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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.  Multiple Intramuscular Gouty Tophi Mimicking Deep Tissue Abscesses: A Case Report 
Introduction:
Gout is a common metabolic disorder resulting from supersaturation of uric acid in extracellular fluid and deposition of monosodium urate monohydrate crystals in tissues triggering inflammatory response. Depositions of uric acid crystal outside articular structures cause tophi and are commonly found at peripheral areas of the body which have a lower temperature. Deposition of uric acid crystals in the central area of the body is not uncommon and may be overlooked.
Case presentation:
A 55-year-old Pacific Islander man with a history of chronic tophaceous gout was admitted because of acute right knee pain. Physical examination revealed signs of inflammation over the right knee. Arthrocentesis was performed but no synovial fluid obtained. The patient was empirically treated with prednisone, colchicine, and febuxostat. On the next day, there was progression of inflammation up to the right mid-thigh. MRI of the right femur was obtained to exclude abscess and necrotizing faciitis. Multiple pockets of abscesses were identified within the vastus medialis and vastus intermedius adjacent to the femoral shaft. This prompted immediate surgical consultation and incision and drainage. Intraoperative findings revealed healthy muscles and deposition of soft-tan material in the vastus medialis and vastus intermedius along and above the shaft of the femur. Culture of the surgical aspirate was negative and pathology showed needle-shaped structures consistent with uric acid crystals. Empiric antibiotic was discontinued. The patient's condition improved after treatment for acute gout. Pegloticase was also added to the treatment regimen during an outpatient follow up visit with his rheumatologist. At six month follow up, the patient reported excellent improvements in clinical symptoms.
Discussion:
Atypical presentations of chronic tophaceous gout can be a great mimicker, causing diagnostic challenges for clinicians. Our patient who had multiple intramuscular tophi presented with abrupt signs and symptoms of inflammation of lower extremity resembling cellulitis, abscess, or necrotizing fasciitis. On MRI, tophi typically exhibit low signal on T1-weighted images and medium to high signal on T2-weighted images, indicating the presence of cellular tissues surrounding or infiltrating the crystalline mass. The vascularity of this tissue influences the degree of MRI post-contrast enhancement on T2-weighted images. With varying degrees of cellular response and vascularity, distinguishing tophi from abscesses by MRI is still difficult.
Conclusion:
Our report focuses on the fact that tophi can also trigger acute inflammatory responses mimicking those of acute infection. At atypical locations, it can lead to misdiagnosis and inappropriate treatment. MRI is not a sensitive tool to differentiate abscess from tophaceous gout. Tissue diagnosis obtained from biopsy or aspiration is warranted to guide appropriate treatment and distinguish these different entities.
PMCID: PMC4175947
3.  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
4.  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
5.  Gout  
BMJ 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
6.  Gout 
BMJ 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
7.  New and improved strategies for the treatment of gout 
The Western world appears to be in the midst of the third great gout epidemic of all time. In this century, gout is increasing in prevalence despite an increased understanding of its risk factors and pathophysiology, and the availability of reasonably effective treatment. The main cultural factors responsible for this appear to be diet, obesity, ethanol use and medications. Excess fructose consumption is a newly recognized modifiable risk factor. The debate has been renewed concerning hyperuricemia as an independent risk factor for renal insufficiency and cardiovascular disease. Prevention is still rooted in lifestyle choices. Existing treatments have proven to be unsatisfactory in many patients with comorbidities. New treatments are available today and on the horizon for tomorrow, which offer a better quality of life for gout sufferers. These include febuxostat, a nonpurine inhibitor of xanthine oxidase with a potentially better combination of efficacy and safety than allopurinol, and investigational inhibitors of URAT-1, an anion exchanger in the proximal tubule that is critical for uric acid homeostasis. New abortive treatments include interleukin-1 antagonists that can cut short the acute attack in 1 to 2 days in persons who cannot take nonsteroidal anti-inflammatory drugs, colchicine or corticosteroids. Lastly, newer formulations of uricase have the ability to dissolve destructive tophi over weeks or months in patients who cannot use currently available hypouricemic agents. Diagnostically, ultrasound and magnetic resonance imaging offer advanced ways to diagnose gout noninvasively, and just as importantly, a way to follow the progress of tophus dissolution. The close association of hyperuricemia with metabolic syndrome, hypertension and renal insufficiency ensures that nephrologists will see increasing numbers of gout-afflicted patients.
doi:10.2147/IJNRD.S6048
PMCID: PMC3108771  PMID: 21694941
hyperuricemia; metabolic syndrome; tophi; colchicine; febuxostat; allopurinol
8.  Effect of Fenofibrate in Combination with Urate Lowering Agents in Patients with Gout 
Background
To assess the efficacy of fenofibrate treatment in combination with urate lowering agents in patients with gout.
