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1.  Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout 
Core evidence  2010;4:25-36.
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.
PMCID: PMC2899777  PMID: 20694062
febuxostat; gout; hyperuricemia; evidence
2.  Management of hyperuricemia in gout: focus on febuxostat 
Gout is the most common inflammatory arthritis in an elderly population, and can be diagnosed with absolute certainty by polarization microscopy. However, diagnosis may be challenging because atypical presentations are more common in the elderly. Management of hyperuricemia in the elderly with gout requires special consideration because of co-medication, contra-indications, and risk of adverse reactions. Urate-lowering agents include allopurinol and uricosuric agents. These also must be used sensibly in the elderly, especially when renal function impairment is present. However, if used at the lowest dose that maintains the serum urate level below 5.0 to 6.0 mg/dL (0.30 to 0.36 mmol/L), the excess urate in the body will eventually be eliminated, acute flares will no longer occur, and tophi will resolve. Febuxostat, a new xanthine oxidase inhibitor, is welcomed, as few alternatives for allopurinol are available. Its pharmacokinetics and pharmacodynamics are not significantly altered in patients with moderate renal function or hepatic impairment. Its antihyperuricemic efficacy at 80 to 120 mg/day is better than “standard dosage” allopurinol (300 mg/day). Long-term safety data and efficacy data on tophus diminishment and reduction of gout flares have recently become available. Febuxostat may provide an important option in patients unable to use allopurinol, or refractory to allopurinol.
PMCID: PMC2817937  PMID: 20169038
aging; febuxostat; hyperuricemia; gout; pharmacotherapy; xanthine oxidase
3.  Febuxostat: A Novel Agent for Management of Hyperuricemia in Gout 
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.
doi:10.4103/0250-474X.100231
PMCID: PMC3480742  PMID: 23112391
Gout; hyperuricemia; xanthine oxidase inhibitor
4.  Febuxostat in the management of hyperuricemia and chronic gout: a review 
Febuxostat is a novel, potent, non-purine selective xanthine oxidase inhibitor, which in clinical trials demonstrated superior ability to lower and maintain serum urate levels below 6 mg/dL compared with conventionally used doses of allopurinol. Febuxostat was well tolerated in long term treatment in patients with hyperuricemia including those experiencing hypersensitity/intolerance to allopurinol. Dose adjustment appears unnecessary in patients with mild to moderate renal or liver insufficiency or advanced age. The most common adverse reactions reported were abnormal liver function tests, headache, and gastrointestinal symptoms, which were usually mild and transient. However, whether hepatotoxicity becomes a limitation in the use of febuxostat needs to be determined in further studies. An increased frequency of gout flares occurs for a prolonged period after treatment initiation, as with any aggressive lowering of serum urate, and prolonged prophylaxis with colchicine or NSAIDs is usually required. Febuxostat has been granted marketing authorization by the European Commission in early 2008 for the treatment of chronic hyperuricemia and gout. Febuxostat is the first major treatment alternative for gout in more than 40 years and is a promising alternative to allopurinol, although continued long-term surveillance on safety and efficacy is required.
PMCID: PMC2643102  PMID: 19337428
febuxostat; TEI-6720; TMX-67; gout; hyperuricemia; xanthine oxidase inhibitor
5.  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) 
Annals of the Rheumatic Diseases  2006;65(10):1312-1324.
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.
doi:10.1136/ard.2006.055269
PMCID: PMC1798308  PMID: 16707532
EULAR; gout; guidelines; treatment
6.  The effect of febuxostat to prevent a further reduction in renal function of patients with hyperuricemia who have never had gout and are complicated by chronic kidney disease stage 3: study protocol for a multicenter randomized controlled study 
Trials  2014;15:26.
Background
Hyperuricemia is a risk factor for the onset of chronic kidney disease (CKD) and is significantly associated with the progression of CKD. However, there is no sufficient evidence by interventional research supporting a cause-effect relationship. Hyperuricemic patients without gouty arthritis, whose serum urate (SUA) concentration is ≥8.0 mg/dL and who have a complication, are treated by pharmacotherapy in addition to lifestyle guidance. Nevertheless, there is no evidence that rationalizes pharmacotherapy for patients with hyperuricemia who have no complication and whose SUA concentration is below 9.0 mg/dL.
