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Background: Migraine affects up to 40% of people with multiple sclerosis (PwMS). This study aimed to evaluate the effectiveness and safety of the combination of antibodies (mAbs) against CGRP (anti-CGRP mAbs) with disease-modifying treatments (DMTs) for MS (mAb and non-mAbs) and their impact on MS disease course., Methods: This retrospective, multicentric study included PwMS from 14 MS Centers, treated with an anti-CGRP mAb and a stable treatment with DMTs. MS outcome measures included clinical relapses, EDSS score, and MRI activity from the year before starting anti-CGRP mAbs at the time of initiation (baseline) and last follow-up. Migraine outcomes included reductions in Monthly Headache Days (MHDs) and analgesic use. Adverse events (AEs) were recorded., Results: Twenty-five patients were included (mean age of 39.4 ± 9.7 years). Nine PwMS (36.0%) were treated with non-mAb DMTs and 16 (64.0%) with mAb DMTs. During the concurrent treatment, six patients (24.0%) stopped anti-CGRP mAbs after 12.7 ± 11.6 months due to ineffectiveness (n = 3) migraine sustained improvement (n = 2) and AEs (n = 1). MHDs significantly decreased from baseline (22.0 ± 8.2) to the last follow-up (11.5 ± 13.7) (p = 0.002). EDSS score did not significantly change from the year before initiating anti-CGRP mAb (1.9 ± 1.4) to baseline (1.9 ± 1.4) and last follow-up (1.9 ± 1.5)(p = 0.497). Two patients (8.0%) had a clinical relapse, and one (4.0%) had MRI activity during treatment with anti-CGRP mAbs. Overall, DMTs were discontinued in two patients (8%). Mild AEs were reported in 2 PwMS (8.0%), none leading to discontinuation., Conclusions: Long-term treatment with anti-CGRP mAbs and DMTs for MS showed safety and effectiveness with no significant effect on MS disease course., Competing Interests: Declaration of competing interest CT received travel funding and/or speaker honoraria from Alexion, Almirall, Biogen, Horizon, Merck, Novartis, Roche, Sanofi. MDF participated on advisory boards and steering committees for and received speaker or writing honoraria, research support and funding for travelling from Alexion, BMS, Bayer, Biogen Idec, Genzyme, Horizon, Janssen, Merck, Mylan, Novartis, Roche, Siemens Healthineers, Teva and Viatris. Other authors have no conflicting interests related to this manuscript. MV has received research funding and speaker/advisory board fees from Biogen, Merck, Novartis, Roche., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Introduction: Cannabinoids are approved for spasticity and pain in multiple sclerosis (MS). In 2017 the prevalence of current users in the Italian general population was 10.2%, while data on Italian MS patients are limited., Methods: From March 2022 to February 2023, we conducted a multicenter, cross-sectional study. Adult MS patients completed an anonymous online survey. The primary outcome was the estimated prevalence of unprescribed cannabis current use. Cannabis use patterns and associations with clinical and socio-demographical variables were investigated. The binomial method was used to estimate 95% confidence interval (95% CI) for primary outcome., Results: 5620 patients were invited and 2024 (36.0%) were included (mean age 45.2 years, females 64.5%). Relapsing remitting form was the most frequent (77.3%). Median expanded disability status scale (EDSS) was 2.0. The proportion of current users was 15.5% (95% CI 13.9-17.1) and 36.4% of them disclosed to their physician their unprescribed cannabis use. 15.0% patients were former users while 69.5% never used cannabis. Current users more frequently reported a medical use (i.e., current medical users) compared to former users (p < 0.001). 41.1% of never users would use cannabis if it was legal. Young age, being male, and a free marital status were associated with current use. Current medical users had higher disability, spasticity and pain, reduced quality of life, concomitant neurological/psychiatric drugs and analgesics use. Unprescribed cannabis appeared relatively safe, with limited addiction risk, and reported clinical benefits, including concomitant medications reduction., Conclusion: Unprescribed cannabis use is common in patients with MS in Italy, with observed prevalence seemingly superior to the general population, often intended for medical use and without the disclosure to the treating physician, although with potential clinical benefits., Competing Interests: Declarations Conflicts of interest Dr. R. Giossi received support for congress participation from Mylan and acted as a consultant for Daiichi-Sankyo, outside this work. Prof. M. Filippi is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Horizon, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Horizon, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Horizon, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Dr. C. Zanetta received compensation for speaking activities, and/or consulting services, from Alexion, Astrazeneca, Biogen, Bristol-Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi. Dr. C. Antozzi received funding for traveling from Teva, Merck and Biogen. Dr. L. Brambilla received honoraria for speaking from Novartis, Roche, Horizon, and for traveling from Sanofi-Genzyme, Merck-Serono, Novartis, Horizon and Roche; she acted as an Advisory Board member of Sanofi-Genzyme, Novartis and Merck-Serono and she is involved as principal investigator in clinical trials for Roche and Merck-Serono. Dr. P. Confalonieri has received honoraria for speaking or consultation fees from Novartis, Bristol Myers and Biogen, has received funding for travel to attend scientific events or speaker honoraria from Merck-Serono, Biogen Idec, Mylan and Roche. He has also received institutional research support from Merk-Serono, Novartis and Roche. He is also principal investigator in clinical trials for Novartis and Roche. Dr. S.G. Crisafulli received support for congress participation from Mylan, Merck-Serono, Novartis. He acted as an Advisory Board member for Novartis. Dr. P. Annovazzi received honoraria for lecturing and participation in advisory boards, and/or travel expenses for attending congresses and meetings from Alexion, Almirall, Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva and Viatris. Dr. C. Barrilà participated in improvements groups for Biogen, Sanofi, Novartis, and Merck. Dr. M. Ronzoni received honoraria for congress participation and/or advisory board from Alexion, Almirall, Biogen, Bristol Meyers Squibb, Horizon, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. Dr. S. Gustavsen has received support for congress participation from Merck and Sanofi. Dr. V. Torri Clerici acted as an Advisory Board member of Biogen Idec and Novartis, and received funding for travelling and honoraria for speaking or writing from Teva, Novartis, Genzyme, Almirall. She received support for research project by Almirall. Other authors have nothing to disclose., (© 2024. The Author(s).)

