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

Sep 29, 2026

Uploaded by Kyle

Systemic lupus erythematosus (SLE) is characterized by an increased type I interferon (IFN)-regulated gene expression pattern, termed an IFN signature. The IFN-centered research trajectory began with observations in Uppsala that malignant-disease patients receiving type I IFN sometimes developed autoimmune disease, including SLE. Subsequent work identified endogenous IFN-inducers activating plasmacytoid dendritic cells and clarified mechanisms driving continuous IFN synthesis. Risk genes and IFN-linked molecules support therapeutic targeting, including anifrolumab and emerging IFN-pathway inhibitors.

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Introduction

Interferon production and treatment of patients with malignant diseases in Uppsala

IFN signature, endogenous IFN-inducers, and therapeutic implications

REVIEW ARTICLE Systemic lupus erythematosus: from an adverse event of interferon administration to a disease with new treatment options Lars Rönnblom Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden 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 IIFN system in SLE and therapeutic implications are discussed. ARTICLE HISTORY Received: 31 October 2025 Revised: 18 November 2025 Accepted: 18 November 2025 Published: 17 December 2025 KEYWORDS Systemic lupus erythematosus; interferon; etiology; pathogenesis; autoimmune; autoantibodies; immune complex; plasmacytoid dendritic cells; natural interferon producing cells; treatment; anifrolumab Professor Lars Rönnblom, winner University Rudbeck Award 2025. of the Medical Faculty of Uppsala Introduction Systemic lupus erythematosus (SLE) is considered the prototype autoimmune disease because a large number of different autoantibodies (Abs) are produced, and most organs can be affected during the disease course. The clinical picture is very heterogeneous and spans from a relatively mild disease with skin and joint manifestations to a life-threatening disease with involvement of major organs, including the central nervous system (1) . The different SLE subsets overlap, and a milder disease can progress over time to a more severe disease phenotype. The disease mainly affects women during their childbearing age and patients with SLE have a considerably reduced quality of life and increased mortality. For instance, the age-specific standard mortality rate in patients with SLE 19–39 years old is more than 12 times higher than in the general population (2) . In contrast to rheumatoid arthritis, few new therapies for SLE have been developed and approved during the last decades. There are several reasons for this, but the diversity of the clinical manifestations, the unpredictable disease course as well as the complexity of the immune aberrations in SLE, all contribute to a CONTACT Lars Rönnblom [Lars.Ronnblom@medsci.uu.se](Lars.Ronnblom@medsci.uu.se)[ ](Lars.Ronnblom@medsci.uu.se)© 2025 The Author(s). Published by Upsala Medical Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)), which permits unrestricted use, distribution, and reproduction in any medium, prov

FAQs

What is the IFN signature in systemic lupus erythematosus (SLE)?

SLE patients show increased expression of type I IFN-regulated genes, known as the IFN signature.

How did the adverse event of interferon administration contribute to SLE research?

In Uppsala, some malignant-disease patients treated with type I IFN developed autoimmune diseases including SLE, triggering intensive investigation into the type I IFN system in spontaneously occurring SLE.

Which current and emerging therapies targeting the type I IFN system are discussed?

Anifrolumab, an antibody against the type I IFN receptor, is approved based on clinical trial efficacy. Other early-phase drugs targeting IFN signaling molecules in pathways such as BCDA-2, TLR7/8, and TYK2 are also mentioned.

Sep 29, 2026

Uploaded by Kyle