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Background: Neurofilament light chain (NFL) is a biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). However, while most agree that NFL levels predict disease activity and worsening, the predictive value of NFL on future relapse risk remains uncertain., Objective: The primary aim was to evaluate the predictive value of age-corrected serum NFL (sNFL) ratio on relapse risk in highly active relapsing-remitting MS patients (RRMS) treated with natalizumab. A secondary aim was to investigate the predictive value of sNFL ratios for MRI activity., Methods: From January 1, 2006, to December 31, 2010, 355 patients initiated natalizumab treatment at the Danish Multiple Sclerosis Center. 305 patients were anti-natalizumab antibodies negative and had at least one blood sample available for sNFL analysis using single molecule array analysis at baseline, three, six, or 12 months. The patients were either treatment-naïve (n = 8), switching from interferon-β or glatiramer acetate (n = 253), or switching from mitoxantrone (n = 44). An age-corrected ratio was calculated for sNFL. Time to first relapse was calculated from baseline and after re-baseline at 90 days. Data were collected from baseline until the two-year follow-up or end of treatment and included disease duration, expanded disability status scale, previous treatments, relapses 12 months prior to natalizumab initiation, smoking intensity, body mass index, and body weight. In addition, the patients underwent annual MRI of the brain., Results: The sNFL ratio was increased in 173 of 287 samples (60.3 %) at baseline, in 119 of 246 samples (48.8 %) at month three, in 109 of 287 samples (38.0 %) at month six, and in 82 of 270 samples (30.4 %) at month 12. The sNFL ratio continuously declined over 12 months with significant decreases for every measuring timepoint: baseline vs. three months p = 3.0 × 10 -6 ; three months vs. six months p = 3.2 × 10 -5 ; six months vs. 12 months p = 0.002. Univariate Cox regression analysis showed that time to first relapse from 1) natalizumab initiation and from 2) re-baseline was associated with the number of relapses in the previous 12 months (hazard ratio 1.31 per relapse, 95 % CI = 1.2-1.5, p = 2.0 × 10 -6 ; and 1.21 per relapse, 95 % CI = 1.1-1.4, p = 0.002, respectively). sNFL ratio at re-baseline was negatively associated with relapse risk (hazard ratio 0.82 per unit; 95 % CI = 0.7-1.0; p = 0.049). A multivariable Cox regression analysis of relapse risk from re-baseline showed that the number of relapses in the 12 months prior to natalizumab treatment (hazard ratio 1.29; 95 % CI = 1.1-1.5; p = 6.0 × 10 -4 ) and smoking (hazard ratio 1.51 per 20 cigarettes per day; 95 % CI = 1.0-2.2; p = 0.030) were associated with increased risk of relapse; sNFL ratio was associated with a lower risk of relapse (hazard ratio = 0.736 per unit; 95 % CI = 0.6-0.9 p = 0.007). In univariate logistic regression analyses, the sNFL ratio at 12 months and values above the 75th and the 90th percentile predicted MRI activity in the following year (odds ratio [OR] = 2.0, 95 % CI = 1.2-3.6, p = 0.012; OR = 2.2, 95 % CI = 1.2-4.1, p = 0.014; and OR = 2.8, 95 % CI = 1.1-6.7, p = 0.026)., Conclusion: In this highly active RRMS cohort, high sNFL ratios reflected previous relapse activity and decreased after initiation of treatment but were not associated with increased relapse risk in the following two years. Pre-treatment relapses and smoking on treatment were predictors of relapse risk after re-baselining at 90 days. MRI activity in year two was predicted by sNFL ratios at month 12., Competing Interests: Declaration of competing interest H. Højsgaard Chow reports non-financial support from Merck, non-financial support from Teva, non-financial support from Biogen, non-financial support from Roche, outside the submitted work and personal support from the Warwara Larsen Foundation. E. Rosa Petersen has nothing to declare. A. Olsson has nothing to declare. J. Hejgaard Laursen has nothing to declare. M. Bredahl Hansen has nothing to declare. A. Bang Oturai has nothing to declare. P. Soelberg Sørensen has received personal compensation for consultations, serving on scientific advisory boards, steering committees, independent data monitoring committees or have received honoraria as speaker from Biogen, Merck, Novartis, TEVA, and BMS/Celgene. H. Bach Søndergaard has nothing to declare. F. Sellebjerg reports grants from Biogen, grants from Danish Multiple Sclerosis Society, during the conduct of the study; grants and personal fees from Biogen, personal fees from Lundbeck, grants and personal fees from Merck, grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Sanofi Genzyme, outside the submitted work; and Professor F. Sellebjerg is section editor on Multiple Sclerosis and Related Disorders., (Copyright © 2024. Published by Elsevier B.V.)

Background: Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva., Methods: Paired serum and saliva samples from a small cohort of relapsing-remitting multiple sclerosis patients were measured for levels of intact NAT, total NAT, IgG and IgG4., Results: Intact NAT concentration was dependent on both total NAT and endogenous IgG4 levels. Low endogenous IgG4 led to a higher ratio of intact NAT to total NAT, while the opposite was observed in subjects with high endogenous IgG4. Serum and saliva measurements show good concordance., Conclusions: Intact NAT concentration is influenced by both NAT pharmacokinetics and endogenous IgG4 levels. Patients with low IgG4 levels can have high concentrations of intact NAT even with lower levels of total NAT, which may explain cases of NAT-associated progressive multifocal leukoencephalopathy (PML) in such patients. Monitoring both forms of NAT could better guide dosing, maximizing drug efficacy and safety., Competing Interests: Declaration of competing interest At the time of writing, Dr. Bradley Messmer was CSO of Aegirbio AB and received stock compensation from Aegirbio AB. J. Foley has received research support from Biogen, Octave, and Genentech. He received speakers' honoraria from Biogen. He has participated in advisory boards for Biogen, Horizon, Sandoz, and TG Therapeutics. He is the founder of InterPro Biosciences. L.J.P, I.F.P, R.H, T.H and E.T.C report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To quantify the probability that monthly intravenous (IV) and subcutaneous (SC) natalizumab (NTZ) had similar efficacy in relapsing-remitting multiple sclerosis (RRMS), non-inferiority of efficacy of NTZ-SC versus NTZ-IV on combined MRI unique active lesions number (CUAL) was explored re-analysing the REFINE data set. Non-inferiority margins were selected equal to 25%/33%/50% fractions of the effect size of NTZ-IV versus placebo observed in the AFFIRM study. Ninety-nine RRMS were included. NTZ-SC resulted not inferior to NTZ-IV on CUAL for all margins at 2.5% significance level, and, in worst-case scenario, its effect over NTZ-IV did not exceed 3.5% (or 2.8%) of the effect of NTZ-IV versus placebo., 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: F.M. discloses consulting honoraria from Novartis and Daiichi-Sankyohas. A.Mat. has no competing interests to declare that are relevant to the content of this article. A.Mar. reports speaking honoraria from Sanofi, Biogen, Janssen and Novartis; non-financial support from Biogen, Novartis, Janssen and Sanofi, outside the submitted work. L.M. reports non-financial support and speaker honoraria from Biogen, Novartis, Merck Serono, Genzyme and Teva and Viatris.

