Critical revision of the medical treatment of gout in Brazil

Valderilio Feijó Azevedo Maicon Piana Lopes Nathan Marostica Catholino Eduardo dos Santos Paiva Vitor Andrei Araújo Geraldo da Rocha Castelar Pinheiro About the authors

ABSTRACT

Gout is considered the most common form of inflammatory arthritis in men over 40 years. The authors present a brief review of the current treatment of gout and discuss the existing pharmacological limitations in Brazil for the treatment of this disease. Although allopurinol is still the main drug administered for decreasing serum levels of uric acid in gout patients in this country, the authors also present data that show a great opportunity for the Brazilian drug market for the treatment of hyperuricemia and gout and especially for patients using private and public (SUS) health care systems.

Keywords:
Gout; Hyperuricaemia; Treatment; Gouty arthritis; Medicines

RESUMO

A gota é considerada a forma mais comum de artrite inflamatória em homens acima de 40 anos. Os autores apresentam uma breve revisão sobre o tratamento atual da gota e discutem as limitações farmacológicas existentes no Brasil para o tratamento dessa enfermidade. Apesar de o alopurinol ainda ser a principal medicação para a redução dos níveis de uricemia de pacientes com gota no país, os autores também apresentam dados que apontam para uma grande oportunidade para o mercado farmacológico brasileiro em relação ao tratamento da hiperuricemia e da artrite gotosa e especialmente para pacientes usuários de sistemas privados de saúde e do SUS (Sistema Único de Saúde).

Palavras-chave:
Gota; Hiperuricemia; Tratamento; Artrite gotosa; Medicamentos

Introduction

Gout is a disease characterized by an accumulation of monosodium urate (MSU) crystals in the joints, synovial tissue, bone, and skin, regardless of the presence or absence of clinical manifestations.11 Bardin T, Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol. 2014;26:186-91.,22 Perez-Ruiz F, Herrero-Beites AM. Evaluation and treatment of gout as a chronic disease. Adv Ther. 2012;29:935-46. This accumulation is a result of a persistent hyperuricemia.11 Bardin T, Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol. 2014;26:186-91. The MSU crystals are the solid form of uric acid, the final product of purine metabolism; these crystals can accumulate in organic tissue.33 George J, Struthers AD. Role of urate, xanthine oxidase and the effects of allopurinol in vascular oxidative stress. Vasc Health Risk Manag. 2009;5:265-72. The purines are a result of the breakdown of mononucleotides, substances derived from those nitrogenous bases that make up DNA and RNA. In the biological process of urate production, the compounds are, in their last stages, metabolized into xanthine which, in turn, is irreversibly oxidized to produce uric acid by the action of the enzyme xanthine oxidase,44 Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006;58:87-114.,55 Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids. 2008;27:608-19. which comprises the arsenal of peroxisomes in the majority of cells.33 George J, Struthers AD. Role of urate, xanthine oxidase and the effects of allopurinol in vascular oxidative stress. Vasc Health Risk Manag. 2009;5:265-72. Circulating uric acid (UA) in the blood maintain its physiological levels at concentrations around 6.0 mg/dL,66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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. and the excess is eliminated by the kidneys.77 Lipkowitz MS. Regulation of uric acid excretion by the kidney. Curr Rheumatol Rep. 2012;14:179-88. Under physiological conditions, circulating UA can take part in antioxidant, oxidant, and pro-inflammatory reactions; such participations are more evident when circulating UA is found in high serum concentrations.55 Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids. 2008;27:608-19.

Hyperuricemia is defined as the high urate serum concentration, at approximately 6.8 mg/dL, which is the limit of solubility of the urate.11 Bardin T, Richette P. Definition of hyperuricemia and gouty conditions. Curr Opin Rheumatol. 2014;26:186-91. Above this level of solubility, MSU crystals may accumulate in the tissues, especially in a case of chronic, untreated hyperuricemia. In addition to disturbances in the generation or clearance of uric acid, hyperuricemia can be initiated or accelerated in patients with kidney and cardiac transplant, as these are usually associated with chronic kidney disease and the use of loop diuretics.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206. UA may be associated with different multifactorial disorders, whether dependently or independently. There is a direct relationship between UA levels and development and progression of cardiovascular disease.99 Park JW, Ko DJ, Yoo JJ, Chang SH, Cho HJ, Kang EH, et al. Clinical factors and treatment outcomes associated with failure in the detection of urate crystal in patients with acute gouty arthritis. Korean J Intern Med. 2014;29:361-69.

10 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.

11 Stack AG, Hanley A, Casserly LF, Cronin CJ, Abdalla AA, Kiernan TJ, et al. Independent and conjoint associations of gout and hyperuricaemia with total and cardiovascular mortality. QJM. 2013;106:647-58.

12 Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout. Part I: diagnosis. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-11.

13 Maruhashi T, Nakashima A, Soga J, Fujimura N, Idei N, Mikami S, et al. Hyperuricemia is independently associated with endothelial dysfunction in postmenopausal women but not in premenopausal women. BMJ Open. 2013;3:e003659.

14 Duskin-Bitan H, Cohen E, Goldberg E, Shochat T, Levi A, Garty M, et al. The degree of asymptomatic hyperuricemia and the risk of gout. A retrospective analysis of a large cohort. Clin Rheumatol. 2014;33:549-53.
-1515 Pasalic D, Marinkovic N, Feher-turkovic L. Review. Uric acid as one of the important factors in multifactorial disorders - facts and controversies. Biochem Med (Zagreb). 2012;22:63-75. There is also evidence of a positive association between UA levels and hypertension,1212 Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout. Part I: diagnosis. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-11.,1616 Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin North Am. 2014;40:155-75. kidney disease,1616 Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin North Am. 2014;40:155-75. and the risk of coronary events.1717 Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation. 2007;116:894-900. Furthermore, disorders of purine metabolism or in the process of elimination of uric acid, or an increase in protein intake1818 Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004;350:1093-103. may contribute to the elevation of UA.

