NAD+ Deficiency in Arthritis Patients Reversed by NMN and NR: Latest Study Findings

Spanish researchers characterize NAD+ boosting compounds’ efficacy against falling NAD+ in rheumatoid arthritis patients’ immune cells, with nicotinamide riboside (NR) and nicotinamide producing promising effects.

By Bennett M. Sherman

Key Points

  • Rheumatoid arthritis patients display significant blood nicotinamide adenine dinucleotide (NAD+) deficiencies, which correlate with higher disease severity.
  • Treating arthritis patient immune cells with NR raises NAD+ levels and reduces inflammatory factors.

Rheumatoid arthritis, an inflammatory disease where one’s own immune system degrades joints and tendons, affects about 1% to 2% of the US population. Although researchers have linked inflammation to the disease, little is known about underlying factors contributing to it. Moreover, declining NAD+ levels have been tied to numerous age-related diseases, but whether faltering NAD+ levels are behind rheumatoid arthritis hadn’t been investigated, until now.

Published in Arthritis and Rheumatology, Villalba and colleagues from the University of Córdoba in Spain show rheumatoid arthritis patients have significantly less blood NAD+ than healthy adults and that the lower their NAD+ levels, the worse their symptoms are. Treating blood immune cells (peripheral blood mononuclear cells [PBMCs]) from arthritis patients with NAD+ boosters NR and nicotinamide significantly boosts their NAD+ levels, while NMN doesn’t. Moreover, NR and nicotinamide substantially reduce the activity of genes for inflammatory proteins like interleukin-6 (IL-6), while NMN confers modest benefits against these genes. These findings suggest that faltering NAD+ levels contribute to rheumatoid arthritis disease severity and that supplementing with the NAD+ boosters NR or nicotinamide can alleviate joint swelling.

Lower NAD+ Levels Predict Greater Arthritis Severity

To find out whether, like many other age-associated conditions, lower NAD+ levels underlie rheumatoid arthritis, Villalba and colleagues measured blood NAD+ in arthritis patients. Compared to healthy adults, their NAD+ levels were lower. These findings hint that lower NAD+ levels correlate with rheumatoid arthritis.

To confirm that lower NAD+ levels contribute to rheumatoid arthritis, Villalba and colleagues split the rheumatoid arthritis patients into three groups based on their NAD+ levels: Clusters 1 through 3. Cluster 1 had the lowest NAD+ levels, Cluster 3 had the highest, and Cluster 2 had intermediate NAD+ levels. Intriguingly, based on a disease activity score (DAS28) measured by assessing the amount of inflammation in joints throughout the body, Cluster 1 (with the lowest NAD+ levels) had the highest average disease severity. Cluster 3 (with the highest NAD+ levels) had the lowest average disease severity. These results suggest that lower NAD+ levels predict a higher degree of disease severity in rheumatoid arthritis patients.

(Perez-Sanchez et al., 2023 | Arthritis and Rheumatology) Lower NAD+ levels are tied to greater disease severity in rheumatoid arthritis patients. Arthritis patients were split into three clusters, depending on their blood plasma NAD+ levels. Cluster 1 with the lowest NAD+ had the highest disease activity (disease severity), while Cluster 3 with the highest NAD+ levels had the lowest.

Lower NAD+ levels were associated with rheumatoid arthritis, and boosting NAD+ has been shown to mitigate numerous age-related diseases in animal models. Along those lines, the Spain-based researchers measured whether NAD+ boosters could restore NAD+ levels in arthritis patient PBMCs. They found that while rheumatoid arthritis patient PBMCs had NAD+ levels nearly cut in half, NR and nicotinamide more than restored their NAD+ concentrations. NMN treatments showed a statistical trend toward increasing PBMC NAD+ levels, but NMN’s results weren’t significant. These data suggest that NR and nicotinamide can restore blood immune cell NAD+ levels in rheumatoid arthritis patients.

(Perez-Sanchez et al., 2023 | Arthritis and Rheumatology) NR and nicotinamide restore blood NAD+ levels in rheumatoid arthritis patients. Rheumatoid arthritis patients (RA) have about half the NAD+ in immune cells compared to healthy blood donors (HD). NR (RA + NR) and nicotinamide (RA + NAM) substantially restore immune cell NAD+ for the patients, while NMN (RA + NMN) has non-significant boosting effects.

To find how increasing NAD+ in arthritis patients’ PBMCs affects proteins involved in inflammation, Villalba and colleagues measured gene activity for an inflammatory protein — IL-6 — following NAD+ booster treatment. They found that IL-6 gene activity levels increased ~20-fold in rheumatoid arthritis patients’ PBMCs compared to healthy donors, yet NR and nicotinamide cut IL-6 gene activity back to healthy donor levels. Although NMN treatment significantly reduced IL-6 levels, also, it only reduced IL-6 levels about four-fold. These results suggest that NAD+ booster supplementation may decrease inflammation, especially in blood immune cells that could play a role in triggering joint degradation for rheumatoid arthritis patients.

(Perez-Sanchez et al., 2023 | Arthritis and Rheumatology) NR, nicotinamide, and NMN dramatically reduce inflammatory protein IL-6 gene activity in arthritis patient immune cells. IL-6 gene activity is about 20 times higher in rheumatoid arthritis patient immune cells (RA) compared to healthy immune cell donors (HD). NR (RA + NR) and nicotinamide (RA + NAM) reduce arthritis immune cell NAD+ levels to levels of healthy donors, while NMN (RA + NMN) has a more modest effect.

“Our findings could pave the way for the development of clinical trials to evaluate the therapeutic effects of NAD+ boosters in patients with [rheumatoid arthritis] and related diseases,” said Villalba and colleagues.

Increasing NAD+ to Counter Rheumatoid Arthritis

The study didn’t test NAD+ boosters’ capacity to alleviate swelling and joint pain in rheumatoid arthritis patients, so future clinical studies will need to test whether they benefit joint health. Another study showed that the NAD+-boosting molecule urolithin A promotes joint health in an arthritis mouse model. No other known studies have tested the benefits of NAD+ boosters NR, nicotinamide, or NMN against arthritis. This means that researchers can seize this opportunity to capitalize on the positive results showing NR and nicotinamide work against arthritis by following up with a clinical trial.

Whether NR or nicotinamide prove beneficial as treatments for rheumatoid arthritis, the study provides the first evidence that faltering NAD+ levels predict worse arthritis severity. As such, measuring arthritis patient blood NAD+ levels may help predict who would respond better to treatments based on patient disease severity. Moreover, treating arthritis patients with NR or nicotinamide may help improve the efficacy of additional arthritis treatments applied to patients.

Model and Dosage

Model: Arthritis patient whole blood and peripheral blood mononuclear cells

Dosage: 1 mM NR, nicotinamide, or NMN


Perez-Sanchez, C., Escudero-Contreras, A., Cerdó, T., Sánchez-Mendoza, L.M., Llamas-Urbano, A., Arias-de la Rosa, I., Pérez-Rodriguez, M., Muñoz-Barrera, L., Abalos-Aguilera, M.d.C., Barbarroja, N., Calvo, J., Ortega-Castro, R., Ruiz-Vilches, D., Moreno, J.A., Burón, M.I., González-Reyes, J.A., Collantes-Estevez, E., Lopez-Pedrera, C. and Villalba, J.M. (2023), Preclinical characterization of pharmacological NAD+ boosting as a promising therapeutic approach in Rheumatoid Arthritis. Arthritis Rheumatol. Accepted Author Manuscript.

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