Evolution or revolution in urate-lowering therapies for gout?
Urate-lowering therapies (ULT) have been subject to a revolution in the last decade. Sudden, intense, and rapid developments in clinical evidence have accumulated in recent years, changing concepts and attitudes of clinicians and academics.
Changing concepts in the pathophysiology of gout
During the 20th century gout was considered to be a “metabolic” disease , mostly due to endogenous or exogenous overproduction of uric acid. The discovery of allopurinol, a drug targeting mainly xanthine oxidase in the purine catabolic pathway, seemed to support the theory that uric acid overproduction was the main mechanism involved in the pathogenesis of gout, except for patients with renal function impairment. However, recent evidence has identified inefficient renal excretion of uric acid as the main pathophysiologic mechanism leading to hyperuricemia, leading to the proposal of the concept of a ‘urate transportome’, a molecular complex of renal uric acid transporters, such as URAT1, Glut9, and ABCG2 [2,3], and other membrane proteins involved in renal urate transport. . Gout has therefore evolved from a disease thought to be caused by metabolic overindulgence to one that is primarily renal in origin, genetically programmed and environmentally modulated: a “transportopathy”.
Heterogeneity in clinical presentation and clinical history of patients with gout has resulted in the investigation of intrinsic systemic and tissue factors associated with urate crystal nucleation and deposition, and tissue response to urate crystals . This information will enhance our understanding of the biological basis of gout and will be of the utmost importance when evaluating proper serum urate (sUA) targets for therapy, setting the most convenient moment to start ULT, and treatment and prophylaxis of crystal-induced inflammation [6,7].
Revised approaches to managing gout
Considering the general approach to ULT, most previously established concepts have been revised. An allopurinol dose of 300 mg may not be enough to lower sUA levels in certain patients, and up-titration of doses, switching, and combining medications to obtain optimal sUA levels should be considered. Tailoring ULT choices depending on comorbidities, pharmacodynamics, and pharmacokinetics has led to a number of alternative approaches to better attain the desired outcomes: properly targeted sUA that consequently leads to avoidance of flares, prevention of structural damage, and reduction of urate crystal deposition and its associated subclinical inflammation. Treat to target strategies have been recommended  and adopted, and there is now a greater awareness of the importance of education to help patients learn about their condition and the risks and benefits of treatment options, to manage their expectations regarding long-term therapy, and to empower them to achieve determined therapeutic goals.,
Development of new urate-lowering medications
Historically, drug development failures in other indications have been the most common source of urate-lowering medications in the 20th century: allopurinol was a failed anti-mitotic; benzbromarone a failed antihypertensive; and sulfinpyrazone a failed nonsteroidal anti-inflammatory drugs. Most recently, new medications have been designed to specifically target key molecules in the metabolism of uric acid. For example, febuxostat and topiroxostat are potent, specific inhibitors of xanthine oxidase, pegloticase is an uricolytic medication, and verinurad is to date the most potent URAT1 inhibitor to be tested in clinical trials . These new developments may enhance an individualized approach to therapy and optimization of outcomes. Whilst combination therapy has previously been mostly empiric and based on small, open-label, non-comparative studies; the advent of lesinurad, a uricosuric medication labeled to be used in combination with xanthine oxidase inhibitors, has resulted in three double-blind combination therapy trials.
Development of new urate-lowering medications has been associated with concurrent evaluation of comparators, namely allopurinol. We have learned more about allopurinol in the last ten years than in the previous half century [10,11]. In addition, clinical trials with new medications allow us to obtain data not only on head to head comparisons, but also the meta-analysis and network meta-analysis of indirect comparisons, along with post-hoc analyses independent of treatment assignment but based on therapeutic target achievement.
The gout revolution is an ideal opportunity to improve the management of this “curable” disease and obtain a sustainable benefit for patients afflicted with the most frequent cause of arthritis in the adult population. It is therefore vital that there is an increased knowledge and awareness among care givers (and patients) of appropriate management options for hyperuricemia in patients with gout. This collection on gout management presents a readable, comprehensive, and accessible overview of the most recent knowledge in the field. Enjoy!
About the author
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- Nakanishi T, Ohya K, Shimada S, Anzai N, Tamai I. Functional cooperation of URAT1 (SLC22A12) and URATv1 (SLC2A9) in renal reabsorption of urate. Nephrol Dial Transplant 2013; 28(3):603-611.
- Nakayama A, Matsuo H, Takada T, Ichida K, Nakamura T, Ikebuchi Y et al. ABCG2 is a high-capacity urate transporter and its genetic impairment increases serum uric acid levels in humans. Nucleosides Nucleotides Nucleic Acids 2011; 30(12):1091-1097.
- Anzai N, Jutabha P, Amonpatumrat-Takahashi S, Sakurai H. Recent advances in renal urate transport: characterization of candidate transporters indicated by genome-wide association studies. Clin Exp Nephrol 2012; 16(1):89-95..
- Chhana A, Lee G, Dalbeth N. Factors influencing the crystallization of monosodium urate: a systematic literature review. BMC Musculoskelet Disord 2015; 16:296.
- Rasheed H, McKinney C, Stamp LK, Dalbeth N, Topless RK, Day R et al. The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets. PLoS One 2016; 11(1):e0147939.
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- Kiltz U, Smolen J, Bardin T, Cohen SA, Dalbeth N, Doherty M et al. Treat-to-target (T2T) recommendations for gout. Ann Rheum Dis 2016; 76(4):632-638.
- Shen Z, Gillen M, Miner JN, Bucci G, Wilson DM, Hall JW. Pharmacokinetics, pharmacodynamics, and tolerability of verinurad, a selective uric acid reabsorption inhibitor, in healthy adult male subjects. Drug Des Devel Ther 2017; 11:2077-2086.
- Stamp LK, Barclay ML, O'Donnell JL, Zhang M, Drake J, Frampton C et al. Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level. Clin Pharmacol Ther 2011; 90(3):392-398.
- Kannangara DRW, Graham GG, Wright DFB, Stocker SL, Portek I, Pile KD et al. Individualising the dose of allopurinol in patients with gout. Br J Clin Pharmacol 2017; 83(9):2015-2026.