinol. Rasburicase represents an effective alternative to allopurinol to promptly reduce uric acid levels, improve patient’s electrolyte status, and reverse renal insufficiency. The drug, initially studied in pediatric patients with acute lymphoblastic leukemia and aggressive non-Hodgkin lymphoma, seems to show comparable benefit in adults with similar lymphoid malignancies or at high risk of tumor lysis syndrome. Current and future trials will evaluate alternative doses and different schedules of rasburicase to maintain its efficacy while reducing its cost. The review provides a comprehensive and detailed review of pathogenesis, laboratory, and clinical presentation of TLS together with clinical studies already performed both in pediatric and adult patients.

Acute tumour lysis syndrome (ATLS) is a metabolic derangement (hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia) associated with lymphoproliferative malignancies. The nature and severity of the metabolic alterations are variable. Major complications are oliguric acute renal failure and delays in initiating chemotherapy. Current management of ATLS includes hydration, alkalinization, diuretics, when indicated, and the reduction of uric acid levels using allopurinol or urate oxidase. Allopurinol inhibits xanthine oxidase, an enzyme that catalyses the conversion of hypoxanthine and xanthine to uric acid. Urate oxidase (Uricozyme), a naturally occurring proteolytic enzyme in many mammals, degrades uric acid to allantoins, which are ten times more soluble than uric acid and easily eliminated by the kidneys. Recently, Sanofi Research isolated a recombinant urate oxidase (SR29142) as a cDNA clone from Aspergillus flavus, expressed in the yeast strain Saccharomyces cerevisiae. Preclinical studies have documented its biological effects as a urolytic enzyme. Twenty-eight healthy male volunteers received SR29142, and a rapid decline of uric acid below measurable levels was seen within 4 h in all patients receiving a dose of more than 0.10 mg kg(-1). Currently, SR29142 is undergoing clinical studies in both Europe and the USA in patients with acute leukaemias or B-cell non-Hodgkin's lymphoma to demonstrate its efficacy and safety in this population of patients at highest risk of developing ATLS or its life-threatening sequelae.

Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys.

Recent studies have confirmed that gout is an inborn error of metabolism. It has now become evident that the hyperuricemia associated with gout might occur either due to overproduction of uric acid, underexcretion of uric acid or a combination of these processes. Furthermore, patients with excessive purine synthesis may have a specific enzyme defect resulting in altered feedback inhibition of purine synthesis. A neurological disease manifest by mental retardation, choreo-athetosis, aggressive behavior, lip-biting and self-mutilation and associated with decidedly increased purine biosynthesis serves as a prototype of this kind of disorder. Other defects in regulation of purine biosynthesis have been postulated but their existence not yet confirmed.

It has been demonstrated that urate crystals which are deposited from hyperuricemic body fluids set up an acute inflammatory reaction by means of a variety of chemical mediators. Thus, acute gouty arthritis is now recognized as an example of “crystal induced” synovitis.

The treatment of gout consists of (1) the control of acute gouty attacks, and (2) the maintenance of normal serum uric acid concentrations. This latter may be achieved either with uricosuric drugs or with xanthine oxidase inhibition. With these principles in mind, it is now possible to avoid many of the severe crippling effects of gout and to restore the vast majority of gouty patients to useful and productive lives.

Gout is the most common form of inflammatory arthritis in the elderly. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into the transporters that handle uric acid in the kidney as well as possible links between these transporters, hyperuricemia, and hypertension. The treatment of established hyperuricemia has also seen new developments. Febuxostat and PEG-uricase are two novel treatments that have been evaluated and shown to be highly effective in the management of hyperuricemia, thus enlarging the therapeutic options available to lower uric acid levels. Monosodium urate (MSU) crystals are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment, and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR)-2, TLR-4, and CD14. Intracellularly, MSU crystals activate multiple processes that lead to the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome complex that in turn processes pro-interleukin (IL)-1 to yield mature IL-1β, which is then secreted. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances in the understanding of hyperuricemia and gout provide new therapeutic targets for the future.

Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.

BACKGROUND—Because serious adverse reactions to allopurinol have been related to a reduce creatinine clearance rate and prolonged half life of oxypurinol, it has been recommended that the dose should be adjusted according to the rate of creatinine clearance. However, in some patients with gout the dose is not sufficient to reduce serum levels of uric acid (⩽390 µmol/l) and to halt disease progression.
OBJECTIVE—To determine the prevalence of adverse reactions attributable to allopurinol in patients with primary gout according to dose and creatinine clearance rate.
METHODS—Data on 120 patients with gout receiving allopurinol, in whom the starting dose was adjusted according to creatinine clearance rate and later increased in some patients to control the disease, were retrospectively reviewed. Two groups were compared: group A, 52 patients receiving creatinine clearance adjusted maintenance doses of allopurinol and group B, 68 patients receiving non-adjusted higher maintenance doses of allopurinol.
RESULTS—During follow up 57% required higher allopurinol doses than those recommended according to their creatinine clearance rate. Only five (4%) of 120 consecutive patients developed allopurinol related adverse reactions: four minor skin reactions and one allopurinol hypersensitivity syndrome (AHS). Three of these (including the case of AHS) occurred in group A and two in group B (p=NS). The duration of allopurinol treatment was the same in both groups (group A: 2.3 (3.3) years; group B: 3.7 (4.8) years). No patient in group A, but 44% in group B had a creatinine clearance rate of <50 ml/min. None of the patients received concomitant diuretics, ampicillin, or azathioprine.
CONCLUSIONS—No increase was seen in the prevalence of adverse reactions to allopurinol in patients who received higher allopurinol maintenance doses than those recommended according to creatinine clearance rate.



