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Urate-lowering therapy for asymptomatic hyperuricaemia: A need for caution
Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]
Contents lists available at ScienceDirect
Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Urate-lowering therapy for asymptomatic hyperuricaemia: A need for caution☆ Lisa Stamp, FRACP, PhDa,n, Nicola Dalbeth, FRACP, MDb a b
Department of Medicine, University of Otago, Christchurch, 2 Riccarton Ave, P.O. Box 4345, Christchurch, New Zealand Department of Medicine, University of Auckland, Auckland, New Zealand
a r t i c l e in fo
Keywords: Hyperuricaemia Asymptomatic Urate-lowering therapy
a b s t r a c t Objective: The observed associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease are receiving increasing interest. The potential role of urate-lowering therapy in the management of these “non-gout diseases” has been raised, and in some countries it is already recommended. However, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia, much remains unknown about the causal role of urate in these “non-gout diseases” and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is potential for serious adverse effects associated with urate-lowering therapies with recent evidence suggesting that asymptomatic hyperuricaemia may be an independent risk factor for the potentially fatal allopurinol hypersensitivity syndrome. Methods: Pubmed was searched in January 2016 using the search term “asymptomatic hyperuricaemia”. Results and Conclusions: Herein, we discuss the issues related to treating asymptomatic hyperuricaemia, which at present seems premature. & 2016 Elsevier Inc. All rights reserved.
Introduction The management of asymptomatic hyperuricaemia has been debated in the medical literature since the 1970s with reported benefits focusing on prevention of gout, urolithiasis or uric acid nephropathy [1,2]. While the associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease have also been recognised for some time, there has been a renewed interest in these relationships and the potential role of urate-lowering therapy in the management of these “non-gout diseases.” This has led to renewed interest in whether individuals with asymptomatic hyperuricaemia should be treated with urate-lowering therapy [3]. Indeed, in some countries, the treatment of asymptomatic hyperuricaemia is recommended [4]. However, much remains unknown about the causal role of urate in these “non-gout diseases,” and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia,
and there is potential for serious adverse effects with uratelowering therapies. The aim of this review is to outline the issues and evidence in regard to the use of urate-lowering therapy for treatment of asymptomatic hyperuricaemia. PubMed was searched in January 2016 using the search term “asymptomatic hyperuricaemia.”
Definition of hyperuricaemia There is currently no consensus on the definition of hyperuricaemia. It can be defined in several ways: according to population values, pathophysiological cut-point or levels associated with disease risk (Table 1). The definition is particularly important when considering treating asymptomatic hyperuricaemia and needs to be considered separately for gout and for “non-gout diseases.” Definition of “asymptomatic hyperuricaemia” with respect to gout and symptomatic monosodium urate crystal deposition
☆ L.K.S. has received grant funds from Ardea Biosciences, outside the current work. N.D. has received consulting fees, speaker fees or grants from the following companies: Takeda, Menarini, Teijin, Pfizer, Crealta, Cymabay, Fonterra, Ardea Biosciences and AstraZeneca, outside the submitted work. n Corresponding author. E-mail address: [email protected] (L. Stamp).
http://dx.doi.org/10.1016/j.semarthrit.2016.07.015 0049-0172/& 2016 Elsevier Inc. All rights reserved.
It is important to note that while the risk of developing gout increases with rising serum urate concentrations, not all people with even very high urate concentrations will develop gout. For example, in the Normative Aging Study, only 22% individuals with
L. Stamp, N. Dalbeth / Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]
2
Table 1 Potential definitions for hyperuricaemia (Adapted with permission from Bardin and Richette [5]) Definition Statistical/laboratory-based definition Physiological definition Based on risk of developing disease Based on therapeutic target for disease treatment
Problems
Serum urate 4 two standard deviations above the mean for the Variation based on ethnicity, age and time healthy population Differences between men and women Based on the in vivo saturation point of urate when Altered by temperature and pH monosodium urate crystals may develop Altered by cartilage matrix proteins Unknown Risk of gout increases with the degree of hyperuricaemia but not all with hyperuricaemia develop symptomatic gout May differ between conditions Established for gout o6 mg/dl (0.36 mmol/l) for all patients, May differ between conditions o5 mg/dl (0.30 mmol/l) for severe disease Unknown for “non-gout diseases” Need large long-term clinical trials to establish therapeutic targets for both gout and “non-gout diseases”
very high serum urate concentrations ( Z9 mg/dl, 0.54 mmol/l) developed symptomatic gout over a 5-year period [6]. For people with lower urate concentrations (but still above the pathophysiological and population-based thresholds for definition of hyperuricaemia), the risk of developing symptomatic gout was even lower; for example, for those with serum urate 7–7.9 mg/dl (0.42– 0.47 mmol/l), 2% developed symptomatic gout over 5 years, and for those with serum urate 8–8.9 mg/dl (0.48–0.53 mmol/l), 4.1% developed symptomatic gout over 5 years [6]. Thus, while elevated urate concentration is a critical risk factor for the development of gout, it alone is insufficient to cause gout. There are a number of other risk factors for the development of gout with complex interactions between these variables (Fig.). Hyperuricaemia is the central risk factor symptomatic for developing gout. In people with hyperuricaemia, other factors such as alcohol consumption, diuretic use and increase in BMI may further increase the risk of developing gout [7]. Accurate prediction of an individual with asymptomatic hyperuricaemia developing gout is currently not possible, and the development of a clinical risk score for future assessment of gout, such as is used in cardiovascular disease, which includes degree of hyperuricaemia in conjunction with clinical and laboratory variables may be helpful in this regard. Asymptomatic urate crystal deposition can be non-invasively recognised with new advanced imaging techniques such as dualenergy CT (DECT) and high-resolution ultrasound [8–11]. Both microscopic and advanced imaging studies clearly indicate that in some asymptomatic individuals with hyperuricaemia, deposition of monosodium urate crystals can occur without the associated inflammatory response that is responsible for the clinical signs and symptoms of gout. It is unknown what proportion of these individuals with asymptomatic monosodium urate crystal deposition will progress to symptomatic gout.
Medicaons Diurecs Calcineurin inhibitors (cyclopsorin, tacrolimus) Pyrazinamide
Other Increasing age Chronic kidney disease BMI Hypertension Hyperlipidaemia Menopause
Hyperuricaemia and gout Genec factors Gender Ethnicity SLC2A9 ABCG2 Genec variants in other urate transporters
Dietary factors Purine rich food (red meat, seafood) Alcohol (beer, spirits) Sugar-sweetened beverages
Fig. Variables associated with risk of hyperuricaemia and gout.
Definition of asymptomatic hyperuricaemia with respect to “non-gout diseases” A number of conditions have been associated with hyperuricaemia including hypertension, cardiovascular disease and chronic kidney disease. We need to consider how these “associations” are incorporated into the definition of asymptomatic hyperuricaemia or whether they actually represent symptomatic hyperuricaemia. This distinction is important as it might alter whether urate-lowering therapy should be considered. Conceptually, if urate has a pathogenic role in these conditions then it could be argued that they represent symptomatic hyperuricaemia. However, the causal link between urate and these conditions is controversial. Many prospective observational studies have shown that elevated serum urate concentrations are associated with development of hypertension, cardiovascular disease and chronic kidney disease. For example, in a meta-analysis of 25 observational studies examining the role of hyperuricaemia on incident hypertension, hyperuricaemia was associated with development of hypertension (unadjusted relative risk ¼ 1.73; 95% CI: 1.46–2.06 and adjusted relative risk ¼ 1.48; 95% CI: 1.33–1.65) [12]. In a meta-analysis of 26 observational studies, elevated serum urate was associated with increased risk of coronary heart disease incidence (unadjusted relative risk ¼ 1.34; 95% CI: 1.19–1.49 and pooled relative risk ¼ 1.09; 95% CI: 1.03–1.16) and coronary heart disease mortality (unadjusted relative risk ¼ 1.46; 95% CI: 1.20– 1.73 and pooled relative risk ¼ 1.16; 95% CI: 1.01–1.30) [13]. Similar findings have been observed with stroke incidence (relative risk ¼ 1.41; 95% CI: 1.05–1.76) and stroke mortality (relative risk ¼ 1.36; 95% CI: 1.03–1.69) in a meta-analysis of six observational studies [14]. In a meta-analysis of 11 observational studies examining cardiovascular and all-cause mortality, elevated serum urate concentration was associated with increased risk of all-cause mortality (relative risk ¼ 1.24; 95% CI: 1.09–1.42) and cardiovascular mortality (relative risk ¼ 1.37; 95% CI: 1.19–1.57) [15]. In a meta-analysis of 13 observational studies, hyperuricaemia was associated with development of chronic kidney disease in patients with normal renal function (summary odds ratio ¼ 2.35; 95% CI: 1.59–3.46) [16]. A key limitation of many of the observational studies examining the role of urate on “non-gout diseases” is that different definitions of hyperuricaemia have been used (often based on categories of serum urate within the study population rather than a specific value or threshold), so it is unclear whether there is a specific cut-point that is associated with increased risk of disease. However, it seems apparent from most observational studies that serum urate concentrations below the level associated with gout risk are associated with development of these “non-gout diseases.” These findings have important implications when considering the threshold for treatment of asymptomatic hyperuricaemia.
