Triggers of Gout Flares from Local to Systemic Perspectives

Gout is the most common type of inflammatory arthritis, caused by MSU crystal deposition in the joint, resulting from chronic hyperuricemia. Typically, the first clinical presentation is a gout flare characterized by severe pain, redness, joint swelling, and limited mobility. Despite continuous exposure to increased serum urate concentration followed by MSU crystal formation, flares are unpredictable and intermittent when poorly managed. Acute gout flares follow a two-step model: firstly, MSU crystals build up and, secondly, an endogenous or exogenous triggering event is needed. Once both triggers are given, resident macrophages initiate an acute inflammatory response. However, these additional factors are still under debate and increased serum urate concentrations alone are insufficient to ignite gout flares. In this review, we aim to sharpen our understanding of the unique characteristics responsible for transitioning from an asymptomatic state to acute joint inflammation observed in gout patients. We focus on integrating joint mechanisms during a gout flare, such as NLRP3 inflammasome activation, macrophage heterogeneity changes, and local physicochemical conditions with systemic influences from immunometabolism and genetic variation to explain the interindividual variability in flare susceptibility.