Neutralizing antibodies and efficacy of interferon β-1a -: A 4-year controlled study

Objective: To determine the incidence and clinical significance of neutralizing antibody (NAb) formation in patients with relapsing multiple sclerosis ( MS) who participated in the European Interferon Beta-1a IM Dose-Comparison Study. Methods. Patients were randomized to treatment with interferon beta-1a (IFN beta-1a) 30 mu g or 60 mu g IM once weekly for up to 4 years. Serum samples obtained at baseline and every 3 months thereafter were screened for the presence of IFN binding antibodies by ELISA. Patients whose results were seropositive on ELISA were screened for the presence of NAbs using an antiviral cytopathic effect assay. Patients were considered to be positive for NAbs ( NAb+) if the baseline NAb titer was 0 and two or more consecutive postbaseline titers were >= 20. Patients were considered to be negative for NAbs ( NAb -) if the baseline NAb titer was 0 and all postbaseline NAb titers were < 5. Results: The proportion of patients who became NAb + was lower in patients who received 30 mu g of IFN beta-1a than in those who received 60 mu g (7/400 [1.8%] vs 19/395 [4.8%]; p = 0.02). The mean time to NAb + status was 14.5 +/- 6.2 months. Compared with patients who remained NAb -, NAb + patients showed the following: higher relapse rates from months 12 to 48 ( p = 0.04), higher rate of mean change ( worsening) in Expanded Disability Status Scale score from baseline to month 48 ( p = 0.01), greater number of T1 gadolinium-enhanced lesions at months 24 and 36 ( p = 0.02 and 0.03), and greater accrual of new or enlarging T2 lesions from month 12 to months 24 and 36 ( p = 0.05 and 0.09) Conclusions: Neutralizing antibodies ( NAbs) to interferon beta-1a (IFN beta-1a), as observed with other IFN beta s used in the treatment of multiple sclerosis, reduce the therapeutic benefits measured by relapses and MRI activity. Data from this study also suggest NAbs to IFN beta-1a reduce treatment benefits as measured by change in Expanded Disability Status Scale score.