Tomas Kalincik1, Ibrahima Diouf2, Sifat Sharmin2, Charles Malpas2, Tim Spelman2, Dana Horakova2, Eva Kubala Havrdova2, Maria Trojano2, Guillermo Izquierdo2, Alessandra Lugaresi2, Alexandre Prat2, Marc Girard2, Pierre Duquette2, Pierre Grammond2, Vilija Jokubaitis2, Anneke van der Walt2, Francois Grand'Maison2, Patrizia Sola2, Diana Ferraro2, Vahid Shaygannejad2, Raed Alroughani2, Raymond Hupperts2, Murat Terzi2, Cavit Boz2, Jeannette Lechner-Scott2, Eugenio Pucci2, Vincent Van Pesch2, Franco Granella2, Roberto Bergamaschi2, Daniele Spitaleri2, Mark Slee2, Steve Vucic2, Radek Ampapa2, Pamela McCombe2, Cristina Ramo-Tello2, Julie Prevost2, Javier Olascoaga2, Edgardo Cristiano2, Michael Barnett2, Maria Laura Saladino2, Jose Luis Sanchez-Menoyo2, Suzanne Hodgkinson2, Csilla Rozsa2, Stella Hughes2, Fraser Moore2, Cameron Shaw2, Ernest Butler2, Olga Skibina2, Orla Gray2, Allan Kermode2, Tunde Csepany2, Bhim Singhal2, Neil Shuey2, Imre Piroska2, Bruce Taylor2, Magdolna Simo2, Carmen-Adella Sirbu2, Attila Sas2, Helmut Butzkueven2. 1. From CORe (T.K., I.D., S.S., C.M.), Department of Medicine, University of Melbourne; MS Centre (T.K., I.D., S.S., C.M.), Department of Neurology, Royal Melbourne Hospital, Australia; Karolinska Institute (T.S.), Stockholm, Sweden; Department of Neuroscience (T.S., V.J., A.v.d.W., O.S., H.B.), Central Clinical School, Monash University, Melbourne; Burnet Institute (T.S.), Melbourne, Australia; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), General University Hospital and Charles University in Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Hospital Universitario Virgen Macarena (G.I.), Sevilla, Spain; Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University "G. d'Annunzio," Chieti; Department of Biomedical and Neuromotor Sciences (A.L.), University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Hopital Notre Dame (A.P., M.G., P.D.), Montreal; CHUM and Universite de Montreal (A.P., M.G., P.D.); CISSS Chaudière-Appalache (P.G.), Levis, Canada; Department of Neurology (V.J., A.v.d.W., O.S., H.B.), Alfred Hospital, Melbourne, Australia; Neuro Rive-Sud (F. Grand'Maison), Quebec, Canada; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Isfahan University of Medical Sciences (V.S.), Isfahan, Iran; Amiri Hospital (R. Alroughani), Kuwait City, Kuwait; Zuyderland Ziekenhuis (R.H.), Sittard, the Netherlands; Medical Faculty (M. Terzi), 19 Mayis University, Samsun; KTU Medical Faculty Farabi Hospital (C.B.), Karadeniz Technical University, Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; UOC Neurologia (E.P.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Brussels, Belgium; University of Parma (F. Granella); C. Mondino National Neurological Institute (R.B.), Pavia; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.S.), Italy; Flinders University (M. Slee), Adelaide; Westmead Hospital (S.V.), Sydney, Australia; Nemocnice Jihlava (R. Ampapa), Czech Republic; University of Queensland (P.M.), Brisbane; Royal Brisbane and Women's Hospital (P.M.), Brisbane, Australia; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; CSSS Saint-Jérôme (J.P.), Canada; Hospital Universitario Donostia (J.O.), Paseo de Begiristain, San Sebastián, Spain; Hospital Italiano (E.C.), Buenos Aires, Argentina; Brain and Mind Centre (M.B.), University of Sydney, Australia; INEBA-Institute of Neuroscience Buenos Aires (M.L.S.), Argentina; Hospital de Galdakao-Usansolo (J.L.S.-M.), Galdakao, Spain; Liverpool Hospital (S. Hodgkinson), Sydney, Australia; Jahn Ferenc Teaching Hospital (C.R.), Budapest, Hungary; Craigavon Area Hospital (S. Hughes), UK; Jewish General Hospital (F.M.), Montreal, Canada; Deakin University (C.S.), Geelong; Monash Medical Centre (E.B.), Melbourne, Australia; South East Trust (O.G.), Belfast, UK; Perron Institute (A.K.), University of Western Australia, Nedlands; Institute of Immunology and Infectious Diseases (A.K.), Murdoch University; Sir Charles Gairdner Hospital (A.K.), Perth, Australia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences (B.S.), Mumbai, India; St Vincents Hospital (N.S.), Fitzroy, Melbourne, Australia; Veszprém Megyei Csolnoky Ferenc Kórház zrt (I.P.), Veszprem, Hungary; Royal Hobart Hospital (B.T.), Australia; Semmelweis University Budapest (M. Simo), Hungary; Central Military Emergency University Hospital (C.