Background: To compare Expanded Disability Status Scale (EDSS) trajectories over time between Multiple Sclerosis (MS) groups with pediatric (POMS), adult (AOMS) and late (LOMS) onset, and between patients with and without progression independent of relapse activity (PIRA)., Methods: Patients with a first visit within 1 year from onset, ≥ 5-year follow-up and ≥ 1 visit every 6 months were selected from the Italian MS Register. Adjusted disability trajectories were assessed by longitudinal models for repeated measures. Comparisons between groups and between patients with and without PIRA in subgroups were performed by evaluating the yearly differences of mean EDSS score changes versus baseline (delta-EDSS). A first CDA event was defined as a 6-months confirmed disability increase from study baseline, measured by EDSS (increase ≥ 1.5 points with baseline EDSS = 0; ≥ 1.0 with baseline EDSS score ≤ 5.0 and ≥ 0.5 point with baseline EDSS > 5.5). PIRA was defined as a CDA event occurring more than 90 days after and more than 30 days before the onset of a relapse., Results: 3777 MS patients (268 POMS, 3282 AOMS, 227 LOMS) were included. The slope of disability trajectories significantly diverged in AOMS vs POMS starting from the second year of follow-up (Year 2: delta2-EDSS 0.18 (0.05; 0.31), p = 0.0054) and then mean delta2-EDSS gradually increased up to 0.23 (0.07; 0.39, p = 0.004) at year 5. Patients with PIRA had significant (p < 0.0001) steeper increase in EDSS scores than those without PIRA in all groups, although in POMS, the disability trajectories began to diverge later and at a lesser extent with delta-EDSS score of 0.48 vs 0.83 in AOMS and 1.57 in LOMS, at 3 years after the first PIRA., Conclusions: Age is relevant in determining disability progression in MS. POMS shows a less steep increase in EDSS scores over time than older patients. The effect of PIRA in accelerating EDSS progression is less pronounced in POMS than in AOMS and LOMS., (© 2024. The Author(s).)

With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms. Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS. Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control. This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In multiple sclerosis (MS), alongside the physical symptoms, individuals often grapple with anxiety and depressive symptoms as prevalent comorbidity. Mood disturbances, frequently undertreated in clinical practice, significantly impact the quality of life of individuals with MS, exacerbating disability and hindering overall well-being. Furthermore, traditional antidepressant therapies are often associated with adverse events, such as sexual side effect, weight gain, which could limit their use in these patients. Vortioxetine is one of the most innovative antidepressant drugs in the current pharmacopeia. Its pharmacological profile includes serotonin reuptake inhibition, antagonism for hydroxytryptamine (HT) receptors 5-HT3, 5-HT1D and 5-HT7, partial agonism for 5-HT1B, and agonism for 5-HT1A. It has been shown to have a beneficial effect on depression-related cognitive dysfunction, as well as on anxiety, depression, anhedonia and emotional blunting. Recently a potential anti-inflammatory action was also described. Limited clinical studies have specifically explored the efficacy of vortioxetine in treating depressive symptoms in MS. However, extrapolating from existing research in major depressive disorder, it is plausible that vortioxetine's multimodal mechanism could provide a favorable therapeutic approach. This position paper, which summarizes the output of annual clinical meeting held by the DMSTs in MS Italian Study Group, is focused on the possible role that vortioxetine could play as symptomatic treatment (ST) of depressed patients with MS, hypothesizing a direct impact on the clinical course of the disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy., Methods: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data., Results: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032)., Discussion: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective., (© 2024. The Author(s).)

Background: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed., Methods: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance., Results: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic., Conclusions: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Gallo reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Merck Serono that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Mylan ITALIA Srl that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Sanofi Genzyme that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Teva Health that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lorena Lorefice reports a relationship with Biogen that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Sanofi Genzyme that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Merck Serono that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Teva Health that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Almirall Ltd that includes: speaking and lecture fees. Alvino Bisecco reports a relationship with Biogen that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Roche that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Merck & Co Inc that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Celgene Corp Los Angeles that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Sanofi Genzyme that includes: consulting or advisory and speaking and lecture fees. Massimiliano Calabrese reports a relationship with Biogen that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Celgene Corp Los Angeles that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Sanofi Genzyme that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Merck Serono that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Novartis that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Roche that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with International Progressive MS Alliance that includes: funding grants. Massimiliano Calabrese reports a relationship with Ministry of Health that includes: funding grants. Massimiliano Di Filippo reports a relationship with Bayer AG that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Biogen Italy that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Sanofi Genzyme that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Merck & Co Inc that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Mylan ITALIA Srl that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Roche that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Siemens Healthineers that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Teva Health that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Teva Health that includes: board membership. Gioacchino Tedeschi reports a relationship with Roche that includes: board membership. Gioacchino Tedeschi reports a relationship with Eli Lilly Italy that includes: board membership. Gioacchino Tedeschi reports a relationship with Allergan US that includes: board membership. Gioacchino Tedeschi reports a relationship with Sanofi-Aventis US LLC that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Merck Serono Ltd that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Bayer Schering Pharma AG that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Biogen Italy that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Clinicians are increasingly recognizing the importance of shared decision-making in complex treatment choices, highlighting the importance of the patient's rationale and motivation for switching therapies. This study aimed to evaluate the association between different modalities of changing multiple sclerosis (MS) treatments, cognitive profile and attitude and preferences of patients concerning treatment choice., Methods: This multicenter cross-sectional study was conducted at 28 Italian MS centers in the period between June 2016 and June 2017. We screened all MS patients treated with any DMT, with a treatment compliance of at least 80% of therapy administered during the 3 last months who needed to modify MS therapy because of efficacy, safety or other reasons during a follow-up visit. At the time of switching the symbol digit modalities test (SDMT) and the Control Preference Scale (CPS) were evaluated. According to the CPS, patients were classified as "active" (i.e. who prefer making the medical decision themselves), "collaborative" (i.e. who prefer decisions be made jointly with the physician), or "passive" (i.e. who prefer the physician make the decision)., Results: Out of 13,657 patients recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%) patients, 69.6% were female and with mean age 40.6 ± 10.5 years, were enrolled. According to the CPS score evaluation, a significant high percentage of patients (51.1%) were considered collaborative, 74 patients (22.5%) were passive, and 60 (18.2%) patients were active. Stratifying according to CPS results, we found a higher SDMT score among collaborative patients compared to active and passive ones (45.8 ± 12.3 versus 41.0 ± 13.2 versus 41.7 ± 12.8, p < 0.05)., Conclusion: In this study, the CPS evaluation showed that more than 50% of patients who needed to change therapy chose a "collaborative" role in making treatment decision. Cognitive profile with SDMT seems to correlate with patients' preference on treatment decision, showing better scores in collaborative patients., Competing Interests: Declaration of Competing Interest Francesco Patti has received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he also served as advisory board member the following companies: Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Clara G. Chisari has received grants for congress participation from Almirall, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Simona Toscano declares no conflict of interest. Pietro Annovazzi has received honoraria for lecturing and participation in advisory boards, and/or travel expenses for attending congresses and meetings from Almirall, Biogen Idec, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and TEVA. Paola Banfi has received support for attendance to scientific meetings from Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. Roberto Bergamaschi has received honoraria for lectures, travel and registration coverage for attending several national or international congresses or symposia from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Aventis, Sanofi Genzyme, and TEVA. Raffaella Clerici has received speaker's honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Novartis, and Sanofi Genzyme. Marta Zaffira Conti declares there is no conflict of interest. Antonio Cortese has received speaker honoraria, travel grants, advisory boards member honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. Roberta Fantozzi has received consulting fees and honoraria for advisory boards from Biogen Idec, Merck Serono, Novartis, Roche, and TEVA Diana Ferraro declares there is no conflict of interest. Mariano Fischetti declares there is no conflict of interest. Maura Frigo declares there is no conflict of interest. Maurizia Gatto declares there is no conflict of interest. Paolo Immovilli has received speaking honoraria, consulting fees, advisory board honoraria from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Stefania Leoni declares there is no conflict of interest. Simona Malucchi has received speaker's honoraria and consulting fees, honoraria in advisory boards from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA Giorgia Maniscalco has received honoraria for public speaking and advisory boards from Biogen, Novartis, and Merck Serono. Girolama Alessandra Marfia is an Advisory Board member of Biogen Idec, Sanofi Genzyme, Merck-Serono, Novartis, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, and TEVA. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and TEVA Damiano Paolicelli has received honoraria for consultancy and/or speaking from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Paola Perini has received speaker honoraria and consulting fees from Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Carlo Serrati declares no conflict of interest. Rocco Totaro has received speaker's honoraria, consulting fee, honoraria for advisory boards, support for attendance of scientific meetings from Alfa Wasserman, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi genzyme, and TEVA. Gabriella Turano has received support for attendance to scientific meetings from Almirall, Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. Paola Valentino has received speaker's honoraria and consulting fee, honoraria for advisory boards from Biogen Idec, Novartis, Merck Serono, Sanofi Genzyme, and TEVA. Mauro Zaffaroni has received honoraria for lecturing or participating for advisory boards or travel funding from Almirall, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. Cristina Zuliani has received speaker's honoraria and consulting fees, honoraria for advisory boards, support for attendance of scientific meetings from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen Idec, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and TEVA. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi Genzyme, and TEVA. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA., (Copyright © 2022. Published by Elsevier B.V.)

Background and Objectives: We sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD)., Methods: In a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up., Results: Seventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) ( p = 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) ( p = 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) ( p = 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy <7 days from onset (6.7-fold reduced odds of relapsing course, OR 0.15, 95% CI 0.03-0.61, p = 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03-0.80, p = 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01-0.50, p = 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) ( p = 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33-33.26, p = 0.021)., Discussion: At first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1)., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines., Objective: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs)., Methods: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT., Results: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p  < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p  < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p  = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p  = 0.02)., Conclusions: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.

Objectives: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS)., Methods: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery ("treatment approach," (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery ("conservative approach," (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire., Results: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6-10.6, p  = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4-7.9 p  = 0.007). We found no major development abnormalities in children., Discussion: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.

Background: Patients with multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) that can expose them to reactivation of potential occult hepatitis B virus (HBV) infection (pOBI). We aimed to evaluate the MS Centers behavior regarding HBV screening and prophylaxis in a large cohort of MS patients receiving anti-CD20 or cladribine., Methods: Retrospective, multicentric study recruiting Italian MS patients treated with rituximab, ocrelizumab and cladribine., Results: We included 931 MS patients from 15 centers. All but 38 patients performed a complete HBV screening. Patients' age > 50 years was significantly associated with no history of vaccination and HBsAb titres < 100 mIU at baseline (p < 0.001). No significant correlation was found between post-vaccination HBsAb titres and type of treatment (p = 0.5), pre-or post-therapy vaccination (p = 0.2) and number of previous DMTs (p = 0.2). Among pOBI patients (n = 53), 21 received antiviral prophylaxis, while only 13 had HBV DNA monitoring and 19 patients neither monitored HBV DNA nor received prophylaxis., Conclusions: Baseline HBV screening in patients receiving anti-CD20 and cladribine is a consolidated practice. Nonetheless, HBV vaccination coverage is still lacking in such population and age is a significant factor associated with low HBV protection. Rituximab, ocrelizumab and cladribine did not impair HBV vaccine response. Almost 35% of pOBI patients fail to receive HBVr prevention. Management of HBV prophylaxis could be improved in MS patients and further prospective studies are needed to assess the effectiveness of prophylactic strategies in such patients., (© 2022. The Author(s).)

Earlier diagnosis, access to disease-modifying therapies (DMTs), and improved supportive care have favorably altered the disease course of multiple sclerosis (MS), leading to an improvement in long-term outcomes for people with MS (PwMS). This success has changed the medical characteristics of the population seen in MS clinics. Comorbidities and the accompanying polypharmacy, immune senescence, and the growing number of approved DMTs make selecting the optimal agent for an individual patient more challenging. Glatiramer acetate (GA), a moderately effective DMT, interacts only minimally with comorbidities, other medications, or immune senescence. We describe here several populations in which GA may represent a useful treatment option to overcome challenges due to advanced age or comorbidities (e.g., hepatic or renal disease, cancer). Further, we weigh GA's potential merits in other settings where PwMS and their neurologists must base treatment decisions on factors other than selecting the most effective DMT, e.g., family planning, conception and pregnancy, or the need for vaccination., Competing Interests: MM received consulting and/or speaking fees, research support or travel grants from Almirall, Bayer Schering, Biogen, CSL Behring, Sanofi-Genzyme, Merck, Novartis, Teva, Roche, Viatris (Mylan). JC received personal compensation for consulting for Biogen, Bristol-Myers Squibb, Convelo, Genentech, Janssen, NervGen, Novartis, and PSI; speaking for H3 Communications; and serving as an Editor of Multiple Sclerosis Journal. CW is a partner at Lycalis sprl. His organization has received compensation for consulting and speaking from Viatris (Mylan), Merck KAaG, Roche, Immunic, BMS Celgene, Novartis, Teva, Synthon, 2BBB, ICON, and Desitin. WB has received speaker honoraria and/or participated in advisory boards for Biogen, Celgene, Merck, Novartis, Roche, Sanofi and Viatris. PA received honoraria for lecturing and/or participation in advisory boards, and/or travel expenses for attending congresses and meetings from Almirall, Biogen, BMS-Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, Teva Italia, and Viatris. CK received speaker honoraria and/or participated in advisory boards for Alexion, Biogen, Celgene, CSL Behring, Janssen-Cilag, MedDay, Merck, Novartis, Roche, Sanofi Genzyme, Teva and Viatris., (Copyright © 2022 Mirabella, Annovazzi, Brownlee, Cohen, Kleinschnitz and Wolf.)

