Gout. Novel therapies for treatment of gout and hyperuricemia

Abstract

In the past few decades, gout has increased not only in prevalence, but also in clinical complexity, the latter accentuated in part by a dearth of novel advances in treatments for hyperuricemia and gouty arthritis. Fortunately, recent research reviewed here, much of it founded on elegant translational studies of the past decade, highlights how gout can be better managed with cost-effective, well-established therapies. In addition, the advent of both new urate-lowering and anti-inflammatory drugs, also reviewed here, promises for improved management of refractory gout, including in subjects with co-morbidities such as chronic kidney disease. Effectively delivering improved management of hyperuricemia and gout will require a frame shift in practice patterns, including increased recognition of the implications of refractory disease and frequent noncompliance of patients with gout, and understanding the evidence basis for therapeutic targets in serum urate-lowering and gouty inflammation.

Figure 1

The NLRP3 inflammasome and IL-1β processing and secretion in crystal-induced inflammation. The figure shows monosodium urate crystal interaction with phagocytes, with crystal recognition at the macrophage surface mediated by innate immune mechanisms, in part employing Toll-like receptor (TLR)2 and TLR4 and associated MyD88 signaling, Fc receptors, and integrins. Crystal uptake with consequent phagolysosome destabilization, and reactive oxygen species generation and lowering of cytosolic K⁺ all appear to promote activation of the NLRP3 (cryopyrin) inflammasome. Consequent endoproteolytic activation of caspase-1, which drives pro-IL-1β maturation, and consequent secretion of mature IL-1β is a major mechanism stimulating experimental gouty inflammation, and appears to be implicated in human gouty arthritis, as discussed in the text.

Figure 2

Effects of URAT1, GLUT9, and ABCG2 on urate anion disposition by the renal proximal tubule epithelial cell and inhibitory effects of the uricosurics probenecid and benzbromarone on renal urate reabsorption by inhibition of both URAT1 and GLUT9. The schematic summarizes the effects of the uricosurics probenecid and benezbromarone on urate handling in the renal proximal tubule epithelial cell by the URAT1 (SLC22A12) and GLUT9 (SLC2A9) transporters identified as linked with serum urate levels and gout susceptibility in genetic studies, including recent genome-wide association studies. Urate reabsorption at the apical membrane, which interfaces with the tubule lumen, is mediated in large part by the anion exchange function of URAT1. At the basolateral membrane, the hexose transport facilitator GLUT9 electrogenically transports urate anion into the peritubular interstitium, where urate is reabsorbed into the circulation. Recent genome-wide association studies and functional genomics analyses have also uncovered a substantial role for ABCG2 in secretion of urate into the proximal tubule lumen. The depicted model is a simplification, since other molecules that affect urate disposition in the proximal tubule and distally in the nephron are not depicted here, and effects of certain other drugs on renal urate disposition by inhibiting URAT1 or GLUT9 or other transporters are not represented. ABCG, ATP binding cassette sub-family G; GLUT, glucose transporter; URAT1, urate transporter 1.

Figure 3

Comparison of allopurinol, oxypurinol, and febuxostat structures. Allopurinol and its long-lived major active metabolite oxypurinol (both pictured) inhibit xanthine oxidase, as does febuxostat (pictured), which, in contrast to the other two agents, does not have a purine-like backbone.

Figure 4

Enzymatic activity of uricase (uric acid oxidase). Uricase oxidizes uric acid, which is sparingly soluble, to the highly soluble end product allantoin, which is readily excreted in the urine. In doing so, uricase generates not only intermediate forms of uric acid that are subject to further metabolism (including 5-hydroxyisourate), but also the oxidant hydrogen peroxide as a byproduct of the enzymatic reaction. During evolution, humans and higher primates lost expression of not only uricase, but also enzymes that rapidly degrade intermediate forms of uric acid generated by uric acid oxidation.

Figure 5

Molecular models of the uricase tetramer and of the PEGylated uricase pegloticase containing strands of 10 kDa polyethylene glycol (PEG) linked to each uricase tetramer. (a) Schematic model of the uricase tetramer, based on the crystal structure of Aspergillus flavus uricase. Each subunit is shown in a different color (red, blue, green, or yellow). (b) Space-filling model of the A. flavus uricase tetramer, showing the characteristic tunnel (or barrel) structure of the native enzyme tetramer. (c) Space-filling model of A. flavus uricase tetramer, rotated around the vertical axis so that the tunnel is not visible. (d) Space-filling model of the uricase tetramer in the same orientation as in (b) but to which nine strands of 10 kDa PEG per uricase subunit are attached. The structures of the PEG strands (shown in various shades of gray) were generated as described in [54]. The scale of (d) is about half that of (a-c). Figure 5 and the legend are reprinted with permission from [54].