1. Gout therapeutics: new drugs for an old disease
Dr Christopher M Burns, MD, Prof Robert L Wortmann, MD 
The Lancet 
Volume 377, Issue 9760, Pages (January 2011)
DOI: /S (10)
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2. Figure 1
Targets for intervention in the treatment and prophylaxis of gout
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3. Figure 2
Chemical structures of xanthine, allopurinol and its metabolite oxypurinol, and febuxostat
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4. Figure 3
Molecular models of uricase tetramer (A–C) and of pegloticase containing 36 strands of 10-kDa poly(ethylene glycol) (PEG) per uricase tetramer (D)
(A) Cartoon model, (B) space-filling model showing tunnel, and (C) space-filling model rotated around the vertical axis so that the tunnel is not visible, of uricase tetramer with subunits in different colours, based on crystal structure of A flavus uricase tetramer. (D) Space-filling model of uricase tetramer, in the same orientation as in (B), with nine strands of 10 kDa poly(ethylene glycol) attached to each uricase subunit. The scale of (D) is about half that of (A–C). Reprinted from reference 39 with permission of authors and publisher (Elsevier).
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5. Figure 4
Present understanding of uric acid reabsorption and effects of uricosuric drugs in the proximal renal tubule
Filtered uric acid is exchanged for monocarboxylates through URAT1 and dicarboxylates through OAT4 on the apical side of the tubule cell. SLC2A9v2 (GLUT9ΔN) also transports uric acid into the cell, then SLC2A9v1 (GLUT9) transports it out of the cell through the basolateral membrane and back into the circulation, along with glucose and fructose. OAT1 and OAT3 are involved in the movement of uric acid through the basolateral membrane, although details are unclear. RDEA594 seems to be distinct from traditional uricosuric drugs in that it inhibits only URAT1 and not the basolateral transporters. The sodium-dependent monocarboxylate transporters SLC5A8 and SLC5A12 and dicarboxlyate transporter SLC13A3 are also shown. Transporters involved in uric acid secretion into the tubule are not shown. See text for references. Modified from reference 60 with permission of authors and publisher (Oxford University Press©).
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6. Figure 5
Central role of the innate immune system and the NALP3 inflammasome in acute gout
Monosodium urate crystals are recognised on the surface of monocytes by innate immune system receptors such as toll-like receptors 2 and 4, fragment-crystallisable receptors and integrins. The crystals are taken up by the cell and recognised by the NALP3 (cryopyrin) inflammasome. Activation of caspase follows, with cleavage of the precursor prointerleukin 1β to active interleukin 1β. The proinflammatory cytokine interleukin 1β is then secreted from the cell, along with interleukin 18 and tumour necrosis factor α. This signal is amplified through the recruitment of other cells and the acute gout attack ensues. 65–69
FC=fragment crystallisable.
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7. Figure 6
Elucidation of the molecular details behind the characterisation of the acute attack of gout, from twinge, to full-blown flare, to subsequent resolution
On the basis of more than 20 years of research, along with new studies using the murine air pouch model of gout, three distinct phases are likely at play. These phases are an early proinflammatory cytokine-driven phase after activation of the inflammasome, an amplification phase marked by tissue damage, and a late resolution phase, in which anti-inflammatory mediators predominate. 65–69 Immune recognition of crystals is also dependent on proteins coating the crystals such as immunoglobulin and apolipoprotein E which are pro-inflammatory and anti-inflammatory, respectively. Specific mediators in each phase have been or potentially could be exploited therapeutically.
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