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Cite this article: Camerota A, Mastroiacovo D, Bocale R, Desideri G (2014) Therapeutic Challenges in the Management of Chronic Hyperuricemia and Gout in the Elderly. Ann Gerontol Geriatric Res 1(3): 1012.

*Corresponding authorGiovambattista Desideri, University of L’Aquila, Department of Life, Health, and Environmental Sciences, Viale S. Salvatore, Delta 6 Medicina, 67100 Coppito, L’Aquila, Italy, Tel: 39 0863 499254; Fax: 39 0863 499244; E-mail:

Submitted: 27 July 2014

Accepted: 27 October 2014

Published: 30 October 2014

Copyright© 2014 Desideri et al.

OPEN ACCESS

Keywords•Gout•Hyperuricemia•Xanthine oxidase inhibitors•Cardiovascular risk

Review Article

Therapeutic Challenges in the Management of Chronic Hyperuricemia and Gout in the ElderlyAntonio Camerota1, Daniela Mastroiacovo1, Raffaella Bocale2 and Giovambattista Desideri1*1Department of Life, Health and Environmental Sciences, University of L’Aquila, Italy2Complesso Integrato Columbus, Italy

Abstract

Gout is the most common inflammatory arthritis in the elderly population. The incidence and prevalence of gout in the elderly is increasing. Apart from its high frequency, gout is associated with disability, poor quality of life and increased mortality and therefore represents an ever increasing public health concern. Furthermore, substantial experimental and epidemiological evidence exists supporting the link between elevated levels of serum uric acid and several comorbidities including cardiovascular and kidney diseases. The cornerstone of effective gout management is the long-term lowering of serum urate below saturation concentrations (<6 mg/dL or <360 μmol/L) in order to promote crystal dissolution and prevent monosodium urate crystal formation. It is of great interest whether urate lowering strategies can also lower cardiovascular risk and some preliminary studies in both animal and human subjects suggest that they might. The management of gout includes not only pharmacological approaches, but also a number of non-pharmacological interventions aiming at lessening attack risk, lowering uric acid levels and promoting general health while preventing the development of comorbidities. The two xanthine oxidase inhibitors currently available are effective as long-term urate lowering therapy although the greater efficacy and high tolerability of febuxostat as a urate lowering agent has to be adequately considered especially when the reduction of serum uric acid levels to achieve the target is particularly ambitious and/or the presence of comorbidities increases the risk of adverse effects. Associated comorbidities and cardiovascular risk factors should also be addressed as an important part of the management of gout.

INTRODUCTIONThe prevalence and incidence of chronic hyperuricemia and

gout have risen in many countries over the last few decades, mainly because of the changes in dietary habits and an increased prevalence in comorbidities that promote hyperuricemia, including hypertension, obesity, metabolic syndrome, type 2 diabetes mellitus and chronic kidney disease [1,2]. Other factors responsible for the rising prevalence of chronic hyperuricemica and gout include the widespread prescription of drugs, including salycilate and diuretics, for cardiovascular diseases [3]. Gout is currently the most common inflammatory arthritis in developed countries, especially in elderly population with a prevalence between 0.9% in Italy and 3.9% in the USA and with an increasing incidence in Italy and other developed countries [1,2]. Apart from its high frequency, gout in the elderly is associated with disability, poor quality of life and increased mortality and

therefore represents an ever increasing public health concern [4]. Furthermore, a growing body of evidence suggests a patho-physiological involvement of chronic hyperuricemia and gout in cardiovascular and renal diseases [5-9] supporting the intriguing hypothesis that these clinical conditions can potentially be prevented and/or treated by lowering high serum uric acid levels [10].