Methods/Design
The FEATHER (FEbuxostat versus placebo rAndomized controlled Trial regarding reduced renal function in patients with Hyperuricemia complicated by chRonic kidney disease stage 3) study is a prospective, multicenter, double-blind, randomized, placebo-controlled trial of febuxostat—a novel, nonpurine, selective, xanthine oxidase inhibitor. The present study will enroll, at 64 medical institutions in Japan, 400 Japanese patients aged 20 years or older who have hyperuricemia without gouty arthritis, who present CKD stage 3, and whose SUA concentration is 7.1-10.0 mg/dL. Patients are randomly assigned to either the febuxostat or the control group, in which febuxostat tablets and placebo are administered orally, respectively. The dosage of the study drugs should be one 10-mg tablet/day at weeks 1 to 4 after study initiation, increased to one 20-mg tablet/day at weeks 5 to 8, and elevated to one 40-mg tablet/day at week 9 and then maintained until week 108. The primary endpoint is estimated glomerular filtration rate (eGFR) slope. The secondary endpoints include the amount and percent rate of change in eGFR from baseline to week 108, the amount and percent rate of change in SUA concentration from baseline to week 108, the proportion of patients who achieved an SUA concentration ≤6.0 mg/dL, and the incidence of renal function deterioration.
Discussion
The present study aims to examine whether febuxostat prevents a further reduction in renal function as assessed with eGFR in subjects and will (1) provide evidence to indicate the inverse association between a reduction in SUA concentration and an improvement in renal function and (2) rationalize pharmacotherapy for subjects and clarify its clinical relevance.
Trial registration
UMIN Identifier: UMIN000008343
doi:10.1186/1745-6215-15-26
PMCID: PMC3899617  PMID: 24433285
Xanthine oxidase inhibitor; Urate-lowering therapy; Reduced renal function; Hyperuricemia; Chronic kidney disease; Randomized controlled study; Placebo
7.  Gout 
Clinical Evidence  2011;2011:1120.
Introduction
Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of treatments to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, corticotropin (ACTH), non-steroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, xanthine oxidase inhibitors, advice to lose weight, advice to reduce alcohol intake, and advice to reduce dietary intake of purines.
Key Points
Gout is characterised by deposition of urate crystals, causing acute monoarthritis and crystal deposits (tophi) in the skin. Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.Diagnosis is usually clinical, supported by presence of hyperuricaemia.Risk factors are those associated with hyperuricaemia, including: older age; non-white ethnicity; obesity; consumption of alcohol, meat, and fish; and use of diuretics.Hyperuricaemia may be associated with an increased risk of cardiovascular events; we don't know whether it is an independent risk factor.
We don't know whether NSAIDs reduce pain and tenderness in an acute attack of gout, although they are commonly used in clinical practice. They are associated with increased risks of gastrointestinal, and possible cardiovascular, adverse effects. Indometacin is widely used to treat acute gout despite the absence of RCT evidence of benefit. Etoricoxib is as effective as indometacin with reduced risks of gastrointestinal adverse effects.
Colchicine may be more effective than placebo at improving symptoms in acute gout. Its use is limited by the high incidence of adverse effects; although these may be reduced with low-dose colchicine regimens. Low-dose colchicine may be as effective at reducing pain in gout and may produce fewer adverse effects than high-dose colchicine.
We don't know whether intra-articular or parenteral corticosteroids, or corticotropin (ACTH), improve symptoms in acute gout. Oral corticosteroids seem as effective as NSAIDs and may have fewer short-term adverse events.
We don't know whether colchicine prevents attacks of gout in people with prior episodes, but it may reduce the risk of an attack in a person starting allopurinol treatment.
We don't know whether advice to lose weight or reduce alcohol or dietary purine intake prevents further attacks of gout.
