Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate

M Hughes,T Moore,J Manning,J Wilkinson,G Dinsdale,C Roberts,A Murray,A.L Herrick

doi:10.1016/j.mvr.2016.12.008

Abstract

ObjectivesIn patients with systemic sclerosis (SSc), fingertip digital ulcers (DUs) are believed to be ischaemic, and extensor surface DUs a result of mechanical factors/microtrauma. Our aim was to assess blood flow response to topical glyceryl trinitrate (GTN) compared to placebo in SSc DUs, looking for differences in pathophysiology between fingertip and extensor lesions. MethodThis was a double-blind, randomised, crossover, placebo-controlled study. Sixteen (6 fingertip, 10 extensor) DUs were each studied twice (one day apart): once with GTN and once with placebo ointment. Perfusion at the DU centre (‘DUCore’) and periphery (‘DUPeriphery’), as measured by laser Doppler imaging was performed before and immediately after ointment application, then every 10min, up to 90min post-application. We calculated the area under the response curve (AUC) and the ratio of peak perfusion to baseline, then compared these between GTN and placebo. ResultsPerfusion was lower in the DUCore compared to the DUPeriphery (ratio of 0.52). The microvessels of the DUCore were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. The AUC and peak/baseline perfusion difference in means (ratio, 95% confidence interval) between GTN and placebo at the DUCore were 1.2 (1.0–1.6) and 1.2 (1.0–1.5) respectively, and at the DUPeriphery were 1.1 (0.8–1.6) and 1.0 (0.9–1.2) respectively. ConclusionDUs (both fingertip and extensor) were responsive to topical GTN, with an increase in perfusion to the ischaemic DU centre. If both fingertip and extensor DUs have a (potentially reversible) ischaemic aetiology, this has important treatment implications.

Highlights

Digital ulcers (DUs) are a major cause of pain and disability in patients with systemic sclerosis (SSc) (Bérezné et al, 2011; Mouthon et al, 2014), and are a biomarker of disease progression, including death (Mihai et al, 2016)
LDI perfusion data could not be extracted for two extensor DUs, or from the GTN day for a third extensor DU, because the DU could not be confidently identified on the grey-scale images
The key finding of this study is that we have demonstrated the responsiveness of the DU microvessels to GTN compared to placebo at the centre of the DU, and that this response occurs in both fingertip and extensor DUs

Summary

Introduction

Digital ulcers (DUs) are a major cause of pain and disability in patients with systemic sclerosis (SSc) (Bérezné et al, 2011; Mouthon et al, 2014), and are a biomarker of disease progression, including death (Mihai et al, 2016). Relatively little is known about SSc-related DU pathophysiology. It is currently believed that fingertip DUs are ischaemia-driven, while those which occur over the extensor surfaces are related to mechanical abnormalities and microtrauma (Hachulla et al, 2007). An ischaemic component to DUs, with reduced perfusion to the centre of the DU compared to the periphery (Ruaro et al, 2015), including in extensor surface DUs (Murray et al, 2016). A number of recent randomised controlled trials have excluded extensor DUs (Matucci-Cerinic et al, 2011; Hachulla et al, 2016; Khanna et al, 2016), presumably on the basis that if these ulcers are not ischaemic, they are unlikely to benefit from vasoactive therapies

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