Wegeners granulomatosis and other diseases associated with antineutrophil cytoplasmic antibodies

Wegener's granulomatosis is a disease in which a granulomatous vasculitis results in inflammatory lesions of the upper and lower airways, particularly the paranasal sinuses and the lung. Other organs which may be involved include the kidney, with disease ranging from mild focal glomerulonephritis to a diffuse necrotizing glomerulonephritis, the joints with frank arthritis, small vessel vasculitis of the skin, and ocular disease ranging from conjunctivitis to scleromalacia perforans.

The severity of the disease can range from very mild and limited to severe multiorgan disease, which, prior to cytotoxic therapy, was uniformly fatal. While the biopsy demonstrating a granulomatous vasculitis remains a gold standard in the diagnosis of Wegener's granulomatosis, the ability to make the diagnosis has been facilitated with the recent identification of an antibody to cytoplasmic antigens detected in ethanol-fixed neutrophils.

These antibodies identified by indirect immuno-florescence are seen in two primary patterns. One is a coarse granular cytoplasmic pattern (c-ANCA) and the second a perinuclear pattern (p-ANCA). Further research has identified proteinase 3 as the antigen causing the c-ANCA. The p-ANCA is a result of an antibody to myeloperoxidase. Depending on the extent and severity of the disease, c-ANCA is seen with 60-90% sensitivity and greater than 90% specificity in Wegener's granulomatosis. c-ANCA is seen in much lower frequency in other vasculitis, as well as infectious diseases.

p-ANCA is less specifically associated with the disease and is seen in Churg-Strauss vasculitis, as well as other vasculitides and autoimmune diseases.

With the sensitivity/specificity of c-ANCA/ antiproteinase 3 antibody in Wegener's granulomatosis, aggressive investigation as to its etiopathologic role has been undertaken. However, its definitive role remains to be elucidated. It is hypothesized that the antiproteinase 3 antibodies interact with surface proteinase 3 on granulocytes and endothelial cells, subsequently triggering the inflammatory cascade that results in the granulomatous vasculitis and inflammation. However, contrary to what one would conclude, neither the level of c-ANCA nor the change in c-ANCA levels predict severity of disease or changes in disease activity. Further studies are necessary to more completely define the role of the antineutrophil cytoplasmic antibodies in their associated disease states.

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