-A.S.), Bucharest; Titu Maiorescu University (C.-A.S.), Bucharest, Romania; BAZ County Hospital (A.S.), Miskolc, Hungary; and Box Hill Hospital (H.B.), Melbourne, Australia. tomas.kalincik@unimelb.edu. 2. From CORe (T.K., I.D., S.S., C.M.), Department of Medicine, University of Melbourne; MS Centre (T.K., I.D., S.S., C.M.), Department of Neurology, Royal Melbourne Hospital, Australia; Karolinska Institute (T.S.), Stockholm, Sweden; Department of Neuroscience (T.S., V.J., A.v.d.W., O.S., H.B.), Central Clinical School, Monash University, Melbourne; Burnet Institute (T.S.), Melbourne, Australia; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), General University Hospital and Charles University in Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Hospital Universitario Virgen Macarena (G.I.), Sevilla, Spain; Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University "G. d'Annunzio," Chieti; Department of Biomedical and Neuromotor Sciences (A.L.), University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Hopital Notre Dame (A.P., M.G., P.D.), Montreal; CHUM and Universite de Montreal (A.P., M.G., P.D.); CISSS Chaudière-Appalache (P.G.), Levis, Canada; Department of Neurology (V.J., A.v.d.W., O.S., H.B.), Alfred Hospital, Melbourne, Australia; Neuro Rive-Sud (F. Grand'Maison), Quebec, Canada; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Isfahan University of Medical Sciences (V.S.), Isfahan, Iran; Amiri Hospital (R. Alroughani), Kuwait City, Kuwait; Zuyderland Ziekenhuis (R.H.), Sittard, the Netherlands; Medical Faculty (M. Terzi), 19 Mayis University, Samsun; KTU Medical Faculty Farabi Hospital (C.B.), Karadeniz Technical University, Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; UOC Neurologia (E.P.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Brussels, Belgium; University of Parma (F. Granella); C. Mondino National Neurological Institute (R.B.), Pavia; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.S.), Italy; Flinders University (M. Slee), Adelaide; Westmead Hospital (S.V.), Sydney, Australia; Nemocnice Jihlava (R. Ampapa), Czech Republic; University of Queensland (P.M.), Brisbane; Royal Brisbane and Women's Hospital (P.M.), Brisbane, Australia; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; CSSS Saint-Jérôme (J.P.), Canada; Hospital Universitario Donostia (J.O.), Paseo de Begiristain, San Sebastián, Spain; Hospital Italiano (E.C.), Buenos Aires, Argentina; Brain and Mind Centre (M.B.), University of Sydney, Australia; INEBA-Institute of Neuroscience Buenos Aires (M.L.S.), Argentina; Hospital de Galdakao-Usansolo (J.L.S.-M.), Galdakao, Spain; Liverpool Hospital (S. Hodgkinson), Sydney, Australia; Jahn Ferenc Teaching Hospital (C.R.), Budapest, Hungary; Craigavon Area Hospital (S. Hughes), UK; Jewish General Hospital (F.M.), Montreal, Canada; Deakin University (C.S.), Geelong; Monash Medical Centre (E.B.), Melbourne, Australia; South East Trust (O.G.), Belfast, UK; Perron Institute (A.K.), University of Western Australia, Nedlands; Institute of Immunology and Infectious Diseases (A.K.), Murdoch University; Sir Charles Gairdner Hospital (A.K.), Perth, Australia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences (B.S.), Mumbai, India; St Vincents Hospital (N.S.), Fitzroy, Melbourne, Australia; Veszprém Megyei Csolnoky Ferenc Kórház zrt (I.P.), Veszprem, Hungary; Royal Hobart Hospital (B.T.), Australia; Semmelweis University Budapest (M. Simo), Hungary; Central Military Emergency University Hospital (C.-A.S.), Bucharest; Titu Maiorescu University (C.-A.S.), Bucharest, Romania; BAZ County Hospital (A.S.), Miskolc, Hungary; and Box Hill Hospital (H.B.), Melbourne, Australia.
