Digital ulcers in systemic sclerosis: investigating the outcome measures of treatment efficacy, pathophysiology, and the development of local treatments

UoM administered thesis: Phd

  • Authors:
  • Michael Hughes

Abstract

Introduction: Digital ulcers (DUs) are responsible for much of the pain and disability associated with systemic sclerosis (SSc), and are a biomarker of internal organ involvement and poor prognosis. DUs are often used as the primary end-point in SSc clinical trials, although the reliability of rheumatologists in grading DUs is poor to moderate at best. Fingertip DUs are believed to be ischaemic in aetiology, whereas, extensor DUs are thought to occur due to mechanical factors and recurrent microtrauma. Treatments for DUs are often poorly tolerated due to systemic vasodilation. The overarching aim was to investigate the definition and objective measurement of SSc-related DUs, their pathophysiology, and a new light treatment.Method: Five studies were undertaken. (1) A web-based study in which photographs of digital lesions were graded, all either with or without clinical context. (2) A pilot study to assess the feasibility and tolerability of high-frequency ultrasound (HFUS) imaging to measure DUs. (3) A retrospective study examining whether thermographic abnormalities are associated with DUs. (4) A double-blind, randomised, crossover, controlled study of glyceryl trinitrate (GTN) to explore the pathophysiology of DUs in SSc. (5). A feasibility study of a novel light (red, infrared and blue) device to treat SSc-related DUs.Results: (1) 51 rheumatologists graded greater than or equal to4500 images. The clinical context (without vs with, weighted kappa statistic) did not significantly improve the intra- (0.32,0.36) or inter-rater (0.64,0.71) reliability. (2) HFUS was performed on 15 DUs and was well tolerated and feasible in the majority. DU measurement was possible in most (n=13) DUs, the mean DU depth and width were 0.99mm and 5.74mm, respectively. (3) Patients (n=138) with abnormal (compared to normal) thermography were more likely (adjusted odds ratio = 2.84) to develop future DUs, including multiple episodes. (4) 16 DUs were studied; the microvessels of the DU centre were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. There was less of a clear signal in the DU periphery. (5) Light treatment was safe, feasible and well tolerated (46 light treatments administered in 8 patients, one studied on three separate occasions). There was a significant improvement (change in visual analogue score per visit) in DUs as assessed by both patient (-7.1, P=

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Original languageEnglish
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Award date31 Dec 2016