Methods
Fourteen male patients with chronic tophaceous or recurrent acute attacks of gout were evaluated in an open-label pilot study of the hypolipidemic agent, fenofibrate (Lipidil Supra® 160 mg/d). Patients were stable on urate lowering agents (allopurinol or benzbromarone) for ≥three months without acute attack for the most recent one month before participating. All patients were being treated with established doses of urate lowering agents without modification throughout the study. Clinical and biochemical assessments including serum uric acid, creatinine, liver function test and fasting serum lipid were measured at (1) baseline (2) after two months of fenofibrate treatment and (3) two months after fenofibrate was withdrawn.
Results
Serum uric acid was lowered by 23% after two months of fenofibrate treatment (6.93±2.16 vs. 5.22±1.16 mg/dL; p=0.016). Triglyceride levels were also reduced after fenofibrate treatment (p=0.001). However, this effect was reversed after the withdrawal (p=0.002) of the drug. Alkaline phosphatase was reduced after fenofibrate treatment (p=0.006), but increased 21% after the withdrawal of the drug (p=0.002). By contrast, serum levels of high density lipoprotein and creatinine were increased 9% (p=0.018) and 12% (p=0.006), respectively; however, both levels were significantly decreased to the baseline levels upon withdrawal of fenofibrate.
Conclusions
Fenofibrate can effectively reduce uric acid levels in addition to its known hypolipidemic effect. Fenofibrate may be used as a potential urate lowering agent in patients with gout, especially in those with coexisting hyperlipidemia.
doi:10.3904/kjim.2006.21.2.89
PMCID: PMC3890742  PMID: 16913436
Fenofibrate; Gout; Hyperuricemia; Hyperlipidemia
9.  SLC2A9 Is a High-Capacity Urate Transporter in Humans 
PLoS Medicine  2008;5(10):e197.
Background
Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man.
Methods and Findings
We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200–500 μM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 μM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case–control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size −0.12 mm Hg, 95% CI −0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size −0.03 mm Hg, 95% CI −0.39 to 0.31, p = 0.82).
Conclusions
This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.
Editors' Summary
Background.
Blood is continually pumped around the human body to deliver the chemicals needed to keep the body's cells alive and to take cellular waste products to the kidneys where they are filtered out of the blood and excreted in the urine. In healthy people, the levels of nutrients and waste products in serum (the liquid part of blood) fall within “normal” ranges but in ill people these levels can be very different. For example, serum uric acid (urate) levels are usually increased in people with gout. In this arthritic condition, uric acid crystallizes in the joints (often those in the big toe) and causes swelling and intense pain. Increased serum urate levels, which are also associated with high blood pressure, diabetes, and several other important conditions, can be caused by eating food that is rich in chemicals called purines (for example, liver, dried beans, and port). The body also converts its own purines into uric acid so genetic variations in the enzymes involved in purine breakdown can alter serum urate levels, as can variations in the rate of urate removal from the body by the kidneys. Urinary urate excretion is controlled by urate transporters, proteins that carry urate into and out of the kidney cells. Uricosuric drugs, which are used to treat gout, reduce serum urate levels by inhibiting a urate transporter that reabsorbs urate from urine.
Why Was This Study Done?
Several urate transporters have already been identified but recently, using an approach called genome-wide association scanning, scientists found that some genetic variants of a human gene called SLC2A9 are more common in people with high serum urate levels than in people with normal levels. SLC2A9 encodes a glucose transporter (a protein that helps to move the sugar glucose through cell membranes) and is highly expressed in the kidney's main urate handling site. Given these facts, could SLC2A9 (the protein made from SLC2A9) be a urate transporter as well as a glucose transporter? In this study, the researchers investigate this possibility and also ask whether genetic variations in SLC2A9 might be responsible for the association between serum urate levels and high blood pressure.
What Did the Researchers Do and Find?
