# Systemic lupus erythematosus: from an adverse event of interferon administration to a disease with new treatment options

## TL;DR

This paper reviews how the role of type I interferon in systemic lupus erythematosus was discovered and how it led to new treatment options for the disease.

## Contribution

The paper highlights the identification of endogenous IFN-inducers and the development of new therapeutic targets in SLE.

## Key findings

- Endogenous IFN-inducers in SLE patients activate plasmacytoid dendritic cells to produce IFN.
- Anifrolumab, an antibody against the type I IFN receptor, is now approved for treating SLE.
- Several other drugs targeting IFN signaling pathways are in early clinical trials for SLE.

## Abstract

Patients with systemic lupus erythematosus (SLE) display an increased expression of type I interferon (IFN)-regulated genes, a so-called IFN signature. This discovery was preceded by the observation in Uppsala that patients with malignant diseases treated with type I IFN occasionally developed autoimmune diseases, including SLE. The adverse event of IFN treatment was the start of an intensive search for the role of the type I IFN system in patients with spontaneously occurring SLE. A key finding by our group was the detection in patients with SLE of endogenous IFN-inducers that could activate plasmacytoid dendritic cells (pDC) to IFN production. Further studies revealed the mechanisms by which these cells are triggered to a continuous IFN synthesis. We could also identify a large number of risk genes for SLE and several molecules connected to type I IFN production and response. My group early on suggested the possibility that some of these molecules are suitable therapeutic targets in SLE, but also other IFN-driven diseases. Antibodies against the type I IFN receptor (anifrolumab) have recently shown efficacy in clinical trials for SLE, and anifrolumab is now approved as a treatment for this disease. Several other drugs targeting critical molecules in the IFN signaling pathways – including BCDA-2 (Blood Dendritic Cell Antigen 2), TLR7/8 (Toll-like receptor 7/8), and TYK2 (Tyrosine Kinase 2) – are currently in early clinical phases, potentially expanding therapeutic options for SLE. In this review, several important observations regarding the role of the type I IFN system in SLE and therapeutic implications are discussed.