Systemic sclerosis (SSc; scleroderma) is a multi-organ systemic disease characterized by activation of immune cells, which results in vascular dysfunction (vasculopathy) and subsequent scarring (fibrosis). SSc has a higher than expect prevalence in the US military. Although SSc is heterogeneous in the extent of organ involvement and prognosis, it is accepted that all SSc cases have a progressive and usually devastating course. Since vasculopathy precedes fibrosis in this disease, a focus on understanding its natural history and preventative measures for vascular dysfunction has profound implications. On a national level there are 5,766 SSc patients (ICD-9 710.1) presently cared for in the Veterans Health Administration (VHA). While there is no cure for SSc, studies of therapeutics that can help slow disease progression are valuable to our Veterans. This proposal addresses the solicitation for projects with attention to SSc requested by President Obama after reviewing potential contamination of water at Camp Lejeune. Our proposal is a patient-centered outreach for our Veterans with SSc to inform and prevent catastrophic end- stage vascular abnormalities, including digital ulcers, pulmonary arterial hypertension (PAH) and scleroderma renal crisis in SSc. Additionally, we propose a novel application of a therapeutic for this disease. Our pilot work suggests that measurement of endothelial dysfunction with flow mediated dilatation (FMD) holds promise as novel method to assess disease progression as well as the therapeutic efficacy of the pharmacologic compound tetrahydrobiopterin (BH4) in SSc. We believe that BH4, which targets the endothelium, has great promise to reduce SSc-related tissue hypoxia, end organ damage, and potentially may impact underlying disease progression. The objectives of the proposed studies are to take our pilot work forward. In our first aim, we will adopt an integrative approach and validate a novel, non-invasive technique, FMD to define vasculopathy in SSc. In our second aim, we will examine if BH4 is effective in ameliorating vascular dysfunction in patients with SSc. In our third aim, we will determine the role of oxidative stress in BH4- mediated improvements in vascular function in patients with SSc. Our overarching goal of these aims is to improve vasculopathy detection and management in our Veterans with SSc. A better understanding of the initiating insult and natural progression of SSc vasculopathy is needed in order to develop therapeutics with a goal of curing/treating the underlying disease. This project has the potential to impact not only our Veterans with SSc, but also those with vascular abnormalities including digital ulcers, PAH, and renal crisis. This proposal represents a potential major therapeutic advance for our Veterans with SSc.

Public Health Relevance

Systemic sclerosis (SSc) is a devastating illness for our Veterans. In this study, our team of investigators at the Salt Lake City VAMC will perform a patient-centered outreach for our Veterans with SSc to inform and prevent catastrophic end-stage vascular abnormalities, including digital ulcers, pulmonary arterial hypertension (PAH), and scleroderma renal crisis (SRC) in SSc. We propose a novel application of flow mediated dilatation (FMD) and use of a therapeutic (BH4) for this disease. This proposal represents a potential major therapeutic advance for our Veterans with SSc which will impact not only our Veterans with SSc, but also those with vascular abnormalities including digital ulcers, PAH, and SRC.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01CX001183-05
Application #
10134975
Study Section
Immunology A (IMMA)
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
VA Salt Lake City Healthcare System
Department
Type
DUNS #
009094756
City
Salt Lake City
State
UT
Country
United States
Zip Code
84148
Clifton, Heather L; Machin, Daniel R; Groot, H Jonathan et al. (2018) Attenuated nitric oxide bioavailability in systemic sclerosis: Evidence from the novel assessment of passive leg movement. Exp Physiol 103:1412-1424
Khanna, Dinesh; Denton, Christopher P; Lin, Celia J F et al. (2018) Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis 77:212-220
Frech, Tracy M; Hess, Rachel; Biber, Joshua et al. (2018) Can Routine Use of Patient-Reported Outcomes Help Guide Systemic Sclerosis Chronic Disease Care? J Clin Rheumatol 24:272-274
Merz, Erin L; Kwakkenbos, Linda; Carrier, Marie-Eve et al. (2018) Factor structure and convergent validity of the Derriford Appearance Scale-24 using standard scoring versus treating 'not applicable' responses as missing data: a Scleroderma Patient-centered Intervention Network (SPIN) cohort study. BMJ Open 8:e018641
Pauling, John D; Domsic, Robyn T; Saketkoo, Lesley A et al. (2018) Multinational Qualitative Research Study Exploring the Patient Experience of Raynaud's Phenomenon in Systemic Sclerosis. Arthritis Care Res (Hoboken) 70:1373-1384
Frech, Tracy M; Mar, Diane (2018) Gastrointestinal and Hepatic Disease in Systemic Sclerosis. Rheum Dis Clin North Am 44:15-28
Machin, Daniel R; Clifton, Heather L; Richardson, Russell S et al. (2017) Acute oral tetrahydrobiopterin administration ameliorates endothelial dysfunction in systemic sclerosis. Clin Exp Rheumatol 35 Suppl 106:167-172
Pauling, John D; Frech, Tracy M; Domsic, Robyn T et al. (2017) Patient participation in patient-reported outcome instrument development in systemic sclerosis. Clin Exp Rheumatol 35 Suppl 106:184-192
Allred, Deanna; Frech, Tracy M; McComber, Cynthia et al. (2017) Chronic Multiorgan Rare Disease: The Role of the Nurse Practitioner as a Leader of the Healthcare Team. J Med Pract Manage 32:413-416
Machin, Daniel R; Gates, Phillip E; Vink, Hans et al. (2017) Automated Measurement of Microvascular Function Reveals Dysfunction in Systemic Sclerosis: A Cross-sectional Study. J Rheumatol 44:1603-1611

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