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Back ground and purpose. The development of neutralizing antibodies (NAbs) against interferon beta (IFN-β) during IFN-β treatment in multiple sclerosis (MS) patients has been a significant clinical problem. Persistent, high-titer NAbs-IFN-β reduce or eliminate biological activity of IFN-β therapies for MS and are associated with reduction in efficacy. Therapeutic plasma exchange (TPE) removes the circulating antibodies that are thought to be active in the diseases, so we hypothesized that TPE can restore the ability of IFN-β to induce the Myxovirus Resistance Protein A (MxA) mRNA expression and the maintenance plasmapheresis can sustain the bioavailability of IFN-β. Methods. Eligible patients under went primarily four separate plasma exchange sessions and after the induction TPE sessions they were transferred to the maintenance plasma pheresis. Bioactivity of interferon beta was expressed as in vivo MxA mRNA induction in whole blood using real time PCR. Results. Six patients with RRMS and low IFN-β bioavailability detected by the MxA mRNA response were included. Four patients after induction plasmapheresis be came biological responders. In two patients an in crease of MxA mRNA expression was found, but the values persisted be low the cut-off and the patients remained as "poor biological responders". The effect of maintenance plasmapheresis was quite transient: MxA mRNA expression values reverted to the base line levels after one or two months. Conclusion. Plasma exchange may restore the bioavailability of IFN-β in some patients, but the effect of maintenance plasmapheresis on the bioavailability of IFN-β is transient. [ABSTRACT FROM AUTHOR]

Detection of neuronal antibodies for autoimmune encephalitis and paraneoplastic neurological syndromes relies on commercially available cell-based assays and lineblots. However, lineblots may reveal the presence of neuronal antibodies in patients with various non-autoimmune etiologies. Herein we describe patients with non-autoimmune etiologies (cohort B) and detectable neuronal antibodies and compare them to definite cases of autoimmune encephalitis (cohort A) for differences in clinical data. All patients positive for at least one neuronal antibody were retrospectively evaluated for autoimmune encephalitis and/or paraneoplastic neurological syndrome between 2016 and 2022. 39 cases in cohort B and 23 in cohort A were identified. In cohort B, most common diagnoses were neurodegenerative disorders in 9/39 (23.1%), brain tumors in 6/39 (15.4%) while most common detected antibodies were anti-titin (N10), anti-recoverin (N11), anti-Yo (N8) and all were detected in serum only. Differential aspects between cohort A and B were CSF pleocytosis (14/23 (60.8%) vs 11/35 (31.4%), p = 0.042, respectively), MRI features suggestive of encephalitis (6/23 (26.1%) vs 0 (0%), p = 0.002, respectively) and epilepsy restricted to temporal lobes (14/23 (60.9%) vs 2/30 (6.7%), p = 0.0003, respectively). A large proportion of lineblot results were non-specific when only serum was tested and were frequently found in non-autoimmune neurological conditions., (© 2024. The Author(s).)