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Although the observational data are relatively consistent over many studies, it is unclear whether urate is causal or whether the observed associations are due to unmeasured (or inadequately adjusted) confounders. Mendelian randomisation is an analysis method that uses genetic data to examine causation in the setting of an association that is potentially complicated by confounding. A large and comprehensive Mendelian randomisation analysis has demonstrated the validity of this approach for urate, showing that serum urate is causal for the development of gout, but failing to demonstrate a causal relationship between urate and blood pressure, coronary heart disease, ischaemic stroke, heart failure or markers of kidney function [17]. Other Mendelian randomisation studies have also failed to show a causal relationship between urate and hypertension, coronary artery disease or chronic kidney disease [18–20]. These data raise major uncertainty about the therapeutic benefit of urate-lowering therapy for prevention or treatment of “non-gout diseases” associated with hyperuricaemia.
Potential benefits and risks of urate-lowering therapy Potential benefits and risks of urate-lowering therapy in people with symptomatic gout and asymptomatic monosodium urate crystal deposition In individuals with symptomatic gout, there is a clear indication for urate-lowering therapy. Symptomatic gout most often presents as acute gout flares. Advanced disease with tophi, joint damage and chronic gouty arthropathy typically presents many years after the initial flare, but occasionally occurs early in the symptomatic disease course. The symptoms of gout such as acute flares and tophi are a direct consequence of monosodium urate crystal deposition and the subsequent immune response to these crystals. The rationale for urate-lowering therapy in individuals with symptomatic gout is based on lowering the urate sufficiently to allow dissolution of monosodium urate crystals. Monosodium urate crystals form in vitro when serum urate super-saturation concentrations are reached, approximately 6.8 mg/dl (0.41 mmol/ l) at 371C and 6.0 mg/dl (0.36 mmol/l) at 351C. Previous studies have shown that sustained reduction in serum urate to o 6.0 mg/ dl (0.36 mmol/l) results in a dissolution of monosodium urate crystals, reduction and eventually cessation of gout flares and resolution of tophi [21,22]. In contrast, untreated gout can lead to progressive monosodium urate crystal deposition, development of joint erosion, chronic gouty arthritis and tophi. Thus, there are clear benefits to urate-lowering therapy. As with all medication, there are risks of adverse effects with urate-lowering therapies. Each therapeutic option has a unique side effect profile (Table 2). Of particular concern has been the severe adverse reactions such as allopurinol hypersensitivity syndrome (AHS). Whilst these severe adverse events are rare, they can be fatal. The risk of AHS can be minimised by screening for HLA-B*5801 in high-risk populations (such as people of Han
Chinese and Korean ancestry), and using alternative uratelowering agents in HLA-B*5801 carriers [23]. Starting allopurinol at low dose (such as a daily dose of 1.5 mg/unit eGFR) may also reduce the risk of AHS [24]. The newer xanthine oxidase inhibitor febuxostat can be associated with hepatotoxicity and hypersensitivity reactions albeit rarely. On balance, given the rarity of these severe adverse reactions, the benefits of urate-lowering therapy in individuals with symptomatic disease are thought to outweigh the potential risks. For individuals with hyperuricaemia and asymptomatic monosodium urate crystal deposition, the rationale for treatment is less clear. Asymptomatic crystal deposition could be considered sufficient evidence of urate deposition disease or a significant predictor of future symptomatic gout, thus warranting urate-lowering therapy despite the absence of symptoms. It is reasonable to assume that urate-lowering therapy will result in dissolution of the monosodium urate crystal deposits, and therefore prevention of symptomatic disease in the future. However, the prognostic importance of asymptomatic monosodium urate crystal deposition is unclear; specifically it is unknown what proportion of these individuals will develop symptomatic gout, and without this information, it is difficult to accurately assess the risk–benefit ratio of therapy.
Potential benefits and risks of urate-lowering therapy in individuals with “non-gout diseases” associated with hyperuricaemia The observed association of hyperuricaemia with hypertension, cardiovascular disease and chronic kidney disease has led to the suggestion that urate-lowering therapy should be used in the management of these conditions. A number of small clinical trials have examined the effects of urate-lowering therapy in hypertension, cardiovascular disease and chronic kidney disease in people without gout (Table 3). The majority of studies have examined the effects of the xanthine oxidase inhibitors such as allopurinol or febuxostat. Few studies have examined the effects on blood pressure specifically (Table 3). A meta-analysis in 2013 reported on 10 clinical studies with a total of 738 individuals [25]. All studies used allopurinol as the urate-lowering therapy. In subjects who received allopurinol, the mean decrease in systolic blood pressure was 3.3 mmHg (95% CI: 1.4–5.3 mmHg) and mean decrease in diastolic blood pressure was 1.3 mmHg (95% CI: 0.1–2.5 mmHg) compared to placebo [25]. These studies of hypertension have also highlighted that the benefits of urate lowering may be restricted to specific populations. For example, studies examining the effects of urate-lowering therapy in hypertensive adults have not shown a consistent benefit while the two studies in adolescents have both shown a significant reduction in blood pressure (Table 3). There is much interest in the role of urate-lowering therapy in cardiovascular disease given the epidemiological data. Two studies have examined the effects of allopurinol/oxypurinol in heart failure with both showing no clinical benefit [26,27]. One study
Table 2 Potential adverse effects with commonly used urate-lowering therapies Drug
Important side effects
Contraindications
Allopurinol
Rash Abnormal liver function tests Allopurinol hypersensitivity syndrome/DRESS/SCAR Abnormal liver function tests Hypersensitivity Urolithiasis Blood dyscrasias
Hypersensitivity to allopurinol HLA-B*5801 carrier Azathioprine use Use with caution in heart failure and ischaemic heart disease Azathioprine use Urolithiasis
Febuxostat Probenecid
3
4
Table 3 Clinical trials of urate-lowering therapy in “non-gout diseases”
Reference
Study design and duration
Hypertension Feig et al Randomised, [38] double-blind, placebocontrolled crossover trial 4 weeks
KostkaJeziorny et al [44]
Randomised
Goicoechea et al [45] Siu et al [46]
Prospective RCT 24 months Prospective RCT 12 months
Cardiovascular disease Goicoechea Prospective RCT et al [47] 5-year follow-up of 2010 RCT Terawaki Prospective survey et al [48] Norman et al [28]
Inclusion criteria
Number of subjects
Allopurinol 200 mg bid vs. placebo
Age: 11–17 years
N ¼ 30
Febuxostat 10–40 mg daily If on allopurinol at baseline either continued or switched to febuxostat
Newly diagnosed, never treated stage 1 hypertension Serum urate Z 6 mg/dl eGFR 30–59 ml/min/1.73 m2 Serum urate Z 7 mg/dl
N ¼ 45
Outcomes
Allopurinol resulted in a significant decrease in causal and ambulatory BP
Mean change in systolic BP: 6.9 mmHg and diastolic BP: 5.1 mmHg Significant reduction in blood pressure with febuxostat compared to control at 12 weeks
Febuxostat 10–60 mg daily to achieve SU r6.0 mg/dl
Serum urate Z 8 mg/dl eGFR r45 ml/min/1.73 m2
N ¼ 70
No significant change in blood pressure
Allopurinol 300 mg/dl
Serum urate 4 7 mg/dl
48 hypertensive and 21 normotensive N ¼ 150
