Abstract
Objective:
To analyze NAD+ metabolism in Rheumatoid Arthritis (RA) patients, its association with disease activity and clinical outcomes, and the therapeutic potential of pharmacological NAD+ boosting.
Methods:
253 subjects were included in the study. In a first cohort, comprising 153 RA patients and 56 healthy donors, NAD+ levels and NAD+ -related gene pathways were assessed. 92 inflammatory molecules were analyzed by proximity extension assay. In a second cohort of 44 RA patients starting anti-TNF drugs, changes in NAD+ levels and their association with clinical response after three months were evaluated. Mechanistic studies were performed ex-vivo on RA-PBMCs to test beneficial effects of NAD+ boosters such as nicotinamide (NAM) and nicotinamide riboside (NR).
Results:
Reduced NAD+ levels were found in RA, in line with altered activity and expression of genes involved in NAD+ consumption (SIRTs, PARPs, CD38), transport (Connexin-43) and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a RA group with the highest inflammatory profile, the lowest NAD+ levels, and the highest disease activity (DAS28). NAD+ levels were modulated by anti-TNF therapy in parallel with the clinical response. In vitro studies using RA-PBMCs, showed that NR and NAM increased NAD+ levels via NAMPT and NMNAT and reduced their pro-oxidative, pro-apoptotic and pro-inflammatory status.
Conclusion:
RA patients display altered NAD+ metabolism, directly linked to their inflammatory and disease activity status, and reverted by anti-TNF therapy. The preclinical beneficial effects of NAD+ boosters in RA-leukocytes, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds. This article is protected by copyright. All rights reserved.
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