Background: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial., Objective: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy., Methods: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model., Results: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06-2.84; p = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12-1.74; p = 0.003), younger age (aHR = 0.95; 95% CI 0.91-0.99; p = 0.022) and shorter DMD exposure over the follow-up ( p < 0.008)., Conclusion: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity.

Objective: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, disimmune disease of the central nervous system whose etiology and pathogenesis remain poorly understood, due to its complex and multifactorial nature. Evidence of a bidirectional connection linking the gut microbiome with the intestinal barrier and the immune system (the gut-brain axis) may have implications for the pathogenesis of inflammatory demyelinating diseases such as MS. This narrative review summarizes the evidence for the gut-brain axis involvement in the pathogenesis of MS and examines the role of gut-oriented interventions in MS., Patients and Methods: We reviewed all available studies in PubMed concerning gut-directed interventions and MS. This research was conducted using different combinations of pertinent keywords (multiple sclerosis, immune-mediated inflammatory diseases, autoimmune diseases, first demyelinating event, neurocognition, neurological disorders, neurology practice, risk factors, taxonomic biomarkers, nutrition, diet, dietary additives, complementary treatment, gut bacteria, gut microbiome, microbiome, gut-brain axis, epidemiology, alpha-linolenic acid, fermentative metabolites, fat, saturated fat, monounsaturated fat, polyunsaturated fat, omega-3 fatty acids, calorie restricted diet, fasting, fecal microbiome, fecal microbiota transplantation, animal testing)., Results: There is an emerging evidence that alterations in the gut microbiome and increased intestinal permeability may be causative factors in the complex interplay between nutrition, metabolic status and the immune-inflammatory response in patients with MS. This suggests the possibility that modification of lifestyle and the microbiome, for example by specific diets or fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers, may positively influence the pathogenesis of MS., Conclusions: Although the role of nutritional factors in the pathogenesis of MS remains to be established, there is evidence that appropriate gut-directed interventions such as diet, nutritional supplementation or fecal transplantation may modulate the inflammatory response and improve the course of MS as a complementary treatment in the disease.

Background and Purpose: Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab., Methods: Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation., Results: We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow-up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous-year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression-free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re-baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years., Conclusions: Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To identify baseline factors associated with disease activity in patients with relapsing-remitting multiple sclerosis (RRMS) under teriflunomide treatment., Methods: This was an independent, multi-centre, retrospective post-marketing study. We analysed data of 1,507 patients who started teriflunomide since October 2014 and were regularly followed in 28 Centres in Italy. We reported the proportions of patients who discontinued treatment (after excluding 32 lost to follow-up) and who experienced clinical disease activity, i.e., relapse(s) and/or confirmed disability worsening, as assessed by the Expanded Disability Status Scale (EDSS). Decision tree-based analysis was performed to identify baseline factors associated with clinical disease activity during teriflunomide treatment., Results: At database lock (September 2020), approximately 29% of patients (430 out of 1,475) discontinued teriflunomide because of disease activity (~ 46%), adverse events (~ 37%), poor tolerability (~ 15%), pregnancy planning (~ 2%). Approximately 28% of patients experienced disease activity over a median follow-up of 2.75 years: ~ 9% had relapses but not disability worsening; ~ 13% had isolated disability worsening; ~ 6% had both relapses and disability worsening. The most important baseline factor associated with disease activity (especially disability worsening) was an EDSS > 4.0 (p < 0.001). In patients with moderate disability level (EDSS 2.0-4.0), disease activity occurred more frequently in case of ≥ 1 pre-treatment relapses (p = 0.025). In patients with milder disability level (EDSS < 2.0), disease activity occurred more frequently after previous exposure to ≥ 2 disease-modifying treatments (p = 0.007)., Conclusions: Our study suggests a place-in-therapy for teriflunomide in naïve patients with mild disability level or in those who switched their initial treatment for poor tolerability. Adverse events related with teriflunomide were consistent with literature data, without any new safety concern., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

The prevalence of trigeminal neuralgia (TN) in patients with Multiple Sclerosis (MS) is higher than in the general population and its management can be particularly challenging due to a number of reasons including high recurrence rates, lack of MS-specific treatment guidelines and uncertainties about pain pathophysiology. Aim of this cross-sectional, multicentre survey was to gather information on the current treatment modalities and options of MS-related TN across 23 Italian MS centres. Initial medical management (carbamazepine or oxcarbazepine) of MS-related TN was fairly homogeneous throughout Italian centres. The most commonly available surgical procedure was microvascular decompression, but the frequency and types of surgical procedures available locally differed considerably throughout MS centers, and were unavailable in one quarter of them. This survey reveals some of the issues that could hamper an optimal patient management and underlines the need for a consensus on MS-related TN to support health-care professionals in their approach to this challenging condition and to facilitate the development of local guidelines aimed at ensuring equity in access to care and treatment optimization., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS., Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected., Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline., Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS., (© 2020 European Academy of Neurology.)