Gouty manifestations may occur in three phases: acute crises (1), intercritical period (2), which occurs between crises, is completely asymptomatic, and has a variable duration. At the beginning of the disease this period can last for years; however, it tends to become gradually shorter with the progression of the disease. Chronic arthropathy (3), the most advanced stage, is characterized by multiple and/or persistent crises.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206.

Several events can trigger acute attacks of gout, including excessive alcohol intake, metabolic stress (such as the observed in acute myocardial infarction or surgery) or, more commonly, sudden changes in UA levels, as occurs after the beginning urate reduction therapy, leading to a resorption of MSU crystals.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206. Acute gout is recognized as one of the most painful experiences, comparable to labor pains and visceral colic, such as nephritic colic.1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83. A flare begins when macrophages present in the synovial fluid phagocyte the crystals and initiate the inflammatory cascade, releasing mediators and promoting neutrophil chemotaxis.2020 Cronstein BN, Sunkureddi P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013;19:19-29.

The classical clinical presentation of gout is an acute inflammatory arthritis, which usually is a single-joint, recurrent, intense, self-limiting process.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206.,1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83.,2121 Sicras-Mainar A, Navarro-Artieda R, Ibáñez-Nolla J. Uso de recursos e impacto económico de los pacientes con gota: estudio multicéntrico de ámbito poblacional. Reumatol Clin. 2013;9:94-100. In about 50% of cases, arthritis occurs in the first metatarsophalangeal joint, being known as podagra.1212 Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout. Part I: diagnosis. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-11.,2222 Alderman MH. Podagra, uric acid, and cardiovascular disease. Circulation. 2007;116:880-3.,2323 Simkin PA. The pathogenesis of podagra. Ann Intern Med. 1977;86:230-3. The joints of the ankle and knee are common sites of arthritis.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206. Oligoarticular and polyarticular impairment is less common,2424 Lioté F, Lancrenon S, Lanz S, Guggenbuhl P, Lambert C, Saraux A, et al. GOSPEL: Prospective survey of gout in France. Part I: design and patient characteristics (n = 1003). Bone Spine. 2012;79:464-70. but this can occur in patients with long-standing, untreated gout, as well as in patients with a marked and significant reduction of uric acid levels, arising from the urate-lowering therapy. Some prodromes, such as pain, discomfort, and limitation of movement, may indicate the onset of an acute gout episode.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206.

Tophi are macroscopic collections visible MSU crystals by clinical examination, and usually indicate a long-standing disease which has not been treated.2525 Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, Herrero-Beites A, Ruiz-Lucea E, Garcia-Erauskin G, et al. Treatment of chronic gout in patients with renal function impairment: an open, randomized, actively controlled study. J Clin Rheumatol. 1999;5:49-55.,2626 Dalbeth N, Collis J, Gregory K, Clark B, Robinson E, Mcqueen FM. Tophaceous joint disease strongly predicts hand function in patients with gout. Rheumatology. 2007;46:1804-7. The presence of tophi is related to an increase of structural damage2727 Dalbeth N, Clark B, McQueen F, Doyle A, Taylor W. Validation of a radiographic damage index in chronic gout. Arthritis Care Res. 2007;57:1067-73. and loss of joint function,2626 Dalbeth N, Collis J, Gregory K, Clark B, Robinson E, Mcqueen FM. Tophaceous joint disease strongly predicts hand function in patients with gout. Rheumatology. 2007;46:1804-7. and its occurrence is directly related to increased serum urate levels.2525 Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, Herrero-Beites A, Ruiz-Lucea E, Garcia-Erauskin G, et al. Treatment of chronic gout in patients with renal function impairment: an open, randomized, actively controlled study. J Clin Rheumatol. 1999;5:49-55. The urate-lowering therapy is associated with a reduction of tophi formation, as well as to the regression of existing formations.2828 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;47:356-60. Chronic gout also leads to a restriction of joint mobility, joint swelling, and a radiologically apparent deformity.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206. Well-defined ‘punched-out’ type lesions, especially when showing an eggshell edge (overhanging bony edges - Martel signal) are characteristic radiologic findings indicating a longstanding, serious, untreated chronic gout.2929 Monu JUV, Pope TL. Gout: a clinical and radiologic review. Radiol Clin North Am. 2004;42:169-84.

Epidemiology

Despite the wide variation of data between different countries, it is believed that the prevalence of gout has increased over the last six years.1616 Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin North Am. 2014;40:155-75. The US study National Health Interview found an increase in the prevalence of self-reported gout, from 4.8/1000 in 19673030 Lawrence RC, Hochberg MC, Kelsey JL, McDuffie FC, Medsger TA, Felts WR, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol. 1989;16:427-41. to 9.4/19963131 Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26-35. in 1996. According to the Johns Hopkins Precursors Study, in 1991 the incidence of gout in the United States was estimated at 1.73 per 1000 population.3232 Roubenoff R, Klag MJ, Mead LA, Liang KY, Seidler AJ, Hochberg MC. Incidence and risk factors for gout in white men. JAMA. 1991;266:3004-7. In Brazil, there is a lack of epidemiological studies in this area.

The reasons for the apparent increase in the incidence of gout over the last few years have not been clarified, although several risk factors have already been described. Hyperuricemia is directly linked to gout, since 10% of patients with hyperuricemia develop gout, and 90% of patients with gout have high concentrations of UA.3333 Pillinger MH, Goldfarb DS, Keenan RT. Gout and its comorbidities. Bull NYU Hosp Jt Dis. 2010;68:199-203. The Framingham study indicated an dose-dependent increase in the relative risk to gout development with increasing UA levels. Other risk factors related to gout indicated in the same study were alcohol intake, body mass index, and blood pressure.1616 Roddy E, Choi HK. Epidemiology of gout. Rheum Dis Clin North Am. 2014;40:155-75.,2424 Lioté F, Lancrenon S, Lanz S, Guggenbuhl P, Lambert C, Saraux A, et al. GOSPEL: Prospective survey of gout in France. Part I: design and patient characteristics (n = 1003). Bone Spine. 2012;79:464-70.,3232 Roubenoff R, Klag MJ, Mead LA, Liang KY, Seidler AJ, Hochberg MC. Incidence and risk factors for gout in white men. JAMA. 1991;266:3004-7.,3434 Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet. 2004;363:1277-81.

