Therapeutic Modulation of NAD+ Metabolism in Inflammatory Rheumatic Disorders by TNFi and NAD+ Precursors

Beatriz Vellón-García¹, Gema Dolores García-Delgado², Adrián Llamas Urbano³, Yas Hanaee³, Pedro Ortiz Buitrago⁴, Christian Merlo⁵, Maria del carmen abalos-aguilera⁵, julio Manuel Martinez Moreno⁶, Iván Arias de la Rosa⁷, María Dolores López-Montilla⁸, Rafaela Ortega-Castro⁹, Jerusalén Calvo¹⁰, Lourdes Ladehesa¹¹, Clementina López Medina¹², María Ángeles Puche-Larrubia¹³, Nuria Barbarroja¹⁴, Eduardo Collantes estévez¹⁵, Alejandro Escudero-contreras⁵, Chary López pedrera¹⁶, Jose manuel Villalba¹⁷ and Carlos Pérez Sánchez¹⁸, ¹Rheumatology Service/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba/ Reina Sofia University Hospital, Córdoba, Spain/Department of Cell Biology, Physiology and Immunology, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain, Cordoba, Spain, ²Rheumatology Service/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba/ Reina Sofia University Hospital, Córdoba, Spain/Department of Cell Biology, Physiology and Immunology, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain., Cordoba, Spain, ³Cobiomic Bioscience SL. EBT University of Cordoba/IMIBIC, Cordoba, Spain., Cordoba, Spain, ⁴Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), Cordoba, Andalucia, Spain, ⁵Rheumatology Service/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/University of Cordoba/ Reina Sofia University Hospital, Córdoba, Spain, Cordoba, Spain, ⁶Cobiomic Bioscience SL. EBT University of Cordoba/IMIBIC, Cordoba, Spain, Cordoba, Spain, ⁷IMIBIC/FIBICO/Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso; Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Toledo, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Toledo, Spain., Córdoba, Spain, ⁸Rheumatology Department, Reina Sofía University Hospital, Cordoba/IMIBIC/University of Cordoba., CORDOBA, Spain, ⁹Rheumatology service/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ Reina Sofia University Hospital/ University of Cordoba, Spain, Cordoba, Andalucia, Spain, ¹⁰IMIBIC / Reina Sofia Hospital / University of Cordoba, Córdoba, Spain, ¹¹IMIBIC-Reina Sofia Hospital-University of Cordoba, Cordoba, Spain, Cordoba, Spain, ¹²Department of Medicine, Hospital Universitario Reina Sofia, University of Cordoba, IMIBIC, Cordoba, Spain, ¹³Reina Sofia University Hospital, Granada, Spain, ¹⁴Rheumatology service/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ Reina Sofia University Hospital/ University of Cordoba, Spain/CobiomicBioscience S.l, Cordoba, Spain, Cordoba, Spain, ¹⁵Maimonides Institute for Biomedical Research of Córdoba (IMIBIC) / Department of Medical and Surgical Sciences, Faculty of Medicine, University of Córdoba, Spain, Cordoba, Spain, ¹⁶Rheumatology service/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ Reina Sofia University Hospital/ University of Cordoba, Spain, Cordoba, Spain, ¹⁷Department of Cell Biology, Physiology and Immunology, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain, Cordoba, Spain, ¹⁸Rheumatology service/Maimonides Institute for Research in Biomedicine of Cordoba (IMIBIC)/ Reina Sofia University Hospital/ University of Cordoba, Spain/ CobiomicBioscience S.l, Cordoba, Spain, Cordoba, Spain

Meeting: ACR Convergence 2025

Keywords: Anti-TNF Drugs, Biomarkers, Genomics and Proteomics, Inflammation, Therapy, complementary

Session Information

Date: Sunday, October 26, 2025

Title: (0098–0114) Spondyloarthritis Including Psoriatic Arthritis – Basic Science Poster

Session Type: Poster Session A

Session Time: 10:30AM-12:30PM

Background/Purpose: This study aims to:Characterize the NAD+ metabolome in CIRDs and their association with clinical traits.Evaluate the impact of TNFi therapy on NAD+ metabolome alterations.Test the potential of a group of NAD+ boosters to restore NAD+ alterations and promote anti-inflammatory effects.