Background: The detection of antibodies to myelin oligodendrocyte glycoprotein (MOG) is fundamental for the identification of MOG antibody-associated disorders (MOGAD), and the differential diagnosis of acquired demyelinating syndromes of the CNS, among which multiple sclerosis (MS). We compared the diagnostic performance of four cell-based assays (CBAs) for their detection., Methods: Consecutive sera from 204 patients with 'possible MOGAD' (55), MS (112), and other neurological disorders (OND, 37) were tested for MOG-IgG with a live-CBA with anti-heavy-and-light chain secondary-antibody (LCBA-IgG H+L ), and a live-CBA for IgG 1 (LCBA-IgG 1 ). A subgroup of 71 patients was additionally tested with a live-CBA with anti-Fcγ secondary-antibody (LCBA-IgG Fcγ ), and a commercial fixed-CBA with anti-Fcγ secondary-antibody (FCBA-IgG Fcγ ) . RESULTS: Fifty-seven/204 patients (27.9%) were MOG-IgG-positive. Sensitivity was 89.1% (CI:77.8-95.9) and specificity 93.3% (CI:88.0-96.7) for LCBA-IgG H+L , and 74.6% (CI:61.0-85.3) and 100% (CI:97.6-100) for LCBA-IgG 1 . Eighteen of 57 (31%) samples showed discrepant results (all negative on LCBA-IgG 1 ); of these, three with 'possible MOGAD' showed high-titer MOG-IgG (≥ 1:640), and positivity for MOG-IgG 2 , whereas 15/18 had low-titer MOG-IgG (1:160/1:320) and mixed diagnoses (5 'possible MOGAD', 6 MS, 4 OND). In the subgroup analysis, sensitivity was 92.3% (CI:79.1-98.4) and specificity 97.0% (CI:83.8-99.9) for LCBA-IgG Fcγ , and 87.2% (CI:72.6-95.7) and 97.0% (CI:83.8-99.9) for FCBA-IgG Fcγ ., Conclusions: LCBA-IgG 1 showed the highest specificity but can miss MOG-IgG 2 reactivities, whose meaning warrants further investigations. Titration of samples tested with LCBA-IgG H+L / IgG Fcγ is important for meaningful interpretation of the results. In the subgroup analysis, LCBA-IgG Fcγ yielded the highest accuracy, and FCBA-IgG Fcγ good specificity, but it was at risk of false-negative results.

Background: Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies. In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group., Methods: RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ 2 )., Results: Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ 2 =4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ 2 =7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ 2 =0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ 2 =0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ 2 =2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p = 0.02; τ 2 =5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p = 0.02; τ 2 =1.00)., Discussion: We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies., Competing Interests: Declaration of competing interest Marcello Moccia has received research grants from ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from Biogen, Merck, Novartis, and Roche; and consulting fees from Veterans Evaluation Services. Maria Chiara Buscarinu has received honoraria from Allmiral, Teva, Biogen, Meck, Roche, Sanofi-Genzyme and Novartis. Paola Cavalla has received honoraria from Biogen, Merck, Teva, Roche, Novartis and Sanofi-Genzyme; travel support for conferences from Biogen, Merck, Teva, Roche, Novartis and Sanofi-Genzyme. Cinzia Cordioli has received honoraria from Novartis, Merck Serono, Almirall, and Biogen. Massimiliano Di Filippo has received honoraria and travel support for conferences from Bayer, Biogen, Sanofi-Genzyme, Merck, Mylan, Novartis, Roche and Teva. Alberto Gajofatto has received honoraria from Biogen and Merck; and travel support for conferences from Merck. Antonio Gallo has received honoraria from Merck, Teva, Roche, and Sanofi-Genzyme; and travel support for conferences from Merck, Teva, Roche, and Sanofi-Genzyme. Alice Laroni has received research grants from Fondazione Italiana Sclerosi Multipla, Italian Ministry of Health and Italian Ministry of University; and honoraria from Merck, Biogen, Sanofi, Roche, and Novartis. Viviana Nociti has received honoraria from Teva, Bayer, Novartis, Roche, Mylan, Biogen, Merk and Sanofi-Genzyme; and travel support for conferences from Teva, Biogen, Sanofi-Genzyme, Roche and Novartis. Damiano Paolicelli has received honoraria from Biogen, Merck, Bayer, Sanofi-Aventis, Teva, Novartis, and Genzyme. Luca Prosperini has received honoraria from Biogen, Celgene, Genzyme, Merck, Mylan, Novartis, Roche, and Teva; and research grants from Genzyme and Fondazione Italiana Sclerosi Multipla. Marta Radaelli has received honoraria from Merck, Roche, Sanofi-Genzyme, and Novartis; and travel support for conferences from Merck, Roche, Sanofi-Genzyme, and Novartis. Paolo Ragonese has received honoraria from Biogen, Merck, Novartis, Roche, Teva, Sanofi-Genzyme; travel support for conferences from Biogen-Idec, Merck-Serono, Roche and Sanofi-Genzyme; and research grants from Almyral and Roche. Carla Tortorella has received honoraria from Merck, Teva, Roche, Sanofi-Genzyme, Novartis, and Biogen; and travel support for conferences from Merck, Teva, Roche, Sanofi-Genzyme, Novartis, and Biogen. Claudio Gasperini has received honoraria from Almirall, Bayer, Biogen, Teva, Bayer, Sanofi-Genzyme, Merck, Roche, Novartis and Sanofi-Genzyme. Other authors have nothing to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data., Methods: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity., Results: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis., Conclusion: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity., Classification of Evidence: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. AIMS: The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. RESULTS: The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.