Allopurinol resulted in a significantly greater decrease in systolic and diastolic blood pressure compared to the control group Addition of allopurinol did not result in a significant improvement in BP over chlorthalidone alone
Adolescents 12–19 years Newly diagnosed treatment naive essential hypertension SU 4 5.5 mg/dl
N ¼ 52
Significantly greater mean reduction in systolic and diastolic BP in allopurinol group
Untreated mild–moderate hypertension stage I/II
N ¼ 84
No significant change in blood pressure after addition of allopurinol
eGFR o 60 ml/min
N ¼ 113
No significant change in BP
N ¼ 54
No significant change in BP
At median follow-up of 84 months allopurinol group significantly less CV events in the allopurinol group (HR ¼ 0.43; 95% CI: 0.21–0.88; p ¼ 0.88) Over a mean of 183.4 months of follow-up, use of allopurinol was associated with fewer cardiovascular events (IHD, CHF and stroke); HR ¼ 0.34; p ¼ 0.04 Compared to placebo, allopurinol increased the median time to ST depression, increased the time to chest pain and increased the total exercise time
2
eGFR 4 60 ml/min/1.73 m Allopurinol 300 or 600 mg daily to achieve Stage 1 hypertension African American 18–65 years SU o 5.5 mg/dl vs. placebo added to chlorthalidone (25 mg/d) and potassium Non-significant renal disease chloride (20–40 mEq/d) Enalapril alone vs. enalapril plus allopurinol enalapril 0.15 mg/kg/d to maximum 20 mg/d Allopurinol 5 mg/kg/d in two divided doses to maximum 300 mg/d Antihypertensive therapy with either perindopril or hydrochlorothiazide for 8 weeks then allopurinol 150 mg daily added 8 weeks Allopurinol 100 mg/d vs. usual care
Allopurinol 100 or 200 mg/d vs. usual care Daily proteinuria 40.5 g and/or creatinine 41.35 mg/dl (4120 mmol/l) and o4.50 mg/dl (o400 mmol/l) at baseline; and o40% increase in serum Cr level and daily proteinuria within the 3 months before screening Serum urate 4 7.6 mg/dl
Allopurinol 100 mg/d vs. usual care
eGFR o 60 ml/min/1.73 m2
N ¼ 107
Allopurinol vs. no allopurinol
Hypertensive nephropathy eGFR o 45 ml/min/1.73 m2
N ¼ 178
Angiographically documented coronary artery disease, positive exercise test and stable chronic angina for at least 2 months
N ¼ 65
Allopurinol 600 mg daily vs. placebo Randomised, double-blind, placebo-controlled cross-over trial 12-week trial
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Tanaka et al Prospective, open[39] label, parallelgroup, randomised controlled trial 12 weeks Shibagaki Open-label, nonet al [40] controlled, 24week study Kanbay et al Non-randomised [41] trial 12 weeks Segal et al Randomised, [42] double-blind, placebocontrolled trial 8 weeks Assadi [43] Randomised, openlabel trial 8 weeks
Urate-lowering therapy
Hare et al [27]
Randomised, double-blind, placebocontrolled parallel-group study 24 weeks
Oxypurinol 600 mg/daily vs. placebo
Allopurinol (up to 600 mg/d) vs. placebo Givertz et al Randomised, [26] placebocontrolled, double-blind trial 24 weeks
Kanbay et al Randomised [49] prospective study 4 months Kao et al [50]
Shi et al [51]
Liu 2015 [52]
Goicoechea et al [45]
No difference in composite end point of heart failure morbidity, mortality and quality of life
Post hoc analysis suggested benefit in subjects with elevated SU and SU reduction with oxypurinol therapy N ¼ 253
No significant difference in clinical status between groups
SU Z 9.5 mg/dl
Allopurinol 100 or 200 mg/d vs. usual care Daily proteinuria 40.5 g and/or creatinine 41.35 mg/dl N ¼ 54 (4120 mmol/l) and o4.50 mg/dl (o 400 mmol/l) at baseline; and o40% increase in serum Cr level and daily proteinuria within the 3 months before screening Serum urate 47.6 mg/dl Allopurinol 300 mg/day in hyperuricaemic Serum urate 4 7 mg/dl Normal kidney function vs. no treatment in subjects with hyperuricaemia or normouricaemia
Placebo-controlled, Allopurinol 300 mg/d vs. placebo randomised, double-blind parallel-group study 9 months Allopurinol 100–300 mg/d vs. usual care Prospective, randomised, parallel openlabelled controlled trial 6 months Randomised, open, parallel controlled trial 3 years Prospective RCT 24 months
One hospitalisation for heart failure within preceding 18 months, attendance at ED with IV therapy for heart failure or new therapy for heart failure Symptomatic heart failure Left ventricular ejection fraction r40%
N ¼ 405
LVH on echocardiography CKF stage 3 (eGFR ¼ 30–60 ml/min/1.73 m2)
IgA nephropathy Proteinuria: 0.15–2.0 g/24 h Albumin 4 3.5 g/dl
Creatinine o 3 mg/dl Serum urate 4 6 mg/dl in women and 4 7 mg/dl in men Allopurinol 100 mg daily, titrated to Type 2 diabetes maintain serum urate o 0.36 mmol/l vs. Serum urate ¼ 0.42–0.476 mmol/l usual care
N ¼ 105 (72 hyperuricaemic and 33 normouricaemic controls) N ¼ 67
Significant reduction in serum urate in those receiving allopurinol 16% of subjects receiving allopurinol had a significant deterioration in kidney function (serum creatinine increase 4 40% of baseline) or dialysis dependence after 12 months compared to 46.1% of controls (p ¼ 0.015) Allopurinol led to significant reduction in serum urate and increase in eGFR at 4 months compared to baseline No significant change between baseline and 4 months in hyperuricaemic and normouricaemic controls No significant difference in the change in eGFR at 9 months between groups
N ¼ 40
No significant difference in the eGFR or the change in eGFR at 6 months between groups
N ¼ 176
At 3 years, serum urate, urine albumin excretion rate and creatinine had reduced significantly and eGFR increased significantly in those receiving allopurinol vs. usual care Serum urate decreased significantly in allopurinol group eGFR decreased in control group and increased in allopurinol group Allopurinol slowed kidney disease progression (defined as decrease 40.2 ml/min/1.73 m2 per month) compared to control group At median follow-up of 84 months, allopurinol group significantly decreased serum urate, and decrease in eGFR was significantly less in allopurinol group Initiation of dialysis, doubling of creatinine and/or 50% decrease in eGFR occurred in 2/57 allopurinol-treated and 6/56 control patients Treatment with allopurinol reduced the hazard rate for renal event by 68% (HR ¼ 0.32; 95% CI: 0.15–0.69; p ¼ 0.004) Non-significant increase in eGFR in febuxostat group at 6 months
Allopurinol 100 mg/d vs. usual care
eGFR o 60 ml/min/1.73 m2
N ¼ 113
Goicoechea et al [47]
Prospective RCT 5-year follow-up of 2010 RCT
Allopurinol 100 mg/d vs. usual care
eGFR o 60 ml/min/1.73 m2
N ¼ 107
Sircar et al [53]
Double-blind, randomised,
Febuxostat 40 mg daily vs. placebo
eGFR ¼ 15–60 ml/min/1.73 m2 Serum urate Z 7 mg/dl
N ¼ 108
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Chronic kidney disease Siu et al Prospective RCT [46] 12 months
New York Heart Association functional class III/IV Left ventricular ejection fraction r40%
5
6
Table 3 (continued ) Study design and duration
parallel-group, placebocontrolled trial 6 months Tanaka et al Prospective, open[39] label, parallelgroup, randomised controlled trial 12 weeks Sezai et al Single-blind, [54] randomised controlled trial 6 months
Shibagaki et al [40]
Open-label, noncontrolled study, 24- week study
Urate-lowering therapy
Inclusion criteria
Number of subjects
Age: 18–65 years
Febuxostat 10–40 mg daily If on allopurinol at baseline, either continued or switched to febuxostat
eGFR ¼ 30–59 ml/min/1.73 m2 Serum urate Z 7 mg/dl
Target serum urate r6.0 mg/dl, febuxostat eGFR r 60 ml/min/1.73 m2 Serum urate Z 8 mg/dl up to 60 mg/d or allopurinol up to 300 mg/d for allopurinol Undergoing cardiac surgery In subjects with eGFR r 30 ml/min/ Not on urate-lowering therapy 1.73 m2, maximum febuxostat 40 mg daily and allopurinol 200 mg daily Febuxostat 10–60 mg daily to achieve SU Serum urate Z 8 mg/dl r 6.0 mg/dl eGFR r 45 ml/min/1.73 m2
Outcomes Significant decrease in eGFR in placebo group
N ¼ 45
Significant reduction in serum urate with febuxostat compared to control but no significant difference in eGFR between febuxostat and control groups
N ¼ 109
