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Abstract Number: 1485

RNA Transcripts From Peripheral Blood Mononuclear Cells As Predictors Of Clinical Responsiveness In Rheumatoid Arthritis Subjects Treated With Abatacept

Matthew Henkel1, Fang Du2, Donald M. Jones3, Erich R Wilkerson2, William Horne4, Jay K. Kolls5, Marc C. Levesque6 and Mandy McGeachy1, 1Medicine, Univeristy of Pittsburgh, Pittsburgh, PA, 2Medicine, University of Pittsburgh, Pittsburgh, PA, 3Rheumatology & Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, 4Pediatrics, University of Pittsburgh, Pittsburgh, PA, 5Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, 6Division of Rheumatology and Clinical Immunology, University of Pittsburgh Department of Medicine, Pittsburgh, PA

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Abatacept and rheumatoid arthritis (RA), RNA

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Session Information

Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy II

Session Type: Abstract Submissions (ACR)

Background/Purpose: Biologics, including abatacept (CTLA4Ig), improve outcomes for many RA patients.  However, approximately 40-50% of RA patients fail to respond to abatacept, and there are currently no biomarkers that predict responsiveness.  Analysis of a defined panel of peripheral blood mononuclear cell (PBMC) gene transcripts is a non-invasive and technically feasible approach for routine clinical use to predict abatacept responsiveness.  Advances in transcriptome profiling techniques (RNA-Seq) now allow high-throughput “deep-sequencing” of relatively small amounts of input RNA.  Direct detection of transcripts by RNA-Seq offers several advantages over conventional microarrays: high sensitivity, low background signal, high dynamic range and accuracy of transcript quantification and high reproducibility.

Methods: We analyzed RNA samples derived from PBMC from 6 subjects treated with abatacept ± oral DMARDs and ± prednisone who were enrolled in the Rheumatoid Arthritis Comparative Effectiveness Research (RACER) registry at the University of Pittsburgh.  Five of 6 subjects were anti-CCP positive and all 6 RA subjects had active disease at baseline (mean DAS28-CRP ± SD; 4.4 ± 0.7) despite recent TNF inhibitor therapy.  Based on DAS28-CRP scores at baseline and at 6 months after abatacept initiation, 3 of the RA subjects were deemed responders (DDAS28-CRP = -1.3 ± 1.0) and 3 non-responders (DDAS28 = 0.1 ± 0.8).  PBMC RNA samples from the 6 RA subjects were analyzed by RNA-Seq prior to receiving abatacept and approximately 2 months (6 to 10 weeks) after abatacept initiation.  We identified genes that differed at baseline between abatacept responders and non-responders, and for responders and non-responders, genes that changed between baseline and 2 months by ≥ 1.3 fold with p < 0.05 (t test).

Results: There was relatively little overlap between responders and non-responders when analyzing RNA transcript changes from baseline to 2 months (< 10 transcripts).  A substantially larger proportion of transcripts were significantly altered (increased or decreased) from baseline to 2 months in responders (6339 transcripts) compared to non-responders (117 transcripts).  We analyzed expression of genes related to T and B cell function, analyzing baseline predictors of response (different at baseline between responder and non-responder groups) and 2 month predictors of response (different at 2 months versus baseline). We found that PBMC RNA transcripts for IgG isotypes and IL-17 were good 2-month predictors of a 6-month clinical response, but baseline levels of these transcripts did not predict efficacy.  In contrast, IL6R transcripts were a good baseline predictor of efficacy but did not change from baseline to 2 months.

Conclusion: These data support the sensitivity of RNA-Seq as an assay for responses to biologic therapies in PBMC from RA patients.  These RNA-Seq results, with only three subjects per group demonstrate the great potential of this technique to elucidate both mechanistic and biomarker-related pathways altered in PBMC by therapy.  Future studies will validate these results in prospectively collected samples and expand these analyses to other biologic therapies.


Disclosure:

M. Henkel,
None;

F. Du,
None;

D. M. Jones,

Genentech and Biogen IDEC Inc.,

2;

E. R. Wilkerson,

Genentech and Biogen IDEC Inc.,

2;

W. Horne,
None;

J. K. Kolls,
None;

M. C. Levesque,

Genentech and Biogen IDEC Inc.,

2,

Genentech and Biogen IDEC Inc.,

5;

M. McGeachy,
None.

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