We don't know whether sulfinpyrazone reduces the risk of recurrent attacks compared with placebo or other treatments.
We don't know whether xanthine oxidase inhibitors reduce the risk of recurrent attacks in the long term when compared with placebo or other treatments. Higher doses of febuxostat may increase the risks of gout attacks within the first 8 weeks of treatment compared with placebo, and compared with allopurinol.
PMCID: PMC3275296  PMID: 21575286
8.  Gout  
Clinical Evidence  2008;2008:1120.
Introduction
Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of treatments to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, corticotrophin (ACTH), non-steroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, xanthine oxidase inhibitors, advice to lose weight, advice to reduce alcohol intake, advice to reduce dietary intake of purines.
Key Points
Gout is characterised by deposition of urate crystals, causing acute monoarthritis and crystal deposits (tophi) in the skin. Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.Diagnosis is usually clinical, supported by signs of hyperuricaemia.Risk factors are those associated with increased serum urate concentrations, including: older age; non-white ethnicity; obesity; consumption of alcohol, meat, and fish; and use of diuretics.Hyperuricaemia may be associated with an increased risk of cardiovascular events; we don't know whether it is an independent risk factor.
We don't know whether NSAIDs reduce pain and tenderness in an acute attack of gout, although they are commonly used in clinical practice. They are associated with increased risks of gastrointestinal, and possible cardiovascular, adverse effects. Indometacin is widely used to treat acute gout despite the absence of RCT evidence of benefit. Etoricoxib is as effective as indometacin with reduced risks of gastrointestinal adverse effects.
Although it has been widely used for many years, we don't know whether oral colchicine improves symptoms in acute gout. Its use is limited by the high incidence of adverse effects.
We don't know whether intra-articular, parenteral or oral corticosteroids, or corticotropin (ACTH), improve symptoms in acute gout.
We don't know whether colchicine prevents attacks of gout in people with prior episodes, but it may reduce the risk of an attack in a person starting allopurinol treatment. We don't know whether advice to lose weight or reduce alcohol or dietary purine intake prevents further attacks of gout.We don't know whether allopurinol or febuxostat, orsulfinpyrazone reduce the risk of recurrent attacks compared with placebo or other treatments.
PMCID: PMC2907998  PMID: 19445790
9.  Efficacy and Safety of Febuxostat in Patients with Hyperuricemia and Gout 
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.
doi:10.1177/1759720X11416405
PMCID: PMC3383531  PMID: 22870483
hyperuricemia; febuxostat; gout; safety profile; efficacy profile
10.  The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age 
BMC Geriatrics  2012;12:11.
Background
The incidence of gout rises with increasing age. Management of elderly (≥65 years) gout patients can be challenging due to high rates of comorbidities, such as renal impairment and cardiovascular disease, and concomitant medication use. However, there is little data specifically addressing the efficacy and safety of available urate-lowering therapies (ULT) in the elderly. The objective of this post hoc analysis was to examine the efficacy and safety of ULT with febuxostat or allopurinol in a subset of elderly subjects enrolled in the CONFIRMS trial.
Methods
Hyperuricemic (serum urate [sUA] levels ≥ 8.0 mg/dL) gout subjects were enrolled in the 6-month, double-blind, randomized, comparative CONFIRMS trial and randomized, 1:1:1, to receive febuxostat, 40 mg or 80 mg, or allopurinol (200 mg or 300 mg based on renal function) once daily. Flare prophylaxis was provided throughout the study duration.
Study endpoints were the percent of elderly subjects with sUA <6.0 mg/dL at the final visit, overall and by renal function status, percent change in sUA from baseline to final visit, flare rates, and rates of adverse events (AEs).