SU is significantly lower in febuxostat group compared to allopurinol group No significant difference in eGFR between allopurinol and febuxostat groups at 1, 3 or 6 months
N ¼ 70
eGFR increase by 7.4% from baseline in CKD 3b and decreased in CKD 4 and 5 Multivariate analysis showed SU at week 24, % reduction in SU and absolute reduction in SU, all independent variables for increase in eGFR
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Reference
L. Stamp, N. Dalbeth / Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]
reported benefit with allopurinol in patients with stable angina [28]. Four meta-analyses have been published on the effects of uratelowering therapy in chronic kidney disease. The most recent metaanalysis which included 19 RCTs with a total of 992 participants reported a pooled estimate of eGFR in favour of allopurinol over placebo with a mean difference of 3.2 ml/min/1.73 m2 (95% CI: 0.16–6.2 ml/min/1.73 m2) [29]. Wang et al [30] included studies from the Chinese biomedical literature and included 11 RCTs and reported that urate-lowering therapy was associated with a reduction in serum creatinine and beneficial effects on eGFR. All four meta-analyses conclude that there is currently insufficient evidence to support urate lowering, highlighting the need for adequately powered randomised controlled trials. Of particular concern when treating individuals with asymptomatic hyperuricaemia is the risk of medication-related adverse events, particularly serious adverse events. Serious adverse events with allopurinol, including fatal hypersensitivity reactions, have been reported in people receiving allopurinol for asymptomatic hyperuricaemia [31,32]. A recent large population-based study from Taiwan reported an increased risk of allopurinol hypersensitivity syndrome (OR ¼ 2.08; 95% CI: 1.94–2.24) as well as an increased risk of mortality related to allopurinol hypersensitivity syndrome (OR ¼ 2.32; 95% CI: 1.79–3.01) in those treated for asymptomatic hyperuricaemia [33]. Furthermore, comorbid cardiovascular and kidney diseases also increased the risk of allopurinol hypersensitivity syndrome and allopurinol hypersensitivity syndrome-related mortality [33]. Urate is also an anti-oxidant and as such has beneficial effects. Within the central nervous system, urate is an important scavenger of free radicals such as glutamate that is toxic for the brain, and urate may be beneficial in acute stroke [34]. Low serum urate has been linked to neuro-degenerative disorders such as Parkinson’s disease [35]. The optimal serum urate to balance the risk of gout and neurological disorders remains to be determined. However, the associations with neurological disorders highlight the potential negative effects of urate lowering. Given these data and the limited data on efficacy in “non-gout diseases,” it appears at present that the risks of urate-lowering therapy are potentially greater than any benefits and caution should be exercised. While urate-lowing therapies per se may not currently be appropriate in “non-gout diseases,” consideration of the effects on urate of medications used in the management of co-morbidities may be appropriate. For example, many people with hypertension and/or chronic kidney disease receive diuretics such as furosemide that can increase serum urate. Consideration of alternate agents such as losartan that not only reduce blood pressure but also reduce serum urate may be appropriate [36].
Problems with the current literature The currently available literature assessing the treatment of asymptomatic hyperuricaemia is hampered by an inconsistent approach with regard to populations studied and dose and duration of urate-lowering therapy. Thus, numbers needed to treat for benefit and harm cannot be accurately calculated. Many variables will influence the risk–benefit assessment of uratelowering therapy for asymptomatic hyperuricaemia including (1) patient characteristics such as age and co-morbidities, (2) whether there is a target urate that must be achieved to provide benefit will have implications for dosing of urate-lowering therapies, (3) the duration of urate lowering and (4) whether the mechanism of urate lowering is important, for example, xanthine oxidase inhibition vs. increasing renal urate excretion. The interaction between these variables will also need to be considered particularly with
7
regard to dosing of urate-lowering therapies. For example, treating chronic kidney disease with 300 mg allopurinol daily might be effective but risky, while treating with 100 mg daily might have the same outcome with less risk.
A proposed agenda to clarify the role of urate-lowering therapy for asymptomatic hyperuricaemia In order to understand the role of urate-lowering therapy for asymptomatic hyperuricaemia, adequately powered clinical trials with clinically relevant end points (for both gout and “non-gout diseases”) are essential to carefully examine the benefits and risks of such a strategy. It is not sufficient to use observational data alone to support interventions for asymptomatic biochemical abnormalities in clinical practice, noting the frequent lack of concordance between observational studies and randomised controlled trials [37]. A key question for studies examining the role of urate-lowering therapy in asymptomatic hyperuricaemia is whether the benefits of preventing the first attack of gout outweigh the risks of long-term urate-lowering therapy, particularly when urate-lowering therapy can be associated with lifethreatening complications, albeit rarely. The benefit–risk assessment for prevention of gout is likely to be substantially altered if there is also clinical evidence demonstrating benefit for cardiovascular or renal end points. Key issues that need to be addressed with regard to treating “non-gout diseases” include the appropriate patient population and age group. Whether there is a “target serum urate concentration” or a specific drug dose rather than urate being effective, as well as the duration of urate-lowering therapy for each clinically relevant end point will need to be carefully defined through a clinical trial programme. Whether xanthine oxidase inhibitors and uricosuric agents have similar effects suggesting that urate reduction per se is what is required rather than xanthine oxidase inhibition also needs to be clarified. Until such clinical trials are completed and conclusively demonstrate benefit over risk of treatment, urate-lowering therapy for asymptomatic hyperuricaemia cannot be supported.
Author contributions L.K.S. and N.D. conceived the idea, wrote and approved the article. References [1] Fessel W, Siegelaub A, Johnson E. Correlates and consequences of asymptomatic hyperuricaemia. Arch Int Med 1973;132:44–54. [2] Liang M, Fries J. Asymptomatic hyperuricaemia: the case for conservative management. Ann Intern Med 1978;88:666–70. [3] Levy G, Cheetham T. Is it time to start treating asymptomatic hyperuricaemia? Am J Kidney Dis 2015;66:933–5. [4] Yamanaka H. Japanese guideline for the management of hyperuricaemia and gout: second edition. Nucleosides Nucleotides Nucleic Acids 2011;30:1018–29. [5] Bardin T, Richette P. Defintion of hyperuricaemia and gouty conditions. Curr Opin Rheumatol 2014;26:186–91. [6] Campion E, Glynn R, DeLabry L. Asymptomatic hyperuricaemia: risks and consequence in the normative aging study. Am J Med 1987;82:421–6. [7] Lin K-C, Lin H-Y, Chou P. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricaemic men in a prospective study. J Rheumatol 2000;27:1501–5. [8] Dalbeth N, House ME, Aati O, Tan P, Franklin C, Horne A, et al. Urate crystal deposition in asymptomatic hyperuricaemia and symptomatic gout: a dual energy CT study. Ann Rheum Dis 2015;74:908–11. [9] Puig J, de Miguel E, Castillo M, Rocha A, Martínez M, Torres R. Asymptomatic hyperuricemia: impact of ultrasonography. Nucleosides Nucleotides Nucleic Acids 2008;27:592–5. [10] Pineda C, Amezcua-Guerra L, Solano C, et al. Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study. Arthritis Res Ther 2011;13:R4.
