TY - JOUR
T1 - Analysis of Apoptosis in Peripheral Blood and Synovial Tissue Very Early After Initiation of Infliximab Treatment in Rheumatoid Arthritis Patients
AU - Wijbrandts, Carla A.
AU - Remans, Philip H.
AU - Klarenbeek, Paul L.
AU - Wouters, Diana
AU - van den Bergh Weerman, Marius A.
AU - Smeets, Tom J.
AU - Vervoordeldonk, Margriet J.
AU - Baeten, Dominique
AU - Tak, Paul P.
PY - 2008
Y1 - 2008
N2 - Objective. Infliximab treatment results in a decrease in synovial cellularity as early as 48 hours after initiation of therapy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether infliximab induces apoptosis within the first 24 hours after infusion. Methods. The percentage of apoptotic cells was determined by flow cytometry in blood drawn from 21 patients directly before, I hour after, and 24 hours after infliximab infusion. Synovial tissue samples obtained before, I hour after (n = 5), or 24 hours after (n = 5) initiation of therapy were subjected to immunohistochemistry to detect active caspase 3 and to TUNEL assay and electron microscopy to detect apoptosis. In addition, plasma levels of nucleosomes (generated during apoptosis) and C4b/c (an indicator of complement activation) were measured. Results. There were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infliximab treatment. Circulating lymphocyte counts were increased within 1 hour after infusion (P <0.05). There was no definite evidence of apoptosis induction in the synovium, except in 1 patient 24 hours after the infliximab infusion. Consistent with these results, there was no increase in nucleosome levels nor were there signs of complement activation. Conclusion. Our findings indicate that the rapid decrease in synovial cellularity observed after initiation of anti-tumor necrosis factor antibody therapy cannot be explained by apoptosis induction at the site of inflammation. It is tempting to speculate that the striking effects on synovial inflammation may be explained by other mechanisms, such as decreased migration toward the synovial compartment and reduced retention in the inflamed synovium
AB - Objective. Infliximab treatment results in a decrease in synovial cellularity as early as 48 hours after initiation of therapy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether infliximab induces apoptosis within the first 24 hours after infusion. Methods. The percentage of apoptotic cells was determined by flow cytometry in blood drawn from 21 patients directly before, I hour after, and 24 hours after infliximab infusion. Synovial tissue samples obtained before, I hour after (n = 5), or 24 hours after (n = 5) initiation of therapy were subjected to immunohistochemistry to detect active caspase 3 and to TUNEL assay and electron microscopy to detect apoptosis. In addition, plasma levels of nucleosomes (generated during apoptosis) and C4b/c (an indicator of complement activation) were measured. Results. There were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infliximab treatment. Circulating lymphocyte counts were increased within 1 hour after infusion (P <0.05). There was no definite evidence of apoptosis induction in the synovium, except in 1 patient 24 hours after the infliximab infusion. Consistent with these results, there was no increase in nucleosome levels nor were there signs of complement activation. Conclusion. Our findings indicate that the rapid decrease in synovial cellularity observed after initiation of anti-tumor necrosis factor antibody therapy cannot be explained by apoptosis induction at the site of inflammation. It is tempting to speculate that the striking effects on synovial inflammation may be explained by other mechanisms, such as decreased migration toward the synovial compartment and reduced retention in the inflamed synovium
U2 - https://doi.org/10.1002/art.23989
DO - https://doi.org/10.1002/art.23989
M3 - Article
C2 - 18975323
SN - 0004-3591
VL - 58
SP - 3330
EP - 3339
JO - Arthritis and rheumatism
JF - Arthritis and rheumatism
IS - 11
ER -