Lublin, F. D. et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83, 278–286 (2014).

Article  PubMed  PubMed Central  Google Scholar 

Kappos, L. et al. Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 77, 1132–1140 (2020).

Article  PubMed  Google Scholar 

Lublin, F. D. et al. How patients with multiple sclerosis acquire disability. Brain 145, 3147–3161 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Lassmann, H. Multiple sclerosis pathology. Cold Spring Harb. Perspect. Med. 8, a028936 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Kuhlmann, T. et al. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 22, 78–88 (2023).

Article  PubMed  Google Scholar 

Ocrevus (ocrelizumab) product information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761053s012lbl.pdf (Genentech, Inc., Roche Group, 2018).

European Medicines Agency (EMA). Assessment Report: Ocrevus. https://www.ema.europa.eu/en/documents/variation-report/ocrevus-h-c-004043-x-0039-epar-assessment-report-variation_en.pdf (2017).

Mayzent (siponimod) product information. https://www.novartis.com/us-en/sites/novartis_us/files/mayzent.pdf (Novartis Pharmaceuticals Corporation, 2023).

Novartis Pharma GmbH. Mayzent summary of product characteristics. ema.europa.eu/en/documents/product-information/mayzent-epar-product-information_en.pdf (2023).

Montalban, X. et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N. Engl. J. Med. 376, 209–220 (2017).

Article  CAS  PubMed  Google Scholar 

Kappos, L. et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 391, 1263–1273 (2018).

Article  CAS  PubMed  Google Scholar 

Dalla Costa, G. et al. A wearable device perspective on the standard definitions of disability progression in multiple sclerosis. Mult. Scler. 30, 103–112 (2024).

Article  PubMed  Google Scholar 

Hechenberger, S. et al. Information processing speed as a prognostic marker of physical impairment and progression in patients with multiple sclerosis. Mult. Scler. Relat. Disord. 57, 103353 (2022).

Article  PubMed  Google Scholar 

Koch, M. W. et al. Reliability of outcome measures in clinical trials in secondary progressive multiple sclerosis. Neurology 96, e111–e120 (2021).

Article  CAS  PubMed  Google Scholar 

Lublin, F. et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 387, 1075–1084 (2016).

Article  CAS  PubMed  Google Scholar 

LaRocca, N. G. et al. The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability. Mult. Scler. 24, 1469–1484 (2018).

Article  PubMed  Google Scholar 

Zhang, T. et al. CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis. Effects of physical comorbidities on disability progression in multiple sclerosis. Neurology 90, e419–e427 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Salter, A., Lancia, S., Kowalec, K., Fitzgerald, K. C. & Marrie, R. A. Investigating the prevalence of comorbidity in multiple sclerosis clinical trial populations. Neurology 102, e209135 (2024).

Article  PubMed  PubMed Central  Google Scholar 

Marrie, R. A. et al. Etiology, effects and management of comorbidities in multiple sclerosis: recent advances. Front. Immunol. 14, 1197195 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Chard, D. & Trip, S. A. Resolving the clinico-radiological paradox in multiple sclerosis. F1000Res 6, 1828 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Jacobsen, C. et al. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J. Neurol. Neurosurg. Psychiatry 85, 1109–1115 (2014).

Article  PubMed  Google Scholar 

Ghione, E. et al. Brain atrophy is associated with disability progression in patients with MS followed in a clinical routine. Am. J. Neuroradiol. 39, 2237–2242 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zivadinov, R. et al. Clinical relevance of brain atrophy assessment in multiple sclerosis. Implications for its use in a clinical routine. Expert Rev. Neurother. 16, 777–793 (2016).

Article  CAS  PubMed  Google Scholar 

Rocca, M. A. et al. Brain MRI atrophy quantification in MS: from methods to clinical application. Neurology 88, 403–413 (2017).

Article  PubMed  PubMed Central  Google Scholar 

Kim, Y., Varosanec, M., Kosa, P. & Bielekova, B. Confounder-adjusted MRI-based predictors of multiple sclerosis disability. Front. Radiol. 2, 971157 (2022).

Article  PubMed  PubMed Central  Google Scholar 

Ingle, G. T. et al. Primary progressive multiple sclerosis: a 5-year clinical and MR study. Brain 126, 2528–2536 (2003).

Article  CAS  PubMed  Google Scholar 

University of California SFMSETet al. Silent progression in disease activity-free relapsing multiple sclerosis. Ann. Neurol. 85, 653–666 (2019).

Article  Google Scholar 

Sprenger, T. et al. Association of brain volume loss and long-term disability outcomes in patients with multiple sclerosis treated with teriflunomide. Mult. Scler. 26, 1207–1216 (2020).

Article  CAS  PubMed  Google Scholar 

Tsivgoulis, G. et al. The effect of disease modifying therapies on disease progression in patients with relapsing–remitting multiple sclerosis: a systematic review and meta-analysis. PLoS ONE 10, e0144538 (2015).

Article  PubMed  PubMed Central  Google Scholar 

Sormani, M. P., Arnold, D. L. & De Stefano, N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann. Neurol. 75, 43–49 (2014).

Article  PubMed  Google Scholar 

Guevara, C. et al. Prospective assessment of no evidence of disease activity-4 status in early disease stages of multiple sclerosis in routine clinical practice. Front. Neurol. 10, 788 (2019).

Article  PubMed  PubMed Central  Google Scholar 

Rovira, À. et al. Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process. Nat. Rev. Neurol. 11, 471–482 (2015).

Article  PubMed  Google Scholar 

Hanninen, K. et al. Thalamic atrophy without whole brain atrophy is associated with absence of 2-year NEDA in multiple sclerosis. Front. Neurol. 10, 459 (2019).

Article  PubMed  PubMed Central  Google Scholar 

van de Pavert, S. H. P. et al. DIR-visible grey matter lesions and atrophy in multiple sclerosis: partners in crime? J. Neurol. Neurosurg. Psychiatry 87, 461–467 (2016).

Article  PubMed  Google Scholar 

Calabrese, M. et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing–remitting multiple sclerosis. Arch. Neurol. 66, 1144–1150 (2009).

Article  PubMed  Google Scholar 

Popescu, B. F. G. et al. What drives MRI-measured cortical atrophy in multiple sclerosis. Mult. Scler. 21, 1280–1290 (2015).

Article