Evaluation of digital ischemia in scleroderma with multiparametric MRI

PROJECT SUMMARY/ABSTRACT Systemic sclerosis (SSc) or scleroderma is a chronic multisystem autoimmune disorder. The underlying pathophysiology includes innate/adaptive immune system abnormalities, endothelial injury with small vessel vasculopathy, and fibroblast activation with subsequent fibrosis. Digital ischemia/digital loss is a feared complication of SSc. Prospective studies report that an estimated 50% of patients with SSc experience digital ulcerations over 5 years of follow-up, and 20% experience finger amputation secondary to ischemia. The currently available clinical tools for the assessment and monitoring of the underlying pathophysiology (vasculopathy, tissue ischemia and fibrosis) are only semi-quantitative. The dearth of quantitative tools to evaluate potential treatments has resulted in patients with SSc enduring significant morbidity. Here we propose to use multiparametric magnetic resonance imaging (MRI) in patients with SSc for a comprehensive quantitative assessment of vasculopathy, tissue hypoxia, and fibrosis in the hands, which contributes the most to patient disability in SSc. In Aim 1, we will test quantitative MRI biomarkers to complement established clinical assessments of vasculopathy, ischemia, and fibrosis. In SubAim1a, we will test whether quantitative MRI physiologic biomarkers correlate with clinical assessment of vasculopathy, ischemia, and fibrosis. In SubAim1b, we will determine the association between MRI physiological biomarkers and vascular symptoms and complications (digital ulcers and digital loss). In Aim 2, we will test whether short-term changes in quantitative MRI biomarkers can predict long-term changes (12 and 24 months) in symptoms and vascular complications. Collectively, this work will provide new noninvasive imaging biomarkers to inform prevention and treatment interventions and to monitor effectiveness of therapy for digital ischemia. Cardiovascular disease is the leading cause of death in patients with rheumatoid arthritis and systemic lupus erythematosus. Peripheral vascular disease is the leading cause of disability in SSc. The applicant’s long-term goal is to become a leader in cardiovascular imaging in patients with autoimmune rheumatic diseases. The applicant is already an expert in cardiac imaging. Now, formal training in peripheral vascular imaging is necessary. We propose a focused, intense career development training plan which will include 1) mentorship from a team of experts led by the primary mentor, an expert in peripheral vascular imaging, 2) advanced didactic coursework on peripheral vascular imaging, quantitative image analysis and machine learning, and 3) hands-on experience with peripheral MRI techniques (guided by an expert MRI physicist, co-mentor) and quantitative image analysis with integration of machine learning (guided by expert image analysis/machine learning advisor). The proposed work will center on an established cohort of clinically well characterized SSc patients, but the skill sets obtained will be broadly applicable. At this award’s conclusion, the candidate will emerge as an expert in peripheral vascular imaging in rheumatic diseases and be poised to assume the role of independent investigator.