High Blood Press Cardiovasc Prev DOI 10.1007/s40292-014-0051-6
REVIEW ARTICLE
Therapeutic Approaches to Chronic Hyperuricemia and Gout Davide Grassi • Roberto Pontremoli Raffaella Bocale • Claudio Ferri • Giovambattista Desideri
•
Received: 12 January 2014 / Accepted: 24 March 2014 Ó Springer International Publishing Switzerland 2014
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 lmol/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 D. Grassi C. Ferri G. Desideri (&) Department of Life, Health and Environmental Sciences, University of L’Aquila, Viale S. Salvatore, Delta 6 Medicina, 67100 Coppito, L’Aquila, Italy e-mail: [email protected] R. Pontremoli Department of Internal Medicine, University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy R. Bocale Complesso Integrato Columbus, Rome, Italy
oxidase inhibitors currently available are effective as longterm 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. Keywords Gout Hyperuricemia Xanthine oxidase inhibitors Cardiovascular risk
1 Introduction Gout is currently one of the most common causes of inflammatory arthritis in most industrialised countries [1]. Recent epidemiological surveys have suggested that the prevalence and incidence of hyperuricemia and gout have risen in many countries over the last few decades, mainly because of the changes of dietary habits and an increased prevalence of comorbidities that promote hyperuricemia, including hypertension, obesity, metabolic syndrome, type 2 diabetes mellitus and chronic kidney disease [2, 3]. Other factors responsible for the rising prevalence of gout include widespread prescriptions of drugs, including salicylate and diuretics, for cardiovascular diseases [4]. 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 [5, 6]. During the last few years a growing body of evidence demonstrated that high serum uric acid levels with or without gout are also associated with cardiovascular
D. Grassi et al.
diseases such as hypertension, coronary heart disease, peripheral vascular disease and stroke [7–9]. Despite 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 [10]. The management of patients with gout implies the control of risk factors related to hyperuricaemia, the effective and rapid control of acute attacks and the persistent reduction of serum uric acid levels. 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 [1].
2 Management of Acute Flares Gout is due to increased concentrations of uric acid in the blood which provokes deposition of monosodium urate crystals in supersaturated extracellular fluids of the joints and soft tissues [1] (Fig. 1). Indeed, demonstration of monosodium urate crystals in synovial fluid or tophus aspirates permits a definitive diagnosis of gout [11]. Monosodium urate crystals are pro-inflammatory stimuli that can initiate, amplify and sustain an intense inflammatory response [1]. Thus, therapeutic targets for the management of an acute gout flare are suppressing the expression, secretion and signaling of inflammatory cytokines. In mild-to-moderate disease (B6 of 10 on a 0–10 pain visual analogue scale), monotherapy with non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids or oral colchicine is recommended [12–15]. Effective management of an acute gout attack should begin treatment within 24 h of symptom onset when the response to colchicine has an high clinical diagnostic value [12–15]. 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 [16]. 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 intra-articular steroids with each of the other options) [12–15]. Low-dose colchicine is better tolerated and is as effective as a high dose, as suggested by the results of a randomized study [12–15].
the serum uric acid below the saturation point for monosodium urate (\6 mg/dL or\360 lmol/L) [12, 14, 15, 17]. The management of chronic hyperuricemia 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 [12, 14, 15, 17] (Fig. 1). Dietary recommendations suggest to avoid 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 [17]. Weight loss in those who are overweight, smoking cessation and exercise are also recommended as general lifestyle health considerations in patients with gout [17]. Cardiometabolic comorbidities, common in the gout population, are associated with a higher burden of disease, as reflected by an increased risk of flares [18]. Changing medications associated with hyperuricaemia (e.g. diuretics) may also help to control serum uric acid levels, while other comorbid conditions should be carefully managed [14]. When urate-lowering therapy is indicated, the xanthine oxidase inhibitors allopurinol and febuxostat are the options of choice [14, 15, 17]. The uricosuric agent probenecid is recommended as an alternative first-line agent when at least one xanthine oxidase inhibitor is contraindicated [12, 17]. However, probenecid presents overall moderate efficacy, is not indicated in patients with renal failure and has the potential for several drug-drug interactions [12, 14, 17]. Although no data on the efficacy with 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 [15]. Pegloticase, a pegylated-uricase, is a potent and expensive drug able to promote a dramatic reduction of uricemia and rapid disappearance of tophi. Unfortunately high antibody titers develop in 40 % of patients leading to reduced efficacy and infusion reactions [1, 19]. Pegloticase, which has been recently approved in the USA for the treatment of severe, treatment-refractory chronic gout, has to be administered bimonthly intravenously [19]. 3.1 Allopurinol
3 Management of Chronic Hyperuricemia The cornerstone of effective gout management is long-term serum urate lowering below saturation concentrations in order to promote crystal dissolution and prevent monosodium urate crystal formation thus representing a curative approach [12, 14, 15, 17]. This is achieved by maintaining
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. 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 [12, 14, 15, 17]. Allopurinol is mainly excreted in urine and its
Therapeutic Approaches to Chronic Hyperuricemia and Gout Fig. 1 Uric acid metabolism and urate lowering strategies (modified from Ref. [54])
Diet + nucleotide turnover
Synthesis inhibitor • Febuxostat
Inosine
• Allopurinol • Oxipurinol
Hypoxanthine
Enzymatic oxidation
Xanthine oxidase Xanthina
Pegylated-uricase
Xantyne ossidase Allantoin
Uricase
Urate
Excretory mechanisms
Normal serum levels human: 4-6 mg/dL mouse:
