Background Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by hyperplasia of synovial tissues, leading to the destruction of joint structures. TNF inhibitors, including anti-TNF-α antibodies and soluble TNF receptors, have been shown to result in characteristic discoid fibrosis in the deep lining layer of the synovium, probably by their action on synovial cells thereof. Tocilizumab, anti-IL6 receptor antibody, also has comparable beneficial effects in the treatment of RA. However, detailed mechanism actions of tocilizumab have not been fully understood.
Objectives The current studies were therefore designed to determine the characteristic features of synovial tissues of RA patients treated by tocilizumab.
Methods Synovial tissues were obtained during the joint surgical operations from 13 RA patients who had been treated with tocilizumab for at least 4 months (4-47months), 7 of whom had been previously received TNF inhibitors. As a control, synovial tissues were similarly obtained from 13 RA patients who had been received TNF inhibitors and from 10 RA patients who had not been given any biological agents. Synovial tissues were fixed in formaldehyde and embedded in paraffin. The sections were evaluated by hematoxylin and eosin stain and Masson trichrome stain as well as by immunohistological staining with anti-CD31 in which the microvessel densities were quantitated under microscopy.
Results The most prominent changes in the synovium from RA patients with TNF inhibitors are degeneration of synovial cells and discoid fibrosis in the deep lining layer. By contrast, perivascular fibrosis with decreased vasculatures in the deep sublining layer and marked degeneration of the lining layer appeared to be typical changes in the synovium from RA patients treated with tocilizumab irrespective of the previous use of TNF inhibitors. Notably, microvessel densities in patients treated with tocilizumab with or without previous TNF inhibitors were significantly decreased compared with those in patients with TNF inhibitors alone or in patients with non-biological DMARDS (figure).
Conclusions These results suggest that inhibition of vascularization is a primary action of tocilizumab, leading to the marked degeneration of synovial cells in the lining layers.
Acknowledgements The authors thank Dr. Masahisa Kyogoku for helphul advice.
Disclosure of Interest None declared