Remaining Anti-Neutrophil Cytoplasm Antibody Positive After Induction Therapy Increases

Remaining anti-neutrophil cytoplasm antibody positive after induction therapy increases relapse risk in ANCA vasculitis: Observation from the long term follow up of the CYCLOPS and IMPROVE trials

Matthew David Morgan1, Matthew Szeto1, Jennifer Marsh1, Michael Walsh2, David Jayne3, Kerstin Westman4, Niels Rasmussen5, Thomas F Hiemstra3, Oliver Flossman6, Annelies Berden7, Peter Hoglund4, Lorraine Harper1 on behalf of the European Vasculitis Study Group. 1 University of Birmingham UK, 2 McMaster University Canada, 3 Addenbrooke’s Hospital UK, 4 Lund University Sweden, 5 Statens Serum Institut Denmark, 6 Royal Berkshire Hospital UK, 7 Leiden University Medical Centre Netherlands.

Introduction: Relapse of disease is a frequent problem in anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV). We examined whether ANCA status after induction therapy increased subsequent relapse risk.

Methods: ANCA positive patients in two randomised controlled trials, CYCLOPS and IMPROVE were switched from cyclophosphamide induction therapy to either azathioprine or mycophenolate mofetil (MMF) after 3 to 6 months having achieved clinical remission. We classified patients as being either ANCA positive or ANCA negative at the time they started maintenance therapy and compared these groups in terms of time-to-first –relapse.

Results: of 252 patients, 102 (40%) experienced at least one relapse during the follow up period. At time of switch from induction to maintenance therapy, 111 were ANCA positive, of whom 55 (50%) relapsed, compared to 141 who were ANCA negative of whom 47 (33%) relapsed. In multivariable time-to-event analysis the reduced risk of relapse was only observed in initially anti-proteinase 3 (PR3) ANCA patients who became negative (HR 0.57 (0.38 – 0.84) p=0.004) and not in myeloperoxidase specific ANCA patients who became ANCA negative (HR 0.56 (0.27 – 1.15) p=0.11). Multivariable survival analysis also confirmed previous findings that increased risk of relapse was also associated with PR3-ANCA at diagnosis, better renal function, pulsed rather than continuous cyclophosphamide for remission induction and mycophenolate mofetil rather than azathioprine for remission maintenance therapy. In addition increased age was associated with a reduced risk of relapse. Comparing multivariable models of survival including either ANCA status at trial entry or ANCA status at the time of starting maintenance therapy suggested that persistent PR3-ANCA positivity at time of starting maintenance therapy was a better predictor of relapse than PR3-ANCA positivity at presentation.

Conclusion: Remaining PR3 ANCA positive at switch to maintenance is significantly associated with an increased risk of relapse.