Study Description:

Systemic lupus erythematosus (SLE) occurs predominantly in women and is driven by type I interferon dysregulation and neutrophil hyperresponsiveness. Neutrophils in females have reduced mitochondrial bioenergetic capacity which affects immunometabolism. Nicotinamide adenine dinucleotide (NAD)+ boosting with nicotinamide riboside blunts type 1 IFN activation in-vivo in monocytes of healthy subjects and ex-vivo in SLE subjects. These findings support the proposal of the hypothesis that NAD+ boosting by NR supplementation will modulate metabolic pathways in lupus and blunt type 1 interferon signaling. Moreover, as type 1 interferon drives endothelial dysfunction, linked to increased cardiovascular risk, the effect of NR on endothelial function will be examined.

Objectives:

Primary Objective: Evaluate the effect of NR vs. placebo on immunometabolic and inflammatory remodeling in female SLE subjects:

Exploratory Objective: Compare and characterize myeloid cell bioenergetic and immunometabolic profiles in healthy control and SLE female subjects

Endpoints:

Primary Endpoint:

The primary end point will be to assess the effect of NR on blunting type I IFN signaling by measuring monocytic secretion of IFN-beta secretion compared to baseline in response to placebo vs. NR supplemented in SLE study subjects.

Exploratory Endpoints:

Healthy control vs. SLE subjects:

• Compare type I IFN transcript profiles in monocytes and neutrophils at baseline and in response to activation.
• Assess cell bioenergetics including: 1) monocyte and neutrophil metabolic flux mass spectroscopy of 13C-glucose and 13Cglutamine analysis to investigate their metabolic fates; (iii) Mitochondrial oxygen consumption (using glucose, amino acid, and fatty acid substrates) and glycolysis rates.

SLE baseline vs. NR/placebo supplementation:

Baseline vs. 6 weeks of NR/placebo:

-Assess effect of NR on bioenergetics by measuring steady-state metabolite levels comparing changes in placebo vs. NR groups in monocytes and neutrophils.

Baseline vs. 12 weeks of NR/placebo:

• Whole blood NAD+ levels (batched and measured at the end of study enrollment period)
• Explore effects of NR on gene regulation using monocyte and neutrophils by RNA-seq and chromatin remodeling analysis.
• Determine the effect of NR vs placebo on endothelial dysfunction in SLE subjects

Study Description:

Systemic lupus erythematosus (SLE) occurs predominantly in women and is driven by type I interferon dysregulation and neutrophil hyper-responsiveness. Neutrophils in females have reduced mitochondrial bioenergetic capacity which affects immunometabolism. Nicotinamide adenine dinucleotide (NAD)+ boosting with nicotinamide riboside blunts type 1 IFN activation in-vivo in monocytes of healthy subjects and ex-vivo in SLE subjects. These findings support the proposal of the hypothesis that NAD+ boosting by NR supplementation will modulate metabolic pathways in lupus and blunt type 1 interferon signaling. Moreover, as type 1 interferon drives endothelial dysfunction, linked to increased cardiovascular risk, the effect of NR on endothelial function will be examined.

Objectives:

Primary Objective: Evaluate the effect of NR vs. placebo on immunometabolic and inflammatory remodeling in female SLE subjects:

Exploratory Objective: Compare and characterize myeloid cell bioenergetic and immunometabolic profiles in healthy control and SLE female subjects

Endpoints:

Primary Endpoint:

The primary end point will be to assess the effect of NR on blunting type I IFN signaling by measuring monocytic secretion of IFN-beta secretion compared to baseline in response to placebo vs. NR supplemented in SLE study subjects.

Exploratory Endpoints:

Healthy control vs. SLE subjects:

• Compare type I IFN transcript profiles in monocytes and neutrophils at baseline and in response to activation.
• Assess cell bioenergetics including: 1) monocyte and neutrophil metabolic flux mass spectroscopy of 13C-glucose and 13C-glutamine analysis to investigate their metabolic fates; (iii) Mitochondrial oxygen consumption (using glucose, amino acid, and fatty acid substrates) and glycolysis rates.

SLE baseline vs. NR/placebo supplementation:

Baseline vs. 6 weeks of NR/placebo:

-Assess effect of NR on bioenergetics by measuring steady-state metabolite levels comparing changes in placebo vs. NR groups in monocytes and neutrophils.

Baseline vs. 12 weeks of NR/placebo:

• Whole blood NAD+ levels (batched and measured at the end of study enrollment period)
• Explore effects of NR on gene regulation using monocyte and neutrophils by RNA-seq and chromatin remodeling analysis.
• Determine the effect of NR vs placebo on endothelial dysfunction in SLE subjects

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

SLE subjects:

• Female subjects 18 years or older who meets > 3 of 11 modified Am. Coll. of Rheumatology (ACR) (1997) Revised Criteria for SLE and mild/moderate disease activity defined as an SLE Disease Activity Index 2000(SLEDAI 2K) between zero and less than or equal to 14 at screening;
• If on glucocorticoids, the dose must be less than or equal to 20 mg daily and stable for at least 4 weeks prior to screening;
• If on hydroxychloroquine or other antimalarials such as chloroquine or quinacrine, dose must have been stable for the 12 weeks prior to screening. The max. allowed doses - hydroxychloroquine 400 mg/day, chloroquine phosphate 500 mg/day and quinacrine 100 mg/day;
• If on immunosuppressive drugs (methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus); dose must have been stable for the 12 weeks prior to screening
• Subjects of childbearing potential must agree to practice effective birth control for the duration of the study;
• Stated willingness to comply with all study procedures and availability for the duration of the study;
• Agreement to adhere to Lifestyle Considerations throughout study duration;
• Ability of subject to understand and the willingness to sign a written informed consent document.
• If on vitamin B3 or tryptophan supplementation at screening, willing to stop it at least 6 weeks before the baseline visit.

Control subjects:

• Female subjects 18 years or older
• No history of autoimmune or inflammatory disease
• If on vitamin B3 or tryptophan supplementation at screening, willing to stop it at least 6 weeks before the blood draw visit.

EXCLUSION CRITERIA:

SLE Subjects:

• Active renal or central nervous system disease or major renal or hepatic dysfunction;
• Treatment with rituximab, belimumab or any other biologic agent within the 6 months prior to screening
• Treatment with cyclophosphamide or IVIG within the 6 months prior to screening and or increase in glucocorticoid dose within 4 weeks of screening;
• Pregnancy or lactation (nursing)
• Treatment with another investigational drug or other intervention within 6 months of screening

Control Subjects:

• Inability to sign consent
• Pregnancy or nursing

Pregnant women are excluded from participation on this study. Self-reported pregnancy status may be accepted from female control participants of child-bearing potential for a blood draw which is considered a minimal risk procedure.