1,25-dihydroxy Vitamin D3 and Interleukin-6 Blockade Synergistically Regulate Rheumatoid Arthritis by Suppressing Interleukin-17 Production and Osteoclastogenesis

Background: Immune cells express the vitamin (vit) D receptor, and vit D is a potent immune-modulator. A negative correlation between serum vit D levels and rheumatoid arthritis (RA) disease activity has been reported. Therefore, we aimed to investigate if the sufficient serum vit D level is helpful to control disease activity in RA patients treated with interleukin (IL)-6 receptor antibody tocilizumab. Methods: RA patients taking tocilizumab were enrolled, and data were collected retrospectively. Disease activity scores (DAS) 28, serum vit D levels, modified Sharp scores of hand X-ray at the time of tocilizumab initiation, and follow-up data were analysed. Peripheral blood mononuclear cells were differentiated into T-helper (Th) 17 or osteoclasts in the presence of various concentrations of tocilizumab and/or 1,25(OH)(2)D. Th17 proportions were analysed by fluorescence-activated cell sorting. Supernatant cytokine levels were determined by enzyme-linked immunosorbent assay. Results: Among 98 RA patients taking tocilizumab, 34 (34.7%) had sufficient serum 25(OH) D levels (>= 30 ng/mL) when tocilizumab was initiated. At 24 weeks, vit D sufficient patients had greater DAS28 reduction (64.6% +/- 15.5% vs. 52.7% +/- 20.7%, P= 0.004), and lower disease activity (91.2% vs. 70.3%, P= 0.018) or remission (82.4% vs. 57.8%, P= 0.014). These differences in DAS28 reduction and the proportion of patients with remission persisted at 48 weeks. However, there was no significant difference in hand and wrist erosion progression. In vitro, tocilizumab and 1,25(OH)(2)D treatment synergistically suppressed IL-17 production and osteoclastogenesis. Conclusion: RA patients treated with IL-6 antibody show a better response when they have sufficient serum vit D. Tocilizumab and 1,25(OH)(2)D synergistically suppress IL-17 production and osteoclast differentiation in RA patients.