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Background: Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets., Methods: We performed a cross sectional study on PB B cells in MS patients treated with interferon-β (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++)., Results: Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-β treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages., Conclusion: Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-β and fingolimod treated patients which might contribute to the drugs' mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: C.L. Kemmerer: reports no disclosures. V. Pernpeitner: reports no disclosures. C. Ruschil: reports no disclosures. A. Abdelhak: received research funding from the German multiple sclerosis society (DMSG) as well as travel grants from Teva and Novartis all not related to this work. M. Scholl: reports no disclosures. U. Ziemann: UZ has received honoraria from Biogen Idec GmbH, Bayer Vital GmbH, Bristol Myers Squibb GmbH, Pfizer, CorTec GmbH, Medtronic GmbH, and grants from European Research Council, German Research Foundation, German Ministry of Education and Research, Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV, all not related to this work. M. Krumbholz: receives financial support from Sanofi-Genzyme, Merck, Novartis, Biogen, Celgene and Roche, not related to this study. B. Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Desitin; holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. M.C. Kowarik: receives financial support from Merck, Sanofi-Genzyme, Novartis, Biogen, Celgene and Roche, not related to this study. The competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

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.

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.

Background: Natalizumab (NTZ) is a drug that has been widely used in the treatment of multiple sclerosis (MS). NTZ is very effective in suppressing inflammation, but if treatment is suspended many patients will experience relapses., Objective: To investigate if quantification of γδ T cells and HLA-DR+ NK cells could predict early disease reactivation after NTZ suspension., Methods: Absolute counts of γδ T cells and HLA-DR+ NK cells in whole blood were determined with flow cytometry in fifteen patients treated with NTZ. NTZ treatment was then withdrawn and patients were followed with clinical visits and MR investigations., Results: Patients with recurrent disease had higher absolute counts of γδ T cells 129 (±156) cells/μl in comparison to patients with stable disease 50.0 (±51.0) cells/μl but the difference was not statistically significant and largely driven by outliers. Patients with recurrent and stable disease had similar absolute counts of HLA-DR+ NK cells., Conclusion: Quantification of γδ T cells and HLA-DR+ NK cells could not predict active disease after NTZ suspension.

Background: Progressive multifocal leukoencephalopathy (PML) is one of the major risks of natalizumab therapy. Despite introduction of the currently employed PML risk stratification algorithm, the incidence of natalizumab-associated PML cases is not decreasing., Objectives: We addressed the following questions: How do natalizumab-treated multiple sclerosis patients and their treating physicians assess and deal with PML risk? Is PML risk the real reason for natalizumab discontinuation?, Methods: 699 natalizumab-treated multiple sclerosis patients and 99 physicians were included in this prospective observational study. Questionnaires were completed at 5 different time points. Patients were stratified into 5 subgroups according to the presence of PML risk factors (prior immunosuppression, anti-JCV antibody status, treatment duration). Patients with prior immunosuppression (n = 30, treated by n = 7 physicians) were excluded from analyses, because patient numbers were too small. Patients' anti-JCV antibody index was not considered because data recruitment ended in 2014. Using Bayesian network and regression analysis, we examined the relationship between different patient- and physician-related factors and patients' discontinuation of natalizumab., Results: Patients of all subgroups and physicians assessed the PML risk as low. Overall patient adherence to natalizumab was high (87%). Only 13% of patients discontinued therapy. Natalizumab treatment cessation was associated with different patient- and physician-related factors (physicians' assessment of general PML risk, number of treated patients per year, natalizumab treatment duration, relapses during the course of study) upon which only physicians' judgment on treatment continuation, patients' perception of personal PML risk, and JCV seroconversion showed significant relationships., Conclusion: According to the currently employed risk stratification algorithm, the objective PML risk probably doesn't play a dominant role in a patients' decision to continue or stop natalizumab treatment. The decision-making process is rather guided by subjective views and experiences of patients and treating neurologists. Treating physicians should consider this discrepancy in their advice to improve the risk-benefit-ratio for the individual patient.

