Vitamin D to Improve Endothelial Function in SLE

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.

Inclusion Criteria:

- Diagnosis of SLE per 1997 American College of Rheumatology Criteria(at least 4
criteria present)

- Documented Vitamin D deficiency

- Able to give informed consent

Exclusion Criteria:

- Using tobacco products

- Pregnant/Planning pregnancy

- Known Hypercalcemia (Serum Ca >10.4)

- Known Hypercalcuria (Calcium/Creatinine >0.8)

- Chronic active lupus nephritis or end stage renal disease or kidney stones

- Known Hyperparathyroidism

- Known chronic viral/mycobacterial infections

- Uncontrolled medical disease - Pl judgment

- Current drug or alcohol abuse

- Anticipated poor compliance/known neuropsychiatric disorders

- Hx of cardiovascular events (i.e. Ml, PVD, CVE)

- Subjects taking medications known to affect FMD in lupus subjects such as but not
limited to fish oil, statins, will remain on stable doses throughout the study.