ACR Boston 2014 | Daily Highlights

Granulomatosis with Polyangiitis or Microscopic Polyangiitis: Long-Term Outcomes of the Prospective Wegent Trial Comparing Azathioprine Vs Methotrexate for Remission-Maintenance in 126 Patients

Abstract: 1864
Presenter: Xavier Puéchal
Co-Authors: Christian Pagnoux, Elodie Perrodeau, Mohamed Hamidou, Jean-Jacques Boffa, Xavier Kyndt, François Lifermann, Thomas Papo, Dominique Merrien, Amar Smail, Philippe Delaval, Catherine Hanrotel-Saliou, Bernard Imbert, Chahéra Khouatra, Marc Lambert, Charles Leské, Kim Heang Ly, Edouard Pertuiset, Pascal Roblot, Marc Ruivard, Jean-François Subra, Jean-Francois Viallard, Benjamin Terrier, Pascal Cohen, Luc Mouthon, Philippe Ravaud and Loïc Guillevin for the French Vasculitis Study Group

Results of the previously reported randomized–controlled WEGENT trial demonstrated that, at 28 months, methotrexate (MTX) is as effective as azathioprine (AZA) for maintaining remission of granulomatosis with polyangiitis (GPA, Wegener's) or severe microscopic polyangiitis (MPA) (NEJM 2008;359:2790–803). The long-term outcomes of patients included in the WEGENT trial were analyzed in this study.

Methods:
Long-term outcomes were ascertained for 126 patients enrolled in the WEGENT trial between 1999 and 2004. Data on survival, relapse, immunosuppressant use, cancer, infection and cardiovascular morbidity were collected. All patients were analyzed according to their randomization group. Demographic, clinical and laboratory parameters at trial entry were evaluated as potential prognostic factors for death or relapse in multivariate models.

Results:
Median follow-up was 11.8 years. The 10-year overall survival rate was 74.8% [95% CI 64.5–86.9] for the AZA arm and 79.9% [95% CI 70.3–90.7] for the MTX arm, with no between-arm survival difference (HR MTX vs AZA = 0.79 [95% CI 0.37–1.70]; P=0.55). No long-term between-arm differences were observed for adverse events, severe adverse events, infections, cancer, relapses and severe relapses. The 10-year survival rate without relapse was 26.3% [95% CI 17.3–40.1] in the AZA arm and 35.1% [95% CI 24.9-49.4] in the MTX arm, with no significant between-arm difference (HR MTX vs AZA = 0.78 [95% CI 0.51–1.20]; P=0.26). The 10-year survival rate without severe side effects was also comparable for the two groups (HR MTX vs AZA = 1.02 [95% CI 0.64–1.63]; P=0.93), as was survival without relapse and severe side effects (HR MTX vs AZA = 1.04 [95% CI 0.66–1.63]; P=0.87). Taking into account only the 97 GPA patients, no between-arm differences were observed for these survival parameters. Survival without relapse was shorter for GPA than MPA patients (HR 2.16 [95% CI 1.22–3.83]; P=0.009). Multivariate analyses retained the glucocorticoid dose at the end of the scheduled 12-month maintenance-drug regimen (HR 1.18 [95% CI 1.09–1.29]; P<0.001), glucocorticoid duration (HR 1.01 [95%CI 1.00–1.02]; P<0.04), and PR3-ANCA–positivity (HR 3.68 [95% CI 2.07–6.55]; P<0.001) as being significantly prognostic of long-term relapses. Each additional month or mg of glucocorticoid at the end of the maintenance regimen increased the probability of relapse or death by 1% or 15%, respectively.

Conclusions:
This long-term analysis confirmed that AZA and MTX are comparable options for maintaining GPA or MPA remission. It showed that the overall survival is good, even though relapses and adverse events remain matters of concern. Further studies are needed to reduce the long-term relapse rate of ANCA-associated vasculitides.

Disclosure of Interest:
X. Puéchal, None; C. Pagnoux, None; E. Perrodeau, None; M. Hamidou, None; J. J. Boffa, None; X. Kyndt, None; F. Lifermann, None; T. Papo, None; D. Merrien, None; A. Smail, None; P. Delaval, None; C. Hanrotel-Saliou, None; B. Imbert, None; C. Khouatra, None; M. Lambert, None; C. Leské, None; K. H. Ly, None; E. Pertuiset, None; P. Roblot, None; M. Ruivard, None; J. F. Subra, None; J. F. Viallard, None; B. Terrier, None; P. Cohen, None; L. Mouthon, None; P. Ravaud, None; L. Guillevin for the French Vasculitis Study Group, None.

Comment:
This long-term trial confirms equal utility of azathioprine (AZA) and MTX for maintenance treatment of GPA and MPA with regard to 10-years overall survival (74.8% and 79.9%). There is no difference observed for adverse events, severe adverse events, infections, cancer, relapses and severe relapses. Relapes are more often observed in GPA compared to MPA due to PR3-ANCA-positivity being significantly prognostic of long-term relapses. Relapse rates over time are still high in both treatment groups (10-years survival without relapse is 26.3% for AZA and 35.1% for MTX) and reinforce the necessity of other treatment regimens to reduce the long-term relapse rate in AAV.

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