Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR..
INTRODUCTION: Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials.
METHODS: Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels.
RESULTS: Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52 and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-λ protein levels, and impacted apoptosis-associated and neutrophil extracellular trap-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and γδT cells and a decrease of monocytes following anifrolumab treatment.
DISCUSSION: Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Annals of the rheumatic diseases - (2024) vom: 03. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Baker, Tina [VerfasserIn] |
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| Links: |
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| Themen: |
Autoimmune Diseases |
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| Anmerkungen: |
Date Revised 03.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1136/ard-2023-225445 |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM370592808 |
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| 245 | 1 | 0 | |a Type I interferon blockade with anifrolumab in patients with systemic lupus erythematosus modulates key immunopathological pathways in a gene expression and proteomic analysis of two phase 3 trials |
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| 520 | |a © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR. | ||
| 520 | |a INTRODUCTION: Anifrolumab is a type I interferon (IFN) receptor 1 (IFNAR1) blocking antibody approved for treating patients with systemic lupus erythematosus (SLE). Here, we investigated the immunomodulatory mechanisms of anifrolumab using longitudinal transcriptomic and proteomic analyses of the 52-week, randomised, phase 3 TULIP-1 and TULIP-2 trials | ||
| 520 | |a METHODS: Patients with moderate to severe SLE were enrolled in TULIP-1 and TULIP-2 and received intravenous anifrolumab or placebo alongside standard therapy. Whole-blood expression of 18 017 genes using genome-wide RNA sequencing (RNA-seq) (pooled TULIP; anifrolumab, n=244; placebo, n=258) and 184 plasma proteins using Olink and Simoa panels (TULIP-1; anifrolumab, n=124; placebo, n=132) were analysed. We compared treatment groups via gene set enrichment analysis using MetaBase pathway analysis, blood transcriptome modules, in silico deconvolution of RNA-seq and longitudinal linear mixed effect models for gene counts and protein levels | ||
| 520 | |a RESULTS: Compared with placebo, anifrolumab modulated >2000 genes by week 24, with overlapping results at week 52 and 41 proteins by week 52. IFNAR1 blockade with anifrolumab downregulated multiple type I and II IFN-induced gene modules/pathways and type III IFN-λ protein levels, and impacted apoptosis-associated and neutrophil extracellular trap-associated transcriptional pathways, innate cell activating chemokines and receptors, proinflammatory cytokines and B-cell activating cytokines. In silico deconvolution of RNA-seq data indicated an increase from baseline of mucosal-associated invariant and γδT cells and a decrease of monocytes following anifrolumab treatment | ||
| 520 | |a DISCUSSION: Type I IFN blockade with anifrolumab modulated multiple inflammatory pathways downstream of type I IFN signalling, including apoptotic, innate and adaptive mechanisms that play key roles in SLE immunopathogenesis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Autoimmune Diseases | |
| 650 | 4 | |a Biological Therapy | |
| 650 | 4 | |a Lupus Erythematosus, Systemic | |
| 700 | 1 | |a Sharifian, Hoda |e verfasserin |4 aut | |
| 700 | 1 | |a Newcombe, Paul J |e verfasserin |4 aut | |
| 700 | 1 | |a Gavin, Patrick G |e verfasserin |4 aut | |
| 700 | 1 | |a Lazarus, Mark N |e verfasserin |4 aut | |
| 700 | 1 | |a Ramaswamy, Madhu |e verfasserin |4 aut | |
| 700 | 1 | |a White, Wendy I |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrari, Nicola |e verfasserin |4 aut | |
| 700 | 1 | |a Muthas, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Tummala, Raj |e verfasserin |4 aut | |
| 700 | 1 | |a Morand, Eric F |e verfasserin |4 aut | |
| 700 | 1 | |a Furie, Richard |e verfasserin |4 aut | |
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