Serum and tissue biomarkers associated with CRESS and STAR response to B‐cell targeted therapy in TRACTISS trial of Sjogren's syndrome-Reference-Cited by-同舟云学术

Serum and tissue biomarkers associated with CRESS and STAR response to B‐cell targeted therapy in TRACTISS trial of Sjogren's syndrome

Published:2023-12-10 Issue: Volume: Page:
ISSN:2326-5191
Container-title:Arthritis & Rheumatology
language:en
Short-container-title:Arthritis & Rheumatology

Author:

Pontarini E¹^ORCID,Sciacca E¹²,Chowdhury F¹³,Grigoriadou S¹,Rivellese F¹⁴,Murray‐Brown WJ¹,Lucchesi D¹^ORCID,Fossati‐Jimack L¹,Nerviani A¹⁴,Jaworska E¹^ORCID,Ghirardi GM¹,Giacomassi C¹,Emery P⁵^ORCID,Ng WF⁶,Sutcliffe N⁴,Everett CC⁷^ORCID,Fernandez C⁷,Tappuni AR³⁴,Seror R⁸⁹,Mariette X⁸⁹,Porcher R¹⁰¹¹,Cavallaro G¹²,Pulvirenti A¹³,Verstappen GMPJ¹⁴^ORCID,de Wolff L¹⁴^ORCID,Arends S¹⁴,Bootsma H¹⁴,Lewis MJ¹⁴^ORCID,Pitzalis C¹⁴^ORCID,Bowman SJ¹⁵,Bombardieri M¹⁴,

Affiliation:

1. William Harvey Research Institute Queen Mary University of London

2. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry Queen Mary University of London London United Kingdom

3. Institute of Dentistry Queen Mary University of London

4. Bart's Health NHS Trust London UK

5. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK. NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust Leeds UK

6. Translational and Clinical Research Institute, Newcastle University, Newcastle‐upon‐Tyne, UK and NIHR Newcastle Clinical Research Facility Newcastle upon Tyne UK

7. Leeds Institute for Clinical Trials Research, University of Leeds Leeds UK

8. Universite’ Paris‐Saclay, Le Kremlin‐ Bicetre France

9. Assistance Publique‐Hôpitaux de Paris (AP‐HP), Hôpital Bicêtre Le Kremlin‐ Bicêtre France

10. Université Paris Cité, Centre de Recherche Épidémiologie et Statistiques (CRESS‐UMR1153), INSERM, INRAE Paris France

11. Centre d’Épidémiologie Clinique, Assistance Publique‐ Hôpitaux de Paris (AP‐HP), Hôtel‐Dieu F‐75004 Paris France

12. University of Catania Catania Italy

13. Bioinformatics Unit University of Catania Italy

14. University Medical Center Groningen University of Groningen Groningen Netherlands

15. University Hospitals Birmingham NHS Foundation Trust Birmingham UK

Abstract

ObjectivesTo identify peripheral and salivary gland (SG) biomarkers of response/resistance to B‐cell depletion based on the novel concise CRESS (cCRESS) and candidate STAR composite endpoints.MethodsLongitudinal analysis of peripheral blood and SG biopsies pre‐ and post‐treatment from the TRACTISS trial combining FACS immunophenotyping, serum cytokines and SG bulk‐RNA‐sequencing.ResultsRituximab 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 downregulated genes involved in immune‐cell recruitment, lymphoid organization alongside antigen presentation, and T‐cell co‐stimulatory pathways. In the peripheral compartment, rituximab downregulated immunoglobulins and autoantibodies together with proinflammatory cytokines and chemokines. Interestingly, STAR responders displayed significantly higher baseline levels of CXCL13, IL‐22, IL‐17A, IL‐17F and TNFα while a longitudinal analysis of serum T‐cell‐related cytokines showed selective reduction in both STAR and cCRESS responders. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with responders showing significant decrease in SG B‐cell infiltration and reduced expression of transcriptional gene modules related to T‐cell costimulation, complement activation and FcγR engagement. Finally, cCRESS and STAR response was associated with a significant improvement in SG exocrine function, linked to transcriptional evidence of SG epithelial and metabolic restoration.ConclusionsRituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function linked 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.

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Publisher

Wiley

Subject

Immunology,Rheumatology,Immunology and Allergy

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