The researchers first expressed SLC2A9 in frog eggs, a type of cell that does not have its own urate transporter. They found that urate rapidly moved into eggs expressing SLC2A9 but not into control eggs, that SLC2A9 transported urate about 50 times faster than glucose, and that glucose stimulated SLC2A9-mediated urate transport. Similarly, overexpression of SLC2A9 in human embryonic kidney cells more than doubled their urate uptake. Conversely, when the researchers used a technique called RNA interference to reduce the expression of mouse SLC2A9 in mouse cells that normally makes this protein, urate transport was reduced. Next, the researchers looked at two small parts of SLC2A9 that vary between individuals (so-called single polynucleotide polymorphisms) in nearly 900 men who had had their serum urate levels and urinary urate excretion rates measured. They found that certain genetic variations at these two sites were associated with increased serum urate levels and decreased urinary urate excretion. Finally, the researchers used a statistical technique called meta-analysis to look for an association between one of the SLC2A9 gene variants and blood pressure. In two separate meta-analyses that together involved more than 20, 000 participants in several studies, there was no association between this gene variant and blood pressure.
What Do These Findings Mean?
Overall, these findings indicate that SLCA9 is a high capacity urate transporter and suggest that this protein plays an important part in controlling serum urate levels. They provide confirmation that common genetic variants in SLC2A9 affect serum urate levels to a marked degree, although they do not show exactly which genetic variant is responsible for increasing serum urate levels. They also provide important new insights into how the kidneys normally handle urate and suggest ways in which this essential process may sometimes go wrong. Thus, these findings could eventually lead to new treatments for gout and possibly for other diseases that are associated with increased serum urate levels.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050197.
The UK National Health Service Direct health encyclopedia provides detailed information for patients about gout
MedlinePlus provides links to many sources of information about gout (in English and Spanish), including “What is gout?”, an easy-to-read guide from the US National Institutes of Arthritis and Musculoskeletal and Skin Diseases
Wikipedia also has pages on gout, uric acid, and SCL2A9 (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The Arthritis Research Campaign also has information on gout
Mark Caulfield and colleagues show that theSLC2A9 gene, which encodes a facilitative glucose transporter, is also a high-capacity urate transporter.
doi:10.1371/journal.pmed.0050197
PMCID: PMC2561076  PMID: 18842065
10.  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
11.  Uric acid and chronic kidney disease: which is chasing which? 
Nephrology Dialysis Transplantation  2013;28(9):2221-2228.
Serum uric acid is commonly elevated in subjects with chronic kidney disease (CKD), but was historically viewed as an issue of limited interest. Recently, uric acid has been resurrected as a potential contributory risk factor in the development and progression of CKD. Most studies documented that an elevated serum uric acid level independently predicts the development of CKD. Raising the uric acid level in rats can induce glomerular hypertension and renal disease as noted by the development of arteriolosclerosis, glomerular injury and tubulointerstitial fibrosis. Pilot studies suggest that lowering plasma uric acid concentrations may slow the progression of renal disease in subjects with CKD. While further clinical trials are necessary, uric acid is emerging as a potentially modifiable risk factor for CKD.
Gout was considered a cause of CKD in the mid-nineteenth century [1], and, prior to the availability of therapies to lower the uric acid level, the development of end-stage renal disease was common in gouty patients. In their large series of gouty subjects Talbott and Terplan found that nearly 100% had variable degrees of CKD at autopsy (arteriolosclerosis, glomerulosclerosis and interstitial fibrosis) [2]. Additional studies showed that during life impaired renal function occurred in half of these subjects [3]. As many of these subjects had urate crystals in their tubules and interstitium, especially in the outer renal medulla, the disease became known as gouty nephropathy. The identity of this condition fell in question as the presence of these crystals may occur in subjects without renal disease; furthermore, the focal location of the crystals could not explain the diffuse renal scarring present. In addition, many subjects with gout also had coexistent conditions such as hypertension and vascular disease, leading some experts to suggest that the renal injury in gout was secondary to these latter conditions rather than to uric acid per se [4]. Indeed, gout was removed from the textbooks as a cause of CKD, and the common association of hyperuricemia with CKD was solely attributed to the retention of serum uric acid that is known to occur as the glomerular filtration rate falls.
