Wegener’s granulomatosis: Is biologic therapy useful?

Abstract

Wegener's granulomatosis (WG) is a complex autoimmune disorder that has been transformed from a uniformly lethal process to a chronic disease with a relapsing-remitting course. In the setting of frequent relapses, the need to manage cumulative disease damage and drug toxicities has spurred the identification and development of new potent and directed therapies. Biologic agents, which offer the potential for remission-induction and drug-sparing approaches to treat WG, have been studied in several small, open-label clinical series and one large, randomized, placebo-controlled clinical trial. This article discusses the results of these trials and the potential of these biologic agents to treat WG.

Treatment of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

“…Because activated CD4 T cells producing T-helper type 1 cytokines seem to play a crucial role in AAV, 32 there exists a rationale for the use of Tlymphocyte blocking therapies (Figure 1). The infusion of antithymocyte globulin causes rapid, deep depletion of T lymphocytes.…”

“…90 Furthermore, the intrinsic ability of rituximab to reduce autoantibody levels remains unproven because ANCA may persist after infusion despite B cell depletion. 32 This may be because ANCA can be continuously produced by long-lived plasma cells. It is possible that rituximab acts through immunological mechanisms other than the suppression of ANCA production (eg, by inhibiting B celldependent T cell functions).…”

“…The rationale for the use of TNF-␣ blockers in AAV stems from (1) a positive correlation between TNF-␣ serum levels and disease activity; (2) the presence of TNF-␣ in vasculitic lesions; (3) in vitro evidence for a role of TNF-␣ in neutrophil priming ( Figure 2); (4) the efficacy of TNF-␣ blockade in suppressing vasculitis in an animal model 31 ; and (5) the predominance of T-helper cells with a Thelper type 1 cytokine repertoire including TNF-␣ in Wegener granulomatosis granulomata ( Figure 1). 32 The Wegener's Granulomatosis Etanercept Trial (WGET) 27,28 assessed the efficacy of etanercept in the treatment of Wegener granulomatosis. One hundred eight patients were randomly assigned to receive etanercept or placebo in addition to standard therapy (corticosteroids plus cyclophosphamide for patients with severe disease and corticosteroids plus methotrexate for patients with limited disease).…”

Targeted Biologic Approaches to the Treatment of Systemic Vasculitis

“…The rationale for using T-lymphocyte blocking therapy in ANCA-associated vasculitis comes from several observations including the finding of T cells in active vasculitic lesions, the proliferation of T-helper cells from patients with Wegener's granulomatosis on stimulation with PR3, the overproduction of Th1 cytokines (INF-γ and TNF-α) by T cells from Wegener's granulomatosis patients, and the correlation of soluble markers of T-cell activation with disease activity [58]. There is very limited clinical data on the use of anti-CD52 (alemtuzumab), a lymphocytedepleting humanized anti-CD52 monoclonal antibody used in the treatment of lymphoproliferative disorders.…”

Immunotherapy for antineutrophil cytoplasmic antibody–associated vasculitis: challenging the therapeutic status quo?

“…This, together with greater insight into AAV pathogenesis, has prompted interest in biological agents. A more 'pathogenesis-oriented' therapeutic approach could overcome the deficiencies of current therapies by ablating key immune pathways with less toxicity [11]. We will discuss the role of the biological treatments most used in AAV, paying special attention to their pathogenesis and the immunological rationale of biological agents.…”