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1.  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
2.  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
3.  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
4.  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
5.  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
6.  Allopurinol treatment and its effect on renal function in gout: a controlled study. 
Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys.
PMCID: PMC1000865  PMID: 7039523
7.  Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study 
Heart  2002;87(3):229-234.
Objective: To examine whether allopurinol is associated with any alteration in mortality and hospitalisations in patients with chronic heart failure (CHF). This hypothesis is based on previous data that a high urate concentration is independently associated with mortality with a risk ratio of 4.23 in CHF.
Design: Retrospective cohort study.
Setting: Medicines Monitoring Unit, Ninewells Hospital, Dundee, UK.
Patients: 1760 CHF patients divided into four groups: those on no allopurinol, those on long term low dose allopurinol, those on short term low dose allopurinol, and those on long term high dose allopurinol.
Main outcome measures: Total mortality, cardiovascular mortality, cardiovascular hospitalisations, cardiovascular mortality or hospitalisations.
Results: Long term low dose allopurinol was associated with a significant worsening in mortality over those who never received allopurinol (relative risk 2.04, 95% confidence interval (CI) 1.48 to 2.81). This may be because low dose allopurinol is insufficient to negate the adverse effect of a high urate concentration. However, long term high dose (≥ 300 mg/day) allopurinol was associated with a significantly better mortality than longstanding low dose allopurinol (relative risk 0.59, 95% CI 0.37 to 0.95). This may mean that high dose allopurinol can fully negate the adverse effect of urate and return the mortality to normal.
Conclusions: Long term high dose allopurinol may be associated with a better mortality than long term low dose allopurinol in patients with CHF because of a dose related beneficial effect of allopurinol against the well described adverse effect of urate. Further work is required to substantiate or refute this finding.
PMCID: PMC1767024  PMID: 11847159
uric acid; xanthine oxidase; allopurinol; mortality; chronic heart failure
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  Febuxostat for treating chronic gout 
Background
Gout is the most common inflammatory arthritis in men over 40 years and has an increasing prevalence among postmenopausal women. Lowering serum uric acid levels remains one of the primary goals in the treatment of chronic gout. In clinical trials, febuxostat has been shown to be effective in lowering serum uric acid levels to < 6.0 mg/dL.
Objectives
To evaluate the benefits and harms of febuxostat for chronic gout.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from inception to July 2011. The ClinicalTrials.gov website was searched for references to trials of febuxostat. Our search did not include any restrictions.
Selection criteria
Two authors independently reviewed the search results and disagreements were resolved by discussion. We included any controlled clinical trial or open label trial (OLT) using febuxostat at any dose.
Data collection and analysis
Data and risk of bias were independently extracted by two authors and summarised in a meta-analysis. Continuous data were expressed as mean difference and dichotomous data as risk ratio (RR).
Main results
Four randomised trials and two OLTs with 3978 patients were included. Risk of bias differed by outcome, ranging from low to high risk of bias. Included studies failed to report on five to six of the nine outcome measures recommended by OMERACT. Patients taking febuxostat 120 mg and 240 mg reported more frequent gout flares than in the placebo group at 4 to 28 weeks (RR 1.7; 95% CI 1.3 to 2.3, and RR 2.6; 95% CI 1.8 to 3.7 respectively). No statistically significant differences were observed at 40 mg and 80 mg. Compared to placebo, patients on febuxostat 40 mg were 40.1 times more likely to achieve serum uric acid levels < 6.0 mg/dL at 4 weeks (95% CI 2.5 to 639), with an absolute treatment benefit of 56% (95% CI 37% to 71%). For febuxostat 80 mg and 120 mg, patients were 68.9 and 80.7 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit compared to placebo (95% CI 13.8 to 343.9, 95% CI 16.0 to 405.5), respectively; with an absolute treatment benefit of 75% and 87% (95% CI 68 to 80% and 81 to 91%), respectively. Total discontinuation rates were significantly higher in the febuxostat 80 mg group compared to placebo (RR 1.4; 95% CI 1.0 to 2.0, absolute risk increase 11%; 95% CI 3 to 19%). No other differences were observed.
