Interferon-alpha can identify a distinct subgroup of patients with Sjögren's disease years before diagnosis, early research shows.
A persistent interferon-alpha signal can identify a biologically distinct subgroup of patients with Sjögren’s disease up to 14 years before diagnosis, with researchers saying the findings provide some of the strongest evidence yet for a precision medicine approach to the autoimmune condition.
The study, published this month in The Lancet Rheumatology, found that around 60% of people with Sjögren’s disease have elevated IFNα, defining an immunologically distinct disease endotype that differs biologically rather than clinically from other patients.
“These data have important implications for future research, clinical practice, trial design, and therapeutic development,” the researchers wrote.
“First, the findings provide clinical evidence, supported by clear preclinical evidence, that elevated IFNα can drive a Sjögren’s disease endotype and accurately define the level of heterogeneity.
“Second, we provide biomarkers that might be of use in stratifying clinical trial design and also for the early identification of at-risk individuals.
“Third, we provide biological proof of principle that long-standing and potentially undiagnosed elevation of IFNα can establish persistent immune dysregulation, which might respond only partly to IFNAR blockade, highlighting the challenges of targeting this pathway.
“Together these findings inform precision medicine approaches and future trial design.”
The researchers analysed samples from 177 patients in the UK Primary Sjögren’s Syndrome Registry alongside proteomic data from more than 47,000 participants in the UK Biobank, including 257 people with Sjögren’s disease.
Among these, 137 had blood collected before diagnosis, allowing researchers to examine immune changes during the preclinical phase of disease.
Elevated IFNα concentrations were found in 61% of patients with established disease.
Those patients shared a distinctive immune profile characterised by lymphopenia, hypergammaglobulinaemia, multiple autoantibodies, and strong autoimmunity against the Ro52/TRIM21 antigen, despite having similar disease activity scores and patterns of organ involvement to patients without elevated interferon levels.
To investigate disease development before symptoms emerged, the researchers developed a five-protein interferon signature that could be applied to UK Biobank proteomic data.
The signature was consistently elevated for up to 14 years before diagnosis, suggesting abnormal interferon activity begins long before Sjögren’s disease is clinically recognised.
The study also addressed a longstanding question in Sjögren’s disease research – whether interferon activation drives disease or simply reflects immune dysregulation already underway.
Using a novel transgenic mouse model that chronically overexpressed IFNα, the researchers reproduced many of the hallmark immune abnormalities seen in patients, including cytopenias, elevated immunoglobulin levels, antinuclear antibodies, and autoreactivity against TRIM21.
Blocking the type I interferon receptor improved several inflammatory features but had only limited effects on established autoantibody production, suggesting prolonged interferon exposure may create immune abnormalities that become only partly reversible.
In an accompanying commentary, researchers from the Netherlands said the combination of human cohort data and mechanistic animal studies represented a major strength because it allowed the investigators to report a potentially causal role for IFNα in Sjögren’s disease.
“On the other hand, a study in systemic lupus erythematosus indicated that anti-SSA/Ro autoantibodies might precede chronic type I IFN activity,” they wrote.
“Of note, data on anti-nuclear antibody-positivity including anti-SSA/Ro were not available for the biobank samples used by Forbes and colleagues. Thus, the directionality of the relationship between autoantibodies and IFNα in humans remains uncertain.
“We speculate that IFNα and autoantibodies might exert a cumulative, rather than sequential, effect in driving disease pathogenesis.
“That being said, effects of chronic IFNα elevation on patients’ immune and non-immune cells are evident and suggest a pathogenic role, at least in a subgroup of patients.”
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They said the findings nevertheless strengthened the case for using ultrasensitive IFNα measurement to identify biologically distinct patient groups.
“Overall, 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’s disease,” they wrote.
“With several promising treatments on the horizon for Sjögren’s disease, validation and broad implementation of such tools will hopefully be accelerated.”
The study authors agreed that future clinical trials should move beyond treating Sjögren’s disease as a single entity.
About 40% of patients in their cohort did not have elevated IFNα, highlighting the likelihood that interferon-independent disease pathways existed and would require different therapeutic approaches.
They also identified reduced circulating TRIM21 protein as a potential biomarker for future disease, with low concentrations strongly associated with subsequent Sjögren’s disease diagnosis and with the later development of secondary Sjögren’s disease in patients with systemic lupus erythematosus.
“As such, these findings have the potential to support precision prevention approaches in Sjögren’s disease, which might enable the identification of at-risk individuals early in their disease course who might benefit the most from targeted treatment,” the researchers concluded.
“Therefore, this work developed tools that are of practical use for disease stratification, trial design, and risk prediction.”
