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Rheumatology Advance Access originally published online on October 27, 2007
Rheumatology 2007 46(12):1773-1778; doi:10.1093/rheumatology/kem222
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation

C. E. Vergunst1, D. M. Gerlag1, H. Dinant1,2, L. Schulz3, M. Vinkenoog1, T. J. M. Smeets1, M. E. Sanders1, K. A. Reedquist1 and P. P. Tak1

1Division of Clinical Immunology and Rheumatology, Academic Medical Centre/University, of Amsterdam, The Netherlands, 2Jan van Breemen Institute, Amsterdam, The Netherlands and 3Promics Ltd., Brisbane, Australia.

Correspondence to: P. P. Tak, MD, PhD, Division of Clinical Immunology and Rheumatology, F4-218, Academic Medical Centre/University of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands. E-mail: p.p.tak{at}amc.uva.nl


  Abstract

Objectives. All complement pathways lead to the formation of C5a, which is believed to contribute to the influx and activation of C5a-receptor (C5aR) bearing cells into the joints of patients with rheumatoid arthritis (RA). Studies in animal models of RA have suggested therapeutic potential of C5aR blockade. In this study, we examined the effects of the C5aR blockade on synovial inflammation in RA patients.

Methods. We performed a double-blind, placebo-controlled study using an orally administered C5aR-antagonist. Twenty-one patients with active RA were randomized 2:1 to treatment with a C5aR-antagonist AcF- (OpdChaWR) (PMX53) vs placebo for 28 days. Serum concentrations of PMX53 were determined. Synovial tissue was obtained at baseline and after 28 days of treatment for pharmacodynamic analysis using immunohistochemistry and digital image analysis.

Results. All patients completed the study. Areas under the curve (AUCs) of PMX53 in patients’ blood samples showed a mean of 40.8 nmol h/l. There was neither decrease in cell infiltration, nor changes in key biomarkers associated with clinical efficacy after active treatment. In addition, there was no trend towards clinical improvement in the C5aR-antagonist-treated group compared with placebo nor was there a correlation between the AUC and clinical response.

Conclusions. Treatment with PMX53 did not result in a reduction of synovial inflammation despite reaching serum levels of PMX53 that block C5aR-mediated cell activation in vitro. The data suggest that C5aR blockade does not result in reduced synovial inflammation in RA patients.

KEY WORDS: Rheumatoid arthritis, C5a, Complement, Clinical trial

Submitted 17 April 2007; Accepted 18 June 2007


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