Background: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years., Methods: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement., Results: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Irene Schiavetti reports a relationship with Roche, Biogen, Horizon, Novartis, Hoya, Hippocrates Research, D.M.G Italia, Eyepharma, DreamsLab that includes: consulting or advisory. Livia Pasquali reports a relationship with Alexion, Biogen, Sanofi, Merck, Novartis, Roche that includes: consulting or advisory and travel reimbursement. Elisabetta Signoriello reports a relationship with Almirall, Biogen, Genzyme, Novartis, Teva that includes: board membership and travel reimbursement. Maria Pia Sormani reports a relationship with Biogen Idec, Merck Serono, Teva, Genzyme, Roche, Novartis, GeNeuro, Medday that includes: consulting or advisory. Jessica Frau reports a relationship with Biogen, Bristol, Novartis, Genzyme, Merck, Teva, Alexion that includes: board membership, consulting or advisory, and speaking and lecture fees. Daniele Caliendo reports a relationship with Merck that includes: funding grants. Alessio Signori reports a relationship with Roche, Horizon, Novartis that includes: speaking and lecture fees. Andrea Surcinelli reports a relationship with Roche, Merck, Biogen, Sanofi, Novartis that includes: travel reimbursement. Simona Bonavita reports a relationship with Novartis, Merck-Serono, Alexion, BMS, Biogen, Roche, Janssen-Cilag, Horizon that includes: speaking and lecture fees and travel reimbursement. Roberta Fantozzi reports a relationship with Novartis, Roche, Merck Serono, Bristol-Myers Squibb that includes: board membership and consulting or advisory. Antonio Carotenuto reports a relationship with Almirall, ECTRIMS- MAGNIMS, Biogen, Roche, Sanofi-Genzyme, Merck, Ipsen, Novartis that includes: funding grants. Doriana Landi reports a relationship with Biogen, Merck Serono, Teva, Bristol Myers Squibb, Mylan, Novartis, Roche, Horizon, Alexion, Sanofi-Genzyme, Novartis, Bayer-Schering that includes: speaking and lecture fees and travel reimbursement. Giacomo Lus reports a relationship with Biogen Idec, Merck Serono, Novartis, Sanofi- Aventis Pharmaceuticals, Teva neuroscience that includes: funding grants. Eleonora Cocco reports a relationship with Biogen, Merck, Novartis, Roche, Genzyme that includes: consulting or advisory and funding grants. Matteo Lucchini reports a relationship with Biogen, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Almirall, Horizon, Bayer that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Girolama Alessandra Marfia reports a relationship with Almirall, Bayer-Schering, Biogen, Sanofi Genzyme, Merck Serono, Novartis, Teva, Mylan, Bristol Mayers Squibb, Roche, Biogen that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Matteo Foschi reports a relationship with Merck, Biogen, Sanofi, Roche, Novartis that includes: consulting or advisory and travel reimbursement. Massimiliano Mirabella reports a relationship with Bayer Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva, Mylan, Almirall, CSL Behring, Roche, Ultragenix that includes: board membership, consulting or advisory, speaking and lecture fees, and travel reimbursement. Diego Centonze reports a relationship with Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, Protagon, Sandoz, Bristol-Myers Squibb, Alexion, Mitsubishi, Teva, Celgene that includes: board membership, funding grants, and non-financial support. 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Natalizumab is a humanized monoclonal antibody with high efficacy and an acceptable safety profile used in the treatment of patients with multiple sclerosis (MS)., Objective: Our aim was to report data regarding long-term administration of Natalizumab in patients with Relapsing-Remitting Multiple Sclerosis (RRMS) from our clinic., Methods: A retrospective observational study was performed including RRMS patients who underwent treatment with ≥ 24 Natalizumab infusions. We analyzed EDSS values, the relapse rate and the rate and type of adverse events related to Natalizumab administration., Results: 51 subjects were included with a predominance of women (62.74%), with an average age of 40.43±1.49 years, a mean disease duration of 9.86±0.7 years and mean number of Natalizumab infusions of 45.58±2.74. An increased number of patients (80.39%) were relapse-free and a mild reduction of the mean EDSS value following Natalizumab initiation in patients who had not been treated with other disease modifying therapies anteriorly was observed. Among the encountered adverse events such as increased liver transaminases (13.72%), local infections (7.84%) and dysmenorrhea in one patient were registered in this study. The rate of severe adverse events was 3.92 and no cases of Progressive Multifocal Leukoencephalopathy (PML) were registered., Conclusion: Natalizumab proves to be effective, has an adequate safety profile and can be administered with good tolerability for a rather extended period of time, provided that the patients are closely monitored., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing-remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpB OCR 0.485, CI 95% 0.264-0.893, p = 0.020). This result was confirmed also for 12-month MRI activity (ExpB OCR 0.248 CI 95% 0.065-0.948, p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile., (© 2021. The Author(s).)

