药理学提高NAD水平作为类风湿关节炎一种有前景的治疗方法的临床前特征研究

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

作者信息

Perez-Sanchez Carlos, Escudero-Contreras Alejandro, Cerdó Tomás, Sánchez-Mendoza Luz Marina, Llamas-Urbano Adrián, la Rosa Iván Arias-de, Pérez-Rodriguez Miguel, Muñoz-Barrera Laura, Del Carmen Abalos-Aguilera María, Barbarroja Nuria, Calvo Jerusalem, Ortega-Castro Rafaela, Ruiz-Vilchez Desiree, Moreno Juan Antonio, Burón María Isabel, González-Reyes José Antonio, Collantes-Estevez Eduardo, Lopez-Pedrera Chary, Villalba José Manuel

机构信息

Rheumatology Service, Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, and Department of Cell Biology, Immunology and Physiology, Agrifood Campus of International Excellence, University of Córdoba, Campus de Excelencia Internacional Agroalimentario (ceiA3), Córdoba, Spain; Cobiomic Bioscience.

Rheumatology Service, IMIBIC, Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain.

出版信息

Arthritis Rheumatol. 2023 Oct;75(10):1749-1761. doi: 10.1002/art.42528. Epub 2023 Jul 28.

DOI:10.1002/art.42528

PMID:37094367

Abstract

OBJECTIVE

We 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.

METHODS

Our 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.

RESULTS

Reduced 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.

CONCLUSION

RA 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.

摘要

目的

我们分析了类风湿关节炎（RA）患者的NAD代谢、其与RA疾病活动及临床结局的关联，以及药理学增强NAD的治疗潜力。

方法

我们的研究纳入了253名参与者。在第一个队列中，包括153名RA患者和56名健康供体，我们评估了NAD水平及与NAD相关的基因通路。我们通过邻近延伸分析检测了92种炎症分子。在第二个队列中，包括44名开始使用抗肿瘤坏死因子（抗TNF）药物的RA患者，我们评估了3个月后NAD水平的变化及其与临床反应的关联。对RA患者外周血单个核细胞（PBMC）进行体外机制研究，以测试NAD增强剂（如烟酰胺和烟酰胺核苷）的有益作用。

结果

在RA样本中发现NAD水平降低，这与参与NAD消耗（沉默调节蛋白、聚[ADP-核糖]聚合酶、CD38）、转运（连接蛋白43）和生物合成（烟酰胺磷酸核糖转移酶、烟酰胺单核苷酸腺苷转移酶）的基因活性和表达改变一致。无监督聚类分析确定了一组炎症特征最高、NAD水平最低且疾病活动度最高的RA患者（如28个关节疾病活动评分所示）。抗TNF治疗在调节临床反应的同时也调节了NAD水平。使用RA患者PBMC进行的体外研究表明，烟酰胺核苷和烟酰胺通过烟酰胺磷酸核糖转移酶和烟酰胺单核苷酸腺苷转移酶增加NAD水平，并降低其促氧化、促凋亡和促炎状态。