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Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis
P Barrera1, A Blom, P L van Lent
1University Hospital Nijmegen, The Netherlands.
Objective:
To assess whether intraarticular (IA) administration of clodronate liposomes results in local macrophage depletion in patients with rheumatoid arthritis (RA). Primary goals were to address both the immunohistologic and potential toxic effects of this approach. Moreover, the correlation between immunohistologic findings and clinical assessments of disease activity and cartilage damage were assessed.
Methods:
An open study was conducted in consecutive RA patients who were scheduled for knee joint replacement in our department. Synovial biopsy tissue was obtained from the knee joint at 2 weeks before and at the time of surgery. This protocol was controlled for safety and immunohistologic concordance in 6 patients. One week before surgery, 10 patients received a single IA dose of clodronate liposomes. Staining of synovial tissue for cell markers (CD68, CD14, CD3, CD38) and adhesion molecules (vascular cell adhesion molecule 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 standard 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 fibroblast-like synoviocytes, T cells, or plasma cells. No immunohistologic changes were observed in the control group. The procedure was well tolerated. The levels of ICAM-1 and VCAM-1 in the sublining layers correlated with the extent of macroscopic synovitis (P < 0.0005 and P < 0.005, respectively). The expression of ICAM-1 and CD14 in the sublining correlated with the levels of C-reactive protein (P < 0.0005 and P < 0.01, respectively). Cartilage destruction was correlated only with the expression of CD68 in the sublining (P = 0.02).
Conclusion:
A single IA administration of clodronate liposomes leads to macrophage depletion and decreased expression of adhesion molecules in the synovial lining in patients with longstanding RA. The procedure is well tolerated, and its therapeutic potential is currently under investigation. The expression of adhesion molecules in the sublining layers reflects ongoing inflammation.
Insights
Intraarticular clodronate liposomes deplete macrophages and reduce adhesion molecules in rheumatoid arthritis (RA) patients. This well-tolerated treatment shows potential for managing RA inflammation and cartilage damage.
Area of Science:
- Immunology
- Rheumatology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) is characterized by chronic inflammation driven by macrophages in the synovium.
- Targeting synovial macrophages is a potential therapeutic strategy for RA.
- Clodronate liposomes are known to deplete macrophages.
Purpose of the Study:
- To evaluate the efficacy of intraarticular (IA) clodronate liposomes in depleting macrophages in RA patients.
- To assess the safety and immunohistologic effects of IA clodronate liposomes.
- To correlate immunohistologic findings with clinical disease activity and cartilage damage.
Main Methods:
- Open study in RA patients undergoing knee replacement.
- Synovial biopsy before and at surgery.
- IA clodronate liposomes administered 1 week before surgery in 10 patients.
- Immunohistochemical staining for cell markers (CD68, CD14, CD3, CD38) and adhesion molecules (VCAM-1, ICAM-1).
- Clinical disease activity and cartilage damage assessed.
Main Results:
- IA clodronate liposomes significantly reduced CD68-positive cells and ICAM-1/VCAM-1 expression in the synovial lining.
- No significant effects on fibroblast-like synoviocytes, T cells, or plasma cells.
- Procedure was well tolerated with no observed toxic effects.
- Adhesion molecule expression correlated with synovitis and C-reactive protein levels.
- Cartilage destruction correlated with CD68 expression.
Conclusions:
- IA clodronate liposomes effectively deplete macrophages and decrease adhesion molecules in the synovium of RA patients.
- The treatment is well-tolerated and shows therapeutic potential for RA.
- Synovial adhesion molecule expression reflects ongoing inflammation and disease severity.