Background: The COVID-19 pandemic challenges multiple sclerosis services to be innovative in delivering infusible therapies. To reduce time in clinical settings, and potential staff or space losses, we implemented rapid infusion protocols for selected patients., Objective: To analyse the rate of infusion related reactions and patient experience of rapid infusions of natalizumab and ocrelizumab. To document time reduction patients spent in clinical settings during the COVID-19 pandemic., Methods: Patients with prior exposure to at least three natalizumab or two 300mg ocrelizumab infusions were approved for rapid protocols. A retrospective audit and survey were completed., Results: We analysed 269 rapid natalizumab infusions and 100 rapid ocrelizumab infusions. Infusion related reactions during the natalizumab or ocrelizumab infusions occurred in two patients (1.52%) and eight patients (8%), respectively. All infusion related reactions were mild to moderate and did not require infusion discontinuation. No infusion reactions occurred during the post-infusion observation. Patient experience was positive., Conclusion: Frequency or severity of infusion related reactions in rapid infusions were no different compared to published data. In the setting of COVID-19, pandemic rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Natalizumab (NTZ) is one of the most effective treatment options for multiple sclerosis (MS) treatment. Our study aimed to evaluate the effectiveness of NTZ when administered according to the extended dosing strategy compared with standard 4-weekly administration in a large Italian MS population., Materials and Methods: This retrospective multicentre study included patients with relapsing-remitting MS (RR-MS) who received NTZ administrations between the 1 June 2012 and the 15 May 2018 and were followed by the 'Italian MS Register'. All patients with MS were stratified into two groups based on NTZ administration schedule: standard interval dosing (SID) patients who received infusions on average from 28 to 32 days (median 30) and extended interval dosing (EID) including patients who have been infused with interval between 33 and 49 days (median 43). Clinical data were assessed at baseline (before starting NTZ), after 12 (T1) and 24 months (T2) of treatment., Results: Out of 5231 patients with RR-MS screened, 2092 (mean age 43.2±12.0, 60.6% women) were enrolled. A total of 1254 (59.9%) received NTZ according to SID, and 838 (40.1%) according to EID. At 12 and 24 months, no differences in terms of annualised relapse rate and disability status were found between the two groups. Progression index and confirmed disability worsening were similar between the two groups., Discussion: The use of NTZ with an extended interval schedule showed similar effectiveness compared with SID. Unchanged clinical efficacy of EID schedule may raise the question of a possible advantage in terms of tolerability and safety., Competing Interests: Competing interests: CGC has received grants for congress participation from Almirall, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme and Teva. GS received speaker’s honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. PR has received grants for speaking activities from Biogen, Merck Serono, Novartis, TEVA and grants for congress participation from Almirall, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA. LMG received speaker’s honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. SB received speaker’s honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. AL received speaker’s honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. MTF received speaker’s honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. ElC received speaker’s honoraria, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. FG received honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. MT received speaker’s honoraria, consulting fees, honoraria in advisory boards, support for attendance of scientific meetings from Meck Serono, Biogen, Novartis, Teva and Sanofi Genzyme. FP has received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA; he also served as advisory board member the following companies: Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme and TEVA., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Limited comparative effectiveness data for rituximab (RTX) versus natalizumab (NTZ), fingolimod (FTY), and dimethyl fumarate (DMF) for the treatment of multiple sclerosis (MS) exist., Methods: Clinician-reported data on patients prescribed RTX, NTZ, FTY, or DMF for the treatment of MS at the Rocky Mountain MS Center at the University of Colorado were retrospectively collected. Outcomes included a composite effectiveness measure consisting of clinical relapse, contrast-enhancing lesions, and/or new T2 lesions, individual effectiveness outcomes, and discontinuation. Logistic regression was used on patients matched by propensity scores and using average treatment effect on treated doubly robust weighting estimator., Results: A total of 182, 451, 271, and 342 patients initiated RTX, NTZ, FTY, and DMF and were followed for 2 years. Before and after adjustment, the odds of experiencing disease activity was significantly higher for FTY [adjusted OR (aOR) = 3.17 (95% CI: 1.81-5.55), P < 0.001].and DMF [aOR = 2.68 (95% CI:1.67-4.29), P < 0.001], and similar for NTZ [aOR = 1.36 (95% CI:0.83-2.23), P = 0.216] versus RTX. When examining months 6-24, NTZ demonstrated higher odds of disease activity compared to RTX [aOR = 2.21 (95% CI: 1.20-4.06), P = 0.007]. Similar odds of discontinuation were seen between NTZ and RTX [aOR = 1.39 (95% CI: 0.88-2.20), P = 0.157]; however, FTY [aOR = 2.02 (95% CI: 1.24-3.30), P = 0.005] and DMF [aOR = 3.27 (95% CI: 2.15-4.97), P < 0.001] had greater odds of discontinuation than RTX., Interpretation: RTX demonstrated superior effectiveness and discontinuation outcomes compared to FTY and DMF. Although RTX demonstrated similar effectiveness and discontinuation compared to NTZ, RTX had superior effectiveness during months 6-24 and fewer discontinuations when excluding discontinuations due to insurance issues. Results suggest superiority of RTX in reducing disease activity and maintaining long-term treatment in a real-world MS cohort., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: The risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCPyV), is the main limitation to the use of natalizumab, highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Establishing the PML risk against expected benefits represents an obligatory requirement of MS treatment algorithm. In order to achieve this goal, the aims of this study were to establish if JCPyV-DNA detection and non-coding control region (NCCR) arrangements could play a role of biomarkers, supporting anti-JCPyV antibodies measurement, actually the only parameter for PML risk stratification., Methods: Thirty RRMS patients in treatment with natalizumab were enrolled. Urine and blood samples were collected according to this calendar: baseline (T0), 4 (T1), 8 (T2), 12 (T3), 16 (T4), 20 months (T5) after beginning of natalizumab therapy. After JCPyV DNA extraction, a specific quantitative-PCR (Q-PCR) and arrangements' analysis of NCCR and Viral Capsid Protein 1 (VP1) were carried out., Results: Q-PCR detected JCPyV DNA in urine and blood from baseline (T0) to 20 natalizumab infusions (T5), although JC viral load in urine was significantly higher compared to viremia, at all selected time points. A contextual analysis of the anti-JCPyV-antibodies versus JCPyV-DNA detection revealed that viral DNA preceded the antibodies' presence in the serum. During the first year of natalizumab treatment, sequences isolated from blood displayed an archetype JCPyV NCCR structure with the occurrence of point mutations, whereas after one year NCCR re-organizations were observed in plasma and PBMC with duplication of NF-1 binding site in box F, duplication of box C and partial or total deletion of box D. VP1 analysis showed the amino acid change mutation S269F in plasma and S267L in PBMC, involving the receptor-binding region of VP1. Phylogenetic analysis suggested a stability and a similarity across different isolates of the JCPyV VP1., Conclusions: We highly recommend considering JCPyV-DNA detection and NCCR re-organizations as viral biomarkers in order to accurately identify JCPyV-infected patients with a specific humoral response not yet detectable and to identify NCCR arrangements correlated with the onset of neurovirulent variants., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Many natalizumab treated patients experience end of dose interval (EDI) symptoms towards the end of the administration cycle. Natalizumab has previously shown to influence cytokine profiles in relapsing remitting MS patients. We hypothesize that EDI symptoms might be explained by variability in serum cytokine levels during natalizumab treatment., Methods: 42 relapsing remitting MS patients were included. Participants were evaluated before natalizumab administration (day 0) and 7 days afterwards (day 7). At both time points fatigue, depressed mood and cognition were evaluated using the fatigue severity scale (FSS), the visual analogue scale for fatigue (VAS-F), the symbol digit modality test (SDMT) and the inventory for depressive symptomatology (IDS-SR). Serum samples were tested for concentrations of IL-6, IFN-γ and TNF-α at both timepoints. On day 7 an additional EDI questionnaire was completed. Data were analyzed with SPSS by means of non-parametric tests., Results: EDI symptoms were reported by 59.5%. Although fatigue was most frequently reported, fatigue scales did not significantly change from day 0 to 7 in (fatigued) EDI patients. Mood and cognition significantly ameliorated in both EDI and non-EDI patients. Cytokines remained stable at day 0 vs 7 except for a significant increase in IFN-γ. On day 0, IFN-γ concentration was positively correlated with a depressed mood in the whole cohort, and with mood and fatigue in the EDI group. Depressed mood positively whilst cognition negatively correlated with IFN-γ concentration on day 0 in the EDI subgroup reporting fatigue. No significant correlations between IL-6 nor TNF-α and symptom scores could be found., Conclusion: In our study EDI symptoms could not be objectified since EDI and non-EDI groups did not differ in terms of change in mood, cognition and fatigue between day 0 and 7 suggesting that symptom recrudescence could be a subjective experience. Although our results need to be interpreted cautiously, we found no clear correlation between studied serum cytokines concentrations and the occurrence of EDI symptoms., Competing Interests: Declaration of Competing Interest This study was sponsored by Biogen as an investigator-initiated trial. The authors maintained full editorial control of all content. Dekeyser Cathérine: has received travel compensation from Biogen; De Pue Annelien: has received travel compensation from Biogen; Sieben Anne: nothing to disclose; Algoed Luc: has received travel compensation from Biogen; Vanhijfte Liesbeth: nothing to disclose; Sarah Gerlo: nothing to disclose; Laureys Guy: has received travel compensations, consultancy and speakers fees from Biogen, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: In the Brazilian public healthcare system, natalizumab is recommended as fourth-line treatment for relapsing-remitting multiple sclerosis (RRMS). Although natalizumab has already demonstrated higher effectiveness compared with fingolimod in some studies, this real-world study was conducted to evaluate annualized hospitalization rates (AHR) in Brazil for both treatments when switching from platform therapies. As secondary goals, we analyzed RRMS treatment patterns and hospitalization profiles., Material and Methods: We extracted data from the DATASUS database of patients with MS (ICD-10 G35) who initiated treatment from January 2012 to December 2017. Two cohorts were screened for different purposes. Cohort 1 was used to analyze treatment patterns and hospitalization profiles and was defined as individuals who had at least one claim related to MS therapies and had received at least two lines of treatment. The second cohort, which was a subset of the first, was used to compare natalizumab's and fingolimod's AHR reduction from previous treatment lines and included patients switching from platform therapy to one of these two drugs. Cohort 2 adjustment was assessed through two different statistical methods: propensity score (PS) and inverse probability weighting (IPW)., Results: Of 29,410 patients screened, 2,876 were included in cohort 1. Three quarters of hospitalizations reported in this cohort were for treatment of MS relapse. Cohort 2 included 1,005 patients, and natalizumab was more commonly used (n = 540) than fingolimod (n = 465). Both PS and IPW analyses showed that patients treated with natalizumab had a statistical significantly reduction in AHR compared with first-line treatment (p<0.01 for both PS and IPW), while fingolimod did not result in significant reduction in AHR (p = 0.20 for PS and p = 0.17 for IPW)., Conclusion: This study provides real-world evidence of natalizumab's and fingolimod's effectiveness in terms of AHR, with an increased reduction in AHR with natalizumab. The findings of this study also provide information to support disease management and healthcare planning in the Brazilian public healthcare system., Competing Interests: Ricardo Papaléo Rosim and Jéssica Rigolon are employees of Biogen Brazil; Guilherme Silva Julian is an employee of IQVIA Brazil who was contracted by Biogen to conduct the study. Estela Cristina Carneseca is an employee of Proestat Consultoria who was also contracted to conduct the analysis. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: We aimed to investigate whether wearing-off symptoms at the end of the natalizumab dosing interval were associated with clinical and demographic patient characteristics or natalizumab receptor occupancy (RO) on leukocytes., Methods: In this cross-sectional study of 40 patients with relapsing-remitting MS (RRMS) receiving natalizumab at the Department of Neurology, Haukeland University Hospital, we recorded clinical and demographic data including age, body mass index (BMI), working status, smoking habits, disease characteristics, treatment duration, vitamin D levels, and wearing-off symptoms. We quantified neurofilament light chain in serum and measured natalizumab RO in leukocyte subtypes by high-parameter mass cytometry. Associations with wearing-off symptoms were analyzed., Results: Eight (20.0%) patients who reported regular occurrence of wearing-off symptoms, 9 (22.5%) who sometimes had wearing-off symptoms, and 23 (57.5%) who did not have wearing-off symptoms were evaluated. Patients who regularly had wearing-off symptoms had lower natalizumab RO than patients who reported having such symptoms sometimes or never. The former group also had higher BMI and higher frequency of sick leave. High BMI was associated with low RO. No other demographic or disease characteristics were associated with the phenomenon., Conclusions: Low RO may explain the wearing-off phenomenon observed in some patients with RRMS treated with natalizumab, and high BMI may be the underlying cause., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Natalizumab (NTZ) is a humanized monoclonal antibody used in the treatment of relapsing remitting multiple sclerosis. Although NTZ is usually well-tolerated, infusion-related reactions (IRRs) may occur, and the patients have to be monitored during the infusion and for one hour afterwards., Objective: To identify frequency and severity of IRRs during NTZ infusions and one-hour post-infusion observation period in a clinical practice setting., Methods: Multicenter, observational study involving three Swiss (Lugano, St. Gallen and Luzern) and two Italian (Milano and Napoli) tertiary MS centers. Predisposing factors to IRRs were investigated using multivariate Cox regression models., Results: A total of 11'133 infusions received by 302 MS patients were analyzed (68.9% females, median age 33.6 years, median EDSS 2.5). IRRs occurred in 24 (8%) patients during NTZ infusions and in 7 (2%) during one-hour post-infusion. Only 8 patients needed pharmacological treatment, of whom 7 during NTZ infusion. Age, sex and history of allergies were not associated with risks for IRR. The frequency of post infusion IRRs after the fifth cycle was low compared to that during the first four infusions (0.83% vs 0.06%)., Conclusion: In our cohort, NTZ associated IRR mainly occurred during the infusion period compared to the one-hour observational period. Also, the first IRR exclusively occurred within the first 4 NTZ administrations. However, further multi-center studies with a larger sample size are needed to capture rare and serious events that could emerge during the observational period and to make clinical recommendations., Competing Interests: Declaration of Competing Interest Zecca C, Gobbi C received financial support for scientific activity, congress participation and speaking bureau from Almirall, Biogen, Bayer, CelleGene, Genzyme, Merck-Serono, Novartis, Roche, Teva Pharma. Sacco R, Disanto G, Maraffi I, Candrian U and Schwegler G declare that they have no conflict of interest Kamm CP has received honoraria for lectures as well as research support from Biogen, Novartis, Almirall, Bayer Schweiz AG, Teva, Merck, Sanofi Genzyme, Roche, Celgene and the Swiss MS Society (SMSG). Rossi S acted as an Advisory Board member of Biogen, Bayer Schering, Merck, Teva, Novartis, Genzyme, Mylan and received travel funding from Biogen, Merck, Teva, Novartis, Bayer Schering, Genzyme, Almirall, and received honoraria for consultancy, speaking or writing from Biogen, Merck, Teva, Novartis, Bayer Schering, Genzyme, Roche. She received support for research projects by Teva, Merck and Bayer Schering and is involved as principal investigator in clinical trials for Teva, Novartis, Biogen and Roche. Gallo A received honoraria for speaking and travel grants from Biogen, Sanofi-Aventis, Merck, Genzyme, Teva, and Novartis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting., Methods: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse., Results: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation., Conclusion: High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort., Competing Interests: Declaration of Competing Interest The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. IR has received research grants (The Finnish Medical Foundation, Orion Research Foundation sr) and reimbursement of travel expenses (Novartis). PH has received research grants (Biogen, Sanofi Genzyme), reimbursement of travel expenses and/or honoraria for lectures/consultations (Allergan, Biogen, Merck, NordicInfu Care, Roche, Sanofi Genzyme, SNY, Teva). JK has served on the scientific advisory board for Merck and Roche. SS has been the congress representative of Mikkeli Central Hospital sponsored by industry and has received honoraria for lectures/consultations (Biogen, Merck, Novartis, Sanofi Genzyme, Teva). AMR has received reimbursement of travel expenses and/or honoraria for lectures/consultations (Merck, Sanofi Genzyme, Novartis, Teva). HK has received honoraria for lectures/consultations (Biogen, Merck, Novartis, Roche, Sanofi Genzyme, Teva). TM, MN and TS have no conflict to declare., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective. Quantitatively summarize patient preferences for European licensed relapsing-remitting multiple sclerosis (RRMS) disease-modifying treatment (DMT) options. Methods. To identify and summarize the most important RRMS DMT characteristics, a literature review, exploratory physician interviews, patient focus groups, and confirmatory physician interviews were conducted in Germany, the United Kingdom, and the Netherlands. A discrete choice experiment (DCE) was developed and executed to measure patient preferences for the most important DMT characteristics. The resulting DCE data ( n =799 and n =363 respondents in the United Kingdom and Germany, respectively) were analyzed using Bayesian mixed logit models. The estimated individual-level patient preferences were subsequently summarized using 3 additional analyses: the quality of the choice data was assessed using individual-level R 2 estimates, individual-level preferences for the available DMTs were aggregated into DMT-specific preference shares, and a principal component analysis was performed to explain the patients' choice process. Results. DMT usage differed between RRMS patients in Germany and the United Kingdom but aggregate patient preferences were similar. Across countries, 42% of all patients preferred oral medications, 38% infusions, 16% injections, and 4% no DMT. The most often preferred DMT was natalizumab (26%) and oral DMT cladribine tablets (22%). The least often preferred were mitoxantrone and the beta-interferon injections (1%-3%). Patient preferences were strongly correlated with patients' MS disease duration and DMT experience, and differences in patient preferences could be summarized using 8 principle components that together explain 99% of the variation in patients' DMT preferences. Conclusion. This study summarizes patient preferences for the included DMTs, facilitates shared decision making along the dimensions that are relevant to RRMS patients, and introduces methods in the medical DCE literature that are ideally suited to summarize the impact of DMT introductions in preexisting treatment landscapes.

