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Background: Biomarkers of neuronal and axonal damage (serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP)) may provide insight into the aetiology of natalizumab wearing-off symptoms (WoSs)., Objectives: We investigated the longitudinal association between and predictive value of sNfL and sGFAP and the occurrence of WoS in MS patients treated with natalizumab., Methods: We performed longitudinal measurements of sNfL and sGFAP in NEXT-MS trial participants who completed a questionnaire about WoS., Results: A total of 364 participants were included. In total, 55.5% presented with WoS and 44.5% without WoS during natalizumab treatment. Longitudinal analyses showed no association between sNfL and sGFAP levels and WoS at any timepoint. Biomarker levels at baseline did not predict first-time WoS occurrence., Conclusion: Acute and chronic neuronal and axonal damage are most likely not the underlying cause of WoS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: A.A.T. has nothing to disclose. M.H.J.W. has nothing to disclose. L.B. has nothing to disclose. L.M.Y.G. has nothing to disclose. E.H. has accepted (speaker and congress) fees from Merck Serono, Biogen Idec, Roche and Sanofi Genzyme. E.M.P.E.Z. reports advisory boards/consultancy fees for Merck, Novartis, Genzyme and Roche. L.C.v.R. has nothing to disclose. C.E.P.v.M. has nothing to disclose. A.V. has nothing to disclose. J.P.M. has nothing to disclose. B.H.A.W. has nothing to disclose. N.F.K. has nothing to disclose. E.L.J.H. has nothing to disclose. J.J.J.v.E. reports honoraria for advisory boards and/or speakers fee from Merck Serono, Biogen Idec, Sanofi Genzyme, Roche and Novartis. C.M.R. has nothing to disclose. J.J.K. has nothing to disclose. M.E. has nothing to disclose. J.N. has nothing to disclose. J.v.G. has nothing to disclose. L.G.F.S. has nothing to disclose. M.E.K. has nothing to disclose. E.P.J.A. has nothing to disclose. G.W.v.D. has nothing to disclose. W.H.B. has nothing to disclose. E.M.M.S. has nothing to disclose. B.W.v.O. has nothing to disclose. B.A.d.J. has nothing to disclose. B.M.J.U. reports research support and/or consultancy fees from Genzyme, Biogen Idec, Novartis, Teva Pharmaceutical Industries, Merck Serono, Roche and Immunic Therapeutics. T.R. received funding for research from Genmab and consultancy fees from Novartis. J.K. received research grants for multicentre investigator-initiated trials DOT-MS trial, ClinicalTrials.gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds) (ClinicalTrials.gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche Ltd, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche Ltd, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution) and adjudication committee of MS clinical trial of Immunic (payments to institution only). Z.L.E.v.K. has nothing to disclose. C.E.T. reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no. 831434); has a research contract with Celgene; serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation and is editor of a Neuromethods book Springer.

Background: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear., Methods: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured., Results: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients., Conclusion: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: G.D.C., M.P., T.C., F.S., B.C., A.H., and R.G. report no disclosures. VM has received honoraria for activities with Biogen, Merck, Bayer, TEVA and Sanofi-Genzyme as a speaker. L.M. has received honoraria for speaking in scientific meetings and for advisory board from Biogen TEVA, Sanofi-Genzyme, and Merck. R.F. has received honoraria for speaker activities from Biogen, Merck, Novartis, Roche and Teva. L.L. has received honoraria for consulting services and/or speaking activity from Biogen, Novartis and Excemed. G.C. has received personal compensation for consulting services and/or speaking activities from Novartis, Teva, Sanofi, Sanofi-Genzyme, Merck, Biogen, Excemed, Serono Symposia International Foundation, Roche, Almirall, Receptos, Celgene and Forward Pharma.

Cases of herpes zoster (HZ) in patients with MS on natalizumab (NTZ) have been documented. In this study, we assessed lymphocyte subsets in NTZ-treated patients with HZ compared to matched controls without HZ. Twenty unvaccinated patients developed HZ while on NTZ for an incidence rate of 12.3 per 1000 patient-years. These patients had lower CD8+% and higher CD4+:CD8+ ratios ( p ⩽ 0.01) than non-HZ matched controls. Two patients with relapsing-remitting MS developed HZ twice while on NTZ. These findings underscore the importance of pre-NTZ HZ vaccination due to potential HZ risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.A.S. has grant funding from the National MS Society and has consulted for Biogen, Genentech, Teva, Banner, Sanofi, and Cellgene. The remaining authors have no conflicts to declare.

Background and Objectives: Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups., Methods: A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed., Results: Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2])., Discussion: S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

Background and Objectives: Although pediatric-onset multiple sclerosis (POMS) is characterized by a more rapid accumulation of CNS inflammation than adult-onset MS (AOMS), the therapeutic algorithms applied in POMS are usually based on AOMS therapeutic outcomes. To define a high-efficacy treatment (HET)-based strategy to treat POMS, we designed an observational retrospective study aimed at evaluating the efficacy and safety of natalizumab (NTZ) in naïve POMS and AOMS., Methods: Starting from 160 patients, we applied a 2:1 (adult:pediatric) matching on propensity scores and obtained 32 patients with NTZ-treated POMS and 64 with AOMS, estimated from a multivariable logistic regression model. All patients were clinically and radiologically followed up every 6 months for a mean period of 46.0 ± 26.9 months., Results: Following re-baseline at month 6, no difference (log-rank test: p = 0.924) in new and enlarging T2 white matter lesions, postcontrast T1 lesions, and relapse rate were observed between POMS and AOMS throughout the study. Progression independent of relapse activity (PIRA) was never observed in POMS, while 9 of 64 patients with AOMS (12.5%) had PIRA events during the follow-up (40.0 ± 25.9 months; log-rank p value 0.0156). JCV seroconversion rate during NTZ infusion did not differ between POMS and AOMS (log-rank test p = 0.3231). Finally, no serious adverse event was observed in both POMS and AOMS., Discussion: The favorable outcomes observed on clinical, especially in PIRA, and radiologic parameters strongly support the use of NTZ as a first-choice HET in POMS.

Objective: No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register., Methods: Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score-matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan-Meier curves were used to show cumulative probabilities of reaching outcomes., Results: In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score-matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab- and 10 ocrelizumab-treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab- and 15 ocrelizumab-treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59-1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57-2.66; p = 0.60) and 6.0 (0.93, 0.32-2.68; p = 0.89)., Interpretation: Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off., (© 2024. The Author(s).)

Introduction: One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined., Objective: The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity., Methods: This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity., Results: Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression ( p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod ( p < 0.001)., Conclusion: Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.Z. has received honoraria for lectures from Biologix, Biogen, Janssen, Hikma Pharmaceuticals, Novartis, Merck, Roche, and Sanofi-Genzyme. She received travel grants from Novartis, Merck, and Roche and a research grant from Biogen. She received two research grants from Biogen, one research grant from Merck, and two research grants from MENACTRIMS. She has no conflict of interest related to this study. B.Y. has received speaker honoraria from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi; research grants from Bayer, Biogen, Merck, Novartis, and Pfizer; and advisory board honoraria from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi. He has no conflict of interest related to this study. A.A.-A. has received honoraria from Novartis, Sanofi, Biologix, Merck, Roche, Biogen, and Bayer. He serves on the scientific advisory boards of Novartis, Merck, and Roche. He has no conflict of interest related to this study. R.G. has received research grant from Roche and advisory board honoraria from Biogen, Hikma, Merck, Roche, and Sanofi. He has no conflict of interest related to this study. S.M. received a MENACTRIMS clinical research grant (2020) but has no conflict of interest related to this study. R.A.-R., S.F.A., S.K., N.E.-A., A.A.-M., J.A.-K., A.C., J.I., N.S., J.M., F.M.R.H.M., A.A.-H., P.S., H.D., and F.B. declare that there is no conflict of interest.

Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer-bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.

Background: Use of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established., Methods: In accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included., Results: The overall incidence of clinical relapse during washout periods ranging from 4.4-10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02-0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %., Conclusions: This systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jennifer Massey reports a relationship with Biogen that includes: speaking and lecture fees. Jennifer Massey reports a relationship with Novartis that includes: speaking and lecture fees. 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. Published by Elsevier B.V.)

Background: After natalizumab discontinuation severe relapses can occur despite pregnancy, but third trimester exposure is associated with neonatal haematological abnormalities (HA). The best time point for stopping natalizumab during pregnancy is unclear., Methods: Prospective, observational cohort with 350 natalizumab exposed pregnancies from the German Multiple Sclerosis and Pregnancy Registry. Clinical disease activity and neonatal outcomes are compared between women with natalizumab discontinuation during (1st Trim-group) versus after the first trimester (maintaining-group) and for subgroup analysis before (<30-subgroup) or after (≥30-subgroup) the 30th gestational week (gw)., Results: Baseline characteristics did not significantly differ between the 1st Trim-group (n=179; median exposure duration: 2.60 gw, IQR 1.30-3.60) and the maintaining-group (n=171; median exposure duration: 30.9 gw, IQR 26.9-33.3). Fewer relapses occurred during pregnancy and the postpartum year in the maintaining-group (25.7%) compared with the 1st Trim-group (62.6%; p<0.001). Women in ≥30-subgroup had a significantly lower relapse risk in the first 6 months postpartum (relapse rate ratio: 0.36, 95% CI: 0.15 to 0.84). In total, 7.5% retained meaningful disability 12 months postpartum. No significant effect on neonatal outcomes were observed, but anaemia (OR: 2.62, 95% CI: 1.12 to 6.52) and thrombocytopaenia (OR: 2.64, 95% CI: 1.15 to 6.46) were significantly more common in the ≥30-subgroup. 21.8% of all neonates were born small for gestational age, independent of the timing of natalizumab discontinuation., Conclusion: Continuing natalizumab during pregnancy after gw 30 decreases the relapse risk postpartum going along with a higher risk for HA in the newborns. These results add relevant knowledge as a basis for informed risk-benefit discussion., Competing Interests: Competing interests: The German MS and pregnancy registry is partly supported by the Innovation Fund of the Federal Joint Committee, Almirall, Biogen, Teva Pharma, Novartis, Roche and Merck. ST received speakers' honoraria from Bayer Healthcare and Biogen GmbH, payment for manuscript writing from HEXAL AG as well as sponsorship for congress participation from Biogen GmbH. NL has nothing to disclose. SH has nothing to disclose. RG has received speaker honoraria and research support from Bayer-Schering Healthcare, Biogen-Idec Germany, Chugai, Eisai, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi-Genzyme and TEVA, has received consulting honoraria from CSL Behring, Baxter, Janssen and Talecris and has stock options in Bayer, Merck and Roche. KH has received speaker honoraria and research support from Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Roche and Teva, has received support for congress participation from Bayer, Biogen, Merck, Roche, Sanofi Genzyme and Teva, and has served on scientific advisory boards for Bayer, Biogen, Sanofi, Teva, Roche, Novartis and Merck., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Natalizumab is a monoclonal antibody used to treat patients with relapsing-remitting multiple sclerosis. Anemia is a recognized side effect, but it is usually mild and of a short duration when natalizumab is stopped. Here, we describe a case of a young woman with severe and especially long lasting anemia associated with treatment with natalizumab, persisting up to a year after treatment was stopped., Case Presentation: A 24 year-old Caucasian woman with relapsing-remitting multiple sclerosis developed severe transfusion dependent anemia after 27 infusions with natalizumab, which was her first and only treatment for her multiple sclerosis. Extensive hematologic diagnostics did not reveal any malignant cause or any other plausible non-malignant cause for her anemia. The bone marrow was found to be hypercellular, with a maturation arrest of the erythropoiesis and with grade 1-2 fibrosis. No specific treatment for the anemia was given. The hemoglobin level showed signs of spontaneous increase after nearly one year after natalizumab was discontinued., Conclusion: Severe anemia can be caused by treatment with natalizumab. This case adds information to the few other similar reported cases, demonstrating the potential duration of the anemia, as well as detailed description of hematologic findings. The mechanism is most likely due to inhibition of α4 subunit of the α4β1-integrin, which is present on both lymphocytes and erythroid precursor cells., (© 2024. The Author(s).)

Background: Multiple sclerosis (MS) predominantly affects women of childbearing age. Due to the risk of teratogenicity, women with active multiple sclerosis (MS) who require high-efficacy therapies (HET) may need to discontinue treatment during pregnancy. Fingolimod and Natalizumab withdrawal increases the risk of disease reactivation, a risk not commonly associated with anti-CD20 therapies. However, comparative data are limited during pregnancy and post-partum. Our aim was to compare evidence of disease activity during pregnancy and post-partum in women treated with HET (anti-CD20 therapies, Natalizumab or Fingolimod) before conception, whether or not exposed during pregnancy., Methods: In this single-center retrospective study, we included consecutive pregnancies of relapsing-remitting MS patients and classified them in three groups according to the last HET used before conception: « anti-CD20 » « Natalizumab (NTZ) » and « Fingolimod (FGD) ». The main outcome was annualized relapse rate (ARR) during pregnancy and post-partum., Results: We included 66 pregnancies: 21, 24 and 21 in anti-CD20, NTZ and FGD groups respectively. Overall, mean ARR (SD) increased from 0.36 (0.6) during the preconception year to 0.60 (1.3) during pregnancy and to 1.03 (2.0) in the first 3 months post-partum. Mean ARR in anti-CD20 group (0.09 (0.3)) during pregnancy and the first 3 months post-partum was lower compared with NTZ (0.48 (0.6); p = 0,09) and FGD (1.50 (1.8); p = 0.001) groups. Proportion of pregnancies with radiological activity during pregnancy and post-partum in anti-CD20 group (5.2 %) was lower compared with NTZ (63.1 %; p < 0.001) and FGD (72.2 %; p < 0.001) groups. There was no significant difference in the evolution of EDSS score from conception to post-partum between each group (p = 0.75)., Conclusion: Evidence of disease activity was significantly lower in patients exposed to anti-CD20 therapies before conception. This study suggests that use of anti-CD20 therapies is an efficient option to prevent disease reactivation during pregnancy and post-partum., Competing Interests: Declaration of competing interest O. Sahloul has nothing to disclose. C. Louapre reports personal fees from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva and research grant from Biogen, outside the submitted work. Y. Beigneux has nothing to disclose. C. Lubetzki reports research grant from Merck Serono, Roche, and personal fees for advisory board participation from ReWind, outside the submitted work. E. Maillart has received consulting or travel fees from Alexion, Biogen, Janssen, Novartis, Sanofi, Teva and Merck Serono, and research grant from Biogen, none related to the present work. T. Roux reports personal fees from Alexion, Biogen, Celgene, Merck, Novartis, Sanofi, Teva outside the submitted work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

