Correspondence
Maintenance Therapy for Vasculitis Associated with Antineutrophil Cytoplasmic Autoantibodies
N Engl J Med 2003; 349:2072-2073November 20, 2003
- Article
To the Editor:
In their report on maintenance therapy for vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) (July 3 issue),1 Jayne et al. conclude that the level of exposure to cyclophosphamide can be safely reduced in patients with ANCA-associated vasculitis by switching to azathioprine once remission has been achieved. As the authors point out, and as is noted in the accompanying Perspective article by Langford,2 follow-up was limited to 18 months. It was thought unlikely that extended follow-up would reveal significant differences in the rates of relapse. We present some data that may challenge this assumption.
From 1990 through 1996, new patients at our center were treated with oral cyclophosphamide (2 mg per kilogram of body weight per day, tapered by 25 mg every three months), whereas from 1997 to 2001, patients were increasingly switched to azathioprine (1.5 to 2.0 mg per kilogram per day, tapered by 25 mg every three months) after three months of remission achieved with cyclophosphamide therapy. In both schemes, treatment was discontinued after 18 to 24 months. Overall, 88 patients received cyclophosphamide only, and 48 were switched to azathioprine. Treatment with prednisolone was similar in both cohorts. The mean age at diagnosis was 53 years (range, 14 to 83); there was renal involvement in 104 patients (76 percent); the mean (±SD) Birmingham Vasculitis Activity Score was 23±9; ANCA against proteinase 3 and myeloperoxidase were detected in 102 patients (75 percent) and 34 patients (25 percent), respectively. These characteristics did not differ significantly between the two cohorts and are similar to the clinical characteristics of the patients in the study by Jayne et al.
We analyzed the actuarial rates of relapse-free survival among patients treated with cyclophosphamide only and among those who were switched to azathioprine (Figure 1Figure 1
Disease-free Survival among 136 Patients with Vasculitis Associated with Autoantibodies to Neutrophil Cytoplasmic Antigens.). Data for patients who did not have a relapse were censored on May 1, 2003, or at the time of death. Three patients died without having a relapse or findings compatible with active vasculitis (one died of myocardial infarction, and two of disseminated carcinoma of the colon). At 18 months, the rate of relapse-free survival was 88.6 percent in the cyclophosphamide group and 89.6 percent in the azathioprine group — results that are similar to those reported by Jayne et al. (86.3 percent and 84.5 percent, respectively). However, at five years of follow-up, relapse-free survival was 42.3 percent in the azathioprine group, as compared with 57.4 percent in the cyclophosphamide group. The difference between the curves nearly reached statistical significance (relative risk by the log-rank test, 1.51; 95 percent confidence interval, 0.92 to 2.68; P=0.099).These data indicate that relapses of ANCA-associated vasculitis occur predominantly after therapy has been discontinued, as reported by Hoffman et al.3 Moreover, our data challenge the conclusion of Jayne et al. that switching from cyclophosphamide to azathioprine after three months of remission does not lead to an increase in the rate of relapse, since their follow-up may have been too short. We recently found that the persistence of ANCA at the time when a patient is switched to azathioprine is a risk factor for relapse.4 Whether extending treatment with azathioprine in some or all patients might reduce the number of relapses without increasing the rate of treatment-related toxic effects should be studied.
4 ReferencesJan-Stephan F. Sanders, M.D.
Marjan C. Slot, M.D.
Coen A. Stegeman, M.D., Ph.D.
University Hospital Groningen, 9713 GZ Groningen, the Netherlands1
Jayne D ,Rasmussen N ,Andrassy K , et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36-44
Full Text | Web of Science | Medline2
Langford CA . Treatment of ANCA-associated vasculitis. N Engl J Med 2003;349:3-4
Full Text | Web of Science | Medline3
Hoffman GS ,Kerr GS ,Leavitt RY , et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-498
Web of Science | Medline4
Slot MC, Cohen Tervaert JW, Boomsma MM, Stegeman CA. A positive PR3-ANCA titer at switch to azathioprine therapy is associated with a disquieting relapse rate in ANCA-associated vasculitis. Arthritis Rheum (in press).
