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Background: In the field of research for new validated surrogate biomarkers of treatment efficacy, disease activity and progression in Multiple Sclerosis (MS), serum neurofilament light-chain (sNFL) are actually the best candidate for MS patient monitoring. However, before they can be implemented in clinical practice, their usefulness as additional red flag routine measure must be demonstrated. To tackle the problem, this real-life cross-sectional study at the Regional Referring Center for Multiple Sclerosis (CRESM) aims to characterize sNFL levels and prevalence of elevated sNFL, according to our age-dependent cut-off values, in a large group of patients with different types of MS and treatment conditions., Methods: 908 serum samples from as many MS patients being admitted at CRESM for diagnostic definition and/or during routinary treatment monitoring were consecutively collected between January 2019 and January 2020. sNFL levels were measured by single molecule array (Simoa™) technology on SR-X instrument using NF-light assays (Quanterix); results were interpreted using previously published cut-off values., Results: Primary and Secondary Progressive MS (PPMS, SPMS) forms demonstrate higher levels and prevalence of elevated sNFL (PPMS= 32 %, SPMS= 21 %) compared to the Relapse and Remitting one (RRMS = 12 %). Besides, naïve samples of RRMS and PPMS subtypes showed higher prevalence of elevated sNFL (RRMS naïve= 31 %, PPMS naïve=67 %) compared to samples from patients treated for more than 12 months (RRMS treat>12m= 9 %, PPMS treat>12m= 19 %); treated SPMS patients demonstrated higher sNFL levels and a prevalence (22 %) of elevated sNFL compared to RRMS treated patients. Focusing on RRMS, no statistical difference was found between groups of patients treated for whatever time (up to or more than 60 months) and with either DMT type (high or low-efficacy DMT). Finally, RRMS patients treated with all DMTs for more than 12 months, with the exception of teriflunomide and alemtuzumab showed a prevalence of elevated sNFL in the range of 5-10 %., Conclusion: in a real-world setting comprising about 1000 MS patients, sNFL quantification was elevated in 5-to-67 % of patients, in different MS forms and treatment conditions. Elevated levels of sNFL must be considered a red-flag suggesting the need of a further clinical monitoring in any circumstance, as it can be indicative of new inflammation, ongoing degeneration or co-morbidities. This study supports the introduction of sNFL quantification in everyday patient management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Bertolotto reports financial support was provided by Roche SpA. Antonio Bertolotto reports financial support was provided by Italian Multiple Sclerosis Association. Paola Valentino reports a relationship with Biogen that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Roche SpA that includes: speaking and lecture fees and travel reimbursement. Paola Valentino reports a relationship with Merck & Co Inc that includes: funding grants. Paola Valentino reports a relationship with Quanterix Corp that includes: funding grants. Simona Malucchi reports a relationship with Biogen that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Merck & Co Inc that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Simona Malucchi reports a relationship with Roche SpA that includes: speaking and lecture fees and travel reimbursement. Serena Martire reports a relationship with Biogen that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Serena Martire reports a relationship with Novartis that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Almirall that includes: board membership, consulting or advisory, and funding grants. Antonio Bertolotto reports a relationship with Bayer that includes: board membership and consulting or advisory. Antonio Bertolotto reports a relationship with Biogen that includes: board membership, consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Genzyme Corporation that includes: board membership and consulting or advisory. Antonio Bertolotto reports a relationship with Novartis that includes: funding grants, speaking and lecture fees, and travel reimbursement. Antonio Bertolotto reports a relationship with Sanofi that includes: speaking and lecture fees and travel reimbursement. Antonio Bertolotto reports a relationship with Associazione San Luigi Gonzaga ONLUS that includes: funding grants. Antonio Bertolotto reports a relationship with Fondazione per la Ricerca Biomedica ONLUS that includes: funding grants. Antonio Bertolotto reports a relationship with Mylan Pharmaceuticals Inc that includes: funding grants. Antonio Bertolotto reports a relationship with Italian Multiple Sclerosis Association that includes: funding grants. Rugiada Bottero reports a relationship with Novartis that includes: consulting or advisory. Rugiada Bottero reports a relationship with Sanofi that includes: consulting or advisory. Rugiada Bottero reports a relationship with Merck that includes: consulting or advisory. Alessia Di Sapio reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Sanofi that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Alessia Di Sapio reports a relationship with Alexion that includes: speaking and lecture fees and travel reimbursement. Alessia Di Sapio reports a relationship with Merck that includes: travel reimbursement. Alessia Di Sapio reports a relationship with Genzyme Corporation that includes: travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Neurofilament light chains (NfL) are cytoskeletal biomarkers of axonal damage, about 40-fold higher in cerebrospinal fluid (CSF) compared to serum, and requiring ultrasensitive techniques to be measured in this latter fluid., Objectives: To compare CSF and serum NfL levels in multiple sclerosis (MS) patients using different platforms., Methods: 60 newly diagnosed relapsing-remitting MS patients (38 females; median age: 36.5 years, range: 15-60) were enrolled before steroid or disease-modifying treatments. CSF and serum NfL were measured with: the commercial Ella™ microfluidic platform (Bio-Techne), the Lumipulse™ Chemiluminescent Enzyme ImmunoAssay (Fujirebio), and the SIMOA™ on the SR-X instrument using NF-light assays (Quanterix)., Results: CSF and serum NfL absolute levels strongly correlated between assays, although being more elevated with Ella™. Passing-Bablok regression showed high agreement in measuring CSF NfL between assays (with greater proportional difference using Ella™), and very high agreement for serum comparing SIMOA™ and Lumipulse™. Similarly, the Bland-Altman comparison evidenced lower biases for Lumipulse™ for both fluids., Conclusions: CSF and serum NfL in naïve MS patients are reliably measured with all assays. Although not interchangeable, SIMOA™ and Lumipulse™ showed high agreement for serum and CSF values., Competing Interests: Declaration of competing interest Conflicts of interest/Competing interests: none for all authors for this work; Ethics approval: local Ethical Committee approvals (Comitato Etico Interaziendale AOU "Maggiore della Carità" di Novara, ASL BI, ASL NO, ASL VCO): CE 060/2022 and 260/2022). Consent to participate/consent for publication: written consent obtained from all participants; Availability of data and material: data available on request., (Copyright © 2023. Published by Elsevier B.V.)

