Identification of Therapeutic Lag in Multiple Sclerosis

Izanne Roos (1) , Emmanuelle Leray (2, 3, 4, 5, 6) , Federico Frascoli (7) , Romain Casey (8, 9, 10) , Dana Horakova , Eva Havrdova , Maria Trojano (11) , Guillermo Izquierdo Ayuso , Sara Eichau Madueno , Francesco Patti , Marco Onofrj (12) , Alessandra Lugaresi (12) , Alexandre Prat , Marc Girard (13) , Pierre Duquette , Serkan Ozakbas , Pierre Grammond , Patrizia Sola , Diana Ferraro (14) , Roberto Bergamaschi (15) , Cavit Boz , Elisabetta Cartechini , Maria Jose Sa , Murat Terzi , Raed Alroughani , Francois Grand'Maison , Franco Granella , Gerardo Iuliano , Raymond Hupperts , Jeannette Lechner-Scott , Daniele Litterio A. Spitaleri , Vincent van Pesch , Aysun Soysal , Julie Prévost-Zuddas , Eduardo Aguera Morales , Francisco Javier Olascoaga Urtaza , Recai Turkoglu , Youssef Sidhom , Riadh Gouider , Bart van Wijmeersch , Helmut Butzkueven , Charles Malpas , Sandra Vukusic (9) , Tomas Kalincik (1)

1 Melbourne Medical School [Melbourne]
2 REPERES - Recherche en Pharmaco-épidémiologie et Recours aux Soins
3 EA 4069 - Epidémiologie, Evaluation et Politiques de Santé
4 EHESP - École des Hautes Études en Santé Publique [EHESP]
5 METIS - Département Méthodes quantitatives en santé publique
6 CoRHASI - Collectif de recherche handicap, autonomie et société inclusive
7 Swinburne University of Technology [Melbourne]
8 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
9 HCL - Hospices Civils de Lyon
10 Fondation Eugène Devic EDMUS
11 Polytechnic University of Bari / Politecnico di Bari
12 Ud'A - Università degli studi "G. d'Annunzio" Chieti-Pescara [Chieti-Pescara]
13 McGill University = Université McGill [Montréal, Canada]
14 UNIMORE - Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia
15 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico

Objective: To develop a method that allows identification of the time to full clinically manifest effect of multiple sclerosis (MS) treatments (‘therapeutic lag’) on clinical disease activity.Background: In MS, treatment start or switch is prompted by evidence of disease activity, often presenting as relapses or disability progression. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear.Design/Methods: Data from MSBase, a multinational MS registry, and OFSEP, the French national registry, were used. Patients diagnosed with MS, minimum 1-year exposure to MS treatment, minimum 3-year pre-treatment 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 in the analysis. 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 represents the point of stabilisation of treatment effect, after the maximum treatment effect was observed. The method was developed using MSBase, and externally validated in OFSEP. A merged MSBase-OFSEP cohort was used for all subsequent analyses.Results: 11180 eligible treatment epochs were identified for analysis of relapses and 4088 treatment epochs for disability progression. There were no significant differences between the results of discovery and validation analyses. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12–30 weeks. The duration of therapeutic lag for disability progression was calculated for 7 therapies and ranged between 30–70 weeks.Conclusions: We have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies. This method will be applied in studies that will evaluate the effect of patient and disease characteristics on therapeutic lag.

Mots clés: Multiple sclerosis

Domaines: Sciences du Vivant [q-bio]

Izanne Roos, Emmanuelle Leray, Federico Frascoli, Romain Casey, Dana Horakova, et al.. Identification of Therapeutic Lag in Multiple Sclerosis. Neurology, 2020, 94 (15). ⟨hal-02929403⟩