Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation.
OBJECTIVE
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.
Vergunst
C E
CE
Division of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands.
Gerlag
D M
DM
Dinant
H
H
Schulz
L
L
Vinkenoog
M
M
Smeets
T J M
TJ
Sanders
M E
ME
Reedquist
K A
KA
Tak
P P
PP
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000175:diagnosis* / Q000188:drug therapy*; D001182:Arthroscopy; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D011336:Probability; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000187:drug effects; D013585:Synovitis / Q000188:drug therapy / Q000517:prevention & control*; D016896:Treatment Outcome
C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a