Background: The earliest detection of progressive multifocal leukoencephalopathy (PML) is crucial in Natalizumab (NTZ)-treated Multiple Sclerosis (MS) patients. This study aims to assess serum Neurofilaments (sNFL) ability to early detect PML in longitudinal patients' follow-up., Methods: NFL were retrospectively measured in four PML cases occurred at the Regional Referring Center for MS (CRESM, Italy), in samples collected since one year before PML diagnosis, at PML diagnosis, during PML and in post-PML follow-up. sNFL levels were interpreted according to previously defined reference values. Clinical examination and EDSS were performed at each NTZ infusion. Routinary MRI was undertaken every six months; after PML diagnosis, MRI was performed according to clinical evaluation. sNFL were also measured in 45 NTZ-treated patients experiencing NEDA-3 status for at least 12 months., Results: Patients showed different PML onsets and manifestations: in 3 patients routinary brain MRI revealed radiological signs of PML preceding different clinical manifestations, while in one patient brain MRI was performed after the clinical onset. PML diagnosis was defined at the time of the first detection of JCV DNA in cerebrospinal fluid. The following different PML phases were considered: 1. Basal (up to 4 months before PML diagnosis): sNFL values were in the normal range in all patients' samples, except for one (median 9.1 pg/ml, range 6.2-15.1 pg/ml) 2. Pre-PML (within 3 months before PML diagnosis): sNFL were elevated in all available samples (median 19.50 pg/ml, range 15.50-33.80 pg/ml). 3. PML diagnosis: sNFL were elevated in all patients (median 59.20 pg/ml, range 11.1-101.50 pg/ml). 4. PML/IRIS: during this phase, sNFL levels reached their peak (median 96.35 pg/ml, range 20.5-272.9) in all patients. 5. Post-PML (recovery phase, starting from the first MRI without enhancement, up to the end of follow-up): sNFL levels showed a decrease (median 12.80 pg/ml, range 9.30-30.60); however, based on reference values, sNFL were still elevated in 2 out of 4 patients at the end of their follow-up (622 and 887 days after PML diagnosis). sNFL were always elevated when MRI scan suggested a suspicious of PML. In NEDA-3 patients, sNFL levels were in the normal range in all patients' samples (median 4.7 pg/ml, range 1.4-8.6 pg/ml)., Conclusion: Elevated sNFL were observed not only at PML diagnosis, but also in pre-PML phase. At PML recovery, sNFL weren't normalized in all patients' samples, suggesting ongoing neuronal degeneration. sNFL represent a reliable biomarker and should be introduced in clinical practice as an additional/alternative parameter to MRI to early detect and monitor PML., Competing Interests: Declaration of Competing Interest Valentino Paola received speaker honoraria from Roche, research support from Merck and grant support from Quanterix. Malucchi Simona received speaker honoraria from Biogen and Roche. Bava Cecilia Irene: nothing to discose Martire Serena: nothing to discose Capobianco Marco served on the scientific advisory board of Biogen, Sanofi Genzyme, Novartis, Roche, Becton-Dickinson, Alexion and Horizon and received speaker honoraria from Almirall, Biogen, Novartis, Sanofi Genzyme. Malentacchi Maria: nothing to discose Sperli Francesca: nothing to discose Oggero Alessandra: nothing to discose Di Sapio Alessia received personal compensation for speaking and consulting by Biogen, Novartis, Roche, Sanofi and Alexion and has been reimbursed by Merck, Biogen, Genzyme and Roche for attending several conferences. Bertolotto Antonio served on the scientific advisory board of Almirall, Bayer, Biogen, and Genzyme; received speaker honoraria from Biogen, Novartis and Sanofi and grant support from Almiral, Biogen, Associazione San Luigi Gonzaga ONLUS, Fondazione per la Ricerca Biomedica ONLUS, Mylan, Novartis and the Italian Multiple sclerosis Society., (Copyright © 2023 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.)

