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Lookup NU author(s): Professor Fai NgORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.Objective: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints. Methods: Longitudinal analysis of peripheral blood and SG biopsies was performed pre- and post-treatment from the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing. Results: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class-switched memory B cells within the SG. Furthermore, rituximab significantly down-regulated genes involved in immune-cell recruitment, lymphoid organization alongside antigen presentation, and T cell co-stimulatory pathways. In the peripheral compartment, rituximab down-regulated immunoglobulins and auto-antibodies together with pro-inflammatory cytokines and chemokines. Interestingly, patients classified as responders according to STAR displayed significantly higher baseline levels of C-X-C motif chemokine ligand-13 (CXCL13), interleukin (IL)-22, IL-17A, IL-17F, and tumor necrosis factor-α (TNF-α), whereas a longitudinal analysis of serum T cell–related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS-responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ-receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration. Conclusion: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification. (Figure presented.).
Author(s): Pontarini E, Sciacca E, Chowdhury F, Grigoriadou S, Rivellese F, Murray-Brown WJ, Lucchesi D, Fossati-Jimack L, Nerviani A, Jaworska E, Ghirardi GM, Giacomassi C, Emery P, Ng WF, Sutcliffe N, Everett C, Fernandez C, Tappuni A, Seror R, Mariette X, Porcher R, Cavallaro G, Pulvirenti A, Verstappen GM, de Wolff L, Arends S, Bootsma H, Lewis MJ, Pitzalis C, Bowman SJ, Bombardieri M
Publication type: Article
Publication status: Published
Journal: Arthritis and Rheumatology
Year: 2024
Pages: epub ahead of print
Online publication date: 10/12/2023
Acceptance date: 04/12/2023
Date deposited: 05/03/2024
ISSN (print): 2326-5191
ISSN (electronic): 2326-5205
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/art.42772
DOI: 10.1002/art.42772
Data Access Statement: The SG RNA-sequencing (RNA-seq) data, including longitudinal expression of individual genes and their transcript level according to histology, clinical parameters, and clinical response, in pSS patients recruited in the TRACTISS trial, are publicly available at the interactive web interface https://tractiss.hpc.qmul.ac.uk/
PubMed id: 38073013
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