Is there a role for TNFα blockade in ANCA-associated vasculitis and glomerulonephritis?

Tumour necrosis factor alpha (TNF alpha) is a cytokine that is pivotal in the inflammatory response. Blockade of TNF alpha 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 TNF alpha in the pathophysiology of disease, including increased expression of TNF alpha mRNA in leucocytes and in renal tissue. Importantly, TNF alpha 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), TNF alpha enhances glomerular injury and TNF alpha blockade using soluble TNF alpha receptor or anti-TNF alpha antibody ameliorates disease. Mice deficient in TNF alpha 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-TNF alpha antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis), anti-TNF alpha 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-TNF alpha antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNF alpha antibody. There are several clinical studies demonstrating a response to anti-TNF alpha antibody in patients with AAV refractory to conventional treatment, and in some of these, the addition of anti-TNF alpha antibody was the only change in treatment. We suggest that further investigation of TNF alpha blockade in AAV is warranted.