CLINICAL PRESENTATIONElderly gout includes gout commencing at >65 years of age

and those with chronic persistent gout that started before age 65. This differs from classical gout found in middle-aged subjects in several respects: poly-articular presentation with upper-extremity joint involvement, fewer acute gouty episodes, indolent clinical course and an increased incidence of tophi [11]. From an epidemiological standpoint, gout in the elderly tends to have a

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more equal gender distribution and there is a stronger association with comorbidities including hypertension, metabolic syndrome, diabetes, acute myocardial infarction and stroke [5,6,11-13]. A positive association between high circulating levels of uric acid and dementia syndrome has also recently been described which, at least in part, is independent of most cardiovascular, cerebrovascular and metabolic risk factors [12]. Gouty arthritis, when not adequately attended to, can be a functionally disabling disease that can lead to a substantial decrease in quality of life in the elderly population [4]. The diagnosis of gout can be more challenging in the elderly than in younger persons due to mimicking other types of arthritis including septic and rheumatoid arthritis [14-16]. In addition, gout can be mistaken for changes that are usually attributed to osteoarthritis. Indeed, tophi can supervene on Heberdenʼs and Bouchardʼs nodes. Some of the distinguishing features of gouty arthritis are the asymmetrical distribution of the tophaceous joint swelling and the presence of typical radio-graphic findings of tophaceous gout [14,15]. The gold standard in establishing the diagnosis is the demonstration of the presence of monosodium urate crystals, typified as negatively birefringent needle-shaped crystals on light and polarizing microscopy of synovial fluid [17,18]. Interestingly, monosodium urate crystals were detected in asymptomatic joints of patients with gout [19]. Silent deposition of monosodium urate crystals as a result of hyperuricemia may lead to early destructive skeletal changes: a large percentage of patients with gout and normal radiographs have occult destructive arthropathy detectable by advanced imaging, such as MRI and/or ultrasound [20]. Ultrasound evaluation can identify a wide spectrum of sub-clinical morphostructural changes suggestive of gouty arthritis in both intra and extra-articular structures in asymptomatic individuals. These observations are of great clinical relevance, requiring careful reconsideration of the management of asymptomatic chronic hyperuricemia: although chronically elevated serum urate has not typically been considered to play a pathogenetic role in tissue damage, the ultrasound evidence reported above might warrant the use of urate lowering agents also in patients with persistent hyperuricemia without clinical signs of gout [12,21].

Therapeutic management

A fundamental prerequisite of gout is hyperuricemia which is defined as the presence of serum uric acid levels above 6 mg/dL which approximately mark the saturation point of monosodium urate at physiological temperature and pH [17,22]. The pathophysiological model portrays, in the presence of hyperuricemia, the intra-articular deposition of monosodium uratecrystals which is responsible for the onset of an acute attack and chronic arthropathy [17,22]. The current management of patients with gout is based on this simplified model and thus implies the control of risk factors related to hyperuricemia, the effective and rapid control of acute attacks and the persistent reduction of serum monosodium urate levels [23-26]. The goals of treatment are to end the pain of acute flares, prevent future attacks and slow or prevent formation of tophi and kidney stones. These effects can be achieved by maintaining the serum uric acid below the saturation point for monosodium urate [23-26]. However, managing gout in the elderly is clinically challenging as people in this demographic segment have lower creatinine

clearance and a greater frequency of comorbidities which may impair handling of the uric acid load. This, combined with the associated concomitant medication use, which impacts both renal function and uric acid, may further increase serum uric acid levels [27]. In this regard, high rates of inappropriate prescribing patterns of gout medications related to contraindicated concomitant medications for other comorbidities has recently been documented [28]. Gout management can be further complicated by low therapeutic compliance; older gout patients have suboptimal adherence to urate lowering treatment compared with therapies for other chronic illnesses [29].

