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To the Editor:

We thank Drs. Langford and Hoffman for their interest in our study. The NORAM trial was designed to test the efficacy of MTX-based first-line therapy for patients with early systemic antineutrophil cytoplasmic antibody–associated vasculitis (AAV) (1). At presentation, patients with early systemic AAV do not have disease manifestations that threaten vital organ function, such as severe glomerulonephritis. Inflammation of the ear, nose, and throat (ENT) area is a typical feature of this vasculitis syndrome. Indeed, this was the case in the NORAM cohort, and comparable findings were made in the Wegener's Granulomatosis Etanercept Trial (WGET) cohort among patients with limited GPA (defined as patients without significant renal disease or disease manifestations threatening vital organ function) (2). In addition, the NORAM long-term followup study suggests that patients with early systemic AAV are likely to experience recurrent disease but that their risk of developing end-stage renal disease is low. In the WGET cohort, patients with limited disease were more likely than those with severe disease to experience exacerbation of previous disease at trial entry, and their disease also tended not to progress to a severe phenotype. Thus, the NORAM and WGET data indicate that early systemic/limited AAV constitutes a form of AAV characterized by a high occurrence of ENT manifestations, a high risk of relapsing disease activity, and a low risk of severe nephropathy.

We agree with Drs. Langford and Hoffman that the early cessation of immunosuppressive therapy dictated by the NORAM protocol probably had a negative effect on relapse-free survival in the cohort, as was stated in both the original article on the NORAM trial (1) and the Discussion section of the current long-term followup study. We also agree that we did not provide definitive data demonstrating that the relapse rate was higher after induction therapy with MTX than after first-line therapy with CYC. The difference in cumulative relapse-free survival between treatment groups was of borderline significance. It is of interest to note that lower CYC exposure has been shown to be associated with a higher subsequent relapse rate in other cohorts as well (3, 4). However, we do not make the recommendation that prolonged CYC administration should be preferred to MTX as first- line therapy for early systemic AAV, and we do not believe that this can be extrapolated from our findings. As outlined in the Discussion section, the treatment strategy of the NORAM trial is not in accordance with modern recommendations, and our data can only be used to evaluate the efficacy of MTX-based first-line therapy as per the NORAM protocol.

The NORAM patients initially treated with MTX experienced less stable disease remission than those assigned to CYC-based first-line therapy, as shown by the analyses of relapse-free survival and the differences observed between treatment groups with regard to medication exposures during followup. Despite the weaknesses of the NORAM treatment protocol, we consider this observation to be of clinical importance. Thus, for patients with early systemic AAV who experience a relapsing disease course despite therapy with disease-modifying antirheumatic drugs and prednisolone, steroid-sparing treatment strategies should be considered to avoid the prolonged exposure to corticosteroids that was required for many of the patients in the MTX group of the NORAM cohort.

Acknowledgements

Dr. de Groot has received consulting fees, speaking fees, and/or honoraria from Amgen, Janssen-Cilag, Roche, Berlin Chemie, and Abbott (less than $10,000 each).

  • 1
    De Groot K, Rasmussen N, Bacon PA, Tervaert JW, Feighery C, Gregorini G, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis Rheum 2005; 52: 24619.
  • 2
    The Wegener 's Granulomatosis Etanercept Trial Research Group. Limited versus severe Wegener's granulomatosis: baseline data on patients in the Wegener's Granulomatosis Etanercept Trial. Arthritis Rheum 2003; 48: 2299309.
  • 3
    Neumann I, Kain R, Regele H, Soleiman A, Kandutsch S, Meisl FT. Histological and clinical predictors of early and late renal outcome in ANCA-associated vasculitis. Nephrol Dial Transplant 2005; 20: 96104.
  • 4
    Harper L, Morgan MD, Walsh M, Hoglund P, Westman K, Flossmann O, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis 2012; 71: 95560.

Mikkel Faurschou MD, PhD*, Kerstin Westman MD, PhD†, Niels Rasmussen MD‡, Kirsten de Groot MD§, Oliver Flossmann MRCP¶, Peter Höglund MD, PhD**, David Jayne MD, FRCP††, * Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, † Skane University Hospital, Malmo, Sweden, and Lund University, Lund, Sweden, ‡ Statens Serum Institut, Copenhagen, Denmark, § Klinikum Offenbach GmbH, Offenbach, Germany, ¶ Royal Berkshire Hospital, Reading, UK, ** Skane University Hospital, and Lund University, Lund, Sweden, †† Addenbrooke's Hospital, Cambridge, UK.