35 Zhang Y, Woods R, Chaisson CE, Neogi T, Niu J, McAlindon TE, et al. Alcohol consumption as a trigger of recurrent gout attacks. Am J Med. 2006;119, 800e13-8.

36 Zhang Y, Chen C, Choi H, Chaisson C, Hunter D, Niu J, et al. Purine-rich foods intake and recurrent gout attacks. Ann Rheum Dis. 2012;71:1448-53.

37 Kok VC, Horng J-T, Chang W-S, Hong Y-F, Chang T-H. Allopurinol therapy in gout patients does not associate with beneficial cardiovascular outcomes: a population-based matched-cohort study. PLoS One. 2014;9:e99102.

38 Bhole V, De Vera M, Rahman MM, Krishnan E, Choi H. Epidemiology of gout in women: fifty-two-year followup of a prospective cohort. Arthritis Rheum. 2010;62:1069-76.
-3939 Richette P, Clerson P, Périssin L, Flipo R-M, Bardin T. Revisiting comorbidities in gout: a cluster analysis. Ann Rheum Dis. 2015;74:142-7. It is known that both overweight and obesity can increase the endogenous production of uric acid.4040 Lyngdoh T, Vuistiner P, Marques-Vidal P, Rousson V, Waeber G, Vollenweider P, et al. Serum uric acid and adiposity: deciphering causality using a bidirectional mendelian randomization approach. PLoS One. 2012;7:e39321. The relative risk of incidence of gout is 1.95 in men with body mass index (BMI) between 25 and 29.9 kg/m2, compared to the relative risk of 1.00 when BMI is between 21 and 22.9 kg/m2. The same study noted an increase in the relative risk, to 2.97, when BMI is greater than 35 kg/m2.4141 Ishikawa-Takata K, Ohta T, Moritaki K, Gotou T, Inoue S. Obesity, weight change, and risks for hypertension, diabetes, and hypercholesterolemia in Japanese men. Eur J Clin Nutr. 2002;56:601-7. Other studies have added the consumption of purine-rich food and soft drinks sweetened with fructose as risk factors for hyperuricemia and gout. Conversely, dairy products, coffee, and vitamin C have been linked to a protective effect for developing gout.3636 Zhang Y, Chen C, Choi H, Chaisson C, Hunter D, Niu J, et al. Purine-rich foods intake and recurrent gout attacks. Ann Rheum Dis. 2012;71:1448-53.,4242 Choi HK. A prescription for lifestyle change in patients with hyperuricemia and gout. Curr Opin Rheumatol. 2010;22:165-72.

43 Suresh E, Das P. Recent advances in management of gout. QJM. 2012;105:407-17.

44 Stamp LK, O’Donnell JL, Frampton C, Drake JM, Zhang M, Chapman PT. Clinically insignificant effect of supplemental vitamin C on serum urate in patients with gout: a pilot randomized controlled trial. Arthritis Rheum. 2013;65:1636-42.
-4545 Choi HK, Willett W, Curhan G. Coffee consumption and risk of incident gout in men a prospective study. Arthritis Rheum. 2007;56:2049-55.

Diagnosis

The gold standard in the diagnosis of gout is the observation of monosodium urate crystals under compensated polarized light microscopy; for this examination, these crystals exhibit negative birefringence. The sample should be preferably collected from newly affected joints, as well as from previously affected joints.1212 Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout. Part I: diagnosis. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-11.

Nonetheless, in a typical clinical presentation, the clinical diagnosis is reasonably accurate, being acceptable in the absence of microscopy or rheumatologists. This diagnosis, however, is not definitive.1212 Zhang W, Doherty M, Pascual E, Bardin T, Barskova V, Conaghan P, et al. EULAR evidence based recommendations for gout. Part I: diagnosis. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1301-11.

Although a common clinical practice, the use of classification criteria for diagnostic purposes has evolved over the last decade.4646 Taylor WJ, Fransen J, Dalbeth N, Neogi T, Schumacher HR, Brown M, et al. Performance of classification criteria for gout in early and established disease. Ann Rheum Dis. 2016;75:178-82. Nevertheless, recently a diagnostic criterion for easy use, developed for primary care, showed good performance in secondary care, with a good positive predictive value in the diagnosis of gout when the analysis of synovial fluid is not available.4747 Kienhorst LBE, Janssens HJEM, Fransen J, Janssen M. The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study. Rheumatology (Oxford). 2015;54:1329-30.

After verification of the presence of MSU crystals in the joint environment, one must quantify this deposition, as well as its extent and the induced structural damage. In addition to history and physical examination, imaging studies such as X-rays, ultrasound, and dual emission computed tomography can be useful to assess the chronic phase of the disease and the damage done.4848 Pérez Ruiz F, Ruiz López J, Herrero Beites AM. Influence of the natural history of disease on a previous diagnosis in patients with gout. Reumatol Clínica (English Ed). 2009;5:248-51. The differential diagnoses should always be considered, especially in oligoarticular or polyarticular presentation, which may mimic several diseases, such as rheumatoid arthritis and spondyloarthropathies. In the case of a monoarticular presentation, septic arthritis should always be discarded.88 Perez-Ruiz F, Castillo E, Chinchilla SP, Herrero-Beites AM. Clinical manifestations and diagnosis of gout. Rheum Dis Clin North Am. 2014;40:193-206.

Treatment

Basically, the treatment of gout can be divided into two stages: acute flare management and long-term therapy (Table 1). In the first stage, it is critical to relieve the pain, reducing inflammation and joint impairment; for this purpose, the patient must be treated with anti-inflammatory agents; in the second stage, the aim is to decrease UA concentrations, as well as to prevent new crises. Anti-inflammatories are no longer appropriate in this stage, where both pharmacological measures and non-pharmacological procedures should be adopted.2828 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;47:356-60.,4949 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;51:321-5.

50 Alele JD, Kamen DL. The importance of inflammation and vitamin D status in SLE-associated osteoporosis. Autoimmun Rev. 2010;9:137-9.

51 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;36:1273-82.

