TOPLINE

Patients with elevated interferon (IFN) alfa levels formed a distinct subtype of Sjögren disease that was detectable years before diagnosis, and mice engineered to overproduce IFN alfa developed similar immune changes that only partly reversed after blocking the IFN receptor.

METHODOLOGY

• Researchers analyzed data from two human cohorts and ran experiments on mice to assess whether elevated IFN alfa levels drive an endotype of Sjögren disease and how early these changes appear before diagnosis.
• They included 177 patients with Sjögren disease (median age, 57.5 years; 92% women) and 36 healthy individuals enrolled in a UK registry between 2009 and 2012. Furthermore, they included 257 patients with Sjögren disease (mean age, 58.6 years; 90% women) and 47,606 without the disease recruited between 2006 and 2010 from a UK Biobank project, some with samples taken years before diagnosis.
• IFN alfa levels were measured using a highly sensitive test and were compared with gene activity, immune cell counts, antibody levels, and disease symptoms to identify a distinct disease subtype. Prediagnostic blood samples were used to determine how early the changes could be detected before Sjögren disease was diagnosed.
• The researchers developed a five-protein IFN response signature, Sjögren IFN Alfa Response in Olink (SIRO), from proteomic data and applied it to the UK Biobank cohort to track IFN alfa-related changes for up to 14 years before and 30 years after diagnosis.
• They engineered a transgenic mouse model with chronic IFN alfa overexpression to test whether it directly caused the immune changes and evaluated whether blocking the type 1 IFN receptor could reverse immune abnormalities.

TAKEAWAY

• About 61% of people with Sjögren disease in the registry had elevated IFN alfa levels (> 0.279 pg/mL), and their IFN alfa levels strongly correlated with a type 1 IFN gene expression signature (Spearman r, 0.92; P < .0001).
• Patients with high IFN alfa levels had lower white cell, lymphocyte, and neutrophil counts; higher immunoglobulin (Ig)G and IgA levels; and more autoantibodies (P < .05 for all). They were more often anti-tripartite motif-containing protein 21 (TRIM21)/Ro52-positive, and very low blood TRIM21 protein levels predicted the onset of Sjögren disease (P < .0001).
• The five-protein SIRO proteomic score was higher in individuals who later developed Sjögren disease and showed IFN-related signals up to 14 years before diagnosis in UK Biobank samples.
• In mice engineered to overproduce IFN alfa, the researchers reproduced the same disease features seen in patients and found that blocking IFN alfa signaling improved some of these features but not others.

IN PRACTICE

“We advocate that tools to provide a more detailed insight into active molecular pathways, including but not limited to the type I IFN pathway, should be implemented in clinical practice to aid clinicians in the management and treatment of Sjögren disease,” Gwenny M. Verstappen, PharmD, PhD, and Zana Brkic, MD, PhD, wrote in a comment accompanying the journal article.

SOURCE

The study was led by Deborah Forbes, MB ChB, University of Edinburgh, Edinburgh, Scotland. It was published online on July 2, 2026, in The Lancet Rheumatology.

LIMITATIONS

The study lacked prediagnostic samples from the registry cohort. Only 177 participants were included from the UK registry cohort, which limited the statistical power. The mouse model did not develop the Sjögren disease-specific lymphocytic foci seen in humans.

DISCLOSURES

The study received funding from the Precision Medicine Alliance Scotland, the Wellcome Trust, the Medical Research Council UK Research and Innovation, and Deutsche Forschungsgemeinschaft. Several authors reported receiving fellowships, scholarships, and/or research grants from multiple sources including the funding agencies. Many authors reported providing consultations, receiving research grants, earning royalties, and having employment or roles in industry-sponsored clinical trials. Detailed disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.