Gout is associated with a markedly increased risk of cardiovascular mortality, which is largely mediated by interleukin (IL)-1β-driven endothelial dysfunction. This study investigated the phase-specific effects of the recombinant human IL-1 receptor antagonist (UA007) on vascular endothelial function across different clinical stages of gout.

This post-hoc analysis utilized data from two early-phase clinical trials: a Phase I randomized, placebo-controlled trial in inter-critical gout (UA007 90 mg single dose, n=8; placebo, n=2) and a Phase IIa single-arm trial in acute gout flares (UA007 90 mg/day for 3 consecutive days, n=14). Endothelial function was serially evaluated using both a functional gold-standard measure—brachial artery flow-mediated dilation (FMD)—and a comprehensive panel of serum biomarkers reflecting key pathophysiological pathways, including endothelial activation (VCAM-1, ICAM-1, E-Selectin, ET-1), oxidative stress (ADMA, MDA, PCO, NT), and inflammation (IL-1β, IL-6, IL-8, IL-18, CRP).

In the inter-critical phase, UA007 induced rapid and parallel suppression of IL-1β (approximately 50% reduction at 4 hours), downstream inflammatory markers (IL-6, IL-8, IL-18), and multiple endothelial dysfunction biomarkers, with maximal effects observed at 4 hours (all p<0.05). This coordinated biomolecular improvement was accompanied by a significant 84% increase in FMD at 3 hours (13.74±4.01% vs. baseline 7.47±3.11%, p<0.001). The placebo group showed no significant changes at any time point. During acute flares, UA007 significantly reduced systemic inflammation (CRP, IL-6, IL-8, IL-18) and improved select endothelial markers (E-Selectin, MDA) at 72 hours (all p<0.05), alongside a delayed but significant improvement in FMD (25.99±17.41% vs. baseline 18.76±10.90%, p=0.048). Notably, circulating IL-1β levels remained unchanged throughout the flare phase (p=0.216), indicating dissociation between IL-1β suppression and vascular benefit in this context.

UA007 exerts a dual-phase vascular action: rapid, IL-1β-dependent endothelial repair in inter-critical gout versus delayed, IL-1β-independent vascular improvement during acute flares. These findings highlight distinct vascular pathophysiology across different stages of gout and provide a compelling rationale for developing phase-specific therapeutic strategies aimed at mitigating the excess cardiovascular risk associated with this disease.