52 Sundy JS, Baraf HSB, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306:711-20.
-5353 Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis. 2007;66:1056-8.

Table 1
Management of acute and chronic gout.

Regarding drug prescription, both for the acute management and long-term therapy, some l variables can influence the choice of medication, such as availability, cost, efficacy, and clinical indications due to potential comorbidities of the patient. Hypertension, cardiovascular disease, chronic kidney disease, and diabetes are examples of commonly occurring conditions associated with gout that should be taken into consideration before the implementation of an appropriate treatment.5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41.

Management of acute flares

For low- or moderate-intensity attacks (pain index ≤ 6 on a scale from 0 to 10) involving one to three small joints or one to two large joints, monotherapy is recommended. It can be initiated with both nonsteroidal anti-inflammatory drugs and colchicine or corticosteroids.5555 Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64:1431-46.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapy for early treatment of acute gouty arthritis5656 Schlesinger N. Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs. 2004;64:2399-416. and, due to the intensity of crisis, these agents can be administered in maximum dosages.66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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. This class includes drugs of different pharmacokinetic and pharmacodynamic properties, but with a similar action: they exert an anti-inflammatory function by inhibiting the cyclooxygenase (COX) enzymes, which catalyze the conversion of arachidonic acid derived from membrane phospholipids to prostaglandins.5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41.,5757 Dalbeth N, Haskard DO. Mechanisms of inflammation in gout. Rheumatology (Oxford). 2005;44:1090-6. NSAIDs can be non-selective (such as ibuprofen, indomethacin, and naproxen), with inhibition of COX-1 and COX-2, or selective, with inhibition of COX-1 (such as aspirin) or COX-2 (like celecoxib and other “coxibs”).5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41.,5858 Burns CM, Wortmann RL. Latest evidence on gout management: what the clinician needs to know. Ther Adv Chronic Dis. 2012;3:271-86. Among the NSAIDs commonly prescribed to patients with gout, indomethacin has been traditionally used.5959 Li T, Chen SL, Dai Q, Han XH, Li ZG, Wu DH, et al. Etoricoxib versus indometacin in the treatment of Chinese patients with acute gouty arthritis: a randomized double-blind trial. Chin Med J (Engl). 2013;126:1867-71. However, there is evidence that any NSAID has a similar effect in reducing the acute inflammatory activity in gout.1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83. Since gouty patients often have comorbid conditions and the prescribed dosages of anti-inflammatory drugs are high, proton pump inhibitors can be used in order to prevent gastrointestinal damage, such as ulceration, bleeding, and perforation. In this context, COX-2 inhibitors may have the same effect as COX-1 inhibitors, and may be a good option for patients with gastrointestinal disorders, such as gastroesophageal reflux disease and peptic ulcer.6060 National T, Centre C. National clinical guideline for care and management in adults. However, due to their renal and cardiovascular toxicity, the use of these drugs should be carefully considered and individualized.

Colchicine, an alkaloid derived from meadow saffron extracts,5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41. is also recommended in first-line treatment.66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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.,5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41.,5555 Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64:1431-46. Several effects of this substance have already been reported, being the inhibition of cell division (by binding to tubulin of microtubules and prevent spindle formation) the best-known effect.5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41. In gout, this function directly affects the activity of neutrophils by preventing diapedesis, Lysosomal mobilization, and degranulation, which releases not only pro-inflammatory substances, but also leukocytic chemotactic agents.6161 Terkeltaub RA. Colchicine update: 2008. Seminars Arthritis Rheum. 2009;38:411-9. Moreover, colchicine inhibits the formation of inflamassome NLRP3 (intracellular multiprotein structure important for the processing and release of inflammatory cytokines IL-1 and IL-18), induced by crystals of uric acid.5757 Dalbeth N, Haskard DO. Mechanisms of inflammation in gout. Rheumatology (Oxford). 2005;44:1090-6.,6161 Terkeltaub RA. Colchicine update: 2008. Seminars Arthritis Rheum. 2009;38:411-9. The metabolism of colchicine is processed by the cytochrome P450 family and thus this drug may interact with other drugs metabolized by this pathway.5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41. Moreover, the renal and hepatic function of patients must be assessed before the use of colchicine.1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83. Regarding dosage, the recommendations of the European League Against Rheumatism - EULAR66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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. and those of the American College of Rheumatology - ACR are different.6262 Crittenden DB, Pillinger MH. The year in gout: 2011-2012. Bull NYU Hosp Jt Dis. 2012;70:145-51. The former organization recommends a maximum dose of 0.5 mg three times a day; conversely, the latter proposes a dose of 1.2 g, followed by another administration of 0.6 mg one hour later, repeated at 12 h. ACR guidelines also propose that the treatment with colchicine will lead to better results if started within 24 h of the onset of symptoms, not exceeding 36 h and remaining until the attack is suppressed. Intravenous administration of colchicine is extremely toxic and is not recommended.66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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.

Anti-inflammatory steroids, or systemic corticosteroids (SC), have several known effects in suppression of the inflammatory response, such as suppression of the immune response, inhibition of prostaglandins and leukotrienes, direct inhibition of pro-inflammatory transcription factors, and inhibition of cytokines such as IL-1, IL-6, IL-8, and TNF-α.5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41.,6363 Riccardi C, Bruscoli S, Migliorati G. Molecular mechanisms of immunomodulatory activity of glucocorticoids. Pharmacol Res. 2002;45:361-8. In addition, SC upregulate genes for anti-inflammatory factors, involving phospholipase A2 blockers.5858 Burns CM, Wortmann RL. Latest evidence on gout management: what the clinician needs to know. Ther Adv Chronic Dis. 2012;3:271-86. As to the administration route, there are several options for corticosteroids - oral, intravenous, intramuscular or intra-articular.1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83. The oral use is indicated when there is a failure in treatment with colchicine and/or NSAIDs, or when these drugs are not indicated.5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41. Evidence are lacking as to what is the ideal dosage for this treatment; Janssens et al. demonstrated that a daily dose of prednisolone 35 mg is equivalent to 500 mg of naproxen twice daily.6464 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;371:1854-60. Intramuscular administration of steroids is an option; but its use is limited to intra-hospital environment and, moreover, there is also no consensus on the dose to be used.1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83. An intra-articular corticosteroid injection after joint aspiration is considered the ideal treatment for acute gout, since the pain relief occurs quickly (due to a decrease in the intra-articular pressure caused by the inflammatory process), and the corticosteroid, with its minimal systemic absorption, promotes a larger local effect.66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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.

