Type I interferon (IFN) is the term for a family of cytokines acting through a common receptor, known as IFNAR. Though functions are diverse, broadly speaking IFNs act in the innate immune system, providing rapid early host response to viral infection. Viruses activate IFN production largely through activating nucleic acid sensors including toll-like receptors (TLRs) 7–9 as well as other intracellular pathways, which have evolved to detect the presence of nucleic acids in the cytoplasm. Ligation of IFNAR leads to a cascade of inflammatory responses and enhances activation of the adaptive immune system.

It is now understood that these pathways of response to nucleic acid can be activated in diseases ranging from hereditary interferonopathies to acquired autoimmune interferonopathies, of which SLE is the archetype. Evidence of activation of the IFN system through increased expression of sets of IFN-regulated genes, known as the IFN signature, was first detected in SLE over 20 years ago. Other evidence for the role of IFN in SLE includes exacerbation of animal models of lupus by IFN treatment and induction of lupus-like clinical phenotypes in humans treated with IFN for other diseases.

Early clinical trials of IFN-blocking therapies had limited success, associated with incomplete suppression of the expression of IFN signatures. More recently, a monoclonal antibody to IFNAR, anifrolumab, demonstrated efficacy in a Phase 3 trial, after prior success in Phase 2 and positive results against all but the primary endpoint in another Phase 3 study. ^1–3 Broadly, anifrolumab treatment resulted in reduced disease activity, improved skin, joint and flare outcomes, and increased rates of glucocorticoid tapering, with acceptable safety notwithstanding included increased rates of herpes zoster reactivation.⁴

The potential applications of IFN blocking treatments in the management of systemic lupus erythematosus (SLE) driven by this evidence base will be explored.

Learning Objectives

• Describe the biology of type I IFN in autoimmune disease

• Discuss the evidence for the role of type I IFN in the pathogenesis of SLE

• Explain early clinical trial data supporting the role of type I IFN in SLE

• Describe the efficacy and safety of anifrolumab in the treatment of SLE

• Discuss future directions in IFN inhibition in SLE

References

1. Furie RA, Morand EF, Bruce IN, et al. Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. The Lancet Rheumatology. 2019;1(4):e208-e19.

2. Furie R, Khamashta M, Merrill JT, et al. Anifrolumab, an Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017;69(2):376–86.

3. Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. New England Journal of Medicine. 2019;382(3):211–21.

4. Tummala R, Abreu G, Pineda L, et al.Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials. Lupus Sci Med. 2021;8(1).