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[33] Yang C-Y, Chen C-H, Deng S-T, et al. Allopurinol use and risk of fatal hypersensitivity reactions: a nationwide population-based study in Taiwan. JAMA Intern Med 2015;175:1550–7. [34] Chamorro A, Dirnagl U, Urra X, Planas A. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol 2016;15:869–81. [35] Shen C, Guo Y, Luo W, Lin C, Ding M. Serum urate and the risk of Parkinson’s disease: results from a meta-analysis. Can J Neurol Sci 2013;40:73–9. [36] Fan Y, Wei F, Lang Y, Wang S-Y. Losartan treatment for hypertensive patients with hyperuricaemia in Chinese population: a meta-analysis. J Hypertens 2015;33:681–8. [37] Tai V, Grey A, Bolland M. Results of observational studies: analysis of findings from the Nurses’ Health Study. PLoS One 2014;9:e110403. [38] Feig D, Soletsky B, Johnson R. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension. J Am Med Assoc 2008;300:924–32. [39] Tanaka K, Nakayama M, Kanno M, et al. Renoprotective effects of febuxostat in hyperuricemic patients with chronic kidney disease: a parallel-group, randomized, controlled trial. Clin Exp Nephrol 2015;9:1044–53. [40] Shibagaki Y, Ohno I, Hosoya T. Kimura K. Safety, efficacy and renal effect of febuxostat in patients with moderate-to-severe kidney dysfunction. Hypertens Res 2014;37:919–25. [41] Kanbay M, Ozkara A, Selcoki Y, et al. Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearance, and proteinuria in patients with normal renal function. Int Urol Nephrol 2007;39:1227–33. [42] Segal M, Srinivas T, Mohandas R, et al. The effect of the addition of allopurinol on blood pressure control in African Americans treated with a thiazide-like diuretic. J Am Soc Hypertens 2015;9:610–9. [43] Assadi F. Allopurinol enhances the blood pressure lowering effect of enalapril in children with hyperuricemic essential hypertension. J Nephrol. 2014;27: 51–6. [44] Kostka-Jeziorny K, Uruski P, Tykarski A. Effect of allopurinol on blood pressure and aortic compliance in hypertensive patients. Blood Press 2011;20:104–10. [45] Goicoechea M, de Vinuesa S, Verdalles U, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol 2010;5:1388–93. [46] Siu Y-P, Leung K-T, Tong M, Kwan T-H. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51–9. [47] Goicoechea M, de Vinuesa S, Verdalles U, et al. Allopurinol and progression of CKD and cardiovascular events: long term followup of a randomised controlled trial. Am J Kidney Dis 2015. http://dx.doi.org/10.1053/j.ajkd.2014.11.016. [48] Terawaki H, Nakayama M, Miyazawa E, et al. Effect of allopurinol on cardiovascular incidence amoung hypertensive nephropathy patients: the Gonryo study. Clin Exp Nephrol 2013;17:549–53. [49] Kanbay M, Huddam B, Azak A, et al. A randomized study of allopruinol on endothelial function and estimated glomerular filtration rate in asymptomatic hyperuricaemic subjects with normal renal function. Clin J Am Soc Nephrol 2011;6:1887–94. [50] Kao M, Ang D, Gandy S, et al. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol 2011;22:1382–9. [51] Shi Y, Chen W, Jalal D, et al. Clinical outcome of hyperuricaemia in IgA nephropathy: a retrospective cohort study and randomized controlled trial. Kidney Blood Press Res 2012;35:153–60. [52] Liu P, Chen Y, Wang B, Zhang F, Wang D, Wang Y. Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricaemia: a three year randomized parallel-controlled trial. Clin Endocrinol 2015;83:475–82. [53] Sircar D, Chatterjee S, Waikhom R, et al. Efficacy of febuxostat for slowing the GFR decline in patients with CKD and asymptomatic hyperuricaemia: a 6month double-blind, randomized, placebo-controlled trial. Am J Kidney Dis 2015;66:945–50. [54] Sezai A, Soma M, Nakata K, et al. Comparison of febuxostat and allopurinol for hyperuricaemia in cardiac surgery patients with chronic kidney disease (NUFLASH trial for CKD). J Cardiol 2015;66:298–303.
Contents lists available at ScienceDirect
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Urate-lowering therapy for asymptomatic hyperuricaemia: A need for caution☆ Lisa Stamp, FRACP, PhDa,n, Nicola Dalbeth, FRACP, MDb a b
Department of Medicine, University of Otago, Christchurch, 2 Riccarton Ave, P.O. Box 4345, Christchurch, New Zealand Department of Medicine, University of Auckland, Auckland, New Zealand
a r t i c l e in fo
Keywords: Hyperuricaemia Asymptomatic Urate-lowering therapy
a b s t r a c t Objective: The observed associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease are receiving increasing interest. The potential role of urate-lowering therapy in the management of these “non-gout diseases” has been raised, and in some countries it is already recommended. However, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia, much remains unknown about the causal role of urate in these “non-gout diseases” and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is potential for serious adverse effects associated with urate-lowering therapies with recent evidence suggesting that asymptomatic hyperuricaemia may be an independent risk factor for the potentially fatal allopurinol hypersensitivity syndrome. Methods: Pubmed was searched in January 2016 using the search term “asymptomatic hyperuricaemia”. Results and Conclusions: Herein, we discuss the issues related to treating asymptomatic hyperuricaemia, which at present seems premature. & 2016 Elsevier Inc. All rights reserved.
Introduction The management of asymptomatic hyperuricaemia has been debated in the medical literature since the 1970s with reported benefits focusing on prevention of gout, urolithiasis or uric acid nephropathy [1,2]. While the associations of hyperuricaemia with hypertension, cardiovascular disease and kidney disease have also been recognised for some time, there has been a renewed interest in these relationships and the potential role of urate-lowering therapy in the management of these “non-gout diseases.” This has led to renewed interest in whether individuals with asymptomatic hyperuricaemia should be treated with urate-lowering therapy [3]. Indeed, in some countries, the treatment of asymptomatic hyperuricaemia is recommended [4]. However, much remains unknown about the causal role of urate in these “non-gout diseases,” and there is currently a lack of evidence about the effects of urate lowering on disease progression. In addition, there is no consistent definition of hyperuricaemia or asymptomatic hyperuricaemia,
and there is potential for serious adverse effects with uratelowering therapies. The aim of this review is to outline the issues and evidence in regard to the use of urate-lowering therapy for treatment of asymptomatic hyperuricaemia. PubMed was searched in January 2016 using the search term “asymptomatic hyperuricaemia.”
Definition of hyperuricaemia There is currently no consensus on the definition of hyperuricaemia. It can be defined in several ways: according to population values, pathophysiological cut-point or levels associated with disease risk (Table 1). The definition is particularly important when considering treating asymptomatic hyperuricaemia and needs to be considered separately for gout and for “non-gout diseases.” Definition of “asymptomatic hyperuricaemia” with respect to gout and symptomatic monosodium urate crystal deposition
☆ L.K.S. has received grant funds from Ardea Biosciences, outside the current work. N.D. has received consulting fees, speaker fees or grants from the following companies: Takeda, Menarini, Teijin, Pfizer, Crealta, Cymabay, Fonterra, Ardea Biosciences and AstraZeneca, outside the submitted work. n Corresponding author. E-mail address: [email protected] (L. Stamp).
http://dx.doi.org/10.1016/j.semarthrit.2016.07.015 0049-0172/& 2016 Elsevier Inc. All rights reserved.
It is important to note that while the risk of developing gout increases with rising serum urate concentrations, not all people with even very high urate concentrations will develop gout. For example, in the Normative Aging Study, only 22% individuals with
L. Stamp, N. Dalbeth / Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]
2
Table 1 Potential definitions for hyperuricaemia (Adapted with permission from Bardin and Richette [5]) Definition Statistical/laboratory-based definition Physiological definition Based on risk of developing disease Based on therapeutic target for disease treatment
Problems
Serum urate 4 two standard deviations above the mean for the Variation based on ethnicity, age and time healthy population Differences between men and women Based on the in vivo saturation point of urate when Altered by temperature and pH monosodium urate crystals may develop Altered by cartilage matrix proteins Unknown Risk of gout increases with the degree of hyperuricaemia but not all with hyperuricaemia develop symptomatic gout May differ between conditions Established for gout o6 mg/dl (0.36 mmol/l) for all patients, May differ between conditions o5 mg/dl (0.30 mmol/l) for severe disease Unknown for “non-gout diseases” Need large long-term clinical trials to establish therapeutic targets for both gout and “non-gout diseases”
very high serum urate concentrations ( Z9 mg/dl, 0.54 mmol/l) developed symptomatic gout over a 5-year period [6]. For people with lower urate concentrations (but still above the pathophysiological and population-based thresholds for definition of hyperuricaemia), the risk of developing symptomatic gout was even lower; for example, for those with serum urate 7–7.9 mg/dl (0.42– 0.47 mmol/l), 2% developed symptomatic gout over 5 years, and for those with serum urate 8–8.9 mg/dl (0.48–0.53 mmol/l), 4.1% developed symptomatic gout over 5 years [6]. Thus, while elevated urate concentration is a critical risk factor for the development of gout, it alone is insufficient to cause gout. There are a number of other risk factors for the development of gout with complex interactions between these variables (Fig.). Hyperuricaemia is the central risk factor symptomatic for developing gout. In people with hyperuricaemia, other factors such as alcohol consumption, diuretic use and increase in BMI may further increase the risk of developing gout [7]. Accurate prediction of an individual with asymptomatic hyperuricaemia developing gout is currently not possible, and the development of a clinical risk score for future assessment of gout, such as is used in cardiovascular disease, which includes degree of hyperuricaemia in conjunction with clinical and laboratory variables may be helpful in this regard. Asymptomatic urate crystal deposition can be non-invasively recognised with new advanced imaging techniques such as dualenergy CT (DECT) and high-resolution ultrasound [8–11]. Both microscopic and advanced imaging studies clearly indicate that in some asymptomatic individuals with hyperuricaemia, deposition of monosodium urate crystals can occur without the associated inflammatory response that is responsible for the clinical signs and symptoms of gout. It is unknown what proportion of these individuals with asymptomatic monosodium urate crystal deposition will progress to symptomatic gout.