Corticotropin (ACTH) is a hormone secreted by the pituitary gland, which directly influences steroids secretion by the adrenal glands, stimulating the production of cortisol, corticosterone, and androgens.5454 Schlesinger N. Treatment of acute gout. Rheum Dis Clin North Am. 2014;40:329-41.,6565 Ritter J, Dubin Kerr L, Valeriano-Marcet J, Spiera H. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol. 1994;21:696-9. For a while, ACTH represented an alternative therapy in acute gouty arthritis when administered in intramuscular injections. The mechanism of action of this hormone in patients suffering gout is not established; It is known that the ACTH may inhibit peripherally gouty inflammation, by activating the melanocortin receptor type 3, which would be a secondary effect.6565 Ritter J, Dubin Kerr L, Valeriano-Marcet J, Spiera H. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol. 1994;21:696-9.,6666 Daoussis D, Antonopoulos I, Andonopoulos AP. ACTH as a treatment for acute crystal-induced arthritis: update on clinical evidence and mechanisms of action. Semin Arthritis Rheum. 2014;43:648-53. Axelrod and Preston concluded that patients treated with intramuscular ACTH experienced pain relief faster than those treated with oral indomethacin when comparing the effects of these drugs in patients with an acute gout attack.6767 Axelrod D, Preston S. Comparison of parenteral adrenocorticotropic hormone with oral indomethacin in the treatment of acute gout. Arthritis Rheum. 1988;31:803-5.

Another possible therapy target is IL-1, a cytokine involved in gouty inflammation. MSU crystals stimulate IL-1 production and secretion in synovial monocytes and mononuclear cells, and activate the inflammasome NLRP3, thus justifying the validity of inhibiting this interleukin in the treatment.6868 Busso N, Ea H-K. The mechanisms of inflammation in gout and pseudogout (CPP-induced arthritis). Reumatism. 2011;63:230-7.

69 Kuipers MT, Aslami H, Vlaar APJ, Juffermans NP, Tuip-de Boer AM, Hegeman M, et al. Pre-treatment with allopurinol or uricase attenuates barrier dysfunction but not inflammation during murine ventilator-induced lung injury. PLoS One. 2012;7:e50559.
-7070 Terkeltaub RA, Schumacher HR, Carter JD, Baraf HS, Evans RR, Wang J, et al. Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator. Arthritis Res Ther. 2013;15:R25.IL-1 inhibitors are anakinra, canakinumab, and rilonacept, all of which are biological.2020 Cronstein BN, Sunkureddi P. Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol. 2013;19:19-29.,7070 Terkeltaub RA, Schumacher HR, Carter JD, Baraf HS, Evans RR, Wang J, et al. Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator. Arthritis Res Ther. 2013;15:R25.,7171 Ramiro S, Gaujoux-Viala C, Nam JL, Smolen JS, Buch M, Gossec L, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014;73:529-35. These drugs should be prescribed only when all previously administered agents were discarded by failure or inability to treat. Nonetheless, this is still a high-cost treatment, especially when compared with NSAIDs, and these the medications are not licensed in most countries. Finally, there is evidence that ice packs applied to the inflamed site can be an adjuvant procedure for pharmacological treatment.7272 Schlesinger N, Detry MA, Holland BK, Baker DG, Beutler AM, Rull M, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol. 2002;29:331-4.

Long-term gout therapy has two goals: to reduce circulating levels of urate to a level below the saturation point, keeping UA < 6.0 mg/dL, and to prevent the formation of new urate crystals.66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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. The most effective method for achieving this goal is the urate-lowering therapy (ULT) and several classes of drugs can be used in current clinical practice. However, ULT should not be restricted only to drugs, as the non-pharmacological treatment of gout plays a significant role in the prevention of new crises.7373 Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study. Ann Rheum Dis. 2013;72:826-30.

The first step after the resolution of an acute gouty arthritis episode is to explain to the patient the nature of the attack, making him/her aware of the possible etiology and the changes in lifestyle that can prevent new crises from happening. Therefore, it is essential to obtain a good medical history, centered on family history, clinical history, and lifestyle habits. Therefore, it can be said that the treatment of gout in its chronic form is an individualized task.7474 Spencer K, Carr A, Doherty M. Patient and provider barriers to effective management of gout in general practice: a qualitative study. Ann Rheum Dis. 2012;71:1490-5. Therefore, patients should be informed of all non-modifiable risk factors that can accelerate gout, such as age, ethnicity, and gender. As for modifiable risk factors - such as hyperuricemia, obesity, hypertension, dyslipidemia, ischemic cardiovascular disease, diabetes mellitus, chronic kidney disease, dietary factors, and abrupt changes in the levels of urate - guidance on control measures, such as reducing body mass, alcohol consumption, consumption of purine-rich foods, such as red meat and seafood, and consumption of fructose-rich beverages and foods, such as apple and orange, is absolutely critical.1818 Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004;350:1093-103.,1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83.,7575 Chaichian Y, Chohan S, Becker MA. Long-term management of gout: nonpharmacologic and pharmacologic therapies. Rheum Dis Clin North Am. 2014;40:357-74.

The aforementioned comorbidities also deserve attention and should be controlled. A relevant topic is the attention to the medications used by the patient. Diuretics, both thiazides and especially loop diuretics, increase the risk of incidence of gout, including patients with stable disease.7676 Hunter DJ, York M, Chaisson CE, Woods R, Niu J, Zhang Y. Recent diuretic use and the risk of recurrent gout attacks: the online case-crossover gout study. J Rheumatol. 2006;33:1341-5. Furthermore, Choi, H. et al., in an observational cohort study, demonstrated that beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers (with the exception of losartan) increase the level of UA by reducing the renal excretion of uric acid, whereas losartan and calcium channel blockers increase the renal excretion of uric acid.7777 Choi HK, Soriano LC, Zhang Y, Rodríguez LAG. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ. 2012;344:d8190.

