Tumour necrosis factor alpha (TNFaα) is a cytokine that is pivotal in the inflammatory response. Blockade of TNFaα has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question of whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNFaα in the pathophysiology of disease, including increased expression of TNFaα mRNA in leucocytes and in renal tissue. Importantly, TNFaα can induce leucocyte cell membrane expression of the autoantigens involved in vasculitis [proteinase 3 and myeloperoxidase (MPO)], thus priming cells for the effects of ANCA. In rodent models of anti-GBM disease (nephrotoxic nephritis), TNFaα enhances glomerular injury and TNFaα blockade using soluble TNFaα receptor or anti-TNFaα antibody ameliorates disease. Mice deficient in TNFaα are protected from nephrotoxic nephritis and this effect is dependent mainly on intrinsic renal cells. A mouse model of anti-MPO antibody-induced glomerulonephritis is enhanced by LPS, and this effect is blocked by anti-TNFaα antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis), anti-TNFaα antibody improves renal pathology and also reduces leucocyte transmigration, as shown by intravital microscopy. In clinical studies, the Wegener's Granulomatosis Etanercept Trial (WGET) showed no benefit of additional etanercept versus standard therapy. However, there are several reasons why the results of the WGET study do not rule out the use of anti-TNFaα antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNFaα antibody. There are several clinical studies demonstrating a response to anti-TNFaα antibody in patients with AAV refractory to conventional treatment, and in some of these, the addition of anti-TNFaα antibody was the only change in treatment. We suggest that further investigation of TNFaα blockade in AAV is warranted.
CITATION STYLE
McAdoo, S. P., & Pusey, C. D. (2017). Is there a role for TNFaα blockade in ANCA-associated vasculitis and glomerulonephritis? Nephrology Dialysis Transplantation. Oxford University Press. https://doi.org/10.1093/ndt/gfw361
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