Abstract
Gout is a chronic disease of monosodium urate crystal deposition, which typically presents as recurrent episodes of severe, painful inflammatory arthritis. Persistent crystal deposition can also lead to chronic gouty arthritis, tophi, and erosive gout. Hyperuricemia is the central biochemical precursor for gout and results from an imbalance between urate production and excretion. In most people with gout, hyperuricemia results from impairment of renal and gut excretion. Activation of the NLRP3 inflammasome by deposited monosodium urate crystals, leading to mature interleukin-1β release, is central to initiation of the gout flare, with subsequent amplification by neutrophils, proinflammatory cytokines, chemokines, and other soluble mediators. Termination of the gout flare is regulated by macrophage differentiation, release of antiinflammatory soluble mediators, and formation of aggregated neutrophil extracellular traps (NETs) that degrade proinflammatory cytokines. The tophus is a chronic foreign body granuloma-like structure containing collections of monosodium urate crystals. Joint damage in advanced gout is strongly linked to intraarticular tophi, with activation of catabolic pathways leading to focal cartilage and bone degradation. Large genetic studies have revealed many candidate genes associated with hyperuricemia and gout, particularly genes involved in urate transport such as SLC2A9 and ABCG2, but also metabolic pathways, regulation of inflammation, and regulation of gene expression.