Background: Multiple sclerosis (MS) predominantly affects women of child-bearing potential. Pregnancy in MS is still a controversial issue lacking standardized treatment recommendations., Objective: To examine the reciprocal effects of pregnancy, MS, and disease-modifying treatment (DMT)., Methods: We analyzed 387 pregnancies in 239 women with relapsing remitting multiple sclerosis (RRMS) and ⩾1 pregnancy, establishment of diagnosis >1 year before conception, and ⩾2 years of follow-up after delivery. Relapse rates and Expanded Disability Status Scale (EDSS) scores were compared in the year before conception, during pregnancy, and 2 years postpartum. Binary logistic regression was used to investigate predictors of risk for relapses and disability progression during pregnancy and postpartum., Results: Risk of relapse and disability progression during pregnancy was predicted by pre-conception relapse activity, higher EDSS score at conception, use of highly effective disease-modifying treatment (H-DMT) pre-conception, and prolonged washout period. Postpartum relapse and disability progression was associated with relapse activity pre-conception and during pregnancy and use of H-DMT pre-conception. Early restart of DMT reduced the risk of postpartum relapse., Conclusion: A personalized approach in planning pregnancy in women with MS while on H-DMT needs to be adopted. It seems reasonable maintaining natalizumab closer to conception and restarting the drug early postpartum to reduce the considerable risk of disease reactivation during early pregnancy and after delivery.

