Delay from treatment start to full effect of immunotherapies for multiple sclerosis
Language English Country England, Great Britain Media print
Document type Journal Article, Multicenter Study, Observational Study, Research Support, Non-U.S. Gov't
PubMed
32947619
DOI
10.1093/brain/awaa231
PII: 5908734
Knihovny.cz E-resources
- Keywords
- multiple sclerosis, therapeutic lag,
- MeSH
- Time Factors MeSH
- Adult MeSH
- Immunologic Factors administration & dosage MeSH
- Immunosuppressive Agents administration & dosage MeSH
- Cohort Studies MeSH
- Middle Aged MeSH
- Humans MeSH
- Follow-Up Studies MeSH
- Natalizumab administration & dosage MeSH
- Disease Progression * MeSH
- Prospective Studies MeSH
- Registries MeSH
- Multiple Sclerosis diagnostic imaging drug therapy physiopathology MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Observational Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Immunologic Factors MeSH
- Immunosuppressive Agents MeSH
- Natalizumab MeSH
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.
Central Clinical School Monash University Melbourne 3004 Australia
Centro Hospitalar Universitário de São João and Universidade Fernando Pessoa 4249 004 Porto Portugal
CHUM MS Center and Universite de Montreal Montreal H2L 4M1 Canada
CISSS Chaudière Appalache Lévis Levis G6X 0A1 Canada
Cliniques universitaires Saint Luc Brussels 1200 BXL Belgium
CORe Department of Medicine University of Melbourne Melbourne 3050 Australia
CSSS Saint Jérôme Saint Jérôme QC J7Z 0H6 Canada
Department of Biomedical and Neuromotor Sciences University of Bologna Bologna Italy
Department of Clinical Neurosciences University of Cambridge Cambridge CB2 0QQ UK
Department of General Medicine Parma University Hospital Parma 43126 Italy
Department of Medicine and Surgery University of Parma Parma 43126 Italy
Department of Neurology Austin Health Heidlberg 3084 Australia
Department of Neurology Box Hill Hospital Monash University Melbourne 3128 Australia
Department of Neurology Faculty of Medicine University of Debrecen Debrecen 4032 Hungary
Department of Neurology John Hunter Hospital Hunter New England Health Newcastle 2305 Australia
Department of Neurology Razi Hospital 2010 Tunis Manouba Tunisia
Department of Neurology The Alfred Hospital Melbourne 3004 Australia
Department of Neuroscience Azienda Ospedaliera Universitaria Modena 41100 Italy
Department of Neuroscience Imaging and Clinical Sciences University G d'Annunzio 66100 Chieti Italy
Dokuz Eylul University Konak Izmir 35220 Turkey
Faculty of Medicine and Dental Health Sciences University of Melbourne Melbourne 3050 Australia
Flinders University Adelaide 5042 Australia
GF Ingrassia Department University of Catania Catania 95123 Italy
Haydarpasa Numune Training and Research Hospital Selimiye Mahallesi Istanbul 34668 Turkey
Hospital Universitario Reina Sofia Cordoba 14004 Cordoba Spain
Hospital Universitario Virgen Macarena Sevilla 41009 Spain
IRCCS Mondino Foundation Pavia 27100 Italy
KTU Medical Faculty Farabi Hospital Karadeniz Technical University Trabzon 61080 Turkey
Medical Faculty 19 Mayis University Kurupelit Samsun 55160 Turkey
Melbourne MS Centre Department of Neurology Royal Melbourne Hospital Melbourne 3050 Australia
Policlinico G Rodolico 95123 Catania Italy
Rehabilitation and MS Centre Overpelt and Hasselt University Hasselt 3900 Belgium
Rennes University EHESP REPERES EA 7449 Rennes France
Royal Brisbane and Women's Hospital Herston 4029 Australia
School of Medicine and Public Health University Newcastle 2308 Australia
University of Lyon Claude Bernard University Lyon 1 F 69000 Lyon France
University of Queensland St Lucia 4072 Australia
UOC Neurologia Azienda Sanitaria Unica Regionale Marche AV3 Macerata 62100 Italy
Zuyderland Ziekenhuis Sittard Sittard 6131 BK The Netherlands
References provided by Crossref.org
Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis
