Treatments that directly target interferon (IFN) or downstream IFN-related molecules are emerging as potential treatment options for patients with systemic lupus erythematosus (SLE). Researchers at the 2024 Congress of Clinical Rheumatology (CCR) East presented data from various studies that support a role for IFN-based treatment strategies in patients with SLE.

Following these proceedings, featured expert Anca D. Askanase, MD, MPH, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Askanase’s clinical perspectives on these findings are presented here.

In the early 1990s, the concept of IFN as an important cytokine in the pathogenesis of SLE was introduced. This concept was initially challenging to test because measuring IFN in serum is complicated; researchers were unable to replicate original reports of high IFN levels in patients with active SLE, which eventually led to a decreased interest in the potential role of IFN in SLE. Eventually, however, reports began emerging on patients with hepatitis B who were being treated with IFN and were developing lupus-like syndrome. This caused the concern about IFN being a big player in SLE to resurface. Because of the challenges in measuring serum IFN directly, researchers began using downstream IFN-responsive genes, known as the IFN gene signature, as a proxy marker of IFN activation. As we learned how to measure the IFN gene signature, it became clearer that people with active SLE have an elevated IFN gene signature.

We now know that IFN is one of the primary mediators in the pathophysiology of SLE, along with B cells, myeloid cells, and other cytokines for some patients. IFN has effects on many cell types, including plasmacytoid dendritic cells, fibroblasts, epithelial cells, and neutrophils. The activation of these cell types via the IFN receptor leads to intracellular signaling through the JAK/STAT pathway, with some of the biggest JAK/STAT players being JAK1, TYK2, STAT1, and STAT2. Understandably, blocking the IFN pathway has become a significant research focus in the treatment of SLE over the past decade.

Confidence in the efficacy of IFN blockers in SLE became more relevant in 2019 and 2020 with the publication of results from the phase 3 TULIP-1 and TULIP-2 trials, respectively, of the IFN receptor blocker anifrolumab. These results were reviewed at CCR East 2024 in a presentation by Ronald van Vollenhoven, MD, PhD, titled “Targets for Biologics in SLE – Precision Medicine in the Works.” In the context of his discussion regarding biologics in SLE, Dr van Vollenhoven highlighted the favorable efficacy and safety profiles of anifrolumab vs placebo in patients with moderate to severe SLE.

Subsequent studies have found that inhibiting different elements of the IFN signaling cascade may also allow for good responses in patients with SLE. Indeed, some of the emerging and investigational anti–IFN-related treatments were also highlighted at CCR East 2024. For example, Dr van Vollenhoven discussed 2 investigational IFN-based treatments for SLE in his presentation: the TYK2 inhibitor deucravacitinib and the anti-BDCA2 receptor antibody litifilimab. Deucravacitinib, which works downstream of IFN, was recently approved by the US Food and Drug Administration (FDA) for the treatment of psoriasis. The 48-week, phase 2 deucravacitinib study in SLE highlighted by Dr van Vollenhoven found higher response rates for several outcome measures, including the SLE Responder Index (SRI-4), the British Isles Lupus Assessment Group–Based Composite Lupus Assessment (BICLA), the Cutaneous Lupus Erythematosus Disease Area and Severity Index–50 (CLASI-50), the Lupus Low Disease Activity State (LLDAS), and active joint counts compared with placebo. Regarding litifilimab, Dr van Vollenhoven reviewed the findings from 2 studies published in The New England Journal of Medicine showing significantly better outcomes with litifilimab vs placebo in patients with SLE and cutaneous lupus erythematosus.

Finally, a poster presented at CCR East 2024 by Merrill et al of a phase 2 study of the upadacitinib-plus-elsubrutinib combination ABBV-599 has drawn a lot of attention. In the study, patients with SLE were randomized 1:1:1:1:1 to 30 mg of the JAK inhibitor upadacitinib, 60 mg of the selective BTK inhibitor elsubrutinib, high-dose ABBV-599 (30 mg of upadacitinib and 60 mg of elsubrutinib), low-dose ABBV-599 (15 mg of upadacitinib and 60 mg of elsubrutinib), or placebo. The investigators reported that high-dose ABBV-599 and upadacitinib 30 mg monotherapy demonstrated acceptable safety and resulted in significant improvements in SLE disease activity and flares through 48 weeks of treatment.

Overall, these presentations at CCR East 2024 bring together a lot of evidence to suggest that IFN is a key cytokine and that IFN blockers are likely to be very successful in treating the symptoms and the pathogenesis of SLE.