REVIEW ARTICLE
Therapeutic Approaches to Chronic Hyperuricemia and Gout Davide Grassi • Roberto Pontremoli Raffaella Bocale • Claudio Ferri • Giovambattista Desideri
•
Received: 12 January 2014 / Accepted: 24 March 2014 Ó Springer International Publishing Switzerland 2014
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 lmol/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 D. Grassi C. Ferri G. Desideri (&) Department of Life, Health and Environmental Sciences, University of L’Aquila, Viale S. Salvatore, Delta 6 Medicina, 67100 Coppito, L’Aquila, Italy e-mail: [email protected] R. Pontremoli Department of Internal Medicine, University of Genoa and IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genoa, Italy R. Bocale Complesso Integrato Columbus, Rome, Italy
oxidase inhibitors currently available are effective as longterm 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. Keywords Gout Hyperuricemia Xanthine oxidase inhibitors Cardiovascular risk
1 Introduction Gout is currently one of the most common causes of inflammatory arthritis in most industrialised countries [1]. Recent epidemiological surveys have suggested that the prevalence and incidence of hyperuricemia and gout have risen in many countries over the last few decades, mainly because of the changes of dietary habits and an increased prevalence of comorbidities that promote hyperuricemia, including hypertension, obesity, metabolic syndrome, type 2 diabetes mellitus and chronic kidney disease [2, 3]. Other factors responsible for the rising prevalence of gout include widespread prescriptions of drugs, including salicylate and diuretics, for cardiovascular diseases [4]. 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 [5, 6]. During the last few years a growing body of evidence demonstrated that high serum uric acid levels with or without gout are also associated with cardiovascular
D. Grassi et al.
diseases such as hypertension, coronary heart disease, peripheral vascular disease and stroke [7–9]. Despite 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 [10]. The management of patients with gout implies the control of risk factors related to hyperuricaemia, the effective and rapid control of acute attacks and the persistent reduction of serum uric acid levels. 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 [1].
2 Management of Acute Flares Gout is due to increased concentrations of uric acid in the blood which provokes deposition of monosodium urate crystals in supersaturated extracellular fluids of the joints and soft tissues [1] (Fig. 1). Indeed, demonstration of monosodium urate crystals in synovial fluid or tophus aspirates permits a definitive diagnosis of gout [11]. Monosodium urate crystals are pro-inflammatory stimuli that can initiate, amplify and sustain an intense inflammatory response [1]. Thus, therapeutic targets for the management of an acute gout flare are suppressing the expression, secretion and signaling of inflammatory cytokines. In mild-to-moderate disease (B6 of 10 on a 0–10 pain visual analogue scale), monotherapy with non-steroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids or oral colchicine is recommended [12–15]. Effective management of an acute gout attack should begin treatment within 24 h of symptom onset when the response to colchicine has an high clinical diagnostic value [12–15]. 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 [16]. 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 intra-articular steroids with each of the other options) [12–15]. Low-dose colchicine is better tolerated and is as effective as a high dose, as suggested by the results of a randomized study [12–15].
the serum uric acid below the saturation point for monosodium urate (\6 mg/dL or\360 lmol/L) [12, 14, 15, 17]. The management of chronic hyperuricemia 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 [12, 14, 15, 17] (Fig. 1). Dietary recommendations suggest to avoid 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 [17]. Weight loss in those who are overweight, smoking cessation and exercise are also recommended as general lifestyle health considerations in patients with gout [17]. Cardiometabolic comorbidities, common in the gout population, are associated with a higher burden of disease, as reflected by an increased risk of flares [18]. Changing medications associated with hyperuricaemia (e.g. diuretics) may also help to control serum uric acid levels, while other comorbid conditions should be carefully managed [14]. When urate-lowering therapy is indicated, the xanthine oxidase inhibitors allopurinol and febuxostat are the options of choice [14, 15, 17]. The uricosuric agent probenecid is recommended as an alternative first-line agent when at least one xanthine oxidase inhibitor is contraindicated [12, 17]. However, probenecid presents overall moderate efficacy, is not indicated in patients with renal failure and has the potential for several drug-drug interactions [12, 14, 17]. Although no data on the efficacy with 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 [15]. Pegloticase, a pegylated-uricase, is a potent and expensive drug able to promote a dramatic reduction of uricemia and rapid disappearance of tophi. Unfortunately high antibody titers develop in 40 % of patients leading to reduced efficacy and infusion reactions [1, 19]. Pegloticase, which has been recently approved in the USA for the treatment of severe, treatment-refractory chronic gout, has to be administered bimonthly intravenously [19]. 3.1 Allopurinol
3 Management of Chronic Hyperuricemia The cornerstone of effective gout management is long-term serum urate lowering below saturation concentrations in order to promote crystal dissolution and prevent monosodium urate crystal formation thus representing a curative approach [12, 14, 15, 17]. This is achieved by maintaining
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. 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 [12, 14, 15, 17]. Allopurinol is mainly excreted in urine and its
Therapeutic Approaches to Chronic Hyperuricemia and Gout Fig. 1 Uric acid metabolism and urate lowering strategies (modified from Ref. [54])
Diet + nucleotide turnover
Synthesis inhibitor • Febuxostat
Inosine
• Allopurinol • Oxipurinol
Hypoxanthine
Enzymatic oxidation
Xanthine oxidase Xanthina
Pegylated-uricase
Xantyne ossidase Allantoin
Uricase
Urate
Excretory mechanisms
Normal serum levels human: 4-6 mg/dL mouse:
