Novel Steroid-Sparing SLE Solution: ACR24 - European Medical Journal Novel Steroid-Sparing SLE Solution: ACR24 - AMJ

Novel Steroid-Sparing SLE Solution: ACR24

EVIDENCE supporting a novel therapeutic target for systemic lupus erythematosus (SLE), the E3 ubiquitin ligase “E3-X”, was presented at ACR Convergence 2024 in Washington, D.C. This research may contribute to movement away from reliance on glucocorticoids, a cornerstone of SLE treatment but notorious for their severe side effects.

SLE, driven by B-cell dysregulation and type I interferon (IFN) activation, presents a complex therapeutic challenge. Current treatments often rely on glucocorticoids, which, while effective in controlling inflammation, present risks of irreversible organ damage. The study highlighted glucocorticoid-induced leucine zipper (GILZ), a protein central to glucocorticoids’ anti-inflammatory effects but without their adverse outcomes, as a potential game-changer.

Authors from Monash University, Melbourne, Australia, targeted E3-X, which regulates GILZ abundance, to demonstrate significant anti-inflammatory effects in cellular and animal models. In mouse models deficient in E3-X, researchers observed enhanced GILZ expression, a 5-10-fold improvement in glucocorticoid sensitivity, and suppressed inflammatory cytokine production such as TNF, IL-6, and MCP-1. Proteomics data confirmed a broad reduction in IFN-driven pathways.

In vivo, E3-X deficiency protected against peritoneal inflammation and ameliorated classic SLE symptoms, including splenomegaly and autoantibody production, in the Lyn-/- lupus model. Human data showed elevated E3-X expression in patients with SLE, particularly those with high IFN activity, correlating with disease severity as measured by SLEDAI-2K scores.

By inhibiting E3-X, researchers could potentially harness the anti-inflammatory benefits of glucocorticoids without the risks, signaling a promising future for targeted SLE therapies.

Reference: Miceli I et al. A Novel E3 Ligase of GILZ: Validation of a Steroid-sparing Therapeutic Target in SLE. Abstract 1646. ACR Convergence 2024, November 16-19, 2024.

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