Methods: Twenty seven patients with gout were included in a fenofibrate plus anti-hyperuricaemic agents combination study, and 25 in a losartan plus anti-hyperuricaemic agents combination study. Serum uric acid concentration, uric acid clearance, and 24 hour urinary uric acid excretion were measured before and two months after the addition of fenofibrate (300 mg once daily) or losartan (50 mg once daily) to anti-hyperuricaemic agents.

Results: Combination therapy of fenofibrate or losartan with anti-hyperuricaemic agents, which included benzbromarone (50 mg once daily) or allopurinol (200 mg twice a day), significantly reduced serum uric acid concentrations in accordance with increased uric acid excretion.

Conclusion: A combination of fenofibrate or losartan with anti-hyperuricaemic agents is a good option for the treatment of gout patients with hypertriglyceridaemia and/or hypertension, though the additional hypouricaemic effect may be modest.

Using the Intralipid lipid tolerance test we could not demonstrate any direct effect of serum triglyceride on uric acid or any influence of hyperuricaemia on triglyceride removal. This result supports previous studies suggesting that hyperuricaemia and hypertriglyceridaemia are linked through the association of obesity and alcohol excess rather than a direct cause and effect mechanism. It was possible to demonstrate significant reductions of serum triglyceride in patients with gout by reducing either their alcohol intake or body weight. Reduction of serum uric acid by probenecid had no effect on serum triglyceride or cholesterol. Similarly, allopurinol had no significant effect on serum triglyceride, but a significant fall of serum cholesterol was observed.

Multiple sclerosis (MS) is a progressive demyelinating process considered as an autoimmune disease, although the causes of this pathology have not been yet fully established. Similarly to other neurodegenerations, MS is characterized by a series of biochemical changes affecting to different extent neuronal functions; great attention has been given to oxidative/nitrosative stress and to alterations in mitochondrial functions. According to previous data, MS patients show significant changes in the circulating concentrations of different metabolites, although it is still unclear whether uric acid undergoes to decrease, increase, or no change under this pathological condition. In this study, we report the serum metabolic profile in terms of purines, pyrimidines, creatinine, malondialdehyde, ascorbic acid, nitrite, and nitrate in a group of 170 MS patients. The results show increase in circulating uric acid and other oxypurines (hypoxanthine and xanthine), as well as in uridine and β-pseudouridine. The concomitant increase in circulating creatinine, malondialdehyde, nitrite, and nitrate, and decrease in ascorbic acid, demonstrates that MS induces alteration in energy metabolism and in oxidants/antioxidants balance that can be monitored in serum of MS patients.

This study compared the effects of azapropazone and indomethacin plus allopurinol in the management of acute gout and hyperuricaemia. A group of 93 patients predominantly based in general practice were randomly allocated to the two treatment regimens (azapropazone (days 1-225) or indomethacin (1-28) followed by allopurinol (29-225)) on a double-blind double dummy basis. Azapropazone produced a substantial reduction in serum uric acid levels by day 4 compared with day 1 (P<0.002) and was superior to indomethacin with regard to recorded levels of serum uric acid at day 4 (P<0.01) and day 28 (P<0.05). From day 28 onwards allopurinol produced and azapropazone maintained similar reductions in serum uric acid. Both treatments rapidly controlled the initial acute attacks of gout and both produced side effects similar in frequency and nature. Fewer breakthrough attacks of gout occurred in the azapropazone group (12) than the indomethacin/allopurinol group (21).

Although the results achieved in both treatment groups were similar it has been shown that azapropazone is effective monotherapy for controlling both acute attacks of gout and hyperuricaemia.

Hypercalcemia has been widely associated with granulomatous processes. This is due to enhanced extra-renal conversion of calcidiol to calcitriol by activated macrophages within the granuloma. Symptomatic hypercalcemia due to granulomatous disorders is not common, with the incidence in sarcoidosis ranging from 10–20%. Large aggregates of monosodium urate crystals in patients with longstanding chronic tophaceous gout can serve as the inciting antigen for the development of granuloma, but hypercalcemia has not been described in this context. We report a case of symptomatic hypercalcemia due to gouty tophi induced granulomatous inflammation. Long term treatment with immunosuppressants, in addition to bisphosphonates and uric acid lowering therapy, has led to stabilization of serum calcium levels and other lab parameters indicative of granulomatous burden.

