Abstract
Gout is currently one of the most common causes of inflammatory arthritis in most industrialised countries. 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. 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 long-term serum urate lowering below saturation concentrations (<6 mg/dL or <360 μmol/L) in order to promote crystal dissolution and prevent monosodium urate crystals formation. The management of gout includes not only pharmacological approaches, but also a number of nonpharmacologic interventions aiming at lessening attack risk, lowering uric acid levels and promoting general health while preventing the development of comorbidities. It is of great address whether urate lowering strategies can also lower cardiovascular risk and some preliminary studies in both animal and human subjects suggest that they might. Patient education and appropriate lifestyle advice are core aspects of management of hyperuricemia and gout. The two xanthine oxidase inhibitors currently available are effective as long-term urate lowering therapy although the greater efficacy and good tolerability 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 increases the risk of adverse effects. Associated comorbidities and cardiovascular risk factors should be also addressed as an important part of the management of chronic hyperuricemia and gout.
Similar content being viewed by others
References
Richette P, Bardin T. Gout. Lancet. 2010;375:318–28.
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(10):3136–41.
Trifirò G, Morabito P, Cavagna L, Ferrajolo C, Pecchioli S, Simonetti M, Bianchini E, Medea G, Cricelli C, Caputi AP, Mazzaglia G. Epidemiology of gout and hyperuricaemia in Italy during the years 2005–2009: a nationwide population-based study. Ann Rheum Dis. 2013;72(5):694–700.
McAdams DeMarco MA, Maynard JW, Baer AN, Gelber AC, Young JH, Alonso A, Coresh J. 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;64:121–9.
Becker MA, Schumacher HR, Benjamin KL, et al. Quality of life and disability in patients with treatment-failure gout. J Rheumatol. 2009;36:1041–8.
Lottmann K, Chen X, Schadlich PK. Association between gout and all-cause as well as cardiovascular mortality: a systematic review. Curr Rheumatol Rep. 2012;14:195–203.
Feig D, Kang D-H, Johnson R. Uric acid and cardiovascular risk. NEJM. 2008;359(17):1811–21.
Grassi D, Ferri L, Desideri G, Di Giosia P, Cheli P, Del Pinto R, Properzi G, Ferri C. Chronic hyperuricemia, uric acid deposit and cardiovascular risk. Curr Pharm Des. 2013;19:2432–8.
Borghi C. Uric acid as a cross-over between rheumatology and cardiovascular disease. Curr Med Res Opin. 2013;29(Suppl3):1–2.
Doherty M, Jansen TL, Nuki G, Pascual E, Perez-Ruiz F, Punzi L, So AK, Bardin T. Gout: why is this curable disease so seldom cured? Ann Rheum Dis. 2012;71(11):1765–70.
Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, Gerster J, Jacobs J, Leeb B, Lioté F, McCarthy G, Netter P, Nuki G, Perez-Ruiz F, Pignone A, Pimentão J, Punzi L, Roddy E, Uhlig T, Zimmermann-Gòrska I. 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;65:1301–11.
Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, Gerster J, Jacobs J, Leeb B, Lioté F, McCarthy G, Netter P, Nuki G, Perez-Ruiz F, Pignone A, Pimentão J, Punzi L, Roddy E, Uhlig T, Zimmermann-Gòrska I, 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(10):1312–24.
Khanna D, Khanna PP, Fitzgerald JD, Singh MK, Bae S, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, DE Furst, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R, American College of Rheumatology. 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;64:1447–61.
Bardin T, Desideri G. How to manage patients with gout. Curr Med Res Opin. 2013;29(Suppl 3):17–24.
Manara M, Bortoluzzi A, Favero M, Prevete I, Scirè CA, Bianchi G, Borghi C, Cimmino MA, D’Avola GM, Desideri G, Di Giacinto G, Govoni M, Grassi W, Lombardi A, Marangella M, MatucciCerinic M, Medea G, Ramonda R, Spadaro A, Punzi L, Minisola G. Italian Society of Rheumatology recommendations for the management of gout. Reumatismo. 2013;65(1):4–21.
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(9627):1854–60.
Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh M, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia G, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, DE Furst, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R. 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;64:1431–46.
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;66:1311–5.
Reinders MK, Jansen TL. New advances in the treatment of gout: review of pegloticase. Ther Clin Risk Manage. 2010;6:543–50.
Conway N, Schwartz S. Diagnosis and management of acute gout. Med Health R I. 2009;92:356–8.
Rundles RW, Metz EN, Silberman HR. Allopurinol in the treatment of gout. Ann Intern Med. 1966;64:229–58.
Yu TF. The effect of allopurinol in primary and secondary gout. Arthritis Rheum. 1965;8:905–6.
Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem. 2003;278:1848–55.
Becker MA, Kisicki J, Khosravan R, Wu J, Mulford D, Hunt B, MacDonald P, Joseph-Ridge N. 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;23:1111–6.
Takano Y, Hase-Aoki K, Horiuchi H, Zhao L, Kasahara Y, Kondo S, Becker MA. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 2005;76:1835–47.