PB006 (Tyruko ® ) is the first biosimilar of the reference monoclonal anti-α4-integrin antibody natalizumab. It is approved for use in the same indications for which reference natalizumab is approved, as a single disease-modifying therapy in adults with highly active relapsing-remitting multiple sclerosis (RRMS). PB006 has similar physicochemical and pharmacodynamic properties to those of reference natalizumab, and the pharmacokinetic similarity of the agents has been demonstrated in a study in healthy subjects. PB006 demonstrated clinical efficacy similar to that of reference natalizumab in patients with RRMS, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of PB006 were similar to those of reference natalizumab, and switching from reference natalizumab to PB006 appeared to have no impact on tolerability or immunogenicity. The role of reference natalizumab in the management of RRMS is well established and PB006 provides an effective biosimilar alternative for patients requiring natalizumab therapy., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The diagnosis of multiple sclerosis (MS) in women of reproductive age is associated with many uncertainties regarding childbearing and lactation. Pregnancies of MS patients are not usually considered high-risk pregnancies per se. The likelihood of pregnancy complications or adverse pregnancy outcomes is not increased by the disease; however, a careful planning of pregnancy is important in order to choose the treatment option with the greatest benefit for the mother and the least possible risk for the baby. For highly active courses of the disease, anti-CD20 antibodies, cladribine, or continued administration of natalizumab show the best data. Patients with MS can be supported in their desire to breastfeed. If women have had a very active disease course, it is recommended that treatment should be started as soon as possible postpartum. Interferon-beta preparations, glatiramer acetate and ofatumumab are also approved for use during breastfeeding but off-label breastfeeding is also possible with other monoclonal antibodies., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Multiple sclerosis (MS) is a chronic inflammatory, immune-mediated disease affecting the central nervous system. Natalizumab, an FDA-approved monoclonal antibody for MS, has been explored for its off-label extended interval dosing (EID), suggesting a potential reduction in the risk of progressive multifocal leukoencephalopathy (PML) compared to standard interval dosing (SID). Our objective was to assess the efficacy and safety of EID in comparison to SID for natalizumab treatment in patients with MS., Methods: We searched PubMed, Embase, WOS, Scopus, Ovid, Science Direct, Clinical trials.gov, and Cochrane Library. Our assessed outcomes were clinical relapses, MRI activity, change in expanded disability status scale [EDSS], and the risk of PML. The EID group was defined as 5 to 8 weeks [EID (Q5-8W)]. The analysis was conducted using RevMan ver. 5.4. The effect estimates were presented as a risk ratio [RR] or mean difference with 95% confidence intervals [CI] using SID group as the reference for comparisons., Results: Fourteen studies met our inclusion criteria: 2 RCTs, 1 switched single-arm trial, and 12 observational studies. No significant differences were found in all efficacy outcomes of interest. Risk of clinical relapses [RR = 0.90, (95%CI 0.80, 1.02)], risk of new or newly enlarging T2 hyperintense MRI lesions [RR = 0.78, (95%CI 0.59, 1.04)], risk gadolinium enhancing lesions [RR = 1.30, (95%CI 0.98, 1.72)], change in EDSS [MD = 0.09 (95%CI - 0.57, 0.76)], risk of PML [RR = 1.09, 95%CI (0.24, 4.94)]., Conclusion: In summary, our meta-analysis indicates that natalizumab maintains its effectiveness under extended interval dosing [up to 8 weeks], presenting comparable risks for clinical relapses, MRI lesions, EDSS, and PML. Caution is advised given study limitations and heterogeneity. Robust conclusions necessitate well-designed high-quality prospective studies., (© 2024. The Author(s).)

Background: Up to two thirds of patients with multiple sclerosis (MS) under natalizumab report a resurgence of symptoms at the end of the natalizumab cycle (wearing-off (WO) effect). At the outbreak of COVID-19, in line with the international recommendations for MS management, our centre switched all clinically stable patients on natalizumab therapy for more than one year from standard interval dosing (SID) to extended interval dosing (EID) with every six weeks infusions. This study aimed to evaluate the impact of EID in WO in MS patients under natalizumab., Methods: An observational retrospective study in patients with MS under natalizumab on EID was conducted. A questionnaire regarding current (on EID) and past (on SID) experience of WO effect was applied., Results: Seventy-six patients were included. No significant differences were found in the annual relapse rate after the switch to EID (p = 0.083). However, there was a significant increase in the proportion of patients complaining of WO from 38.2% to 56.6% (p = 0.001). Moreover, patients with WO on SID, referred a significant increase in severity (p = 0.019) and duration of WO symptoms (p = 0.029), due to an anticipation of the symptoms relative to the day of natalizumab infusion (p = 0.019), when switching to EID. Symptoms improved with treatment maintenance in 23.3% of patients; instead, a reduction in interval dosing was needed in 54.8% with symptom improvement., Conclusion: WO affects a significant proportion of MS patients under natalizumab. Its prevalence, severity, and duration increase on EID, therefore despite clinical effectiveness maintenance of this posology should be individualized., Competing Interests: Declaration of competing interest Inês Correia, Carla Nunes, Carmo Macário, and Sónia Batista have received consulting fees from Biogen, Merck Serono, Novartis, Sanofi Genzyme, Bristol Myers Squibb, Roche, and Janssen. Lívia Sousa has received consulting fees from Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Roche. Catarina Bernardes, Catarina Fernandes and Carolina Cunha have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study., Methods: We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised β-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models., Results: We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87)., Discussion: Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS., Classification of Evidence: This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.

Background: Multiple sclerosis (MS) frequently affects women of childbearing age and pregnant women., Objective: To assess the use of MS disease-modifying therapies (DMTs) during pregnancy in France over the last decade, marked by an increasing DMTs availability., Methods: All pregnancies ended from April 2010 to December 2021 in women with MS were identified based on the nationwide Mother-Child Register EPI-MERES, built from the French National Health Data System ( Système National des Données de Santé (SNDS))., Results: Of a total of 20,567 pregnancies in women with MS, 7587 were exposed to DMT. The number of DMT-exposed pregnancies markedly increased from 1079 in 2010-2012 to 2413 in 2019-2021 (+124%), especially those exposed to glatiramer acetate, natalizumab, dimethyl fumarate, and anti-CD20. Among pregnancies of women on DMT 6 months before pregnancy, 78.0% underwent DMT discontinuation and 7.6% switched DMT, generally before (33.0% and 77.0%, respectively) or during the first trimester of pregnancy (58.3% and 17.8%, respectively). DMT discontinuation decreased from 84.0% in 2010-2012 to 72.4% in 2019-2021 and was less frequent among women aged ⩾35 years and those socioeconomically disadvantaged., Conclusion: Despite MS therapeutic management adaptations to pregnancy, exposure during pregnancy to treatments whose safety profile has not yet been clearly established has increased sharply over the last decade., Competing Interests: Data AvailabilityAccording to data protection and the French regulation, the authors cannot publicly release the data from the French National Health Data System (SNDS). However, any person or structure, public or private, for-profit or non-profit, is able to access SNDS data upon authorization from the French Data Protection Office (CNIL Commission Nationale de l’Informatique et des Libertés) to carry out a study, a research, or an evaluation of public interest (https://www.snds.gouv.fr/SNDS/Processus-d-acces-aux-donnees and https://www.indsante.fr/). Here is a non-author point of contact where data requests can be sent https://www.health-data-hub.fr/contact. Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Fingolimod may be associated with risk of developing cardiovascular disease (CVD). Studies including reference groups and long follow-up are scarce., Objectives: We hypothesized that patients treated with fingolimod would be at higher risk of developing CVD compared to patients treated with natalizumab., Methods: A nationwide 12-year cohort study linking individual-level data from the Danish Multiple Sclerosis Registry with health registries on 2095 adult patients with multiple sclerosis (MS) without any health records of CVD at follow-up start. Exposure to fingolimod and natalizumab was defined by the first treatment of at least 3 months. Cohort entry was from 2011 to 2018. We defined CVD as a composite measure, including hypertension, ischemic heart disease, atrial fibrillation, heart failure, and stroke. We used multivariable adjusted Cox regression., Results: There were 28.8 and 17.4 CVD events per 1000 person-years in fingolimod and natalizumab groups, respectively. Compared to natalizumab-treated patients, fingolimod-treated patients had a higher risk of CVD (hazard ratio (HR) = 1.57; 95% confidence interval (CI) = 1.18-2.08). Hypertension comprised 200 of 244 CVD events., Conclusion: We found an increased risk of CVD in patients with MS treated with fingolimod. This increased risk was mainly due to hypertension., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Elisabeth Framke, Lau Caspar Thygesen, and Morten Malmborg have nothing to disclose. Morten Schou reports lecture fees from Novartis, Astra Zeneca, Bohringer, and Novo outside the current work. Finn Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. Melinda Magyari has served on scientific advisory board, as consultant for, received support for congress participation or speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Alexion, and Bristol Myers Squibb. The Danish MS Registry received research support from Biogen, Genzyme, Roche, Merck, and Novartis.

