Dept. of Neurology-Neuroimmunology; Vall d'Hebron University Campus; Multiple Sclerosis Centre of Catalonia (Cemcat)

Author Of 1 Presentation

Biomarkers and Bioinformatics Poster Presentation

P0020 - A down-regulation of the type I interferon signaling pathway is associated with the response to teriflunomide in multiple sclerosis. (ID 1584)

Abstract

Background

Teriflunomide is an oral first-line treatment of patients with relapsing-remitting multiple sclerosis (RRMS) that has been shown to decrease clinical relapses, reduce brain magnetic resonance imaging (MRI) activity, and slow progression of disability. However, the drug exhibits only limited effectiveness and does not produce clinical benefits in a proportion of MS patients.

Objectives

We aimed to identify differentially expressed genes and cellular pathways associated with the responder and non-responder status in RRMS patients treated with teriflunomide by means of RNA sequencing (RNA-seq).

Methods

RRMS patients treated with teriflunomide were classified into those with No evidence of disease activity (NEDA 3) and those with EDA after 12 months of treatment. Eleven responders [8 females; mean age (standard deviation): 45.8 years (4.5)] and 10 non-responders [8 females; 41.8 years (10.3)] were included in the study. RNA-seq was performed in RNA samples isolated from peripheral blood mononuclear cells before and after 12 months of teriflunomide treatment. 100 bp, paired-end RNA sequencing was performed by using DNAseqTM Technology. Comparative analysis of differentially expressed genes between responders and non-responders was performed at baseline and after 12 months of treatment. Pathway analysis was based on KEGG database using statistically significant genes.

Results

Pathway analysis revealed the type I interferon (IFN) signaling pathway as the most significantly associated with the responder phenotype after 12 months of teriflunomide treatment (p<0.0001). In this context, expression levels for genes known to be predominantly or selectively induced by type I IFNs such as SP100, ZBP1, IFI27, ISG20, IFITM1, IFITM2, MX1, STAT1, PARP9, IFI35, RGS1, RSAD2, IFI44L, IRF1, DDX58, IFI6, IFIT1 and IFIT5 were significantly reduced by the effect of teriflunomide after 12 months of treatment in responders compared to non-responders. At baseline, expression levels for type I IFN genes were similar between responders and non-responders.

Conclusions

Type I IFNs are known to activate dendritic cells, enhance humoral immunity, and favor Th1 immune responses. A down-regulation of type I IFN genes after 12 months of treatment may explain the beneficial effect of teriflunomide in responders. Mechanistic studies are currently underway to investigate the functional implication of the type I interferon signaling pathway in the response to teriflunomide.

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Presenter Of 1 Presentation

Biomarkers and Bioinformatics Poster Presentation

P0020 - A down-regulation of the type I interferon signaling pathway is associated with the response to teriflunomide in multiple sclerosis. (ID 1584)

Abstract

Background

Teriflunomide is an oral first-line treatment of patients with relapsing-remitting multiple sclerosis (RRMS) that has been shown to decrease clinical relapses, reduce brain magnetic resonance imaging (MRI) activity, and slow progression of disability. However, the drug exhibits only limited effectiveness and does not produce clinical benefits in a proportion of MS patients.

Objectives

We aimed to identify differentially expressed genes and cellular pathways associated with the responder and non-responder status in RRMS patients treated with teriflunomide by means of RNA sequencing (RNA-seq).

Methods

RRMS patients treated with teriflunomide were classified into those with No evidence of disease activity (NEDA 3) and those with EDA after 12 months of treatment. Eleven responders [8 females; mean age (standard deviation): 45.8 years (4.5)] and 10 non-responders [8 females; 41.8 years (10.3)] were included in the study. RNA-seq was performed in RNA samples isolated from peripheral blood mononuclear cells before and after 12 months of teriflunomide treatment. 100 bp, paired-end RNA sequencing was performed by using DNAseqTM Technology. Comparative analysis of differentially expressed genes between responders and non-responders was performed at baseline and after 12 months of treatment. Pathway analysis was based on KEGG database using statistically significant genes.

Results

Pathway analysis revealed the type I interferon (IFN) signaling pathway as the most significantly associated with the responder phenotype after 12 months of teriflunomide treatment (p<0.0001). In this context, expression levels for genes known to be predominantly or selectively induced by type I IFNs such as SP100, ZBP1, IFI27, ISG20, IFITM1, IFITM2, MX1, STAT1, PARP9, IFI35, RGS1, RSAD2, IFI44L, IRF1, DDX58, IFI6, IFIT1 and IFIT5 were significantly reduced by the effect of teriflunomide after 12 months of treatment in responders compared to non-responders. At baseline, expression levels for type I IFN genes were similar between responders and non-responders.

Conclusions

Type I IFNs are known to activate dendritic cells, enhance humoral immunity, and favor Th1 immune responses. A down-regulation of type I IFN genes after 12 months of treatment may explain the beneficial effect of teriflunomide in responders. Mechanistic studies are currently underway to investigate the functional implication of the type I interferon signaling pathway in the response to teriflunomide.

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