• Winston Dzau, Sifat Sharmin, Francesco Patti, Guillermo Izquierdo, Sara Eichau, Alexandre Prat, Marc Girard, Pierre Duquette, Marco Onofrj, Alessandra Lugaresi, Serkan Ozakbas, Oliver Gerlach, Cavit Boz, Pierre Grammond, Murat Terzi, Maria Pia Amato, Daniele La Spitaleri, Cristina Ramo-Tello, Davide Maimone, Elisabetta Cartechini, Katherine Buzzard, Olga Skibina, Anneke van der Walt, Helmut Butzkueven, Gerardo Iuliano, Aysun Soysal, and Tomas Kalincik.
• Neuroimmunology Centre, Department of Neurology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
• J. Neurol. Neurosurg. Psychiatr. 2023 Dec 1; 94 (12): 984991984-991.

BackgroundWhether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy.MethodsThis observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression.Results10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found.ConclusionsEarly disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS.Trial Registration NumberAustralian New Zealand Clinical Trials Registry (ACTRN12605000455662).© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

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