Abstract
OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled 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 MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 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). CONCLUSION: Continued treatment with MS 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 evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled 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 MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 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). CONCLUSION: Continued treatment with MS 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 evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
Authors: Nathaniel Lizak; Charles B Malpas; Sifat Sharmin; Eva Kubala Havrdova; Dana Horakova; Guillermo Izquierdo; Sara Eichau; Alessandra Lugaresi; Pierre Duquette; Marc Girard; Alexandre Prat; Catherine Larochelle; Maria Trojano; Francois Grand'Maison; Pierre Grammond; Patrizia Sola; Diana Ferraro; Raymond Hupperts; Roberto Bergamaschi; Cavit Boz; Vincent Van Pesch; Daniele Spitaleri; Murat Terzi; Tomas Kalincik Journal: JAMA Neurol Date: 2020-11-01 Impact factor: 18.302
Authors: R Philip Kinkel; Craig Kollman; Paul O'Connor; Thomas Jock Murray; Jack Simon; Douglas Arnold; Rohit Bakshi; Bianca Weinstock-Gutman; Staley Brod; Joanna Cooper; Pierre Duquette; Eric Eggenberger; Warren Felton; Robert Fox; Mark Freedman; Steven Galetta; Andrew Goodman; Joseph Guarnaccia; Stanley Hashimoto; Steven Horowitz; Jeffrey Javerbaum; Lloyd Kasper; Michael Kaufman; Lloyd Kerson; Michelle Mass; Kottil Rammohan; Merrell Reiss; Loren Rolak; John Rose; Thomas Scott; John Selhorst; Robert Shin; Craig Smith; William Stuart; Stephen Thurston; Michael Wall Journal: Neurology Date: 2006-01-25 Impact factor: 9.910
Authors: Daniel Ontaneda; Emma Tallantyre; Tomas Kalincik; Sarah M Planchon; Nikos Evangelou Journal: Lancet Neurol Date: 2019-07-30 Impact factor: 44.182
Authors: Johannes Lorscheider; Vilija G Jokubaitis; Tim Spelman; Guillermo Izquierdo; Alessandra Lugaresi; Eva Havrdova; Dana Horakova; Maria Trojano; Pierre Duquette; Marc Girard; Alexandre Prat; François Grand'Maison; Pierre Grammond; Eugenio Pucci; Cavit Boz; Patrizia Sola; Diana Ferraro; Daniele Spitaleri; Jeanette Lechner-Scott; Murat Terzi; Vincent Van Pesch; Gerardo Iuliano; Roberto Bergamaschi; Cristina Ramo-Tello; Franco Granella; Celia Oreja-Guevara; Helmut Butzkueven; Tomas Kalincik Journal: Neurology Date: 2017-08-09 Impact factor: 9.910
Authors: Marcus D'Souza; Özgür Yaldizli; Roland John; Deborah R Vogt; Athina Papadopoulou; Elisabeth Lucassen; Milena Menegola; Michaela Andelova; Frank Dahlke; Franz Schnyder; Ludwig Kappos Journal: Mult Scler Date: 2016-07-11 Impact factor: 6.312
Authors: Jordana Hughes; Vilija Jokubaitis; Alessandra Lugaresi; Raymond Hupperts; Guillermo Izquierdo; Alexandre Prat; Marc Girard; Pierre Duquette; Francois Grand'Maison; Pierre Grammond; Patrizia Sola; Diana Ferraro; Cristina Ramo-Tello; Maria Trojano; Mark Slee; Vahid Shaygannejad; Cavit Boz; Jeanette Lechner-Scott; Vincent Van Pesch; Eugenio Pucci; Claudio Solaro; Freek Verheul; Murat Terzi; Franco Granella; Daniele Spitaleri; Raed Alroughani; Jae-Kwan Jun; Adam Fambiatos; Anneke Van der Walt; Helmut Butzkueven; Tomas Kalincik Journal: JAMA Neurol Date: 2018-11-01 Impact factor: 18.302
Authors: Yoav Ben-Shlomo; Richard Lilford; Jacqueline Palace; Martin Duddy; Michael Lawton; Thomas Bregenzer; Feng Zhu; Mike Boggild; Benjamin Piske; Neil P Robertson; Joel Oger; Helen Tremlett; Kate Tilling; Charles Dobson Journal: J Neurol Neurosurg Psychiatry Date: 2018-09-21 Impact factor: 10.154
Authors: Joke Temmerman; Floris Van Der Veken; Sebastiaan Engelborghs; Kaat Guldolf; Guy Nagels; Dirk Smeets; Gert-Jan Allemeersch; Lars Costers; Marie B D'hooghe; Anne-Marie Vanbinst; Jeroen Van Schependom; Maria Bjerke; Miguel D'haeseleer Journal: J Clin Med Date: 2022-01-20 Impact factor: 4.241