Systemic sclerosis (SSc) is a complex, multifactorial autoimmune disease characterized by fibrosis and vasculopathy in skin and various internal organs such as the lungs, kidneys and heart disease with no specific treatment. Pulmonary arterial hypertension (PAH) is a common complication of SSc, and compared to other subgroups of PAH patients, responds poorly to currently approved vasodilators. Oxidative damage is a well- defined component of lung disease in SSc as well as in other organs and pathology studies have shown evidence of oxidative damage in SSc lungs. Dimethyl fumarate (DMF), recently been approved as a treatment for multiple sclerosis, triggers the general response to oxidative damage through Nrf2, resulting in the induction of multiple enzymes designed to counteract the oxidative process. DMF reduces inflammation driven by the NFB pathway, especially in endothelial cells. Preclinical studies by our group as well as other groups have shown that DMF inhibits PAH in murine models. In addition multiple markers of oxidative stress are elevated in patients with SSc and SSc-PAH, suggesting that this is an important pathway mediating vascular damage in SSc-PAH. On the basis of these studies, we propose a double-blinded, placebo-controlled study of DMF added to stable background, standard of care PAH therapy in SSc‐PAH patients, comparing the change in 6-minute walk distance (6MWD) at 24 weeks to baseline in DMF compared to placebo treated patients. We will recruit 34 patients from three centers with large SSc and PAH patient populations at University of Pittsburgh, Boston University and Johns Hopkins Medical Centers to account for up to 20% dropout, leaving 28 patients for analysis. We will also study safety to ensure no unexpected adverse effects are related to DMF in these patients To provide further information about target engagement and reinforce potential clinical efficacy, we will examine biomarkers of oxidative stress and of PAH. To assess the effect of DMF on markers of SSc-PAH, we will compare changes from baseline to 24-weeks in levels of B-type natriuretic peptide, Endostatin, Endothelin- 1, Endoglin, Vascular Endothelial Growth Factor, von Willebrand Factor, and Vascular Cellular Adhesion Molecule 1, as well as peripheral blood mononuclear cell RNA expression biomarkers: IL13RA1, CCR1, JAK2 and MRC, comparing DMF to placebo treated patients. We will examine the performance of each of these markers as potential pharmacodynamic biomarkers by comparing their levels longitudinally to changes in 6MWD. To assess the effect of DMF treatment on markers of oxidative stress, we will measure markers of lipid, DNA, and prostaglandin oxidation, comparing changes after treatment to baseline levels in DMF compared to placebo treated patients. In addition, we will measure markers of NFB activation, IL-6 and CCL2, again comparing changes in levels in DMF to placebo treated patients. These studies should provide strong clinical support for larger phase 2/3 studies of DMF for SSc-PAH in the future. They should also provide new insight into the mechanism of action of DMF in humans.

This project proposes to provide early data supporting development of a new medication, dimethyl fumarate, for patients with systemic sclerosis complicated by pulmonary arterial hypertension. Current medications for this disease are not very effective, so we expect this medication might have a more dramatic effect to improve patient's health and longevity.