Rituximab abrogates joint destruction in rheumatoid arthritis by inhibiting osteoclastogenesis

• Published in: Annals of the rheumatic diseases Vol. 71; no. 1; pp. 108 - 113
• Main Authors: Boumans, Maria J H, Thurlings, Rogier M, Yeo, Lorraine, Scheel-Toellner, Dagmar, Vos, Koen, Gerlag, Danielle M, Tak, Paul P
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.01.2012; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Adult; Aged; Antibodies, Monoclonal, Murine-Derived - pharmacology; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - blood; Arthritis, Rheumatoid - diagnostic imaging; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - pathology; Biological and medical sciences; Biomarkers - blood; Biopsy; Bone loss; Bone Resorption - drug therapy; Cloning; Collagen (type I); Cytokines; Disease Progression; Diseases of the osteoarticular system; Enzyme-linked immunosorbent assay; Female; Follow-Up Studies; Foot Joints - diagnostic imaging; Hand; Hand Joints - diagnostic imaging; Humans; Immunofluorescence; Immunoglobulins; Immunohistochemistry; Immunomodulators; Inflammation; Inflammatory joint diseases; Joint diseases; Male; Medical sciences; Middle Aged; Osteocalcin; Osteocalcin - blood; Osteoclastogenesis; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - physiology; Osteogenesis - drug effects; Osteoprogenitor cells; Osteoprotegerin; Osteoprotegerin - metabolism; osteoprotegerin receptors; Pharmacology. Drug treatments; Proteins; Radiography; RANK Ligand - metabolism; Rheumatoid arthritis; Rituximab; Serum levels; Studies; Synovial Membrane - drug effects; Synovial Membrane - metabolism; Synovial Membrane - pathology; Synovium; TRANCE protein; Tumor necrosis factor-TNF; Urine; Young Adult; Antineoplastic agent; Immunomodulator; Immunopathology; Chronic; Rheumatoid arthritis; Diseases of the osteoarticular system; Rheumatology; Rituximab; Autoimmune disease; Inflammatory joint disease; Immunosuppressive agent; Joint
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2011-200198

Objectives 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.