RT Journal Article
T1 Delay from treatment start to full effect of immunotherapies for multiple sclerosis.
A1 Roos, Izanne
A1 Leray, Emmanuelle
A1 Frascoli, Federico
A1 Casey, Romain
A1 Brown, J William L
A1 Horakova, Dana
A1 Havrdova, Eva K
A1 Trojano, Maria
A1 Patti, Francesco
A1 Izquierdo, Guillermo
A1 Eichau, Sara
A1 Onofrj, Marco
A1 Lugaresi, Alessandra
A1 Prat, Alexandre
A1 Girard, Marc
A1 Grammond, Pierre
A1 Sola, Patrizia
A1 Ferraro, Diana
A1 Ozakbas, Serkan
A1 Bergamaschi, Roberto
A1 Sa, Maria Jose
A1 Cartechini, Elisabetta
A1 Boz, Cavit
A1 Granella, Franco
A1 Hupperts, Raymond
A1 Terzi, Murat
A1 Lechner-Scott, Jeannette
A1 Spitaleri, Daniele
A1 Van Pesch, Vincent
A1 Soysal, Aysun
A1 Olascoaga, Javier
A1 Prevost, Julie
A1 Aguera-Morales, Eduardo
A1 Slee, Mark
A1 Csepany, Tunde
A1 Turkoglu, Recai
A1 Sidhom, Youssef
A1 Gouider, Riadh
A1 Van Wijmeersch, Bart
A1 McCombe, Pamela
A1 Macdonell, Richard
A1 Coles, Alasdair
A1 Malpas, Charles B
A1 Butzkueven, Helmut
A1 Vukusic, Sandra
A1 Kalincik, Tomas
K1 multiple sclerosis
K1 therapeutic lag
K1 Cohort studies
K1 Disease progression
AB In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
PB Oxford University Press
YR 2020
FD 2020-06-01
LK http://hdl.handle.net/10668/16279
UL http://hdl.handle.net/10668/16279
LA en
NO Roos I, Leray E, Frascoli F, Casey R, Brown JWL, Horakova D, det al. Delay from treatment start to full effect of immunotherapies for multiple sclerosis. Brain. 2020 Sep 1;143(9):2742-2756
DS RISalud
RD Apr 8, 2025