Is There a Role for TNF-α in Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis? Lessons from Other Chronic Inflammatory Diseases

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is the most common cause of rapidly progressive glomerulonephritis and immune-mediated pulmonary renal syndrome. Now that the acute manifestations of the disease generally can be controlled with immunosuppressive drugs, ANCA-associated vasculitis has become a chronic and relapsing inflammatory disorder. The need to develop safer and more effective treatment has led to great interest in the mediators of chronic inflammation. There are many lessons to be learned from studies of other chronic inflammatory diseases, particularly rheumatoid arthritis (RA). The identification of a TNF-alpha-dependent cytokine cascade in the in vitro cultures of synovium in joints of patients with RA led to studies of TNF blockade in experimental models of arthritis and subsequently to clinical trials. These have culminated in the widespread introduction of anti-TNF therapy not only in RA but also in Crohn disease, ankylosing spondylitis, and several other chronic inflammatory disorders. Following a similar investigative pathway, studies that show the importance of TNF production by leukocytes and intrinsic renal cells in glomerulonephritis have been followed by the demonstration of the effectiveness of TNF blockade in several experimental models of glomerulonephritis and vasculitis. In experimental autoimmune vasculitis, improvement in disease was paralleled by a reduction in leukocyte transmigration, as demonstrated by intravital microscopy. The benefit of infliximab (a mAb to TNF) in ANCA-associated vasculitis was recently reported in a prospective open-label study. However, the use of etanercept (a soluble TNF receptor fusion protein) was not found to be of significant benefit in a randomized, controlled trial in patients with Wegener granulomatosis. Therefore, there is a need for further evaluation of the use of anti-TNF antibodies in patients with ANCA-associated glomerulonephritis.