Natalizumab (Tysabri®, NTZ) is a monoclonal autoantibody approved for treatment of relapsing-remitting multiple sclerosis. NTZ inhibits leukocyte migration across the blood-brain barrier, preventing autoreactive cells from inciting an inflammatory immune response. This immunosuppression is highly efficacious in attenuating the risk of relapse of disease, but has been associated with opportunistic central nervous system (CNS) infections, most notably progressive multifocal leukoencephalopathy. Varicella-zoster and herpes simplex viruses have also been associated with NTZ, inciting a spectrum of disease, including encephalitis, meningitis, and acute retinal necrosis. While rare, these infections can result in devastating outcomes even when promptly identified and treated.   We present a case of combined CNS varicella zoster vasculitis and acute retinal necrosis in a 57-year-old woman maintained on monthly Natalizumab therapy, who presented with headache and visual field deficits.

Background: The phenomenon of pseudoatropy after initiation of anti-inflammatory therapy is believed to be reversible, but a rebound in brain volume following cessation of highly-effective therapy has not been reported., Objectives: To evaluate brain volume change in a treatment interruption study (RESTORE) in which relapsing-remitting multiple sclerosis (RRMS) patients were randomized to switch from natalizumab to placebo, from natalizumab to once-monthly intravenous methylprednisolone (IVMP), or to remain on natalizumab., Methods: T2 lesion volume (T2LV), baseline normalized brain volumes, and follow-up percent brain volume changes (PBVC) were calculated. Approximate T2 relaxation-time (pT2) was calculated within the brain mask and the T2 lesions to estimate changes in water content. Linear mixed effects models were used to detect differences in T2LV, pT2 in whole brain, pT2 in T2-weighted lesions, and PBVC among the placebo, natalizumab, and IVMP groups. We also estimated contributions of T2LV and pT2 (in whole brain and T2 lesions) to PBVC., Results: T2LV increased in the placebo group (by 0.66 ml/year, p<0.0001) and IVMP (+1.98 ml/year, p = 0.05) groups relative to the natalizumab group. The rates of PBVC were significantly different: -0.239%/year with continued natalizumab and +0.126 %/year after switch to placebo (p = 0.03), while the IVMP group showed brain volume loss (-0.74 %/ year, p = 0.08). pT2 was not statistically different between the groups (p ≥ 0.29) and did not have significant effects on PBVC (p ≥ 0.25)., Conclusion: The increase in the brain volume in patients witching from natalizumab to placebo is consistent with reversal of so-called pseudoatrophy after starting natalizumab., Competing Interests: Declaration of Competing Interest Dr. Nakamura: has received personal fee for licensing from Biogen; has received research funding from Department of Defense, National Institutes of Health, National MS Society, Novartis, Genzyme, and Biogen. Dr. Elliott is an employee of NeuroRx. Dr. Lee has nothing to disclose. Dr. Narayanan has nothing to disclose. Dr. Arnold reports consulting fees from Biogen, Celgene, Frequency Therapeutics, Genentech, Merck, Novartis, Race to Erase MS, Roche, and Sanofi-Aventis, Shionogi, Xfacto Communications, grants from Immunotec and Novartis, and an equity interest in NeuroRx. S.N. has received research funding from the Canadian Institutes of Health Research, the International Progressive MS Alliance, the Myelin Repair Foundation, Immunotec, and F. Hoffman LaRoche; he is a consultant for Sana Biotech, has received a speaker's honorarium from Novartis Canada, and is a part-time employee of NeuroRx Research., (Copyright © 2023. Published by Elsevier B.V.)

Background/objective: The use of natalizumab (NAT) in multiple sclerosis (MS) may be complicated by progressive multifocal leukoencephalopathy (PML), a rare and life-threatening opportunistic brain infection. We aimed to analyze the course of MS after PML recovery together with the long-term outcome of NAT-associated PML (NAT-PML) in Austria., Methods: Retrospective study based on identification of cases in the nationwide Austrian MS treatment registry (AMSTR) and MS centers with review of patient records. The expanded disability status scale (EDSS) was used to measure neurological disability and outcome., Results: As of December 2022, we identified 15 NAT-PML cases in Austria; only 20% occurred after 2016, when increased vigilance commenced. Two patients did not survive acute PML, and an additional patient died five years later, yielding a mortality rate of 20%. Seizures occurred exclusively in patients with pronounced EDSS increase. Gadolinium (Gd)-enhancement on brain magnetic resonance imaging (MRI) on PML suspicion was associated with minor changes of post-PML neurological disability. Long-term follow-up of up to 132 months (median 76 months) was available in 11/15. The overall median EDSS increased from 3.5 at pre-PML to 6.5 at the last assessment. Regarding inflammatory MS-related disease activity during the observation period, one single individual experienced an MS relapse and another patient had two Gd-enhancing brain lesions. Three patients converted to progressive MS within three years from PML and the EDSS further increased in 6/11., Conclusions: The number of NAT-PML cases is decreasing over time. While many patients accumulated severe persistent neurological deficits compared to pre-PML, inflammatory MS-related disease activity after PML recovery was rare., (© 2023. The Author(s).)