Studies comparing the effects of natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS) are limited. We aimed to compare natalizumab and fingolimod effects on clinical, neuropsychological, and MRI measures in RRMS patients after 2 years of treatment. RRMS patients starting natalizumab (n = 30) or fingolimod (n = 25) underwent neurologic, neuropsychological, and brain MRI assessments at baseline, month (M) 6, M12, and M24. Volumes of lesions, brain, gray matter (GM), white matter (WM), and deep GM were measured. Fifteen healthy controls (HC) were also scanned at baseline and M24. Treatment groups were matched for baseline variables. At M24 versus baseline, both drugs reduced the relapse rate (p value < 0.001), stabilized disability, and improved cognitive function (fingolimod: p value = 0.03; natalizumab: p value = 0.01), without between-group differences. The natalizumab group had a higher proportion of freedom from MRI activity (67% vs 36%, p value = 0.02) and no evidence of disease activity-3 (NEDA-3) (57% vs 28%, p value = 0.04). At M24 vs M6, brain (- 0.35%, p value = 0.002 [fingolimod]; - 0.42%, p value < 0.001 [natalizumab]), GM (- 0.62%, p value < 0.001 [fingolimod]; - 0.64%, p value < 0.001 [natalizumab]), and WM (- 0.98%, p value < 0.001 [fingolimod]; - 0.99%, p value < 0.001 [natalizumab]) atrophy progressed at higher rates than in HC, but similarly between treatment groups, whereas only the natalizumab group showed deep GM atrophy (- 0.79%, p value = 0.02) (p value vs fingolimod not significant). In both groups, atrophy progression was correlated with lesion accumulation (r from - 0.49 to - 0.36, p values from 0.013 to 0.05), whereas no correlation was found between clinical and MRI changes. Natalizumab and fingolimod reduce disease activity and improve cognition in RRMS. Natalizumab seems superior to limit lesion accumulation, whereas both drugs similarly modify atrophy progression.

Background: In natalizumab treated patients several hematopoietic abnormalities including erythroblasts, myeloblasts and neutrophilic precursors in peripheral blood have been described. So far, long term effects of the hematopoietic changes have not been reported., Objective: To describe hematopoietic abnormalities in longitudinally monitored MS patients treated with natalizumab. Patients treated with dimethyl fumarate, teriflunomide and fingolimod served as controls. Secondly, the relation between natalizumab serum levels and the occurrence of hematopoietic abnormalities was explored., Methods: 212 natalizumab treated patients were included, 91 patients with available baseline samples (998 follow-up samples) were compared with patients with dimethyl fumarate (n = 166, 1154 samples), teriflunomide (n = 38, 228 samples) and fingolimod (n = 114, 853 samples). One hundred twenty one patients without baseline samples (1952 follow-up samples) were included in the follow-up group., Results: More than half of all natalizumab treated patients developed hematopoietic abnormalities, almost a quarter had erythroblasts. Natalizumab use was associated with an increased risk of developing abnormalities in comparison to oral treatment, with a corrected hazard ratio of 2.3, 10.0 and 8.1 in comparison to fingolimod, dimethyl fumarate and teriflunomide respectively. No difference in developing abnormalities was observed in relation to natalizumab serum concentrations. None of the patients developed a hematologic malignancy during follow up., Conclusion: Hematopoietic abnormalities are common during natalizumab treatment. Given the lack of consequences of this finding during long-term follow-up, it is generally justifiable to refrain from further diagnostic procedures when observing hematopoietic abnormalities in patients using natalizumab., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus (JCV) seronegative patients with early relapsing-remitting multiple sclerosis (RRMS). The objective of this prespecified 2-year interim analysis was to determine the effectiveness of natalizumab in establishing and maintaining no evidence of disease activity (NEDA) in early RRMS., Methods: Patients aged 18-65 years had an RRMS diagnosis < 3 years prior to screening, an Expanded Disability Status Scale (EDSS) score ≤ 4.0, and anti-JCV antibody negative status. Magnetic resonance imaging was performed at baseline and yearly thereafter. Cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were evaluated at 2 years. NEDA (no 24-week-confirmed EDSS worsening, no relapses, no gadolinium-enhancing lesions, and no new/newly enlarging T2-hyperintense lesions) was evaluated over 2 years. The Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Score (MSIS-29) were assessed at baseline and 1 and 2 years. Statistical analysis used summary statistics and frequency distributions., Results: The study population (N = 222) had early RRMS, with mean (standard deviation [SD]) time since diagnosis of 1.6 (0.77) years and mean (SD) baseline EDSS score of 2.0 (1.13). NEDA was achieved in 105 of 187 patients (56.1%) during year 1 and 120 of 163 (73.6%) during year 2. Over 2 years, 76 of 171 patients (44.4%) attained overall NEDA. Probabilities of 24-week-confirmed EDSS worsening and improvement were 14.1% and 28.4%, respectively. After 2 years, patients exhibited significant improvements from baseline in SDMT (n = 158; mean [SD]: 4.3 [11.8]; p < 0.001) and MSIS-29 physical (n = 153; mean [SD]: - 3.9 [14.7]; p = 0.001), psychological (n = 152; mean [SD]: - 2.0 [7.9]; p < 0.001), and quality-of-life (n = 153; mean [SD]: - 6.0 [21.3]; p < 0.001) scores., Conclusions: These results support natalizumab's effectiveness over 2 years, during which nearly half of early RRMS patients achieved NEDA. During year 2, nearly 75% of patients exhibited NEDA. Over 2 years, patients continued to experience significant cognitive and quality-of-life benefits. These results are limited by the lack of a comparator group to determine the extent of a placebo effect., Trial Registration: clinicaltrials.gov, NCT01485003 , registered 5 December 2011.

Background: NTZ is approved in Russia for the treatment of highly active relapsing remitting multiple sclerosis and is reimbursed via federal budget program. However, no data about NTZ treatment in Russia and the effect of federal reimbursement have been performed so far., Objective: To characterize the population of patients receiving natalizumab and assess the efficacy and risk-management plan (RMP) implementation of NTZ therapy in routine clinical practice in Russia., Methods: We analyzed data for 334 patients, who received at least one infusion of NTZ. Relapse rate, MRI activity, NEDA-3 status after 2 years were assessed. Anti-JC virus antibodies status and RMP implementation were evaluated. Drop-out rate and reasons for therapy discontinuation were analyzed., Results: Patients switched to natalizumab in Russia are mainly female (63%), with median EDSS score of 3.5 and high disease activity: 93% had at least 1 relapse and 58% had both T1Gd+ and new T2 lesion a year before therapy initiation. Introduction of federal reimbursement allowed patients with less relapses to start therapy with natalizumab. The only predictor of 6-month progression was EDSS score at the baseline of therapy (HR = 2.1375, 95%CI 1.0026-4.5570, p = 0.0492). 82% patients reached NEDA-3 at 24 month of therapy. 25% of patients discontinued NTZ for reasons: tolerability (14.5%), JCV antibody status (61%), and patient's decision (17%). RMP was implemented in only 36% patients., Conclusion: Natalizumab appeared to have high efficacy in Russian clinical practice. Federal reimbursement allowed less active patients to start natalizumab. More efforts should be done to improve RMP implementation., Competing Interests: E.Evdoshenko has received honoraria for lectures and speaking in the past 2 years from Merck, Biogen, Roche, Johnson & Johnson, Novartis, GlaxoSmithKline, Sanofi, Genzyme, Generium. A.Stepanova has nothing to declare. M.Shumilina has received honoraria for consulting services in the field of scientific and educational activities (educational services, scientific articles, participation in expert councils, participation in clinical trials, etc.) in the past 2 years from Roche, Johnson & Johnson/Janssen, Genzyme/Sanofi, Novartis, Generium. M.Davydovskaya has received honoraria for lectures from Janssen, Roche, Sanofi, Biogen, Novartis, Merck, Biocad, Generium. N.Khachanova has received honoraria for participation in clinical trials from Actelion Pharmaceuticals, Generium, TG Therapeutics, Osmotica Pharmaceuticals US LLC, Sanofi-Aventis, Rosh, Novartis, Biogen, Teva, Octapharma AG. N.Neofidov has received honoraria for lectures and speaking in the past 2 years Genzyme/Sanofi. I.Kalinin has nothing to declare. E.Popova has received honoraria for consulting services in the field of scientific and educational activities (educational services, scientific articles, participation in expert councils, participation in clinical trials, etc.) in the past 2 years from Roche, Johnson & Johnson/Janssen, Sanofi, Biocad, Generium. E.Dubchenko has nothing to declare. N.Pozhidaeva has nothing to declare. A.Volkov has received honoraria for lectures from Janssen S.Sivertseva has received honoraria for lectures and speaking in the past 2 years from Merck, Biogen, Roche, Johnson & Johnson, Novartis, GlaxoSmithKline, Sanofi, Genzyme, Generium. A.Prilenskaya has nothing to declare. N.Malkova has received honoraria as member of working groups, advisory boards, and participated in clinical trials supported by Biogen / Janssen, Merck, Teva, Novartis, Sanofi-Genzyme, Cellgene, Biocad, Generium. D.Korobko participated in clinical trials supported by Biogen, Teva, Novartis, Sanofi-Genzyme, Cellgene, Biocad, Generium. I.Vergunova participated in clinical trials supported by Biogen, Teva, Novartis, Sanofi-Genzyme, Cellgene, Biocad. S.Shchur has nothing to declare. G.Makshakov has received honoraria for lectures and speaking in the past 2 years from Roche, Johnson & Johnson/Janssen and Genzyme. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Long-term treatment of multiple sclerosis with natalizumab (NTZ) carries the risk of a devastating complication in the form of an encephalopathy caused by a reactivation of a latent John Cunningham virus infection (progressive multifocal leucoencephalopathy, PML). Early diagnosis is associated with considerably better prognosis. Quantitative EEG as an objective, rater-independent technique provides high sensitivity (88%) and specificity (82%) for the diagnosis of NTZ-PML. Combination of diagnostic modalities addressing static morphological (brain MRI) as well as functional (EEG) pathologic changes may improve risk management programmes.

