Patterns and predictors of multiple sclerosis phenotype transition
Authors: Pontieri Luigi , Greene Nupur , Wandall-Holm Malthe Faurschou , Geertsen Svend Sparre , Asgari Nasrin , Jensen Henrik Boye , Illes Zsolt , Schäfer Jakob , Jensen Rikke Marie , Sejbæk Tobias , Weglewski Arkadiusz , Mahler Mie Reith , Poulsen Mai Bang , Prakash Sivagini , Stilund Morten , Kant Matthias , Rasmussen Peter Vestergaard , Svendsen Kristina Bacher , Sellebjerg Finn , Magyari Melinda 
Published: November 2024

Abstract
Currently, there are limited therapeutic options for patients with non-active secondary progressive multiple sclerosis. Therefore, real-world studies have investigated differences between patients with relapsing-remitting multiple sclerosis, non-active secondary progressive multiple sclerosis and active secondary progressive multiple sclerosis. Here, we explore patterns and predictors of transitioning between these phenotypes. We performed a cohort study using data from The Danish Multiple Sclerosis Registry. We included patients with a relapsing-remitting phenotype, registered changes to secondary progressive multiple sclerosis and subsequent transitions between relapsing and non-relapsing secondary progressive multiple sclerosis, which was defined by the presence of relapses in the previous 2 years. We analysed predictors of transitioning from relapsing-remitting multiple sclerosis to relapsing and non-relapsing secondary progressive multiple sclerosis, as well as between the secondary progressive states using a multi-state Markov model. We included 4413 patients with relapsing-remitting multiple sclerosis. Within a median follow-up of 16.2 years, 962 were diagnosed with secondary progressive multiple sclerosis by their treating physician. Of these, we classified 729 as non-relapsing and 233 as relapsing secondary progressive multiple sclerosis. The risk of transitioning from relapsing-remitting to non-relapsing secondary progressive multiple sclerosis included older age (hazard ratio per increase of 1 year in age: 1.044, 95% confidence interval: 1.035–1.053), male sex (hazard ratio for female: 0.735, 95% confidence interval: 0.619–0.874), fewer relapses (hazard ratio per each additional relapse: 0.863, 95% confidence interval: 0.823–0.906), higher expanded disability status scale (hazard ratio per each additional point: 1.522, 95% confidence interval: 1.458–1.590) and longer time on disease-modifying therapies (hazard ratio per increase of 1 year in treatment, high-efficacy disease-modifying therapy: 1.095, 95% confidence interval: 1.051–1.141; hazard ratio, moderate-efficacy disease-modifying therapy: 1.073, 95% confidence interval: 1.051–1.095). We did not find significant predictors associated with the transition from relapsing secondary progressive multiple sclerosis to non-relapsing secondary progressive multiple sclerosis, whereas older age (hazard ratio per increase of 1 year in age: 0.956, 95% confidence interval: 0.942–0.971) prevented the transition from non-relapsing secondary progressive multiple sclerosis to relapsing secondary progressive multiple sclerosis. Our study suggests that transitioning from relapsing-remitting multiple sclerosis to non-relapsing secondary progressive multiple sclerosis depends on well-known factors affecting diagnosing secondary progressive multiple sclerosis. Further transitions between non-relapsing and relapsing secondary progressive multiple sclerosis are only affected by age. These findings add to the knowledge of non-active secondary progressive multiple sclerosis, a patient group with unmet needs in terms of therapies.