Background: In people with multiple sclerosis treated with interferon-beta or glatiramer acetate, new MRI lesions and relapses during the first year of treatment predict a poor prognosis., Objective: To study this association in those receiving natalizumab., Methods: Data were collected on relapses, new MRI activity, and Modified Rio Score after initiation of natalizumab in an observational cohort of 161 patients with high baseline disability. These were correlated with Expanded Disability Status Scale (EDSS) progression at years 1, 2, 3, and 3-7 after treatment initiation, versus pre-treatment baseline., Results: 46/161 patients had a relapse in the first year and 44/161 had EDSS progression by year 2. Relapses and Modified Rio Score in the first year of treatment predicted EDSS progression at year 1 and 2 after treatment initiation. However, this effect disappeared with longer follow-up. Paradoxically, there was a trend towards inflammatory activity on treatment (first year Modified Rio Score, relapses, and MRI activity) predicting a lower risk of EDSS progression by years 3-7, although this did not reach statistical significance. Those with and without EDSS progression did not differ in baseline age, EDSS, or pre-treatment relapse rate. Relapses in year 0-1 predicted further relapses in years 1-3., Conclusions: Breakthrough inflammatory activity after natalizumab treatment is predictive of short-term outcome measures of relapses or EDSS progression, but does not predict longer term EDSS progression, in this cohort with high baseline disability., Competing Interests: This study received no specific funding or sponsorship. Dr. Raffel, Dr. Gafson, Dr. Dahdaleh, and Dr. Jones declare that there is no conflict of interest and report no disclosures. Dr. Malik has received travel grants to educational meetings from Biogen Idec and honoraria from Biogen Idec, which have been used exclusively for clinical research, outside the submitted work. Dr. Nicholas has received grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Biogen Idec, personal fees from Genzyme, personal fees from Roche, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV)., Objective: To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions., Methods: An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated., Results: Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01)., Conclusion: Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Prosperini declares received consulting fees from Biogen and Novartis; speaker honoraria from Biogen, Genzyme, Novartis and Teva; travel grants from Biogen, Genzyme, Novartis and Teva; research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and Genzyme. Dr. Prosperini also acts as member of steering committee AIFA (Agenzia Italiana del Farmaco) on natalizumab. Dr. De Rossi received speaker honoraria from Biogen and Teva and travel grants from Biogen, Teva and Merk Serono. Dr. Scarpazza has nothing to disclose. Dr. Moiola received honoraria for speaking or for advisory board from Sanofi-Genzyme, Biogen, Novartis and Teva. Dr. Cosottini received speaker honoraria from Biogen. Dr. Gerevini received speaker honoraria from Biogen. Dr. Capra received consulting fees from Novartis and Biogen, and lecture fees and/or travel grants from Novartis, Biogen, Genzyme and Sanofi-Aventis.

MicroRNAs fine-tune the regulation of Th1/Th17 lymphocyte subsets in multiple sclerosis. We investigated the expression of miRNAs (previously associated with mycobacterial and viral infections) in MS patients and healthy donors (HD) following 6 months natalizumab therapy. In addition, Th1/Th17 cytokines and the presence of anti-EBNA1/VCA IgG in MS patients with different pattern of miRNA expression have been evaluated. MiR-155, miR-26a, miR-132, miR-146a and Th1/Th17 cytokines expression was detected by RT-real time PCR; moreover anti-EBNA1 and VCA IgG titres were measured by ELISA. We observed an up-regulation of miR-155 (p value = 0.009) and miR-132 (p value = 0.04) in MS patients compared to HD. In MS patients, IL-17a (p = 0.037), IFN γ (p = 0.012) and TNFα (p = 0.015) but not IL-6 were over-expressed compared to HD. Two different miRNAs patterns associated to the expression of different cytokines were observed in the MS cohort. Moreover, a down-regulation of miR-155 and miR-26a was seen in MS patients during and after natalizumab therapy. MS patients that over-expressed miR-155 showed a higher EBNA1 IgG titer than MS patients with high levels of miR-26a. In conclusions the expression of particular miRNAs modulates the pro-inflammatory cytokine expression and the humoral response against EBV and this expression is natalizumab regulated.