1,25(OH)2D3 REINFORCES IL-10 INDUCTION UNDER DUAL INHIBITION OF TNFα AND IL-17A IN CCR6+ MEMORY Th17 CELLS MEDIATED SYNOVIAL INFLAMMATION

Background: Pro-inflammatory cytokines are therapeutic targets in the treatment of inflammatory arthritis. Blockade of TNFα has been registered for many immune-mediated inflammatory diseases, including the treatment of rheumatoid arthritis (RA). Also, specific antibodies against IL-17A are approved for the treatment of patients with psoriatic arthritis (PsA). However, these monotherapies do not reach sufficient response in all patients. Active vitamin D (1,25(OH) 2 D 3 ) has potent anti-inflammation property for many immune cells, including Th17 cells. Objectives: We aim to assess the effects of dual application of anti-TNFα and IL-17A in a T cell-derived synovitis model and evaluate whether 1,25(OH) 2 D 3 could provide additive value. Methods: CCR6 CD25 memory Th17 cells were sorted from peripheral mononuclear cells (PBMCs) of healthy donors and co-cultured with synovial fibroblasts (SF) derived from rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients for 3 days, with or without adalimumab (anti-TNFα antibody), secukinumab (anti-IL-17A antibody), or 1,25(OH) 2 D 3 . Treatment effects were evaluated by measuring cytokine levels in the supernatant. Results: Compared to single treatments, dual blockade of TNFα and IL-17A did not provide additional value compared to individual treatment in suppressing IL-17A, IL-22, and TNFα in contrast to IL-8. However, when combined with 1,25(OH) 2 D 3 , a comprehensive regulatory effect on controlling the interplay between CCR6 memory Th17 cells and SF was noted. This triple treatment demonstrated better suppression of T cell-derived cytokines (IL-17A and IFN-γ). Also, IL-22 was downregulated, which could not be achieved by inhibition of the cytokines alone. Furthermore, triple therapy showed stronger inhibition of fibroblasts producing cytokines, such as IL-6 and IL-8. Interestingly, the application of 1,25(OH) 2 D 3 together with TNFα and IL-17A blockade strongly and significantly induced the production of the anti-inflammatory cytokine IL-10, which was higher compared to treatment with anti-TNFα and/or anti-IL-17A, or 1,25(OH) 2 D 3 alone. Conclusion: The combination of 1,25(OH) 2 D 3 with dual blockade of TNFα and IL-17A showed not only suppression of the targeted proinflammatory cytokine(s) but also the induction of IL-10. This suggests a more comprehensive regulatory effect on T cell-derived synovitis which may be a promising therapeutic strategy to improve therapy in patients with inflammatory arthritis. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared. DOI: 10.1136/annrheumdis-2024-eular.5429 Keywords: Fibroblasts, Cytokines and Chemokines, Adaptive immunity, Vitamin D, Biological DMARD Citation: , volume 83, supplement 1, year 2024, page 591Session: Inflammatory arthritis (Poster View)

Fibroblasts, Cytokines and Chemokines, Adaptive immunity, Vitamin D, Biological DMARD