Initiating guideline-concordant gout treatment improves arterial endothelial function and reduces intercritical inflammation: a prospective observational study

Michael Toprover,Aaron Garza Romero,Svetlana Krasnokutsky,Talia F Igel,Fatmira Curovic,Virginia C Pike,Daisy Bang,Cheongeun Oh,Binita Shah,Michael H Pillinger,Deana Lazaro,Stuart D Katz

doi:10.1186/s13075-020-02260-6

Michael Toprover, Aaron Garza Romero + Show 10 more

Open Access

https://doi.org/10.1186/s13075-020-02260-6

Copy DOI

Abstract

BackgroundPatients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes. We conducted a prospective observational study to assess whether initiating guideline-concordant gout therapy with colchicine and a urate-lowering xanthine oxidase inhibitor (XOI) improves arterial function and reduces inflammation.MethodsThirty-eight untreated gout patients meeting American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for gout and ACR guidelines for initiating urate-lowering therapy (ULT) received colchicine (0.6 mg twice daily, or once daily for tolerance) and an XOI (allopurinol or febuxostat) titrated to ACR guideline-defined serum urate (sU) target. Treatment was begun during intercritical periods. The initiation of colchicine and XOI was staggered to permit assessment of a potential independent effect of colchicine. Brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent (smooth muscle) arterial responsiveness, respectively. High-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, myeloperoxidase (MPO) concentrations, and erythrocyte sedimentation rate (ESR) assessed systemic inflammation.ResultsFour weeks after achieving target sU concentration on colchicine plus an XOI, FMD was significantly improved (58% increase, p = 0.03). hsCRP, ESR, IL-1β, and IL-6 also all significantly improved (30%, 27%, 19.5%, and 18.8% decrease respectively; all p ≤ 0.03). Prior to addition of XOI, treatment with colchicine alone resulted in smaller numerical improvements in FMD, hsCRP, and ESR (20.7%, 8.9%, 13% reductions, respectively; all non-significant), but not IL-1β or IL-6. MPO and NMD did not change with therapy. We observed a moderate inverse correlation between hsCRP concentration and FMD responsiveness (R = − 0.41, p = 0.01). Subgroup analyses demonstrated improvement in FMD after achieving target sU concentration in patients without but not with established cardiovascular risk factors and comorbidities, particularly hypertension and hyperlipidemia.ConclusionsInitiating guideline-concordant gout treatment reduces intercritical systemic inflammation and improves endothelial-dependent arterial function, particularly in patients without established cardiovascular comorbidities.

Highlights

Patients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes
Prior to addition of xanthine oxidase inhibitor (XOI), treatment with colchicine alone resulted in smaller numerical improvements in flow-mediated dilation (FMD), High-sensitivity C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) (20.7%, 8.9%, 13% reductions, respectively; all nonsignificant), but not IL-1β or IL-6
Management guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) emphasize that most gout patients should be treated with a urate-lowering therapy (ULT), ideally a xanthine oxidase inhibitor (XOI), to a serum urate of ≤ 6.0 mg/dL, or potentially ≤ 5.0 mg/ dL in the case of patients with tophaceous gout [12,13,14]

Summary

Introduction

Patients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes. Several studies suggest that colchicine use may be associated with a reduction in cardiac events both in gout patients [16, 17] and in non-gout patients at high cardiovascular risk [18, 19]. These studies were either retrospective or open-label or, in the case of the randomized Colchicine Cardiovascular Outcomes (COLCOT) trial, showed benefit largely through reductions in the cardiovascular endpoint of urgent revascularization [18]. Delineating the underlying mechanism(s) of potential gout treatment benefit remains of pressing importance

Methods

Results

Discussion

Conclusion