Results
Of 2,269 subjects enrolled, 374 were elderly. Febuxostat 80 mg was significantly more efficacious (82.0%) than febuxostat 40 mg (61.7%; p < 0.001) or allopurinol (47.3%; p < 0.001) for achieving the primary efficacy endpoint. Febuxostat 40 mg was also superior to allopurinol in this population (p = 0.029). In subjects with mild-to-moderate renal impairment, significantly greater ULT efficacy was observed with febuxostat 40 mg (61.6%; p = 0.028) and febuxostat 80 mg (82.5%; p < 0.001) compared to allopurinol 200/300 mg (46.9%). Compared to allopurinol 200/300 mg, the mean percent change in sUA from baseline was significantly greater for both febuxostat 80 mg (p < 0.001) and febuxostat 40 mg (p = 0.011) groups. Flare rates declined steadily in all treatment groups. Rates of AEs were low and comparable across treatments.
Conclusions
These data suggest that either dose of febuxostat is superior to commonly prescribed fixed doses of allopurinol (200/300 mg) in subjects ≥65 years of age with high rates of renal dysfunction. In addition, in this high-risk population, ULT with either drug was well tolerated.
Trial registration
clinicaltrials.gov NCT#00430248
doi:10.1186/1471-2318-12-11
PMCID: PMC3368715  PMID: 22436129
11.  Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy 
Arthritis Research & Therapy  2013;15(5):R137.
Introduction
Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy.
Methods
Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR.
Results
Among 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo).
Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than nonresponders (30/93; 32%).
Conclusions
Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy.
Trial registrations
NCT00325195, NCT01356498
doi:10.1186/ar4318
PMCID: PMC3979037  PMID: 24286509
12.  Developments in the scientific and clinical understanding of gout 
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.
doi:10.1186/ar2509
PMCID: PMC2592794  PMID: 18947374
13.  Tophaceous Gout and Renal Insufficiency: A New Solution for an Old Therapeutic Dilemma 
Case Reports in Medicine  2011;2011:397646.
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.
doi:10.1155/2011/397646
PMCID: PMC3099210  PMID: 21629805
14.  Advances in the management of gout: Critical appraisal of febuxostat in the control of hyperuricemia 
Gout recently passed rheumatoid arthritis to become the most common inflammatory arthritis in the United States (US). However, epidemiologic studies indicate that the quality of gout management is suboptimal owing to both patient and physician issues. Only three options for urate-lowering therapy are currently available in the US: allopurinol, probenecid, and recently, febuxostat. Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function. Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels. In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect. Febuxostat is a new medication that may offer several advantages and can be given as an alternative to allopurinol. We review the basic biology and clinical performance of febuxostat, and consider the potential utility of this agent in comparison to the older, better-established gout therapeutics.
PMCID: PMC3108781  PMID: 21694922
allopurinol; gout suppressants; nephrolithiasis; uric acid; urolithiasis
15.  Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout 
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.
PMCID: PMC1838823  PMID: 17396159
Urate oxidase; allantoin; rasburicase; hyperuricemia; tumor lysis syndrome; acute renal failure; gout; allopurinol; uric acid
16.  Latest evidence on gout management: what the clinician needs to know 
Until recently, the last drug approved for the treatment of gout by the United States Food and Drug Administration was allopurinol in 1966. Since 2008, two new drugs for the treatment of gout, febuxostat and pegloticase, have been approved in the US. Febuxostat has been approved in the EU and pegloticase approval is anticipated. A new single-ingredient colchicine preparation is available in the US, and the treatment recommendations for the use of colchicine in acute gout have evolved, now favoring a low-dose regimen. Several other exciting drugs are in development. Herein, we review some of basic principles in the diagnosis and staging of gout. We then examine current treatment principles, with particular attention to febuxostat and pegloticase, offering suggestions as to where they might fit into a modern therapeutic algorithm for gout treatment. We then present available data on several exciting new agents in development, including interleukin-1 inhibitors, and relate them to advances in our understanding of gout pathogenesis. We conclude with some important nonpharmacologic principles for optimal management of this ancient and eminently treatable disease. Dedicated gout research, going on quietly in the background of other breathtaking advances in rheumatology, is now paying off. This comes at a time when the number of patients affected by gout continues to rise, mainly due to an epidemic of obesity. An effort to improve lifestyle choices as a society and better management of the disease by clinicians should have a positive impact on gout incidence and outcome in our lifetimes.
doi:10.1177/2040622312462056
PMCID: PMC3539261  PMID: 23342241
febuxostat; gout; hyperuricemia; inflammasome; interleukin-1; pegloticase; uric acid
17.  Diabetes and gout: efficacy and safety of febuxostat and allopurinol 
Diabetes, Obesity & Metabolism  2013;15(11):1049-1055.
