BACKGROUND: High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4-6 years after disease onset. METHODS: In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0-2 years (early) or 4-6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0-10, with higher scores indicating increased disability), at 6-10 years after disease onset, assessed with a linear mixed-effects model. FINDINGS: We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7-8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of -0·98 (95% CI -1·51 to -0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6-10 year follow-up period. INTERPRETATION: High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6-10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. FUNDING: National Health and Medical Research Council Australia and MS Society UK.

Aarhus University Hospital Aarhus Denmark

Central Clinical School and Department of Neurology Box Hill Hospital Monash University Melbourne VIC Australia

CHUM and Universite de Montreal Montreal QC Canada

CISSS Chaudière Appalache Levis QC Canada

Cliniques Universitaires Saint Luc Brussels Belgium

CORe Department of Medicine University of Melbourne Melbourne VIC Australia

Department of Basic Medical Sciences Neuroscience and Sense Organs University of Bari Bari Italy

Department of Biomedical and Neuromotor Science University of Bologna Bologna Italy

Department of Clinical Neuroscience Institute of Neuroscience and Physiology at Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Clinical Neuroscience Karolinska Institute Stockholm Sweden

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Clinical Sciences Danderyd Hospital Karolinska Institute Stockholm Sweden

Department of Medicine and Surgery University of Parma Parma Italy

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University Prague Czech Republic

Department of Neurology Royal Melbourne Hospital Melbourne VIC Australia

Department of Neurology The Alfred Hospital Melbourne VIC Australia

Department of Neuroscience Azienda Ospedaliera Universitaria Modena Italy

General University Hospital Prague Czech Republic

Hopital Notre Dame Montreal QC Canada

Hospital Universitario Virgen Macarena Sevilla Spain

IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy

IRCCS Mondino Foundation Pavia Italy

Neuro Rive Sud Longueuil QC Canada

New York University Langone Medical Centre New York NY USA

NMR Research Unit Queen Square Multiple Sclerosis Centre University College London Institute of Neurology London UK

School of Medicine and Medical Sciences University College Dublin Dublin Ireland

St Vincent's University Hospital Dublin Ireland

Université Catholique de Louvain Ottignies Louvain la Neuve Belgium

Zuyderland Ziekenhuis Sittard Netherlands

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