Protein Quantification Using Mass Spectrometry Methods to Predict Response to Abatacept and Methotrexate Combination Therapy in Rheumatoid Arthritis

A Obry^1,2, P Cosette², T Lequerré^1,3, Maria-Antonietta d'Agostino⁴, C Gaillez⁵, M Le Bars⁶ and O Vittecoq^1,3, ¹Inserm 905, Institute for Biomedical Research, University of Rouen, Rouen, France, ²UMR 6270 CNRS, PISSARO Proteomic Facility, IRIB, Normandy University, University of Rouen, Rouen, France, ³Department of Rheumatology, Rouen University Hospital, Rouen, France, ⁴AP-HP Ambroise Paré Hospital, Boulogne-Billancourt, France, ⁵Formerly of Bristol-Myers Squibb, Rueil-Malmaison, France, ⁶Bristol-Myers Squibb, Rueil-Malmaison, France

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Abatacept, proteomics, rheumatoid arthritis (RA) and treatment

Session Information

Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy VI: Biomarkers and Predictors of Rheumatoid Arthritis Disease Response and Outcomes

Session Type: Abstract Submissions (ACR)

Background/Purpose: Targeted biologic therapies with different mechanisms of action are commonly used in RA. Abatacept is a recombinant fusion protein that inhibits T-cell co-stimulatory molecules required for T-cell activation. Overall, 57.1% of patients reached LDA (DAS28 [CRP] ≤3.2) after 6 months of treatment with abatacept and MTX in the open-label abatacept Power Doppler Ultrasonography APPRAISE study, in patients with RA and inadequate MTX response.¹ Treatment choice may be optimized by the identification of predictive protein markers of patient response to treatment. The aim of this study was to identify, by mass spectrometry-based quantification methods, a protein signature from peripheral blood mononuclear cells (PBMC) to predict abatacept/MTX response. Methods: In total, 104 patients with active RA and inadequate MTX response were treated with approved doses of abatacept and MTX. For this analysis, patients were categorized as abatacept responders (DAS28 ≤3.2 [LDA]) (n= 30) or abatacept non-responders (DAS28 >3.2) (n=6) following 6 months of treatment. Proteins extracted from PBMCs from responders and non-responders at baseline and 6 months were analyzed. A ‘label-free’ approach was designed to compare the whole PBMC proteome for the 72 samples; the proteome of each sample was extracted and then in-gel digested. The resulting peptides were analyzed by high-resolution mass spectrometry (MS). Protein quantification was performed by comparing extracted ion currents with dedicated software for quantitation from MS data. Three differential analyses were conducted: (i) between responders and non-responders before treatment; (ii) between responders before and after treatment; (iii) between non-responders before and after treatment. Results: These investigations revealed 30 proteins exhibiting differential expression between responders and non-responders before treatment: 28 proteins were down-regulated and 2 proteins were up-regulated in responders compared with non-responders. In our cohort, this combination of potential biomarkers could predict a good treatment response with 86.67% sensitivity and 66.67% specificity. In our second analysis, after 6 months of abatacept/MTX treatment 29 proteins were down-regulated in responders, while 30 proteins were up-regulated in non-responders, without overlap between these two sets of proteins. Several pathways were recruited in responders, including focal adhesion or leukocyte trans-endothelial migration, whereas immune system response was the main pathway among the over-expressed proteins in non-responders. Conclusion: Our investigations identified a combination of potential biomarkers able to predict patient response to abatacept/MTX treatment in this dataset. We also demonstrated a decrease in the expression of proteins involved in cell migration in treatment responders and an enhanced immune response in treatment non-responders from our dataset. These exploratory findings require further validation and confirmation in another trial. 1. D’Agostino MA, et al. Arthritis Rheum 2012;64(Suppl):S352.

Disclosure:

A. Obry,
None;

P. Cosette,
None;

T. Lequerré,

Bristol-Myers Squibb,

M. A. d’Agostino,

Bristol-Myers Squibb, AbbVie,

C. Gaillez,

Bristol-Myers Squibb, Novartis,

Novartis Pharma AG,

M. Le Bars,

Bristol-Myers Squibb,

O. Vittecoq,
None.

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