Current state of biologicals in the management of systemic vasculitis.

Conventional immunosuppressive treatment of systemic vasculitides has improved their often fatal outcome, but is burdened by cytotoxic side effects and frequent relapses. Recent advances in the therapy of systemic vasculitides with biologicals have helped to establish new options for patients resistant to conventional treatment. Moreover, early intervention aiming to interfere with specific targets important in the break of tolerance and/or persistence of the autoimmune response might further improve the prognosis of autoimmune vasculitides such as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). In vitro and in vivo studies suggest that the interaction of ANCA and cytokine (TNF-alpha, IL-1)-primed neutrophils results in premature neutrophil activation and degranulation, subsequent endothelial cell damage, and further leukocyte recruitment. For one of the AAV, Wegener's granulomatosis, recent ex vivo data have provided evidence that WG-granulomata might provide the necessary "proinflammatory environment" for the break of tolerance and display features of lymphoid-like tissue neoformation, in which autoimmunity to "Wegener's autoantigen" proteinase 3 PR3 could be sustained. Blocking TNF-alpha and eliminating autoreactive B cells seem promising treatment targets to interfere with these fundamental disease processes. While the recombinant TNF-alpha receptor/IgG1 fusion protein etanercept, in addition to standard therapy with subsequent tapering of standard medications, was found to be not effective for maintenance of remission, open clinical studies suggest a beneficial effect of the anti-TNF-alpha antibody infliximab in addition to standard therapy for the induction of remission in patients with refractory AAV. Peripheral B cell depletion with the anti-CD20 antibody rituximab also induced remissions in AAV in uncontrolled trials.