The exact time to start ULT is not well established; by consensus, ULT should be started when the gout is well established and in a relatively serious level, i.e. recurrent attack (two or more per year), or a flare in a patient with chronic kidney disease stage 2 or higher; the presence of one or more tophi on clinical or imaging examination6262 Crittenden DB, Pillinger MH. The year in gout: 2011-2012. Bull NYU Hosp Jt Dis. 2012;70:145-51.; joint damage, or nephrolithiasis. Several studies show that once started, ULT should not be discontinued because of the risk of recurrence of acute arthritis.7878 Van Lieshout-Zuidema MF, Breedveld FC. Withdrawal of longterm antihyperuricemic therapy in tophaceous gout. J Rheumatol. 1993;20:1383-5.,7979 Perez-Ruiz F, Atxotegi J, Hernando I, Calabozo M, Nolla JM. Using serum urate levels to determine the period free of gouty symptoms after withdrawal of long-term urate-lowering therapy: a prospective study. Arthritis Care Res. 2006;55:786-90.

The xanthine oxidase inhibitors are drugs that reduce the concentration of urate by inhibiting its synthesis. The enzyme xanthine oxidase (XO) catalyzes the two last stages of purine metabolism in humans: conversion from hypoxanthine to xanthine and from xanthine to urate.44 Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006;58:87-114.,8080 Nomura J, Busso N, Ives A, Matsui C, Tsujimoto S, Shirakura T, et al. Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep. 2014;4:4554. There are two drugs capable of inhibiting this enzyme: allopurinol and febuxostat.

Allopurinol is considered as a first-line drug in reducing urate, i.e., the drug is effective in up to 90% of patients.7373 Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study. Ann Rheum Dis. 2013;72:826-30. Its use is well established and is administered only once daily; furthermore, it is inexpensive and relatively safe.66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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. Thus, it is the most prescribed drug in ULT.8181 Stocker SL, McLachlan AJ, Savic RM, Kirkpatrick CM, Graham GG, Williams KM, et al. The pharmacokinetics of oxypurinol in people with gout. Br J Clin Pharmacol. 2012;74:477-89. Both allopurinol as its main active metabolite, oxypurinol, are non-specific competitive inhibitors of hypoxanthine oxidase and xanthine oxidase, respectively. Therefore, both drugs are able to reduce the production of uric acid, leading to an increase of xanthine and hypoxanthine concentrations in extracellular fluid.7373 Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: proof-of-concept observational study. Ann Rheum Dis. 2013;72:826-30.,8181 Stocker SL, McLachlan AJ, Savic RM, Kirkpatrick CM, Graham GG, Williams KM, et al. The pharmacokinetics of oxypurinol in people with gout. Br J Clin Pharmacol. 2012;74:477-89.,8282 Wertheimer AI, Davis MW, Lauterio TJ. A new perspective on the pharmacoeconomics of colchicine. Curr Med Res Opin. 2011;27:931-7. Oxypurinol accounts for 90% of the bioavailability of allopurinol and is preferably excreted via the kidneys.8181 Stocker SL, McLachlan AJ, Savic RM, Kirkpatrick CM, Graham GG, Williams KM, et al. The pharmacokinetics of oxypurinol in people with gout. Br J Clin Pharmacol. 2012;74:477-89.

The allopurinol dose adjustment should be individualized, starting with 100 mg and increasing in that same amount each month until urate levels are under control (target for uricemia ≤ 6.0 mg/dL, or ideally 5.0 mg/dL) with a maximum of 900 mg.5555 Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64:1431-46. The best established daily dose is 300 mg; however, in this dosage approximately half of the patients achieve disease control.8383 Schumacher HR, Becker MA, Wortmann RL, MacDonald PA, Hunt B, Streit J, et al. 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 Care Res. 2008;59:1540-8.,8484 Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450-61. Side effects appear in up to 20% of patients, with gastrointestinal intolerance, nausea, and cutaneous rash being the most common events.8585 Kim SC, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study. Arthritis Care Res. 2013;65:578-84. In 1984, hypersensitivity syndrome to allopurinol (now known as DRESS - drug reaction or rash with eosinophilia and systemic symptoms)8585 Kim SC, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study. Arthritis Care Res. 2013;65:578-84. was described, involving fever, cutaneous rash, eosinophilia, hepatitis, progressive renal failure and death due to multiple-organ vasculitis.5858 Burns CM, Wortmann RL. Latest evidence on gout management: what the clinician needs to know. Ther Adv Chronic Dis. 2012;3:271-86. Steven-Johnson syndrome and toxic epidermal necrolysis can join this clinical picture, or occur in isolation (known as SCAR - severe cutaneous adverse reactions).8585 Kim SC, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study. Arthritis Care Res. 2013;65:578-84. These reactions occur more frequently in patients with pre-existing renal impairment, or taking diuretic drugs.5858 Burns CM, Wortmann RL. Latest evidence on gout management: what the clinician needs to know. Ther Adv Chronic Dis. 2012;3:271-86. There is also evidence of increased risk for hypersensitivity reactions in those patients who started this therapy recently.8585 Kim SC, Newcomb C, Margolis D, Roy J, Hennessy S. Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study. Arthritis Care Res. 2013;65:578-84.

