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Original Investigation
January 15, 2019

Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis

Author Affiliations
  • 1Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
  • 2NMR Research Unit, Queen Square Multiple Sclerosis Centre, University College London, Institute of Neurology, London, United Kingdom
  • 3Clinical Outcomes Research Unit, Melbourne Brain Centre, University of Melbourne, Melbourne, Australia
  • 4Department of Neurology and Center of Clinical Neuroscience, General University Hospital, Prague, Czech Republic
  • 5Charles University in Prague, Katerinska, Czech Republic
  • 6Hospital Universitario Virgen Macarena, Sevilla, Spain
  • 7Hopital Notre Dame, Montreal, Canada
  • 8CHUM and Universite de Montreal, Montreal, Canada
  • 9Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy
  • 10Department of Neuroscience, Imaging and Clinical Sciences, University G. d’Annunzio, Chieti, Italy
  • 11C. Mondino National Neurological Institute, Pavia, Italy
  • 12CISSS Chaudi’re-Appalache, Centre-Hospitalier, Levis, Canada
  • 13Amiri Hospital, Qurtoba, Kuwait City, Kuwait
  • 14Zuyderland Medical Center, Sittard-Geleen, the Netherlands
  • 15University of Queensland, Brisbane, Australia; Royal Brisbane and Women's Hospital
  • 16Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
  • 17Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy
  • 18Neuro Rive-Sud, Greenfield Park, Quebec, Canada
  • 19Medical Faculty, Ondokuz Mayis University, Kurupelit, Turkey
  • 20School of Medicine and Public Health, University Newcastle, Australia
  • 21Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, Australia
  • 22Asaf Harofen Medical Center, Beer-Yaakov, Zerifin, Israel
  • 23Flinders University, Adelaide, Australia
  • 24Isfahan University of Medical Sciences, Isfahan, Iran
  • 25UOC Neurologia, Azienda Sanitaria Unica Regionale Marche, Macerata, Italy
  • 26University of Parma, Parma, Italy
  • 27Department of Medicine, University of Melbourne, Melbourne, Australia
  • 28Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia
  • 29Department of Neurology, Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales, Cardiff, United Kingdom
  • 30Department of Neurology, Southmead Hospital, and Clinical Neurosciences, University of Bristol, Bristol, United Kingdom
  • 31Abertawe Bro, Morgannwg University Local Health Board, Swansea, United Kingdom
  • 32Center of Clinical Neuroscience, Department of Neurology, MS Center Dresden, Dresden, Germany
  • 33School of Medicine and Medical Sciences, University College Dublin, St Vincent’s University, Hospital, Dublin, Ireland
  • 34Institute for Psychological Medicine and Clinical Neurosciences, Cardiff University, Wales
  • 35Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia
JAMA. 2019;321(2):175-187. doi:10.1001/jama.2018.20588
Key Points

Question  Among patients with relapsing-remitting multiple sclerosis (MS), what is the association between disease-modifying therapies (DMTs) and the risk of conversion to secondary progressive multiple sclerosis (MS)?

Findings  In this cohort study involving 1555 patients with relapsing-remitting MS, initial treatment with fingolimod, natalizumab, or alemtuzumab was associated with a lower risk of conversion to secondary progressive MS compared with interferon beta or glatiramer acetate (hazard ratio, 0.66).

Meaning  These findings, considered along with the risks associated with these therapies, may help inform decisions regarding disease-modifying treatment selection for patients with relapsing-remitting MS.

Abstract

Importance  Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

Objective  To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.

Design, Setting, and Participants  Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.

Exposures  The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).

Main Outcome and Measure  Conversion to objectively defined secondary progressive MS.

Results  Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).

Conclusions and Relevance  Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies’ risks, may help inform decisions about DMT selection.

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