Preclinical Characterization of Pharmacologic NAD⁺ Boosting as a Promising Therapeutic Approach in Rheumatoid Arthritis

Abstract

ObjectiveWe analyzed NAD+ metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD+ boosting.MethodsOur study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD+ levels and NAD+‐related gene pathways. We analyzed 92 inflammatory molecules by proximity extension assay. In the second cohort, comprising 44 RA patients starting anti–tumor necrosis factor (anti‐TNF) drugs, we evaluated changes in NAD+ levels and their association with clinical response after 3 months. Mechanistic studies were performed ex vivo on peripheral blood mononuclear cells (PBMCs) from patients with RA to test the beneficial effects of NAD+ boosters, such as nicotinamide and nicotinamide riboside.ResultsReduced NAD+ levels were found in RA samples, in line with altered activity and expression of genes involved in NAD+ consumption (sirtuins, poly[ADP‐ribose] polymerase, CD38), transport (connexin 43), and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a group of RA patients with the highest inflammatory profile, the lowest NAD+ levels, and the highest disease activity (as shown by the Disease Activity Score in 28 joints). NAD+ levels were modulated by anti‐TNF therapy in parallel with the clinical response. In vitro studies using PBMCs from RA patients showed that nicotinamide riboside and nicotinamide increased NAD+ levels via NAMPT and NMNAT and reduced their prooxidative, proapoptotic, and proinflammatory status.ConclusionRA patients display altered NAD+ metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti‐TNF therapy. The preclinical beneficial effects of NAD+ boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds.

Unveiling the Nexus: Cellular Metabolomics Unravels the Impact of Estrogen on Nicotinamide Metabolism in Mitigating Rheumatoid Arthritis Pathogenesis

“…Using pathway and enrichment analysis, we found that nicotinate and nicotinamide (NAD + ) metabolism (Figure 3A,B) was highly impacted by E2l treatment on RA-FLS, which depicts its close regulation with RA pathogenesis. Boosting NAD + metabolism has been identified as an anti-inflammatory strategy in treating RA patients [70]. In our analysis, we discovered that estradiol treatment in RA-FLS increased the concentration of NAD + and its associated metabolite, 1-MNA (Figure 3C,D), showing that therapeutic horizons of estrogen extend to the regulation of positive metabolic alterations in RA.…”

NAMPT/SIRT1 Expression Levels in White Blood Cells Differentiate the Different Rheumatoid Arthritis Subsets: An Inspiration from Traditional Chinese Medicine

“… 30 However, a recent study revealed that boosting NAMPT-NAD was beneficial for RA patients. 31 Meanwhile, SIRT1 expression is usually deficient in rheumatic subjects. As a result, SIRT1 up-regulation is taken as a feasible anti-rheumatic approach.…”

NAD+ Precursors and Intestinal Inflammation: Therapeutic Insights Involving Gut Microbiota

“…Recently, it has been found through the analysis of plasma samples that individuals with RA exhibit lower average levels of NAD+ and NADH metabolites than their healthy counterparts [78]. Additionally, a change in NAD+ metabolism has also been detected in RA patients, which is directly linked to the disease's inflammatory state, and can be reversed with anti-TNF therapy [78].…”

“…Recently, it has been found through the analysis of plasma samples that individuals with RA exhibit lower average levels of NAD+ and NADH metabolites than their healthy counterparts [78]. Additionally, a change in NAD+ metabolism has also been detected in RA patients, which is directly linked to the disease's inflammatory state, and can be reversed with anti-TNF therapy [78]. Furthermore, the potential of using NAD+ enhancers to restore NAD+ levels has been proposed as a potential new clinical strategy to combat inflammation in these patients [78] In this context, treatment with high doses of sustained NAM demonstrated a substantial benefit for RA patients [79,80]; however, its effect on gut permeability was not further studied.…”