Renewed interest in uric acid as a cause of CKD occurred when it was realized that invalid assumptions had been made in the arguments to dismiss uric acid as a risk factor for CKD [5]. The greatest assumption was that the mechanism by which uric acid would cause kidney disease would be via the precipitation as crystals in the kidney, similar to the way it causes gout. However, when laboratory animals with CKD were made hyperuricemic, the renal disease progressed rapidly despite an absence of crystals in the kidney [6]. Since this seminal study, there has been a renewed interest in the potential role uric acid may have in both acute and CKD. We briefly review some of the major advances that have occurred in this field in the last 15 years.
doi:10.1093/ndt/gft029
PMCID: PMC4318947  PMID: 23543594
uric acid; gout; allopurinol; hyperuricemia; chronic kidney disease
12.  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
13.  Efficacy and safety of febuxostat in the treatment of hyperuricemia in stable kidney transplant recipients 
Background
Post-transplant hyperuricemia (PTHU), defined as serum uric acid concentration ≥7.0 mg/dL or need for treatment with allopurinol or benzbromarone, reduces long-term allograft survival in kidney transplant recipients. Febuxostat, a new nonpurine selective xanthine oxidase inhibitor, is well tolerated in patients with moderate renal impairment. However, its efficacy and safety in kidney recipients with PTHU is unclear. We therefore assessed the efficacy and safety of febuxostat in stable kidney transplant recipients with PTHU.
Methods
Of 93 stable adult kidney transplant recipients, 51 were diagnosed with PTHU (PTHU group) and 42 were not (NPTHU group). Of the 51 patients with PTHU, 26 were treated with febuxostat (FX group) and 25 were not (NFX group), at the discretion of each attending physician. One-year changes in serum uric acid concentrations, rates of achievement of target uric acid (<6.0 mg/dL), estimated glomerular filtration rates in allografts, and adverse events were retrospectively analyzed in the FX, NFX, and NPTHU groups.
Results
The FX group showed significantly greater decreases in serum uric acid (−2.0±1.1 mg/dL versus 0.0±0.8 mg/dL per year, P<0.01) and tended to show a higher rate of achieving target uric acid levels (50% versus 24%; odds ratio 3.17 [95% confidence interval 0.96–10.5], P=0.08) than the NFX group. Although baseline allograft estimated glomerular filtration rates tended to be lower in the FX group than in the NFX group (40±14 mL/min/1.73 m2 versus 47±19 mL/min/1.73 m2), changes in allograft estimated glomerular filtration rate were similar (+1.0±4.9 mL/min/1.73 m2 versus −0.2±6.9 mL/min/1.73 m2 per year, P=0.50). None of the patients in the FX group experienced any severe adverse effects, such as pancytopenia or attacks of gout, throughout the entire study period. Nephrologists were more likely than urologists to start febuxostat in kidney transplant recipients with PTHU (69% versus 8%).
Conclusion
Treatment with febuxostat sufficiently lowered uric acid levels without severe adverse effects in stable kidney transplant recipients with PTHU.
doi:10.2147/DDDT.S56597
PMCID: PMC3933431  PMID: 24600205
post-transplant hyperuricemia; febuxostat; uric acid; chronic kidney disease
14.  Veterans Affairs databases are accurate for gout-related health care utilization: a validation study 
Arthritis Research & Therapy  2013;15(6):R224.
Introduction
The aim of this study was to assess the accuracy of Veterans Affairs (VA) databases for gout-related health care utilization.
Methods
This retrospective study utilized VA administrative and clinical databases. A random sample of gout patients with visits (outpatient, inpatient or emergent/urgent care) with or without the diagnosis of gout (International Classification of Diseases, ninth revision, common modification ICD-9-CM code of 274.x or 274.xx) at the Birmingham VA hospital was selected. A blinded abstractor performed a review of VA electronic health records for the documentation of gout or gout-related terms (gouty arthritis, tophaceous gout, tophus/tophi, acute gout, chronic gout, podagra, urate stones, urate or uric acid crystals and so on) in the chief complaint, history of present illness or assessment and plan for the visit; this constituted the gold standard for gout-related utilization. The accuracy of database-derived gout-related claims was assessed by calculating sensitivity, specificity, and positive and negative predictive values (PPV and NPV).
Results
Of 108 potential visits, 85 outpatient, inpatient or urgent care/emergency room visits to a health care provider (85 patients: 84 men and 1 woman with a mean age of 63 years) and retrievable data from medical records constituted the analyzed dataset. Administrative claims for gout-related utilization with ICD-9 code for gout were accurate with a PPV of 86%, specificity of 95%, sensitivity of 86% and NPV of 95%.
