TNF inhibitors induce discoid fibrosis in the sublining layers of the synovium with degeneration of synoviocytes in rheumatoid arthritis

We determined the characteristic features of synovial tissues of rheumatoid arthritis (RA) patients treated by TNF inhibitors in order to delineate their mechanism of action. Synovial tissues were obtained during the joint surgical operations from 12 RA patients who had been treated with TNF inhibitors in addition to disease modifying antirheumatic drugs (DMARDs) for at least 5 months (5–25 months) (RA-TNFinh), and from 12 RA patients who had been treated with DMARDs alone (RA-DMARD), and were evaluated under light microscopy. There were no significant differences in disease duration, serum CRP levels, DAS28, Steinbrocker’s stages on X-ray and treatment regimen except for TNF inhibitors between RA-TNFinh and RA-DMARD. The most prominent changes in the synovium from RA-TNFinh were discoid fibrosis in the subliming layers of the synovium with degeneration and detachment of synoviocytes and marked decrease in vasculatures. There was no significant difference in these synovial features between RA patients with infliximab and those with etanercept. Interestingly, appearance of osteoclasts was observed in RA-TNFinh (3 out of 12 patients) and in RA-DMARD (1 out of 12 patients). These results indicate that not only infliximab, but etanercept might have direct actions on synovial cells in the deep lining layers of the synovium, leading to the discoid fibrosis thereof. Moreover, the data confirm that the deep lining or sublining layers of the synovium are the most important portions that steer the disease process of RA synovitis.