To the Editor:

Faurschou and colleagues (1) recently reported on the long-term outcomes of the NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate) trial, which compared methotrexate (MTX) to cyclophosphamide (CYC) for remission induction in nonsevere granulomatosis with polyangiitis (Wegener's) (GPA) or microscopic polyangiitis (MPA). While MTX and CYC were equally effective in inducing remission assessed at 6-month followup, the authors note that MTX was less effective in sustaining remission over time (1, 2).

We are concerned that some readers might extrapolate from this conclusion that CYC would be preferred to MTX for remission induction in patients with mild to moderate GPA or MPA. That inference would ignore several important points that could compromise patient care. It is important to recall that studies of MTX in vasculitis are rooted in the discovery that long-term treatment with CYC has numerous severe and permanent side effects (3). MTX was chosen as an alternative agent for study because of its long history of relatively safe use in the treatment of rheumatoid arthritis. In the earliest studies, MTX was used in patients with mild to moderate GPA (4). Subsequent studies of severe GPA and MPA also demonstrated the efficacy of MTX in the maintenance of remission, through a staged approach in which treatment was switched from CYC to MTX after initial marked improvement or remission that often occurred within 3–6 months (5, 6). Given the safety profile of MTX as compared to CYC, the concerns about limiting duration of treatment with MTX were not the same as they were for CYC.

The most critical factor influencing relapse in the NORAM trial is likely to be duration of treatment. Patients received oral MTX at an initial dosage of 15 mg/week, which was escalated to 20–25 mg/week by 12 weeks. This treatment was maintained until month 10 and then tapered and discontinued by month 12. In patients randomized to receive CYC, treatment was also tapered and discontinued by month 12. At 18 months, 6 months after these agents were discontinued, the relapse rates in both groups were higher than the rates observed in other standardized trials in which maintenance therapy was continued over longer time periods (7). While the optimal duration of maintenance therapy remains uncertain, these results indicate that high relapse rates result when effective maintenance agents are discontinued within 12 months of inducing remission. If we accept that 1) GPA and MPA are not yet curable, 2) the agents we use to treat GPA and MPA have a dose-threshold effect for benefit (as with all drugs), and 3) discontinuation of therapy is usually associated with relapses in most patients within 1–2 years, then reducing an effective dose of a relatively safe, well-tolerated agent or stopping treatment entirely would be expected to yield results similar to those reported in this study.

The conclusions of the NORAM long-term analysis are of additional concern because outcome measures were recorded via a questionnaire, there were no recommended standards for long-term treatment and monitoring or choice and dosage of immunosuppressive agents provided, and although there was a trend, there was no statistically significant difference in long-term relapse-free survival between the MTX and CYC groups (P = 0.056). The interpretation of this outcome is further limited because confidence intervals for the data were not provided. Thus, these methods and statistical results do not provide a definitive basis from which to conclude that the relapse rate is higher with MTX as compared to CYC.

A valuable alternative conclusion that can be drawn from this study is that the use of MTX as prescribed in the original protocol is associated with a high rate of relapse after treatment discontinuation. More prolonged use of maintenance therapies appears to have lower relapse rates. Limiting the duration of exposure to CYC remains an important goal, which MTX has helped to achieve, both in remission induction for nonsevere disease and in remission maintenance after treatment with CYC for severe disease.

  • 1
    Faurschou M, Westman K, Rasmussen N, de Groot K, Flossmann O, Hoglund P, et al. Long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody– associated vasculitis. Arthritis Rheum 2012; 64: 347277.
  • 2
    De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis Rheum 2005; 52: 24619.
  • 3
    Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener's granulomatosis: a prospective analysis of 158 patients. Ann Intern Med 1992; 116: 48898.
  • 4
    Hoffman GS, Leavitt RY, Kerr GS, Fauci AS. The treatment of Wegener's granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum 1992; 35: 13229.
  • 5
    Langford CA, Talar-Williams C, Barron KS, Sneller MC. A staged approach to the treatment of Wegener's granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance. Arthritis Rheum 1999; 42: 266673.
  • 6
    Villa-Forte A, Clark TM, Gomes M, Carey J, Mascha E, Karafa MT, et al. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience. Medicine (Baltimore) 2007; 86: 26977.
  • 7
    Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349: 3644.

Carol A. Langford MD, MHS*, Gary S. Hoffman MD*, * Cleveland Clinic, Cleveland, OH.