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Observational Study
. 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

J William L Brown  1   2   3 , Alasdair Coles  1 , Dana Horakova  4   5 , Eva Havrdova  4   5 , Guillermo Izquierdo  6 , Alexandre Prat  7   8 , Marc Girard  7   8 , Pierre Duquette  7   8 , Maria Trojano  9 , Alessandra Lugaresi  10 , Roberto Bergamaschi  11 , Pierre Grammond  12 , Raed Alroughani  13 , Raymond Hupperts  14 , Pamela McCombe  15 , Vincent Van Pesch  16 , Patrizia Sola  17 , Diana Ferraro  17 , Francois Grand'Maison  18 , Murat Terzi  19 , Jeannette Lechner-Scott  20   21 , Schlomo Flechter  22 , Mark Slee  23 , Vahid Shaygannejad  24 , Eugenio Pucci  25 , Franco Granella  26 , Vilija Jokubaitis  27   28 , Mark Willis  29 , Claire Rice  30 , Neil Scolding  30 , Alastair Wilkins  30 , Owen R Pearson  31 , Tjalf Ziemssen  32 , Michael Hutchinson  33 , Katharine Harding  34 , Joanne Jones  1 , Christopher McGuigan  33 , Helmut Butzkueven  27   28   35 , Tomas Kalincik  3   27   28 , Neil Robertson  34 ; MSBase Study Group
Affiliations
Observational Study

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

J William L Brown et al. JAMA. .

Erratum in

  • Incorrect Affiliation.
    [No authors listed] [No authors listed] JAMA. 2020 Apr 7;323(13):1318. doi: 10.1001/jama.2020.2604. JAMA. 2020. PMID: 32259213 Free PMC article. No abstract available.