Background: Patient-reported outcomes (PRO) are increasingly utilized as part of the routine clinical assessment in people with multiple sclerosis (pwMS). The long-term effect of disease modifying therapies (DMTs) and their discontinuation on PRO measures remains largely unknown., Methods: Two pwMS groups treated with natalizumab were selected from the New York State MS Consortium (NYSMSC) database. The first group utilized long-term follow-up data of pwMS that either still continue natalizumab treatment or discontinued. Minimal requirement of three visits (before natalizumab initiation, during treatment and after discontinuation/latest follow-up) was implemented. The second group consisted of pwMS that completed PRO questionnaire on the day of the infusion and 7 days later PROs were assessed using the LIFEware System™ that assesses limitations in multiple physical and psychosocial domains. Additional physical disability was assessed using Expanded Disability Status Scale (EDSS) and Timed 25-ft walk test (T25FWT). PRO reports were Rasch-transformed, ranging from 0 to 100, with higher scores indicating a better outcome. Linear mixed-effect models and paired analyses were utilized., Results: Within the prospective cohort, 242 pwMS were followed on average of 6.5 years. Greater number of PRO domains worsened in the 141 pwMS that discontinued natalizumab when compared to 101 pwMS that remained on the drug (10 vs. 2 PRO domains). PwMS that discontinued natalizumab had significant decline in PROs regarding lower extremities, bladder and bower control and psychosocial aspects (feeling lonesome). Contrarily, pwMS that continued natalizumab had significant improvement in bladder and bowel PRO measures. Seven days after the natalizumab infusion, the 67 pwMS from the prospective cohort reported improvement in PRO measures of fatigue (62.8 vs. 66.4, p = 0.019), bladder limitations (80.3 vs. 85.0, p = 0.012), and feelings of lonesomeness (81.2 vs. 88.0, p = 0.009)., Conclusion: Continuous natalizumab treatment provides long-term stability or improvement in PRO measures. Natalizumab also provides short term improvements recorded after the infusion., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We present a case of a woman in her 30s with relapsing-remitting multiple sclerosis, treated with natalizumab, who developed ophthalmic varicella zoster virus (VZV) infection, with subsequent vasculopathy causing cerebral ischaemic lesions. She was treated with acyclovir, prednisolone and acetylsalicylic acid and fully recovered. VZV vasculopathy is associated with stroke and immunomodulating treatments may increase the risks of these adverse events. To date, nine VZV-related vasculopathy cases in patients treated with natalizumab have been reported in English literature and are summarised in this paper. Although rare, VZV intracerebral vasculopathy is an important differential diagnosis in patients with unexplained new-onset neurological symptoms after a herpes zoster infection. Treatment guidelines for VZV vasculopathy and for continuing treatment of multiple sclerosis after such an event are currently not established., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: While natalizumab (NTZ) is an effective therapy for multiple sclerosis (MS), it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). After 20 years (2002-2022) of experience with NTZ at our center, we observed no cases of PML., Objectives: We evaluated the likelihood of experiencing PML in a subset of our treatment cohort, as well as reviewed treatment practices at our center that may mitigate PML risk., Methods: For this retrospective study, we reviewed patient characteristics, treatment practices, and clinical and MRI findings in patients receiving NTZ from 2006 to 2020. Observation of no PML cases was compared to the global and US PML incidences, and to the expected incidence based on published risk estimates., Results: 766 patients were evaluated. The number of NTZ infusions received ranged from 1 to 126, with a mean of 28. Patients received neurological examination prior to each infusion, which sometimes resulted in a pause in therapy to rule out PML if clinical worsening occurred. Extended interval dosing (EID) was the overall dosing schedule for 31% of patients. EID did not result in higher rates of radiological disease worsening than standard interval dosing (SID) patients. Depending on the analysis conducted, the finding of 0 PML cases in our cohort ranged from slightly unexpected to slightly expected., Conclusions: The utilization of EID as well as regular clinical monitoring of patients may have lowered PML risk while still maintaining NTZ efficacy., Competing Interests: Declaration of Competing Interest BOK: Speaker and/consultant for Sanofi Genzyme, Biogen, Alexion, Bristol Myer Squibb, Horizon, Celgene, Novartis, Genentech, EMD Serono, Argenix, Janssen, and TG Therapeutics. RRM: Spouse is an employee of Neurocrine Biosciences, and owns stock in Ascendis Pharma and Rhythm Pharmaceuticals. TO: No conflict of interest reported. SB: No conflict of interest reported. EL: No conflict of interest reported. TP: No conflict of interest reported. PV: No conflict of interest reported., (Copyright © 2023. Published by Elsevier B.V.)

Background and Objectives: The use of highly effective multiple sclerosis (MS) disease-modifying therapies (DMTs) is rapidly increasing. Yet, little is known about their real-world risks of infections. The goals of this study were to assess the comparative risk of outpatient and serious infections across DMTs in a large, diverse, U.S. cohort and determine whether such risks are attributable to DMTs, having MS, or other factors., Methods: We conducted a retrospective cohort study of Kaiser Permanente Southern California members from 2008 through 2020 with MS and non-MS controls matched on age, sex, race, and ethnicity. MS treatments, serious (those requiring hospitalization) and outpatient infections, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHR) and risk ratios (aRR) were estimated using the Cox and Poisson regression, respectively., Results: Six thousand, six hundred and twenty-six patients with MS with 11,929 treatment episodes (2,487 rituximab, 546 natalizumab, 298 fingolimod, 4,629 interferon-beta/glatiramer acetate, IFN/GLAT, and 3,969 untreated) and 33,550 population controls were included in the analyses. The average age at treatment start ranged from 38.9 to 49.2 years, and 74% were women. Untreated (aRR = 1.39, [95% CI = 1.35-1.44]) and IFN/GLAT-treated patients with MS (aRR = 1.60, [95% CI = 1.56-1.65]) had a higher risk of outpatient infections and serious infections (aHR = 2.97, [95% CI = 2.65-3.32 and aHR = 2.31, [95% CI = 2.04-2.62], respectively) compared with controls. Rituximab (aRR = 1.19, [95% CI = 1.14-1.25]), fingolimod (aRR = 1.22, [95% CI = 1.09-1.37]), and to a lesser extent, natalizumab treatment (aRR = 1.08, [95% CI = 0.97-1.20]) were associated with an increased risk of outpatient infections compared with IFN/GLAT. Rituximab (aHR = 1.41, [95% CI = 1.09-1.84]) and natalizumab (aHR = 1.40, [95% CI = 0.96-2.04]) treatment were associated with a similar increased risk of serious infections compared with IFN/GLAT. The only treatment-specific association identified was fingolimod with outpatient herpetic infections. Higher comorbidity index, previous hospitalization for infections, and advanced disability significantly increased the risk of serious infections independent of DMTs. Hospitalization for UTI-related pseudorelapses accounted for 24%-48% of serious infections., Discussion: Patients with MS have higher risks of outpatient and serious infections compared with patients without MS. The risk of outpatient infections was similarly increased by rituximab and fingolimod and serious infections by rituximab and natalizumab compared with IFN/GLAT. Steps to minimize risks include optimizing bladder care, comorbidity prevention, varicella vaccination, and considering discontinuing or avoiding DMT use in patients with advanced disability and/or previous hospitalizations for infections., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

After more than 2 decades of recommending an escalating strategy for the treatment of most patients with multiple sclerosis, there has recently been considerable interest in the use of high-efficacy therapies in the early stage of the disease. Early intervention with induction/high-efficacy disease-modifying therapy may have the best risk-benefit profile for patients with relapsing-remitting multiple sclerosis who are young and have active disease, numerous focal T2 lesions on spinal and brain magnetic resonance imaging, and no irreversible disability. Although we have no curative treatment, at least seven classes of high-efficacy drugs are available, with two main strategies. The first strategy involves the use of high-efficacy drugs (e.g., natalizumab, sphingosine 1-phosphate receptor modulators, or anti-CD20 drugs) to achieve sustained immunosuppression. These can be used as a first-line therapy in many countries. The second strategy entails the use of one of the induction drugs (short-term use of mitoxantrone, alemtuzumab, cladribine, or autologous hematopoietic stem cell transplant) that are mainly recommended as a second-line or third-line treatment in patients with very active or aggressive multiple sclerosis disease. Early sustained immunosuppression exposes patients to heightened risks of infection and cancer proportionate to cumulative exposure, and induction drugs expose patients to similar risks during the initial post-treatment period, although these risks decrease over time. Their initial potential safety risks should now be revisited, taking account of long-term data and some major changes in their regimens: natalizumab with the long-term monitoring of John Cunningham virus; use of monthly courses of mitoxantrone with maximum cumulative doses of 36-72 mg/m 2 , followed by a safer disease-modifying drug; cladribine with only 2-weekly treatment courses required in years 1 and 2 and no systematic treatment for the following 2 years; alemtuzumab, whose safety and clinical impacts have now been documented for more than 6 years after the last infusion; and autologous haematopoietic stem cell transplant, which dramatically reduces transplantation-related mortality with a new regimen and guidelines. Escalation and induction/high-efficacy treatments need rigorous magnetic resonance imaging monitoring. Monitoring over the first few years, using the MAGNIMS score or American Academy of Neurology guidelines, considerably improves prediction accuracy and facilitates the selection of patients with relapsing-remitting multiple sclerosis requiring aggressive treatment., (© 2023. The Author(s).)

