Performance of laser-derived imaging for assessing digital perfusion in clinical trials of systemic sclerosis-related digital vasculopathy: a systematic literature review

Background: Raynaud's phenomenon (RP) and digital ulcers (DU) are important features of digital vasculopathy in systemic sclerosis (SSc). Laser Doppler flowmetry (LDF), Laser Doppler Imaging (LDI) and Laser Speckle Contrast Imaging (LSCI) can non-invasively quantify digital perfusion and may be useful outcome measures for SSc-RP and/or SSc-DU clinical trials. We undertook a systematic literature review to evaluate the performance of laser-derived imaging as outcome measures in clinical trials of SSc-related digital vasculopathy. Methods: Standardized searches (EMBASE and MEDLINE) identified trials that incorporated laser-derived imaging of digital vasculopathy in adult subjects with SSc. Data was extracted (by >2 reviewers) on study design, laser endpoints, and reported outcomes. Study quality was assessed using validated instruments (PROSPERO 2019:CRD42019142409). Results: Of 126 identified articles, full data extraction was undertaken from 29 studies. Fifteen randomized and 14 non-randomized trials (total of 689 SSc patients with mean 23.8/study) have evaluated a broad range of oral, intravenous and topical interventions for SSc-RP (n = 11), digital perfusion alone (n = 15) and SSc-DU (n = 3). The studies were published between 1987 and 2019 (17/29 since 2010) and incorporated LDF (11/29), LDI (15/29) and LSCI (4/29, including one with LDF); with LSCI and LDI more commonly incorporated in recent trials. Most studies (16/29, 55%) reported improvement in digital perfusion following intervention, often concordant with patient- and clinician-derived outcomes. Conclusions: Establishing laser-derived methods as a surrogate for SSc-related digital vasculopathy will greatly support drug development. Full-field perfusion of the digits (with/without provocation testing) is a promising clinical trial outcome measure for trials of SSc-related digital vasculopathy.