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Rheumatoid arthritis

Control of TH17 cell activity in RA by a combination of vitamin D receptor signaling and TNF-blockade

Regulating T helper type 17 (TH17) cell-mediated inflammation is a key therapeutic goal in inflammatory autoimmune diseases such as rheumatoid arthritis (RA). According to research from the Netherlands published in Annals of the Rheumatic Diseases, treatment with 1,25(OH)2D3−an active vitamin D metabolite−plus an anti-TNF agent inhibits TH17 cell activity and blocks synovial inflammation in RA”, whereas this is not achieved by TNF-blockade alone.

“...1,25(OH)2D3 plus an anti-TNF agent inhibits TH17 cell activity and blocks synovial inflammation in RA...”

Previous work has shown that 1,25(OH)2D3 inhibits IL-17A production by T cells. “Based on these findings we hypothesized that vitamin D receptor pathway activation by 1,25(OH)2D3 may directly regulate the pathogenic activity of TH17 cells from patients with RA”, explains Erik Lubberts, the lead researcher on this study.

To test this hypothesis the authors investigated the effects of 1,25(OH)2D3 or TNF-blockade, or both, on cytokine expression in co-cultures of TH17 cells and RA synovial fibroblasts from patients with early RA, and in RA synovial biopsy cultures from patients with established disease undergoing knee joint replacement surgery. Levels of the proinflammatory cytokines IL-17A, IL-22, IL-6 and IL-8, and of the matrix metalloproteinases MMP-1 and MMP-3, were reduced in cultures after stimulation with 1,25(OH)2D3 in comparison with control cultures or those to which just an anti-TNF agent was added. “We found that 1,25(OH)2D3, in contrast to TNF-blockade, directly regulates TH17 cytokine expression in cultures”, says Lubberts. A combination of 1,25(OH)2D3 and TNF-blockade had additive effects on reducing the levels of these mediators of inflammation and joint destruction in comparison with anti-TNF agents alone. As Lubberts states, “1,25(OH)2D3 in combination with TNF-blockade is essential to fully neutralize pathological TH17 cell activity in RA synovial inflammation”.

“This study shows the therapeutic potential of 1,25(OH)2D3 and TNF-blockade combination as a treatment to control synovial inflammation in RA, in particular in the presence of IL-17/TH17 cell activity,” concludes Lubberts. “Future research will focus on the identification of 1,25(OH)2D3 targets in T cells.”

Original research paper

  1. 1

    van Hamburg J. P. et al. TNF blockade requires 1,25(OH)2D3 to control human TH17-mediated synovial inflammation. Ann. Rheum. Dis. doi: 10.1136/annrheumdis-2011-200424

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Buckland, J. Control of TH17 cell activity in RA by a combination of vitamin D receptor signaling and TNF-blockade. Nat Rev Rheumatol 8, 124 (2012). https://doi.org/10.1038/nrrheum.2012.3

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