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, David L. Boyle ², Sanna Rosengren ², Benazir Saleem ¹, Richard J Reece ¹, Laura A Rhodes ¹, Aleksandra Radjenovic ¹, Anne English ¹, Haiqing Tang ³, George Vratsanos ³, Philip O'Connor ⁴, Gary S Firestein ⁵ and Paul 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

^* To whom correspondence should be addressed. E-mail: p.emery{at}leeds.ac.uk.

Accepted 3 August 2008

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.