RESEARCH - Mode of action of Orencia in RA patients having failed TNF blockade: a histological, gene expression and dynamic MRI pilot study

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Ann Rheum Dis. Published Online First: 4 September 2008.

doi:10.1136/ard.2008.091876

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Extended Report

Mode of action of abatacept in rheumatoid arthritis patients having

failed TNF blockade: a histological, gene expression and dynamic MRI

pilot study

Maya H Buch 1, L. Boyle 2, Sanna Rosengren 2, Benazir Saleem 1,

J Reece 1, A 1, Aleksandra Radjenovic 1, Anne

English 1, Haiqing Tang 3, Vratsanos 3, Philip O'Connor 4,

S Firestein 5 and Emery 1*

1 University of Leeds, United Kingdom

2 University of California, Uzbekistan

3 Bristol-Myers Squibb, United States

4 Leeds General Infirmary, United Kingdom

5 UCSD School of Medicine, United States

Abstract

Objectives: Abatacept is the only agent currently approved to treat

rheumatoid arthritis (RA) that targets the co-stimulatory signal

required for full T-cell activation. There have been no studies of its

effect on the synovium, the primary site of pathology. The aim of this

study was to determine the synovial effect of abatacept in patients

with RA and an inadequate response to tumor necrosis factor- (TNF-)

blocking therapy.

Methods: This first mechanistic study incorporated both dynamic

contrast-enhanced magnetic resonance imaging (DCE-MRI) and

arthroscopy-acquired synovial biopsies before and 16 weeks after

therapy, providing tissue for immunohistochemistry and quantitative

real-time polymerase chain reaction (PCR) analyses.

Results: Sixteen patients (13 female) were studied; all had previously

failed TNF- blocking therapy. Fifteen patients completed the study.

Synovial biopsies showed a small reduction in cellular content, which

was significant only for B cells. The quantitative PCR showed a

reduction in expression for most inflammatory genes (Wald statistic of

p < 0.01 indicating a significant treatment effect), with particular

reduction (95% CI) in interferon- of -52% (-73, -15, p < 0.05); this

correlated well with MRI improvements. In addition, favourable changes

in the osteoprotegerin and receptor activator of nuclear factor B

levels were noted. DCE-MRI showed a reduction of 15–40% in MRI

parameters.

Conclusion: These results indicate that abatacept reduces the

inflammatory status of the synovium without disrupting cellular

homeostasis. The reductions in gene expression influence bone

positively and suggest a basis for the recently demonstrated

radiologic improvements that have been seen with abatacept treatment

in patients with RA.

http://ard.bmj.com/cgi/content/abstract/ard.2008.091876v2?papetoc

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