Ancillary Study to the TRUST Trial: Coronary Dual-Energy CT for the Resolution of Coronary Monosodium Urate Deposits with Urate-Lowering Therapy (TRUST CORODECT)

About This Grant

ABSTRACT: Gout is the most common inflammatory arthritis worldwide caused by the deposition of monosodium urate (MSU) crystals. The disease burden of gout is high and continues to rise, with >12 million US adults being affected by gout. In addition to causing recurrent and excruciating flares of arthritis, gout is independently associated with cardiovascular disease (CVD) and contributes to premature mortality. This premature mortality among patients with gout persists even after adjusting for atherosclerotic CVD risk factors, suggesting that gout-specific mechanisms contribute to premature mortality among patients with gout. One hypothesized gout-specific mechanism is the direct deposition of MSU crystals in the vasculature, which can activate the NLRP3 inflammasome and interleukin-1ß pathway locally; this same pathway is heavily implicated in the pathogenesis of atherosclerotic CVD in response to cholesterol crystals. Multiple pathology and optical coherence tomography studies have demonstrated evidence of microscopic MSU crystals in the vasculature. Subsequently, there has been surging interest in the use of dual-energy computed tomography (DECT) for the non-invasive identification of macroscopic MSU crystals in the vasculature. Building on this interest, and our recent multi-center cross-sectional coronary DECT study (CORODECT) in which we found that patients with gout had 2.7-fold higher odds of having DECT findings consistent with vascular MSU deposition compared to controls, we propose to conduct the first-ever longitudinal study to determine if effective urate-lowering therapy leads to the reduction in these vascular MSU lesions. This imaging study will be ancillary to the multi-center Treat-to-Target Serum Urate versus Treat-to- Avoid Symptoms in Gout: A Randomized Controlled Trial (TRUST; U01 AR080985). In this time-sensitive proposal, we will obtain DECT scans of the coronary arteries and bilateral feet at baseline and month 18 among TRUST participants (all with serum urate ≥6 mg/dL) randomized to treat-to-target serum urate (TTT-SU, intensive urate-lowering) versus treat-to-avoid-symptoms (TTASx, symptom-focused management). Aim 1 will assess whether TTT-SU is associated with greater reductions in vascular MSU deposit volumes and numbers than TTASx over 18 months (we hypothesize TTT-SU will be more effective), whilst Aim 2 will assess the correlations between baseline MSU volumes in the feet and vasculature, and correlations in changes in MSU volumes at these sites. TRUST provides an unparalleled opportunity to conduct a longitudinal DECT study among patients with well-phenotyped gout recruited from primary care practices, taking full advantage of the randomization of the intervention, to fill a critical evidence gap in our understanding of the role of vascular MSU deposits as a gout-specific mechanism contributing to CVD and premature mortality. The anticipated findings will provide compelling rationale and immediately actionable evidence for the use of ULT as a cardioprotective intervention among patients with gout.