Author/Editor Response
Concern about late toxic effects of cyclophosphamide therapy in patients with vasculitis has inspired the design of protocols that aim to minimize exposure to cyclophosphamide or use alternative agents for patients with mild presentations.1 Our study concluded that in ANCA-associated vasculitis, cyclophosphamide exposure could be reduced by the substitution of azathioprine after three months of treatment. Sanders et al. found a nonsignificant increase in the rate of relapse with azathioprine at five years in comparison with continued cyclophosphamide treatment in a nonrandomized study. It is important to note that at 18 months, they found no difference in the rates of relapse, which is in line with our results. Furthermore, the apparent increase in the rate of relapse with azathioprine began only at two years, after the discontinuation of treatment. This finding comes as no surprise, since previous studies have demonstrated that after the discontinuation of therapy, patients with a higher cumulative exposure to cyclophosphamide have a lower rate of relapse.2 In addition, Sanders et al. used lower doses of azathioprine than we used in our study. We are currently evaluating long-term maintenance therapy with azathioprine, and we and others are evaluating alternative maintenance therapies, including mycophenolate mofetil and etanercept.3,4 Meanwhile, growing evidence supports the ANCA test's predictive value for relapse, especially when the test is performed at the time of the discontinuation of treatment.
4 ReferencesDavid Jayne, M.D.
Addenbrooke's Hospital, Cambridge CB2 2QQ, United KingdomNiels Rasmussen, M.D.
Rigshospitalet, DK-2100 Copenhagen, Denmark1
Rasmussen N . European therapeutic trials in ANCA-associated systemic vasculitis: disease scoring, consensus regimens and proposed clinical trials. Clin Exp Immunol 1995;101:Suppl 1:29-34
CrossRef2
Guillevin L ,Cordier JF ,Lhote F , et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. Arthritis Rheum 1997;40:2187-2198
CrossRef | Web of Science | Medline3
Jayne D . Update on the European Vasculitis Study Group trials. Curr Opin Rheumatol 2001;13:48-55
CrossRef | Web of Science | Medline4
The WGET Research Group
CrossRef | Medline
- Citing Articles (8)
Citing Articles
1
Cees G. M. Kallenberg. (2010) Pathophysiology of ANCA-Associated Small Vessel Vasculitis. Current Rheumatology Reports 12:6, 399-405
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Sandra Figueiredo, Laurentino Mendes Leal, António Morais, Adriana Magalhães, Teresa Oliveira, Venceslau Hespanhol, Carlos Dias, Gabriela Fernandes. (2009) Granulomatose de Wegener – Envolvimento otológico, nasal, laringotraqueal e pulmonar. Revista Portuguesa de Pneumologia (English Edition) 15:5, 929-935
CrossRef3
Pagnoux, Christian, Mahr, Alfred, Hamidou, Mohamed A., Boffa, Jean-Jacques, Ruivard, Marc, Ducroix, Jean-Pierre, Kyndt, Xavier, Lifermann, François, Papo, Thomas, Lambert, Marc, Le Noach, José, Khellaf, Mehdi, Merrien, Dominique, Puéchal, Xavier, Vinzio, Stéphane, Cohen, Pascal, Mouthon, Luc, Cordier, Jean-François, Guillevin, Loïc, . (2008) Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis. New England Journal of Medicine 359:26, 2790-2803
Full Text4
C. Pagnoux. (2007) Maladie de Wegener. La Revue de Médecine Interne 28, S261-S262
CrossRef5
Fatma Dedeoglu, Robert P. Sundel. (2007) Vasculitis in Children. Rheumatic Disease Clinics of North America 33:3, 555-583
CrossRef6
Cees GM Kallenberg, Peter Heeringa, Coen A Stegeman. (2006) Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides. Nature Clinical Practice Rheumatology 2:12, 661-670
CrossRef7
Christian Pagnoux, Boris Bienvenu, Loïc Guillevin. (2006) The spectrum of granulomatous vasculitides. Future Rheumatology 1:6, 729-750
CrossRef8
David Jayne. (2005) How to induce remission in primary systemic vasculitis. Best Practice & Research Clinical Rheumatology 19:2, 293-305
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