Date: Sunday, October 21, 2018
Session Title: Rheumatoid Arthritis – Etiology and Pathogenesis Poster I
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: 1) To test the relationship among ACPAs and levels of adipocytokines and atherosclerosis in RA patients. 2) To analyze the effects of ACPAs on the AT function: adipocyte differentiation, macrophage polarization and lipid accumulation, and 3) To evaluate the effects tocilizumab (TCZ) or infliximab (IFX) on the metabolic alterations induced by ACPAs on AT.
Methods: Human study: 75 RA patients and 40 healthy donors were included. Serum levels of adipocytokines were evaluated. Carotid intima media thickness (CMIT) was evaluated as atherosclerosis marker. In vitro studies: IgGs-ACPAs were isolated from serum of RA patients. 3T3-L1 cells were treated with IgG-NHS or IgG-ACPAs alone or in combination with IFX or TCZ during several stages of the adipocyte differentiation. M0 macrophages were treated with IgG-NHS or IgG-ACPAs alone or in combination with IFX or TCZ. Ex vivo experiments: Subcutaneous AT samples were obtained from 8 obese patients through bariatric surgery. AT samples were treated ex vivo with IgGs-NHS or IgG-ACPAs alone or in combination with bDMARDs. Protein and gene expression of molecules involved in adipogenesis, inflammation, insulin signaling and lipid accumulation was analyzed
Results: RA patients had elevated levels of leptin/adiponectin ratio, visfatin and inflammatory markers in serum. These alterations were associated with the ACPAs levels. Disease activity and CMIT were associated with ACPAs, leptin/adiponectin ratio, levels of visfatin and inflammatory markers. IgG-ACPAs induced M1 polarization state and impaired insulin signaling in M0 macrophages. 3T3-L1 fibroblast treated with IgG-ACPAs at day 0 showed an impaired adipocyte differentiation. Genes involved in insulin signaling were reduced. Treatment with IFX and TCZ restore adipocyte differentiation and improved insuling signaling. In human AT, the treatment with IgGs-ACPAs increased the inflammation, accompanied by a downregulation of genes involved in lipid accumulation, adipogenesis and insulin signaling. bDMARDs reverted inflammatory and metabolic alterations on human AT explants.
1) ACPAs are related to high levels of adipocytokines in RA patients, suggesting its action on AT dysfunction, contributing to the increased CVD risk. 2) In vitro, ACPAs impairs AT function, acting in both, macrophages and adipocytes, inducing inflammation, impairing adipogenesis and lipid accumulation, and favoring an IR state. 3) TCZ and IFX might reverse the metabolic alterations induced in AT by ACPAs. 4) Targeting these autoantibodies would be an excellent therapeutic strategy to restore AT function and reduce the CVD related to RA. Funded by ISCIII(PI17/01316, CP15/00158 and RIER RD16/0012/0015) co-funded with FEDER.
To cite this abstract in AMA style:Barbarroja N, Arias de la Rosa I, Ruiz-Ponce M, de la Rosa-Garrido MD, Ruiz-Limon P, Jiménez-Gómez Y, Perez-Sanchez C, Abalos-Aguilera MC, Guzman-Ruiz R, Malagon MDM, Tinahones FJ, Collantes-Estévez E, Lopez-Pedrera C, Escudero-Contreras A. Antibodies to Citrullinated Protein Antigens (ACPAs) Induce Adipose Tissue Dysfunction Contributing to the Cardiovascular Disease Risk in Rheumatoid Arthritis. Modulation By Biological Dmards [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/antibodies-to-citrullinated-protein-antigens-acpas-induce-adipose-tissue-dysfunction-contributing-to-the-cardiovascular-disease-risk-in-rheumatoid-arthritis-modulation-by-biological-dmards/. Accessed April 8, 2020.
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