Delay from treatment start to full effect of immunotherapies for multiple sclerosis

Izanne Roos (1, 2) , Emmanuelle Leray (3, 4, 5) , Federico Frascoli (6) , Romain Casey (7) , J William L Brown (8) , Dana Horakova (9) , Eva Havrdova (9) , Maria Trojano (10) , Francesco Patti (11) , Guillermo Izquierdo (12) , Sara Eichau (12) , Marco Onofrj (13) , Alessandra Lugaresi (14) , Alexandre Prat (15) , Marc Girard (15) , Pierre Grammond , Patrizia Sola , Diana Ferraro (16) , Serkan Ozakbas (17) , Roberto Bergamaschi (18) , Maria José Sá (19) , Elisabetta Cartechini , Cavit Boz (20) , Franco Granella (21) , Raymond Hupperts (22) , Murat Terzi (23) , Jeannette Lechner-Scott (24) , Daniele Spitaleri , Vincent van Pesch (25) , Aysun Soysal (26) , Javier Olascoaga (27) , Julie Prevost , Eduardo Aguera-Morales (28) , Mark Slee , Tunde Csepany , Recai Turkoglu (29) , Youssef Sidhom , Riadh Gouider , Bart van Wijmeersch (30) , Pamela Mccombe (31) , Richard Macdonell , Alasdair Coles (32) , Charles Malpas (33) , Helmut Butzkueven (34) , Sandra Vukusic , Tomas Kalincik (33) , Pierre Duquette (35) , Francois Grand'Maison , Gerardo Iuliano (36) , Cristina Ramo-Tello , Claudio Solaro , Jose Antonio Cabrera-Gomez , Maria Edite Rio , Ricardo Fernandez Bolaños , Vahid Shaygannejad , Celia Oreja-Guevara , Jose Luis Sanchez-Menoyo , Thor Petersen , Ayse Altintas , Michael Barnett , Shlomo Flechter , Yara Fragoso , Maria Pia Amato , Fraser Moore , Radek Ampapa , Freek Verheul , Suzanne Hodgkinson , Edgardo Cristiano , Bassem Yamout , Guy Laureys , Jose Andres Dominguez , Cees Zwanikken , Norma Deri , Eniko Dobos , Carlos Vrech , Ernest Butler , Csilla Rozsa , Tatjana Petkovska-Boskova , Rana Karabudak , Cecilia Rajda , Jabir Alkhaboori , Maria Laura Saladino , Cameron Shaw , Neil Shuey , Steve Vucic , Angel Perez Sempere , Jamie Campbell , Imre Piroska , Bruce Taylor , Anneke van Der Walt , Ludwig Kappos , Etienne Roullet , Orla Gray , Magdolna Simo , Carmen-Adella Sirbu , Bruno Brochet , François Cotton , Jérôme de Sèze , Armelle Dion , Pascal Douek , Francis Guillemin , David Laplaud , Christine Lebrun-Frenay , Thibault Moreau , Javier Olaiz , Jean Pelletier , Claire Rigaud-Bully , Bruno Stankoff , Romain Marignier , Marc Debouverie , Gilles Edan , Jonathan Ciron , Aurélie Ruet , Nicolas Collongues , Catherine Lubetzki , Patrick Vermersch , Pierre Labauge (37, 38) , Gilles Defer , Mikaël Cohen , Agnès Fromont , Sandrine Wiertlewsky , Eric Berger , Pierre Clavelou , Bertrand Audoin , Claire Giannesini , Olivier Gout , Eric Thouvenot , Olivier Heinzlef , Abdullatif Al-Khedr , Bertrand Bourre , Olivier Casez , Philippe Cabre , Alexis Montcuquet , Alain Créange , Jean-Philippe Camdessanché , Justine Faure , Aude Maurousset , Ivania Patry , Karolina Hankiewicz , Corinne Pottier , Nicolas Maubeuge (39) , Céline Labeyrie (40) , Chantal Nifle

1 University of Melbourne
2 The Royal Melbourne Hospital
3 REPERES - Recherche en Pharmaco-épidémiologie et Recours aux Soins
4 EHESP - École des Hautes Études en Santé Publique [EHESP]
5 METIS - Département Méthodes quantitatives en santé publique
6 Swinburne University of Technology [Melbourne]
7 UCBL - Université Claude Bernard Lyon 1
8 CAM - University of Cambridge [UK]
9 Medicine Charles University and General Faculty Hospital in Prague
10 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
11 Unict - Università degli studi di Catania = University of Catania
12 Hospital Universitario Virgen Macarena [Séville]
13 University "G. d'Annunzio" of Chieti-Pescara [Chieti]
14 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
15 UdeM - Université de Montréal
16 University of Modena and Reggio Emilia
17 DEÜ - Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir]
18 IRCCS Mondino Foundation
19 Universidade Fernando Pessoa
20 KTU Medical Faculty Farabi Hospital
21 UNIPR - Università degli studi di Parma = University of Parma
22 Zuyderland Ziekenhuis
23 Medical Faculty [Samsun, Turkey]
24 UoN - University of Newcastle [Callaghan, Australia]
25 UCL - Université Catholique de Louvain = Catholic University of Louvain
26 Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases
27 Hospital Universitario Donostia
28 Hospital Universitario Reina Sofía de Córdoba
29 Haydarpasa Numune Training and Research Hospital
30 UHasselt - Hasselt University
31 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
32 Hitachi Cambridge Laboratory [University of Cambridge]
33 University of Melbourne
34 Monash University [Melbourne]
35 CR CHUM - Centre de Recherche du Centre Hospitalier de l’Université de Montréal
36 Ospedali Riuniti di Salerno
37 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
38 UM - Université de Montpellier
39 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
40 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]

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.

Mots clés: Multiple sclerosis; Immunotherapies

Domaines: Santé publique et épidémiologie

Izanne Roos, Emmanuelle Leray, Federico Frascoli, Romain Casey, J William L Brown, et al.. Delay from treatment start to full effect of immunotherapies for multiple sclerosis. Brain - A Journal of Neurology , 2020, 143 (9), pp.2742-2756. ⟨10.1093/brain/awaa231⟩. ⟨hal-02955197⟩