Systemic Sclerosis (SSc) Vasculopathy: Improved Clinical Monitoring and Treatment
Condition: Rheumatologic Disease
MeSH terms: Rheumatic Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Collagen Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed 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 and third aim (which is reported
      in this PRS report) will examine if BH4 is effective in ameliorating vascular dysfunction in
      patients with SSc and 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.
    

Intervention name(s): BH4; Vasculopathy assessment; Placebo
Intervention type(s): Drug; Diagnostic Test; Drug
Intervention description(s): BH4 10 mg/kg/day given once to a total of 12 SSc patients; Non-invasive technique, flow mediated dilatation (FMD) to define vasculopathy in SSc.; On the experimental days, patients reported to the laboratory after having consumed a standardized breakfast and oral BH4 (10mg/kg) or placebo five hours prior to their arrival. All measurements were taken at the same time of day to eliminate any diurnal effects. All participants abstained from alcohol, caffeine, and exercise for ≥12 hours prior to the study. Additionally, vasodilatory medications were discontinued 12 hours prior to study visit. In premenopausal women, measurements were performed during the early follicular phase of the menstrual cycle. All measurements were made under quiet, comfortable, ambient (~22°C) laboratory conditions.
Other intervention name(s): Kuvan; Kuvan; Placebo from IDS
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Twelve systemic sclerosis SSc patients were studied 5 hours after oral BH4 administration (10 mg/kg body weight) or placebo on separate days using controlled, counterbalanced, double-blind, crossover experimental design.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science