Aim Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents.
Methods Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) ≥8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial.
Results Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m2) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhoea and URIs as the most common adverse events.
Conclusions Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.
doi:10.1111/dom.12135
PMCID: PMC3902994  PMID: 23683134
clinical trial; diabetes mellitus; drug utilisation
18.  Concordance of the management of chronic gout in a UK primary‐care population with the EULAR gout recommendations 
Annals of the Rheumatic Diseases  2007;66(10):1311-1315.
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 μmol/l) and was less often >360 μmol/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.
doi:10.1136/ard.2007.070755
PMCID: PMC1994300  PMID: 17504843
gout; primary health care; lifestyle risk reduction; allopurinol; EULAR recommendations
19.  The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial 
Introduction
The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.
Methods
Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.
Results
Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.
Conclusions
Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.
Clinical Trial Registration
NCT00430248
doi:10.1186/ar2978
PMCID: PMC2888216  PMID: 20370912
20.  Pegloticase for Treatment of Tophaceous Polyarticular Gout 
This is a case report of a patient with treatment resistant gout who was prescribed pegloticase and developed a severe reaction. A 30-year-old Hawaiian-Filipino man presented with a nine-year history of gout that progressed from episodic monoarticular arthritis, treated with aspiration and corticosteroid injections, to more aggressive disease with more frequent attacks requiring escalation of therapy. He was treated with systemic corticosteroids, colchicine and nonsteroidal anti-inflammatory drugs, but then required allopurinol. Despite aggressive therapy, the patient continued to have hyperuricemia and tophi developed even after treatment with febuxostat and probenicid. The patient became wheel chair bound due to his pain and, at that point, the decision was made to initiate treatment with pegloticase. The patient initially experienced significant improvement with treatment; however, he soon began to have elevation in his serum uric acid levels and developed a severe reaction during treatment.
PMCID: PMC3727571  PMID: 23901393
pegloticase; tophi; treatment resistant gout; infusion reaction
21.  Clinical and health care use characteristics of patients newly prescribed allopurinol, febuxostat and colchicine for gout 
Arthritis care & research  2013;65(12):2008-2014.
Background
Gout is a common inflammatory arthritis with the increasing prevalence in the developed countries. It is well-known that many patients with gout have significant comorbidities and high health care utilization.
Methods
Using US insurance claims data (2009–2011), a population-based cohort study was conducted to describe clinical characteristics and health care utilization patterns in patients with gout newly prescribed allopurinol, febuxostat or colchicine.
Results
There were 25,051 allopurinol, 4,288 febuxostat and 6,238 colchicine initiators. Mean age was 53 years and 83%–87% were male. More than half of patients had hypertension and hyperlipidemia, 20% had diabetes and 10% cardiovascular disease. The mean uric acid level (mg/dl) was similar at baseline ranging from 8.1 to 8.5 across the groups. Compared to allopurinol or colchicine initiators, febuxostat initiators had more comorbidities and greater health care uses including outpatient, inpatient or emergency room visits, both at baseline and during the follow-up. Use of gout related drugs, such as opioids, steroids and non-steroidal anti-inflammatory drugs, was most common in febuxostat and least common in colchicine initiators. The median daily dose at both start and end of treatment was 300mg for allopurinol, 40mg for febuxostat, and 1.2mg for colchicine. The dosage of allopurinol and febuxostat was rarely increased during the follow-up.
