TY - JOUR
T1 - 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
AU - Baker, Tina
AU - Sharifian, Hoda
AU - Newcombe, Paul J.
AU - Gavin, Patrick G.
AU - Lazarus, Mark N.
AU - Ramaswamy, Madhu
AU - White, Wendy I.
AU - Ferrari, Nicola
AU - Muthas, Daniel
AU - Tummala, Raj
AU - Morand, Eric F.
AU - Furie, Richard
AU - Vital, Edward M.
AU - Chamberlain, Chris
AU - Platt, Adam
AU - Al-Mossawi, Hussein
AU - Brohawn, Philip Z.
AU - Csomor, Eszter
N1 - Funding Information:
The authors would like to thank the patients and healthcare providers who participated in this study. The authors would also like to thank the investigators and research staff who contributed to the analysis and interpretation of the data, in particular Karl Nordstr\u00F6m, Manasa Surakala, Abirami Pandian, Priyabrata Panigrahi, Mridul Chaudhary for their contributions to the processing and transferring RNA-seq data, and Dr Deepak Rao for his contribution to the manuscript development. The views expressed in this publication are those of the author(s). Medical writing support was provided by Sofia Fernandes, PhD, of JK Associates, part of Avalere Health. This support was funded by AstraZeneca.
Publisher Copyright:
© 2024 BMJ Publishing Group. All rights reserved.
PY - 2024/8
Y1 - 2024/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85190122797
U2 - 10.1136/ard-2023-225445
DO - 10.1136/ard-2023-225445
M3 - Article
C2 - 38569851
AN - SCOPUS:85190122797
SN - 0003-4967
VL - 83
SP - 1018
EP - 1027
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 8
ER -