Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis

Université Paris Descartes, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France.
New England Journal of Medicine (Impact Factor: 55.87). 01/2009; 359(26):2790-803. DOI: 10.1056/NEJMoa0802311
Source: PubMed


Current standard therapy for Wegener's granulomatosis and microscopic polyangiitis combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such as azathioprine or methotrexate for maintenance therapy. However, azathioprine and methotrexate have not been compared with regard to safety and efficacy.
In this prospective, open-label, multicenter trial, we randomly assigned patients with Wegener's granulomatosis or microscopic polyangiitis who entered remission with intravenous cyclophosphamide and corticosteroids to receive oral azathioprine (at a dose of 2.0 mg per kilogram of body weight per day) or methotrexate (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 methotrexate would be less toxic than azathioprine. The secondary end points were severe adverse events and relapse.
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 azathioprine recipients and 35 methotrexate recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the azathioprine group and 11 patients in the methotrexate group (P=0.11). The primary end point was reached in 7 patients who received azathioprine as compared with 12 patients who received methotrexate (P=0.21), with a corresponding hazard ratio for methotrexate of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the methotrexate group. Twenty-three patients who received azathioprine and 21 patients who received methotrexate had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug.
These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegener's granulomatosis and microscopic polyangiitis after initial remission. ( number, NCT00349674.)

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    • "Ce surrisque infectieux secondaire à l'utilisation du CYC est unanime à l'ensemble des études, mais plus discuté concernant le MTX [6] [13] [25] [26]. L'AZA semble être associé à risque infectieux moindre, bien que l'étude Wegent comparant la tolérance et l'efficacité des traitements d'entretien par MTX et AZA ne retrouve pas de différence de survenue des événements infectieux entre les deux groupes [27]. En revanche, nous trouvions une variation parallèle du délai entre les infections et la dose cumulée de corticoïde, de CYC et d'AZA au moment de l'infection ; seule la dose cumulée de corticoïde était significativement en lien avec un allongement du délai infectieux en analyse multivariée. "
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    ABSTRACT: The aim of this study was to assess the infections occurring in a series of 82 patients followed for a systemic necrotizing vasculitis and to determine potential risk factors. We studied retrospectively the medical files of 23 Churg and Strauss syndrome, 18 periarteritis nodosa, 14 microscopic polyangiitis, and 27 granulomatosis with polyangiitis, over a 15-year period. Infection delay corresponded to the period from treatment to first infection or between two infections. A total of 61 patients developed 147 infections. Causal agent was identified in 70 cases, 42 were bacterial, 20 viral and 8 fungal. Bronchopneumonia was the most frequent infection (43 %). Sixty-two percent of infections occurred within 2 years after vasculitis diagnosis. Seven infections were major, requiring intensive care, with one infection-death related. Pneumocystis prophylaxis concerned 75 % of patients on cyclophosphamide. Significant factors reducing infection delay were initial hypergammaglobulinemia, hypoalbuminemia, lymphopenia, as well as cyclophosphamide and methotrexate treatment. Large quantities of corticosteroids, cyclophosphamide or azathioprine increased infection delay. This result underlines the early occurrence of infectious complications during vasculitis course. Infectious events occurring in systemic necrotizing vasculitis are frequent and occurs early in disease course, and could be prevented with simple prophylactic measures. Vasculitis relapse and infection share similarities and this require permanent clinical vigilance.
    La Revue de Médecine Interne 12/2013; · 1.07 Impact Factor
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    • "The WEGENT study randomised 126 patients to receive either methotrexate or azathioprine as maintenance therapy after successful induction of remission with cyclophosphamide [55]. There were no differences between groups in either relapse or toxicity. "
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    ABSTRACT: Autoantibodies to neutrophil cytoplasmic antigen-associated vasculitis (AAV) is characterised by inflammation of blood vessels. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide transformed AAV from a fatal condition to a largely treatable condition. Over the past 30 years, considerable progress has been made refining immunosuppressive regimens with a focus on minimising toxicity. There is, however, a high unmet need in the treatment of AAV. A proportion of patients are refractory to current therapies; 50% experience a relapse within 5 years and treatment toxicity contributes to mortality and chronic disability. As knowledge of the pathogenesis of vasculitis grows, it is mirrored by the availability of biological agents, which herald a revolution in the treatment of vasculitis. Lymphocyte-targeted and cytokine-targeted agents have been evaluated for the treatment of AAV and are entering the routine therapeutic arena with the potential to improve patient outcomes. As rare diseases, treatment advances in vasculitis depend on international collaborative research networks both to establish an evidence base for newer agents and to develop recommendations for patient management.
    Arthritis research & therapy 04/2012; 14(2):210. DOI:10.1186/ar3797 · 3.75 Impact Factor
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    • "Azathioprine is also widely used in rheumatologic diseases and organ transplantation. Randomized trials comparing methotrexate to azathioprine have shown similar effectiveness for treating ANCA-associated vasculitis [13] and myasthenia gravis [14], and mixed results in rheumatoid arthritis with one small trial showing similar effectiveness [15] and another showing greater effectiveness with methotrexate [16]. Mycophenolate mofetil was shown to be more effective than azathioprine in a randomized trial of patients with Crohn’s disease [17] and for cardiac transplantation [18], but trials in lupus nephritis [19] and renal transplantation [20] found no significant differences. "
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    ABSTRACT: This study aims to determine uveitis specialists' practice patterns, preferences, and perceptions of corticosteroid-sparing therapies for the initial treatment of chronic noninfectious uveitis. A survey was distributed to the American Uveitis Society and Proctor email listservs in order to restrict the respondents to specialists who likely have extensive experience in the use of immunomodulatory therapy. Topics included effectiveness, usage, and preferences related to seven immunomodulatory treatments. Among the 45 responders, the majority (59%) had greater than 10 years of experience treating uveitis. Methotrexate was the most commonly used initial therapy for anterior, intermediate, and posterior/panuveitis (85%, 57%, and 37%), and the most preferred for anterior (55%). Mycophenolate mofetil was the most preferred for intermediate (35%) and posterior/panuveitis (42%). Primary reasons not to prescribe a treatment were effectiveness for azathioprine, safety/tolerability for cyclosporine and cyclophosphamide, and a mixture of cost, safety/tolerability, and difficulty of administration for the biologic drugs. Within the group of highly experienced uveitis specialists, methotrexate is still the most commonly used initial treatment. Although newer biologic drugs are seen as effective, they are not commonly used, or even preferred, as initial corticosteroid-sparing treatment.
    Journal of Ophthalmic Inflammation and Infection 11/2011; 2(1):21-8. DOI:10.1007/s12348-011-0047-5
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