Journal Article

A post-marketing evaluation of the impact of neutralizing antibodies on the effectiveness of interferon beta in relapsing-remitting multiple sclerosis

Pellegrini, F, Trojano, M, Lavolpe, V, Ruggieri, M, D'Onghia, M, Livrea, P, Fuiani, A, Iaffaldano, P, Paolicelli, D

2008

Overview

Background: The impact of Neutralizing antibodies (NAbs) on interferon beta (IFN beta ) efficacy in multiple sclerosis (MS) patients is still object of controversy, therefore there is insufficient information on the utilization of NAb testing in clinical decisions. Objective: To evaluate, in clinical practice, on a large population of relapsing-remitting (RR) MS patients followed up to 5 years, the different clinical response to IFN beta during NAb-positive and NAb-negative statuses. Methods: Sera of 556 RRMS patients treated with IFN beta for a period ranging between 2 and 5 years were longitudinally collected every six to twelve months and evaluated for the presence of NAbs by a cytopathic effect (CPE) assay. Neurological examination by Expanded Disability Status Scale (EDSS) and relapses were scheduled every six months. A patient's NAb-positive status was defined after two consecutive positive titers of NAbs >/= 20 neutralizing units (NU)/mL. Multivariate time-dependent Poisson and Cox models were respectively used to analyze the relapse rate and time to confirmed EDSS score 4 between NAb-positive and NAb-negative statuses. A propensity score (PS) matching analysis, adjusted to the time at which the comparator group first became positive, was performed to assess the robustness of the multivariate models. Results: Fourteen per cent of patients became NAb-positive during the follow-up. A significant increase in relapse rate (IRR=1.39; p=0.0076) was found during the NAb-positive in comparison with NAb-negative periods. PS matching analysis confirmed this significant difference (IRR=1.48; p=0.04) and showed a significant trend to a higher risk in time to confirmed EDSS 4.0 (IRR=2.29; p=0.06) during the NAb-positive periods. Conclusions: This post-marketing survey on a large cohort of RRMS patients confirmed a reduced effectiveness of IFN beta with respect to the disease activity due to NAb positivity. Moreover, an unfavorable effect of NAbs on long-term disability progression was also demonstrated, suggesting that NAb testing may be useful in therapeutic decisions.