Methods: Whole blood samples were collected from 310 subjects: 70 healthy donors (HDs), 80 rheumatoid arthritis (RA) patients, 80 psoriatic arthritis (PsA) patients, and 80 spondyloarthritis (SpA) patients. Key NAD+ pathway metabolites (NAD+, NADH, NAM, NMN, NR, NADP and Tryp) were analyzed using two-dimensional Nuclear Magnetic Resonance. A longitudinal analysis in 90 CIRDs patients, 30 from each disease group, assessed NAD+ metabolome changes after 6 months of TNFi therapy. Peripheral blood mononuclear cells (PBMCs) from 45 patients (15 from each disease group) were treated ex-vivo with NAD+ boosters (NR, NMN, NRT, NRH, and NAR) for 24 hours, followed by intracellular NAD+/NADH measurement. In parallel, secreted inflammatory mediators were assessed (Olink Inflammation Panel, Cobiomic).

Results: RA, PsA and SpA patients showed reduced NAD+/NADH ratio and elevated NAM and NMN levels compared to HDs. RA had decreased NAD+ levels, while PsA and SpA displayed increased NADH levels; SpA also had reduced NADP and elevated Trp levels. These disease-specific NAD+ metabolism alterations correlated with distinct clinical features: in RA, the NAD+/NADH ratio was negatively associated with DAS28, while NADH and NMN correlated positively with CRP, tender and swollen joint counts (TJC and SJC). Autoantibodies correlated positively with NADH levels. In PsA, the NAD+/NADH ratio and NAD+ levels correlated negatively with TJC and SJC, and disease activity (DAPSA) respectively. Uveitis was positively correlated with NAD+ levels, and psoriasis with NAM levels. In SpA, axial forms had a lower NAD+/NADH ratio, with positive correlations between ESR and NMN, entesitis and NADH, and dactylitis with Trp. TNFi therapy induced disease-specific changes in NAD+ metabolites, partially restoring levels toward those seen in HDs. All NAD+ boosters increased intracellular NAD+ in patientes PBMCs, with NRH being the most effective. Boosters also reduced inflammatory mediator secretion, showing disease and booster specific effects.

Conclusion: 1-The NAD⁺ metabolome was altered in CIRDs, with disease-specific disruption patterns associated with key clinical manifestations.2-TNFi treatment normalized NAD⁺ metabolite levels, indicating a potential role in metabolic rebalancing during therapeutic response.3- NAD⁺ boosters increase intracellular NAD⁺ levels and attenuates inflammation, exhibiting both common and disease-specific effects.Targeting the NAD⁺ pathway emerges as a promising therapeutic approach in CIRDs.Supported by: CPS: MICIU (RYC2021-033828-I; PID2022-141500OA-I00); FAR2023-24; JA (PIP-0149-2024); AEI (DIN2022-012766). CLP: ISCIII (PI21/0591, PI24/00959, CD21/00187 y RICOR-21/0002/0033). JMV: RTI2018-100695-B-I00, PID2021-126280OB-I00,P18-RT-4264. AEC: ISCIII (ICI23/00100). CLM, ECE y NBP: ISCIII(PI22/00539 y PMP21/00119); JA (I-0243-2022); MICIU (PID2023-152503OB). Cofinanciados por la UE.

Disclosures: B. Vellón-García: None; G. García-Delgado: None; A. Llamas Urbano: None; Y. Hanaee: None; P. Ortiz Buitrago: None; C. Merlo: None; M. abalos-aguilera: None; j. Martinez Moreno: None; I. Arias de la Rosa: None; M. López-Montilla: None; R. Ortega-Castro: None; J. Calvo: None; L. Ladehesa: None; C. López Medina: None; M. Puche-Larrubia: None; N. Barbarroja: None; E. Collantes estévez: None; A. Escudero-contreras: None; C. López pedrera: None; J. Villalba: None; C. Pérez Sánchez: None.

To cite this abstract in AMA style:

Vellón-García B, García-Delgado G, Llamas Urbano A, Hanaee Y, Ortiz Buitrago P, Merlo C, abalos-aguilera M, Martinez Moreno j, Arias de la Rosa I, López-Montilla M, Ortega-Castro R, Calvo J, Ladehesa L, López Medina C, Puche-Larrubia M, Barbarroja N, Collantes estévez E, Escudero-contreras A, López pedrera C, Villalba J, Pérez Sánchez C. Therapeutic Modulation of NAD+ Metabolism in Inflammatory Rheumatic Disorders by TNFi and NAD+ Precursors [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/therapeutic-modulation-of-nad-metabolism-in-inflammatory-rheumatic-disorders-by-tnfi-and-nad-precursors/. Accessed .

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