The vaccination with live attenuated vaccines is generally not recommended during natalizumab (NTZ), as it is included among immunosuppressive/immunomodulating therapies. Nevertheless, considering the lack of evidence of a non-Central Nervous System (CNS) immunosuppressive effect of NTZ, after a risk/benefit evaluation, we decided to vaccinate four multiple sclerosis (MS) patients (three with an indication to switch to ocrelizumab for high-risk Progressive Multifocal Leukoencephalopathy (PML) and one for pregnancy planning). No vaccine-related adverse events of any type nor varicella zoster virus (VZV) infections were observed. To the best of our knowledge, these case series represent the first description of the good safety profile of anti-VZV vaccination in MS patients during NTZ treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Progressive multifocal leukoencephalopathy is a rare but often fatal complication of some multiple sclerosis treatments. Although it has mainly been associated with natalizumab treatment, its appearance with other immunosuppressive therapies has also been reported., Aims: The aim of this case report is to describe the development of progressive multifocal encephalopathy in a patient with relapsing-remitting multiple sclerosis treated with ocrelizumab without previous use of natalizumab., Conclusions: A summary of the presentation and disease course is provided, presented in the context of the current literature and likely pathophysiology., (© 2023 European Academy of Neurology.)

Natalizumab is a well-established disease-modifying therapy used in active multiple sclerosis (MS). The most serious adverse event is progressive multifocal leukoencephalopathy. For safety reasons, hospital implementation is mandatory. The SARS-CoV-2 pandemic has deeply affected hospital practices leading French authorities to temporarily authorize to administer the treatment at home. The safety of natalizumab home administration should be assessed to allow ongoing home infusion. The aim of the study is to describe the procedure and assess the safety in a home infusion natalizumab model. Patients presenting relapsing-remitting MS treated by natalizumab for over two years, non-exposed to John Cunningham Virus (JCV) and living in the Lille area (France) were included from July 2020 to February 2021 to receive natalizumab infusion at home every four weeks for 12 months. Teleconsultation occurrence, infusion occurrence, infusion cancelling, JCV risk management, annual MRI completion were analyzed. The number of teleconsultations allowing infusion was 365 (37 patients included in the analysis), all home infusions were preceded by a teleconsultation. Nine patients did not complete the one-year home infusion follow-up. Two teleconsultations canceled infusions. Two teleconsultations led to a hospital visit to assess a potential relapse. No severe adverse event was reported. All 28 patients who have completed the follow-up benefited from biannual hospital examination and JCV serologies and annual MRI. Our results suggested that the established home natalizumab procedure was safe using the university hospital home-care department. However, the procedure should be evaluated using home-based services outside the university hospital., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: Natalizumab is a biologic drug for relapsing-remitting multiple sclerosis that may induce the generation of anti-drug antibodies in some patients. Anti-natalizumab antibodies (ANA) increase the risk of adverse events and reduce efficacy, being useful biomarkers for monitoring treatment response., Methods: Retrospective observational study including MS patients treated with natalizumab that experienced infusion-related events (IRE) or disease exacerbations (DE). ANA were tested by Elisa including a screening and a confirmation assay. Patients were further classified as transient (one positive result) or persistent (two or more positive results) ANA., Results: A total of 1251 MS patients were included and 153 (12.3%) had ANA with at least one single point determination, which were more frequent among patients with IRE compared to those with DE (21,6% vs.10.8%) during the first six infusions. Two or more determinations ANA were performed in 184 patients, being 31.5% permanently positive and 7.1% transiently positive. Interestingly, 26.1% of patients that experienced DE had persistent ANA, while 2.6% were transient. In contrast, 43% of patients with IRE had persistent ANA, and 9.3% had transient antibodies. Patients with persistent antibodies had more frequently high levels at the first sampling compared to patients with transient ANA., Conclusion: Real-world evidence shows that the presence of ANA is behind an important percentage of patients treated with natalizumab that experience IRE, as well as DE but in a lower degree. These findings support the need to systematically evaluate ANA towards a personalized management of these patients to avoid undesired complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ciano-Petersen, Aliaga-Gaspar, Hurtado-Guerrero, Reyes, Rodriguez-Bada, Rodriguez-Traver, Brichette-Mieg, Leyva Fernández, Serrano-Castro, Alonso and Oliver-Martos.)

Background and Objectives: In women with highly active multiple sclerosis (MS), suspending rituximab (RTX) for planning pregnancy is associated with low disease reactivation. Whether this strategy reduces the risk of disease reactivity as compared with suspending natalizumab (NTZ) 3 months after conception is unclear., Methods: We retrospectively included women with MS followed in our department during pregnancy and 1 year after birth who suspended NTZ at the end of the first trimester (option mostly proposed before 2016) or suspended RTX/ocrelizumab (RTX/OCR) in the year before conception (option proposed since 2016)., Results: In women who suspended NTZ, 45 pregnancies resulted in 3 miscarriages and 42 live births, including 1 newborn with major malformations. In women who suspended RTX/OCR, 37 pregnancies resulted in 3 miscarriages and 33 live births; 1 pregnancy was terminated for malformation. During pregnancy, relapse occurred in 3/42 (7.1%) patients of the NTZ group and 1/33 (3%) of the RTX/OCR group ( p = 0.6). After delivery, relapse occurred in 9/42 (21.4%) patients of the NTZ group and 0/33 of the RTX/OCR group ( p < 0.01). In the NTZ group, 8/9 relapses occurred in patients who restarted NTZ less than 4 weeks after delivery. The proportion of patients with gadolinium-enhanced and/or new T2 lesions on brain or spinal cord MRI performed after delivery was higher in the NTZ than RTX/OCR group (14/40 [35%] vs 1/31 [3%] patients, p = 0.001), the proportion with EDSS score progression during the period including pregnancy and the year after delivery was higher (7/42 [17%] vs 0/33 patients, p = 0.01), and the proportion fulfilling NEDA-3 during this period was lower (21/40 [53%] vs 30/31 [97%] patients, p < 0.001)., Discussion: Suspending RTX/OCR in the year before conception in women with highly active MS was associated with no disease reactivation during and after pregnancy. As previously reported, stopping NTZ at the end of the first trimester was associated with disease reactivation. In women receiving NTZ who are planning pregnancy, a bridge to RTX/OCR for pregnancy or continuing NTZ until week 34 are both reasonable clinical decisions. The RTX/OCR option is more comfortable for women and reduces the exposure of infants to monoclonal antibodies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians., Objective: Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching., Methods: Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021., Results: Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%)., Conclusions: Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs., Competing Interests: Declaration of Competing Interest Tarunya Arun has nothing to disclose. Carlos Capela has received consulting fees from Janssen, Merck and Roche, has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, has received support for attending meetings and/or travel from Almirall, Bayer, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, has participated on a Data Safety Monitoring Board or Advisory Board for Biogen, Janssen, Merck, Novartis, Roche and Sanofi-Genzyme. Guy Laureys and/or his employer (UZ Ghent) have received financial compensation for congress attendance, consultancy, research and education by Almirall, Biogen, Celgene, Bristol Myers Squibb, Novartis, Roche, Sanofi, Teva. Pietro Iaffaldano and/or his institution has received medical writing support for present manuscript from Novartis, has received grants from Novartis, Biogen and Roche; has received consulting fees from Novartis, Biogen, Sanofi, genzyme, BMS, Merck and Roche; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Biogen, Sanofi and Merck; support for attending meetings and/or travel from Biogen, Sanofi and Merck and participated on a data safety monitoring board or advisory board for Novartis, Biogen, Sanofi, Genzyme, BMS, Merck and Roche. Eddie Jones is an employee of Adelphi Real World. Adelphi Real World received funds from Novartis in exchange for access to the MS DSP data set that was used for analysis. Eddie Jones did not receive any funding directly from Novartis. Patricia Dominguez-Castro, and Simone Hiltl are employees of Novartis Pharma AG. Gustavo Seifer was an employee of Novartis Pharma AG at the time of study design, execution, interpretation and submission. Rainel Sanchez-de la Rosa was an employee of Novartis Pharma AG at the time of study design and execution., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: With the approval of natalizumab in Europe in 2006, the Austrian Multiple Sclerosis Therapy Registry (AMSTR) was established. Here, we present data from this registry about effectiveness and safety of natalizumab in patients treated up to 14 years., Patients/methods: Data retrieved from the AMSTR contained baseline characteristics and biannual documentation of annualised relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score as well as adverse events and reasons for discontinuation on follow-up visits., Results: A total of 1596 natalizumab patients (71% women, n = 1133) were included in the analysis and the observed treatment duration ranged from 0 to 164 months (13.6 years). The mean ARR was 2.0 (SD = 1.13) at baseline, decreasing to 0.16 after 1 year and 0.01 after 10 years. A total of 325 patients (21.6%) converted to secondary progressive multiple sclerosis (SPMS) during the observational period. Of 1502 patients, 1297 (86.4%) reported no adverse events (AE) during follow-up visits. The most common reported AEs were infections and infusion-related reactions. John Cunningham virus (JCV) seropositivity was the most common specified reason for treatment discontinuation (53.7%, n = 607). There were five confirmed cases of Progressive Multifocal Leukoencephalopathy (PML) with 1 death., Conclusion: The effectiveness of natalizumab in patients with active relapsing-remitting multiple sclerosis (RRMS) could be confirmed in our real-world cohort even after follow-up of up to 14 years, though after year 10, there were less than 100 remaining patients. A low number of AE were reported in this nationwide registry study, establishing Natalizumab's favourable safety profile during long-term use., (© 2023. The Author(s).)

