Background/Purpose: Peficitinib is a novel Janus kinase (JAK) inhibitor developed for the treatment of rheumatoid arthritis (RA). Peficitinib has approved in 2019 in Japan, but elucidation of its mechanism of action in RA involving the inflammatory process is still inadequate. So far, we clarified JAK1, JAK2 and JAK3 were expressed in RA synovial tissue and fibroblast-like synoviocytes (FLS), and peficitiib suppress the activation of JAK-STAT pathway on RA FLS. In this study, we examined the role of peficitinib in RA angiogenesis.

Methods: To examine the functional analysis of peficitinib, we performed a proliferation and chemotaxis assays with FLS using THP-1 (human acute monocyte leukemia cell line) and peripheral blood mononuclear cells (PBMC). RA FLS supernatant was obtained from RA FLS-conditioned medium stimulated with IL-6 (100 ng/ml) and IL-6R (100 ng/ml) with or without adding peficitinib (5 μM). RA FLS were stimulated with IL-6 and IL-6R after treated peficitinib for 24 h. Next, to evaluate the effects of peficitinib on RA angiogenesis, we performed in vitro Matrigel tube formation assays using human umbilical vein endothelial cells (HUVECs). Finally, we investigated whether peficitinib suppresses the secretion of FLS inflammatory mediator using ELISA kit. The amounts of VEGF, RANTES/CCL5, MCP-1/CCL2, MMP-3, fractalkine/CX3CL1, ENA78/CXCL5 and IL-8 in IL-6 and IL-6R stimulated peficitinib treated RA FLS conditioned medium were determined.

Results: We found peficitinib treated RA FLS conditioned medium reduced THP-1 migration compared to nontreated RA FLS conditioned medium (number of THP-1 cells migrated ± SEM; 42 ± 3 and 66 ± 6 cells migrated, respectively, p< 0.05). Peficitinib treated RA FLS conditioned medium also reduced PBMC migration compared to nontreated RA FLS conditioned medium (number of PBMC migrated ± SEM; 36 ± 5 and 63 ± 9 cells migrated, respectively, p< 0.05). In addition, peficitinib treated RA FLS showed a 14 ± 2 % decrease in proliferation of RA FLS compared with nontreated RA FLS. In addition, peficitinib treated RA FLS condition medium decreased HUVEC tube formation compared to nontreated RA FLS condition medium (number of endothelial cell tubes formed ± SEM; 9 ± 1 and 13 ± 1, respectively, p< 0.05). Finally, we found peficitinib suppress the secretion of inflammatory mediators in RA FLS. VEGF and MCP-1/CCL2 in RA FLS supernatant was suppressed in peficitinib compared to nontreated (mean ± SEM; VEGF: 77.1 ± 69.5 and 110.4 ± 81.0 pg/ml, MCP-1/CCL2 160.1 ± 65.6 and 846.0 ± 107.1 pg/ml, respectively, p< 0.05).

Conclusion: We demonstrated that peficitinib is involved in the suppression of FLS proliferation, and inhibits the chemotaxis of THP1 and PBMC through inhibition of MCP-1/CCL2. Furthermore, peficitinib suppressed RA angiogenesis through inhibition of VEGF.

« Back to ACR Convergence 2020

ACR Meeting Abstracts - https://acrabstracts.org/abstract/peficitinib-inhibits-angiogenesis-via-suppression-of-vegf-production-in-rheumatoid-arthritis-fibroblast-like-synoviocytes/