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)

Elena Pontarini; Elisabetta Sciacca; Farzana Chowdhury; Sofia Grigoriadou; Felice Rivellese; William J. Murray-Brown; Davide Lucchesi; Liliante Fossati-Jimack; Alessandra Nerviani; Edyta Jaworska; Giulia Maria Ghirardi; Chiara Giacomassi; Paul Emery; Wan Fai Ng; Nurhan Sutcliffe; Colin Everett; Catherine Fernandez; Anwar Tappuni; Raphael Seror; Xavier Mariette; Raphael Porcher; Giulia Cavallaro; Alfredo Pulvirenti; Gwenny M. Verstappen; Liseth de Wolff; Suzanne Arends; Hendrika Bootsma; Miles J. Lewis; Constantino Pitzalis; Simon J. Bowman; Michele Bombardieri

doi:10.1002/art.42772

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)

Elena Pontarini
, Elisabetta Sciacca
, Farzana Chowdhury
, Sofia Grigoriadou
, Felice Rivellese
, William J. Murray-Brown
, Davide Lucchesi
, Liliante Fossati-Jimack
, Alessandra Nerviani
, Edyta Jaworska
, Giulia Maria Ghirardi
, Chiara Giacomassi
, Paul Emery
, Wan Fai Ng
, Nurhan Sutcliffe
, Colin Everett
, Catherine Fernandez
, Anwar Tappuni
, Raphael Seror
, Xavier Mariette

Raphael Porcher, Giulia Cavallaro, Alfredo Pulvirenti, Gwenny M. Verstappen, Liseth de Wolff, Suzanne Arends, Hendrika Bootsma, Miles J. Lewis, Constantino Pitzalis, Simon J. Bowman, Michele Bombardieri

Queen Mary University of London
University of Leeds
Newcastle University
Barts Health NHS Trust
Université Paris-Saclay
Université Paris Cité
University of Catania
University of Groningen
University Hospitals Birmingham NHS Foundation Trust

Research output: Contribution to journal › Article › peer-review

Abstract

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.).

Original language	English
Pages (from-to)	763-776
Number of pages	14
Journal	Arthritis and Rheumatology
Volume	76
Issue number	5
DOIs	https://doi.org/10.1002/art.42772
Publication status	Published - May 2024
Externally published	Yes

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Pontarini, E., Sciacca, E., Chowdhury, F., Grigoriadou, S., Rivellese, F., Murray-Brown, W. J., Lucchesi, D., Fossati-Jimack, L., Nerviani, A., Jaworska, E., Ghirardi, G. M., Giacomassi, C., Emery, P., Ng, W. F., Sutcliffe, N., Everett, C., Fernandez, C., Tappuni, A., Seror, R., ... Bombardieri, M. (2024). 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). Arthritis and Rheumatology, 76(5), 763-776. https://doi.org/10.1002/art.42772

Pontarini, Elena ; Sciacca, Elisabetta ; Chowdhury, Farzana et al. / 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). In: Arthritis and Rheumatology. 2024 ; Vol. 76, No. 5. pp. 763-776.

@article{da41019e7f71423b87161fab3da212ea,

title = "Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sj{\"o}gren Syndrome (CRESS) and Sj{\"o}gren Tool for Assessing Response (STAR) to B Cell{\textendash}Targeted Therapy in the Trial of Anti{\textendash}B Cell Therapy in Patients With Primary Sj{\"o}gren Syndrome (TRACTISS)",

abstract = "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 Sj{\"o}gren Syndrome (cCRESS) and candidate Sj{\"o}gren 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{\textendash}B Cell Therapy in Patients With Primary Sj{\"o}gren 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{\textendash}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 = "Elena Pontarini and Elisabetta Sciacca and Farzana Chowdhury and Sofia Grigoriadou and Felice Rivellese and Murray-Brown, \{William J.\} and Davide Lucchesi and Liliante Fossati-Jimack and Alessandra Nerviani and Edyta Jaworska and Ghirardi, \{Giulia Maria\} and Chiara Giacomassi and Paul Emery and Ng, \{Wan Fai\} and Nurhan Sutcliffe and Colin Everett and Catherine Fernandez and Anwar Tappuni and Raphael Seror and Xavier Mariette and Raphael Porcher and Giulia Cavallaro and Alfredo Pulvirenti and Verstappen, \{Gwenny M.\} and \{de Wolff\}, Liseth and Suzanne Arends and Hendrika Bootsma and Lewis, \{Miles J.\} and Constantino Pitzalis and Bowman, \{Simon J.\} and Michele Bombardieri",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Arthritis \& Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.",

year = "2024",

month = may,

doi = "10.1002/art.42772",

language = "English",

volume = "76",

pages = "763--776",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "5",

}

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 2024, '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)', Arthritis and Rheumatology, vol. 76, no. 5, pp. 763-776. https://doi.org/10.1002/art.42772

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). / Pontarini, Elena; Sciacca, Elisabetta; Chowdhury, Farzana et al.
In: Arthritis and Rheumatology, Vol. 76, No. 5, 05.2024, p. 763-776.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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)

AU - Pontarini, Elena

AU - Sciacca, Elisabetta

AU - Chowdhury, Farzana

AU - Grigoriadou, Sofia

AU - Rivellese, Felice

AU - Murray-Brown, William J.

AU - Lucchesi, Davide

AU - Fossati-Jimack, Liliante

AU - Nerviani, Alessandra

AU - Jaworska, Edyta

AU - Ghirardi, Giulia Maria

AU - Giacomassi, Chiara

AU - Emery, Paul

AU - Ng, Wan Fai

AU - Sutcliffe, Nurhan

AU - Everett, Colin

AU - Fernandez, Catherine

AU - Tappuni, Anwar

AU - Seror, Raphael

AU - Mariette, Xavier

AU - Porcher, Raphael

AU - Cavallaro, Giulia

AU - Pulvirenti, Alfredo

AU - Verstappen, Gwenny M.

AU - de Wolff, Liseth

AU - Arends, Suzanne

AU - Bootsma, Hendrika

AU - Lewis, Miles J.

AU - Pitzalis, Constantino

AU - Bowman, Simon J.

AU - Bombardieri, Michele

PY - 2024/5

Y1 - 2024/5

N2 - 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.).

AB - 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.).

UR - https://www.scopus.com/pages/publications/85185680223

U2 - 10.1002/art.42772

DO - 10.1002/art.42772

M3 - Article

C2 - 38073013

AN - SCOPUS:85185680223

SN - 2326-5191

VL - 76

SP - 763

EP - 776

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

IS - 5

ER -

Pontarini E, Sciacca E, Chowdhury F, Grigoriadou S, Rivellese F, Murray-Brown WJ et al. 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). Arthritis and Rheumatology. 2024 May;76(5):763-776. doi: 10.1002/art.42772

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)

Abstract

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