The Interferon Signature in Lupus: From Phenomenon to Precision Medicine

The Interferon Signature in Lupus: From Phenomenon to Precision Medicine

Prepared by the Hesperion Research Team Systemic lupus erythematosus (SLE) is one of the most heterogeneous autoimmune diseases. Patients can present with different organ involvement, immune pathways, and therapy responses. For years, researchers observed that many lupus patients show an “interferon signature” — an upregulation of type I interferon–inducible genes. Over the last two years, this signature has moved from research curiosity to practical clinical biomarker, helping guide therapy choices and refine clinical trials.

1) What Is the Interferon Signature?

The interferon (IFN-I) signature refers to the pattern of gene expression induced by type I interferons (IFN-α, IFN-β). In lupus patients, this signature is often persistently elevated in blood and tissues, reflecting a state of chronic innate immune activation. Measurement is usually done through gene expression panels covering 5–20 interferon-stimulated genes (ISGs).

2) Recent Advances (2023–2025)

• Standardization: In 2024, multiple groups published harmonized panels and cutoffs for clinical use, moving towards regulatory approval of IFN-signature tests as companion diagnostics.
• Therapy stratification: Patients with high IFN-signature respond better to anifrolumab (anti-IFNAR1 monoclonal antibody), as shown in pooled analyses of phase 3 trials. Patients with low signature may benefit more from alternative pathways (e.g., B-cell targeted therapies).
• Heterogeneity within the signature: Not all IFN signatures are the same. Recent single-cell data show that monocyte-driven IFN signatures predict response differently than plasmacytoid dendritic cell–driven signatures. This helps explain mixed responses in trials.

3) Why It Matters Clinically

• Personalized therapy: IFN testing may soon help rheumatologists decide whether to use anifrolumab versus other options.
• Clinical trials: Stratifying patients by IFN signature reduces heterogeneity and increases power to detect drug effects.
• Prognosis: High IFN signature correlates with more severe disease and risk of flares, making it a useful risk marker.

4) Challenges and Next Questions

• How durable is the signature — does it fluctuate with therapy, remission, or flares?
• What is the optimal cutoff to define “high” versus “low” IFN patients?
• Can the signature predict long-term outcomes, not just short-term drug response?

5) Hesperion’s Perspective

• We include IFN signature in our biomarker atlas for lupus, linking gene expression states to therapy outcomes.
• We advocate that every lupus clinical trial should stratify patients by IFN signature to accelerate drug development.
• We explore integration of IFN panels with other omics (B-cell and T-cell programs) to define combined endotypes.

Conclusion

The interferon signature is no longer just a research marker — it is becoming a clinical tool. By helping match patients with the right therapy, it marks a step towards true precision medicine in lupus. The next few years will show whether it becomes routine in every rheumatology clinic.