Management of acute flares

Therapeutic targets for the management of an acute gout flare up are suppressing the expression, secretion and signaling of inflammatory cytokines. The management of an acute attack of gout is based on the use of non-steroidal anti-inflammatory drugs (NSAIDs), oral colchicine or corticosteroids, preferably in the first 12-24 hours from the onset of symptoms [23,25,26]. The 2006 EULAR recommendations, which were based on RCT analysis, have concluded that colchicine and NSAIDs are of comparable efficacy [23]. In mild-to-moderate disease (≤6 of 10 on a 0-10 pain visual analogue scale), mono-therapy with NSAIDs, systemic corticosteroids or oral colchicine is recommended [25,30]. In order to effectively manage an acute gout attack, treatment should begin within 24 hours of symptom onset when the response to colchicine has a high clinical diagnostic value [31]. With respect to NSAIDs and corticosteroids, a randomized trial showed that oral prednisolone and naproxen are equally effective in the initial treatment of gout arthritis over 4 days [32]. In more severe disease, characterized by intense pain and often a polyarticular presentation, combination therapy is suggested (colchicine and NSAIDs, oral corticosteroids and colchicine, or intraarticular steroids with each of the other options) [23,25,26]. Low-dose colchicine is better tolerated and is as effective as a high dose, as suggested by the results of a randomized study [23,25,26].

Management of chronic hyperuricemia

The management of chronic hyperuricemia includes not only pharmacological approaches but also a number of non-pharmacological interventions aiming at lessening attack risk, lowering uric acid levels, and promoting general health while preventing the development of comorbidities [23,24,26]. Dietary recommendations suggest avoiding organ meats, high-fructose containing foods and excessive alcohol use, to limit large portions or concentrations of meat and seafood, naturally sweet fruit juices, sugar and salt and to encourage consumption of low-fat or nonfat dairy and vegetables [23,24,26]. Weight loss in those who are overweight, smoking cessation and exercise are also recommended as general lifestyle health considerations in patients with gout [24]. Cardiometabolic comorbidities, common in the gout population, are associated with a higher burden of disease, as reflected by an increased risk of flares [33]. Changing medications associated with hyperuricemia (e.g. diuretics) may also help to control serum uric acid levels, while other comorbidities should be carefully managed [30].

There is a dearth of evidence-based information on effective

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Perc

enta

ge o

f Sub

ject

s With

SU

A <

6.0

mg/

dL a p=0.029 vs allopurinol

b p<0.001 vs febuxosta 40 mg c p<0.001 vs allopurinol d p=0.004 vs allopurinol

a

b,c b,c

d

Figure 1 Achievement of serum uric acid (SUA) levels <6.0 mg/dL (all patients and by renal function) during either febuxostator allopurinol treatment in 374 patients with hyperuricemia and gout aged >65 years enrolled in CONFIRMS trial (modified from Ref. 49).

management of urate lowering therapies in elderly patients. Available urate lowering long term therapy options include xanthine oxidase inhibitors, allopurinol and febuxostat, as well as the uricosuric agent probenecid. Probenecid is not effective in gout patients with renal impairment [34] since 30% to 60% of gout patients have some degree of renal dysfunction [35]. Thus, when urate lowering therapy is indicated, the xanthine oxidase inhibitors allopurinol and febuxostat are the options of choice [10,24,26,30]. Although no data on the efficacy of sulphinpyrazone in patients with gout are available, its off label administration is a treatment option as monotherapy for patients in which other urate lowering agents are contraindicated or as a combination drug with a xanthine oxidase inhibitor in treatment-resistant cases [26].

Allopurinol: Allopurinol has been widely used as urate lowering drug over the past 4 decades and it is the most commonly administered drug in the long-term management of gout. Results from non-controlled studies have shown a dose-dependent response to allopurinol of a lowering of 1 mg of serum uric acid levels for every 100 mg of allopurinol increase [36,37]. These results support the need for slow titration of the allopurinol dose till the attainment of target levels. The currently recommended starting dose of allopurinol is 100 mg daily and gradual increments at 2-4 weeks are recommended in light of efficacy and safety data [23,24,26,30]. Allopurinol is mainly excreted in urine and its metabolite, oxypurinol, can accumulate to toxic levels in patients with renal failure. Therefore, lower starting doses are indicated in this group of patients [38]. In the elderly, the usual starting dose of allopurinol is 50-100 mg on alternate days, increased cautiously by 50-100 mg daily every two weeks until serum uric acid levels <6 mg/dL at a minimum are achieved [11]. Previous guidelines have suggested starting doses of allopurinol based on creatinine clearance although it has been shown this may not provide adequate control of hyperuricemia [23,24]. When given at the usual dosage of 300

