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Abstract Number: 0909

Unsupervised Clustering Analysis of Circulating Molecular Profiles in Rheumatoid Arthritis Patients Defines Precise CV Risk. Effects of TNFi, IL6Ri, and JAKinibs

Chary Lopez-Pedrera1, Laura Muñoz-Barrera1, Tomás Cerdó2, Maria Luque-Tevar3, Pilar Font1, Montserrat Romero-Gomez2, Desiree Ruiz-Vilchez4, Sara Remuzgo-Martinez5, Raquel Lopez Mejias6, María Carmen Ábalos-Aguilera7, Rafaela Ortega-Castro1, José Perez-Venegas8, Mª Dolores Ruiz-Montesinos8, Carmen Dominguez8, Carlos Rodriguez-Escalera9, Carmen Romero-Barco9, Antonio Fernandez-Nebro10, Natalia Mena Vazquez10, Jose Luis Marenco11, Julia Uceda Montañez11, Charo Santos12, Nuria Barbarroja1, Mª Angeles Aguirre13, Alejandro Escudero-Contreras2, Eduardo Collantes1, Miguel Ángel González-Gay14 and Carlos Pérez-Sánchez1, 1IMIBIC/University of Cordoba/Reina Sofia Hospital, Cordoba, Spain, 2IMIBIC/University of Cordoba/Reina Sofia Hospital, Córdoba, Spain, 3IMIBIC, Córdoba, Spain, 4Reina Sofia University Hospital, Cordoba, Cordoba, Spain, 5Research Group on Genetic Epidemiology and Atherosclerosis in Systemic Diseases and in Metabolic Bone Diseases of the Musculoskeletal System, IDIVAL; and Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Santander, Spain, 6IDIVAL, Santander, Spain, 7Imibic/ University of Córdoba/ Reina Sofía Hospital, Córdoba, Spain, 8Virgen Macarena University Hospital, Sevilla, Spain, 9Virgen de la Victoria Hospital, Málaga, Spain, 10Regional University Hospital of Málaga, Málaga, Spain, 11Virgen de Valme University Hospital, Sevilla, Spain, 12Virgen de Valme University Hospital, Málaga, Spain, 13Maimonides Institute for Biomedical Research of Córdoba, Cordoba, Spain, 14Department of Medicine and Psychiatry, Universidad de Cantabria; Rheumatology Division, Hospital Universitario Marqués de Valdecilla; Research group on genetic epidemiology and atherosclerosis in systemic diseases and in metabolic diseases of the musculoskeletal system, IDIVAL, Santander, Spain. Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Meeting: ACR Convergence 2022

Keywords: Atherosclerosis, Cardiovascular, proteomics, rheumatoid arthritis, Therapy, alternative

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Session Information

Date: Sunday, November 13, 2022

Title: RA – Diagnosis, Manifestations, and Outcomes Poster II

Session Type: Poster Session B

Session Time: 9:00AM-10:30AM

Background/Purpose: This study aimed to 1) Analyze the circulating inflammatory profile of Rheumatoid Arthritis (RA) patients, in order to recognize distinctive clinical phenotypes associated with CV risk; 2) Evaluate the modulatory effects of TNF inhibitors (TNFi), JAK-STAT inhibitors (JAKInibs) and IL-6R inhibitors (IL6Ri); 3) Characterize underlying molecular mechanisms involved in endothelial dysfunction.

Methods: Two hundred and eight RA patients and 45 healthy donors (HD) were recruited. Serum inflammatory profile was assessed by analyzing 27 cytokines/chemokines -Luminex assays-, and biomolecules related to NETosis and oxidative stress -by base-plate kits-. Parallel extensive clinical analyses were performed. TNFi, JAKinibs and IL-6Ri effects were evaluated, respectively, in 45, 20 and 17 RA patients after 6 months. Lastly, mechanistic in vitro studies were developed in cultured endothelial cells (ECs) and changes in protein expression were evaluated in cell lysates by proximity extension assay technology, analyzing a panel of 88 proteins related to CV disease.

