We searched the PubMed (Medline), EmBase, and Cochrane library databases for articles published in English since 1990 with the search terms “gout”, and “hyperuricemia”. We also searched for “gout” or “hyperuricemia” combined with “treatment”. We searched the reference lists of publications identified through the initial search for further citations. Additionally, we searched the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) websites to access
New Drug ClassGout therapeutics: new drugs for an old disease
Introduction
50 years after McCarty and Hollander rediscovered monosodium urate crystals in gouty joints,1 up to 5 million people in the European Union and a similar number in the USA have gout. This disease is the most common form of inflammatory arthritis in men older than 40 years, and affects 1–2% of adults in developed countries,2, 3, 4, 5 although the best way to estimate the incidence and prevalence of gout is debated.6 The last drug approved by the US Food and Drug Administration for the treatment of gout was allopurinol, in 1965. With approval of febuxostat by the European Medicines Agency in 2008 and by the US Food and Drug Administration in 2009, and with the appearance of several novel drugs in the therapeutic pipeline, a new era in gout treatment is beginning.
In this Review, we discuss febuxostat and several other drugs still in development that target various steps in the pathogenesis of gout (figure 1). New urate-lowering drugs use two traditional strategies: inhibition of xanthine oxidase to reduce production of uric acid and promotion of uricosuria to increase its renal excretion. A new approach uses pegloticase, a polymer-coupled form of uricase, to rapidly reduce serum urate concentrations. We focus on the approved drug febuxostat and on pipeline drugs such as pegloticase, RDEA594, and various interleukin-1 inhibitors in the treatment of gout (table 1). For an update on clinical features of gout, please see the Seminar in The Lancet.7
Section snippets
Approved drug: febuxostat
Febuxostat, 2-[3-cyano-4-(2-methylpropoxy) phenyl]-4-methyl-thiazole-5-carboxylic acid (figure 2), is a potent oral inhibitor of xanthine oxidase, and lowers serum urate concentration in a predictable way in man.8, 9, 10 Unlike allopurinol and its active metabolite oxypurinol, febuxostat is not a purine analogue and inhibits only xanthine oxidase, not other enzymes in the purine and pyrimidine metabolic pathways.10 With 85% absorption 1 h after oral administration, and a half-life of 4–18 h,
Pipeline drug: pegloticase, the mammalian uricase—reversing evolution?
Uricase was lost to man and some non-human primates via a missense mutation in the gene encoding the enzyme.29 In other species, uricase converts urate to allantoin, which is five to ten times more water-soluble and more readily eliminated than urate. Non-recombinant uricase from Aspergillus flavus was developed and used for human tumour lysis syndrome in the late 1960s.30, 31 This syndrome occurs after chemotherapy of rapidly proliferating neoplasms, with profound hyperuricaemia and possible
Pipeline drug: RDEA594—a more selective uricosuric?
In man, most filtered urate is reabsorbed, followed by its secretion and post-secretory reabsorption in the renal proximal tubule, with about 10% excretion in urine.51 Most patients with gout have inefficient renal excretion of uric acid as the mechanism of hyperuricaemia.51, 52 Understanding of these processes has advanced greatly. Urate–anion exchanger transporter 1 (URAT1) has been identified as a primary transporter of uric acid from the tubule lumen into epithelial cells of the proximal
Pipeline drug: interleukin-1 inhibitors—rounding up the number 1 suspect?
In animals, the NALP3 inflammasome and interleukin 1β are crucial players in the gout inflammatory pathway. After cell surface recognition by the innate immune system, including toll-like receptors 2 and 4,69 the monosodium urate crystals are phagocytised by monocytes or macrophages (figure 5). Resultant poorly characterised intracellular changes lead to NALP3 assembly, caspase-1 activation, cleavage of pro-interleukin 1β, and secretion of active interleukin 1β, a major driver of gout
Final observations
Time will tell how febuxostat or the pipeline drugs fit into gout treatment algorithms. At the risk of sounding critical, we remind readers that confusion about how to use long-available drugs is a persisting issue with our management of gout. Addition of new drugs alone will not correct these pre-existing misconceptions. The diagnosis should be substantiated by identification of intra-articular monosodium urate crystals, guidelines about the start of urate-lowering treatment should be
Search strategy and selection criteria
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