Delay from treatment start to full effect of immunotherapies for multiple sclerosis
Izanne Roos1,2, Emmanuelle Leray3,4, Federico Frascoli5, Romain Casey6,7,8,9, J William Brown10, Dana Horakova11, Eva Havrdova11, Maria Trojano12, Francesco Patti13, Guillermo Izquierdo14, Sara Eichau Madueño15, Marco Onofrj16, Alessandra Lugaresi17, Alexandre Prat18, Marc Girard19, Pierre Grammond20, Patrizia Sola21, Diana Ferraro22, Serkan Ozakbas23, Roberto Bergamaschi24, Maria Jose Sa25, Elisabetta Cartechini26, Cavit Boz27, Franco Granella28,29, Oliver Gerlach30, Murat Terzi31, Jeannette Lechner-Scott32, Daniele Litterio A. Spitaleri33, Vincent Van Pesch34, Aysun Soysal35, Javier Olascoaga36, Julie Prevost37, Eduardo Aguera Morales38, Mark Slee39, Tunde Csepany40, Recai Turkoglu41, Youssef Sidhom42, Riadh Gouider43, Bart Van Wijmeersch44, Pamela McCombe45,46, Richard Macdonell47,48, Alasdair Coles10, Charles Malpas1,2, Helmut Butzkueven49,50,51, Sandra Vukusic52,53,54, Tomas Kalincik1,2
1Clinical Outcomes Research Unit, University of Melbourne, 2Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, 3Département METIS, EHESP School of Public Health, 44EA 7449 REPERES, EHESP/Rennes 1 University, 5Faculty of Science, Engineering and Technology, School of Science, Department of Mathematics, Swinburne University of Technology, 6Université Claude Bernard Lyon 1, 7Hospices Civils de Lyon, 8Centre des Neurosciences de Lyon, Observatoire Français de la Sclérose en Plaques, INSERM, 9EDMUS Foundation, 10University of Cambridge, 11Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, 12Policlinico - Bari, 13GF Ingrassia Department, University of Catania, 14Servicio De Neurologia, 15Hospital Universitario Virgen Macarena, 16Department of Neuroscience, Imaging, and Clinical Sciences, University G. díAnnunzio, Chieti, 17IRCCS Istituto delle Scienze Neurologiche di Bologna, 18CHUM Hopital Norte Dame/ Dept of Neurology, 19CHUM MS Center and Universite de Montreal, Montreal, 20Hotel-Dieu De Levis Hospital, 21Nuovo Ospedale Civile S. Agostino-Estense, 22University of Modena and Reggio Emilia, 23DOKUZ EYLUL UNI. FACULTY OF MEDICINE, 24IRCCS Mondino Foundation, 25Centro Hospitalar Universitário de São João and Universidade Fernando Pessoa, 26UOC Neurologia, Azienda Sanitaria Unica Regionale Marche - AV3,, 27KTU Medical Faculty Farabi Hospital, Karadeniz Technical University, 28Department of Medicine and Surgery, University of Parma, 29Department of General Medicine, Parma University Hospital, 30Zuyderland Ziekenhuis, Sittard, 3119 Mayis Universitesi, 32Hunter New England Health, 33Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, 34Cliniques St-Luc, 35Bakirkoy Hospital Of Mental Disorders And Neuro, 36Instituto de Investigación Sanitaria Biodonostia, Hospital Universitario Donostia, 37Neurologie des Laurentides, 38Hospital Universitario Reina Sofia, 39Flinders Medical Centre, Bedford Park, 40University of Debrecen, 41Haydarpasa Numune Training and Research Hospital, Selimiye Mahallesi, 42Department of Neurology, 43Erazi Hospital, 44Rehabilitation & MS-Centre Overpelt, 45University of Queensland, 46Royal Brisbane and Women's Hospital, Butterfield, 47Department of Neurology, Austin Health, 48Faculty of Medicine and Dental Health Sciences, University of Melbourne, 49Central Clinical School, 99 Commercial Rd, Monash University, 50Department of Neurology, The Alfred Hospital, 51Department of Neurology, Box Hill Hospital, 52Hopital Neurologique Pierre Wertheimer, 53Hospices Civils de Lyon, Service de Neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, 54Observatoire Français de la Sclérose en Plaques, Lyon Neuroscience Research Centre, INSERM

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.


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. 


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.


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.

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.