Background: Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited., Research Design and Methods: A retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems., Results: Of 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis., Conclusions: This analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.

Introduction: Natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients infected with John Cunningham virus (JCV). Ocrelizumab has demonstrated efficacy to treat MS; however, its safety in patients previously treated with natalizumab is unclear., Objective: To evaluate the safety and efficacy of ocrelizumab in patients with relapsing MS (RMS) previously treated with natalizumab., Methods: Clinically and radiographically stable RMS patients, ages 18-65 treated with natalizumab for ⩾ 12 months, were enrolled in the study and initiated ocrelizumab 4-6 weeks after their final dose of natalizumab. Relapse assessment, expanded disability status scale, and brain magnetic resonance imaging (MRI) were performed prior to starting ocrelizumab and at months 3, 6, 9, and 12., Results: Forty-three patients were enrolled, and 41 (95%) completed the study. Two patients had a relapse while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. Thirteen serious adverse events (SAEs) were recorded, four of which were considered possibly related to ocrelizumab., Conclusion: Overall, our study indicates clinical and MRI stability for most patients transitioning from natalizumab to ocrelizumab., Clinicaltrials.gov Identifier: NCT03157830.

Importance: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses., Objectives: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab., Design, Setting, and Participants: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023., Exposures: Dimethyl fumarate, fingolimod, and ocrelizumab., Main Outcomes and Measures: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method., Results: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab., Conclusion and Relevance: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

Background: PB006 (Polpharma Biologics S.A; marketed as Tyruko®, Sandoz) is an approved biosimilar to natalizumab (Tysabri®; Biogen [ref-NTZ]). This multicenter, double-blind, randomized, single-dose study was conducted to demonstrate pharmacokinetic/pharmacodynamic (PK/PD) similarity between PB006 and ref-NTZ., Research Design and Methods: Healthy participants ( N  = 453) were randomized to receive 3 mg/kg infusion of PB006, US-licensed, or EU-approved ref-NTZ before an 85-day follow-up. Primary PK endpoint was total natalizumab serum concentration over time; secondary PK endpoints explored concentration changes. Primary PD endpoints compared CD19+ cell counts and percentage α4-integrin receptor saturation, per natalizumab's mechanism of action. Secondary PD endpoints explored serum changes in sVCAM-1 and sMAdCAM-1, CD34+, and CD19+ cells. Safety, tolerability, and immunogenicity were assessed., Results: The primary PK endpoint was met, with 90% confidence intervals (CIs) of the geometric mean for serum test/reference ratios contained within a prespecified margin (0.8-1.25). All primary PD endpoints were met, with 90% and 95% CIs within this similarity margin for baseline-adjusted CD19+ cell counts and percentage α4-integrin receptor saturation. All secondary endpoints were similarly contained, except sVCAM. No notable differences in safety, tolerability, or immunogenicity were observed., Conclusion: Similarity was confirmed, with PB006 demonstrating PK/PD behavior consistent with that of ref-NTZ., Clinical Trial Registration: EudraCT number 2019-003874-15.

Background: Natalizumab is a widely used high-efficacy treatment in multiple sclerosis (MS). Real-world evidence regarding long-term effectiveness and safety is warranted. We performed a nationwide study evaluating prescription patterns, effectiveness, and adverse events., Methods: A nationwide cohort study using the Danish MS Registry. Patients initiating natalizumab between June 2006 and April 2020 were included. Patient characteristics, annualized relapse rates (ARRs), confirmed Expanded Disability Status Scale (EDSS) score worsening, MRI activity (new/enlarging T2- or gadolinium-enhancing lesions), and reported adverse events were evaluated. Further, prescription patterns and outcomes across different time periods ("epochs") were analysed., Results: In total, 2424 patients were enrolled, with a median follow-up time of 2.7 years (interquartile range (IQR) 1.2-5.1). In recent epochs, patients were younger, had lower EDSS scores, had fewer pre-treatment relapses and were more often treatment naïve. At 13 years of follow-up, 36% had a confirmed EDSS worsening. On-treatment ARR was 0.30, corresponding to a 72% reduction from pre-initiation. MRI activity was rare, 6.8% had activity within 2-14 months from treatment start, 3.4% within 14-26 months, and 2.7% within 26-38 months. Approximately 14% of patients reported adverse events, with cephalalgia constituting the majority. During the study, 62.3% discontinued treatment. Of these, the main cause (41%) was due to JCV antibodies, while discontinuations due to disease activity (9%) or adverse events (9%) were less frequent., Conclusion: Natalizumab is increasingly used earlier in the disease course. Most patients treated with natalizumab are clinically stable with few adverse events. JCV antibodies constitute the main cause for discontinuation., Competing Interests: Declaration of Competing Interest MD Buron has received speaker honoraria from Novartis. F Sellebjerg has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, H. Lundbeck A/S, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from , Merck, Novartis, Roche and Sanofi Genzyme. M Magyari has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol Myers Squibb. J Romme Christensen has received speaker honoraria from Biogen. PV. Rasmussen has received speaker honoraria from TEVA, Biogen, Roche and Novartis, support for congress participation from Merck, Roche, Sanofi and TEVA, fees for serving on advisory boards from Merck, Roche, Novartis, Biogen, and Sanofi. PS. Sorensen has received personal compensation for serving on advisory boards for Biogen, Merck, Novartis, Teva; on steering committees or independent data monitoring boards in trials sponsored by Merck, and Novartis; and has received speaker honoraria from Biogen, Merck, Teva, BMS/Celgene, and Novartis. H Joensen, M Kant, D Bech and L Pontieri report no disclosures, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Ten years after its authorization, data about fingolimod use in real-world setting is still scarce. Here we describe the long-term evolution of fingolimod-treated relapsing-remitting MS (RRMS) patients and determine baseline characteristics associated with risk of relapses or disability., Methods: We analyzed baseline characteristics and clinical evolution of 1227 patients with RRMS treated with fingolimod from 2010 to 2019 in 4 French MS referral centers. We used Cox models to determine risks factors of relapses and sustained EDSS worsening., Results: Median follow-up duration was 50 months, and 63% of patients remained fingolimod-treated at the end of follow-up. Mean 5-years annualized relapse rate (ARR) decreased from 0.63 (0.60-0.67) to 0.26 (0.24-0.29, P<0.001), while the mean EDSS rose from 2.5 (2.4-2.6) to 3.0 (2.8-3.1, P<0.001). Female sex, lower age, higher EDSS and use of natalizumab were associated with relapse risk. Female sex was associated with sustained EDSS increase risk., Conclusions: Based on a large real-world cohort, our results confirm the durable reduction of the ARR described in pivot studies. Switching from moderate-efficacy DMT to fingolimod decreased the relapse risk. Switching patients from high-efficacy DMT increased risk of relapse, but the overall five-years ARR remained stable., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Natalizumab (NTZ) and ocrelizumab (OCR) can be used for the treatment of relapsing-remitting multiple sclerosis (RRMS). In patients treated with NTZ, screening for JC virus (JCV) is mandatory, and a positive serology usually requires a change in treatment after 2 years. In this study, JCV serology was used as a natural experiment to pseudo-randomize patients into NTZ continuation or OCR., Methods: An observational analysis of patients who had received NTZ for at least 2 years and were either changed to OCR or maintained on NTZ, depending on JCV serology status, was performed. A stratification moment (STRm) was established when patients were pseudo-randomized to either arm (NTZ continuation if JCV negativity, or change to OCR if JCV positivity). Primary endpoints include time to first relapse and presence of relapses after STRm and OCR initiation. Secondary endpoints include clinical and radiological outcomes after 1 year., Results: Of the 67 patients included, 40 continued on NTZ (60%) and 27 were changed to OCR (40%). Baseline characteristics were similar. Time to first relapse was not significantly different. Ten patients in the JCV + OCR arm presented a relapse after STRm (37%), four during the washout period, and 13 patients in the JCV-NTZ arm (32.5%, p = 0.701). No differences in secondary endpoints were detected in the first year after STRm., Conclusions: The JCV status can be used as a natural experiment to compare treatment arms with a low selection bias. In our study, switching to OCR versus NTZ continuation led to similar disease activity outcomes., (© 2023. The Author(s).)

