Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis

Objective. To assess whether intraarticular (IA) administration of clodrona te liposomes results in local macrophage depletion in patients with rheumat oid arthritis (RA). Primary goals were to address both the immunohistologic and potential toxic effects of this approach. Moreover, the correlation be tween immunohistologic findings and clinical assessments of disease activit y and cartilage damage were assessed. Methods. An open study was conducted in consecutive RA patients who were sc heduled for knee joint replacement in our department. Synovial biopsy tissu e was obtained from the knee joint at 2 weeks before and at the time of sur gery. This protocol was controlled for safety and immunohistologic concorda nce in 6 patients. One week before surgery, 10 patients received a single I A dose of clodronate liposomes, Staining of synovial tissue for cell marker s (CD68, CD14, CD3, CD38) and adhesion molecules (vascular cell adhesion mo lecule 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1]) was assessed by 2 blinded observers. Local and systemic parameters of disease activity were measured before each intervention. Cartilage damage was scored using s tandard radiologic techniques at baseline and during surgery. Results. A single IA dose of clodronate liposomes significantly reduced the number of CD68-positive cells (P = 0.005) and the expression of ICAM-1 and VCAM-1 in the synovial lining (P = 0.013 and P = 0.039, respectively), The intervention did not affect fibroblastlike synoviocytes, T cells, or plasm a cells. No immunohistologic changes were observed in the control group. Th e procedure was well tolerated. The levels of ICAM-1 and VCAM-1 in the subl ining layers correlated with the extent of macroscopic synovitis (P < 0.000 5 and P < 0.005, respectively). The expression of ICAM-1 and CD14 in the su blining correlated with the levels of C-reactive protein (P < 0.0005 and P < 0.01, respectively). Cartilage destruction was correlated only with the e xpression of CD68 in the sublining (P = 0.02). Conclusion. A single IA administration of clodronate liposomes leads to mac rophage depletion and decreased expression of adhesion molecules in the syn ovial lining in patients with longstanding RA. The procedure is well tolera ted, and its therapeutic potential is currently under investigation. The ex pression of adhesion molecules in the sublining layers reflects ongoing inf lammation.