Background: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus-positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0-3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months., Objective: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts., Methods: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6-8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment., Results: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4-32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity., Interpretation: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus-positive patients remains uncertain.

Aim: In active relapsing remitting multiple sclerosis (RRMS) patients requiring second-line treatment, the Dutch National Health Care Institute (ZiN) has not stated a preference for either alemtuzumab, fingolimod, or natalizumab. The aim was to give healthcare decision-makers insight into the differences in cost accumulation over time between alemtuzumab-with a unique, non-continuous treatment schedule-and fingolimod and natalizumab for second-line treatment of active RRMS patients in the Netherlands., Methods: In line with ZiN's assessment, a cost-minimization analysis was performed from a Dutch healthcare perspective over a 5-year time horizon. Resource use was derived from hospital protocols and summaries of product characteristics, and validated by two MS specialists. Unit costs were based on national tariffs and guidelines. Robustness of the base case results was verified with multiple sensitivity and scenario analyses., Results: Alemtuzumab results in cost savings compared to fingolimod and natalizumab from, respectively, 3.3 and 2.8 years since treatment initiation onwards. At 5 years, total discounted costs per patient of alemtuzumab were €79,717, followed by fingolimod with €110,044 and natalizumab with €122,238, resulting in cost savings of €30,327 and €42,522 for alemtuzumab compared to fingolimod and natalizumab, respectively. Key drivers of the model are drug acquisition costs and the proportions of patients that do not require further alemtuzumab treatment after either two, three, or four courses., Limitations: No treatment discontinuation and associated switching between treatments were incorporated. Consequences of JC virus seropositivity while continuing natalizumab treatment (e.g. additional monitoring) were omitted from the base case., Conclusion: The current cost-minimization analysis demonstrates that, from the Dutch healthcare perspective, treating active RRMS patients with alemtuzumab results in cost savings compared to second-line alternatives fingolimod and natalizumab from ∼3 years since treatment initiation onwards. After 5 years, alemtuzumab's cost savings are estimated at €30k compared to fingolimod and €43k compared to natalizumab.

Background: Different retrospective studies compared natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS), with conflicting results. We aimed to explore the prescriptive attitude and the clinical outcome of the two therapies., Methods: We retrospectively included all RRMS patients treated with natalizumab (n=101) or fingolimod (n=78) as their first second-line therapy with at least 24-month follow-up. Demographic and clinical features were recorded to calculate the propensity score (PS). Outcomes of interest were annualized relapse rate (ARR), risk of relapse, and change in the EDSS RESULTS: At baseline, natalizumab patients were younger and had a shorter disease duration, a higher number of relapse in 1 year (1yR) and 2 years (2yR) and overall (ARR-PT) pretherapy, compared to fingolimod patients. On therapy, the proportion of relapsing patients and the mean RR were similar in the two groups. However, the change in the ARR was higher in natalizumab than in fingolimod group (P<.002), but, using PS as a covariate, it was comparable (P=.960). Similarly, the change in EDSS was significantly different for the two groups (P<.004), but not after adjusting for the PS (P=.321)., Conclusion: We observed a comparable efficacy on ARR reduction and on EDSS progression with natalizumab and fingolimod correcting through PS, suggesting that the efficacy difference observed before correction might derive from the clinical attitude in prescribing natalizumab in more active MS patients in real life., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Natalizumab is a humanized monoclonal antibody highly effective in relapsing-remitting multiple sclerosis (MS). Important concerns about its safety have been pointed out mainly because of the risk of progressive multifocal leukoencephalopathy (PML), caused by the opportunistic John-Cunningham virus (JCV). Areas covered: This review analyzes all the safety aspects related to the use and safety of natalizumab in MS patients. Other than PML, post-marketing, safety red-flags have been reported, as liver or haematological serious adverse events. Pregnancy evidences will be pointed out. The risk of PML depends on: concomitant or previous immunosuppression, exposure duration, anti-JCV antibody level. In natalizumab-related PML the average survival is 77%; prognostic features and information for the earliest identification of PML have been identified to maximally reduce its incidence, mortality and morbidity. Expert opinion: Natalizumab is a highly effective drug for MS patients but its safety issues represent a relevant limitation and impose strict clinical surveillance of treated patients. Some post-marketing safety red-flags have been pointed out, with higher attention to severe liver failures and limphoma cases. If PML and its consequences are considered the most relevant issues, a continuous surveillance must be maintained also regarding other possible SAEs like liver diseases and malignancies.

Aim: Studies on multiple sclerosis in Saudi Arabia remain scant, particularly studies on the psychological aspects. This study measures severities of depression, anxiety and stress, and compares them to the used disease-modifying treatment., Materials & Methods: Cross-sectional study using a phone questionnaire targeting 452 Saudi patients with relapsing-remitting multiple sclerosis following in King Khalid University Hospital, King Fahad Medical City or Security Forces Hospital., Results: From 235 patients, 149 used interferons, 58 used fingolimod and 28 used natalizumab. Depression scores were similar among all demographic and drug groups. Interferons versus fingolimod anxiety scores were significantly different (p = 0.035). Stress scores were within normal limits., Conclusion: Mild anxiety was higher among interferon users, which could be due to injection anxiety reasons.

Background: In recent years, a small but increasing number of neurologists choose to extend dose intervals of natalizumab with the aim of reducing the risk of progressive multifocal leukoencephalopathy (PML). This idea is based on the hypothesis that high drug concentrations increase the risk of PML., Objective: We investigated the relation between longitudinal natalizumab concentrations in patients who developed PML and patients who did not develop PML., Methods: In a prospective observational cohort study of 219 patients with relapsing-remitting multiple sclerosis treated with natalizumab, serum samples were taken every 12 weeks prior to natalizumab infusion. In this cohort, 5 patients developed PML and were matched with 10 patients from the cohort who did not develop PML. Natalizumab concentrations were measured in available samples, and the longitudinal results were compared between the two patient groups., Results: Mean natalizumab concentrations in the five patients developing PML was 18.9 µg/mL (standard deviation (SD): ±13.4) versus 23.8 µg/mL (SD: ±11.5) of the control patients. Furthermore, we did not observe a clear rise in concentration levels in patients subsequently developing PML., Conclusion: Our results provide preliminary evidence that contradicts the hypothesis that exposure to elevated concentrations of natalizumab is a relevant risk factor of developing PML.