Background: In the context of the COVID-19 pandemic, French health authorities allowed the home administration of natalizumab by a healthcare-at-home service. We evaluated the patients' perception of care quality following the transition from day-hospital to home natalizumab administration., Methods: Thirty relapsing-remitting multiple sclerosis (MS) patients treated with natalizumab were prospectively evaluated for one year after changing onto a home treatment procedure, using MusiCare, the first MS-specific questionnaire to evaluate patient experience and MusiQol. A numerical rating scale score for satisfaction and a dedicated questionnaire concerning patient experience were completed after each infusion. The primary endpoint was the mean difference in MusiCare score between baseline and 12 months., Results: From June 2020 to November 2021, 306 infusions were performed at home. Three patients withdrew from the study (one lost to follow-up and two preferred to return at the day hospital). No worsening of patient experience or quality of life was observed. The mean scores of the Musicare dimensions were higher at 12 months than at baseline, significantly for the "relationship with healthcare professionals" (p = 0.0203). The MusiQol global score remained stable but the coping and friendship dimensions were significantly better at M12 than at baseline (p = 0.0491 and p = 0.0478, respectively). The satisfaction questionnaire highlighted some pain during the infusions (21.8%) and contradictions between healthcare professionals (17.2%). The mean score for satisfaction with care was 9.1/10. No safety concerns were identified., Conclusion: The positive experience of patients with home natalizumab administration provides an important opportunity to improve the quality of patient care., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. E. Le Page received honoraria for consulting or lectures, invitations for national and international congresses from Biogen, Merck, Teva, Sanofi-Genzyme, Novartis, Alexion, Roche; research support from Teva and Biogen; academic research grants from PHRC and LFSEP, and travel grant from ARSEP Foundation. H. Doyen received honoraria for consulting from Biogen. L. Michel received honoraria for consulting from sanofi, roche, Janssen, celgene, Merck and novartis. S. Lamy, D.Veillard, A. Kerbrat, E. Chretien, A. Ousmen and G. Edan reports no disclosures., (Copyright © 2023. Published by Elsevier B.V.)

Background: Natalizumab (TYSABRI®) 300 mg administered intravenously every-4-weeks (Q4W) is approved for treatment of relapsing-remitting multiple sclerosis but is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Extended natalizumab dosing intervals of approximately every-6-weeks (Q6W) are associated with a lower risk of PML. Primary and secondary clinical outcomes from the NOVA randomized clinical trial (NCT03689972) suggest that effective disease control is maintained in patients who were stable during treatment with natalizumab Q4W for ≥12 months and who then switched to Q6W dosing. We compared additional exploratory clinical and patient-reported outcomes (PROs) from NOVA to assess the efficacy of Q6W dosing., Methods: Prespecified exploratory clinical efficacy endpoints in NOVA included change from baseline in Expanded Disability Status Scale (EDSS) score, Timed 25-Foot Walk (T25FW), dominant- and nondominant-hand 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT). Exploratory patient-reported outcome (PRO) efficacy endpoints included change from baseline in the Treatment Satisfaction Questionnaire for Medication (TSQM), Neuro-QoL fatigue questionnaire, Multiple Sclerosis Impact Scale (MSIS-29), EuroQol 5 Dimensions (EQ-5D-5 L) index score, Clinical Global Impression (CGI)-Improvement (patient- and clinician-assessed) and CGI-Severity (clinician-assessed) rating scales. Estimated proportions of patients with confirmed EDSS improvement were based on Kaplan-Meier methods. Estimates of mean treatment differences for Q6W versus Q4W in other outcomes were assessed by least squares mean (LSM) and analyzed using a linear mixed model of repeated measures or ordinal logistic regression (CGI-scale)., Results: Exploratory clinical and patient-reported outcomes were assessed in patients who received ≥1 dose of randomly assigned study treatment and had ≥1 postbaseline efficacy assessment (Q6W group, n = 247, and Q4W group, n = 242). Estimated proportions of patients with EDSS improvement at week 72 were similar for Q6W and Q4W groups (11.7% [19/163] vs 10.8% [17/158]; HR 1.02 [95% confidence interval [CI], 0.53-1.98]; P = 0.9501). At week 72, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for T25FW (0.00, P = 0.975), 9HPT (dominant [0.22, P = 0.533] or nondominant [0.09, P = 0.862] hand), or SDMT (-1.03, P = 0.194). Similarly, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for any PRO (TSQM, -1.00, P = 0.410; Neuro-QoL fatigue, 0.52, P = 0.292; MSIS-29 Psychological, 0.67, P = 0.572; MSIS-29 Physical, 0.74, P = 0.429; EQ-5D-5 L, 0.00, P = 0.978). For the EQ-5D-5 L, a higher proportion of Q6W patients than Q4W patients demonstrated worsening (≥0.5 standard deviation increase in the EQ-5D-5 L index score; P = 0.0475). From baseline to week 72 for Q6W versus Q4W, odds ratio (ORs) of LSM change in CGI scores did not show meaningful differences between groups (CGI-Improvement [patient]: OR [95% CI] 1.2 [0.80-1.73]; CGI-Improvement [physician]: 0.8 [0.47-1.36]; CGI-Severity [physician]: 1.0 [0.71-1.54])., Conclusions: No significant differences were observed in change from baseline to week 72 between natalizumab Q6W and Q4W groups for all exploratory clinical or PRO-related endpoints assessed. For the EQ-5D-5 L, a higher proportion of Q6W than Q4W patients demonstrated worsening., Competing Interests: Declaration of Competing Interest The authors 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 © 2023. Published by Elsevier B.V.)