BACKGROUND: Although Fingolimod (FGD) and Natalizumab (NTZ) appear to be effective in relapsing-remitting multiple sclerosis (RRMS), they have never been directly compared in a randomized clinical trial (RCT). METHODS AND FINDINGS: We evaluated the comparative efficacy of FGD vs. NTZ using a meta-analytical approach. Data from placebo-controlled RCTs was used for indirect comparisons and observational data was utilized for head-to-head comparisons. We identified 3 RCTs (2498 patients) and 5 observational studies (2576 patients). NTZ was associated with a greater reduction in the 2-year annualized relapse rate (ARR; SMDindirect = -0.24;95% CI: from -0.44 to -0.04; p = 0.005) and with the probability of no disease activity at 2 years (ORindirect:1.82, 95% CI: from 1.05 to 3.15) compared to FGD, while no differences between the two therapies were found in the proportion of patients who remained relapse-free (ORindirect = 1.20;95% CI: from 0.84 to 1.71) and those with disability progression (ORindirect = 0.76;95% CI: from 0.48 to 1.21) at 2 years. In the analysis of observational data, we found no significant differences between NTZ and FGD in the 2-year ARR (SMD = -0.05; 95% CI: from -0.26 to 0.16), and 2-year disability progression (OR:1.08;95% CI: from 0.77 to 1.52). However, NTZ-treated patients were more likely to remain relapse-free at 2-years compared to FGD (OR: 2.19;95% CI: from 1.15 to 4.18; p = z0.020). CONCLUSIONS: Indirect analyses of RCT data and head-to-head comparisons of observational findings indicate that NTZ may be more effective than FGD in terms of disease activity reduction in patients with RRMS. However, head-to-head RCTs are required to independently confirm this preliminary observation.

1st Department of Neurology Eginition Hospital School of Medicine University of Athens Athens Greece

2nd Department of Neurology AHEPA University Hospital Aristotelion University of Thessaloniki Thessaloniki Macedonia Greece

2nd Department of Neurology Attikon Hospital School of Medicine University of Athens Athens Greece

Department of Hygiene and Epidemiology School of Medicine University of Ioannina Ioannina Greece

Department of Neurology Alexandroupolis University Hospital Democritus University of Thrace Alexandroupolis Greece

Department of Neurology School of Medicine University of Ioannina Ioannina Greece

Department of Neurology The University of Tennessee Health Science Center Memphis Tennessee United States of America

Department of Neurology University Hospital of Larissa University of Thessaly Larissa Greece

Department of Neurology University of Patras Medical School Patras Greece

Department of Primary Education University of Ioannina Ioannina Greece

International Clinical Research Center Department of Neurology St Anne's University Hospital in Brno Brno Czech Republic

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