Aim: To compare the cost-effectiveness of different disease-modifying therapies' strategies for treatment of relapsing-remitting multiple sclerosis., Methods: A Markov model was developed to assess the cost-effectiveness and incremental cost-effectiveness ratios for different strategies of using disease-modifying therapies from a US third-party payer perspective. All costs were converted to 2014 US$., Results: Over 20 years, the total costs per patient were estimated at US$161,136.60 for Strategy 1 (symptom management [SM] alone), US$551,650.66 for Strategy 2 (SM and IFN-β-1a), US$703,463.60 for Strategy 3 (SM and natalizumab) and US$670,985.24 for Strategy 4 (SM and alemtuzumab). The accumulated quality-adjusted life years were 10.49, 10.66, 10.69 and 10.71 for each of the four Strategies 1-4, respectively. The resulting incremental cost-effectiveness ratios were 2,297,141.53 comparing Strategy 2 to Strategy 1, and -1,623,918.00 comparing Strategy 4 to Strategy 3., Conclusion: Strategy 1 was the cost-effective strategy for treatment of relapsing-remitting multiple sclerosis when compared with other strategies.

We herein report the case of a 57-year-old woman presenting with a biopsy-proven tumefactive demyelinating lesion as her first clinical event. Subsequently, she displayed a relapsing-remitting course with recurrence of large demyelinating lesions exceeding 2 cm in diameter rather than the small ovoid lesions characteristic of multiple sclerosis. Administration of interferon beta did not suppress the disease activity. Finally, treatment with natalizumab, which is a humanized monoclonal antibody against the cell-adhesion molecule α4-integrin, was initiated, resulting in clinical and radiological stabilization. Our experience here suggests that natalizumab may be an effective therapeutic option for relapsing-remitting tumefactive multiple sclerosis with high disease activity.

: Acute coronary syndrome represents one of the most common causes of admittance to emergency rooms in Western countries. Despite being in the majority of cases the mirror of coronary atherosclerosis, more rare causes could be hidden beyond this presentation, whose identification is often crucial for patients' outcome. We hereby present the case of a 44-year-old woman, with a history of relapsing-remitting multiple sclerosis in treatment with natalizumab, who was admitted to our division for an acute coronary syndrome. At arrival, anaemia and severe thrombocytopenia were observed; thus, no antiplatelet agent was administered. Within a few hours, aphasia occurred. Clinical presentation and the identification of schistocytes at blood smear led to the suspicion of thrombotic thrombocytopenic purpura, which was then confirmed by laboratory analysis. Immediate high-dose steroids and plasma exchange allowed discharging of the patient within a few days without neurological or cardiac sequelae.

Background: Microglia-mediated proteolysis of the triggering receptor expressed on myeloid cells-2 (TREM-2) produces soluble TREM-2 (sTREM-2) that can be measured in cerebrospinal fluid (CSF) samples. Loss-of-function mutations in TREM2 or in the gene encoding its adaptor protein cause the rare Nasu-Hakola disease (NHD). Multiple sclerosis (MS) is an autoimmune disease that in common with NHD is characterized by demyelination and microglial activation., Objective: To investigate the potential utility of sTREM-2 as a biomarker for MS and to follow treatment effects., Methods: sTREM-2 was analyzed in CSF samples from subjects with MS (N = 59); relapsing-remitting MS (RRMS) (N = 36), secondary progressive MS (SPMS) (N = 20) and primary progressive MS (PPMS) (N = 3), and controls (N = 27). CSF levels of sTREM-2 were also assessed before and after treatment of patients with natalizumab or mitoxantrone., Results: CSF levels of sTREM-2 were significantly increased in patients with RRMS, SPMS, and PPMS compared with controls. After natalizumab treatment, the levels of sTREM-2 were normalized to control levels. The levels of sTREM-2 were also reduced after mitoxantrone treatment., Conclusion: Increased CSF levels of sTREM-2, a new marker of microglial activation, in MS and normalization upon treatment with either natalizumab or mitoxantrone support a role for microglial activation in active MS., (© The Author(s), 2016.)

Purpose of Review: This article provides an evidence-based approach to the management of patients with early relapsing multiple sclerosis (MS)., Recent Findings: Numerous clinical trials have shown the role of disease-modifying therapies in reducing relapses and new MRI lesions in patients with relapsing MS. Many of these trials also show the ability of these agents to delay disability progression, and a few suggest that disease-modifying therapies may slow brain atrophy in relapsing MS; however, very few suggest that disease-modifying therapies can improve symptoms or disability. The therapeutic armamentarium of disease-modifying therapies includes five interferon formulations, two versions of glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, and alemtuzumab., Summary: Although multiple disease-modifying therapies exist, the risks of these vary markedly, head-to-head comparator trials are limited, and no prospective biomarkers for treatment efficacy exist; therefore, choosing a disease-modifying therapy for an individual patient with MS is a difficult decision. This difficulty is compounded by limitations in predicting a patient's disease course, and the risk tolerance of the patient and opinions of the care partner need to be factored into the decision analysis as well. After a disease-modifying therapy is chosen, vigilance for clinical or radiographic breakthrough disease is very important, as this may suggest a suboptimal response to the chosen therapy. Furthermore, the role of symptom management and wellness should always remain part of the approach to the patient with MS.

Aims: The main aim of this study was to verify the effect of natalizumab on the levels of circulating catecholamines and indolamine and their possible relation with MS., Methods: For this purpose, 12 healthy individuals (control group) and 12 relapsing-remitting multiple sclerosis patients (RR-MS) were selected. The patients were treated with 300 mg of natalizumab during 56 weeks (1 dose/4 weeks) (MS-56). This selection was based on the McDonalds revision criterion and scheduled to star treatment with natalizumab. Blood samples were taken before treatment (basal level) and after 56 weeks of using natalizumab. Melatonin was measured in serum and in plasma, catecholamines (dopamine, epinephrine, and norepinephrine), carbonylated proteins, 8-hydroxy-2'deoxyguanosine (8OH-dG) and the ratio reduced glutathione/oxidised glutathione (GSH/GSSG)., Results: The epinephrine and dopamine levels diminished in the basal group with respect to the control and did not recover normal levels with the treatment. The melatonin was decreased in RR-MS patients and went back to its normal levels with natalizumab. Norepinephrine was increased in RR-MS and decreased in MS-56 until it equalled the control group., Conclusion: Natalizumab normalizes altered melatonin and norepinephrine levels in MS.

Aim: To evaluate the effect of natalizumab on progression of brain atrophy in multiple sclerosis (MS) patients and to search for a clinical or radiological marker of progression of brain atrophy., Patients and Methods: We retrospectively recorded demographic and clinical data, as well as the corpus callosum index (CCI) using MRI, in MS patients treated with natalizumab for 1-4 years., Results: In the study population (n = 29), baseline mean CCI was 0.37 ± 0.04 and final CCI 0.36 ± 0.04. 17 patients did not develop brain atrophy during follow-up. There was no statistically significant relationship between progression of atrophy and clinical and radiological parameters., Conclusion: Natalizumab may have a neuroprotective effect.

