Vitamin D to Improve Endothelial Function in SLE
Condition: Atherosclerosis; Systemic Lupus Erythematosus
MeSH terms: Atherosclerosis; Lupus Erythematosus, Systemic
Study type: Interventional
Phase: Phase 2

Summary: 
      Determine the effect of vitamin D repletion on flow mediated dilation (FMD, a measure of
      endothelial function) in vitamin D deficient systemic lupus erythematosus (SLE) patients. The
      investigators will enroll vitamin D deficient SLE patients and randomize them to receive
      either 400 IU or 5,000 IU of cholecalciferol (D3) daily and measure change in FMD as a
      measure of EC function at baseline and after 16 weeks of repletion.

      Determine mechanisms by which vitamin D repletion may improve endothelial function in vitamin
      D deficient SLE patients and in vitro.

      Determine effect of oral D3 repletion on the Type I interferon signature in WISH and ECs
      cultured with pre and post plasma from D3 treated lupus patients.

      Determine effect of D3 repletion on the number of circulating apoptotic and non-apoptotic EC
      and EPC ex vivo.

      Determine effect of exogenous 1,25(OH)D on IFN gene signature in WISH and ECs stimulated by
      pretreatment SLE plasma in vitro.

      Determine the effects of exogenous 1,25(OH)D on the phenotype of ECs cultured with
      pretreatment lupus plasma.

      This study is designed to efficiently test our hypothesis and begin to define
      interferon-dependent pathways through which vitamin D repletion can restore clinical and in
      vitro endothelial function.
    

Detailed description: 
      Specific Aim 1. Determine the effect of vitamin D repletion on changes in flow mediated
      dilation (FMD) in vitamin D deficient SLE patients. The investigators hypothesize that
      25(OH)D repletion will improve endothelial function in 25(OH)D deficient lupus patients. For
      this pilot study, the investigators have opted to use a Randomized Phase II screening design
      (36). The screening design is meant to provide preliminary comparisons of an experimental
      treatment to an appropriate control, with the idea that the pilot study would provide
      valuable information to aid in the design of a definitive Phase III evaluation, should the
      experimental treatment prove promising in the Phase II trial. The trial is designed to
      determine the effect of vitamin D repletion with D3 on FMD in vitamin D deficient SLE
      subjects. Approximately 50 SLE subjects will be screened for total 25(OH) vitamin D (25(OH)D)
      levels and inclusion/exclusion criteria. However, screening will continue only until 32
      participants have been enrolled that have total serum 25(OH)vitamin D levels ≤ 20 ng/ml and
      meet inclusion/exclusion criteria. A baseline FMD, interferon (IFN) signature assays, and
      levels of circulating non- and apoptotic endothelial cells (EC) and endothelial progenitor
      cell (EPC) will be performed at the baseline visit. Participants will be will be randomized
      into two equal groups of 16 to receive one of two daily oral D3 doses previously used in
      supplementation trials with no evidence of harm. Group 1 (controls) will receive 400
      international units (IU) of D3 daily. Group 2 will receive 5,000 IU daily. Studies of
      supplementation in subjects deficient in vitamin D demonstrate that supplementation with
      1,000, 5,000, and 10,000 IU daily result in increases in 25(OH)D of 4.8, 36.7, and 63.8 ng/mL
      without evidence of toxicity (37). In this study, steady state levels were achieved at 90
      days. As shown in our preliminary studies, 4,000 IU daily is safe and effective at repletion
      in our lupus clinic population. Some subjects had not achieved steady state at 90 days, so
      the invesitgators have chosen to dose for 16 weeks. The primary endpoint will be a change in
      FMD after 16 weeks of vitamin D repletion. The secondary endpoint will be the reduction in
      IFN signature and level of circulating apoptotic ECs/EPCs in response to vitamin D repletion
      from baseline to 16 weeks.

      Specific Aim 2. Determine mechanisms by which vitamin D repletion may improve endothelial
      function in vitamin D deficient SLE patients and in vitro.

      2.1 Determine effect of oral vitamin D3 repletion on the Type I interferon signature in WISH
      and ECs cultured with pre and post plasma from D3 treated lupus patients. The investigators
      hypothesize that the plasma-induced IFN gene signature will reduce with 25(OH)D repletion.

      2.2 Determine effect of D3 repletion on the number of circulating apoptotic and non-apoptotic
      EC and EPC ex vivo. The investigators hypothesize that D3 repletion will reduce the number of
      apoptotic EC and EPC and increase the number of non-apoptotic EPC in association with
      improved FMD.

      2.3 Determine effect of exogenous 1,25(OH)D on IFN gene signature in WISH and ECs stimulated
      by pretreatment SLE plasma in vitro. This aim is designed to address the specific question of
      whether the effect of vitamin D is at least partially due to a direct rather than indirect
      effect on endothelial response to SLE plasma IFN.

      2.4 Determine the effects of exogenous 1,25(OH)D on the phenotype of ECs cultured with
      pretreatment lupus plasma. This aim was designed to probe the functional significance of
      vitamin D repletion and reduction of the IFN response on the endothelial phenotype.
    

Intervention name(s): Cholecalciferol
Intervention type(s): Drug
Intervention description(s): 5,000 International units versus 400 international units as an active comparator
Other intervention name(s): vitamin D3; Wegman's made by International Vitamin Corporation
Intervention MeSH terms: Vitamin D; Cholecalciferol; Vitamins
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: atherosclerosis; systemic lupus erythematosus; flow mediated dilation; interferon gene signature