Medicaons Diurecs Calcineurin inhibitors (cyclopsorin, tacrolimus) Pyrazinamide
Other Increasing age Chronic kidney disease BMI Hypertension Hyperlipidaemia Menopause
Hyperuricaemia and gout Genec factors Gender Ethnicity SLC2A9 ABCG2 Genec variants in other urate transporters
Dietary factors Purine rich food (red meat, seafood) Alcohol (beer, spirits) Sugar-sweetened beverages
Fig. Variables associated with risk of hyperuricaemia and gout.
Definition of asymptomatic hyperuricaemia with respect to “non-gout diseases” A number of conditions have been associated with hyperuricaemia including hypertension, cardiovascular disease and chronic kidney disease. We need to consider how these “associations” are incorporated into the definition of asymptomatic hyperuricaemia or whether they actually represent symptomatic hyperuricaemia. This distinction is important as it might alter whether urate-lowering therapy should be considered. Conceptually, if urate has a pathogenic role in these conditions then it could be argued that they represent symptomatic hyperuricaemia. However, the causal link between urate and these conditions is controversial. Many prospective observational studies have shown that elevated serum urate concentrations are associated with development of hypertension, cardiovascular disease and chronic kidney disease. For example, in a meta-analysis of 25 observational studies examining the role of hyperuricaemia on incident hypertension, hyperuricaemia was associated with development of hypertension (unadjusted relative risk ¼ 1.73; 95% CI: 1.46–2.06 and adjusted relative risk ¼ 1.48; 95% CI: 1.33–1.65) [12]. In a meta-analysis of 26 observational studies, elevated serum urate was associated with increased risk of coronary heart disease incidence (unadjusted relative risk ¼ 1.34; 95% CI: 1.19–1.49 and pooled relative risk ¼ 1.09; 95% CI: 1.03–1.16) and coronary heart disease mortality (unadjusted relative risk ¼ 1.46; 95% CI: 1.20– 1.73 and pooled relative risk ¼ 1.16; 95% CI: 1.01–1.30) [13]. Similar findings have been observed with stroke incidence (relative risk ¼ 1.41; 95% CI: 1.05–1.76) and stroke mortality (relative risk ¼ 1.36; 95% CI: 1.03–1.69) in a meta-analysis of six observational studies [14]. In a meta-analysis of 11 observational studies examining cardiovascular and all-cause mortality, elevated serum urate concentration was associated with increased risk of all-cause mortality (relative risk ¼ 1.24; 95% CI: 1.09–1.42) and cardiovascular mortality (relative risk ¼ 1.37; 95% CI: 1.19–1.57) [15]. In a meta-analysis of 13 observational studies, hyperuricaemia was associated with development of chronic kidney disease in patients with normal renal function (summary odds ratio ¼ 2.35; 95% CI: 1.59–3.46) [16]. A key limitation of many of the observational studies examining the role of urate on “non-gout diseases” is that different definitions of hyperuricaemia have been used (often based on categories of serum urate within the study population rather than a specific value or threshold), so it is unclear whether there is a specific cut-point that is associated with increased risk of disease. However, it seems apparent from most observational studies that serum urate concentrations below the level associated with gout risk are associated with development of these “non-gout diseases.” These findings have important implications when considering the threshold for treatment of asymptomatic hyperuricaemia.
L. Stamp, N. Dalbeth / Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]
Although the observational data are relatively consistent over many studies, it is unclear whether urate is causal or whether the observed associations are due to unmeasured (or inadequately adjusted) confounders. Mendelian randomisation is an analysis method that uses genetic data to examine causation in the setting of an association that is potentially complicated by confounding. A large and comprehensive Mendelian randomisation analysis has demonstrated the validity of this approach for urate, showing that serum urate is causal for the development of gout, but failing to demonstrate a causal relationship between urate and blood pressure, coronary heart disease, ischaemic stroke, heart failure or markers of kidney function [17]. Other Mendelian randomisation studies have also failed to show a causal relationship between urate and hypertension, coronary artery disease or chronic kidney disease [18–20]. These data raise major uncertainty about the therapeutic benefit of urate-lowering therapy for prevention or treatment of “non-gout diseases” associated with hyperuricaemia.
Potential benefits and risks of urate-lowering therapy Potential benefits and risks of urate-lowering therapy in people with symptomatic gout and asymptomatic monosodium urate crystal deposition In individuals with symptomatic gout, there is a clear indication for urate-lowering therapy. Symptomatic gout most often presents as acute gout flares. Advanced disease with tophi, joint damage and chronic gouty arthropathy typically presents many years after the initial flare, but occasionally occurs early in the symptomatic disease course. The symptoms of gout such as acute flares and tophi are a direct consequence of monosodium urate crystal deposition and the subsequent immune response to these crystals. The rationale for urate-lowering therapy in individuals with symptomatic gout is based on lowering the urate sufficiently to allow dissolution of monosodium urate crystals. Monosodium urate crystals form in vitro when serum urate super-saturation concentrations are reached, approximately 6.8 mg/dl (0.41 mmol/ l) at 371C and 6.0 mg/dl (0.36 mmol/l) at 351C. Previous studies have shown that sustained reduction in serum urate to o 6.0 mg/ dl (0.36 mmol/l) results in a dissolution of monosodium urate crystals, reduction and eventually cessation of gout flares and resolution of tophi [21,22]. In contrast, untreated gout can lead to progressive monosodium urate crystal deposition, development of joint erosion, chronic gouty arthritis and tophi. Thus, there are clear benefits to urate-lowering therapy. As with all medication, there are risks of adverse effects with urate-lowering therapies. Each therapeutic option has a unique side effect profile (Table 2). Of particular concern has been the severe adverse reactions such as allopurinol hypersensitivity syndrome (AHS). Whilst these severe adverse events are rare, they can be fatal. The risk of AHS can be minimised by screening for HLA-B*5801 in high-risk populations (such as people of Han
Chinese and Korean ancestry), and using alternative uratelowering agents in HLA-B*5801 carriers [23]. Starting allopurinol at low dose (such as a daily dose of 1.5 mg/unit eGFR) may also reduce the risk of AHS [24]. The newer xanthine oxidase inhibitor febuxostat can be associated with hepatotoxicity and hypersensitivity reactions albeit rarely. On balance, given the rarity of these severe adverse reactions, the benefits of urate-lowering therapy in individuals with symptomatic disease are thought to outweigh the potential risks. For individuals with hyperuricaemia and asymptomatic monosodium urate crystal deposition, the rationale for treatment is less clear. Asymptomatic crystal deposition could be considered sufficient evidence of urate deposition disease or a significant predictor of future symptomatic gout, thus warranting urate-lowering therapy despite the absence of symptoms. It is reasonable to assume that urate-lowering therapy will result in dissolution of the monosodium urate crystal deposits, and therefore prevention of symptomatic disease in the future. However, the prognostic importance of asymptomatic monosodium urate crystal deposition is unclear; specifically it is unknown what proportion of these individuals will develop symptomatic gout, and without this information, it is difficult to accurately assess the risk–benefit ratio of therapy.
