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

Izanne Roos; Emmanuelle Leray; Federico Frascoli; Romain Casey; J William L Brown; Dana Horakova; Eva Havrdova; Maria Trojano; Francesco Patti; Guillermo Izquierdo; Sara Eichau; Marco Onofrj; Alessandra Lugaresi; Alexandre Prat; Marc Girard; Pierre Grammond; Patrizia Sola; Diana Ferraro; Serkan Ozakbas; Roberto Bergamaschi; Maria José Sá; Elisabetta Cartechini; Cavit Boz; Franco Granella; Raymond Hupperts; Murat Terzi; Jeannette Lechner-Scott; Daniele Spitaleri; Vincent van Pesch; Aysun Soysal; Javier Olascoaga; Julie Prevost; Eduardo Aguera-Morales; Mark Slee; Tunde Csepany; Recai Turkoglu; Youssef Sidhom; Riadh Gouider; Bart van Wijmeersch; Pamela Mccombe; Richard Macdonell; Alasdair Coles; Charles Malpas; Helmut Butzkueven; Sandra Vukusic; Tomas Kalincik; Pierre Duquette; Francois Grand'Maison; Gerardo Iuliano; 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; 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; Céline Labeyrie; Chantal Nifle

doi:10.1093/brain/awaa231

Journal Articles Brain - A Journal of Neurology Year : 2020

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

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Izanne Roos

Function : Author

University of Melbourne

The Royal Melbourne Hospital

Emmanuelle Leray

Function : Author
PersonId : 18386
IdHAL : emmanuelle-leray
ORCID : 0000-0001-8424-4499
IdRef : 099858185

Recherche en Pharmaco-épidémiologie et Recours aux Soins

École des Hautes Études en Santé Publique [EHESP]

Département Méthodes quantitatives en santé publique

Federico Frascoli

Function : Author

Swinburne University of Technology [Melbourne]

Romain Casey

Function : Author

Université Claude Bernard Lyon 1

J William L Brown

Function : Author

University of Cambridge [UK]

Dana Horakova

Function : Author

Medicine Charles University and General Faculty Hospital in Prague

Eva Havrdova

Function : Author

Medicine Charles University and General Faculty Hospital in Prague

Maria Trojano

Function : Author

Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro

Francesco Patti

Function : Author

Università degli studi di Catania = University of Catania

Guillermo Izquierdo

Function : Author

Hospital Universitario Virgen Macarena [Séville]

Sara Eichau

Function : Author

Hospital Universitario Virgen Macarena [Séville]

Marco Onofrj

Function : Author

University "G. d'Annunzio" of Chieti-Pescara [Chieti]

Alessandra Lugaresi

Function : Author

Alma Mater Studiorum Università di Bologna = University of Bologna

Alexandre Prat

Function : Author

Université de Montréal

Marc Girard

Function : Author

Université de Montréal

Pierre Grammond

Function : Author

Patrizia Sola

Function : Author

Diana Ferraro

Function : Author

University of Modena and Reggio Emilia

Serkan Ozakbas

Function : Author

Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir]

Roberto Bergamaschi

Function : Author

IRCCS Mondino Foundation

Maria José Sá

Function : Author

Universidade Fernando Pessoa

Elisabetta Cartechini

Function : Author

Cavit Boz

Function : Author

KTU Medical Faculty Farabi Hospital

Franco Granella

Function : Author

Università degli studi di Parma = University of Parma

Raymond Hupperts

Function : Author

Zuyderland Ziekenhuis

Murat Terzi

Function : Author

Medical Faculty [Samsun, Turkey]

Jeannette Lechner-Scott

Function : Author

University of Newcastle [Callaghan, Australia]

Daniele Spitaleri

Function : Author

Vincent van Pesch

Function : Author

Université Catholique de Louvain = Catholic University of Louvain

Aysun Soysal

Function : Author

Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases

Javier Olascoaga

Function : Author

Hospital Universitario Donostia

Julie Prevost

Function : Author

Eduardo Aguera-Morales

Function : Author

Hospital Universitario Reina Sofía de Córdoba

Mark Slee

Function : Author

Tunde Csepany

Function : Author

Recai Turkoglu

Function : Author

Haydarpasa Numune Training and Research Hospital

Youssef Sidhom

Function : Author

Riadh Gouider

Function : Author

Bart van Wijmeersch

Function : Author

Hasselt University

Pamela Mccombe

Function : Author

The University of Queensland

Richard Macdonell

Function : Author

Alasdair Coles

Function : Author

Hitachi Cambridge Laboratory [University of Cambridge]

Charles Malpas

Function : Author

University of Melbourne

Helmut Butzkueven

Function : Author

Monash University [Melbourne]

Sandra Vukusic

Function : Author
PersonId : 740274
IdHAL : adil-maarouf
ORCID : 0000-0002-6755-496X
IdRef : 164833250

