From flare control to recurrence prevention: immune mechanisms and phase-specific therapeutic targets in gouty...

Gouty arthritis (GA) is a sterile inflammatory disease triggered by monosodium urate (MSU) crystals. With a high global prevalence and a strong tendency toward recurrent attacks, GA frequently leads to joint destruction and disability, imposing a substantial healthcare burden. Its progression and recurrence are governed by a broader immune network. In acute flares, MSU crystals activate pattern-recognition receptors and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, leading to caspase-1 activation, interleukin-1β (IL-1β) release, and rapid neutrophil recruitment. Neutrophils amplify inflammation via proteases, reactive oxygen species, and extracellular traps, while macrophage-neutrophil crosstalk and complement pathways further sustain tissue injury. After clinical resolution, the intercritical phase is not immunologically silent: residual MSU crystals, incomplete clearance of aggregated neutrophil extracellular traps (aggNETs), complement C3/C5a activation, synovial fibroblast metabolic reprogramming, and trained immunity-like reprogramming of monocytes/macrophages may persist. These mechanistic differences suggest stage-specific therapeutic strategies, with acute interventions targeting NLRP3, IL-1β/IL-1R1, C5a/C5aR, and Peptidylarginine Deiminase 4 (PAD4)-mediated NET formation, and recurrence-prevention strategies focusing on IL-1Ra, IL-37, C3/C3aR, aggNET clearance, and myeloid epigenetic reprogramming. Among candidate biomarkers for distinguishing patients at risk of recurrence, serum CA72-4 is the most frequently proposed, while synovial C3a, and HLA-DQA1^high classical monocytes or myeloid epigenetic signatures are emerging candidates; none has been clinically validated. Although IL-1-targeted therapies provide clinical support for immune-targeted intervention in refractory flares, current treatment often controls inflammation without fully preventing recurrence. Thus, this review summarizes the stage-specific mechanisms of acute gout flare and intercritical phase, thereby identifying potential drug targets for relapse prevention and informing phase-adapted strategies to shift gout management from suppressing acute flares toward preventing long-term recurrence by combining urate control with immune modulation.