mg daily allopurinol allows the target uricemia of 6 mg/dL to be reached in only a minority of gouty patients [30,36,37]. On the other hand, raising the dose may lead to an increased risk of toxicities, although further evidence on this issue is required. Up to 20% of patients experience side effects with allopurinol with 5% discontinuing therapy [39]. Although rare, allopurinol can cause a life-threatening reaction consisting of a severe morbilli form or maculopapular rash with vasculitis, hepatitis and renal failure. This carries a 20% mortality risk [40].

Febuxostat: Febuxostat is a non-purine selective inhibitor of xanthine oxidase that exhibits antihyperuricemic activity by reducing the formation of uric acid [41,42]. Differing from allopurinol, febuxostat provides more selective and potent inhibition of both the oxidized and reduced forms of xanthine oxidase and provides more persistent enzyme inhibition and greater hypouricemic activity [42,43].

Primarily metabolized in the liver [41], its pharmacokinetic and pharmacodynamic profiles are not affected by age or by mild-to-moderate hepatic or renal dysfunction [44-46]. Data from a recent meta-analysis of five randomized controlled trials have shown a greater likelihood to reach the therapeutic target of <6.0 mg/dL (360 μmol /L) with febuxostat at 80 mg or more than with 300 mg of allopurinol [26]. Even more recently, another meta-analysis of five randomized controlled trials confirmed these findings showing that patients receiving febuxostat were more likely to achieve a serum uric acid of <6 mg/dL (<360 μmol/L) than allopurinol recipients (RR: 1.56, 95% C.I. 1.22–2.00, I2:92%) [47]. The safety data analysis comparing febuxostat and allopurinol in both meta-analysis also indicated that the risk of any adverse event was slightly higher for febuxostat in comparison with allopurinol (RR: 0.76, 95% CI: 0.59-0.98 for all combined doses of febuxostat and RR: 0.94, 95% CI:0.90–0.99, I2 13%, respectively) [26,47]. A comparison between efficacy and safety of febuxostat and allopurinol in elderly subjects has

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recently been presented as post-hoc analysis of CONFIRMS study which enrolled hyperuricemic gout subjects (serum urate levels ≥ 8.0 mg/dL) 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) for 6 months, according to a double-blind, randomized design [48]. In the cohort of 374 elderly included in the analysis urate lowering treatment with either dose of febuxostat (40 mg or 80 mg) was significantly more efficacious than fixed doses of allopurinol 200/300 mg in achieving the therapeutic serum urate goal <6.0 mg/dL [49]. In the total CONFIRMS study population, the efficacy of febuxostat 40 mg was comparable to that of allopurinol [48]. In this post-hoc analysis, the greater efficacy of febuxostat 40 mg over allopurinol 200/300 mg can be attributed to the very high proportion of elderly patients with mild or moderate renal impairment. Indeed mild or moderate renal impairment was determined in 139 (37.2%) and 229 (61.2%) subjects, respectively [49]. Interestingly, the study population had comorbidities that are commonly found in elderly subjects with gout. In addition to the predominance of renal impairment, the majority of subjects (87.2%) had some history of cardiovascular disease, inclusive of, but not limited to, hypertension (82.4%), coronary artery disease (24.3%), cardiac arrhythmia (21.1%), and myocardial infarction (10.7%) [49]. In addition, 59.6% of elderly subjects had a history of hyperlipidemia and 24.6% were diabetic [49]. Thus, the cohort seems to be quite representative of the real world elderly population. These results suggest that despite high rates of comorbidities, including renal impairment, the hyperuricemia of elderly gout patients may be more effectively managed with approved doses of febuxostat, with low risk of side effects.