Potential benefits and risks of urate-lowering therapy in individuals with “non-gout diseases” associated with hyperuricaemia The observed association of hyperuricaemia with hypertension, cardiovascular disease and chronic kidney disease has led to the suggestion that urate-lowering therapy should be used in the management of these conditions. A number of small clinical trials have examined the effects of urate-lowering therapy in hypertension, cardiovascular disease and chronic kidney disease in people without gout (Table 3). The majority of studies have examined the effects of the xanthine oxidase inhibitors such as allopurinol or febuxostat. Few studies have examined the effects on blood pressure specifically (Table 3). A meta-analysis in 2013 reported on 10 clinical studies with a total of 738 individuals [25]. All studies used allopurinol as the urate-lowering therapy. In subjects who received allopurinol, the mean decrease in systolic blood pressure was 3.3 mmHg (95% CI: 1.4–5.3 mmHg) and mean decrease in diastolic blood pressure was 1.3 mmHg (95% CI: 0.1–2.5 mmHg) compared to placebo [25]. These studies of hypertension have also highlighted that the benefits of urate lowering may be restricted to specific populations. For example, studies examining the effects of urate-lowering therapy in hypertensive adults have not shown a consistent benefit while the two studies in adolescents have both shown a significant reduction in blood pressure (Table 3). There is much interest in the role of urate-lowering therapy in cardiovascular disease given the epidemiological data. Two studies have examined the effects of allopurinol/oxypurinol in heart failure with both showing no clinical benefit [26,27]. One study
Table 2 Potential adverse effects with commonly used urate-lowering therapies Drug
Important side effects
Contraindications
Allopurinol
Rash Abnormal liver function tests Allopurinol hypersensitivity syndrome/DRESS/SCAR Abnormal liver function tests Hypersensitivity Urolithiasis Blood dyscrasias
Hypersensitivity to allopurinol HLA-B*5801 carrier Azathioprine use Use with caution in heart failure and ischaemic heart disease Azathioprine use Urolithiasis
Febuxostat Probenecid
3
4
Table 3 Clinical trials of urate-lowering therapy in “non-gout diseases”
Reference
Study design and duration
Hypertension Feig et al Randomised, [38] double-blind, placebocontrolled crossover trial 4 weeks
KostkaJeziorny et al [44]
Randomised
Goicoechea et al [45] Siu et al [46]
Prospective RCT 24 months Prospective RCT 12 months
Cardiovascular disease Goicoechea Prospective RCT et al [47] 5-year follow-up of 2010 RCT Terawaki Prospective survey et al [48] Norman et al [28]
Inclusion criteria
Number of subjects
Allopurinol 200 mg bid vs. placebo
Age: 11–17 years
N ¼ 30
Febuxostat 10–40 mg daily If on allopurinol at baseline either continued or switched to febuxostat
Newly diagnosed, never treated stage 1 hypertension Serum urate Z 6 mg/dl eGFR 30–59 ml/min/1.73 m2 Serum urate Z 7 mg/dl
N ¼ 45
Outcomes
Allopurinol resulted in a significant decrease in causal and ambulatory BP
Mean change in systolic BP: 6.9 mmHg and diastolic BP: 5.1 mmHg Significant reduction in blood pressure with febuxostat compared to control at 12 weeks
Febuxostat 10–60 mg daily to achieve SU r6.0 mg/dl
Serum urate Z 8 mg/dl eGFR r45 ml/min/1.73 m2
N ¼ 70
No significant change in blood pressure
Allopurinol 300 mg/dl
Serum urate 4 7 mg/dl
48 hypertensive and 21 normotensive N ¼ 150
Allopurinol resulted in a significantly greater decrease in systolic and diastolic blood pressure compared to the control group Addition of allopurinol did not result in a significant improvement in BP over chlorthalidone alone
Adolescents 12–19 years Newly diagnosed treatment naive essential hypertension SU 4 5.5 mg/dl
N ¼ 52
Significantly greater mean reduction in systolic and diastolic BP in allopurinol group
Untreated mild–moderate hypertension stage I/II
N ¼ 84
No significant change in blood pressure after addition of allopurinol
eGFR o 60 ml/min
N ¼ 113
No significant change in BP
N ¼ 54
No significant change in BP
At median follow-up of 84 months allopurinol group significantly less CV events in the allopurinol group (HR ¼ 0.43; 95% CI: 0.21–0.88; p ¼ 0.88) Over a mean of 183.4 months of follow-up, use of allopurinol was associated with fewer cardiovascular events (IHD, CHF and stroke); HR ¼ 0.34; p ¼ 0.04 Compared to placebo, allopurinol increased the median time to ST depression, increased the time to chest pain and increased the total exercise time
2
eGFR 4 60 ml/min/1.73 m Allopurinol 300 or 600 mg daily to achieve Stage 1 hypertension African American 18–65 years SU o 5.5 mg/dl vs. placebo added to chlorthalidone (25 mg/d) and potassium Non-significant renal disease chloride (20–40 mEq/d) Enalapril alone vs. enalapril plus allopurinol enalapril 0.15 mg/kg/d to maximum 20 mg/d Allopurinol 5 mg/kg/d in two divided doses to maximum 300 mg/d Antihypertensive therapy with either perindopril or hydrochlorothiazide for 8 weeks then allopurinol 150 mg daily added 8 weeks Allopurinol 100 mg/d vs. usual care
Allopurinol 100 or 200 mg/d vs. usual care Daily proteinuria 40.5 g and/or creatinine 41.35 mg/dl (4120 mmol/l) and o4.50 mg/dl (o400 mmol/l) at baseline; and o40% increase in serum Cr level and daily proteinuria within the 3 months before screening Serum urate 4 7.6 mg/dl
Allopurinol 100 mg/d vs. usual care
eGFR o 60 ml/min/1.73 m2
N ¼ 107
Allopurinol vs. no allopurinol
Hypertensive nephropathy eGFR o 45 ml/min/1.73 m2
N ¼ 178
Angiographically documented coronary artery disease, positive exercise test and stable chronic angina for at least 2 months
N ¼ 65
Allopurinol 600 mg daily vs. placebo Randomised, double-blind, placebo-controlled cross-over trial 12-week trial
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Tanaka et al Prospective, open[39] label, parallelgroup, randomised controlled trial 12 weeks Shibagaki Open-label, nonet al [40] controlled, 24week study Kanbay et al Non-randomised [41] trial 12 weeks Segal et al Randomised, [42] double-blind, placebocontrolled trial 8 weeks Assadi [43] Randomised, openlabel trial 8 weeks
Urate-lowering therapy
Hare et al [27]
Randomised, double-blind, placebocontrolled parallel-group study 24 weeks
Oxypurinol 600 mg/daily vs. placebo
Allopurinol (up to 600 mg/d) vs. placebo Givertz et al Randomised, [26] placebocontrolled, double-blind trial 24 weeks
Kanbay et al Randomised [49] prospective study 4 months Kao et al [50]
Shi et al [51]
Liu 2015 [52]
Goicoechea et al [45]
No difference in composite end point of heart failure morbidity, mortality and quality of life
Post hoc analysis suggested benefit in subjects with elevated SU and SU reduction with oxypurinol therapy N ¼ 253
No significant difference in clinical status between groups
SU Z 9.5 mg/dl
Allopurinol 100 or 200 mg/d vs. usual care Daily proteinuria 40.5 g and/or creatinine 41.35 mg/dl N ¼ 54 (4120 mmol/l) and o4.50 mg/dl (o 400 mmol/l) at baseline; and o40% increase in serum Cr level and daily proteinuria within the 3 months before screening Serum urate 47.6 mg/dl Allopurinol 300 mg/day in hyperuricaemic Serum urate 4 7 mg/dl Normal kidney function vs. no treatment in subjects with hyperuricaemia or normouricaemia
Placebo-controlled, Allopurinol 300 mg/d vs. placebo randomised, double-blind parallel-group study 9 months Allopurinol 100–300 mg/d vs. usual care Prospective, randomised, parallel openlabelled controlled trial 6 months Randomised, open, parallel controlled trial 3 years Prospective RCT 24 months
One hospitalisation for heart failure within preceding 18 months, attendance at ED with IV therapy for heart failure or new therapy for heart failure Symptomatic heart failure Left ventricular ejection fraction r40%
N ¼ 405
LVH on echocardiography CKF stage 3 (eGFR ¼ 30–60 ml/min/1.73 m2)
IgA nephropathy Proteinuria: 0.15–2.0 g/24 h Albumin 4 3.5 g/dl
Creatinine o 3 mg/dl Serum urate 4 6 mg/dl in women and 4 7 mg/dl in men Allopurinol 100 mg daily, titrated to Type 2 diabetes maintain serum urate o 0.36 mmol/l vs. Serum urate ¼ 0.42–0.476 mmol/l usual care
N ¼ 105 (72 hyperuricaemic and 33 normouricaemic controls) N ¼ 67
Significant reduction in serum urate in those receiving allopurinol 16% of subjects receiving allopurinol had a significant deterioration in kidney function (serum creatinine increase 4 40% of baseline) or dialysis dependence after 12 months compared to 46.1% of controls (p ¼ 0.015) Allopurinol led to significant reduction in serum urate and increase in eGFR at 4 months compared to baseline No significant change between baseline and 4 months in hyperuricaemic and normouricaemic controls No significant difference in the change in eGFR at 9 months between groups
N ¼ 40
No significant difference in the eGFR or the change in eGFR at 6 months between groups
N ¼ 176