Results: Unsupervised-clustering identified 3 clusters representing specific molecular profiles. Clinically, even in the presence of similar disease score (DAS28) and positivity for autoantibodies, cluster 1 (C1) identified RA-patients expressing high inflammatory mediators’ levels, the highest CV-risk score, and a preponderance of atheroma plaques. Conversely, RA-patients conforming C3 showed the lowest inflammatory profile and the lowest CV-risk score. Lastly, C2 characterized an intermediate phenotype. Comparative analyses with a cohort of 98 RA patients presenting previous CV events, demonstrated that their inflammatory profile mimicked that found in C1, supporting the association of this altered shape with the CV status. In vivo, both biological and targeted-synthetic DMARDs’ therapy reduced DAS28-score and re-established normal levels of several altered biomolecules, reflecting a key role in the CV-risk control.

In vitro, RA patients’ serum pool from cluster 1 promoted in cultured ECs increased expression of several CV-related proteins, further prevented-albeit in an specific way- by the pre-incubation with TNFi (Etanercept), JAKinibs (Baricitinib) and anti-IL6Ri (Tocilizumab).

Conclusion:

1. The systemic inflammatory profile of RA identified patients’ subgroups with enhanced CV-risk, not associated with their disease activity status.

2. Both biological and targeted-synthetic DMARDs re-established normal levels of circulating inflammatory biomolecules, reducing the CV-risk in RA.

3. In vitro studies revealed that RA-serum inflammatory mediators directly induced endothelial damage which might be prevented by effect of both, biological and targeted-synthetic DMARDs’ therapy.

Thus, the analysis of the RA patients circulating molecular profile might contribute to improving the personalized clinical management of these patients and their CV risk.

Supported by ISCIII (PI21/005991 and RICOR-RD21/0002/0033) co-financed by FEDER, Fundacion Andaluza de Reumatología (FAR) and Consejería de Conocimiento, Investigación y Universidad de la Junta de Andalucía (P20_01367).


Disclosures: C. Lopez-Pedrera, None; L. Muñoz-Barrera, None; T. Cerdó, None; M. Luque-Tevar, None; P. Font, None; M. Romero-Gomez, None; D. Ruiz-Vilchez, None; S. Remuzgo-Martinez, None; R. Lopez Mejias, None; M. Ábalos-Aguilera, None; R. Ortega-Castro, None; J. Perez-Venegas, None; M. Ruiz-Montesinos, None; C. Dominguez, None; C. Rodriguez-Escalera, None; C. Romero-Barco, None; A. Fernandez-Nebro, None; N. Mena Vazquez, None; J. Marenco, None; J. Uceda Montañez, None; C. Santos, None; N. Barbarroja, None; M. Aguirre, None; A. Escudero-Contreras, None; E. Collantes, None; M. González-Gay, AbbVie/Abbott, Merck/MSD, Janssen, Roche, AbbVie/Abbott, Roche, Sanofi, Eli Lilly, Celgene, Sobi, Merck/MSD; C. Pérez-Sánchez, None.

To cite this abstract in AMA style:

Lopez-Pedrera C, Muñoz-Barrera L, Cerdó T, Luque-Tevar M, Font P, Romero-Gomez M, Ruiz-Vilchez D, Remuzgo-Martinez S, Lopez Mejias R, Ábalos-Aguilera M, Ortega-Castro R, Perez-Venegas J, Ruiz-Montesinos M, Dominguez C, Rodriguez-Escalera C, Romero-Barco C, Fernandez-Nebro A, Mena Vazquez N, Marenco J, Uceda Montañez J, Santos C, Barbarroja N, Aguirre M, Escudero-Contreras A, Collantes E, González-Gay M, Pérez-Sánchez C. Unsupervised Clustering Analysis of Circulating Molecular Profiles in Rheumatoid Arthritis Patients Defines Precise CV Risk. Effects of TNFi, IL6Ri, and JAKinibs [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/unsupervised-clustering-analysis-of-circulating-molecular-profiles-in-rheumatoid-arthritis-patients-defines-precise-cv-risk-effects-of-tnfi-il6ri-and-jakinibs/. Accessed .
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