title: Rituximab abrogates joint destruction in rheumatoid arthritis by inhibiting osteoclastogenesis.
abstract: OBJECTIVE
  To examine how rituximab may result in the inhibition of joint destruction in rheumatoid arthritis (RA) patients.
  
  
  METHODS
  Twenty-eight patients with active RA were treated with rituximab. Radiographs of hands and feet before and 1 year after therapy were assessed using the Sharp-van der Heijde score (SHS). Expression of bone destruction markers was evaluated by immunohistochemistry and immunofluorescence of synovial biopsies obtained before and 16 weeks after the initiation of treatment. Serum levels of osteoprotegerin, receptor activator of nuclear factor κB ligand (RANKL), osteocalcin and cross-linked N-telopeptides of type I collagen (NTx) were measured by ELISA before and 16 weeks post-treatment.
  
  
  RESULTS
  After 1 year, the mean (SD) change in total SHS was 1.4 (10.0). Sixteen weeks after treatment there was a decrease of 99% in receptor activator of nuclear factor κB-positive osteoclast precursors (p=0.02) and a decrease of 37% (p=0.016) in RANKL expression in the synovium and a trend towards reduced synovial osteoprotegerin expression (25%, p=0.07). In serum, both osteoprotegerin (20%, p=0.001) and RANKL (40%, p<0.0001) levels were significantly reduced 16 weeks after treatment, but the osteoprotegerin/RANKL ratio increased (157%, p=0.006). A trend was found towards an increase of osteocalcin levels (p=0.053), while NTx concentrations did not change.
  
  
  CONCLUSIONS
  Rituximab treatment is associated with a decrease in synovial osteoclast precursors and RANKL expression and an increase in the osteoprotegerin/RANKL ratio in serum. These observations may partly explain the protective effect of rituximab on the progression of joint destruction in RA.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, The Netherlands.
authors.forename: Maria J H
authors.initials: MJ
authors.lastname: Boumans
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Thurlings
authors.forename: Lorraine
authors.initials: L
authors.lastname: Yeo
authors.forename: Dagmar
authors.initials: D
authors.lastname: Scheel-Toellner
authors.forename: Koen
authors.initials: K
authors.lastname: Vos
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Gerlag
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology* / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000188:drug therapy; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D033023:Foot Joints / Q000000981:diagnostic imaging; D050823:Hand Joints / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D011859:Radiography; D000069283:Rituximab; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D015415:Biomarkers; D053244:Osteoprotegerin; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D015675:Osteocalcin; D000069283:Rituximab