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Clinical Trial
. 2022 Sep 1;79(9):869-878.
doi: 10.1001/jamaneurol.2022.1929.

Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients With Primary Progressive Multiple Sclerosis

Emilio Portaccio  1 , Mattia Fonderico  1 , Pietro Iaffaldano  2 , Luisa Pastò  1 , Lorenzo Razzolini  1 , Angelo Bellinvia  1 , Giovanna De Luca  3 , Paolo Ragonese  4 , Francesco Patti  5 , Vincenzo Brescia Morra  6 , Eleonora Cocco  7 , Patrizia Sola  8 , Matilde Inglese  9   10 , Giacomo Lus  11 , Carlo Pozzilli  12 , Davide Maimone  13 , Alessandra Lugaresi  14   15 , Paola Gazzola  16 , Giancarlo Comi  17 , Ilaria Pesci  18 , Daniele Spitaleri  19 , Marta Rezzonico  20 , Marika Vianello  21 , Carlo Avolio  22   23 , Francesco O Logullo  24 , Franco Granella  25 , Marco Salvetti  26   27 , Mauro Zaffaroni  28 , Giuseppe Lucisano  2   29 , Massimo Filippi  30   31   32 , Maria Trojano  2 , Maria Pia Amato  1   33 ; Italian Multiple Sclerosis Register Centers Group
Collaborators, Affiliations
Clinical Trial

Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients With Primary Progressive Multiple Sclerosis

Emilio Portaccio et al. JAMA Neurol. .

Abstract

Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking.

Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS.

Design, setting, and participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up.

Main outcomes and measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models.

Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective).

Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data.

Conclusions and relevance: Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Portaccio reported receiving travel grants for participation in advisory board and/or speaking activities from Biogen, Merck, Sanofi Genzyme, Novartis, Roche, Celgene, and Teva and serving on the editorial board of Frontiers in Neurology and Brain Sciences. Dr Ragonese reported receiving speaker honoraria or grants from Biogen, Sanofi Genzyme, Novartis, Teva, Merck, Almirall, and Roche. Dr Patti reported receiving personal fees from Almirall, Bayer, Bristol Myers Squibb, and Novartis and grants from Biogen, Merck, Roche, and Sanofi. Dr Brescia Morra reported receiving personal fees from Biogen, Teva, Genzyme, Bristol Myers Squibb, Novartis, Merck, and Almirall. Dr Cocco reported receiving grants from Biogen, Merck, and Roche and personal fees from Novartis and Sanofi. Dr Inglese reported receiving consultation fees from Biogen, Merck, Novartis, and Roche; speaker fees from Novartis and Roche; and being coeditor of Multiple Sclerosis Journal. Dr Inglese reported receiving research grants from the National Institutes of Health, National Multiple Sclerosis Society, MS Canada, and Federazione Italiana Sclerosi Multipla. Dr Pozzilli reported receiving grants from Roche, Almirall, and Biogen and personal fees from Janssen, Alexion, Merck, Bristol Myers Squibb, and Novartis. Dr Maimone reported receiving personal fees from Biogen, Bayer, Merck, Novartis, Roche, and Sanofi Genzyme. Dr Lugaresi reported receiving personal fees from Biogen, Merck Serono, Novartis, Sanofi Genzyme, Bristol Myers Squibb, Roche, and Teva and grants from Novartis and Sanofi Genzyme. Dr Comi reported receiving personal fees from Sanofi, Janssen, Bristol Myers Squibb, Novartis, and Rewind. Dr Granella reported receiving grants from Roche, Biogen, Novartis, Sanofi, Merck Serono, and Roche. Dr Salvetti reported receiving grants from Biogen and Sanofi and personal fees from Merck and Novartis. Dr Filippi reported receiving consulting services and/or speaking activity fees from Almirall, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, Teva Pharmaceutical Industries; grants from Biogen, Merck-Serono, Novartis, Roche, and Teva Pharmaceutical Industries; and serving as editor-in-chief of the Journal of Neurology and associate editor of Human Brain Mapping, Radiology, and Neurological Sciences. Dr Trojano reported receiving grants from Biogen, Novartis, and Merck and personal fees from Novartis, Biogen, Merck, Roche, Genzyme, and Bristol Myers Squibb. Dr Amato reported receiving grants from Merck Serono, Biogen, Roche, and Mylan and personal fees from Merck Serono, Biogen, Sanofi Genzyme, Novartis, Roche, Mylan, and Bristol Myers Squibb Celgene. No other disclosures were reported.

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