Rituximab Induces an Early Re-Assessment of the Immune and Vascular Systems in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis

Chary Lopez-Pedrera¹, Irene Cecchi², Nuria Barbarroja³, Alejandra Maria Patiño-Trives¹, María Luque Tevar¹, Laura Pérez Sánchez⁴, Alejandro Ibáñez-Costa¹, Ivan Arias de la Rosa⁵, Yolanda Jiménez-Gómez³, Massimo Radin⁶, Rafaela Ortega-Castro³, M. Carmen Castro-Villegas⁷, Jerusalem Calvo-Gutierrez³, Alejandro Escudero-Contreras⁵, Maria Jose Cuadrado⁸, Savino Sciascia⁹, Eduardo Collantes Estevez¹, Maria Ángeles Aguirre Zamorano¹ and Carlos Perez-Sanchez³, ¹IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, ²Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and Valle d’Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, University of Turin, Italy, Turin, Italy, ³Rheumatology service, IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, ⁴IMIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain, ⁵Rheumatology Service, IMIBIC/Reina Sofia Hospital/University of Cordoba, Cordoba, Spain, ⁶Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and Valle d’Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, University of Turin, Italy, Turin, Italy, ⁷Rheumatology Service, IMIBIC/Reina Sofia Hospital/University of Cordoba, Córdoba, Spain, ⁸Clinica Universidad de Navarra, Madrid, Spain, ⁹Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and Valle d’Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, University of Turin, Italy, Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and Valle d’Aosta Network for Rare Diseases, Department of Clinical and Biological Sciences, University of Turin, Italy, Torino, Italy

Meeting: ACR/ARHP Annual Meeting 2018

Keywords: B cells, MicroRNA, Rheumatoid arthritis (RA), rituximab and systemic lupus erythematosus (SLE)

Session Information

Date: Sunday, October 21, 2018

Title: B Cell Biology and Targets in Autoimmune and Inflammatory Disease Poster

Session Type: ACR Poster Session A

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

Background/Purpose: While the role of Rituximab (RTX) in controlling the clinical manifestations of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) has been documented, the mechanisms underlying the interplay between B-cell depletion and pro-inflammatory status leading to clinical response remain unknown. This translational multicenter study explored changes in serologic variables following B-lymphocyte depletion by in vivo Rituximab (RTX) treatment in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) patients and investigated RTX in vitro effects on the activity of other immune cells and on the vascular endothelium.

Methods: Sixteen SLE patients and 16 RA patients treated with RTX were enrolled. Changes in circulating inflammatory mediators, oxidative stress markers, and NETosis-derived products were evaluated at baseline and after 3 months. Serum miRNomes were identified using next-generation sequencing miRNA assay, and RTX-induced changes were delineated. Purified lymphocytes from RA and SLE patients were treated in vitro with RTX for 24h and B-cell depletion and inflammatory profile were evaluated by flow cytometry and RT-PCR respectively. Serum from RA and SLE patients at baseline and after RTX therapy were further added to HUVECs, monocytes, and neutrophils purified from healthy donors and activity profiles were evaluated.

Results: In vivo treatment of SLE and RA patients with RTX caused a significant decrease of disease activity along with a prominent alteration in circulating biomolecules related to inflammation, oxidative stress and NETosis. Reversion in altered expression of miRNAs regulating those molecules was also noticed. The in vitro treatment of SLE and RA purified lymphocytes with RTX significantly decreased the percentage of B lymphocytes, and was also effective in reducing the levels of a cytokine panel integrated by IL-1β, IL-6, IFN-γ and TNF-α. Likewise, the treatment of HUVECs, monocytes and neutrophils -isolated from healthy donors- with serum of SLE and RA patients after 3 months of RTX therapy, prevented the overexpression of pro-thrombotic and pro-inflammatory markers induced by the serum of those patients before RTX therapy, and avoided the induction of NETosis in neutrophils.

Conclusion: 1. The role of B cells in autoimmunity is not confined to the production of auto-antibodies, also playing important roles in shaping the outcome of pathological immune responses. 2. RTX induced an early re-assessment of the pro-inflammatory status in RA and SLE patients, involving a re-establishment of the homeostatic equilibrium in the immune system and the vascular wall, thus paving the way to more tailored therapeutic approaches.

Funded by PI-0285-2017, ISCIII, PI15/01333 and RIER RD16/0012/0015 co-funded with FEDER

Disclosure: C. Lopez-Pedrera, None; I. Cecchi, None; N. Barbarroja, None; A. M. Patiño-Trives, None; M. Luque Tevar, None; L. Pérez Sánchez, None; A. Ibáñez-Costa, None; I. Arias de la Rosa, None; Y. Jiménez-Gómez, None; M. Radin, None; R. Ortega-Castro, None; M. C. Castro-Villegas, None; J. Calvo-Gutierrez, None; A. Escudero-Contreras, None; M. J. Cuadrado, None; S. Sciascia, None; E. Collantes Estevez, None; M. Á. Aguirre Zamorano, None; C. Perez-Sanchez, None.

To cite this abstract in AMA style:

Lopez-Pedrera C, Cecchi I, Barbarroja N, Patiño-Trives AM, Luque Tevar M, Pérez Sánchez L, Ibáñez-Costa A, Arias de la Rosa I, Jiménez-Gómez Y, Radin M, Ortega-Castro R, Castro-Villegas MC, Calvo-Gutierrez J, Escudero-Contreras A, Cuadrado MJ, Sciascia S, Collantes Estevez E, Aguirre Zamorano MÁ, Perez-Sanchez C. Rituximab Induces an Early Re-Assessment of the Immune and Vascular Systems in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/rituximab-induces-an-early-re-assessment-of-the-immune-and-vascular-systems-in-patients-with-systemic-lupus-erythematosus-and-rheumatoid-arthritis/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/rituximab-induces-an-early-re-assessment-of-the-immune-and-vascular-systems-in-patients-with-systemic-lupus-erythematosus-and-rheumatoid-arthritis/