gms | German Medical Science

Background: The Janus kinase inhibitors (JAKi) tofacitinib and baricitinib have extended the opportunities for the therapy of rheumatoid arthritis (RA). Meanwhile, other JAKi have been developed completed successfully phase II trials. Peficitinib, a pan-JAKi and filgotinib, a JAK-1 inhibitor are currently examined in phase III trials. Fibroblast-like synoviocytes (FLS) play a major role in pathogenesis of RA and are able to migrate and invade healthy cartilage [1]. JAK inhibition with tofacitinib decreased the pro-inflammatory response of RA-FLS activated by TNF-α [2], but less is known about the effect of the newer JAKi on unstimulated RA-FLS as well as on IL-1β-activated RA-FLS. Therefore, we examined the effect of different JAKi on the inflammatory response and on the proliferation rate of activated RA-FLS.

Methods: RA-FLS were isolated from synovial tissue of RA patients. The cells were pretreated with different concentrations of JAKi or vehicle control and additionally stimulated with IL-1β. The supernatants were collected and the concentrations of IL-6 and MMP-3 measured by ELISA. Cell proliferation under JAKi was assessed by BrdU incorporation assays. The ApoTox-Glo™ Triplex Assay was performed to exclude effects of JAKi caused by cell toxicity.

Results: RA-FLS were pretreated with JAKi for 2 h and then additionally stimulated with IL-1β (10 ng/ml) for 17 h. Peficitinib at 5 µM decreased IL-6 levels by 66% (p<0.01, n=5) compared to control with IL-1β. Filgotinib did not affect IL-6 levels but reduced MMP-3 release by 43% at 5 µM (p<0.05), n=3). Peficitinib led to a reduction of MMP-3 levels of 46% at 1 µM (n=5, p<0.001) and of 92% at 5 µM (n=5, p<0.0001). Peficitinib reduced the RA-FLS proliferation at 1 µM by 23% (p<0.05, n=4) and at 5 µM by 70% (p<0.001), but did not influence viability, cytotoxicity or apoptosis of RA-FLS (n=3).

Conclusion: Peficitinib decreases both the pro-inflammatory and matrix destructive properties of RA-FLS in vitro. Furthermore, the proliferation rate of RA-FLS and subsequently the capability to form a pannus appears also reduced by peficitinib. Therefore, the new JAKi peficitinib seems to be able to downregulate the destructive activity of RA-FLS.