Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial

Abstract

Objectives: The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV.

Methods: In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity.

Results: Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed.

Conclusions: MTX may be effective and safe for remission-maintenance in AAV.

Trial registration: clinicaltrials.gov NCT00751517.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Trial profile.

*The patients excluded for protocol violation were judged non-adherent to the induction regimen prescribed.

Fig 2

Upper panel. Kaplan-Meier estimate of the time from the start of treatment to remission of the patients who were later assigned to receive cyclophosphamide (CYC) or methotrexate (MTX). Lower panel. Kaplan-Meier estimate of the time from remission to first relapse or death (during the planned 24 month-follow-up) in the cyclophosphamide (CYC) and methotrexate (MTX) groups.

Fig 3. Subgroup analysis of the Kaplan-Meier estimate of the time from remission to first relapse or death (during the planned 24 month-follow-up) in the cyclophosphamide (CYC) and methotrexate (MTX) groups.

The upper panel shows the analysis in patients with GPA or MPA (granulomatosis with polyangiitis or microscopic polyangiitis) while the lower panel shows the analysis in patients with EGPA (eosinophilic granulomatosis with polyangiitis).