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Studies comparing the effects of natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS) are limited. We aimed to compare natalizumab and fingolimod effects on clinical, neuropsychological, and MRI measures in RRMS patients after 2 years of treatment. RRMS patients starting natalizumab (n = 30) or fingolimod (n = 25) underwent neurologic, neuropsychological, and brain MRI assessments at baseline, month (M) 6, M12, and M24. Volumes of lesions, brain, gray matter (GM), white matter (WM), and deep GM were measured. Fifteen healthy controls (HC) were also scanned at baseline and M24. Treatment groups were matched for baseline variables. At M24 versus baseline, both drugs reduced the relapse rate (p value &lt; 0.001), stabilized disability, and improved cognitive function (fingolimod: p value = 0.03; natalizumab: p value = 0.01), without between-group differences. The natalizumab group had a higher proportion of freedom from MRI activity (67% vs 36%, p value = 0.02) and no evidence of disease activity-3 (NEDA-3) (57% vs 28%, p value = 0.04). At M24 vs M6, brain (- 0.35%, p value = 0.002 [fingolimod]; - 0.42%, p value &lt; 0.001 [natalizumab]), GM (- 0.62%, p value &lt; 0.001 [fingolimod]; - 0.64%, p value &lt; 0.001 [natalizumab]), and WM (- 0.98%, p value &lt; 0.001 [fingolimod]; - 0.99%, p value &lt; 0.001 [natalizumab]) atrophy progressed at higher rates than in HC, but similarly between treatment groups, whereas only the natalizumab group showed deep GM atrophy (- 0.79%, p value = 0.02) (p value vs fingolimod not significant). In both groups, atrophy progression was correlated with lesion accumulation (r from - 0.49 to - 0.36, p values from 0.013 to 0.05), whereas no correlation was found between clinical and MRI changes. Natalizumab and fingolimod reduce disease activity and improve cognition in RRMS. Natalizumab seems superior to limit lesion accumulation, whereas both drugs similarly modify atrophy progression.

Effects of Natalizumab and Fingolimod on Clinical, Cognitive, and Magnetic Resonance Imaging Measures in Multiple Sclerosis