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

Abstract

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.

Interest of the Immunohistological Analysis of Architecture and Cells Distribution of the Synovial Membrane in Rheumatoid Arthritis

“…The explanation for those differences between our cohort and other studies could be the occurrence of biological drugs in the treatment of RA in the 2000s, which could have resulted in modifications of synovial inflammatory infiltrate in more recent tissue specimen from treated patients as the ones in this study. In support of this hypothesis, Hirohata et al have demonstrated that TNF inhibitors alter the histological characteristics of the synovium from RA patients [21]. Another result of our study is the absence of difference in synovial architecture between RA and OA patients.…”

“…This study reinforces our knowledge upon the specificity of synovial architecture and cell distribution of inflammatory infiltrate in synovium of patients with RA. Therefore in RA, a systematic histological analysis of synovial biopsy could be interesting for early diagnosis, to establish a prognosis and for treated patient's follow-up [21,37,38]. Indeed, even if a synovial biopsy guided by echography or arthroscopy is an invasive act, it can provide synovial tissue specimen of good quality from the most representative lesions of the joint [39,40].…”

“…Finally, granuloma formation can rarely be found in the RA synovium. Several groups have studied the effect of the different types of anti-rheumatic treatment on synovium tissue architecture and showed that there are various cellular responses depending on the type of drugs, suggesting that the synovitis microarchitecture contributes to the clinical phenotype of RA and to the therapeutic effects of immunomodulatory drugs [20][21][22][23][24][25][26].…”

Phosphorylated Platelet-Derived Growth Factor Receptor-Positive Cells With Anti-apoptotic Properties Accumulate in the Synovium of Patients With Rheumatoid Arthritis

“…In fact, TNF inhibitors have been shown to have high efficacy against RA in humans by suppressing TNF-α and inducing cell death in FLSs (45). SL fibrosis has been reported to occur when TNF inhibitors are used in RA therapy (12). Although TNF inhibitor therapy can be expected to prevent cell accumulation, it might only marginally affect pre-existing cell accumulation (46).…”

“…At present, one of the most effective drugs are tumor necrosis factor (TNF) inhibitors, the therapeutic mechanism of which is reported to be suppressing inflammation by reducing FLS influx into the LL (9). Nonetheless, TNF inhibitor therapy has little effect on FLSs in the SL (9) and has even been reported to cause fibrosis of the SL (12). Therefore, improving SL-FLS accumulation is thought to be difficult with existing therapies (13).…”