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JAMA. 2019 Jan 15;321(2):175-187. doi: 10.1001/jama.2018.20588.

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

Author information

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

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.

PMID:
30644981
DOI:
10.1001/jama.2018.20588

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