Leukocyte migration to the synovial compartment plays an important role in rheumatoid arthritis (RA). The presence of macrophages in the synovium is associated with disease activity (Arthritis Rheum 1997; 40:217–225). Important mediators of leukocyte migration include chemokines and their receptors. This study evaluated the effects of blocking the migration of monocytes/ macrophages and T cells into the joint using a chemokine receptor antagonist.
16 patients were included in a 2-week, double-blind, placebo-controlled randomised phase-Ib-study evaluating the effects of an oral CCR1 antagonist. Synovial tissue was obtained by arthroscopy on day 1 and day 15. Immunohistochemistry was performed to detect CD68, CD3, CD4, CD8, CD55, CD22, and CD138. Sections were analysed using digital image analysis. The results before and after treatment were compared by paired, non-parametric analysis (Wilcoxon signed rank test). A two-sample t-test was used to compare the changes from baseline in the two groups (12 patients in the treatment group versus 4 patients in the placebo group).
After CCR1 blockade, there was a statistically significant decrease in: overall cellularity (reduction of 2065 ± 256 (median ± s.e.m.) to 891 ± 164, P < 0.02), intimal lining layer hyperplasia (269 ± 95 to 181 ± 49, P < 0.02), CD68+ macrophages (2386 ± 261 to 1445 ± 283, P < 0.02), intimal CD68+ macrophages (1201 ± 130 to 496 ± 133, P < 0.03) and CD4+ T cells (432 ± 160 to 215 ± 139, P < 0.02). There also was a decrease in CD8+ T cells (131 ± 44 to 35 ± 31), but the difference was not statistically significant. As expected there was no decrease in the number of CD22+ Bcells, CD138 plasma cells, or CD55+ fibroblast-like-synoviocytes, since these cells do not express CCR1. There was on average no change in the features of synovial biopsy samples from patients who received placebo.
It is feasible to influence the migration of inflammatory cells to the joints by using an oral CCR1 antagonist. This could provide a completely new treatment for RA patients.