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Brown reported receiving travel expenses and nonfinancial support from Biogen, Novartis, Sanofi-Genzyme and personal fees, advisory board fees, and speaking honoraria from Biogen. Dr Coles reported receiving personal fees, honoraria for consulting, and travel expenses for attending meetings from Genzyme and having a patent pending on the dose regimen of alemtuzumab as a treatment of multiple sclerosis. Dr Horakova reported receiving travel fees, consultant fees, and speaker honoraria from Biogen, Novartis, Merck, Roche, Sanofi Genzyme, and Teva and grant support from the Czech Ministry of Education Project Progres. Dr Havrdova reported receiving speakers honoraria from Biogen, Roche, Sanofi-Genzyme, and Merck Serono and serving on advisory boards of Biogen, Sanofi Genzyme, Merck Serono, Celgene and Actelion. Dr Izquierdo reported receiving speaking and advisory board honoraria from Bayer, Biogen, Novartis, Sanofi, Merck Serono, Almirall, Roche, Actelion, Celgene, and Teva. Dr Girard reported receiving personal fees from Biogen, Novartis, Sanofi-Genzyme, Serono, and Teva Canada Innovations and a research grant from the Canadian Institutes of Health Research. Dr Duquette reported receiving support for organized continuing medical education activities and travel fees to attend advisory meetings from EMD Serono, Genzyme, Biogen, and Novartis. Dr Trojano reported receiving speaker honoraria and research grants to her institution from and serving on advisory boards of Biogen, Merck Serono, and Novartis. Dr Lugaresi reported receiving personal fees from Bayer, Biogen, Merck Serono, Novartis, Roach, Sanofi-Genzyme, and Teva and grant support from Bayer, Biogen, Merck Serono, Novartis, Sanofi-Genzyme, and Teva. Dr Bergamaschi reported receiving personal fees for serving on the scientific advisory boards of Biogen, Merck Serono, and Teva; research grants from Almirall, Biogen, Genzyme, and Merck Serono; and lecture honoraria from Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, and Teva. Dr Grammond reports receiving personal fees from Novartis, Serono, Roche, Biogen, and Genzyme and grant support from Roche and Genzyme. Dr Alroughani reports receiving lecture honoraria from and serving on the advisory boards of Bayer, Biogen, Merck, Novartis, Roche, and Sanofi-Genzyme and lecture honoraria from GlaxoSmithKline. Dr Hupperts reported receiving nurse support from Merck and Sanofi and serving on advisory boards of Sanofi, Biogen, and Roche. Dr Van Pesch reported receiving lecture honoraria, consultancy fees, and grant support from Novartis, Sanofi, Roche, and Biogen; grant support from Teva, and consultancy fees from Merck. Dr Sola reported serving on the scientific advisory boards of and receiving grant support from Biogen and Teva; travel fees, lecture honoraria, and grant support from Merck, Sanofi Genzyme, and Novartis; and travel fees and lecture honoraria from Bayer. Dr Ferraro reported receiving lecture honoraria and travel grants from Teva, Biogen, Merck Serono, Sanofi-Genzyme, and Novartis. Dr Grand'Maison reported receiving grants from Novartis, Actelion, Roche, Genzyme, and Serono. Dr Lechner-Scott reported receiving grants support from Biogen, Novartis, and Teva, lecture honoraria and advisory board fees from Biogen, Novartis, Teva, Sanofi, and Roche. Dr Pucci reported receiving travel grants and congress fees from Merck, Biogen, Sanofi Genzyme, Novartis, and Teva and equipment from the Associazione Marchigiana Sclerosi Multipla e altre malattie neurologiche. Dr Granella reported receiving personal fees from Biogen, Sanofi, Roche, and Merck Serono; grant support from Biogen and Sanofi, and nonfinancial support from Biogen, Sanofi, and Merck Serono. Dr Vilija Jokubaitis reported nonfinancial support from Teva, Novartis, and Merck and personal fees from Biogen. Dr Scolding reports receiving grants from Biogen, Sanofi Genzyme, Merck Serono, Teva, and Novartis. Dr Pearson reported receiving speaker and receiving consultancy fees and personal fees from , educational sponsorship and support to the department from Biogen, Sanofi, Roche, Merck, and Novartis and grant support from Biogen and Sanofi. Dr Ziemssen reported receiving grants from Bayer, Biogen, Teva, Merck Serono, Novartis, Sanofi, and Teva and consultancy fees from Almirall, Bayer, Biogen, Genzyme, Novartis, Roche, Sanofi, and Teva. Dr Harding reported receiving grant support from Novartis UK and personal fees from Biogen. Dr Jones reported receiving consulting and lecture fees from Bayer Schering and lecture fees from Genzyme. Dr McGuigan reported receiving grants and personal fees from Actelion, Biogen, Novartis, Roche, and Sanofi Genzyme. Dr Butzkueven reported serving on the Australian and global advisory boards of and receiving lecture fees from Novartis, Biogen, and Merck; consultancy fees from Oxford Pharmagenesis; and a pending institutional research grant from Biogen. Dr Kalincik reported receiving travel expenses, advisory board fees and speaking honoraria from WebMD Global, Roche, Sanofi-Genzyme, Novartis, Teva, BioCSL, Merck, and Biogen and grant support from the Australian National Health and Medical Research Council, the Faculty of Medicine, Dentistry, and Health Sciences of the University of Melbourne Fondation d'Aide pour la Recherche sur la Sclerose en Plaques and Biogen. Dr Robertson reported receiving grants from Novartis, Sanofi Genzyme, and Biogen and honoraria from Roche, Sanofi Genzyme, and Novartis. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. MSBase Study Design of Patients With Multiple Sclerosis (MS)
aWhen recorded, reasons for stopping were included: 341 due to intolerance; 65, inconvenience; 42, pregnancy (or planned pregnancy); 65, inefficacy (relapses, EDSS progression, magnetic resonance imaging activity, or patient perception of lack of improvement); and 15, nonadherence. bIneligible treatments were defined as treatments not licensed for relapsing-remitting MS at the time of the study period (mitoxantrone, cladribine, rituximab, ocrelizumab, siponimod, or autologous stem-cell transplant). DMT indicates disease-modifying therapy; EDSS, Expanded Disability Status Scale.
Figure 2.
Figure 2.. Comparison of the Cumulative Hazard of Conversion to Secondary Progressive Multiple Sclerosis in Untreated Patients vs Matched Treated Patients Compared by Initial Treatment
A, The median follow-up was 7.6 years (interquartile range [IQR], 5.8-9.6); B, 4.5 years (IQR, 4.3-5.1); C, 4.9 years (IQR, 4.4-5.8); and D, 7.4 years (IQR, 6-8.6) years. HR indicates hazard ratio.
Figure 3.
Figure 3.. Comparison of the Cumulative Hazard of Conversion to Secondary Progressive Multiple Sclerosis by Timing of Treatment
A, The median follow-up was 13.4 years (interquartile range [IQR], 11-18.1); B, 7.5 years (IQR, 5.7-9.8); C, 7.7 years (IQR, 5.8-9.7); and D, 5.3 years (IQR, 4.6-6.4). HR indicates hazard ratio.
Figure 4.
Figure 4.. Comparison of Cumulative Hazard of Conversion to Secondary Progressive Multiple Sclerosis for Initial Treatment With Glatiramer Acetate or Interferon Beta vs Fingolimod, Alemtuzumab, or Natalizumab
The median follow-up was 5.8 years (interquartile range, 4.7-8). HR indicates hazard ratio.
See this image and copyright information in PMC

Comment in

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