IFNα Is Associated with a Distinct Immune Endotype in Sjögren’s Disease

Sjögren’s disease is clinically and immunologically heterogeneous, a challenge that may help explain why trials of systemic immunosuppression have struggled to establish effective disease-modifying therapies.

A study published in The Lancet Rheumatology provides evidence that interferon-α (IFNα) is more than a marker of immune activation in some patients. Instead, chronically elevated IFNα appears to drive a distinct Sjögren’s disease endotype that may emerge years before diagnosis.

Tracing the IFNα Signal Before Diagnosis

In this study, investigators combined human cohort analyses with experimental modeling. They directly measured serum IFNα using an ultrasensitive single-molecule ELISA in 177 participants with Sjögren’s disease from the multicenter UK Primary Sjögren’s Syndrome Registry (UKPSSR), alongside 36 healthy controls.

IFNα concentrations were substantially higher in Sjögren’s disease, with a median of 0.503 pg/mL versus 0.035 pg/mL in controls (p<0.0001). Using the healthy-control range as a threshold, 108 of 177 participants (61%) had elevated IFNα.

The researchers then developed the Sjögren IFNα Response in Olink (SIRO) score, a 5-protein signature incorporating CXCL10, TYMP, DDX58, LAMP3, and TNFSF10. Applying this signature to the UK Biobank Pharma Proteomics Project provided an unusual window into the years preceding diagnosis. Among 257 participants with Sjögren’s disease and 47,606 without the disease, SIRO scores were higher in those with Sjögren’s disease and could be detected up to 14 years before diagnosis.

That long preclinical interval raises the possibility that IFN-associated immune dysregulation begins well before Sjögren’s disease becomes clinically apparent.

Similar Clinical Disease, Different Immunology

Elevated IFNα did not identify patients with more clinically active disease, as IFNα concentrations were not associated with European Alliance of Associations for Rheumatology Sjögren’s Syndrome Disease Activity Index (ESSDAI) scores, and investigators found no clear association with organ involvement, anxiety, or fatigue.

The immunologic picture was different. Higher IFNα correlated with lower total white blood cell count, lymphopenia, and neutropenia. It also correlated with higher IgG and IgA concentrations and was associated with antinuclear antibodies and broader autoantibody positivity.

TRIM21/Ro52 emerged as a particularly relevant link. IFNα correlated with TRIM21 transcript expression, and IFNα concentrations were markedly higher among TRIM21 autoantibody-positive patients. In UK Biobank, very low circulating TRIM21 protein concentrations were associated with subsequent Sjögren’s disease diagnosis compared with reference concentrations (adjusted HR, 9.78; 95% CI, 6.41-14.90; P<0.0001). However, this is likely due to the presence of TRIM21 autoantibodies.

Together, these findings may define an IFNα-associated endotype characterized by cytopenias, hypergammaglobulinemia, multiple autoantibodies, and prominent autoreactivity against TRIM21/Ro52.

Moving from Association Toward Causality

The experimental component strengthens the study’s mechanistic argument. Investigators engineered mice to chronically overexpress IFNα4, predominantly in conventional type 1 dendritic cells. The animals developed several features paralleling the human endotype, including leukopenia, B-cell depletion, elevated IgG, antinuclear antibodies, TRIM21 autoantibodies, and increased B-cell infiltration of salivary glands.

Blocking the type 1 interferon receptor (IFNAR1) improved IFN signaling, cytopenias, hematologic abnormalities, and survival. Yet some abnormalities persisted. IgG, antinuclear antibody titers, and TRIM21 autoantibodies did not readily normalize, suggesting that prolonged IFNα exposure may establish immune changes that become partly independent of continued IFN signaling.

That distinction could matter when evaluating IFN-directed therapies: suppressing an initiating pathway after years of immune dysregulation may not immediately reverse every downstream feature.

A Potential Framework for Precision Sjögren’s Care

The findings could support immunologic stratification rather than treating Sjögren’s disease as a mechanistically uniform condition. Approximately 40% of the UKPSSR cohort did not have elevated IFNα, underscoring that an IFN-directed strategy would not necessarily fit every patient.

However, important limitations remain. The UKPSSR analysis included only 177 patients and lacked prediagnostic samples, while UK Biobank relied on an indirect proteomic surrogate rather than direct IFNα measurement. Both Sjögren’s cohorts were predominantly White women, limiting sex-specific and broader population-level conclusions. The mouse model also reproduced immune abnormalities but not the characteristic lymphocytic foci of human Sjögren’s disease.

Still, the convergence of direct IFNα measurement, prediagnostic proteomics, and experimental modeling provides a biologically coherent case for an IFNα-driven Sjögren’s disease endotype. Future studies will need to determine whether biomarkers such as IFNα, SIRO, or TRIM21 can prospectively identify patients most likely to benefit from pathway-directed treatment, and whether intervention earlier in the disease course can prevent immune abnormalities from becoming entrenched.

Reference:
Forbes D, Jorgacevic I, Tarn J, et al. Interferon-α as a precision medicine tool in Sjögren’s disease: a cohort and experimental medicine study. Lancet Rheumatol. 2026;8:e612-e624. doi:10.1016/S2665-9913(26)00038-X.