A recent study published in The Lancet Rheumatology has shown that elevated interferon-α (IFNα) drives a distinct immunological endotype in Sjögren’s disease and can be detected in the blood up to 14 years before clinical diagnosis. The findings provide new evidence supporting immunological stratification and precision medicine approaches in this heterogeneous autoimmune disease while offering potential opportunities for earlier identification of individuals at risk.
Sjögren’s disease is characterised by marked clinical and immunological heterogeneity, which has limited the development of targeted therapies. Although increased type I interferon activity has long been recognised as a feature of the disease, its causal role in disease pathogenesis has remained uncertain. To address this question, investigators combined analyses from two complementary human cohorts with mechanistic studies in a novel transgenic mouse model.
The study utilised data from the UK Primary Sjögren’s Syndrome Registry (UKPSSR), a multicentre observational cohort, and the UK Biobank Pharma Proteomics Project, a large population-based cohort comprising individuals with and without Sjögren’s disease. Ultrasensitive single-molecule enzyme-linked immunosorbent assay (ELISA) and a proteomics-derived oligoprotein interferon signature score were used to characterise IFNα activity over time. A transgenic mouse model with chronic systemic IFNα overexpression was also developed to investigate causality. Individuals with lived experience of Sjögren’s disease contributed to the design of the UKPSSR and the formulation of the research questions.
The UKPSSR included 177 patients with Sjögren’s disease enrolled between August 2009 and March 2012, with a mean age of 57.5 years; 92% were women and 92% were of White ethnicity. The UK Biobank Pharma Proteomics Project included 47,606 individuals without Sjögren’s disease and 257 patients with the disease, including 137 participants whose blood samples had been collected before diagnosis.
Elevated IFNα concentrations were detected in 61% of patients with Sjögren’s disease in the UKPSSR. Importantly, proteomic interferon signatures were detectable up to 14 years before clinical diagnosis in the UK Biobank cohort, indicating that immune dysregulation precedes the onset of clinically apparent disease by many years.
Patients with elevated IFNα exhibited a distinct immunological endotype characterised by cytopenia, hypergammaglobulinaemia, multiple autoantibodies, and autoimmune responses directed against the Sjögren autoantigen TRIM21/Ro52. Despite these immunological differences, their clinical presentation was broadly similar to that of patients with normal IFNα concentrations, suggesting that conventional clinical assessment alone may not adequately distinguish biologically distinct disease subgroups.
Mechanistic experiments further supported a causal role for IFNα. Chronic overexpression of IFNα4 in conventional dendritic cells reproduced key immunological features of the human IFNα-high endotype in the transgenic mouse model. Although blockade of the type I interferon receptor (IFNAR1) partially reversed these abnormalities, persistent immune dysregulation remained, indicating that prolonged IFNα exposure may establish durable immune alterations that are not fully reversible with receptor inhibition.
The investigators concluded that elevated IFNα defines a biologically distinct Sjögren’s disease endotype that can be identified many years before diagnosis. These findings strengthen the rationale for incorporating high-resolution immunological biomarkers into disease classification and clinical trial design. Early identification of individuals with IFNα-driven immune activation may facilitate risk stratification, enable more targeted therapeutic interventions, and support the development of precision medicine strategies not only for Sjögren’s disease but also for other interferon-mediated rheumatological disorders.
Reference
Forbes D, Jorgacevic I, Tarn J, Reid KR, Rioux B, Thompson K, Kleemann KL, McGlasson S, Casement J, Berry J, Müller P, Eberle-Reece H, Haase C, Conn B, Boon L, McDade K, Whiteley W, Roers A, Ng WF, Behrendt R, Hunt D. Interferon-α as a precision medicine tool in Sjögren’s disease: a cohort and experimental medicine study. Lancet Rheumatol. 2026 Aug;8(8):e612-e624.