Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell–Targeted Therapy in the Trial of Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS)

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. Metho...

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Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2024-05, Vol.76 (5), p.763-776
Main Authors: Pontarini, Elena, Sciacca, Elisabetta, Chowdhury, Farzana, Grigoriadou, Sofia, Rivellese, Felice, Murray‐Brown, William J., Lucchesi, Davide, Fossati‐Jimack, Liliante, Nerviani, Alessandra, Jaworska, Edyta, Ghirardi, Giulia Maria, Giacomassi, Chiara, Emery, Paul, Ng, Wan Fai, Sutcliffe, Nurhan, Everett, Colin, Fernandez, Catherine, Tappuni, Anwar, Seror, Raphael, Mariette, Xavier, Porcher, Raphael, Cavallaro, Giulia, Pulvirenti, Alfredo, Verstappen, Gwenny M., Wolff, Liseth, Arends, Suzanne, Bootsma, Hendrika, Lewis, Miles J., Pitzalis, Constantino, Bowman, Simon J., Bombardieri, Michele
Format: Article
Language:English
Subjects:
Antibodies
Antigen presentation
Antigens
B-Lymphocytes - immunology
Biomarkers
Biomarkers - blood
Biopsy
Cell activation
Cell therapy
Chemokine CXCL13
Chemokines
Complement activation
CXCL13 protein
Cytokines
Epithelium
Female
Flow cytometry
Gene expression
Gene sequencing
Humans
Immunoglobulins
Immunological memory
Inflammation
Interleukin-17
Life Sciences
Longitudinal Studies
Lymphocytes
Lymphocytes B
Lymphocytes T
Memory cells
Metabolism
Metastases
Middle Aged
Necrosis
Peripheral blood
Restoration
Rituximab
Rituximab - therapeutic use
RNA sequencing
Salivary gland
Salivary glands
Salivary Glands - immunology
Serum
Sjogren's syndrome
Sjogren's Syndrome - drug therapy
Sjogren's Syndrome - immunology
Stars
Stratification
Therapy
Treatment Outcome
Tumor necrosis factor-TNF
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Summary: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.
ISSN:2326-5191
2326-5205
2326-5205
2326-5191
DOI:10.1002/art.42772