Introduction: Extended interval dosing (EID) of Natalizumab (NAT) has been proposed to reduce progressive multifocal leukoencephalopathy (PML) risk associated with standard interval dosing (SID) in people with multiple sclerosis (MS). Previous studies have suggested that NAT effectiveness is maintained in the great majority of patients who switch from SID to EID; monitoring of disease activity is currently based exclusively on clinical and MRI parameters. Frequent MRI are expensive and not always applicable, underlining the need for biological markers able to detect central nervous system lesions. Serum Neurofilament-light chain (sNFL) currently represents the most promising biomarker of disease activity, prognosis and treatment response in MS, and their clinical suitability is increasingly evident. The objective of the present study is to assess the applicability of sNFL as additional/alternative measure of treatment efficacy during EID regimen., Methods: We measured sNFL by Simoa technology in longitudinal samples from 63 Relapsing Remitting (RR) MS patients switched from SID to EID., Inclusion Criteria: diagnosis of RRMS, age 18-60 years; NAT SID for at least 12 months; NEDA-3 (no evidence of disease activity) for at least 12 months; availability of at least 2 serum samples collected 6 months apart. Patients' follow-up time during EID was at least 12 months and 2 blood samples were collected after at least 6 and 12 months. Clinical examination was performed before each infusion, while MRI 6 and 12 months after NAT initiation and according to PML risk during the whole study., Results: No patients showed clinical or MRI activity during the whole follow-up. sNFL levels measured during SID and EID were comparable, without significant difference between groups. The effect of EID on NFL levels did not show significant effects (LMM, p> 0.05) and sNFL levels did not vary with time during SID or EID protocols (LMM, p> 0.05). Intra-individual sNFL levels demonstrated overall stability during SID and EID (median CV=11% between SID and EID samples). According to our previously published reference values, sNFL levels were in the normal range in all samples, both during SID and EID., Conclusions: Our results suggest that sNFL quantification can be used as an alternative/additional approach to MRI in managing individual patients. The present work provides a new clinical application of sNFL to monitor NAT efficacy., Competing Interests: Declaration of Competing Interest Valentino Paola received speaker honoraria from Biogen, Novartis and Roche, research support from Merck and grant support from Quanterix. Malucchi Simona received speaker honoraria from Biogen. Martire Serena received speaker honoraria from Biogen and Novartis and served on the advisory boards of Biogen and Novartis Bava Cecilia Irene: nothing to discose Capobianco Marco served on the scientific advisory board of Biogen, Sanofi Genzyme, Novartis, and Bayer Schering and received speaker honoraria from Almirall, Biogen, Novartis, Sanofi Genzyme, and Teva. Bertolotto Antonio served on the scientific advisory board of Almirall, Bayer, Biogen, and Genzyme; received speaker honoraria from Biogen, Novartis and Sanofi and grant support from Almiral, Biogen, Associazione San Luigi Gonzaga ONLUS, Fondazione per la Ricerca Biomedica ONLUS, Mylan, Novartis and the Italian Multiple sclerosis Society., (Copyright © 2022. Published by Elsevier B.V.)

Background: Serum Neurofilament Light (sNFL) is the most promising marker for patient's monitoring in Multiple Sclerosis (MS). However, operating reference values for use in clinical practice are still lacking. Here, we defined sNFL reference cut-off values in a cohort of healthy controls (HC) and assessed their performance in Multiple Sclerosis (MS) patients, as well as the intra-individual sNFL variability., Methods: We measured sNFL by single molecule array (Simoa) assay in 79 HC assessing their correlation with age. Changes of sNFL levels were evaluated during a short-term follow-up (median 67 days between consecutive samples) in a subgroup of 27 participants. sNFL were tested in 23 untreated MS patients, at both diagnostic time and start of therapy (median 80 days after), considering disease activity., Results: Findings confirmed a correlation between sNFL levels and age in HC, thus cut-off values specific for age decades were calculated. sNFL did not vary significantly with time during short-term follow-up (median CV 13%). sNFL levels in MS patients were higher and demonstrated a higher variability between diagnostic time and treatment start (median CV 39%). According to cut-off values, "pathologic" sNFL levels were found in 57% of MS patients at diagnostic time, and in 30% of samples at treatment start. In particular, "pathologic" sNFL levels were found in 80% of samples (16/20) obtained during a phase of disease activity, while a total of 85% of samples (22/26) associated with inactive disease showed sNFL in the normal range., Conclusion: This study demonstrates an overall intra-individual stability of sNFL values in the short-term in HC and suggests age-dependent reference cut-off values that could be beneficial for sNFL implementation in clinical practice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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.)

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.)