This research proposal aims to improve the treatment of military members and civilians suffering from diffuse cutaneous systemic sclerosis, also known as scleroderma, a disease that involves the hardening of skin and internal organs. Signs of diffuse cutaneous systemic sclerosis can vary widely from person to person, ranging from mild skin tightness and swelling in the fingers to more devastating and even life-threatening effects on heart, lung, and kidney function. The exact cause of diffuse cutaneous systemic sclerosis is unknown, but it is likely a combination of factors including improper functioning of the immune system, genetics, and environmental triggers. Due to the limited understanding of diffuse cutaneous systemic sclerosis, there is no way of knowing how this disease will progress in an individual patient. Available treatments for diffuse cutaneous systemic sclerosis are only somewhat effective and only in some patients.

The proposed project aims to identify biomarkers, or clues, that can be used to monitor disease activity in individual diffuse cutaneous systemic sclerosis patients with skin fibrosis, or skin hardening. This proposal will aim to help the 95% of systemic sclerosis patients with skin disease by identifying new drug targets and new means to diagnose and monitor the extent of skin disease. Thus, the research addresses the following FY20 Scleroderma Research Program Idea Development Award Focus Areas: (1) Define biomarkers (‘omics and/or molecular markers, cell subsets, imaging, patient-reported outcomes) that help inform therapeutic choices (immunosuppressive/anti-fibrotic) or predict course (morbidity) and quality of life. (2) Secondary analysis of scleroderma, and other similar disease datasets, to identify novel targets and biomarkers that can be validated in existing or new models.

Skin fibrosis is a hallmark of diffuse cutaneous systemic sclerosis that also occurs in a variety of other diseases, including chronic graft-versus-host disease, a syndrome that commonly occurs after stem cell transplantation. Similar to diffuse cutaneous systemic sclerosis, the progression of chronic graft-versus-host disease is hard to predict, symptoms are variable, and treatment is complicated by patient-to-patient variability. Unlike diffuse cutaneous systemic sclerosis, the cause of chronic graft-versus-host disease is somewhat understood. It is thought that transplanted cells, particularly immune cells called T cells, initiate the development of graft-versus-host disease, triggering immune cell signaling leading to tissue damage and fibrosis. Understanding chronic graft-versus-host disease may provide key insights into diffuse cutaneous systemic sclerosis development because the initiating stimulus is more clearly understood.

The common features between diffuse cutaneous systemic sclerosis and chronic graft-versus-host disease suggest that these diseases might also share biomarkers reflecting their onset and progression. This project’s research team has studied gene expression in skin from healthy people and in patients with diffuse cutaneous systemic sclerosis. The goal of the proposed research is to extend these studies to compare gene expression in individuals with diffuse cutaneous systemic sclerosis and chronic graft-versus-host disease. This innovative study approach will likely reveal immune signals common to both conditions, particularly helping to clarify the role(s) of T cells in fibrotic skin disease in both conditions. By dissecting the key signals and cell types that contribute to the development of skin fibrosis, we intend to identify biomarkers of disease severity or progression. We also aim to identify new drug targets that will aid in personalizing treatment in the future. Based on our previous experience, we expect to organize clinical trials to test new drug targets and validate biomarkers identified in this study in the next 5 years.