Session Information
Date: Monday, November 14, 2016
Session Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis - Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Type I interferon (IFN) has been implicated in SLE pathogenesis, and the majority of subjects with SLE have elevated expression of type I IFN-inducible genes in their blood. Anifrolumab, a fully human, IgG1 κ monoclonal antibody against the type I IFN receptor, is in Phase III clinical trials for the treatment of moderate to severe SLE (NCT02446912 and NCT02446899). Understanding other molecular pathways, either dependent on or independent of type I IFN signaling, is critical to elucidating heterogeneous mechanisms in SLE and to identifying subject subsets for personalized disease management.
Methods: Baseline blood samples from adult subjects with moderate to severe SLE from two Phase IIb clinical studies (NCT01438489; N=265, NCT01283139; N=416) were profiled with whole genome array analyses. Type I IFN gene signature status (high or low) was determined by a central laboratory utilizing an analytically validated four gene (IFI27, IFI44, IFI44L, RSAD2) qPCR-based test from subjects’ whole blood. A predetermined, delta Ct-based cut-off point, in the trough of the bimodal distribution, was utilized to segregate IFN-high from IFN-low subjects at baseline. Blood from healthy controls was stimulated ex vivo with IFN-β, IFN-γ, IFN-λ, IFN-ω, or a pool of all IFN-α subtypes, with or without blocking antibodies for each IFN type, to develop IFN-type-specific signatures. Ninety additional cell type and cytokine pathway specific gene signatures derived from the literature were also evaluated with the Phase IIb sample data. A Fisher’s exact test was used for enrichment calculations (signatures cut at median), and comparisons were adjusted for multiplicity through false discovery rate.
Results: 79% of SLE subjects in the combined study population were determined to have an elevated type I IFN gene signature. From the type I IFN signature high subjects, 29/95 signatures evaluated had significant enrichment, including those for B cells (q=1.17E-17, OR=6.4), plasma cells (q=6.96E-11, OR=3.9), and CD40L signaling (q=1.07E-08, OR=3.3), relative to type I IFN-low subjects. In stark contrast, type I IFN signature low subjects had enrichment for eosinophils (q=5.4E-6, OR=0.39), and type II IFN (IFN-γ) specifically inducible gene signatures (q=4.6E-3, OR=0.47). These findings were significant in the combined study population, as well as the NCT01438489 study population, and were either significant or similarly trending for the NCT01283139 population (q<0.05).
Conclusion: SLE subjects who are type I IFN high, had elevated concentrations of B cell, plasma cell, and other inflammatory cytokine pathways. Type I IFN-low subjects, by contrast, were enriched for eosinophil and type II IFN pathways. These observations provide new insights into the molecular heterogeneity underlying SLE and suggest new therapeutic approaches, particularly for type I IFN signature low subjects.
To cite this abstract in AMA style:
Liu H, Higgs B, Rees W, Morehouse C, Streicher K, Brohawn P, Illei G, Ranade K. Type I IFN Signature Low and High SLE Subjects with Moderate to Severe Disease Activity Have Distinct Gene Expression Signatures of Immunologic Pathways and Cell Types [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/type-i-ifn-signature-low-and-high-sle-subjects-with-moderate-to-severe-disease-activity-have-distinct-gene-expression-signatures-of-immunologic-pathways-and-cell-types/. Accessed November 23, 2020.« Back to 2016 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-ifn-signature-low-and-high-sle-subjects-with-moderate-to-severe-disease-activity-have-distinct-gene-expression-signatures-of-immunologic-pathways-and-cell-types/