Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse

Matthew David Morgan, Matthew Szeto, Michael Walsh, David Jayne, Kerstin Westman, Niels Rasmussen, Thomas F Hiemstra, Oliver Flossmann, Annelies Berden, Peter Höglund, Lorraine Harper, European Vasculitis Society, Matthew David Morgan, Matthew Szeto, Michael Walsh, David Jayne, Kerstin Westman, Niels Rasmussen, Thomas F Hiemstra, Oliver Flossmann, Annelies Berden, Peter Höglund, Lorraine Harper, European Vasculitis Society

Abstract

Background: Relapse of disease is frequent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). It is unclear whether persistent ANCA when starting maintenance therapy increases the risk of relapse. We examined the association between ANCA status and relapse in two randomised controlled trials.

Methods: ANCA-positive patients in two trials, CYCLOPS and IMPROVE, were switched from cyclophosphamide to maintenance therapy after achieving clinical remission. We classified patients as being either ANCA-positive or ANCA-negative at the time they started maintenance therapy. We compared the risk of relapse in ANCA-positive and ANCA-negative patients.

Results: Of 252 patients included, 102 (40%) experienced at least one relapse during the follow-up period. At the time of the switch from induction to maintenance therapy, 111 were ANCA-positive, of whom 55 (50%) relapsed, compared to 141 patients who were ANCA-negative, of whom 47 (33%) relapsed. In multivariable time-to-event analysis, a reduced risk of relapse was associated with having become ANCA-negative at the time of switching to maintenance therapy (hazard ratio 0.63, 95% confidence interval 0.42-0.95; p = 0.026). In addition, initial proteinase 3 (PR3)-ANCA, younger age, lower serum creatinine, pulsed cyclophosphamide for remission induction, and mycophenolate mofetil for remission maintenance were all associated with an increased risk of relapse.

Conclusions: Becoming ANCA-negative before the switch to maintenance is associated with a reduced risk of relapse.

Trial registration: CYCLOPS: ClinicalTrials.gov, NCT00430105 . Registered retrospectively on 31 January 2007.

Improve: ClinicalTrials.gov, NCT00307645 . Registered retrospectively on 27 March 2006.

Keywords: ANCA; ANCA-associated vasculitis; Clinical trial; Prognostic factors; Relapse; Treatment; Vasculitis.

Figures

Fig. 1
Fig. 1
Kaplan-Meier survival curves demonstrating the effect of ANCA status at the time of switching to maintenance therapy on all patients (a), and patients who were initially either PR3-ANCA-positive (b) or MPO-ANCA-positive (c). The numbers remaining at risk in the ANCA-positive and ANCA-negative groups at each time point are shown below the appropriate survival curve. ANCA anti-neutrophil cytoplasm antibodies, MPO, myeloperoxidase, PR3 proteinase 3

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