Background: Sjögren disease is a systemic immunological disorder which is difficult to treat, and the immune pathways which initiate and drive disease are poorly defined. There is evidence for an association between the potent antiviral cytokine IFN-α and SjD. Whether or not IFN-α drives SjD is unknown.

Objectives: We sought to characterise the immune endotype of SjD patients with elevated IFN-α using two complimentary cohorts. Then we assessed whether IFN-α drives this SjD endotype and evaluated IFNAR1 blockade as a therapeutic strategy in a mouse model.

Methods: We used single molecule ELISA, and developed an interferon polyprotein score derived from Olink proteomics, to study the role of IFN-α in Sjögren disease. We analysed samples from two cohorts, the UK Primary Sjögren Syndrome Registry (UKPSSR, n=177) and UK Biobank Plasma Proteomics Project (n=47606 without Sjögren, n=257 with Sjögren, including 137 individuals sampled prior to diagnosis) to determine the timecourse and immune endotype associated with elevated IFN-α. To address causality we created a new transgenic mouse model of IFN-α overexpression to demonstrate that chronically elevated IFN-α drives these immunological features.Finally, we trial IFNAR1 blockade in these mice, a novel treatment strategy in SjD.

Results: IFN-α concentrations are elevated in 60% of patients and IFN-α Simoa can be used to stratify Sjögren disease. Individuals with elevated IFN-α display distinct immunological features characterised by cytopenias, hypergammaglobulinaemia, multiple autoantibodies and autoimmunity against the Sjögren-specific autoantigen TRIM21/Ro52. Polyprotein interferon signatures can be detected at least 14 years prior to diagnosis of Sjögren disease in UK Biobank. Plasma TRIM21 protein concentration can be used to predict diagnosis of SjD early.This immunological endotype can be recapitulated in a novel mouse model of systemic chronic IFN-α elevation in which Ifnα4 is overexpressed by conventional dendritic cells, and demonstrates response to IFNAR1 blockade.

Conclusion: Our results demonstrate that decades-long elevation of IFN-α can initiate and drive an immune endotype of Sjögren disease. Ultrasensitive IFN-α Simoa, combined with IFN-related polyprotein biomarkers derived from broad capture proteomics, provide practical tools for disease stratification and early identification of at-risk populations.

REFERENCES: NIL.

Acknowledgements: We thank Thomas Wunderlich for the pSERC vector, the Transgenic Core Facility of the MPI-CBG Dresden for electroporation of ES cells as well as the blastocyst injections, Flow Cytometry Core Facility at the Institute of Experimental Immunology, University Hospital Bonn, and the Next Generation Sequencing Core Facility of the Medical Faculty/West German Genome Center Bonn at the University of Bonn for providing support and instrumentation for the 3’mRNASeq. We thank Barbara Uteß, Christina Hiller and Livia Schulze for excellent technical assistance.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.