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Byline: Giovanni Savettieri (1), Virginia Andreoli (2), Simona Bonavita (3), Rita Cittadella (2), Carlo Caltagirone (4), Maria Carolina Fazio (5), Paolo Girlanda (5), Francesco Pira (6), Maria Liguori (7), Giancarlo Logroscino (8), Alessandra Lugaresi (9), Ugo Nocentini (4), Arturo Reggio (6), Giuseppe Salemi (1), Paolo Serra (2), Gioacchino Tedeschi (3), Lucia Toma (9), Maria Trojano (7), Paola Valentino (10), Aldo Quattrone (2,10,11) Keywords: multiple sclerosis; APOE polymorphism; APOE promoter; MS progression Abstract: Objective: To investigate the association between apolipoprotein E (APOE) polymorphisms and the progression of MS. Methods: We investigated 428 subjects affected by clinically defined MS, with a disease duration of at least three years. We collected data concerning the age at onset of MS, clinical type, disease duration and disability according to the expanded disability status scale (EDSS). We also calculated the progression index (PI) to evaluate disease progression. APOE genotyping and the --491 A/T polymorphism of the APOE promoter were determined. Results: No association was observed between the APOE [epsilon]4 allele and clinical characteristics of our study population. We also investigated the --491 A/T APOE promoter polymorphism in 236 MS subjects and did not find any association between the --491 A/T polymorphism and the selected clinical variables. Conclusions: In our population the APOE [epsilon]4 allele and the --491 A/T APOE promoter polymorphism are not associated with a more rapid course of MS. Author Affiliation: (1) Institute of Neuropsychiatry, University of Palermo, Palermo, Italy (2) Institute of Neurological Sciences, National Research Council, Piano Lago di Mangone (Cosenza), Italy (3) Dept. of Neurological Sciences, 2nd University of Naples, Naples, Italy (4) Cattedra di Neurologia and I.R.C.C.S., Fondazione 'S. Lucia', University of Rome 'Tor Vergata', Rome, Italy (5) Dept. of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy (6) Dept. of Neurological Sciences, University of Catania, Catania, Italy (7) Dept. of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy (8) Dept. of Neurology, Ospedale Miulli, Bari, Italy (9) Dept. of Oncology &amp Neuroscience, University of Chieti 'Gabriele d'Annunzio', Chieti, Italy (10) Institute of Neurology, University Magna Graecia, Catanzaro, Italy (11) Clinica Neurologica, Policlinico Mater Domini, Via T. Campanella, 88100, Catanzaro, Italy Article History: Received Date: 10/10/2002 Accepted Date: 08/05/2003

Background: The introduction of oral disease-modifying therapies (DMTs) for relapsing–remitting multiple sclerosis (RRMS) changed algorithms of RRMS treatment. Objectives: To compare the effectiveness of treatment with dimethyl fumarate (DMF) and teriflunomide (TRF) in a large multicentre Italian cohort of RRMS patients. Materials and Methods: Patients with RRMS who received treatment with DMF and TRF between January 1st, 2012 and December 31st, 2018 from twelve MS centers were identified. The events investigated were "time-to-first-relapse", "time-to-Magnetic-Resonance-Imaging (MRI)-activity" and "time-to-disability-progression". Results: 1445 patients were enrolled (1039 on DMF, 406 on TRF) and followed for a median of 34 months. Patients on TRF were older (43.5 ± 8.6 vs 38.8 ± 9.2 years), with a predominance of men and higher level of disability (p < 0.001 for all). Patients on DMF had a higher number of relapses and radiological activity (p <.05) at baseline. Time-varying Cox-model for the event "time-to-first relapse" revealed that no differences were found between the two groups in the first 38 months of treatment (HRt < 38DMF = 0.73, CI = 0.52 to 1.03, p = 0.079). When the time-on-therapy exceeds 38 months patients on DMF had an approximately 0.3 times lower relapse hazard risk than those who took TRF (HRt>38DMF = 3.83, CI = 1.11 to 13.23, p = 0.033). Both DMTs controlled similarly MRI activity and disability progression. Conclusions: Patients on DMF had higher relapse-free survival time than TRF group after the first 38 months on therapy. [ABSTRACT FROM AUTHOR]

Background: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. Objective: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. Methods: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. Results: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48–2.04), p = 0.98 and 0.81 (0.42–1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00–2.12), p = 0.05]. Conclusion: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY. [ABSTRACT FROM AUTHOR]

Background: A high reactivation of multiple sclerosis (MS) was reported in patients treated with alemtuzumab after fingolimod. We aimed to understand whether this shift enhanced the risk for reactivation in a real-life cohort. Methods: Subjects with relapsing MS, shifting from fingolimod to alemtuzumab were enrolled. We collected the following data: age, sex, disease duration, relapses after fingolimod withdrawal, new T2/gadolinium (Gd)-enhancing lesions in the last magnetic resonance imaging (MRI) during fingolimod and in the first, while on alemtuzumab, lymphocyte counts at alemtuzumab start, and Expanded Disability Status Scale (EDSS) before and after alemtuzumab. Results: We enrolled 77 patients (women 61 (79%); mean age 36.2 years (SD 9.6), and disease duration 12.3 years (SD 6.8) at fingolimod discontinuation; median washout 1.8 months). The annualised relapse rate was 0.89 during fingolimod, 1.32 during washout, and 0.15 after alemtuzumab (p = 0.001). The EDSS changed from a median of 3 (IQR 2–4) at the end of fingolimod to 2.5 after alemtuzumab (IQR 1.5–4) (p = 0.013). The washout length and the lymphocyte count before alemtuzumab were not associated with EDSS change after alemtuzumab (p = 0.59 and p = 0.33, respectively). MRI activity decreased after alemtuzumab compared to that during fingolimod (p = 0.001). At alemtuzumab start, lymphocyte counts were < 0.8 × 103/mL in 21 patients. Conclusions: In our cohort, alemtuzumab reduced relapse, new T2/Gd-enhancing lesions, and EDSS score, as compared to the previous periods (fingolimod/washout). These results were not related to washout length or lymphocyte counts. Therefore, a rapid initiation of alemtuzumab after fingolimod does not seem to be a risk factor for MS reactivation. [ABSTRACT FROM AUTHOR]