Siponimod modulates functional brain connectivity in patients with transitional Multiple Sclerosis

Background Transitional multiple sclerosis represents a critical phase in the evolution from relapsing-remitting multiple sclerosis to secondary-progressive multiple sclerosis for which there is no specific disease-modifying treatment available. Objectives (i) To evaluate the efficacy of siponimod in relapsing-remitting multiple sclerosis on first-line therapy who are likely to be in a transitional stage; (ii) to investigate the potential modulatory effect of Siponimod on functional brain connectivity using resting-state functional MRI. Methods Fifty-five relapsing-remitting multiple sclerosis patients likely to be in a transitional stage were screened. After applying selective exclusion criteria, 16 patients were randomized into two groups: the siponimod group and the first-line group (patients remaining on their own therapy). Patients were assessed longitudinally, at baseline (T0) and six months later (T1), trough neurological evaluations, 3T-MRI scanning, and gait analysis. Voxel-wise methods of image analysis were used to assess longitudinal changes. Results At T0, there were no between-group differences in any considered parameter. Longitudinal resting state MRI analysis of the salience network revealed a significant group-by-time interaction in the cerebellum and temporal lobe. Specifically, patients in the first-line group showed a marked decline in functional connectivity over time, whereas siponimod group patients exhibited relative preservation of connectivity. Conclusion This preliminary and exploratory study suggests that siponimod may exert a protective effect on brain functional networks in transitional multiple sclerosis patients, reflecting a potential neuro-protective mechanism that reduces central inflammation. These findings support further investigation in larger, controlled studies to clarify the role of siponimod in early progressive multiple sclerosis stages.