Background: clinical factors and frequency of disease-modifying therapy (DMT) changes/interruptions in relapsing-remitting multiple sclerosis (RRMS) patients have not been well defined. The aim of this study was to describe reasons of MS treatment modifications in a large cohort of Italian MS patients., Methods: this multicenter, cross-sectional non interventional study (SWITCH) conducted at 28 Italian MS centers, screened, by visit/telephone contact between June 2016 and June 2017, all RRMS patients receiving stable DMT treatment and enrolled patients with change in DMT treatment., Results: out of 13,657 recorded in the log, 409 (3%) changed therapy. Of these, 336 (2.5%), met the study criteria and were considered eligible. Among 303 (90.2% of 336) patients switching, the most common reason was "lack of efficacy" (58.4% of 303). Among 30 (8.9%) patients who interrupted treatment temporarily, the most common reason was pregnancy (40.0% of 30). Out of 3 (0.9%) patients who discontinued treatment permanently, 2 (66.7%) had as first reason as "patient decision". Multivariate analysis showed that EDSS was the only variable with statistically significant effect on changing treatments (r = 8.33; p-value of Type III Sum of Squares = 0.016)., Conclusion: in our study, 303 (90.2% of eligible patients) switched treatment, 30 (8.9%) interrupted treatment temporarily, and 3 (0.9%) discontinued treatment permanently. Efficacy remains the main driving force behind switching behavior, as the primary aim of treatment is to be disease free or reduce disease activity., Competing Interests: Declaration of Competing Interest The authors declare the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.P. has received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he also served as advisory board member the following companies: Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. C.G.C. has received grants for congress participation from Almirall, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. E.D'A. has received grants for speaking activities from Bayer Schering, Biogen Idec, Merck Serono, Novartis, TEVA and grants for congress participation from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. P.A. has received honoraria for lecturing and participation in advisory boards, and/or travel expenses for attending congresses and meetings from Almirall, Biogen Idec, Merck Serono, Mylan, Novartis, Roche, Sanofi Genzyme, and TEVA. P.B. has received support for attendance to scientific meetings from Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. R.B: has received honoraria for lectures, travel and registration coverage for attending several national or international congresses or symposia from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Aventis, Sanofi Genzyme, and TEVA. R.C. has received speaker's honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Novartis, and Sanofi Genzyme. M.C. Author declares there is no conflict of interest. A.C. has received speaker honoraria, travel grants, advisory boards member honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. R.F. has received consulting fees and honoraria for advisory boards from Biogen Idec, Merck Serono, Novartis, Roche, and TEVA. M.Fi. Author declares there is no conflict of interest. M.Fr. has received speaker's honoraria and consulting fees, honoraria for advisory boards, support for attendance of scientific meetings from Biogen Idec, Merck Serono, Novartis, TEVA, and Sanofi Genzyme. M.G. Author declares there is no conflict of interest. P.I. has received speaking honoraria, consulting fees, advisory board honoraria from Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA S.L. Author declares there is no conflict of interest. S.M. has received speaker's honoraria and consulting fees, honoraria in advisory boards from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. G.M. has received honoraria for public speaking and advisory boards from Biogen, Novartis, and Merck Serono. G.A.M. is an Advisory Board member of Biogen Idec, Sanofi Genzyme, Merck-Serono, Novartis, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, and TEVA. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and TEVA. D.P. has received honoraria for consultancy and/or speaking from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. C.S. Author declares there is no conflict of interest. P.P. has received speaker honoraria and consulting fees from Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. P.S. has received speaker's honoraria and consulting fees, honoraria for advisory boards, and travel grants from Biogen Idec, Merck Serono, Novartis, Sanofi genzyme, and TEVA. R.T. has received speaker's honoraria, consulting fee, honoraria for advisory boards, support for attendance of scientific meetings from Alfa Wasserman, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi genzyme, and TEVA. G.T. has received support for attendance to scientific meetings from Almirall, Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme. P.V. has received speaker's honoraria and consulting fee, honoraria for advisory boards from Biogen Idec, Novartis, Merck Serono, Sanofi Genzyme, and TEVA. M.Z. has received honoraria for lecturing or participating for advisory boards or travel funding from Almirall, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and TEVA. C.Z. has received speaker's honoraria and consulting fees, honoraria for advisory boards, support for attendance of scientific meetings from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. D.C. is an Advisory Board member of Almirall, Bayer Schering, Biogen Idec, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA, and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and TEVA. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi Genzyme, and TEVA. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort., Methods: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab., Results: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076)., Conclusion: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age., Competing Interests: Deckaration of Competing Interest None, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: recent studies reported that anti myelin oligodendrocyte glycoprotein (MOG) antibody (ab) related optic neuritis (ON) tend to have characteristics that differ from seronegative ones. The aim of our study was to investigate the clinical characteristics of pediatric anti-MOG ON by comparing anti MOG-ab-seropositive and seronegative patients with ON., Methods: in this retrospective Italian multicentre study, participants were identified by chart review of patients evaluated for acquired demyelinating syndromes of the central nervous system (over the period 2009-2019). We selected patients presenting with ON as their first demyelinating event. Inclusion criteria were age < 18 years at symptoms onset; presentation consistent with ON; negativity of anti-aquaporin 4 antibodies (AQP4). Only patients who were tested for MOG-IgG1-ab with a live cell-based assay were included., Results: 22 patients (10 MOG-ab-positive and 12 MOG-ab-negative) were included. Fundus oculi examination at onset showed disc swelling in 9/10 in the MOG-ab-positive cohort and 2/10 in the seronegative group (P = 0.002). Retinal Fiber Nerve Layer (RFNL) thickness measured by Spectral Domain Optical Coherence Tomography (S-OCT) was increased in the 5/5 MOG-ab-positive patients tested and was normal or reduced in the seronegative patients tested (4/4 patients) (P = 0.024). Visual acuity impairment at onset did not differ significantly between the two groups, but the MOG-ab-positive cohort showed better recovery at follow-up both regarding visual acuity (P = 0.025) and expanded disability status scale (EDSS) (P = 0.013). A final diagnosis of MS was frequent among seronegative patients (6/12, 50%), whereas none of the MOG-ab-positive group received a diagnosis of MS (P = 0.015). Clinical relapse frequency was low in both groups: 2/10 MOG-ab-positive and 2/12 seronegative cases relapsed, with a median follow up of 25 months., Conclusion: optic disc swelling and increased RFNL at baseline are strongly associated with MOG-ab positivity. MOG-ab-positive patients with ON showed better recovery compared to the seronegative ones. The relapse rate was low and did not differ among the two groups., Competing Interests: Declaration of Competing Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study., Methods: Neurologists members of the RIREMS group (Rising Researchers in MS) enrolled MS patients with a TN diagnosis and filled out a spreadsheet comprising their clinical data., Results: Population consisted of 298 patients. First-choice preventive treatments were carbamazepine and oxcarbazepine. A surgical procedure was performed in 81 (30%) patients, most commonly gamma knife stereotactic radiosurgery (37%), followed by microvascular decompression (22%) and radiofrequency thermocoagulation (21%); one third of patients underwent at least two procedures. Surgery was associated with higher disability, male sex and longer interval between MS and TN onset. Patients (77%) who stayed on at least one preventive medication at most recent follow-up, after a mean period of 8 years, had a higher disability compared to the untreated group. Furthermore, patients with higher disability at TN onset were less likely to discontinue their first preventive medication due to pain remission, had bilateral TN more frequently and underwent surgical interventions earlier., Conclusion: MS patients with a higher disability at TN onset and with a longer interval between MS and TN onset had differing clinical features and outcomes: pain was more frequently bilateral, surgery was more frequent and anticipated, and preventive medication discontinuation due to pain remission was less common., Competing Interests: Declaration of Competing Interest Authors report no conflicts of interest in relation to the study., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients., Methods: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring)., Results: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis., Interpretation: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 × 10 3 /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.

