Skeletal Myopathy in Systemic Sclerosis: Devising a Classification Schema Predictive of Outcomes

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PROJECT SUMMARY Skeletal myopathy in systemic sclerosis (SSc) is associated with increased disability and mortality. There is no consensus classification of SSc-associated myopathy that can be utilized to lay the groundwork for understanding muscle disease in scleroderma. We know that there is pathological, serological, and outcome heterogeneity that may be informative in defining distinct subsets of myopathy in SSc. Our preliminary data demonstrate that (1) muscle histopathology is heterogeneous in SSc, (2) patients with a fibrosing myopathy have poor outcomes, in particular cardiac death, and (3) there is intense signal uptake on advanced MRI imaging such as diffusion weighted and tensor imaging and T2 mapping in SSc-associated myopathy which may indicate early disease related changes when compared to conventional muscle MRI. This K23 proposal will first establish a Myopathy cohort (Aim 1), devise a classification schema and test its utility in predicting long term outcomes such as trajectory, cardiopulmonary disease, disability, mortality, and treatment responsiveness(Aim 2), and detect and quantify early disease related muscle changes on advanced muscle MRI (Aim 3). This application is for a K23 award for Julie Paik, MD, MHS, Assistant Professor of Medicine in the Division of Rheumatology at the Johns Hopkins University. Her long term career goal is to become a leading clinical investigator in scleroderma muscle disease in the context of observational cohort studies, state of the art imaging biomarkers, and clinical trial methodology. Her short term goal of devising this classification schema will provide a new gold standard for the validation of external myopathy cohorts in SSc and lay the framework for future studies directed at understanding biological mechanism and developing a therapeutic trial using measurable outcomes such as quantitative muscle MRI. This proposal takes advantage of the rich resources and infrastructure at the Johns Hopkins Scleroderma Center, a recently designated Precision Center of Excellence in 2018. Her mentoring team includes Dr. Laura Hummers and Dr. Fredrick Wigley, both renowned experts in SSc and clinical epidemiology, Dr. Andrew Mammen is an internationally recognized myositis expert, and Dr. Scott Zeger a leader in bio statistical and epidemiological research. Dr. Paik has recruited vital members to her Advisory Committee, composed of mentors and collaborators who have specific expertise relevant to the proposal and are fully supportive of Dr. Paik’s research and career goals. These include Dr. Michael Jacobs (advanced radiological imaging), Dr. Laura Fayad (musculoskeletal radiology), Dr. Andrea Corse (muscle histopathology), Dr. Tom Lloyd (classification schemas in inclusion body myositis), and Dr. Ami Shah (scleroderma translational research). This K23 award will allow Dr. Paik to gain the skills needed to analyze and develop a classification schema of skeletal myopathy in scleroderma, develop expertise in advanced muscle MRI analysis, and build her clinical trial skill set to ultimately support a future R01 proposal.