We have previously demonstrated that therapy with cyclophosphamide was successful as a treatment for Wegener's granulomatosis (WG); however, drug toxicity has limited its use in certain patients. We have therefore evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Forty-two patients who did not have immediately life-threatening disease were studied. Weekly administration of MTX and prednisone resulted in remission of disease in 33/42 patients (79%). Nineteen of the 34 patients achieving remission experienced a relapse of disease. The estimated median time to relapse for all patients achieving remission was 29 months. Eighty percent of these relapses occurred in patients who had discontinued MTX or had reduced their dose to 15 mg/week or less. Thus, MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. We are also investigating the potential for MTX to be used as maintenance therapy in patients in whom cyclophosphamide has induced a disease remission. In this protocol patients receive glucocorticoid plus cyclophosphamide therapy until remission of disease is achieved; cyclophosphamide is then switched to MTX for maintenance of remission. By using this approach, we hope to combine the efficacy of cyclophosphamide with the more favorable toxicity profile of MTX. To date 20 of 24 patients who were switched to MTX after achieving remission on cyclophosphamide remain in remission (median follow-up 20 months). In studies of disease pathogenesis we have found that peripheral blood lymphocytes from patients with active WG produce 10 to 20-fold higher levels of interferon-gamma compared with peripheral blood lymphocytes from normal controls. Increased production of TNF-alpha 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. The addition of recombinant IL-10 to cell cultures suppressed the overproduction of interferon-gamma by WG T cells in a dose-dependent manner. Based on these findings, we have initiated a therapeutic trial of the anti-inflammatory cytokine IL-10 in patients with active Wegener?s granulomatosis. In collaboration with scientists outside the NIAID, we are investigating various genetic factors that could determine disease severity in patients with WG and related systemic vasculitides. Anti-neutrophil cytoplasmic antibodies (ANCA) are present in most patients with WG, and in vitro studies suggest that ANCAs may be involved in disease pathogenesis by inappropriately activating phagocytic cells to induce tissue damage. ANCAs appear to activate phagocytic cells through the receptors for IgG (FcgR). In collaboration with investigators at the University of Alabama, we have used functionally distinct genetic polymorphisms of the FcgRIIIb gene to generate evidence that ANCA-induced activation of neutrophils plays an important role in the pathogenesis of renal disease in WG and polymorphisms at the FcgRIIIb locus are a genetic risk factor for disease severity.
