We have previously demonstrated that therapy with cyclophosphamide (CP) was successful as a treatment for Wegener's granulomatosis (WG); however, drug toxicity has limited its use in many patients. Therefore, we evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Results of these published studies demonstrated that MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. We have also investigated the potential for MTX to be used as maintenance therapy in patients in whom CP has induced a disease remission. In this protocol, patients receive prednisone plus CP therapy until remission of disease is achieved; CP is then switched to MTX for maintenance of remission. This CP/MTX regimen was highly effective and may represent a less toxic alternative to the standard CP regimen for patients with severe disease. In addition, in a small open-label trial we investigated whether the immunosuppressive agent mycophenolate mofetil, could be used in place of MTX for maintenance of CP-induced remission in patients with WG. Preliminary results of this study indicated that mycophenolate mofetil appeared to have efficacy in maintaining remission following CP therapy. Based on these results, we have initiated a phase II randomized trial to assess the comparative efficacy of using MTX versus mycophenolate mofetil for maintaining remission that has been induced by CP and prednisone in patients with WG and related vasculitides. In studies of disease pathogenesis we have found that peripheral blood lymphocytes from patients with active WG produced 10 to 20- fold higher levels of interferon-gamma compared with peripheral blood lymphocytes from normal controls. Increased production of tumor necrosis factor (TNF) by CD4 T lymphocytes and IL-12 by purified monocytes were also noted, but production of IL-4, IL- 5, and IL-10 was not increased. Based on these findings, we have initiated a phase I/II trial to assess the safety, efficacy, and immunologic effects of a recombinant fusion protein that contains the extra cellular portion of the p75 TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc). We are seeking to examine whether TNFR:Fc is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG.