Disruption of memory B-cell trafficking by belimumab in patients with systemic lupus erythematosus.

Autor:	Arends EJ; Expert Center for Lupus-, Vasculitis-, and Complement-Mediated Systemic diseases (LuVaCs), Department of Internal Medicine-Section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands., Zlei M; Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands.; Medical Laboratory, Department of Flow Cytometry, Regional Institute of Oncology, Iasi, Romania., Tipton CM; Lowance Centre for Human Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Department of Medicine, Division of Rheumatology, Emory University, Atlanta, GA, USA., Cotic J; Clinical Statistics, GSK, Middlesex, UK., Osmani Z; Expert Center for Lupus-, Vasculitis-, and Complement-Mediated Systemic diseases (LuVaCs), Department of Internal Medicine-Section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands., de Bie FJ; Department of Immunology, Leiden University Medical Centre, Leiden, The Netherlands., Kamerling SWA; Expert Center for Lupus-, Vasculitis-, and Complement-Mediated Systemic diseases (LuVaCs), Department of Internal Medicine-Section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands., van Maurik A; Clinical Pharmacology and Experimental Medicine, GSK, Hertfordshire, UK., Dimelow R; Clinical Pharmacology Modelling and Simulation, GSK, Hertfordshire, UK., Gregan YI; Clinical Science Immunology, GSK, Collegeville, PA, USA., Fox NL; Clinical Development, GSK, Collegeville, PA, USA., Rabelink TJ; Expert Center for Lupus-, Vasculitis-, and Complement-Mediated Systemic diseases (LuVaCs), Department of Internal Medicine-Section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands., Roth DA; Research and Development, GSK, Collegeville, PA, USA., Sanz I; Lowance Centre for Human Immunology, Emory University School of Medicine, Atlanta, GA, USA., van Dongen JJM; Centro de Investigación del Cáncer-Instituto de Biología Molecular y Celular del Cáncer (CIC-IBMCC, USAL-CSIC-FICUS) and Department of Medicine, University of Salamanca, Salamanca, Spain., van Kooten C; Expert Center for Lupus-, Vasculitis-, and Complement-Mediated Systemic diseases (LuVaCs), Department of Internal Medicine-Section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands., Teng YKO; Expert Center for Lupus-, Vasculitis-, and Complement-Mediated Systemic diseases (LuVaCs), Department of Internal Medicine-Section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2024 Sep 01; Vol. 63 (9), pp. 2387-2398.
DOI:	10.1093/rheumatology/keae286
Abstrakt:	Objectives: Autoreactive memory B cells (MBCs) contribute to chronic and progressive courses in autoimmune diseases like SLE. The efficacy of belimumab (BEL), the first approved biologic treatment for SLE and LN, is generally attributed to depletion of activated naïve B cells and inhibition of B-cell activation. BEL's effect on MBCs is currently unexplained. We performed an in-depth cellular and transcriptomic analysis of BEL's impact on the blood MBC compartment in patients with SLE. Methods: A retrospective meta-analysis was conducted, pooling flow cytometry data from four randomized trials involving 1245 patients with SLE treated with intravenous BEL or placebo. Then, extensive MBC phenotyping was performed using high-sensitivity flow cytometry in patients with mild/moderate SLE and severe SLE/LN treated with subcutaneous BEL. Finally, transcriptomic characterization of surging MBCs was performed by single-cell RNA sequencing. Results: In BEL-treated patients, a significant increase in circulating MBCs, in a broad range of MBC subsets, was established at week 2, gradually returning to baseline by week 52. The increase was most prominent in patients with higher SLE disease activity, serologically active patients and patients aged ≤18 years. MBCs had a non-proliferating phenotype with a prominent decrease in activation status and downregulation of numerous migration genes. Conclusion: Upon BEL initiation, an increase of MBCs was firmly established. In the small cohort investigated, circulating MBCs were de-activated, non-proliferative and demonstrated characteristics of disrupted lymphocyte trafficking, expanding on our understanding of the therapeutic mechanism of B-cell-activating factor inhibition by BEL. Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00071487, NCT00410384, NCT01632241, NCT01649765, NCT03312907, NCT03747159. (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
Databáze:	MEDLINE
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