Infliximab treatment reduces synovial cellularity as early as 48 hours after initiation of treatment, but not by induction of apoptosis
© The Author(s) 2003
Received: 14 January 2003
Published: 24 February 2003
The mechanism of action of TNF-α-targeted therapies, which may have a beneficial effect soon after initiation of treatment in rheumatoid arthritis (RA) patients, is as yet not completely understood. Previous work has shown that TNF-α blockade results in decreased cellularity in the synovium, which can be explained in part by reduced cell migration. In the present study we investigated whether treatment with the chimeric anti-TNF-α antibody infliximab could also reduce cellularity by induction of apoptosis in the RA synovium.
Twenty-four RA patients with active disease (DAS 4.8 or higher), who had failed at least 2 DMARDs, were randomized to receive either infliximab (3 mg/kg) (n = 12) or placebo (n = 12) intravenously. All 24 patients were subjected to an arthroscopic synovial biopsy directly before initiation of treatment. In all 24 patients, a second arthroscopic synovial biopsy of the same index joint was performed 48 hours after the first procedure. After the second arthroscopy, the patients who had initially received placebo were also treated with infliximab (3 mg/kg) in an extension study. A third arthroscopy was performed in all 24 patients on day 28. Immunohistologic analysis was performed using monoclonal antibodies (mAbs) against CD3 (T cells), CD22 (B cells), CD38 (plasma cells), CD68 (macrophages), CD55 (fibroblast-like synoviocytes [FLS]), and granzyme B. In situ detection of apoptosis was performed by TUNEL (transferase-mediated UTP end labeling) assay. Sections were analysed by computer-assisted image analysis. For statistical analysis, the Wilcoxon signed-rank test and the Mann–Whitney U test were used.
As early as 48 hours after initiation of infliximab treatment, there was a significant reduction in the number of intimal macrophages (-49 cells/mm2 ± 67 [median ± SEM]; P = 0.009), which was not observed in the placebo group (+10 ± 54). The number of T cells tended to be decreased in patients treated with infliximab (-52 ± 32) but not in the placebo group (+10 ± 25); this difference did not reach statistical significance. The numbers of B cells, plasma cells, and granzyme B+cells were unchanged 48 hours after treatment with either infliximab or placebo.
Of interest, the TUNEL assay did not reveal any increase in the number of apoptotic cells after infliximab treatment (-0.7 ± 13.6 in the infliximab group; +6.9 ± 10.8 in the placebo group; both not significant). Similarly, the extension study in 24 patients revealed that there was no increase in apoptosis in the synovium on day 28.
Infliximab therapy may reduce the number of inflammatory cells in rheumatoid synovial tissue as early as 48 hours after initiation of treatment, but apparently not by induction of apoptosis. Presumably, decreased cell infiltration primarily results from early inhibition of cell migration.