Tomas Kalincik

Function : Author

University of Melbourne

Pierre Duquette

Function : Author

Centre de Recherche du Centre Hospitalier de l’Université de Montréal

Francois Grand'Maison

Function : Author

Gerardo Iuliano

Function : Author

Ospedali Riuniti di Salerno

Cristina Ramo-Tello

Function : Author

Claudio Solaro

Function : Author

Jose Antonio Cabrera-Gomez

Function : Author

Maria Edite Rio

Function : Author

Ricardo Fernandez Bolaños

Function : Author

Vahid Shaygannejad

Function : Author

Celia Oreja-Guevara

Function : Author

Jose Luis Sanchez-Menoyo

Function : Author

Thor Petersen

Function : Author

Ayse Altintas

Function : Author

Michael Barnett

Function : Author

Shlomo Flechter

Function : Author

Yara Fragoso

Function : Author

Maria Pia Amato

Function : Author

Fraser Moore

Function : Author

Radek Ampapa

Function : Author

Freek Verheul

Function : Author

Suzanne Hodgkinson

Function : Author

Edgardo Cristiano

Function : Author

Bassem Yamout

Function : Author

Guy Laureys

Function : Author

Jose Andres Dominguez

Function : Author

Cees Zwanikken

Function : Author

Norma Deri

Function : Author

Eniko Dobos

Function : Author

Carlos Vrech

Function : Author

Ernest Butler

Function : Author

Csilla Rozsa

Function : Author

Tatjana Petkovska-Boskova

Function : Author

Rana Karabudak

Function : Author

Cecilia Rajda

Function : Author

Jabir Alkhaboori

Function : Author

Maria Laura Saladino

Function : Author

Cameron Shaw

Function : Author

Neil Shuey

Function : Author

Steve Vucic

Function : Author

Angel Perez Sempere

Function : Author

Jamie Campbell

Function : Author

Imre Piroska

Function : Author

Bruce Taylor

Function : Author

Anneke van Der Walt

Function : Author

Ludwig Kappos

Function : Author

Etienne Roullet

Function : Author

Orla Gray

Function : Author

Magdolna Simo

Function : Author

Carmen-Adella Sirbu

Function : Author

Bruno Brochet

Function : Author
PersonId : 773703
ORCID : 0000-0003-3824-2796

François Cotton

Function : Author
PersonId : 170687
IdHAL : francois-cotton
ORCID : 0000-0003-0046-2478
IdRef : 070732035

Jérôme de Sèze

Function : Author

Armelle Dion

Function : Author

Pascal Douek

Function : Author

Francis Guillemin

Function : Author
PersonId : 757347
IdRef : 068536569

David Laplaud

Function : Author

Christine Lebrun-Frenay

Function : Author
PersonId : 770285
ORCID : 0000-0002-3713-2416
IdRef : 074517929

Thibault Moreau

Function : Author

Javier Olaiz

Function : Author

Jean Pelletier

Function : Author
PersonId : 756935
ORCID : 0000-0001-9730-7567
IdRef : 078804868

Claire Rigaud-Bully

Function : Author

Bruno Stankoff

Function : Author
PersonId : 1146488
ORCID : 0000-0002-9631-4674
IdRef : 070067988

Romain Marignier

Function : Author

Marc Debouverie

Function : Author
PersonId : 762777
IdRef : 068986629

Gilles Edan

Function : Author

Jonathan Ciron

Function : Author
PersonId : 795646
ORCID : 0000-0002-3386-6308
IdRef : 137599021

Aurélie Ruet

Function : Author

Nicolas Collongues

Function : Author
PersonId : 764750
ORCID : 0000-0002-3683-5582

Catherine Lubetzki

Function : Author

Patrick Vermersch

Function : Author
PersonId : 762778
ORCID : 0000-0003-0997-8817

Pierre Labauge

Function : Author
PersonId : 759958
ORCID : 0000-0001-7759-8555
IdRef : 059860367

Centre Hospitalier Régional Universitaire [Montpellier]

Université de Montpellier

Gilles Defer

Function : Author

Mikaël Cohen

Function : Author

Agnès Fromont

Function : Author
PersonId : 770976
IdRef : 088126382

Sandrine Wiertlewsky

Function : Author

Eric Berger

Function : Author

Pierre Clavelou

Function : Author

Bertrand Audoin

Function : Author
PersonId : 756934
ORCID : 0000-0002-9860-7657

Claire Giannesini

Function : Author

Olivier Gout

Function : Author
PersonId : 946000
IdRef : 052535118

Eric Thouvenot

Function : Author
PersonId : 758070
ORCID : 0000-0001-8671-7747
IdRef : 094970920

Olivier Heinzlef

Function : Author

Abdullatif Al-Khedr

Function : Author

Bertrand Bourre

Function : Author

Olivier Casez

Function : Author

Philippe Cabre

Function : Author

Alexis Montcuquet

Function : Author

Alain Créange

Function : Author

Jean-Philippe Camdessanché

Function : Author
PersonId : 775005
ORCID : 0000-0002-5282-6707

Justine Faure

Function : Author

Aude Maurousset

Function : Author

Ivania Patry

Function : Author

Karolina Hankiewicz

Function : Author

Corinne Pottier

Function : Author

Nicolas Maubeuge

Function : Author

Centre hospitalier universitaire de Poitiers = Poitiers University Hospital

Céline Labeyrie

Function : Author

Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]

Chantal Nifle

Function : Author

Abstract

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.

Keywords

Multiple sclerosis Immunotherapies

Domains

Santé publique et épidémiologie

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https://ehesp.hal.science/hal-02955197

Submitted on : Thursday, October 1, 2020-3:56:10 PM

Last modification on : Tuesday, April 23, 2024-11:22:11 AM

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hal-02955197 , version 1 (01-10-2020)

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HAL Id : hal-02955197 , version 1
DOI : 10.1093/brain/awaa231
PUBMED : 32947619

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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⟩

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

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