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)
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. , de Wolff Liseth , Arends Suzanne , Bootsma Hendrika , Lewis Miles J. , Pitzalis Constantino , Bowman Simon J. , Bombardieri Michele ,   the Trial for Anti–B Cell Therapy in Patients With Primary Sjögren Syndrome Study Research Group
Published: December 2023

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.

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