Conclusions
VA databases are accurate for gout-related visits. These findings support their use for studies of health services and outcome studies. It remains to be seen if these findings are generalizable to other settings and databases.
doi:10.1186/ar4425
PMCID: PMC3979008  PMID: 24377421
15.  EULAR evidence based recommendations for gout. Part I: Diagnosis. Report of a task force of the standing committee for international clinical studies including therapeutics (ESCISIT) 
Annals of the Rheumatic Diseases  2006;65(10):1301-1311.
Objective
To develop evidence based recommendations for the diagnosis of gout.
Methods
The multidisciplinary guideline development group comprised 19 rheumatologists and one evidence based medicine expert, representing 13 European countries. Ten key propositions regarding diagnosis were generated using a Delphi consensus approach. Research evidence was searched systematically for each proposition. Wherever possible the sensitivity, specificity, likelihood ratio (LR), and incremental cost‐effectiveness ratio were calculated for diagnostic tests. Relative risk and odds ratios were estimated for risk factors and co‐morbidities associated with gout. The quality of evidence was categorised according to the evidence hierarchy. The strength of recommendation (SOR) was assessed using the EULAR visual analogue and ordinal scales.
Results
10 key propositions were generated though three Delphi rounds including diagnostic topics in clinical manifestations, urate crystal identification, biochemical tests, radiographs, and risk factors/co‐morbidities. Urate crystal identification varies according to symptoms and observer skill but is very likely to be positive in symptomatic gout (LR = 567 (95% confidence interval (CI), 35.5 to 9053)). Classic podagra and presence of tophi have the highest clinical diagnostic value for gout (LR = 30.64 (95% CI, 20.51 to 45.77), and LR = 39.95 (21.06 to 75.79), respectively). Hyperuricaemia is a major risk factor for gout and may be a useful diagnostic marker when defined by the normal range of the local population (LR = 9.74 (7.45 to 12.72)), although some gouty patients may have normal serum uric acid concentrations at the time of investigation. Radiographs have little role in diagnosis, though in late or severe gout radiographic changes of asymmetrical swelling (LR = 4.13 (2.97 to 5.74)) and subcortical cysts without erosion (LR = 6.39 (3.00 to 13.57)) may be useful to differentiate chronic gout from other joint conditions. In addition, risk factors (sex, diuretics, purine‐rich foods, alcohol, lead) and co‐morbidities (cardiovascular diseases, hypertension, diabetes, obesity, and chronic renal failure) are associated with gout. SOR for each proposition varied according to both the research evidence and expert opinion.
Conclusions
10 key recommendations for diagnosis of gout were developed using a combination of research based evidence and expert consensus. The evidence for diagnostic tests, risk factors, and co‐morbidities was evaluated and the strength of recommendation was provided.
doi:10.1136/ard.2006.055251
PMCID: PMC1798330  PMID: 16707533
EULAR; guidelines; gout; diagnosis
16.  Allopurinol, Benzbromarone, or a Combination in Treating Patients with Gout: Analysis of a Series of Outpatients 
Objective. To profile a sample of gouty patients treated with allopurinol, benzbromarone, or a combination of these two drugs and to describe the impact of this therapy in reducing uric acid levels. Methods. An observational, transversal study was performed. We evaluated 48 patients diagnosed with gout who were seen at the Outpatient Rheumatology Clinic of the Federal University of Paraná between January 2009 and November 2010. Clinical data, creatinine serum levels, and basal and posttreatment levels of serum urates, transaminases, and bilirubins were recorded. Uric acid levels were measured in a 24-hour urine sample. Patients were divided into three groups: patients given only allopurinol (A), only benzbromarone (B), and both in combined therapy (A + B). Results. The average age of these patients was 56.6 ± 11.4 years, varying from 35 to 81 years. The entire patient group experienced a significant drop in serum urate levels, from 8.5 ± 1.8 mg/dL (0.472 ± 0.1 mmol/L) to 6.7 ± 2.1 mg/dL (0.372 ± 0.116 mmol/L) (P < 0.001), regardless of the prescribed medication. The number of patients taking both drugs whose serum uric acid values fell within normal range (men <7 mg/dL (0.38 mmol/L) and women <6 mg/dL (0.33 mmol/L)) was 85.7% (6/7) while this value for the group taking benzbromarone alone was 75% (3/4) and for the group taking allopurinol alone this number was 51.8% (14/27). Conclusions. The therapeutic combination of benzbromarone and allopurinol significantly decreased serum urate levels in patients with gout when compared to individual use of each of these agents. This finding is especially important in treating patients who cannot control hyperuricemia with monotherapy. Benzbromarone alone or in combination with allopurinol has an important clinical role in controlling hyperuricemia in patients with gout.
doi:10.1155/2014/263720
PMCID: PMC3955622  PMID: 24719620
17.  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
18.  Refractory Gout Attack 
Case Reports in Medicine  2012;2012:657694.
