TY - JOUR
T1 - Neutralizing antibodies to interferon beta-1b multiple sclerosis
T2 - A clinico-radiographic paradox in the beyond trial
AU - Goodin, Douglas S.
AU - Hartung, Hans Peter
AU - O'Connor, Paul
AU - Filippi, Massimo
AU - Arnason, Barry
AU - Comi, Giancarlo
AU - Cook, Stuart
AU - Jeffery, Douglas
AU - Kappos, Ludwig
AU - Bogumil, Timon
AU - Knappertz, Volker
AU - Sandbrink, Rupert
AU - Beckmann, Karola
AU - White, Rick
AU - Petkau, John
AU - Pohl, Christoph
PY - 2012
Y1 - 2012
N2 - Background: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial. Objective: To assess NAb impact in the BEYOND study. Methods: 2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 μg, or glatiramer acetate, 20 mg, and observed for 2-3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors. Results: In the IFNβ-1b 250 μg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNβ-1b 500 μg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250 μg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes.Conclusion: There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.
AB - Background: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial. Objective: To assess NAb impact in the BEYOND study. Methods: 2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 μg, or glatiramer acetate, 20 mg, and observed for 2-3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors. Results: In the IFNβ-1b 250 μg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNβ-1b 500 μg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250 μg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes.Conclusion: There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.
KW - BEYOND study
KW - interferon beta-1b
KW - multiple sclerosis
KW - neutralizing antibodies
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U2 - 10.1177/1352458511418629
DO - 10.1177/1352458511418629
M3 - Article
C2 - 21952094
AN - SCOPUS:84856734786
VL - 18
SP - 181
EP - 195
JO - Multiple Sclerosis
JF - Multiple Sclerosis
SN - 1352-4585
IS - 2
ER -