Taken together the above findings indicate that febuxostat is an effective urate lowering agent in patients with gout and has shown greater efficacy at a dosage of 80 mg or more when compared to allopurinol at the maximum dose of 300 mg in the short-term control of hyperuricemia [26,47]. In addition, treatment with febuxostat seems to be more effective and safe in patients with mild or moderate renal insufficiency when compared to treatment with allopurinol [26,49]. The recommended dose of febuxostat is 80 mg once daily. If serum uric acid is >6.0 mg/dL after two to four weeks, febuxostat 120 mg once daily may be considered [20,25,30].

CONCLUSIONDespite the current in-depth knowledge of the

pathophysiological role of hyperuricemia and gout in human diseases and the availability of valid therapeutic options, the management of patients with gout is still largely suboptimal [50]. As the prevalence of gout among the elderly continues to rise [51,52], optimal management of chronic gout and its underlying hyperuricemia is necessary to improve clinical outcomes and reduce healthcare utilization and associated costs. Achievement and long-term maintenance of serum uric acid levels <6.0 mg/dL leads to reduction of tophi and near-elimination of acute flares [53-57], and may stabilize or improve renal function in gout patients [58]. Both xanthine oxidase inhibitors currently available are effective as long-term urate lowering therapy although the greater efficacy and minor adverse effects of febuxostat as urate lowering agent has to be adequately considered,

especially when the reduction of serum uric acid levels to achieve the target is particularly ambitious and/or the presence of comorbidities increase the risk of adverse effects [26,47]. Chronic hyperuricemia and gout have been also identified as independent risk factors for diabetes, cardiovascular disease, and all-cause and cardiovascular-related mortality [5-9]. Beyond their proven capacity to lower urate levels, it is of great interest whether urate lowering treatments, particularly xanthine oxidase inhibitors, can also lower the risk of cardiovascular events and some preliminary studies in both animal and human subjects suggest that they might [59]. If extra-articular benefits of hyperuricemia treatment will be confirmed, hypouricemic therapy would then decrease the cardiovascular risk of treated patients as well as obviously improve their quality of life via a direct decrement in uric acid-related clinical events and complications

REFERENCES1. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the

US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011; 63: 3136-3141.

2. Trifirò G, Morabito P, Cavagna L, Ferrajolo C, Pecchioli S, Simonetti M. Epidemiology of gout and hyperuricaemia in Italy during the years 2005-2009: a nationwide population-based study. Ann Rheum Dis. 2013; 72: 694-700.

3. McAdams DeMarco MA, Maynard JW, Baer AN, Gelber AC, Young JH, Alonso A. Diuretic use, increased serum urate levels, and risk of incident gout in a population-based study of adults with hypertension: the Atherosclerosis Risk in Communities cohort study. Arthritis Rheum. 2012; 64: 121-129.

4. Becker MA, Schumacher HR, Benjamin KL, Gorevic P, Greenwald M, Fessel J. Quality of life and disability in patients with treatment-failure gout. J Rheumatol. 2009; 36: 1041-1048.

5. Lottmann K, Chen X, Schädlich PK. Association between gout and all-cause as well as cardiovascular mortality: a systematic review. Curr Rheumatol Rep. 2012; 14: 195-203.

6. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008; 359: 1811-1821.

7. Grassi D, Ferri L, Desideri G, Di Giosia P, Cheli P, Del Pinto R. Chronic hyperuricemia, uric acid deposit and cardiovascular risk. Curr Pharm Des. 2013; 19: 2432-2438.

8. Borghi C. Uric acid as a cross-over between rheumatology and cardiovascular disease. Curr Med Res Opin. 2013; 29 Suppl 3: 1-2.