Refractory gout attack is an uncommon problem, since gout flares are usually self-limited. This clinical condition is characterized by serum uric acid higher than 6 mg/Dl or continuous manifestations of recurrent flares, chronic arthritis, and increased tophi. We report in this paper a 69-year-old man with a polyarticular and protracted gout attack, despite usual treatment and low urate sera levels. In order to manage this problem, we reviewed gout pathophysiology and developed a therapeutic solution based on benzbromarone pharmacokinetics. We also review herein new options for gout treatment that could be used in similar cases.
doi:10.1155/2012/657694
PMCID: PMC3523317  PMID: 23304159
19.  Symptomatic hypercalcemia in a patient with chronic tophaceous gout: a case report 
Cases Journal  2008;1:72.
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.
doi:10.1186/1757-1626-1-72
PMCID: PMC2518544  PMID: 18687121
20.  A National Survey of Veterans Affairs Rheumatologists for Relevance of Quality of Care Indicators for Gout Management 
Arthritis care & research  2010;62(9):1306-1311.
Objective
To determine the relevance of current gout Quality indicators (QIs).
Methods
Members of the Veterans Affairs Rheumatology Consortium were invited to participate in an online survey and provide opinions (rank 0–10) regarding existing gout QIs. Opinions sought on each QI were 1) relevance to United States Veterans, 2) likelihood to improve gout care, and 3) ease of electronic capture. Participants were also asked to rank their top 3 gout QIs.
Results
Participating VA rheumatologists were mainly male, of mean age 51.3 years and experienced in the management of gout. All 10 gout QIs were considered relevant, with a score of 8.2 of higher. The initiation of urate lowering therapy, monitoring of urate levels after initiation of urate lowering therapy, and treatment of acute gout with anti-inflammatory agents scored the highest with regards to likely to improving gout care, with the first 2 QIs also felt to be most relevant. Adjustment of initial allopurinol dosing in patients with renal impairment and in those receiving concurrent azathioprine/6-mercaptopurine were perceived as the QIs most amenable to electronic capture. The top ranked QIs were initiation of urate-lowering therapy with frequent gout attacks, serum urate monitoring after initiation of urate lowering therapy and adjustment of initial allopurinol dose to renal function.
Conclusions
In a national survey of VA rheumatologists, most gout QIs were thought to be highly relevant. QIs related to initiation of urate lowering therapy, serum urate monitoring, and initial dosing of allopurinol were ranked the most important for veterans with gout.
doi:10.1002/acr.20192
PMCID: PMC2943024  PMID: 20235197
Quality Indicators; Gout; Veterans Affairs
21.  Urate Lowering Therapy with Febuxostat in Daily Practice—A Multicentre, Open-Label, Prospective Observational Study 
Introduction. Febuxostat, a novel xanthine oxidase inhibitor for the treatment of symptomatic hyperuricemia, showed superiority over allopurinol in the reduction of serum uric acid levels in pivotal studies. Whether this holds true the FORTE (febuxostat in the oral urate lowering treatment: effectiveness and safety) study was conducted to evaluate treatment with febuxostat under daily practice conditions. Materials/Methods. The multicentre, open-label, and prospective observational study was conducted in 1,690 German medical practices from 9/2010 to 5/2011. Safety and efficacy data were assessed at baseline and week 4. Results. Data from 5,592 gout patients (72.6% male, mean age 63.7 years) were collected. Under urate lowering treatment with febuxostat mean serum uric acid levels decreased significantly from 8.9 ± 1.9 mg/dL (534.0 ± 114.6 μmol/L) at baseline to 6.2 ± 2.5 mg/dL (372.0 ± 150.0 μmol/L) at week 4. 67% which reached the mean uric acid target (6.1 ± 1.0 mg/dL [366.0 ± 59.4 μmol/L]). Only 43.1% of patients received concomitant flare prophylaxis. A total of 178 adverse events (mostly gout flares) were reported in 152 patients (2.6%). Conclusion. Febuxostat lowers serum uric acid levels effectively in routine clinical practice. Overall, treatment with febuxostat in both available dosages (80 mg/120 mg) was safe and well tolerated.
