Type I interferons (IFN) play a key role in SLE pathogenesis, and an elevated IFN gene signature (IGS) has been associated with increased disease severity. This study aimed to retrospectively analyze the clinical and serological characteristics of SLE patients based on IFN-high or IFN-low status.

We analyzed a large cohort of 506 patients with SLE from the Toronto Lupus Clinic. Patients were classified as IFN-high or IFN-low based on IGS measured using the DxTerity Modular Immune Profile test. Demographic data, disease activity scores (SLE Disease Activity Index-2000 [SLEDAI-2K], Adjusted Mean SLEDAI-2K [AMS], Adjusted AMS Glucocorticoids [AMSG]), cumulative organ involvement, autoantibody profiles, and medication use were compared between high and IFN-low groups.

Of the 506 patients, 291 (57.5%) were IFN-high and 215 (42.5%) were IFN-low. IFN-high patients were younger at study entry (median 46.3 vs. 54.2 years) and had shorter disease duration (median 14.1 vs. 22.7 years). IFN-high patients had higher disease activity scores (SLEDAI-2K, AMS, AMSG) and were more likely to be on glucocorticoids (38.5% vs. 27%) and immunosuppressants (63.6% vs. 45.6%), particularly mycophenolate (39.5% vs. 24.7%), and had a greater prevalence of positive autoantibodies. Despite higher disease activity, cumulative damage (SDI) was similar between IFN-high and IFN-low groups after multivariable analysis.

Patients with an elevated IGS have more active and severe disease, accumulating more autoantibodies and requiring increased immunosuppression. Retrospective AMS/AMSG analyses further support IGS as a predictor of disease burden. Future studies should explore its role in guiding personalized treatment strategies.