ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1520

Gene Expression Analyses of Abatacept- and Adalimumab-Treated Patients from the Ample Trial

S Bandyopadhyay1, M Maldonado1, M Schiff2, ME Weinblatt3, Roy Fleischmann4 and SE Connolly1, 1Bristol-Myers Squibb, Princeton, NJ, 2University of Colorado, Denver, CO, 3Brigham and Women's Hospital, Boston, MA, 4University of Texas Southwestern Medical Center, Dallas, TX

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: The distinct mechanisms of action (MoA) of abatacept (ABA) and adalimumab (ADA) are expected to manifest in different transcriptional profiles in RA patients (pts). This post-hoc analysis assessed peripheral blood gene expression in RA pts from AMPLE treated with ABA or ADA, and the pharmacodynamic (PD) changes between baseline and month (Mth) 3 that correlate with the magnitude of clinical response. Methods: The AMPLE study has been described elsewhere.1 Peripheral blood mRNA was isolated from 566 pts at baseline and 3 mths. Whole genome transcriptional profiling used Affymetrix U219 chips, representing 18,567 genes. Differentially expressed genes from baseline to Mth 3 were identified for each treatment (fold-change >/< 0.2, adjusted p-value <0.05) using Bioconductor/LIMMA.2 PD-response analysis was done by placing pts in non-overlapping groups based on their ACR response at Mth 3. From this, consensus-stabilized k-means clustering was used to reduce the data into the minimal number of PD clusters for ABA- and ADA-treated pts.3 Genes within these clusters were analyzed by gene-set enrichment analysis (GSEA) to estimate the over-representation of molecular pathways. Results: Pts treated with ABA had 236 genes significantly up-regulated by Mth 3, while ADA treatment had significant up-regulation of 634 genes (Figure). There was overlap on 221 of the genes up-regulated. Treatment with ABA resulted in the down-regulation of 179 genes, while treatment with ADA resulted in the down-regulation of 513 genes. The therapies overlapped on 172 genes. Across therapies, many genes were significantly regulated in one group but not the other (Figure, black dots). K-means clustering based on ACR response groups at Mth 3 resulted in 6 unique patterns of PD per treatment. GSEA identified 118 pathways enriched across the 6 ABA clusters and 119 pathways enriched in the 6 ADA clusters. Among the pathways showing PD response for both therapies were “NFAT in immune response”, “inhibitory PD-1 signaling in T cells” and “T-cell subsets: cell surface markers”. Conclusion: ABA was more selective on modulating gene expression in RA pts, although there was overlap in genes impacted by both therapies. The treatment- and response-dependent clusters might reflect differences related to MoA leading to similar clinical outcomes. Further delineation of the pathways will elucidate how these two agents with unique mechanisms provide comparable efficacy with some differences in safety and tolerability.

  1. Schiff M, et al. Ann Rheum Dis 2014;73:86–94 2. Smyth GK. Limma: linear models for microarray data. In: Gentleman R et al (eds). Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Springer, New York: 2005;397–420 3. Wilkerson M, Waltman P. ConsensusClusterPlus: ConsensusClusterPlus. R package version 1.16.0; 2013 volcano_revised_colored.jpeg


 

Disclosure:

S. Bandyopadhyay,

Bristol-Myers Squibb,

3;

M. Maldonado,

Bristol-Myers Squibb,

3,

Bristol-Myers Squibb,

1;

M. Schiff,

Bristol-Myers Squibb, Abbvie,

5;

M. Weinblatt,

BMS, Crescendo Bioscience, UCB, Abbvie, Roche, Janssen,

5,

BMS, Crescendo Bioscience, UCB,

2;

R. Fleischmann,

AbbVie, Amgen, Astellas, Astra Zeneca, BMS, Celgene, Dynavax, Genzyme, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, Xoma,

2,

AbbVie, Amgen, Astra Zeneca, BMS, Celgene, Janssen, Eli Lilly, Pfizer, Roche, Sanofi-Aventis, UCB,

5;

S. Connolly,

Bristol-Myers Squibb,

1,

Bristol-Myers Squibb,

3.

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-expression-analyses-of-abatacept-and-adalimumab-treated-patients-from-the-ample-trial/