Active vitamin D acts in vitro as an adjuvant to anti-TNFα treatment in a psoriatic synovial fibroblast activation model by modulating human Th17 activity.

Psoriatic arthritis (PsA) is an IL-23/IL-17/TNF-driven inflammatory arthritis, commonly accompanied by vitamin D deficiency. Here, we investigate the interaction between PsA synovial fibroblasts (SFs) and human memory CCR6+Th17 (hmemCCR6+Th17) cells and evaluate the therapeutic effects of TNFα and/or IL-17A inhibitors, and the adjunctive therapy potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). SF derived from PsA biopsies were co-cultured with hmemCCR6+Th17 cells to construct a PsA SF activation model. SF phenotypes were analysed by flow cytometry. Treatments included adalimumab (anti-TNFα), secukinumab (anti-IL-17A), and/or 1,25(OH)2D3, applied alone or in combination. A transwell system was used to assess treatment effects on SF and hmemCCR6+Th17 cells. Cytokines and matrix metalloproteinases (MMPs) were quantified by ELISA. PsA SF were composed of heterogeneous subpopulations and constructed a pro-inflammatory feedback loop with hmemCCR6+Th17 cells. Anti-TNFα and/or anti-IL-17A significantly suppressed proinflammatory cytokines and tissue-destructive mediators in the PsA SF activation model, but showed limited effect on IL-22 and IFNγ. Adding 1,25(OH)2D3 to anti-TNFα treatment effectively overcame the limitations of single anti-TNFα in suppressing Th17 cytokines, while significantly enhancing the inhibition of IL-6, IL-8 and MMPs. In addition, 1,25(OH)2D3 promoted the production of IL-10. TNFα or IL-17A inhibition alone does not completely inhibit the proinflammatory loop between hmemCCR6+Th17 cells and PsA SF, although the combination shows additive effect on suppressing proinflammatory and tissue-destructive mediators. Importantly, 1,25(OH)2D3 plays a complementary role in the treatment of this proinflammatory loop alongside anti-TNFα therapy and significantly induces IL-10. Clinical PsA studies are needed to explore the additional therapeutic potential of this combination.