ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1517

Analysis of Gene Expression Fluctuation with Abatacept Highlights the Involvement of the Proteasome Pathway As a Mechanism of Action of Abatacept in Rheumatoid Arthritis

C Derambure1, O Vittecoq1,2, G Dzangue Tchoupou1, Maria-Antonietta d'Agostino3, P Gaudin4, C Gaillez5, M Le Bars6 and T Lequerré1,2, 1Inserm 905, Institute for Biomedical Research, University of Rouen, Rouen, France, 2Department of Rheumatology, Rouen University Hospital, Rouen, France, 3AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France, 4Department of Rheumatology, University Hospital Grenoble, Grenoble, France, 5Formerly of Bristol-Myers Squibb, Rueil-Malmaison, France, 6Bristol-Myers Squibb, Rueil-Malmaison, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy: Novel therapies, Biosimilars, Strategies and Mechanisms in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Abatacept (ABA) is a biologic therapy targeting T cells, which play a major role in the pathophysiology of RA. Overall, 57.1% of patients reached LDA (DAS28 [CRP] ≤3.2) after 6 months of treatment with ABA and MTX in the open-label ABA Power Doppler Ultrasonography APPRAISE study, in patients with RA and inadequate MTX response.1 The objective of this substudy was to explore gene expression fluctuations and to identify the main molecular mechanism modifications that occur in a subset of ABA-treated patients according to their treatment response. Methods: In this substudy, 19 patients with active RA and inadequate MTX response were treated with approved doses of ABA and MTX. For this analysis, patients were categorized as ABA responders (R; DAS28 ≤3.2 [LDA]) (n=14) or non-responders (NR; DAS28 >3.2) (n=5) following 6 months of treatment. Whole blood was collected in Paxgene tubes for each patient at baseline and 6 months. RNAs were hybridized to a whole human genome 4 x 44K microarray Agilent slide to identify mRNA specifically dysregulated between baseline and 6 months in R and NR patients using GeneSpring GX software and a t-test with false discovery rate correction for multiple testing (p<0.05). Gene ontology (GO), pathways analysis (curated WikiPathways) and text mining via Natural Language processing were performed to identify the molecular mechanisms regulated by ABA in R and NR. Correlations between gene expression fluctuation and changes in DAS28 were assessed to identify the impact of ABA treatment on disease activity. Results: After 6 months of treatment with ABA, no genes were significantly differentially expressed in NR patients, whereas 935 genes were significantly differentially expressed in R patients (p<0.05). Of these genes, 298 were down-regulated at 6 months and 637 were up-regulated compared with baseline. GO allowed us to identify GO terms enriched only in the list of the 637 up-regulated genes. All of these GO terms were relative to the mRNA process (p<0.05). Pathways analysis allowed us to identify 15 curated pathways significantly enriched in the 935 mRNAs dysregulated in R patients (p<0.05). The most significant pathways found to be in agreement with the GO analysis were Hs_mRNA_processing_WP411_45374 (p=0.002) and Hs_Proteasome_Degradation_WP183_45274 (p=0.001). Among the 935 genes identified, 7 up-regulated genes were significantly involved in the proteasome degradation pathway, including 65 proteins in humans. Six gene expression fluctuations (among 935) between baseline and 6 months were correlated with variation of DAS28: 3 positive and 3 negative correlations (p<0.01).

Conclusion: Comparison of gene expression fluctuations between R and NR to abatacept treatment highlighted 935 genes differentially expressed only in R in our cohort. As the proteasome is required for essential immune functions of activated CD4(+) T cells, and can be defined as a molecular target for suppression of deregulated and unwanted T-cell-mediated immune responses, this study suggests a new mechanism of action for abatacept in patients with LDA. Small sample size may be a limitation. 1. D’Agostino MA, et al. Arthritis Rheum 2012;64(Suppl):S352.

Disclosure:

C. Derambure,
None;

O. Vittecoq,
None;

G. Dzangue Tchoupou,
None;

M. A. d’Agostino,

Bristol-Myers Squibb, AbbVie,

8;

P. Gaudin,
None;

C. Gaillez,

Bristol-Myers Squibb, Novartis,

1,

Novartis Pharma AG,

3;

M. Le Bars,

Bristol-Myers Squibb,

3,

Bristol-Myers Squibb,

1;

T. Lequerré,

Bristol-Myers Squibb,

2.

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