Understanding Mechanisms Driving Poor Outcomes in Women with Dermatomyositis

University Of California Los Angeles, Los Angeles CA

Investigators

Abstract

Project Summary Dermatomyositis (DM) is a rare autoimmune disease, affecting predominantly women, particularly Black women, which associates with marked disease-related morbidity as well as a 10-fold increased risk of death. DM is characterized by muscle weakness and skin rashes, but over 70% of patients may also develop interstitial lung disease (ILD), referred to as myositis associated ILD (MA-ILD), a leading driver of early mortality. Our preliminary data suggests that Black women have higher quantitative lung fibrosis scores reflective of irreversible lung damage compared to White women upon specialty center referral. Our data also suggests that microvascular inflammation and impaired paraoxonase 1 (PON1) activity may play pathogenic roles in DM and MA-ILD. Improving disease outcomes and establishing treatment guidelines in a rare disease such as DM requires 1) the integrated analysis and understanding of current diagnostic and treatment practices, and 2) the mechanistic understanding of the disease to develop targeted biomarkers and therapeutics. In Aim 1 we will establish the Southern California Dermatomyositis Disease Network (SCAD), a patient centered, community myositis registry which will recruit patients with DM and MA-ILD syndromes across diverse healthcare systems with a focus on recruitment of underrepresented in medicine (URM) women. In Aim 2 we will investigate whether microvascular disease drives progression of MA-ILD using a novel approach to ILD assessment on computed tomography CT imaging and histochemical and transcriptomic analyses of lung biopsies from MA-ILD patients. We hypothesize that incorporation of a microvascular disease assessment into the current computational evaluation of ILD will more accurately identify the extent of MA-ILD and more accurately predict disease progression and functional lung outcomes compared to traditional assessments and ILD pattern analysis. We hypothesize that histologic analysis will further support microvascular disease involvement in MA-ILD and provide needed insights into disease pathogenesis. In Aim 3 we will assess PON1 activity and a panel of immune and vascular activation markers in serum collected from DM patients participating in the first placebo-controlled trial of intravenous immunoglobulin (IVIg) as well as investigate these pathways in a longitudinal DM and MA-ILD cohort. We hypothesize that the activity of PON1, a major antioxidant protein of HDL, which normally regulates systemic oxidative stress by neutralizing pro-inflammatory lipid mediators, will associate with disease activity and treatment response in women with DM and MA-ILD syndromes. The significance of this work lies in its overall goal to understand a disease that is currently markedly understudied in women, particularly Black women for whom minimal research exists. The work establishes the first community DM registry in the Western US with a focus on understanding disease in URM women and investigates novel pathways driving DM and MA-ILD, which could provide new biomarkers for disease monitoring as well as potential therapeutic targets.