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences., Objectives: To identify prognostic factors for early switch after first therapy choice., Methods: Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models., Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p  = 0.009), natalizumab (HR = 0.13; p  < 0.001), dimethyl-fumarate (HR = 0.60; p  = 0.037), teriflunomide (HR = 0.21; p  = 0.031) as compared to interferons. Younger age (HR = 0.96; p  < 0.001), diagnosis delay (HR = 1.23; p  = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p  = 0.001), and spinal cord lesions (HR = 1.46; p  = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p  = 0.001), fingolimod (HR = 0.35; p  = 0.002), and dimethyl-fumarate (HR = 0.57; p  = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p  = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p  = 0.047)., Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.

Background: The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete., Methods: A total of 695 patients presenting with symptoms suggestive of MS in any of the 22 RIREMS centers underwent a detailed diagnostic workup, including a brain and spinal cord MRI scan, CSF and blood examinations, and a 3-year clinical and radiologic follow-up., Findings: A total of 667 patients completed the study. Alternative diagnoses were formulated in 163 (24.4%) cases, the most frequent being nonspecific neurologic symptoms in association with atypical MRI lesions of suspected vascular origin (40 patients), migraine with atypical lesions (24 patients), and neuromyelitis optica (14 patients). MS was diagnosed in 401 (60.1%) patients according to the 2017 diagnostic criteria. The multivariate analysis revealed that the absence of CSF oligoclonal immunoglobulin G bands (IgG-OB) (odds ratio [OR] 18.113), the presence of atypical MRI lesions (OR 10.977), the absence of dissemination in space (DIS) of the lesions (OR 5.164), and normal visual evoked potentials (OR 3.550) were all independent predictors of an alternative diagnosis., Interpretation: This observational, unsponsored, real-life study, based on clinical practice, showed that diseases that mimicked MS were many, but more than 45% were represented by nonspecific neurologic symptoms with atypical MRI lesions of suspected vascular origin, migraine, and neuromyelitis optica. The absence of IgG-OB and DIS, the presence of atypical MRI lesions, and normal visual evoked potentials should be considered suggestive of an alternative disease and red flags for the misdiagnosis of MS., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

In this retrospective, multicenter, real-world study we collected clinical and magnetic resonance imaging (MRI) data of all patients (n = 40) with relapsing-remitting multiple sclerosis (RRMS) treated with alemtuzumab according to a "free-of-charge" protocol available before the drug marketing approval in Italy. Almost all (39/40) started alemtuzumab after discontinuing multiple disease-modifying treatments (DMTs) because of either lack of response or safety concerns. We considered the proportion of alemtuzumab-treated patients who had no evidence of disease activity (NEDA-3) and disability improvement over a 36-month follow-up period. NEDA-3 was defined as absence of relapses, disability worsening, and MRI activity. Disability improvement was defined as a sustained reduction of ≥ 1-point in Expanded Disability Status Scale (EDSS) score. At follow-up, 18 (45%) patients achieved NEDA-3, 30 (75%) were relapse-free, 33 (82.5%) were EDSS worsening-free, and 25 (62.5%) were MRI activity-free. Eleven (27.5%) patients had a sustained disability improvement. We found no predictor for the NEDA-3 status, while the interaction of higher EDSS score by higher number of pre-alemtuzumab relapses was associated with a greater chance of disability improvement (odds ratio 1.10, p = 0.049). Our study provides real-world evidence that alemtuzumab can promote clinical and MRI disease remission, as well as disability improvement, in a significant proportion of patients with RRMS despite prior multiple DMT failures. The drug safety profile was consistent with data available from clinical trials.

Background and Purpose: There is debate as to whether the apparent rebound after fingolimod discontinuation is related to the discontinuation itself or whether it is due to the natural course of highly active multiple sclerosis (MS). Our aim was to survey the prevalence of severe reactivation and rebound after discontinuation of fingolimod in a cohort of Italian patients with MS., Methods: Patients with relapsing-remitting MS who were treated with fingolimod for at least 6 months and who stopped treatment for reasons that were unrelated to inefficacy were included in the analysis., Results: A total of 100 patients who had discontinued fingolimod were included in the study. Fourteen patients (14%) had a relapse within 3 months after fingolimod discontinuation, and an additional 12 (12%) had a relapse within 6 months. According to this study's criteria, 10 patients (10%) had a severe reactivation. Amongst these patients, five (5%) had a reactivation that was considered to be a rebound., Conclusions: The present study showed that more than 26% of patients are at risk of having a relapse within 6 months after fingolimod discontinuation. Nevertheless, the risk of severe reactivations and rebound is lower than has been previously described., (© 2018 EAN.)

Background: Dimethyl-fumarate (DMF) demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (MS) in randomized clinical trials., Objectives: To track and evaluate post-market DMF profile in real-world setting., Materials and Methods: Patients receiving DMF referred to Italian MS centres were enrolled and prospectively followed, collecting demographic clinical and radiological data., Results: Among the 735 included patients, 45.4% were naïve to disease-modifying therapies, 17.8% switched to DMF because of tolerance, 27.4% switched to DMF because of lack of efficacy, and 9.4% switched to DMF because of safety concerns. Median DMF exposure was 17 months (0-33). DMF reduced the annual relapse rate (ARR) by 63.2%. At 12 and 24 months, 85 and 76% of patients were relapse-free. NEDA-3 status after 12 months of DMF treatment was maintained by 47.5% of patients. 89 and 70% of patients at 12 and 24 months regularly continued DMF. Most frequent adverse events (AEs) were flushing (37.2%) and gastro-enteric AEs (31.1%)., Conclusion: Our post-market study corroborated that DMF is a safe and effective drug. Additionally, the study suggested that naïve patients strongly benefit from DMF and that DMF improved ARR also in patients who were horizontally switched from injectable therapies due to tolerability and efficacy issues.

In this independent, multicenter, retrospective study, we investigated the short-term persistence to treatment with first-line self-injectable or oral disease-modifying treatments (DMTs) in patients with relapsing-remitting multiple sclerosis. Data of patients regularly attending 21 Italian MS Centres who started a self-injectable or an oral DMT in 2015 were collected to: (1) estimate the proportion of patients discontinuing the treatment; (3) explore reasons for discontinuation; (3) identify baseline predictors of treatment discontinuation over a follow-up period of 12 months. We analyzed data of 1832 consecutive patients (1289 women, 543 men); 374 (20.4%) of them discontinued the prescribed DMT after a median time of 6 months (range 3 days to 11.5 months) due to poor tolerability (n = 163; 43.6%), disease activity (n = 95; 25.4%), adverse events (n = 64; 17.1%), convenience (i.e. availability of new drug formulations) and pregnancy planning (n = 21; 1.1%). Although the proportion of discontinuers was higher with self-injectable (n = 107; 22.9%) than with oral DMT (n = 215; 16.4%), the Cox regression model revealed no significant between-group difference (p = 0.12). Female sex [hazard ratio (HR) = 1.39, p = 0.01] and previous exposure to ≥ 3 DMTs (HR = 1.71, p = 0.009) were two independent risk factors for treatment discontinuation, regardless of prescribed DMTs. Our study confirms that persistence to treatment represents a clinical challenge, irrespective of the route of administration.

