It is clear that gene signatures, such as the IFN signature, are meaningful in SLE. The clustering of patients by gene co-expression pathways is a promising approach that may help us fine-tune SLE treatment in the future. 

Consider the phase 2 trial with obexelimab, a CD19-targeted agent that engages FcγRIIb and suppresses B-cell activation. Although the primary end point was not met, several trends suggesting obexelimab efficacy supported further analysis. As our group reported at the EULAR 2020 E-Congress, we were able to identify obexelimab responder clusters that shared low expression of inflammation modules compared with other clusters and high expression of T-cell, immune response, cell cycle, mitochondrial, and B-cell modules. In that group, the treatment effect with obexelimab was markedly increased. During the course of the study, B-cell and plasma cell pathways demonstrated mechanism-related pharmacodynamic effects of obexelimab. Thus, patients with SLE share certain gene expression signatures that may help to improve our ability to select treatments for individual patients and, perhaps, to optimally dose them to a beneficial change in signature.

There are several specific IFN-blocking strategies that are under investigation, and there are also some targets downstream from type I IFN for which we already have agents available. B-lymphocyte stimulator (BLyS) is one of these actionable targets, as the BLyS-specific inhibitor belimumab is approved for lupus around the world. Since BLyS is an IFN-inducible gene, patients with high IFN gene signatures should have markedly higher levels of BLyS. While this is generally known to be true, there are exceptions; the pathways are complex, and this is also where the heterogeneity of SLE comes into play.

Anifrolumab is the furthest along in development of the agents that target the type I IFN pathway. Anifrolumab antagonizes the IFNAR1, the receptor that is responsible for cellular signaling induced by all of the type I IFNs (which include different subtypes of IFN-α, as well as IFN-β, IFN-ε, IFN-κ, and IFN-ω). Patients with SLE, especially those with a high type I IFN gene signature, have the greatest beneficial effects when treated with anifrolumab, but we still have a lot of work to do in order to characterize the exceptions. The Janus kinases (JAKs)/signal transducers and activators of transcription are also involved in mediating signals from IFNs. Tofacitinib, a JAK1/JAK3 inhibitor, was well tolerated in a 2019 phase 1b/2a trial; however, additional studies are needed to determine its efficacy in SLE. Baricitinib, a selective JAK1/JAK2 inhibitor, had a successful phase 2 trial, but the placebo response rate was very high. Phase 3 studies with baricitinib are underway.

It has recently been shown that B cells that emerge from extrafollicular responses and make anti-double-stranded DNA antibodies rely on type I IFN produced by plasmacytoid dendritic cells. Thus, targeting these cells by blocking type I IFN is another conceptually appealing strategy in SLE.