INTERFERON-A MEDIATED THERAPEUTIC RESISTANCE in EARLY RA IMPLICATES EPIGENETIC REPROGRAMMING
Annals of the Rheumatic Diseases
; 81:7-8, 2022.
Article
in English
| EMBASE | ID: covidwho-2008870
ABSTRACT
Background:
An interferon gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients. We previously demonstrated it negatively impacts on initial disease outcomes.Objectives:
To 1) reproduce previous fndings demonstrating the harmful effects of the IGS on early RA clinical outcomes, 2) identify which IFN class is responsible for the IGS and 3) seek evidence that IFN-a exposure contributes to harmful epigenetic footprint at disease onset.Methods:
In a large multicentre inception cohort (n=190) of eRA patients (RA-MAP TACERA) whole blood transcriptome, IGS (MxA, IFI44L, OAS1, ISG15, IFI6) and circulating interferons (IFN)-a,-β,-y and-), was examined at baseline and 6 months in conjunction with disease activity and clinical characteristics. A separate eRA cohort of paired methylome and transcriptome from CD4 T and CD19 B cells (n=41 for each) was used to explore any epigenetic influence of the IGS.Results:
The baseline IGS reproducibly and signifcantly negatively impacts on 6-month clinical outcomes. In the high IGS cohort there was increased DAS-28 (p=0.025) and reduced probability of achieving a good EULAR response (p=0.034) at 6-months. In addition, the IGS in eRA is shown for the frst time to predominantly refect raised circulating IFN-a protein, not other classes of IFN and examination of whole blood upstream nucleic acid sensors expression suggest a RNA trigger. Both the IGS and IFN-a signifcantly fell in parallel at 6 months (p<0.0001), whereas other classes of IFN remained statistically static. There was a signifcant association with IFN-a and RF titre but not ACPA. Comparison of CD4 T and CD19 B cells between IGS high and low eRA patients demonstrated differentially methylated CPG sites and altered transcript expression of disease relevant genes e.g. PARP9, STAT1, EPTSI1 which was similarly, and persistently altered 6 months in the separate TACERA cohort. Differentially methylated CPGs implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1a) which cumulatively suggested IFN-a induced epigenetic changes promoting increased, and sustained, lymphocyte activation, proliferation and loss of anergy in the IGS high cohort.Conclusion:
We validate that the IGS is a robust prognostic biomarker in eRA predicting poor therapeutic response. Its persistent harmful effects may be driven via epigenetic modifcations. These data have relevance for other IFN-a states, such as COVID-19, but also provide a rationale for the initial therapeutic targeting of IFN-a signalling, such as with JAKi, at disease onset in stratifed eRA subsets.
biological marker; CD19 antigen; CD4 antigen; cyclic citrullinated peptide antibody; E1A associated p300 protein; endogenous compound; hypoxia inducible factor 1alpha; interferon; Myxovirus resistance protein A; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; nucleic acid; STAT1 protein; transcription factor; transcription factor EZH2; transcription factor GATA 3; transcription factor NFAT; transcriptome; adult; B lymphocyte; cell proliferation; clinical feature; clinical outcome; cohort analysis; conference abstract; controlled study; coronavirus disease 2019; DAS28; epigenetics; female; gene expression; genetic marker; genetic transcription; human; human cell; lymphocyte activation; major clinical study; male; methylome; multicenter study; outcome assessment; probability; rheumatoid arthritis; sensor; signal transduction; T lymphocyte; treatment response
Full text:
Available
Collection:
Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Annals of the Rheumatic Diseases
Year:
2022
Document Type:
Article
Similar
MEDLINE
...
LILACS
LIS