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December 28, 2020Article

Effect of Disease Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years

View ORCID ProfileTomas 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
First published December 28, 2020, DOI: https://doi.org/10.1212/WNL.0000000000011242
Tomas Kalincik
From the Tomas Kalincik, Sifat Sharmin, Charles Malpas, Ibrahima Diouf; CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, AustraliaTim Spelman; Karolinska Institute, Stockholm, Sweden; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Burnet Institute, Melbourne, AustraliaDana Horakova, Eva Kubala Havrdova; Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University in Prague, Prague, Czech RepublicMaria Trojano; Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, ItalyGuillermo Izquierdo; Hospital Universitario Virgen Macarena, Sevilla, SpainAlessandra Lugaresi; Department of Neuroscience, Imaging and Clinical Sciences, University“G. d’Annunzio”, Chieti, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna; IRCCS Istituto delle Scienze Neurologiche di BolognaAlexandre Prat, Marc Girard, Pierre Duquette; Hopital Notre Dame, Montreal, Canada; CHUM and Universite de Montreal, Montreal, CanadaPierre Grammond; CISSS Chaudière-Appalache, Levis, CanadaVilija Jokubaitis, Anneke van der Walt, Olga Skibina; Department of Neurology, Alfred Hospital, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, AustraliaFrancois Grand'Maison; Neuro Rive-Sud, Quebec, CanadaPatrizia Sola, Diana Ferraro; Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, ItalyVahid Shaygannejad; Isfahan University of Medical Sciences, Isfahan, IranRaed Alroughani; Amiri Hospital, Kuwait City, KuwaitRaymond Hupperts; Zuyderland Ziekenhuis, Sittard, NetherlandsMurat Terzi; Medical Faculty, 19 Mayis University, Samsun, TurkeyCavit Boz; KTU Medical Faculty Farabi Hospital, Karadeniz Technical University, Trabzon, TurkeyJeannette Lechner-Scott; School of Medicine and Public Health, University Newcastle, Newcastle, Australia; Department of Neurology, John Hunter Hospital, Newcastle, AustraliaEugenio Pucci; UOC Neurologia, Azienda Sanitaria Unica Regionale Marche - AV3, Macerata, ItalyVincent Van Pesch; Cliniques Universitaires Saint-Luc, Brussels, BelgiumFranco Granella; University of Parma, Parma, ItalyRoberto Bergamaschi; C. Mondino National Neurological Institute, Pavia, ItalyDaniele Spitaleri; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, ItalyMark Slee; Flinders University, Adelaide, AustraliaSteve Vucic; Westmead Hospital, Sydney, AustraliaRadek Ampapa; Nemocnice Jihlava, Jihlava, Czech RepublicPamela McCombe; University of Queensland, Brisbane, Australia; Royal Brisbane and Women's Hospital, Brisbane, AustraliaCristina Ramo-Tello; Hospital Germans Trias i Pujol, Badalona, SpainJulie Prevost; CSSS Saint-Jérôme, Saint-Jerome, CanadaJavier Olascoaga; Hospital Universitario Donostia, Paseo de Begiristain, San Sebastián, SpainEdgardo Cristiano; Hospital Italiano, Buenos Aires, ArgentinaMichael Barnett; Brain and Mind Centre, University of Sydney, Sydney, AustraliaMaria Laura Saladin; INEBA - Institute of Neuroscience Buenos Aires, Buenos Aires, ArgentinaJose Luis Sanchez-Menoyo; Hospital de Galdakao-Usansolo, Galdakao, SpainSuzanne Hodgkinson; Liverpool Hospital, Sydney, AustraliaCsilla Rozsa; Jahn Ferenc Teaching Hospital, Budapest, HungaryStella Hughes; Craigavon Area Hospital, Craigavon, United KingdomFraser Moore; Jewish General Hospital, Montreal, CanadaCameron Shaw; Deakin University, Geelong, AustraliaErnest Butler; Monash Medical Centre, Melbourne, AustraliaOrla Gray; South East Trust, Belfast, United KingdomAllan Kermode; Perron Institute, University of Western Australia, Nedlands, Australia; Institute of Immunology and Infectious Diseases, Murdoch University, Perth, Australia; Sir Charles Gairdner Hospital, Perth, AustraliaTunde Csepany; Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, HungaryBhim Singhal; Bombay Hospital Institute of Medical Sciences, Mumbai, IndiaNeil Shuey; St Vincents Hospital, Fitzroy, Melbourne, AustraliaImre Piroska; Veszprém Megyei Csolnoky Ferenc Kórház zrt., Veszprem, HungaryBruce Taylor, MD, PhD; Royal Hobart Hospital, Hobart, AustraliaMagdolna Simo, MD; Semmelweis University Budapest, Budapest, HungaryCarmen-Adella Sirbu; Central Military Emergency University Hospital, Bucharest, Romania; Titu Maiorescu University, Bucharest, RomaniaAttila Sas; BAZ County Hospital, Miskolc, HungaryHelmut Butzkueven; Department of Neurology, Alfred Hospital, Melbourne, Australia; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Box Hill Hospital, Melbourne, Australia
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Ibrahima Diouf
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Sifat Sharmin
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Full PDF
Citation
Effect of Disease Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years
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
Neurology Dec 2020, 10.1212/WNL.0000000000011242; DOI: 10.1212/WNL.0000000000011242

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Abstract

Objective To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis, we modelled disability outcomes in 14,717 patients.

Methods We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year and exposed to a multiple sclerosis therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the hazard of 12-month confirmed increase and decrease in disability, EDSS step 6 and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously re-adjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability and MRI activity.

Results 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval 0.43–0.82, p = 0.0016), worsening of disability (0.56, 0.38–0.82, p = 0.0026) and progress to EDSS step 6 (0.33, 0.19–0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50–0.70, p = 10−9) and worsening of disability (0.81, 0.67–0.99, p = 0.043).

Conclusions Continued treatment with multiple sclerosis immunotherapies reduces disability accrual by 19%–44% (95%CI 1%–62%), the risk of need of a walking aid by 67% (95%CI 41%–81%) and the frequency of relapses by 40–41% (95%CI 18%–57%) over 15 years. This study provides the evidence that disease modifying therapies are effective in improving disability outcomes in relapsing-remitting multiple sclerosis over the long-term.

Classification of evidence This study provides class IV evidence that for patients with relapsing-remitting multiple sclerosis, long-term exposure to immunotherapy prevents neurological disability.

  • Received June 13, 2019.
  • Accepted in final form September 23, 2020.
  • © 2020 American Academy of Neurology

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