Developments in the scientific and clinical understanding of gout

Abstract

Gout is the most common form of inflammatory arthritis in the elderly. In the last two decades, both hyperuricemia and gout have increased markedly and similar trends in the epidemiology of the metabolic syndrome have been observed. Recent studies provide new insights into the transporters that handle uric acid in the kidney as well as possible links between these transporters, hyperuricemia, and hypertension. The treatment of established hyperuricemia has also seen new developments. Febuxostat and PEG-uricase are two novel treatments that have been evaluated and shown to be highly effective in the management of hyperuricemia, thus enlarging the therapeutic options available to lower uric acid levels. Monosodium urate (MSU) crystals are potent inducers of inflammation. Within the joint, they trigger a local inflammatory reaction, neutrophil recruitment, and the production of pro-inflammatory cytokines as well as other inflammatory mediators. Experimentally, the uptake of MSU crystals by monocytes involves interactions with components of the innate immune system, namely Toll-like receptor (TLR)-2, TLR-4, and CD14. Intracellularly, MSU crystals activate multiple processes that lead to the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome complex that in turn processes pro-interleukin (IL)-1 to yield mature IL-1 beta, which is then secreted. The inflammatory effects of MSU are IL-1-dependent and can be blocked by IL-1 inhibitors. These advances in the understanding of hyperuricemia and gout provide new therapeutic targets for the future.

Figure 1

Monosodium urate (MSU) crystals activate monocytes via the Toll-like receptor (TLR) pathway and the inflammasome. Binding to TLR and CD14 promotes phagocytosis and cell activation through MYD88-dependent signalling mechanisms. In the cytosol, MSU crystals induce the formation of the NALP-3 (NACHT, LRR, and pyrin domain-containing-3) inflammasome and lead to caspase-1 processing of pro-IL-1β. Activation of the endothelium by IL-1β increases trafficking of neutrophils to the inflammatory site. ASC, apoptosis-associated speck-like protein containing a caspase-associated recruitment domain; IL, interleukin; NF-κB, nuclear factor-kappa-B.