THU0277 Gene Expression in Whole Blood Predicts the Abatacept–Methotrexate Combination Responsiveness in Rheumatoid Arthritis: Preliminary Results from the Power Doppler Ultrasonography Appraise Study
Authors: T. Lequerré, C. Derambure, M.-A. D'Agostino, M. Hiron, P. Gaudin, C. Gaillez, M. Le Bars, O. Vittecoq
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> 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; APPRAISE) study in patients with RA and inadequate response to MTX [1–4]. <h3>Objectives</h3> 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. <h3>Methods</h3> 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 &gt;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 <i>t</i>-test with false discovery rate correction for multiple testing (p&lt;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. <h3>Results</h3> 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&lt;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. <h3>Conclusions</h3> 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. <h3>References</h3> D9Agostino MA et al. Ann Rheum Dis 2012;71(Suppl 3):86. D9Agostino MA, et al. Arthritis Rheum 2012;64(Suppl):S352. D9Agostino MA, et al. Arthritis Rheum 2012;64(Suppl):S353. Lequerre T, et al Arthritis Rheum 2013;65(Suppl):S811. <h3>Disclosure of Interest</h3> : T. Lequerré Grant/research support: BMS, Consultant for: BMS, C. Derambure: None declared, M. D9Agostino: None declared, M. Hiron: None declared, P. Gaudin Consultant for: BMS, C. Gaillez Shareholder of: BMS, Employee of: BMS, M. Le Bars Shareholder of: BMS, Employee of: BMS, O. Vittecoq Consultant for: BMS Advisory Board <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.1567