Azathioprine or Methotrexate for Vasculitis?
By Eric Schned, MD
Pagnoux C, Mahr A, Hamidou A, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;350:2790-2803.
Background: Current standard therapy for Wegener’s granulomatosis [WG] and microscopic polyangiitis [MP] combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such as azathioprine [AZA] or methotrexate [MTX] for maintenance therapy. However, AZA and MTX have not been compared with regard to safety and efficacy.
Methods: In this prospective, open-label, multicenter trial, we randomly assigned patients with WG or MP who entered remission with intravenous [IV] cyclophosphamide and corticosteroids to receive oral AZA (at a dose of 2.0 mg per kilogram of body weight per day) or MTX (at a dose of 0.3 mg per kilogram per week, progressively increased to 25 mg per week) for 12 months. The primary end point was an adverse event requiring discontinuation of the study drug or causing death; the sample size was calculated on the basis of the primary hypothesis that MTX would be less toxic than AZA. The secondary end points were severe adverse events and relapse.
Results: Among 159 eligible patients, 126 (79%) had a remission, were randomly assigned to receive a study drug in two groups of 63 patients each, and were followed for a mean (±SD) period of 29±13 months. Adverse events occurred in 29 AZA recipients and 35 MTX recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the AZA group and 11 patients in the MTX group (P=0.11). The primary end point was reached in 7 patients who received AZA as compared with 12 patients who received MTX (P=0.21), with a corresponding hazard ratio for MTX of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the MTX group. Twenty-three patients who received AZA and 21 patients who received MTX had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug.
Conclusions: These results do not support the primary hypothesis that MTX is safer than AZA. The two agents appear to be similar alternatives for maintenance therapy in patients with WG and MP after initial remission.
Current treatment for most cases of WG and MP continues to be combined corticosteroids and cyclophosphamide, despite the well-recognized risk of serious adverse events (ADE) of both drugs and suboptimal efficacy (relapse rates approach 40% at 30 months).1,2 An advance in treatment of the antineutrophil cytoplasmic antibody–associated vasculitides (AAV) came with the demonstration that a maintenance regimen with a less toxic immunosuppressant, AZA, could prolong the remission of cyclophosphamide.3 Subsequent uncontrolled trials suggested that MTX could provide effective, and probably safer, maintenance therapy for WG than AZA.4