Anna He1, Bernd Merkel1, James William L Brown2, Lana Zhovits Ryerson3, Ilya Kister3, Charles B Malpas1, Sifat Sharmin1, Dana Horakova4, Eva Kubala Havrdova4, Tim Spelman5, Guillermo Izquierdo6, Sara Eichau6, Maria Trojano7, Alessandra Lugaresi8, Raymond Hupperts9, Patrizia Sola10, Diana Ferraro10, Jan Lycke11, Francois Grand'Maison12, Alexandre Prat13, Marc Girard13, Pierre Duquette13, Catherine Larochelle13, Anders Svenningsson14, Thor Petersen15, Pierre Grammond16, Franco Granella17, Vincent Van Pesch18, Roberto Bergamaschi19, Christopher McGuigan20, Alasdair Coles21, Jan Hillert5, Fredrik Piehl5, Helmut Butzkueven22, Tomas Kalincik23. 1. CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia. 2. CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London, Institute of Neurology, London, UK. 3. New York University Langone Medical Centre, New York, NY, USA. 4. Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University Prague, Czech Republic; General University Hospital, Prague, Czech Republic. 5. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden. 6. Hospital Universitario Virgen Macarena, Sevilla, Spain. 7. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy. 8. IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Science, University of Bologna, Bologna, Italy. 9. Zuyderland Ziekenhuis, Sittard, Netherlands. 10. Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy. 11. Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 12. Neuro Rive-Sud, Longueuil, QC, Canada. 13. Hopital Notre Dame, Montreal, QC, Canada; CHUM and Universite de Montreal, Montreal, QC, Canada. 14. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden. 15. Aarhus University Hospital, Aarhus, Denmark. 16. CISSS Chaudière-Appalache, Levis, QC, Canada. 17. Department of Medicine and Surgery, University of Parma, Parma, Italy. 18. Cliniques Universitaires Saint-Luc, Brussels, Belgium; Université Catholique de Louvain, Ottignies-Louvain-la-Neuve, Belgium. 19. IRCCS Mondino Foundation, Pavia, Italy. 20. School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland; St Vincent's University Hospital, Dublin, Ireland. 21. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. 22. Central Clinical School and Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia; Department of Neurology, The Alfred Hospital, Melbourne, VIC, Australia. 23. CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia. Electronic address: tomas.kalincik@unimelb.edu.au.
Abstract
BACKGROUND: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset. METHODS: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model. FINDINGS: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period. INTERPRETATION: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. FUNDING: National Health and Medical Research Council Australia and MS Society UK.
BACKGROUND: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset. METHODS: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model. FINDINGS: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period. INTERPRETATION: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. FUNDING: National Health and Medical Research Council Australia and MS Society UK.
Authors: Kathrine E Attfield; Lise Torp Jensen; Max Kaufmann; Manuel A Friese; Lars Fugger Journal: Nat Rev Immunol Date: 2022-05-04 Impact factor: 53.106
Authors: Tomas Kalincik; Ibrahima Diouf; Sifat Sharmin; Charles Malpas; Tim Spelman; Dana Horakova; Eva Kubala Havrdova; Maria Trojano; Guillermo Izquierdo; Alessandra Lugaresi; Alexandre Prat; Marc Girard; Pierre Duquette; Pierre Grammond; Vilija Jokubaitis; Anneke van der Walt; Francois Grand'Maison; Patrizia Sola; Diana Ferraro; Vahid Shaygannejad; Raed Alroughani; Raymond Hupperts; Murat Terzi; Cavit Boz; Jeannette Lechner-Scott; Eugenio Pucci; Vincent Van Pesch; Franco Granella; Roberto Bergamaschi; Daniele Spitaleri; Mark Slee; Steve Vucic; Radek Ampapa; Pamela McCombe; Cristina Ramo-Tello; Julie Prevost; Javier Olascoaga; Edgardo Cristiano; Michael Barnett; Maria Laura Saladino; Jose Luis Sanchez-Menoyo; Suzanne Hodgkinson; Csilla Rozsa; Stella Hughes; Fraser Moore; Cameron Shaw; Ernest Butler; Olga Skibina; Orla Gray; Allan Kermode; Tunde Csepany; Bhim Singhal; Neil Shuey; Imre Piroska; Bruce Taylor; Magdolna Simo; Carmen-Adella Sirbu; Attila Sas; Helmut Butzkueven Journal: Neurology Date: 2020-12-28 Impact factor: 9.910
Authors: Enric Monreal; Susana Sainz de la Maza; Lucienne Costa-Frossard; Paulette Walo-Delgado; Javier Zamora; José Ignacio Fernández-Velasco; Noelia Villarrubia; Mercedes Espiño; Daniel Lourido; Paloma Lapuente; Inmaculada Toboso; José Carlos Álvarez-Cermeño; Jaime Masjuan; Luisa María Villar Journal: Neurol Neuroimmunol Neuroinflamm Date: 2021-07-22