At 3 years, serum urate, urine albumin excretion rate and creatinine had reduced significantly and eGFR increased significantly in those receiving allopurinol vs. usual care Serum urate decreased significantly in allopurinol group eGFR decreased in control group and increased in allopurinol group Allopurinol slowed kidney disease progression (defined as decrease 40.2 ml/min/1.73 m2 per month) compared to control group At median follow-up of 84 months, allopurinol group significantly decreased serum urate, and decrease in eGFR was significantly less in allopurinol group Initiation of dialysis, doubling of creatinine and/or 50% decrease in eGFR occurred in 2/57 allopurinol-treated and 6/56 control patients Treatment with allopurinol reduced the hazard rate for renal event by 68% (HR ¼ 0.32; 95% CI: 0.15–0.69; p ¼ 0.004) Non-significant increase in eGFR in febuxostat group at 6 months
Allopurinol 100 mg/d vs. usual care
eGFR o 60 ml/min/1.73 m2
N ¼ 113
Goicoechea et al [47]
Prospective RCT 5-year follow-up of 2010 RCT
Allopurinol 100 mg/d vs. usual care
eGFR o 60 ml/min/1.73 m2
N ¼ 107
Sircar et al [53]
Double-blind, randomised,
Febuxostat 40 mg daily vs. placebo
eGFR ¼ 15–60 ml/min/1.73 m2 Serum urate Z 7 mg/dl
N ¼ 108
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Chronic kidney disease Siu et al Prospective RCT [46] 12 months
New York Heart Association functional class III/IV Left ventricular ejection fraction r40%
5
6
Table 3 (continued ) Study design and duration
parallel-group, placebocontrolled trial 6 months Tanaka et al Prospective, open[39] label, parallelgroup, randomised controlled trial 12 weeks Sezai et al Single-blind, [54] randomised controlled trial 6 months
Shibagaki et al [40]
Open-label, noncontrolled study, 24- week study
Urate-lowering therapy
Inclusion criteria
Number of subjects
Age: 18–65 years
Febuxostat 10–40 mg daily If on allopurinol at baseline, either continued or switched to febuxostat
eGFR ¼ 30–59 ml/min/1.73 m2 Serum urate Z 7 mg/dl
Target serum urate r6.0 mg/dl, febuxostat eGFR r 60 ml/min/1.73 m2 Serum urate Z 8 mg/dl up to 60 mg/d or allopurinol up to 300 mg/d for allopurinol Undergoing cardiac surgery In subjects with eGFR r 30 ml/min/ Not on urate-lowering therapy 1.73 m2, maximum febuxostat 40 mg daily and allopurinol 200 mg daily Febuxostat 10–60 mg daily to achieve SU Serum urate Z 8 mg/dl r 6.0 mg/dl eGFR r 45 ml/min/1.73 m2
Outcomes Significant decrease in eGFR in placebo group
N ¼ 45
Significant reduction in serum urate with febuxostat compared to control but no significant difference in eGFR between febuxostat and control groups
N ¼ 109
SU is significantly lower in febuxostat group compared to allopurinol group No significant difference in eGFR between allopurinol and febuxostat groups at 1, 3 or 6 months
N ¼ 70
eGFR increase by 7.4% from baseline in CKD 3b and decreased in CKD 4 and 5 Multivariate analysis showed SU at week 24, % reduction in SU and absolute reduction in SU, all independent variables for increase in eGFR
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Reference
L. Stamp, N. Dalbeth / Seminars in Arthritis and Rheumatism ] (2016) ]]]–]]]
reported benefit with allopurinol in patients with stable angina [28]. Four meta-analyses have been published on the effects of uratelowering therapy in chronic kidney disease. The most recent metaanalysis which included 19 RCTs with a total of 992 participants reported a pooled estimate of eGFR in favour of allopurinol over placebo with a mean difference of 3.2 ml/min/1.73 m2 (95% CI: 0.16–6.2 ml/min/1.73 m2) [29]. Wang et al [30] included studies from the Chinese biomedical literature and included 11 RCTs and reported that urate-lowering therapy was associated with a reduction in serum creatinine and beneficial effects on eGFR. All four meta-analyses conclude that there is currently insufficient evidence to support urate lowering, highlighting the need for adequately powered randomised controlled trials. Of particular concern when treating individuals with asymptomatic hyperuricaemia is the risk of medication-related adverse events, particularly serious adverse events. Serious adverse events with allopurinol, including fatal hypersensitivity reactions, have been reported in people receiving allopurinol for asymptomatic hyperuricaemia [31,32]. A recent large population-based study from Taiwan reported an increased risk of allopurinol hypersensitivity syndrome (OR ¼ 2.08; 95% CI: 1.94–2.24) as well as an increased risk of mortality related to allopurinol hypersensitivity syndrome (OR ¼ 2.32; 95% CI: 1.79–3.01) in those treated for asymptomatic hyperuricaemia [33]. Furthermore, comorbid cardiovascular and kidney diseases also increased the risk of allopurinol hypersensitivity syndrome and allopurinol hypersensitivity syndrome-related mortality [33]. Urate is also an anti-oxidant and as such has beneficial effects. Within the central nervous system, urate is an important scavenger of free radicals such as glutamate that is toxic for the brain, and urate may be beneficial in acute stroke [34]. Low serum urate has been linked to neuro-degenerative disorders such as Parkinson’s disease [35]. The optimal serum urate to balance the risk of gout and neurological disorders remains to be determined. However, the associations with neurological disorders highlight the potential negative effects of urate lowering. Given these data and the limited data on efficacy in “non-gout diseases,” it appears at present that the risks of urate-lowering therapy are potentially greater than any benefits and caution should be exercised. While urate-lowing therapies per se may not currently be appropriate in “non-gout diseases,” consideration of the effects on urate of medications used in the management of co-morbidities may be appropriate. For example, many people with hypertension and/or chronic kidney disease receive diuretics such as furosemide that can increase serum urate. Consideration of alternate agents such as losartan that not only reduce blood pressure but also reduce serum urate may be appropriate [36].
Problems with the current literature The currently available literature assessing the treatment of asymptomatic hyperuricaemia is hampered by an inconsistent approach with regard to populations studied and dose and duration of urate-lowering therapy. Thus, numbers needed to treat for benefit and harm cannot be accurately calculated. Many variables will influence the risk–benefit assessment of uratelowering therapy for asymptomatic hyperuricaemia including (1) patient characteristics such as age and co-morbidities, (2) whether there is a target urate that must be achieved to provide benefit will have implications for dosing of urate-lowering therapies, (3) the duration of urate lowering and (4) whether the mechanism of urate lowering is important, for example, xanthine oxidase inhibition vs. increasing renal urate excretion. The interaction between these variables will also need to be considered particularly with
7
regard to dosing of urate-lowering therapies. For example, treating chronic kidney disease with 300 mg allopurinol daily might be effective but risky, while treating with 100 mg daily might have the same outcome with less risk.
A proposed agenda to clarify the role of urate-lowering therapy for asymptomatic hyperuricaemia In order to understand the role of urate-lowering therapy for asymptomatic hyperuricaemia, adequately powered clinical trials with clinically relevant end points (for both gout and “non-gout diseases”) are essential to carefully examine the benefits and risks of such a strategy. It is not sufficient to use observational data alone to support interventions for asymptomatic biochemical abnormalities in clinical practice, noting the frequent lack of concordance between observational studies and randomised controlled trials [37]. A key question for studies examining the role of urate-lowering therapy in asymptomatic hyperuricaemia is whether the benefits of preventing the first attack of gout outweigh the risks of long-term urate-lowering therapy, particularly when urate-lowering therapy can be associated with lifethreatening complications, albeit rarely. The benefit–risk assessment for prevention of gout is likely to be substantially altered if there is also clinical evidence demonstrating benefit for cardiovascular or renal end points. Key issues that need to be addressed with regard to treating “non-gout diseases” include the appropriate patient population and age group. Whether there is a “target serum urate concentration” or a specific drug dose rather than urate being effective, as well as the duration of urate-lowering therapy for each clinically relevant end point will need to be carefully defined through a clinical trial programme. Whether xanthine oxidase inhibitors and uricosuric agents have similar effects suggesting that urate reduction per se is what is required rather than xanthine oxidase inhibition also needs to be clarified. Until such clinical trials are completed and conclusively demonstrate benefit over risk of treatment, urate-lowering therapy for asymptomatic hyperuricaemia cannot be supported.
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