OBJECTIVES: Type I interferon (IFN) is implicated in systemic lupus erythematosus (SLE) pathogenesis. We aimed to identify type I IFN signaling-dependent and -independent molecular pathways in a large population of patients with SLE. METHODS: Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb studies (NCT01438489, n = 265; NCT01283139, n = 416) were profiled using whole transcriptome array analyses. Type I IFN gene signature (IFNGS) test status (high or low) was determined using a validated qualitative polymerase chain reaction-based test. IFN-type-specific signatures were developed by stimulating healthy blood with IFN-β, IFN-γ, IFN-λ, IFN-ω, or pooled IFN-α. These, and multiple literature-derived cell type and cytokine pathway signatures, were evaluated in individual and pooled study populations. A Fisher's exact test was used for associations, adjusted for false discovery rate. RESULTS: Whole blood samples from IFNGS test-high patients were enriched versus IFNGS test-low patients for CD40L signaling (Q < 0.001), CXC cytokine (Q < 0.001), TLR8-mediated monocyte activation (Q < 0.001), IgG (Q < 0.001), major histocompatibility complex class I (Q < 0.001), and plasma cell (Q < 0.001) gene expression signatures. IFNGS test-low patients had significant enrichment of eosinophil (Q < 0.001), IFN-γ-specific (Q = 0.005), and T-cell or B-cell (Q < 0.001) signatures. Similar enrichment profiles were demonstrated in patients with primary Sjögren's syndrome, systemic sclerosis, and dermatomyositis. CONCLUSIONS: IFNGS test-high patients overexpressed many gene signatures associated with SLE pathogenesis compared with IFNGS test-low patients, reflecting broad immune activation. These results provide new insights into the molecular heterogeneity underlying SLE pathogenesis, highlighting shared mechanisms beyond type I IFN, across several autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01438489 and NCT01283139.
OBJECTIVES: Type I interferon (IFN) is implicated in systemic lupus erythematosus (SLE) pathogenesis. We aimed to identify type I IFN signaling-dependent and -independent molecular pathways in a large population of patients with SLE. METHODS: Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb studies (NCT01438489, n = 265; NCT01283139, n = 416) were profiled using whole transcriptome array analyses. Type I IFN gene signature (IFNGS) test status (high or low) was determined using a validated qualitative polymerase chain reaction-based test. IFN-type-specific signatures were developed by stimulating healthy blood with IFN-β, IFN-γ, IFN-λ, IFN-ω, or pooled IFN-α. These, and multiple literature-derived cell type and cytokine pathway signatures, were evaluated in individual and pooled study populations. A Fisher's exact test was used for associations, adjusted for false discovery rate. RESULTS: Whole blood samples from IFNGS test-high patients were enriched versus IFNGS test-low patients for CD40L signaling (Q < 0.001), CXC cytokine (Q < 0.001), TLR8-mediated monocyte activation (Q < 0.001), IgG (Q < 0.001), major histocompatibility complex class I (Q < 0.001), and plasma cell (Q < 0.001) gene expression signatures. IFNGS test-low patients had significant enrichment of eosinophil (Q < 0.001), IFN-γ-specific (Q = 0.005), and T-cell or B-cell (Q < 0.001) signatures. Similar enrichment profiles were demonstrated in patients with primary Sjögren's syndrome, systemic sclerosis, and dermatomyositis. CONCLUSIONS: IFNGS test-high patients overexpressed many gene signatures associated with SLE pathogenesis compared with IFNGS test-low patients, reflecting broad immune activation. These results provide new insights into the molecular heterogeneity underlying SLE pathogenesis, highlighting shared mechanisms beyond type I IFN, across several autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01438489 and NCT01283139.
Entities:
Keywords:
Anifrolumab; disease pathogenesis; systemic lupus erythematosus; transcriptomics; type I IFN
Authors: Peter E Lipsky; Ronald van Vollenhoven; Thomas Dörner; Victoria P Werth; Joan T Merrill; Richard Furie; Milan Petronijevic; Benito Velasco Zamora; Maria Majdan; Fedra Irazoque-Palazuelos; Robert Terbrueggen; Nikolay Delev; Michael Weiswasser; Shimon Korish; Mark Stern; Sarah Hersey; Ying Ye; Allison Gaudy; Zhaohui Liu; Robert Gagnon; Shaojun Tang; Peter H Schafer Journal: Ann Rheum Dis Date: 2022-04-27 Impact factor: 27.973