The past decade has witnessed an exponential increase of novel therapeutic modalities for a variety of rheumatic disorders, including gout. During the past few years two novel therapeutic agents have been approved by the US Food and Drug Administration for the treatment of hyperuricemia in patients with gout, one of them being febuxostat, a nonpurine selective inhibitor of xanthine oxidase. Review of its pharmacokinetics and pharmacodynamics, efficacy and safety profile, and use in gout patients with comorbid conditions reveals that age and gender have no clinically significant effect and dose adjustments based on age or gender are not required. In addition, febuxostat can be used in patients with mild-to-moderate renal or hepatic involvement. Its overall efficacy and safety profile is comparable and, in certain subsets such as gout patients with mild and moderate renal insufficiency, is superior to allopurinol.

Studies were performed to determine whether hypoglycemia or the glucagon response to hypoglycemia increases uric acid production in glycogen storage disease type I (glucose-6-phosphatase deficiency). Three adults with this disease had hyperuricemia (serum urate, 11.3-12.4 mg/dl) and reduced renal clearance of urate (renal urate clearance, 1.1-3.1 ml/min). These abnormalities were improved in one patient by intravenous glucose infusion for 1 mo, suggesting a role for hypoglycemia and its attendant effects on urate metabolism and excretion. A pharmacologic dose of glucagon caused a rise in serum urate from 11.4 to 13.0 mg/dl, a ninefold increase in urinary excretion of oxypurines, a 65% increase in urinary radioactivity derived from radioactively labeled adenine nucleotides, and a 90% increase in urinary uric acid excretion. These changes indicate that intravenous glucagon increases ATP breakdown to its degradation products and thereby stimulates uric acid production. To observe whether physiologic changes in serum glucagon modulate ATP degradation, uric acid production was compared during saline and somatostatin infusions. Serum urate, urinary oxypurine, radioactivity, and uric acid excretion increased during saline infusion as patients became hypoglycemic. Infusion of somatostatin suppressed these increases despite hypoglycemia and decreased the elevated plasma glucagon levels from a mean of 81.3 to 52.2 pg/ml. These data suggest that hypoglycemia can stimulate uric acid synthesis in glucose-6-phosphatase deficiency. Glucagon contributes to this response by activating ATP degradation to uric acid.

A 21 year old man with a family history of gout and neurological deficits, developed severe idiopathic congestive cardiomyopathy after a long history of typical gouty attacks and neurological abnormalities. Clinical and laboratory evaluations showed borderline mental retardation, ataxia, sensorineural deafness, marked hyperuricaemia, and excessive uric acid excretion in the presence of impaired renal function. None of the known causes of cardiomyopathy was found. Even though red cell hypoxanthine guanine phosphoribosyltransferase enzyme activity was normal, this case probably represents an inborn error of purine metabolism. The association of cardiomyopathy with gout is very unusual. Previously it has been only once described in a single case.

Six generations of a Japanese family had gouty arthritis and progressive nephropathy. Data on nine of 51 women (18%) and 15 of 66 men (23%) with either asymptomatic hyperuricaemia, gouty arthritis, or renal insufficiency were obtained. Renal function in four men and one woman with hyperuricaemia or gouty arthritis was also examined. Urinary excretion of uric acid was decreased in all subjects examined, including the young. Erythrocyte phosphoribosylpyrophosphate synthetase and hypoxanthine-guanine phosphoribosyltransferase activities determined in 10 patients were normal. Some patients had been treated with allopurinol to reduce serum uric acid concentrations, but the treatment did not prevent progression of renal impairment. Transmission of the disease in this large family is considered to be autosomal dominant. The data suggest that the disease in this family is the same entity as that described by other workers--that is, familial urate nephropathy. As far as is known this is the largest family with this disease so far reported.

We report a third case of 2, 8-dihydroxyadenine stones in a child with a complete lack of the adenine salvage enzyme--adenine phosphoribosyltransferase (APRT). The propositus, a 20-month-old girl of consanguineous Arab parents, presented with multiple urinary tract infections and supposed 'uric acid' stones in the right renal pelvis and left ureter. Both parents and one brother were heterzygotes for the defect, in keeping with an autosomal recessive mode of inheritance. In contrast with the other purine salvage enzyme disorder of childhood with true uric acid stones (the Lesch-Nyhan syndrome), uric acid excretion was normal in all family members. As in our previous case, treatment with allopurinol, without alkali, has eliminated the urinary excretion of 2, 8-dihydroxyadenine: the stones were removed surgically. 2, 8-Dihydroxyadenine should be considered in any child thought to have uric acid stones and tests made to distinguish the two compounds.

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