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: 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
Journal: Arthritis & Rheumatology (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. image