Objective: To assess the risk of disease reactivation during pregnancy after natalizumab suspension in women with multiple sclerosis (MS)., Methods: Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents through a 2-factor repeated measures analysis. Predictors of disease activity were assessed through stepwise multivariable logistic regression models., Results: A total of 92 pregnancies were tracked in 83 women receiving natalizumab. Among these pregnancies, 74 in 70 women resulted in live births, with a postpartum follow-up of at least 1 year, and were compared with 350 previously published pregnancies. Relapse rate during and after pregnancy was higher in women treated with natalizumab ( p < 0.001). In multivariable analysis, longer natalizumab washout period was the only predictor of relapse occurrence during pregnancy ( p = 0.001). Relapses in the postpartum year were related to relapses during pregnancy ( p = 0.019) and early reintroduction of disease-modifying drugs (DMD; p = 0.021). Disability progression occurred in 16.2% of patients and was reduced by early reintroduction of DMD ( p = 0.024)., Conclusions: Taken as a whole, our findings indicate that the combination of avoiding natalizumab washout and the early resumption of DMD after delivery could be the best option in the perspective of maternal risk. This approach must take into account possible fetal risks that need to be discussed with the mother and require further investigation., Classification of Evidence: This study provides Class IV evidence that in women with MS, the risk of relapses during pregnancy is higher in those who had been using natalizumab as compared to those who had been using interferon-β or no treatment., (© 2018 American Academy of Neurology.)

Objective: To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA)., Methods: Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed., Results: A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9-8.5, p < 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) was associated with lower length and weight of the babies ( p < 0.001)., Conclusion: Our results showed that natalizumab exposure to up 12 weeks of gestation is associated with an increased risk of SA, although within the limits expected in the general population, whereas the risk of CA needs further investigation. Taking into account the high risk of disease reactivation after natalizumab suspension, pregnancy could be planned continuing natalizumab while strictly monitoring conception., Classification of Evidence: This study provides Class III evidence that in women with MS, natalizumab exposure increases the risk of spontaneous abortion as compared to IFN-β-exposed or untreated patients (OR 3.9, 95% CI 1.9-8.5)., (© 2018 American Academy of Neurology.)

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Economic sustainability is of paramount importance in the rapidly evolving therapeutic scenario of multiple sclerosis (MS). Glatiramoids are a class of drugs whose forefather, glatiramer acetate, has been used as a disease modifying drug (DMD) in patients with MS for over 20 years. Its patent expired in 2015; new versions of such drug are nowadays available on the market, potentially contributing to lowering prices and enhancing a better allocation of economic resources. In this review, we analyze the recommendations underlying the approval of both generic drugs and biosimilars by regulatory authorities, and we provide methodological tools to contextualize the design of studies on these new classes of drugs. We examine in more detail the preclinical and clinical data of Copemyl ® , a new member of the glatiramoid class, focusing on its biological and immunological properties and illustrating randomized controlled trials that led to its authorization.

Objective: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort., Methods: We included newly diagnosed patients (2010-2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch., Results: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04-1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07-1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04)., Conclusions: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment., (© 2017 American Academy of Neurology.)

Objective: To evaluate the risk of relapses during pregnancy and in the first 3 months after delivery in 2 successive pregnancies in a cohort of French and Italian women with multiple sclerosis (MS)., Methods: A total of 93 women were included if they had had 2 pregnancies followed prospectively after MS onset between January 1993 and 2013. The association of a relapse during pregnancy or the first postpartum trimester in pregnancy 1 and pregnancy 2 was evaluated by univariate logistic regression., Results: A majority of women did not experience any exacerbation in the 3 months after delivery (31.2% and 23.7%, respectively, relapsed after pregnancy 1 and 2; p = 0.32). A total of 7.6% had a relapse after both pregnancies. The risk of relapse after pregnancy 2 was not associated with the number of relapses in the prepregnancy year (odds ratio [OR] 1.52 [0.57-4.05]) or during pregnancy (OR 1.57 [0.52-4.79]) or with the occurrence of a relapse after pregnancy 1 (OR 0.86 [0.29-2.50])., Conclusions: Our work provides original data on the evolution of successive pregnancies in MS, showing a similar (and even lower) disease activity in the second pregnancy. There was no correlation of activity in successive pregnancies. Therefore, counseling of women with MS who consider having a second baby should be the same as for the first one., (© 2016 American Academy of Neurology.)

Rituximab (RTX) efficacy in NMO is suggested by several case series. No consensus exists on optimal dosing strategies. At present the treatment schedules more frequently used are 375 mg/m2/week iv for 4 weeks (RTX-A) and 1000 mg iv twice, 2 weeks apart (RTX-B). Aim of this study is to confirm RTX efficacy and safety in the treatment of NMO and to evaluate whether a most favourable dosage regimen exists. Data on RTX-treated NMO patients were collected from 13 Italian Hospitals. 73 patients (64 F), were enlisted. RTX-A was administered in 42/73 patients, RTX-B in 31/73. Median follow-up was 27 months (range 7-106). Mean relapse rate in the previous year before RTX start was 2.2 ± 1.3 for RTX-A and 2.3 ± 1.2 for RTX-B. ARR in the first year of treatment was 0.8 ± 0.9 for RTX-A and 0.2 ± 0.4 for RTX-B, in the second year of treatment was 0.9 ± 1.5 for RTX-A and 0.4 ± 0.8 for RTX-B patients (p = 0.001 for the first year, ns (0.09) for the second year). RTX-B was more effective in delaying the occurrence of a relapse (HR 2.2 (95 % IC 1.08-4.53) p = 0.02). Adverse events were described in 19/73 patients (mainly urinary tract and respiratory infections, and infusion reactions). Two deaths were reported in severely disabled patients. Though with the limitations of an observational study, our data support RTX efficacy in NMO and suggest that high dose pulses might be more effective than a more fractioned dose.