Febuxostat is a highly specific inhibitor of XO; this drug is derived from tiazolocarboxycilic acid. Febuxostat selectively inhibits both the oxidized and reduced form of XO by competitive and non-competitive mechanisms. Its metabolism occurs mainly in the liver, with a little amount excreted in urine3434 Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet. 2004;363:1277-81.,4141 Ishikawa-Takata K, Ohta T, Moritaki K, Gotou T, Inoue S. Obesity, weight change, and risks for hypertension, diabetes, and hypercholesterolemia in Japanese men. Eur J Clin Nutr. 2002;56:601-7.,8686 Harrold LR, Mazor KM, Peterson D, Naz N, Firneno C, Yood RA. Patients’ knowledge and beliefs concerning gout and its treatment: a population based study. BMC Musculoskelet Disord. 2012;13:180. (around 10%).8787 Goldfarb DS, MacDonald PA, Hunt B, Gunawardhana L. Febuxostat in gout: serum urate response in uric acid overproducers and underexcretors. J Rheumatol. 2011;38:1385-9. Due to this feature, febuxostat was shown to be a promising alternative for patients with chronic kidney disease. Moreover, compared with allopurinol, febuxostat does not require dose adjustments and has fewer drug interactions that may limit efficacy or safety.3434 Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet. 2004;363:1277-81.,4141 Ishikawa-Takata K, Ohta T, Moritaki K, Gotou T, Inoue S. Obesity, weight change, and risks for hypertension, diabetes, and hypercholesterolemia in Japanese men. Eur J Clin Nutr. 2002;56:601-7.,8686 Harrold LR, Mazor KM, Peterson D, Naz N, Firneno C, Yood RA. Patients’ knowledge and beliefs concerning gout and its treatment: a population based study. BMC Musculoskelet Disord. 2012;13:180. Among the identified side effects, there are changes in liver function tests, and in some cases, a potential adverse cardiovascular effect. Therefore, febuxostat is not recommended in patients with an impaired heart failure.1919 Rees F, Hui M, Doherty M. Optimizing current treatment of gout. Nat Rev Rheumatol. 2014;10:271-83. Several studies confirm the effectiveness of febuxostat versus allopurinol at a dose of 300 mg, to the point several countries - among them United States, Canada, and 20 European countries - have already allowed its use at daily doses of 40, 80, or 120 mg.8484 Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450-61.,8888 Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, et al. 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. Since 2012, febuxostat is recommended by the ACR as a first-line urate-lowering therapy.8989 Khanna D, FitzGerald JD, Khanna PP, Bae S, Singh M, Neogi T, et al. 2012 American College of Rheumatology guidelines for mmanagement of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64:1431-46. Due mainly to its cost, its use is most suitable in case of failure or impossibility of using allopurinol.9090 Stevenson M, Pandor A. Febuxostate for the management of hyperuricaemia in patients with gout: a nice single technology appraisal. Pharmacoeconomics. 2011;29:133-40.

Uricosuric agents (probenecid, benzbromarone, and sulfinpyrazone) are weak organic acids whose main effect is to increase the renal excretion of uric acid by inhibiting anion transporters in the proximal convoluted tubule (URAT1), responsible for the resorption of urate. Probenecid is the only uricosuric agent currently available in the United States. Benzbromarone was widely available in European, Asian, and South American countries, but it was banned in 2003 following reports of severe liver toxicity and bone marrow suppression.9191 Bach MH, Simkin PA. Uricosuric drugs: the once and future therapy for hyperuricemia? Curr Opin Rheumatol. 2014;26:169-75. Uricosuric drugs are second-line agents in the treatment of gout, becoming first-line only in patients who cannot tolerate them, or when there is no indication for an XO inhibitor. In addition, these drugs increase significantly the concentration of uric acid in the collecting ducts, predisposing to stone formation.6262 Crittenden DB, Pillinger MH. The year in gout: 2011-2012. Bull NYU Hosp Jt Dis. 2012;70:145-51. The uricosuric properties of losartan and fenofibrate have also been described, albeit discreet.9292 Takahashi S, Moriwaki Y, Yamamoto T, Tsutsumi Z, Ka T, Fukuchi M. Effects of combination treatment using anti-hyperuricaemic agents with fenofibrate and/or losartan on uric acid metabolism. Ann Rheum Dis. 2003;62:572-5. A mild but persistent uricosuric effect was observed with the use of vitamin C at daily doses lower than 500 mg.9393 Choi HK, Gao X, Curhan G. Vitamin C intake and the risk of gout in men: a prospective study. Arch Intern Med. 2009;169:502-7.Lesinurade is a promising uricosuric agent, which is currently at a late stage of clinical development, and is a non-nucleoside reverse transcriptase inhibitor. Originally, this drug was developed to treat patients with HIV.9191 Bach MH, Simkin PA. Uricosuric drugs: the once and future therapy for hyperuricemia? Curr Opin Rheumatol. 2014;26:169-75.

Non-primate mammals and some birds do not have urate as an end product of purine metabolism, because in another enzyme, uricase, catalyzes the conversion of urate to allantoin, a soluble and readily excreted product.9494 Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78-84.Pegloticase is a porcine recombinant uricase linked to various ethylene chains to prolong their activity and reduce their immunogenicity.9494 Wu XW, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992;34:78-84. UA levels decrease to very low or undetectable levels a few hours after intravenous administration of pegloticase 8 mg.5252 Sundy JS, Baraf HSB, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306:711-20. Furthermore, repeated infusions promote the resorption of MSU crystal deposits, having an efficient and quick action in the reduction in tophi.9595 Sherman MR, Saifer MGP, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev. 2008;60:59-68.,9696 Baraf HS, Becker MA, Gutierrez-Urena SR, Treadwell EL, Vazquez-Mellado J, Rehrig CD, et al. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res Ther. 2013;15:R137. There are reports of patients that produce antibodies against pegloticase, decreasing its activity and increasing the risk of hypersensitivity reactions.9797 Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther. 2006;8:R12. Currently, pegloticase infusion is licensed in the United States for patients refractory to oral therapy.66 Zhang W, Doherty M, Bardin T, Pascual E, Barskova V, Conaghan P, et al. 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.,6262 Crittenden DB, Pillinger MH. The year in gout: 2011-2012. Bull NYU Hosp Jt Dis. 2012;70:145-51.