Conclusion
Patients who started allopurinol, febuxostat or colchicine for gout generally had hyperuricemia and multiple comorbidities. Febuxostat initiators had more comorbidities and greater use of health care resources and gout-related drugs than other groups. Overall, the dosages of allopurinol or febuxostat remained unchanged over time.
doi:10.1002/acr.22067
PMCID: PMC4096791  PMID: 23861232
gout; allopurinol; febuxostat; colchicine
22.  Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients 
Introduction
Pegloticase, a PEGylated recombinant porcine uricase, is approved for treating refractory gout at a dose of 8 mg intravenous (IV) every 2 weeks. However, during phase 1 testing, pharmacokinetics supported less frequent dosing. Also, single doses of pegloticase unexpectedly induced antibodies (Ab) that bound to polyethylene glycol (PEG). We have conducted a phase 2 trial to evaluate every 3-week dosing, and to further define the Ab response to pegloticase. Organ transplant recipients were included, as they are prone to severe gout that is difficult to manage, and because treatment to prevent graft rejection might influence the immune response to pegloticase.
Methods
Plasma uricase activity (pUox), urate concentration (pUA), and clinical response were monitored during up to 5 infusions in 30 patients, including 7 organ transplant recipients. Depending on whether pUA <6 mg/dL was achieved and maintained, patients were classified as non (NR), persistent (PR), or transient (TR) responders. Ab to pegloticase and 10 kDa mPEG were monitored by enzyme linked immunosorbent assay and specificity was further defined.
Results
We observed 17 PR, 12 TR, and 1 NR; 21 patients (16 PR, 5 TR) received all 5 infusions. Over the 15-week trial, pUA in PR averaged 1.0 ± 0.4 mg/dL; T½ for pUox was approximately 13 days, and area under the curve after dose 5 was approximately 30% higher than after dose 1. PR showed clinical benefit and in some, tophi resolved. In 11 of 12 TR, pUox fell rapidly and hyperuricemia recurred before dose 2. In all TR and NR, loss of response to pegloticase was accompanied by Ab to PEG, which was pre-existing in half of those who had no prior exposure to pegloticase. No PR, and 1 one out of 7 organ transplant recipients, had a sustained Ab response to pegloticase.
Conclusions
Every 3-week dosing is effective and may enhance the utility of pegloticase for treating refractory gout. Ab to PEG, which were pre-existing or induced by treatment, caused rapid loss of efficacy and increased the risk of infusion reactions. Organ transplant recipients can benefit from pegloticase, and may be less prone than non-recipients to developing anti-PEG Ab. Investigation of immunosuppressive strategies to minimize anti-PEG Ab is warranted.
Trial registration
ClincalTrials.gov identifier: NCT00111657
doi:10.1186/ar4500
PMCID: PMC4060462  PMID: 24602182
23.  Impaired response or insufficient dosage? – examining the potential causes of ”inadequate response” to allopurinol in the treatment of gout 
Objectives
Gout is one of the most common forms of arthritis. It is well established that urate lowering therapy that aims for a serum urate less than at least 0.36mmol/l (6mg/dL) is required for successful management of gout. Allopurinol, a xanthine oxidase (XO) inhibitor is the most commonly used urate lowering therapy. However, many patients fail to achieve the target serum urate on allopurinol, these patients can be considered to have “inadequate response” to allopurinol. Herein we examine the potential mechanisms and implications of inadequate response to allopurinol.
Methods
The literature was reviewed for potential causes for failure to reach target serum urate in patients receiving allopurinol.
Results
The two most common causes of inadequate response to allopurinol are poor adherence and under-dosing of allopurinol. Adherent patients who fail to achieve target serum urate on standard doses of allopurinol form a group that could be considered to be “partially resistant” to allopurinol. There are four potential mechanisms for partial allopurinol resistance: decreased conversion of allopurinol to oxypurinol; increased renal excretion of oxypurinol; abnormality in XO structure and or function such that oxypurinol is rendered less effective, and/or drug interactions.