doi:10.1155/2014/123105
PMCID: PMC4167949  PMID: 25276138
22.  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
23.  Gout in the Hmong in the United States: A Retrospective Study 
Objective
To compare characteristics of gout in Hmong patients versus Caucasians and examine if Hmong ethnicity is associated with risk of tophaceous gout.
Methods
A retrospective chart review of Hmong and Caucasian patients with gout in a large health care system (HealthPartners) in St Paul, Minnesota, from 1/2001 to 3/2008, to compare clinical characteristics and risk factors for gout. Multivariable-adjusted hierarchical logistic regressions examined the association of Hmong ethnicity with risk of tophaceous gout, adjusting for age, sex, hypertension, diuretic use and kidney function.
Results
The analytic dataset consisted of 89 Hmong patients and 84 Caucasian controls, all of whom had ethnicity confirmed, an ICD-9 code for gout and had at least two physician-documented diagnoses of gout. The Hmong group was younger (58.3 vs. 66.3 y, p = 0.04), had an earlier onset of symptoms (37.4 vs. 55.0 y, p<0.001) and higher mean serum uric acid levels during follow-up (9.1 vs. 7.6 mg/dl, p ≤ 0.001). Hmong had higher rates of tophaceous gout (31.5% vs. 10.7%, p = 0.001), including hand tophi (21.3% vs. 3.6%, p < 0.001). In multivariable analyses that adjusted for age, sex, hypertension, diuretic use and kidney function, Hmong ethnicity was significantly associated with risk of tophaceous gout, with odds ratio 4.3 (95% CI 1.5, 12.2).
Conclusion
Hmong patients have an earlier onset of gout symptoms. Hmong race is an independent risk factor for tophaceous gout. Future studies need to examine whether genetic or other co-morbid factors predict this higher risk of more severe gout in Hmong.
doi:10.1097/RHU.0b013e3181eeb487
PMCID: PMC3859302  PMID: 20808166
Hmong; Gouty Arthritis; Tophaceous Gout
24.  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
25.  Tophi and frequent gout flares are associated with impairments to quality of life, productivity, and increased healthcare resource use: Results from a cross-sectional survey 
Background
The prevalence of gout is increasing, and most research on the associated burden has focused on serum urate (sUA) levels. The present study quantifies the impact of the presence of tophi and frequency of acute gout attacks on health-related quality of life (HRQOL), productivity, and healthcare resource utilization.
Methods
Patients with self-reported gout (n = 620; 338 in US and 282 across France, Germany, and UK) were contacted based on inclusion in the 2010 US and EU National Health and Wellness Surveys (Kantar Health) and the Lightspeed Research ailment panel. Respondents were categorized into mutually-exclusive groups based on number of gout flares experienced in the past 12 months (0/don’t recall, 1–2, 3, 4–5, 6+), current presence of tophi (none, 1+, or not sure), and sUA level awareness (yes, no). HRQOL (SF-12v2), healthcare provider visits in the last 6 months, and work productivity and activity impairment (WPAI) were compared across groups.
Results
Most patients were males, mean age of 61 years, who reported experiencing at least one acute gout flare in the past 12 months, and 12.3% (n = 76) reported presence of tophi. Among the 27.7% (n = 172) of patients who were aware of their sUA levels, higher sUA was associated with more flares and tophi. Decreased HRQOL was associated with more frequent flares and presence of tophi. In multivariable models predicting outcomes based on presence of tophi and number of flares, both flares (≥4) and tophi (≥1) were associated with HRQOL decrements on physical and mental component summary scores and health utilities (all p < 0.05), after adjustment for age, gender, and time since diagnosis. Flares were also associated with greater activity impairment.
Conclusions
Impairments associated with gout flares and presence of tophi, across patients in the US and EU, underscore the importance of effective management of this potentially curable condition.
doi:10.1186/1477-7525-10-117
PMCID: PMC3499162  PMID: 22999027
Gout; Quality of life; Productivity; Refractory chronic gout

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