A summary of the final stages of purine metabolism, ending with the formation of uric acid, and of the enzymes involved in this process (XO: xanthine oxidase; XDH: xanthine dehydrogenase), is presented. In this process, febuxostat and allopurinol and its most active form, oxypurinol play a role. The excretion of uric acid occurs by renal filtration. Resorption in the loop of Henle, via URAT1 receptors, is the most important factor of urate return into the bloodstream. The uricosuric agents (probenecid, benzbromarone, and sulfinpyrazone) act by decreasing the resorption of urate. Lesinurade, a drug still in a testing process, and losartan would have similar effects. The excess uric acid predisposes to hyperuricemia and formation of urate crystals that, by accumulating in the tissues and joints, generate an intense local inflammatory response, controlled with colchicine, non-steroidal anti-inflammatory drugs, corticosteroids or, less commonly, with canakinumab, an anti-IL1monoclonal antibody. Another consequence of the hyperuricemia, demonstrated in the figure, is the formation of kidney stones. The enzyme uricase, which is not present in mammals, converts uric acid to allantoin, a slightly toxic product that is easily excreted by the kidneys. Pegloticase (pegylated uricase) can perform the same functions of this enzyme (Fig. 1).

Fig. 1
Pharmacologic agents and their mechanism of action for the treatment of gout.

Options and limitations of the Brazilian drug market

Gout is considered the most common form of inflammatory arthritis in men aged over 40 years. Known since ancient times, the so-called “disease of kings” has attracted the attention of clinical investigators over several centuries. However, its treatment has remained largely unchanged for almost a century, until mid-2008, when the FDA advisory board approved the marketing of febuxostat, the first new drug in four decades for gout treatment. Since then, there is still no provision for the entry of this product in Brazil, and many patients with renal failure who would benefit from febuxostat need to import the medication with a medical prescription. In the treatment of an acute attack, colchicine, corticosteroids and a wide range of non-steroidal anti-inflammatory drugs are available in the Brazilian market, and these drugs are used in accordance with the experience of experts. Canakinumab is not a common therapeutic option for acute crises due to its high cost and also to the good response of the acute crises to traditional medications in most cases.

There is no set date for the arrival of Pegloticase, which can be used in patients with refractory chronic tophaceous gout, in the Brazilian market. Rasburicase, which is marketed in Brazil, is used in the prevention and treatment of tumor lysis syndrome, being only approved for use in adult patients with leukemia, lymphoma or solid tumors, who are subjected to cancer therapy, and who are at risk of presenting tumor lysis syndrome or an elevation of uric acid. Due to its off-label indication for tophaceous gout and also to the lack of convenience of its use (since the drug is used intravenously at daily intervals), rasburicase has not been routinely used in the treatment of gout. Furthermore, a precaution is required in patients with a history of atopy, as rasburicase can induce allergic responses. Clinical experience with this agent reveals that the patient should be closely monitored for the emergence of adverse events of an allergic nature, especially skin reactions, and bronchospasm. Nonetheless, a recent systematic review shows that in gouty patients with renal insufficiency, rasburicase, febuxostat, benzbromarone, and allopurinol in association with benzbromarone appear to be effective and safe.9898 Castrejon I, Toledano E, Rosario MP, Loza E, Pérez-Ruiz F, Carmona L. Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis. Rheumatol Int. 2015;35:1127-37.

The use of benzbromarone is prohibited in the US market, but the therapeutic experience in Brazil has been positive, both in monotherapy or associated to allopurinol in refractory cases.9999 Azevedo VF, Buiar PG, Giovanella LH, Severo CR, Carvalho M. Allopurinol, benzbromarone, or a combination in treating patients with gout: analysis of a series of outpatients. Int J Rheumatol. 2014;2014:263720. Although several national pharmaceuticals companies are producing this molecule, some patients complain of sporadic shortage of the product in the domestic market and often opt for a pharmacological manipulation of the product.100100 Doctoralia. Narcaricina - Indicações, posologia, efeitos adversos, perguntas frequentes. Accessed in 16/02/2015. Available in: http://www.doctoralia.com.br/medicamento/narcaricina-12626/forum/falta-do-medicamento-no-mercado-7053
http://www.doctoralia.com.br/medicamento...

There is no doubt that allopurinol has been the primary medication for reducing serum uric acid levels in gout patients in Brazil and recently a meta-analysis showed its impressive safety,101101 van Echteld IA, van Durme C, Falzon L, Landewé RB, van der Heijde DM, Aletaha D. Treatment of gout patients with impairment of renal function: a systematic literature review. J Rheumatol Suppl. 2014;92:48-54. despite reported cases of toxic necroepidermyoisis102102 Ranu H, Jiang J, Ming PS. A case series of allopurinol-induced toxic epidermal necrolysis. Indian J Dermatol. 2011;56:74-6. and death with the use of this product.103103 Rachid A, Magalhães FLGM, Tafarel JR, Schmitz R. Óbito decorrente da síndrome de hipersensibilidade ao alopurinol (SHA). Rev Bras Reumatol. 2004;44:248-50.

Unfortunately, its active metabolite, oxypurinol, which is available on the European market, is also not available in the Brazilian market. However, questionnaire applied to rheumatologists in the 1990s indicated that colchicine was the most prescribed product for the treatment of gout in Brazil.104104 Ferraz MB, Sato EI, Nishie IA, Visioni RA. A survey of current prescribing practices in gouty arthritis and symptomatic hyperuricemia in San Paulo, Brazil. J Rheumatol. 1994;21:374-5.

Recent findings indicating that the elevation of uric acid is an important cardiovascular risk factor has forced a change of scenery in the treatment of patients with hyperuricemia, which should impact the treatment of gouty arthritis in Brazil, as has occurred in other countries.105105 Kim SC, Schneeweiss S, Choudhry N, Liu J, Glynn RJ, Solomon DH. Effects of xanthine oxidase inhibitors on cardiovascular disease in patients with gout: a cohort study. Am J Med. 2015;128:653e7-16. Finally, for the next few years, the authors believe that there is a great opportunity for the Brazilian drug market for the treatment of gout and especially for patients using private and public (SUS) health care systems. Table 2 presents a comparison of the presence of these medicines in the European, US, and Brazilian markets.

Table 2
Status of pharmacological drugs for the treatment of gout, according to the regulatory agency. ANVISA: Agência Nacional de Vigilância Sanitária (Brazil); FDA: Food and Drug Administration (United States); EMA: European Medicines Agency (Europe).

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Publication Dates

  • Publication in this collection
    Jul-Aug 2017

History

  • Received
    20 Oct 2015
  • Accepted
    20 June 2016
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