Background: The evidence on the use of the oral dimethyl-fumarate after the discontinuation of treatment with natalizumab in people with Multiple Sclerosis is still little. Natalizumab discontinuation may induce the recurrence or rebound of the clinical and neuroradiological disease activity. Currently no therapeutic approach has been established to abolish disease reactivation and rebound after natalizumab interruption., Case Presentation: We describe a case of a 21-year-old woman affected from a highly active relapsing-remitting Multiple Sclerosis who developed a clinical and radiological rebound 5 months after the last infusion of natalizumab, while she was being treated with dimethyl-fumarate 240 mg twice daily. She had received a bridge "therapy" with Cyclophosphamide before staring dimethyl-fumarate., Conclusion: We report on this case to stimulate further research to establish whether new current and future drugs available for multiple sclerosis are able to halt the disease rebound after the natalizumab interruption.

A risk for developing progressive multifocal leukoencephalopathy is a major barrier to natalizumab use. Extended dosing intervals have been proposed as a way to maintain therapeutic efficacy and reduce progressive multifocal leukoencephalopathy incidence. This is the first reported case of progressive multifocal leukoencephalopathy in a patient using an extended dosing regimen (300 mg/6 weeks). A close clinical and imaging monitoring allowed early detection, which is a major prognostic factor. A favorable outcome was seen with a therapy comprising plasma exchange therapy, mirtazapine, mefloquine and cidofovir. Further studies will be needed to assess the potential role of extended dosing intervals to improve prognosis in patients receiving natalizumab and also to measure its impact clinically and/or radiologically.

Background and Purpose: Natalizumab discontinuation induces the recurrence of multiple sclerosis disease activity: currently no therapeutic approach has been found able to abolish disease reactivation., Methods: The recurrence of disease activity after natalizumab discontinuation was retrospectively evaluated in 79 patients who had been treated with immunomodulating agents, other first-line therapies, fingolimod or not treated., Results: No differences have been found in clinical or magnetic resonance imaging recurrence of disease activity amongst the groups. Interestingly, no disease reactivation was observed only in one patient treated for 6 months with monthly pulses of cyclophosphamide., Conclusion: Disease modifying treatment or 'no treatment' is unable to abolish disease activity reactivation after natalizumab discontinuation., (© 2014 The Author(s) European Journal of Neurology © 2014 EAN.)

Natalizumab (NTZ) is extremely effective in reducing disease activity in multiple sclerosis (MS) patients but its long-term use is associated with the risk of progressive multifocal leukoencephalopathy (PML). Thus, many patients discontinue NTZ and, after drug withdrawal, most of them face disease reactivation despite immunomodulant (IMD) start. The aim of this study was to evaluate the efficacy of different therapeutic strategies in preventing post-NTZ disease recurrence in a small cohort of patients that underwent repeated NTZ courses. 15 patients underwent two distinct NTZ discontinuations and started IMD after first withdrawal and a second line therapy (mainly fingolimod, FTY) after the second one. They were followed with periodic clinical and neuroradiological evaluations. All patients showed disease reactivation after first withdrawal and 13 out of 15 relapsed after the second one. In both the occasions annualized relapse rate (ARR) significantly increased as compared to on-treatment period (from 0.03 to 1.5 and from 0.26 to 1.71) with no differences between the two NTZ-free periods. Likewise, the mean number of Gd enhancing lesions increased both times to similar values (3.1 and 2.9). Median time to disease recurrence was comparable (4.7 and 5.7 months, p = 0.57). This study demonstrated recurrence of disease activity after two distinct NTZ discontinuations despite the treatment with IMD or more aggressive therapy, when used according to recent safety recommendations. Therefore, we need different therapeutic strategies to cope with the risk of post-NTZ disease recurrence and a "bridging strategy" with an earlier switch to second line drugs should be taken into account.

Background: Natalizumab disease-modifying therapy for relapsing-remitting multiple sclerosis (MS) is efficacious in randomized controlled trials. Few studies have estimated the association between real-world natalizumab persistence behavior and relapse-related outcomes., Objectives: To (a) examine the impact of using natalizumab consistently (i.e., persistent) on relapse-related outcomes as compared with transitioning to inconsistent natalizumab use (i.e., nonpersistent) and (b) examine the impact of other treatment patterns on relapse-related outcomes for those who initiated natalizumab., Methods: Using the IMS PharMetrics Plus claims database (years 2006-2012), we identified MS subjects who initiated natalizumab (no natalizumab claims in year prior) and had at least 2 years of follow-up. Persistence in annual follow-up periods was defined as no 90-day or greater gap in natalizumab therapy. Relapse was an MS-related hospitalization or outpatient visit with intravenous or oral steroid burst claim within 7 days. Analyses compared observations based on changes in natalizumab persistence and natalizumab nonpersistence status from 1 year to the next (e.g., transitioning from persistent to nonpersistent), estimating differences in mean annual relapses and mean annual relapse-related costs., Results: A total of 2,407 natalizumab initiators had at least 2 years of follow-up, yielding 4,770 year-to-year natalizumab treatment patterns where each subject contributed 1, 2, or 3 year-to-year treatment patterns. In the year prior, 3,187 treatment patterns were persistent; 731 (22.9%) of these transitioned to nonpersistence. The remaining 1,583 treatment patterns were nonpersistent in the year prior; 132 (8.3%) of these transitioned to persistence. Persistent to nonpersistent treatment patterns were associated with a mean relapse-rate increase of 0.23 (95% CI = 0.12, 0.35), and a mean increase in relapse-related costs of $1,346 (95% CI = $97, $2,595). Nonpersistent to persistent treatment patterns were associated with a mean relapse-rate decrease of -0.15 (95% CI = -0.32, 0.017) and a mean decrease in relapse-related costs of -$1,369 (95% CI = -$2,761, $23)., Conclusions: Findings suggest that real-world persistent natalizumab users who become nonpersistent have statistically significant increases in annual relapses and relapse-related costs. Those who transition from nonpersistent to persistent have nonsignificant reductions in relapses and their associated costs.

Background and Purpose: Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing-remitting multiple sclerosis, could impact ambulation performance was examined., Methods: A prospective open-label study, TIMER, was conducted in natalizumab-naive patients (n = 215). The timed 25-foot walk (T25FW) and timed 100-m walk (T100MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25FW performance were also examined in a retrospective analysis of natalizumab-treated patients (n = 627) and placebo control patients (n = 315) from the AFFIRM study., Results: In TIMER, a significant increase from baseline in T25FW speed was seen at week 24 (P = 0.0074) and in T100MW speed at weeks 24 and 48 (both P < 0.001). A greater proportion of patients showed clinically meaningful increases (≥20%) in walking speed on the T100MW (25%) than on the T25FW (13%) at week 48 (P = 0.032). In AFFIRM, natalizumab increased the proportion of patients with ≥20% confirmed improvement in T25FW speed at year 2 by 78% versus placebo (P = 0.0133)., Conclusions: Natalizumab increased walking speed in patients with relapsing-remitting multiple sclerosis. The T100MW may be more sensitive to changes in ambulation capacity than the T25FW, and both tests appear to detect clinically meaningful improvements in ambulatory function., (© 2014 Biogen Idec. European Journal Of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening (n = 175) were randomized 1:1:2 to continue natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during natalizumab interruption did not exceed pre-natalizumab levels or levels seen in historical control patients.

Multiple sclerosis (MS) patients treated with natalizumab have a significant reduction in annualized relapse rate; in these patients, a relapse is uncommon but not unexpected. In contrast, the appearance of a severe exacerbation is striking and requires the differential diagnosis with progressive multifocal leukoencephalopathy. Here, we describe a case of a 22-year-old woman with relapsing-remitting MS who developed an unexpected response after the patient׳s fifth natalizumab infusion with an aggressive radiological and clinical evolution. Changing the patient׳s treatment to fingolimod resulted in the absence of new clinical relapses and the absence of active lesions on brain magnetic resonance images (MRI) during the first 12 months of follow-up. We hypothesize that the appearance of natalizumab antibodies in this patient triggered lymphocyte migration to the central nervous system in a rebound phenomenon; this is similar to what occurs during immune reconstitution inflammatory syndrome (IRIS) after removal of natalizumab., (Copyright © 2014 Elsevier B.V. All rights reserved.)