Following our previous therapeutic success with cyclophosphamide (CP) in the treatment of Wegener's granulomatosis (WG), we have gone on to evaluate the safety and efficacy of methotrexate (MTX) as an alternative therapy in this disease. Forty-two patients who did not have immediately life-threatening disease were studied. Glomerulonephritis was present in 21/42 (50%) of patients. The median follow-up was 23.4 months. Weekly administration of MTX and prednisone resulted in remission of disease in 30/42 patients (71%). The median time to remission was 4.2 months. Twelve patients did not achieve remission: three patients had progressive disease that required institution of CP therapy; five patients had clinical improvement but continued to exhibit signs of active disease; two patients developed MTX-induced pneumonitis prior to achieving remission; two patients died of opportunistic infections prior to achieving remission. For the 30 patients who achieved remission: 23% relapsed within 1 year of achieving remission and 40% relapsed within 2 years. The estimated median time to relapse for all patients achieving remission was 29 months. In patients with glomerulonephritis at study entry, relapse occurred earlier (35% by 1 year) than in patients without glomerulonephritis (no relapses at 1 year); however, after 2.5 years the estimated percent of patients who had relapsed was similar in the two groups (50% vs 57%; p=0.1). Eight patients who relapsed were treated with a second course of MTX plus prednisone. A second remission was induced in six out of 8 (75%) patients. MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. In preliminary studies we have used skin blisters induced by suction as a method to study the in vivo inflammatory response of patients with WG. We have shown that patients with active WG produce 50- to 100-fold higher levels of TNF-alpha in blister fluid when compared with normal controls. Such high TNF-alpha levels are not seen in blister fluid from patients with a variety of other inflammatory and infectious diseases. Levels of IL-1beta and IL-6 were also significantly elevated in blister fluid from patients with active WG. These findings have important therapeutic implications since specific inhibitors of TNF-alpha and other pro- inflammatory cytokines are currently available and may be effective in the treatment of WG and related systemic vasculitides.