When comparing allopurinol to febuxostat at 24 to 52 weeks, the number of gout flares was not significantly different between the two groups, except for febuxostat 240 mg (RR 2.3; 95% CI 1.7 to 3.0). Patients on febuxostat 40 mg showed no statistically significant differences in benefits or harms. Patients on febuxostat 80 mg and 120 mg were 1.8 and 2.2 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit (95% CI 1.6 to 2.2, 95% CI 1.9 to 2.5) with an absolute treatment benefit of 29% and 44% (95% CI 25% to 33%, 95% CI 38% to 50%), respectively, at 24 to 52 weeks. Total discontinuation rates were higher for febuxostat 80 mg and 120 mg compared to allopurinol (RR 1.5; 95% CI 1.2 to 1.8, absolute risk increase 11%; 95% CI 6% to 16%; and RR 2.6; 95% CI 2.0 to 3.3, absolute risk increase 20%; 95% CI 3% to 14%, respectively). Discontinuations due to adverse events were similar across groups. Total adverse events were lower for febuxostat 80 mg and 120 mg compared with allopurinol (RR 0.93; 95% CI 0.87 to 0.99, absolute risk increase 6%; 95% CI 0.7% to 11%; and RR 0.90; 95% CI 0.84 to 0.96, absolute risk increase 8%; 95% CI 3% to 13%, respectively). No other relevant differences were noted.
After 3 years of follow-up there were no statistically significant differences regarding effectiveness and harms between febuxostat 80 mg or 120 mg and allopurinol groups (adverse event rate per 100 patient-years 227, 216, and 246, respectively).
Authors’ conclusions
Although the incidence of gout flares requiring treatment may be increased in patients taking febuxostat compared to placebo or allopurinol during early treatment, no such increase in gout flares was observed in the long-term follow-up study when compared to allopurinol. Febuxostat at any dose was shown to be beneficial in achieving serum uric acid levels < 6.0 mg/dL and reducing serum uric acid levels in the period from baseline to final visit when compared to placebo and to allopurinol. However, the grade of evidence ranged from low to high, which indicates that further research is needed.
doi:10.1002/14651858.CD008653.pub2
PMCID: PMC4058893  PMID: 23152264
Allopurinol [adverse effects, therapeutic use]; Chronic Disease; Gout [blood*drug therapy]; Gout Suppressants [adverse effects*therapeutic use]; Hyperuricemia [drug therapy]; Randomized Controlled Trials as Topic; Thiazoles [adverse effects*therapeutic use]; Female; Humans; Male
16.  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
17.  Impact of allopurinol use on urate concentration and cardiovascular outcome 
AIMS
To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes.
METHODS
A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined.
RESULTS
Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl−1. Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95–1.26] and the non-ULT group with urate >6 mg dl−1 (adjusted HR 1.07, 95% CI 0.89–1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9–86.1) per 1000 person years for the 100 mg group, 69.7 (49.6–89.8) for the 200 mg group and 47.6 (38.4–56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50–0.94) and mortality (adjusted HR 0.75, 95% CI 0.59–0.94).
CONCLUSIONS
Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.
doi:10.1111/j.1365-2125.2010.03887.x
PMCID: PMC3080649  PMID: 21395653
allopurinol; cardiovascular event; mortality; urate
18.  Impact of allopurinol use on urate concentration and cardiovascular outcome 
AIMS
To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes.
METHODS
A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined.
RESULTS
Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl−1. Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95–1.26] and the non-ULT group with urate >6 mg dl−1 (adjusted HR 1.07, 95% CI 0.89–1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9–86.1) per 1000 person years for the 100 mg group, 69.7 (49.6–89.8) for the 200 mg group and 47.6 (38.4–56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50–0.94) and mortality (adjusted HR 0.75, 95% CI 0.59–0.94).
CONCLUSIONS
Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.
doi:10.1111/j.1365-2125.2010.03887.x
PMCID: PMC3080649  PMID: 21395653
allopurinol; cardiovascular event; mortality; urate
19.  Allopurinol Therapy in Gout Patients Does Not Associate with Beneficial Cardiovascular Outcomes: A Population-Based Matched-Cohort Study 
PLoS ONE  2014;9(6):e99102.
Introduction
Previous studies have shown an association between gout and/or hyperuricemia and a subsequent increase in cardiovascular disease (CVD) outcomes. Allopurinol reduces vascular oxidative stress, ameliorates inflammatory state, improves endothelial function, and prevents atherosclerosis progression. Accordingly, we tested the hypothesis that a positive association between allopurinol therapy in gout patients and future cardiovascular outcomes is present using a population-based matched-cohort study design.
Methods
Patients aged ≥40 years with newly diagnosed gout having no pre-existing severe form of CVD were separated into allopurinol (n = 2483) and non-allopurinol (n = 2483) groups after matching for age, gender, index date, diabetes mellitus, hypertension, hyperlipidemia, and atrial fibrillation. The two groups were also balanced in terms of uric acid nephrolithiasis, acute kidney injury, hepatitis, and Charlson comorbidity index.
Results
With a median follow-up time of 5.25 years, the allopurinol group had a modest increase in cardiovascular risk [relative risk, 1.20; 95% confidence interval (CI), 1.08–1.34]. A Cox proportional hazard model adjusted for chronic kidney disease, uremia, and gastric ulcer gave a hazard ratio (HR) for cardiovascular outcomes of 1.25 (95% CI, 1.10–1.41) in gout patients receiving allopurinol compared with the non-allopurinol group. In further analysis of patients receiving urate-lowering therapy, the uricosuric agent group (n = 1713) had an adjusted HR of 0.83 (0.73–0.95) for cardiovascular events compared with the allopurinol group.
Conclusions
The current population-based matched-cohort study did not support the association between allopurinol therapy in gout patients with normal risk for cardiovascular sequels and beneficial future cardiovascular outcomes. Several important risk factors for cardiovascular disease, such as smoking, alcohol consumption, body mass index, blood pressure were not obtainable in the current retrospective cohort study, thus could potentially bias the effect estimate.
doi:10.1371/journal.pone.0099102
PMCID: PMC4045898  PMID: 24897240
20.  Lack of change in urate deposition by dual-energy computed tomography among clinically stable patients with long-standing tophaceous gout: a prospective longitudinal study 
Arthritis Research & Therapy  2013;15(5):R160.
Introduction
Dual-energy computed tomography (DECT) has potential for monitoring urate deposition in patients with gout. The aim of this prospective longitudinal study was to analyse measurement error of DECT urate volume measurement in clinically stable patients with tophaceous gout.
Methods
Seventy-three patients with tophaceous gout on stable therapy attended study visits at baseline and twelve months. All patients had a comprehensive clinical assessment including serum urate testing and DECT scanning of both feet. Two readers analysed the DECT scans for the total urate volume in both feet. Analysis included inter-reader intraclass correlation coefficients (ICCs) and limits of agreement, and calculation of the smallest detectable change.
Results
Mean (standard deviation) serum urate concentration over the study period was 0.38 (0.09) mmol/L. Urate-lowering therapy was prescribed in 70 (96%) patients. The median (interquartile range) baseline DECT urate volume was 0.49 (0.16, 2.18) cm3, and change in DECT urate volume was -0.01 (-0.40, 0.28) cm3. Inter-reader ICCs were 1.00 for baseline DECT volumes and 0.93 for change values. Inter-reader bias (standard deviation) for baseline volumes was -0.18 (0.63) cm3 and for change was -0.10 (0.93) cm3. The smallest detectable change was 0.91 cm3. There were 47 (64%) patients with baseline DECT urate volumes <0.91 cm3. Higher serum urate concentrations were observed in patients with increased DECT urate volumes above the smallest detectable change (P = 0.006). However, a relationship between changes in DECT urate volumes and serum urate concentrations was not observed in the entire group.
