THU0047 1, 25(OH)2d3 and dexamethasone additively suppress synovial fibroblast activation by ccr6+ th memory cells and enhance the effect of tnf-alpha blockade. (12th June 2018)

• Record Type: Journal Article
• Authors: Dankers, W.; Dankers, W.; Davelaar, N.; Asmawidjaja, P.S.; Mus, A.M.; Hazes, J.M.; Colin, E.M.; Lubberts, E.
• Is Part Of: Annals of the rheumatic diseases. Volume 77(2018)Supplement 2
• Page Start: 249
• Page End: 249
• Publication Date: 2018-06-12
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-eular.6973
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Despite improvement in treatment of rheumatoid arthritis (RA) over the past decades, insufficient treatment response and treatment resistance in many patients demonstrate the need to develop new therapeutic strategies. Chronic synovial inflammation could be suppressed by targeting activation of RA synovial fibroblasts (RASF) by for example IL-17A-producing CCR6 +T helper memory (memTh) cells. Previously, we have shown that dexamethasone (DEX) combined with the active vitamin D metabolite 1, 25(OH)2 D3 reduces pathogenicity of memTh cells. Objectives: To study the additive effect of 1, 25(OH)2 D3 and DEX on suppressing the pro-inflammatory loop between RASF and CCR6 +memTh cells and explore potential therapeutic applications. Methods: CCR6 +memTh cells from PBMC of healthy donors or treatment-naïve early RA patients were cultured alone or with RASF from established RA patients for three days and treated with or without 1, 25(OH)2 D3, DEX or etanercept. Treatment effects were assessed using ELISA and flow cytometry. Results: CCR6 +memTh produces less of the pro-inflammatory cytokines IL-17A, IL-22 and IFNγ upon exposure to 1, 25(OH)2 D3, and to a lesser extent by DEX. TNFα was only inhibited by the combination of 1, 25(OH)2 D3 and DEX. In contrast, in RASF cultures DEX was the strongest inhibitor of IL-6, IL-8 and tissue-destructive enzymes. As a result, 1, 25(OH)2 D3 and DEX additively inhibited inflammatory mediators in CCR6 +memTh RASF co-cultures. Interestingly, low doses of mainly DEX, but also 1, 25(OH)2 D3, combined with etanercept better suppressed synovial inflammation in this co-culture model compared to etanercept alone. Conclusions: This study suggests that 1, 25(OH)2 D3 and DEX additively inhibit synovial inflammation through targeting different pro-inflammatory mechanisms. Furthermore, low doses of DEX and 1, 25(OH)2 D3 enhance the effect of TNFα blockade in inhibiting RASF activation, providing a basis to improve RA treatment. Disclosure of Interest: None declared