Mayer MD, Khosravan R, Vernillet L, Wu JT, Joseph-Ridge N, Mulford DJ. Pharmacokinetics and pharmacodynamics of febuxostat, a new selective nonpurine inhibitor of xanthine oxidase, in subjects with renal impairment. Am J Ther. 2005;12:22–34.
Garcia-Valladares I, Khan T, Espinoza LR. Efficacy and safety of febuxostat in patients with hyperuricemia and gout. Ther Adv Musculoskelet Disord. 2011;3(5):245–53.
Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, Lademacher C. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the COMFIRMS trial. Arthritis Res Ther. 2010;12:R63.
Edwards NL. Febuxostat: a new treatment for hyperuricaemia in gout. Rheumatology (Oxford). 2009;48(Suppl 2):ii15–9.
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(4):356–60.
Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, Lademacher C, Joseph-Ridge N. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59(11):1540–8.
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(3):367–75.
Yamanaka H, Togashi R, Hakoda M, Terai C, Kashiwazaki S, Dan T, Kamatani N. Optimal range of serum urate concentrations to minimize risk of gouty attacks during anti-hyperuricemic treatment. Adv Exp Med Biol. 1998;431:13–8.
Keenan RT, O’Brien WR, Lee KH, Crittenden DB, Fisher MC, Goldfarb DS, Krasnokutsky S, Oh C, Pillinger MH. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med. 2011;124:155–63.
Jackson RL, Hunt B, MacDonald PA. The efficacy and safety of febuxostat for urate lowering in gout patients ≥65 years of age. BMC Geriatrics. 2012;12:11.
Krishnan E. Inflammation, oxidative stress and lipids: the risk triad for atherosclerosis in gout. Rheumatology. 2010;49:1229–38.
Johnson R, Kang D, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003;41(6):1183–9.
Krishnan E, Svendsen K, Neaton JD, Grandits G, Kuller LH. Long-term cardiovascular mortality among middle-aged men with gout. Arch Intern Med. 2008;168:1104–10.
Grassi D, Desideri G, Di Giacomantonio AV, Di Giosia P, Ferri C. Hyperuricemia and cardiovascular risk. High Blood Press Cardiovasc Prev. 2014 [Epub ahead of print].
Stack AG, Hanley A, Casserly LF, Cronin CJ, Abdalla AA, Kiernan TJ, Murthy BV, Hegarty A, Hannigan A, Nguyen HT. Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. QJM. 2013;106(7):647–58.
Verdecchia P, Schillaci G, Reboldi G, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension. 2000;36(6):1072–8.
Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38(5):1101–6.
Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on the blood pressure of adolescents with newly diagnosed essential hypertension. JAMA. 2008;300:924–32.
Soletsky B, Feig DI. Uric acid causes pre-hypertension in obese adolescents. Hypertension. 2012;60:1148–56.
Kanbay M, Ozkara A, Selcoki Y, Isik B, Turgut F, Bavbek N, Uz E, Akcay A, Yigitoglu R, Covic A. Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearance, and proteinuria in patients with normal renal functions. Int Urol Nephrol. 2007;39:1227–33.
Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt DV, Reaveley DA, Schuler G, Coats AJ, Anker SD, Hambrecht R. Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation. 2002;105:2619–24.
Coghlan JG, Flitter WD, Clutton SM, Panda R, Daly R, Wright G, Ilsley CD, Slater TF. Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 1994;107:248–56.
Castelli P, Condemi AM, Brambillasca C, Fundarò P, Botta M, Lemma M, Vanelli P, Santoli C, Gatti S, Riva E. Improvement of cardiac function by allopurinol in patients undergoing cardiac surgery. J Cardiovasc Pharmacol. 1995;125:119–25.
Sabán-Ruiz J, Alonso-Pacho A, Fabregate-Fuente M, de la Puerta González-Quevedo C. Xanthine oxidase inhibitor febuxostat as a novel agent postulated to act against vascular inflammation. Antiinflamm Antiallergy Agents Med Chem. 2013;12(1):94–9.
Smink PA, Bakker SJ, Laverman GD, Berl T, Cooper ME, de Zeeuw D, et al. An initial reduction in serum uric acid during angiotensin receptor blocker treatment is associated with cardiovascular protection: a post-hoc analysis of the RENAAL and IDNT trials. J Hypertens. 2012;30(5):1022–8.
Savarese G, Ferri C, Trimarco B, Rosano G, Dellegrottaglie S, Losco T, Casaretti L, D’Amore C, Gambardella F, Prastaro M, Rengo G, Leosco D, Perrone-Filardi P. Changes in serum uric acid levels and cardiovascular events: a meta-analysis. Nutr Metab Cardiovasc Dis. 2013;23(8):707–14.
White WB, Chohan S, Dabholkar A, Hunt B, Jackson R. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J. 2012;164:14–20.
Pascual E, Sivera F. Why is gout so poorly managed? Ann Rheum Dis. 2007;66:1269–70.
So A, Thorens B. Uric acid transport and disease. J Clin Invest. 2010;120(6):1791–9.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Grassi, D., Pontremoli, R., Bocale, R. et al. Therapeutic Approaches to Chronic Hyperuricemia and Gout. High Blood Press Cardiovasc Prev 21, 243–250 (2014). https://doi.org/10.1007/s40292-014-0051-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40292-014-0051-6