Conclusions
It is important to determine the reasons for failure to achieve treatment targets with allopurinol, particularly as newer agents become available. The knowledge of the mechanisms for inadequate response may help guide the clinician toward making a therapeutic choice that is more likely to result in achieving the serum urate target.
doi:10.1016/j.semarthrit.2014.05.007
PMCID: PMC4225179  PMID: 24925693
24.  African American patients with gout: efficacy and safety of febuxostat vs allopurinol 
Background
African Americans are twice as likely as Caucasians to develop gout, but they are less likely to be treated with urate-lowering therapy (ULT). Furthermore, African Americans typically present with more comorbidities associated with gout, such as hypertension, obesity, and renal impairment. We determined the efficacy and safety of ULT with febuxostat or allopurinol in African American subjects with gout and associated comorbidities and in comparison to Caucasian gout subjects.
Methods
This is a secondary analysis of the 6-month Phase 3 CONFIRMS trial. Eligible gouty subjects with baseline serum urate (sUA) ≥ 8.0 mg/dL were randomized 1:1:1 to receive febuxostat 40 mg, febuxostat 80 mg, or allopurinol (300 mg or 200 mg depending on renal function) daily. All subjects received gout flare prophylaxis. Primary efficacy endpoint was the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the final visit. Additional endpoints included the proportion of subjects with mild or with moderate renal impairment who achieved a target sUA < 6.0 mg/dL at final visit. Adverse events (AEs) were recorded throughout the study.
Results
Of the 2,269 subjects enrolled, 10.0% were African American and 82.1% were Caucasian. African American subjects were mostly male (89.5%), obese (BMI ≥ 30 kg/m2; 67.1%), with mean baseline sUA of 9.8 mg/dL and mean duration of gout of 10.4 years. The proportions of African American subjects with a baseline history of diabetes, renal impairment, or cardiovascular disease were significantly higher compared to Caucasians (p < 0.001). ULT with febuxostat 80 mg was superior to both febuxostat 40 mg (p < 0.001) and allopurinol (p = 0.004). Febuxostat 40 mg was comparable in efficacy to allopurinol. Significantly more African American subjects with mild or moderate renal impairment achieved sUA < 6.0 mg/dL in the febuxostat 80 group than in either the febuxostat 40 mg or allopurinol group (p < 0.05). Efficacy rates in all treatment groups regardless of renal function were comparable between African American and Caucasian subjects, as were AE rates.
Conclusions
In African American subjects with significant comorbidities, febuxostat 80 mg is significantly more efficacious than either febuxostat 40 mg or allopurinol 200/300 mg. Febuxostat was well tolerated in this African American population.
Please see related article: http://www.biomedcentral.com/1741-7015/10/15
doi:10.1186/1471-2474-13-15
PMCID: PMC3317813  PMID: 22316106
25.  Can racial disparities in optimal gout treatment be reduced? evidence from a randomized trial 
BMC Medicine  2012;10:15.
There is a disproportionate burden of gout in African-Americans in the U.S. due to a higher disease prevalence and lower likelihood of receiving urate-lowering therapy (ULT), compared to Caucasians. There is an absence of strong data as to whether the response to ULT differs by race/ethnicity. BMC Musculoskeletal Disorders recently published a secondary analyses of the CONFIRMS trial, a large randomized controlled, double-blind trial of 2,269 gout patients. The authors reported that the likelihood of achieving the primary study efficacy end-point of achieving serum urate < 6 mg/dl was similar between African-Americans and Caucasians, for all three treatment arms (Febuxostat 40 mg and 80 mg and allopurinol 300/200 mg). More importantly, rates were similar in subgroups of patients with mild or moderate renal insufficiency. Adverse event rates were similar, as were the rates of gout flares. These findings constitute a convincing evidence to pursue aggressive ULT in gout patients, regardless of race/ethnicity. This approach will likely help to narrow the documented racial disparities in gout care.
Please see related article: http://www.biomedcentral.com/1471-2474/13/15
doi:10.1186/1741-7015-10-15
PMCID: PMC3337326  PMID: 22316088
Gout; Disparity; Race; treatment; Febuxostat; Allopurinol; randomized; African-American

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