9. Grassi D, Desideri G, Di Giacomantonio AV, Di Giosia P, Ferri C. Hyperuricemia and cardiovascular risk. High Blood Press Cardiovasc Prev. 2014;.

10. Grassi D, Pontremoli R, Bocale R, Ferri C, Desideri G. Therapeutic Approaches to Chronic Hyperuricemia and Gout. High Blood Press Cardiovasc Prev. 2014;.

11. Fam AG. Gout in the elderly. Clinical presentation and treatment. Drugs Aging. 1998; 13: 229-243.

12. Desideri G, Castaldo G, Lombardi A, Mussap M, Testa A, Pontremoli R. Is it time to revise the normal range of serum uric acid levels? Eur Rev Med Pharmacol Sci. 2014; 18: 1295-1306.

13. Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2007; 57: 109-115.

14. Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yü TF.

Central

Desideri et al. (2014)Email:

Ann Gerontol Geriatric Res 1(3): 1012 (2014) 5/6

Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977; 20: 895-900.

15. Schlesinger N. Diagnosis of gout: clinical, laboratory, and radiologic findings. Am J Manag Care. 2005; 11: S443-450.

16. Shah K, Spear J, Nathanson LA, McCauley J, Edlow JA. Does the presence of crystal arthritis rule out septic arthritis? J Emerg Med. 2007; 32: 23-26.

17. Richette P, Bardin T. Gout. Lancet. 2010; 375: 318-328.

18. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout, part I: diagnosis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006; 65: 1301-1311.

19. Bomalaski JS, Lluberas G, Schumacher HR Jr. Monosodium urate crystals in the knee joints of patients with asymptomatic nontophaceous gout. Arthritis Rheum. 1986; 29: 1480-1484.

20. Carter JD, Kedar RP, Anderson SR, Osorio AH, Albritton NL, Gnanashanmugam S. An analysis of MRI and ultrasound imaging in patients with gout who have normal plain radiographs. Rheumatology (Oxford). 2009; 48: 1442-1446.

21. Pineda C, Amezcua-Guerra LM, Solano C, Rodriguez-Henríquez P, Hernández-Díaz C, Vargas A, et al. Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study. Arthritis Res Ther. 2011; 13: R4.

22. Choi HK, Mount DB, Reginato AM; American College of Physicians; American Physiological Society. Pathogenesis of gout. Ann Intern Med. 2005; 143: 499-516.

23. Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. EULAR Standing Committee for International Clinical Studies Including Therapeutics. 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). Ann Rheum Dis. 2006; 65: 1312-24.

24. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh M, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic non pharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012; 64: 1431-1446.

25. Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012; 64: 1447-1461.

26. Manara M, Bortoluzzi A, Favero M, Prevete I, Scirè CA, Bianchi G, et al. Italian Society of Rheumatology recommendations for the management of gout. Reumatismo. 2013; 65: 4-21.

27. Hanly JG, Skedgel C, Sketris I, Cooke C, Linehan T, Thompson K. Gout in the elderly--a population health study. J Rheumatol. 2009; 36: 822-830.

28. Keenan RT, O’Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med. 2011; 124: 155-163.

29. Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008; 28: 437-443.

30. Bardin T, Desideri G. How to manage patients with gout. Curr Med Res Opin. 2013; 29 Suppl 3: 17-24.

31. Hamburger M, Baraf HS, Adamson TC 3rd, Basile J, Bass L, Cole B. 2011

recommendations for the diagnosis and management of gout and hyperuricemia. Phys Sportsmed. 2011; 39: 98-123.

32. Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet. 2008; 371: 1854-1860.

33. Roddy E, Zhang W, Doherty M. Concordance of the management of chronic gout in a UK primary-care population with the EULAR gout recommendations. Ann Rheum Dis. 2007; 66: 1311-1315.

34. Bartels EC, Matossian GS. Gout: six-year follow-up on probenecid (benemid) therapy. Arthritis Rheum. 1959; 2: 193-202.

35. Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease. Semin Nephrol. 2005; 25: 43-49.

36. Rundles RW, Metz EN, Silberman HR. Allopurinol in the treatment of gout. Ann Intern Med. 1966; 64: 229-258.

37. Yü TF. The effect of allopurinol in primary and secondary gout. Arthritis Rheum. 1965; 8: 905-906.

38. Conway N, Schwartz S. Diagnosis and management of acute gout. Med Health R I. 2009; 92: 356-358.

39. Wortmann RL. Recent advances in the management of gout and hyperuricemia. Curr Opin Rheumatol. 2005; 17: 319-324.

40. Ene-Stroescu D, Gorbien MJ. Gouty arthritis. A primer on late-onset gout. Geriatrics. 2005; 60: 24-31.

41. Becker MA, Kisicki J, Khosravan R, Wu J, Mulford D, Hunt B, et al. Febuxostat (TMX-67), a novel, nonpurine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers. Nucleosides Nucleotides Nucleic Acids. 2004; 23: 1111-1116.

42. Takano Y, Hase-Aoki K, Horiuchi H, Zhao L, Kasahara Y, Kondo S. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 2005; 76: 1835-1847.

43. Mayer MD, Khosravan R, Vernillet L, Wu JT, Joseph-Ridge N, Mulford DJ. Pharmacokinetics and pharmacodynamics of febuxostat, a new non-purine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005; 12: 22-34.

44. Khosravan R, Kukulka MJ, Wu JT, Joseph-Ridge N, Vernillet L. The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol. 2008; 48: 1014-1024.

45. Khosravan R, Grabowski BA, Mayer MD, Wu JT, Joseph-Ridge N, Vernillet L. The effect of mild and moderate hepatic impairment on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol. 2006; 46: 88-102.

46. Hoshide S, Takahashi Y, Ishikawa T, Kubo J, Tsuchimoto M, Komoriya K. PK/PD and safety of a single dose of TMX-67 (febuxostat) in subjects with mild and moderate renal impairment. Nucleosides Nucleotides Nucleic Acids. 2004; 23: 1117-1118.

47. Faruque LI, Ehteshami-Afshar A, Wiebe N, Tjosvold L, Homik J, Tonelli M. A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout. Semin Arthritis Rheum. 2013; 43: 367-375.

48. Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010; 12: R63.

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Ann Gerontol Geriatric Res 1(3): 1012 (2014) 6/6

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Cite this article

49. Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age. BMC Geriatr. 2012; 12: 11.

50. Doherty M, Jansen TL, Nuki G, Pascual E, Perez-Ruiz F, Punzi L. Gout: why is this curable disease so seldom cured? Ann Rheum Dis. 2012; 71: 1765-1770.

51. Arromdee E, Michet CJ, Crowson CS, O’Fallon WM, Gabriel SE. Epidemiology of gout: is the incidence rising? J Rheumatol. 2002; 29: 2403-2406.

52. Wallace KL, Riedel AA, Joseph-Ridge N, Wortmann R. Increasing prevalence of gout and hyperuricemia over 10 years among older adults in a managed care population. J Rheumatol. 2004; 31: 1582-1587.

53. Becker MA, Schumacher HR, MacDonald PA, Lloyd E, Lademacher C. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009; 36: 1273-1282.

54. Schumacher HR Jr, Becker MA, Lloyd E, MacDonald PA, Lademacher

C. Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology (Oxford). 2009; 48: 188-194.

55. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004; 51: 321-325.

56. Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002; 47: 356-360.

57. Perez-Ruiz F, Lioté F. Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum. 2007; 57: 1324-1328.

58. Whelton A, Macdonald PA, Zhao L, Hunt B, Gunawardhana L. Renal function in gout: long-term treatment effects of febuxostat. J Clin Rheumatol. 2011; 17: 7-13.

59. Krishnan E. Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout. Rheumatology (Oxford). 2010; 49: 1229-1238.