Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment

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Abstract

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. 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. This proposal is a patient-centered outreach for our Veterans with SSc to inform and prevent catastrophic endstage vascular abnormalities, including digital ulcers, pulmonary arterial hypertension (PAH) and scleroderma renal crisis in SSc. The study proposes a novel application of a therapeutic for this disease. 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 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.

Description

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. This 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. The investigators 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 first aim will adopt an integrative approach and validate a novel, non-invasive technique, FMD to define vasculopathy in SSc. The second aim will examine if BH4 is effective in ameliorating vascular dysfunction in patients with SSc. The third aim will determine the role of oxidative stress in BH4-mediated improvements in vascular function in patients with SSc. The overarching goal of these aims is to improve vasculopathy detection and management in Veterans with SSc.

Dates

Last Verified:	05/31/2020
First Submitted:	07/28/2015
Estimated Enrollment Submitted:	08/18/2015
First Posted:	08/20/2015
Last Update Submitted:	05/31/2020
Last Update Posted:	06/01/2020
Actual Study Start Date:	12/31/2015
Estimated Primary Completion Date:	12/30/2019
Estimated Study Completion Date:	12/30/2019

Condition or disease

Rheumatologic Disease

Intervention/treatment

Drug: 32

Other: Vasculopathy assessment

Drug: 200

Phase

Arm Groups

Arm	Intervention/treatment
200 Telehealth outreach for Veterans and routine clinic visits	Drug: 200 This will be given to a total of total of 32 SSc patients (16 complicated, 16 uncomplicated)
32 SSc receive BH4 intervention (blinded)	Drug: 32 BH4 is between 5-20 mg/kg/day given to a total of 32 SSc patients (16 complicated, 16 uncomplicated)

Eligibility Criteria

Ages Eligible for Study	18 Years To 18 Years
Sexes Eligible for Study	All
Sampling method	Probability Sample
Accepts Healthy Volunteers	Yes
Criteria	Inclusion Criteria: - Diagnosis of systemic sclerosis (SSc, scleroderma) by ACR/EULAR 2013 criteria. Exclusion Criteria: - Age < 18 - Pregnant or breast feeding - Unwillingness to consent

Outcome

Primary Outcome Measures

1. FMD variables: resting brachial artery diameter, resting forearm blood flow, reactive hyperemia, sheer rate. [3 years]

Validate a non-invasive vascular measurement technique (FMD) through evaluation of vasculopathy in patients with SSc and predict end-stage vasculopathy development (i.e., DU, PAH, and/or SRC), in patients with SSc without previous complications. Routine health assessments and patient reported outcomes (PRO) will be captured and FMD testing will be performed at baseline and at 6 mo intervals during clinic visits. The pilot data suggests FMD may predict patients at risk for DU. The goal is to use the predictive value of FMD to understand the development of SSc vasculopathy complications. The impact of this research will address the current challenge in clinical practice of monitoring and targeting SSc vasculopathy.

Secondary Outcome Measures

1. Vascular smooth muscle reactivity (endothelial independent dilation, EID) [3 years]

16 SSc patients with clinical complications (any or all DU, PAH, SRC) and 16 SSc patients without clinical complications (including SSc patients with a history of DU that have been without a DU for at least 1 month) will be recruited by Dr. Frech from VISN 19 (currently 43 active patients) and be randomly assigned oral BH4 or placebo for 5 consecutive days in a double-blind randomized crossover design. Patients will remain on existing standard of care treatments such as calcium channel blockers, endothelin antagonists, phosphodiesterase inhibitors and/or prostacyclin analogs.

2. Tissue ischemia by Near Infrared Spectroscopy (NIRS): [3 years]

Other Outcome Measures

1. Blood flow; Vmeanpi=(arterial diameter/2)squaredx60 [3 years]

As part as FMD measurement, blood flow will be determined. See Primary outcome description.

2. Shear rate; (s 1)=8Vmean/arterial [3 years]

As part as FMD measurement, blood flow will be determined. See Primary outcome description.

Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment

Keywords

hypoxia

fibrosis

sclerosis

ulcer

antifungal