Conclusions
In patients with tophaceous gout on stable conventional urate-lowering therapy the measurement error for DECT urate volume assessment is substantially greater than the median baseline DECT volume. Analysis of patients commencing or intensifying urate-lowering therapy should clarify the optimal use of DECT as a potential outcome measure in studies of chronic gout.
doi:10.1186/ar4343
PMCID: PMC3978645  PMID: 24286500
21.  Prescription and dosing of urate-lowering therapy, rather than patient behaviours, are the key modifiable factors associated with targeting serum urate in gout 
Background
Long term serum urate (SU) lowering to a target of <0.36 mmol/l (6 mg/dl) is recommended for effective gout management. However, many studies have reported low achievement of SU targets. The aim of this cross-sectional study was to examine the clinical and psychological factors associated with SU targets in patients with gout.
Methods
Patients with gout for <10 years were recruited from primary and secondary care settings. SU target was defined as SU concentration <0.36 mmol/L at the time of the study visit. Both clinical and psychological factors associated with SU target were analysed. The relationship between SU target and measures of gout activity such as flare frequency, tophi, work absences, and Health Assessment Questionnaire-II was also analysed.
Results
Of the 273 patients enrolled into the study, 89 (32.6%) had SU concentration <0.36 mmol/L. Urate-lowering therapy (ULT) use was strongly associated with SU target (p < 0.001). In those patients prescribed ULT (n = 181), allopurinol dose, patient confidence to keep SU under control, female sex, and ethnicity were independently associated with SU target. Other patient psychological measures and health-related behaviours, including adherence scores, were not independently associated with SU target in those taking ULT. Creatinine clearance, diuretic use, age, and body mass index were not associated with SU target. Patients at SU target reported lower gout flare frequency, compared with those not at target (p = 0.03).
Conclusions
ULT prescription and dosing are key modifiable factors associated with achieving SU target. These data support interventions focusing on improved use of ULT to optimise outcomes in patients with gout.
doi:10.1186/1471-2474-13-174
PMCID: PMC3493372  PMID: 22978848
Gout; Urate; Target; Allopurinol
22.  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
23.  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
24.  The Dynamics of Chronic Gout Treatment: medication gaps and return to therapy 
Objective
To identify gaps in therapy with urate-lowering drugs for the treatment of gout as well as factors associated with resuming therapy.
Methods
We identified persons from two integrated delivery systems 18 years or older with a diagnosis of gout who initiated use of a urate-lowering drug from January 1, 2000 through June 30, 2006 and who had a gap in therapy. A gap was defined as a period of over 60 days after the completion of one prescription in which no refill for a urate-lowering drug was obtained. Survival curves were used to assess return to therapy of urate-lowering drugs. Cox proportional hazards analysis estimated the association between covariates and return to therapy.
Results
There were 4,166 new users of urate-lowering drugs (97% received allopurinol) of whom 2,929 (70%) had a gap in therapy. Among those with a gap, in 75% it occurred in the first year of therapy. Fifty percent of patients with a gap returned to therapy within 8 months, and by 4 years it was 75%. Age 45 to 74 (<45 referent) and greater duration of urate-lowering drug use prior to the gap was associated with resuming treatment within one year. In contrast, receipt of NSAIDs or glucocorticoids in the year prior to the gap was associated with a reduced likelihood of resuming therapy.
Conclusions
The majority of gout patients with gaps in urate-lowering drug use returned to treatment. More investigation is needed to better understand why patients may go for months without refilling prescriptions given the clinical consequences of nonadherence.
doi:10.1016/j.amjmed.2009.05.026
PMCID: PMC2813203  PMID: 20102992
persistence; adherence; compliance; gout; urate lowering drugs
25.  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

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