Developing strategies to manage neutralising antibodies – preliminary results from the RENeu study
S. Hodgkinson, L. Sedal, M. Paine, S. Siejka, D. Gorai, H. Butzkueven, E. Willoughby, K. Boundy, D. Booth, F. Mackay, A. Tabensky, L. Sartori, K. Curnow, M. Paine (Liverpool, Melbourne, Launceston, AUS; Auckland, NZ; Adelaide, Sydney, AUS)

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There are currently no clinical guidelines for management of interferon-beta (IFN) treated patients who develop neutralising antibodies (NAbs) to their IFN therapy.

The RENeu study (Recovery of IFN-beta Efficacy in RRMS with Neutralising IFN-beta Antibodies and Reduced Bioactivity) tests the hypothesis that patients who develop persistent NAbs and are unresponsive to IFN as measured by MxA mRNA can (a) become NAb- if their IFN therapy is ceased and their MS is managed by monthly pulsed methylprednisolone treatment (500 mg/day for 3 days) for up to 12 months, and (b) become responsive to IFN if they are reinitiated on the least immunogenic IFN i.e. AVONEX.

The RENeu study will also assess the clinical efficacy and safety of this treatment regimen over 2 years. We report on preliminary results for the first patients enrolled in RENeu.

Thirteen patients (of 20 planned for RENeu) have now commenced treatment with monthly-pulsed prednisolone. Their NAb titres at study entry (CPE) ranged from 40 to >4000 (upper limit of assay). Of these, six patients have received methylprednisolone for up to 12 months, all starting with NAb titres >200.

NAb titres have decreased significantly in 4 of these 6 patients, reaching <20 in one patient and 30 in three. The patient eligible for bioactivity testing (CPE <20) was found to be responsive to injected IFN by the MxA mRNA test and has remained NAb- following subsequent treatment with AVONEX once weekly for 6 months. Most importantly, this patient continues to respond biologically to AVONEX.

A recent report by Petersen et al in 2006 has demonstrated that in 18 patients with NAb titres >200 by CPE, NAb titres remained high for extended periods after discontinuing IFN therapy. The NAb titre only decreased below 100 in one patient, and this did not occur until more than 3 years after ceasing therapy. In contrast, the initial results of the RENeu study show that monthly-pulsed methylprednisolone may be effective in reducing NAb titres. Bioactivity testing is useful for clarifying whether low titre NAbs do impact on patient responsiveness to IFN.