ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1904

Gene Expression In Whole Blood Predicts The Abatacept–Methotrexate Combination Responsiveness In Rheumatoid Arthritis: Preliminary Results From The Power Doppler Ultrasonography IM101-179 Study

T Lequerré1, C Derambure1, Maria-Antonietta d'Agostino2, M Hiron3, P Gaudin4, C Gaillez5, M Le Bars6 and O Vittecoq1, 1Rouen University Hospital & Inserm U905, Rouen, France, 2AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France, 3Rouen University Hospital & Inserm, Rouen, France, 4CHU Hôpital Sud, Grenoble, France, 5Bristol-Myers Squibb, Rueil Malmaison, France, 6Bristol-Myers Squibb, Rueil-Malmaison, France

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

Background/Purpose: The overall response rate (defined as low disease activity [LDA] related to DAS28[CRP]) to abatacept associated with MTX was 57.1% at 6 months in the 6-month open-label abatacept Power Doppler Ultrasonography (PDUS; IM101-179) study in patients with RA and inadequate response to MTX.1-3 The objective of this exploratory analysis was to identify potential predictors of response to the abatacept–MTX combination by whole blood gene expression profiling in order to optimize treatment choice Methods: 104 patients with active RA and inadequate response to MTX were treated with abatacept + MTX at the approved doses. Whole blood in Paxgene tubes was collected for each RA patient at baseline. At 6 months, RA patients were categorized as responders if DAS28 was ≤3.2 (LDA) and non-responders if DAS28 was >3.2. Baseline RNAs from a first set of RA patients (n=44) were hybridized to a whole human genome 4 x 44K microarray Agilent slide to identify a gene combination able to separate responders and non-responders with the GeneSpring GX software. A t-test with false discovery rate correction for multiple testing (p<0.05) was used to determine mRNAs differentially regulated between responders and non-responders. This gene combination was validated with a second set of RA patients (n=32) by qRT-PCR. Results: Among these 104 RA patients, 28 were excluded from the following analysis because of missing clinical data (n=13), poor integrity of whole blood mRNA (RIN< 7) (n=6), low concentration rate for reverse transcription (n=7), qRT-PCR failures (n=2). Responders (n=45) and non-responders (n=31) had similar baseline characteristics.1 In a first set of 44 enrolled RA patients (25 responders and 19 non-responders), 87 mRNAs identified by microarray analysis were expressed as a function of the response to treatment and an unsupervised hierarchical clustering almost perfectly separated these responders from non-responders. The informativeness of 12 of these 87 transcripts (selected with the lowest p-value), as measured by qRT-PCR, was re-assessed in a second set of 32 RA patients (20 responders and 12 non-responders). The combined levels of these 12 transcripts properly classified 23 out of 32 patients with a sensitivity of 80%, a specificity of 66.7%, a positive predictive value of 80%, and a negative predictive value of 66.8%. This combination enriched with more genes is in progress in order to better classify the second set of RA patients.

Conclusion: Our gene profiling results obtained by a non-invasive procedure have generated a list of 12 candidate genes that were associated with a response to abatacept combined with MTX in this study. This combination of genes needs to be further validated in other RA studies to support their utility as a potential diagnostic assay for predicting abatacept response in an effort to personalize treatment for RA.

  1. D’Agostino MA et al. Ann Rheum Dis 2012;71(Suppl 3):86. 2. D’Agostino MA, et al. Arthritis Rheum 2012;64(Suppl):S352. 3. D’Agostino MA, et al. Arthritis Rheum 2012;64(Suppl):S353.  

Disclosure:

T. Lequerré,

Bristol-Myers Squibb,

2,

Bristol-Myers Squibb,

5;

C. Derambure,
None;

M. A. d’Agostino,
None;

M. Hiron,
None;

P. Gaudin,

Bristol-Myers Squibb,

5;

C. Gaillez,

Bristol-Myers Squibb,

1,

Bristol-Myers Squibb,

3;

M. Le Bars,

Bristol-Myers Squibb,

1,

Bristol-Myers Squibb,

3;

O. Vittecoq,

Bristol-Myers Squibb,

5.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-expression-in-whole-blood-predicts-the-abatacept-methotrexate-combination-responsiveness-in-rheumatoid-arthritis-preliminary-results-from-the-power-doppler-ultrasonography-im101-179-stud/