Molecular Characterization of Biologic and Targeted Synthetic DMARDs Effects Through Ex- vivo Studies in Rheumatoid Arthritis Immune Cells

Laura Muñoz-Barrera¹, Carlos Perez-Sanchez², Laura Romero-Zurita¹, Rafaela Ortega Castro³, Jerusalem Calvo⁴, Pilar Font Ugalde¹, Marta Rojas⁵, Ismael Sanchez-Pareja¹, Maria del Carmen Abalos-Aguilera⁶, Desiree Ruiz-Vilchez¹, Christian Merlo-Ruiz¹, Mª Angeles Aguirre⁷, Nuria Barbarroja⁸, Tomás Cerdó¹, Eduardo Collantes Estévez⁹, Marta Alarcon-Riquelme¹⁰, Alejandro Escudero Contreras⁴ and Chary Lopez-Pedrera¹¹, ¹IMIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain, ²IMIBIC, Córdoba, Spain, ³Hospital Reina Sofía, Cordoba, Spain, ⁴Reina Sofia University Hospital, Córdoba, Spain, ⁵Hospital Universitario Reina Sofía, Cordoba, Spain, ⁶Rheumatology Department, Reina Sofia University Hospital/Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain, ⁷Reina Sofía University Hospital/ Rheumatology Department, Córdoba, Spain, ⁸University of Cordoba, Córdoba, Spain, ⁹Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba, Cordoba, Spain, ¹⁰Center for Genomics and Oncological Research (GENYO), Granada, Spain, ¹¹IMIBIC - Reina Sofia Hospital, Córdoba, Spain

Meeting: ACR Convergence 2023

Keywords: Disease-Modifying Antirheumatic Drugs (Dmards), Inflammation, proteomics, rheumatoid arthritis

Session Information

Date: Sunday, November 12, 2023

Title: (0423–0459) RA – Treatments Poster I

Session Type: Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Despite advances in rheumatoid arthritis (RA) treatment, a significant proportion of patients (10-30%) fail to respond to current medications, including biologics. A better characterization of the molecular effects promoted by the drugs might contribute to the development of personalized therapeutic strategies.

Methods: Peripheral blood mononuclear cells (PBMC) and neutrophils from 10 active RA patients were cultured (24h and 12h, respectively), with autologous serum and with either, etanercept, sarilumab, or baricitinib (all 10 micromolar). Changes in cell proliferation and adhesion in PBMCs and NETosis-derived products in supernatants of cell cultures were measured with specific commercial kits. Protein expression changes promoted by each drug were evaluated in supernatants using proximity extension assay (PEA) technology (Olink), analyzing a panel of 92 inflammation-related proteins. To identify if the proteomic signatures susceptible to being modulated by the drugs were present in patients with active disease, we analyzed the same inflammatory profile in the serum of 180 RA patients.

Results: TNFi, IL6Ri, and JAKinibs inhibited proliferation and adhesion in PBMCs from 70% of RA patients, being TNFi and JAKinibs more effective than IL6Ri. RA Neutrophils treated with autologous serum underwent NETosis, which was equally prevented by all inhibitors. Autologous serum increased the secretion of inflammatory proteins by RA PBMCs and neutrophils, while each drug promoted specific changes in proteomic signatures. Thus, TNFi, IL6Ri, and JAKinibs reduced different sets of cytokines, chemokines, and growth factors, with only three reduced (IL7, TNF, FGF23) by all three inhibitors. Lastly, analysis of the circulating inflammatory proteome revealed that approximately 60% of active RA patients exhibited at least one altered proteomic signature associated with the one modulated ex vivo by any of the drugs. Particularly 20% of patients exhibited an altered proteomic signature modulated ex vivo by the 3 drugs, 20 % with two of them, and 20% with only one precise drug.

Conclusion: The distinctive cellular and molecular changes promoted by TNFi, IL6Ri, and JAKinibs in ex vivo assays of RA immune cells, were consistent with specific altered serum profiles observed in subgroups of active RA patients. Such observations provide compelling evidence regarding the therapeutic potential of each therapy, as it aligns with the specific molecular profile alterations exhibited by individual patients at baseline.

Supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking 3TR, ISCIII (PI21/0591, CD21/00187 and RICOR-21/0002/0033), RYC2021-033828-I, and Junta de Andalucía (P20_01367); co-financed by FEDER.

Disclosures: L. Muñoz-Barrera: None; C. Perez-Sanchez: None; L. Romero-Zurita: None; R. Ortega Castro: None; J. Calvo: None; P. Font Ugalde: None; M. Rojas: None; I. Sanchez-Pareja: None; M. Abalos-Aguilera: None; D. Ruiz-Vilchez: None; C. Merlo-Ruiz: None; M. Aguirre: None; N. Barbarroja: None; T. Cerdó: None; E. Collantes Estévez: None; M. Alarcon-Riquelme: None; A. Escudero Contreras: None; C. Lopez-Pedrera: None.

To cite this abstract in AMA style:

Muñoz-Barrera L, Perez-Sanchez C, Romero-Zurita L, Ortega Castro R, Calvo J, Font Ugalde P, Rojas M, Sanchez-Pareja I, Abalos-Aguilera M, Ruiz-Vilchez D, Merlo-Ruiz C, Aguirre M, Barbarroja N, Cerdó T, Collantes Estévez E, Alarcon-Riquelme M, Escudero Contreras A, Lopez-Pedrera C. Molecular Characterization of Biologic and Targeted Synthetic DMARDs Effects Through Ex- vivo Studies in Rheumatoid Arthritis Immune Cells [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/molecular-characterization-of-biologic-and-targeted-synthetic-dmards-effects-through-ex-vivo-studies-in-rheumatoid-arthritis-immune-cells/. Accessed .

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/molecular-characterization-of-biologic-and-targeted-synthetic-dmards-effects-through-ex-vivo-studies-in-rheumatoid-arthritis-immune-cells/