title: Synovial macrophage depletion with clodronate-containing liposomes in rheumatoid arthritis.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University Hospital Nijmegen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Barrera
authors.forename: A
authors.initials: A
authors.lastname: Blom
authors.forename: P L
authors.initials: PL
authors.lastname: van Lent
authors.forename: L
authors.initials: L
authors.lastname: van Bloois
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: N
authors.initials: N
authors.lastname: van Rooijen
authors.forename: M C
authors.initials: MC
authors.lastname: de Waal Malefijt
authors.forename: L B
authors.initials: LB
authors.lastname: van de Putte
authors.forename: G
authors.initials: G
authors.lastname: Storm
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D001706:Biopsy; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000473:pathology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008081:Liposomes; D004002:Clodronic Acid