Systemic sclerosis (SSc) is a rare, complex rheumatic disease involving multiple organ systems with a frequently fatal outcome. It remains perhaps the most difficult rheumatic disease to manage, with limited effective therapies. One of the greatest impediments to finding new treatments is the heterogeneity of patient presentation and disease progression. Clinical markers are unable to predict onset and/or progression of the major complications, such as progressive fibrotic skin disease, pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), each seen in a minority of SSc patients. Identification of biomarkers permitting early recognition of these complications would potentially permit more targeted therapies, but also provide enriched "at risk" populations for enrolling in therapeutic trials. We focus in this Center of Research Translation on identifying biomarkers of SSc complications and progression. Empowered by a very large SSc clinical population, we propose careful clinical evaluations (Clinical-Core B), coupled with powerful molecular approaches (Microarray-Core C) to identify skin, serum and peripheral blood mononuclear cell (PBMC) disease biomarkers. We supplement this with strong translational studies into pathogenesis, probing in highly interactive projects fibrosis, vascular inflammation and the stress response in SSc. In Project 1, Dr. Lafyatis, Center Director, will investigate biomarkers in the skin predicting progressive skin disease. This project will also validate a recently identified 4-gene biomarker and test this biomarker as an outcome measure for a novel, short-duration, open-label trial of a high affinity, pan-anti-TGFp antibody. In project 2, Dr. Farber will identify biomarkers predicting the onset of PAH. In overlap with Project 1, these will be compared to biomarkers of ILD and further explored in a new model of PAH, the adiponectin-/- mouse. In Project 3 Dr. Trojanowska will extend data showing expression of HLA-B35, associated with SSc-PAH, induces a stress/unfolded protein response (UPR), and that stress response genes, ATF4 and ATF6 are more broadly upregulated in SSc. She will define the stress/UPR response in PBMCs and endothelial cells, and in overlap with Projects 1 and 2 investigate how the stress response relates to SSc disease activity.

Public Health Relevance

Systemic sclerosis is a poorly understood and relatively rare, but frequently fatal illness, involving widespread scarring and vascular disease. This project is designed to coordinate multiple scientists and clinicians to accelerate understanding of the disease process through highly interactive patient-oriented studies into markers of disease activity, investigation of pathogenesis and trial of a novel therapeutic.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center (P50)
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Special Emphasis Panel (ZAR1-MLB (M1))
Program Officer
Wang, Yan Z
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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Farina, Antonella; Cirone, Mara; York, Michael et al. (2014) Epstein-Barr virus infection induces aberrant TLR activation pathway and fibroblast-myofibroblast conversion in scleroderma. J Invest Dermatol 134:954-64
Lenna, Stefania; Han, Rong; Trojanowska, Maria (2014) Endoplasmic reticulum stress and endothelial dysfunction. IUBMB Life 66:530-7
Arron, Sarah T; Dimon, Michelle T; Li, Zhenghui et al. (2014) High Rhodotorula sequences in skin transcriptome of patients with diffuse systemic sclerosis. J Invest Dermatol 134:2138-45
Christmann, Romy B; Sampaio-Barros, Percival; Stifano, Giuseppina et al. (2014) Association of Interferon- and transforming growth factor ?-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheumatol 66:714-25
van Bon, Lenny; Affandi, Alsya J; Broen, Jasper et al. (2014) Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis. N Engl J Med 370:433-43
Wu, Minghua; Pedroza, Mesias; Lafyatis, Robert et al. (2014) Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. Arthritis Rheumatol 66:1010-21
Vacca, Alessandra; Meune, Christophe; Gordon, Jessica et al. (2014) Cardiac arrhythmias and conduction defects in systemic sclerosis. Rheumatology (Oxford) 53:1172-7
Gopal, Deepa M; Doldt, Bryan; Finch, Kim et al. (2014) Relation of novel echocardiographic measures to invasive hemodynamic assessment in scleroderma-associated pulmonary arterial hypertension. Arthritis Care Res (Hoboken) 66:1386-94
Christmann, Romy B; Mathes, Allison; Affandi, Alsya J et al. (2013) Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor *. Arthritis Rheum 65:1335-46
Hinchcliff, Monique; Huang, Chiang-Ching; Wood, Tammara A et al. (2013) Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. J Invest Dermatol 133:1979-89

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