Overview

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

Eligibility

• 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.
        Control subjects:
          -  Female subjects 18 years or older
          -  No history of autoimmune or inflammatory disease;
        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;
          -  Dietary vitamin B3 or tryptophan supplementation within 6 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
          -  Dietary vitamin B3 or tryptophan supplementation within 6 weeks
          -  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.