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

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.image