Objective: To assess the differences of treatment outcomes regarding disease activity in patients with highly active relapsing multiple sclerosis (RMS), treated with autologous hematopoietic stem cell transplantation (HSCT) or alemtuzumab (ATZ)., Methods: Open-label prospective single-center observational cohort study, enrolling patients with highly active RMS for treatment with ATZ or HSCT between 2014 and 2021., Results: A total of 50 patients (31/50 (62 %) in HSCT vs 19/50 (38 %) in ATZ group) were included. There were no significant differences in relapse rate, MRI activity or disability worsening between the two study groups during the first two years after treatment onset. However, at 3 to 5 years follow-up, HSCT was superior to ATZ in all the aforementioned aspects. Kaplan-Meier analysis at 5 years post treatment revealed superiority of HSCT in relapse rate (69.6 % vs 95.7 %, p = 0.027), MRI activity (54.5 % vs 75.1 %, p = 0.038) and disability worsening (57.1 % vs 90.9 %, p =  0.031)., Conclusions: ATZ may halt disability progression early in the course of highly active RMS, but the disability starts accumulating later, while in HSCT patients disability improvement is consistent both 3 and 5 years after treatment onset., Competing Interests: Declaration of Competing Interest M.V. Conception and design of the study, primary data analysis, drafting of the manuscript; G.F.K. Overall revision for accuracy of the data, tables and Figures, scientific accuracy of the manuscript; R.K. Concept of the study, revision of the manuscript for scientific accuracy; V.T. Data analysis, drafting of the manuscript, revision for scientific accuracy; N.G. conception and design of the study, acquisition of the data, analysis and interpretation of the data, and drafting of the manuscript, revision for scientific accuracy. All of the authors discussed the results and contributed to and approved the final manuscript., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, is approved in several countries for relapsing multiple sclerosis (RMS)., Objective: To demonstrate the bioequivalence of ofatumumab administered by an autoinjector versus a pre-filled syringe (PFS) and to explore the effect of ofatumumab on B-cell depletion., Methods: APLIOS (NCT03560739) is a 12-week, open-label, parallel-group, phase-2 study in patients with RMS receiving subcutaneous ofatumumab 20 mg every 4 weeks (q4w) (from Week 4, after initial doses on Days 1, 7, and 14). Patients were randomized 10:10:1:1 to autoinjector or PFS in the abdomen, or autoinjector or PFS in the thigh, respectively. Bioequivalence was determined by area under the curve (AUC τ ) and maximum plasma concentration ( C max ) for Weeks 8-12. B-cell depletion and safety/tolerability were assessed., Results: A total of 256 patients contributed to the bioequivalence analyses (autoinjector-abdomen, n = 128; PFS-abdomen, n = 128). Abdominal ofatumumab pharmacokinetic exposure was bioequivalent for autoinjector and PFS (geometric mean AUC τ , 487.7 vs 474.1 h × µg/mL (ratio 1.03); C max , 1.409 vs 1.409 µg/mL (ratio 1.00)). B-cell counts (median cells/µL) depleted rapidly in all groups from 214.0 (baseline) to 2.0 (Day 14). Ofatumumab was well tolerated., Conclusion: Ofatumumab 20 mg q4w self-administered subcutaneously via autoinjector is bioequivalent to PFS administration and provides rapid B-cell depletion.

Background: Brain atrophy, which is associated with cognitive impairment and retinal nerve fiber layer (RNFL) atrophy, is the main biomarker of neurodegeneration in multiple sclerosis (MS). However, data on the relationship between inflammatory markers, such as oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF), and cognition, RNFL atrophy, and brain atrophy are scarce. The aim of this study was to assess the influence of RNFL thickness, brain atrophy markers, intrathecal OCBs, and the immunoglobulin G (IgG) index on cognitive decline over a 5-year period in patients with MS. Methods: This prospective, single-center, observational cohort study included 49 patients with relapsing MS followed up over 5 years. At baseline, the patients underwent brain magnetic resonance imaging (MRI). Cognitive evaluation was performed using the Brief International Cognitive Assessment for MS (BICAMS), and RNFL thickness was assessed using optical coherence tomography (OCT). OCBs and IgG levels in the CSF were evaluated at baseline. The BICAMS, OCT, and MRI findings were re-evaluated after 5 years. Results: A significant reduction in information processing speed, visual learning, temporal RNFL thickness, the Huckman index, and third ventricle mean diameter was found in all 49 patients with relapsing MS over the observation period ( p < 0.05). Of the patients, 63.3% had positive OCBs and 59.2% had elevated IgG indices. The atrophy of the temporal segment and papillomacular bundle and the presence of OCBs were significantly related to a decline in information processing speed in these patients ( p < 0.05). However, brain atrophy markers were not found to be significant on the general linear models. Conclusions: RNFL atrophy and the presence of OCBs were related to cognitive decline in patients with MS over a 5-year follow-up period, thereby suggesting their utility as potential biomarkers of cognitive decline in MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Giedraitiene, Drukteiniene, Kizlaitiene, Cimbalas, Asoklis and Kaubrys.)

Background: Cognition may be affected at least as seriously as physical function during multiple sclerosis (MS) relapse, however MS relapse related cognitive disorders are still underdiagnosed and poorly characterized. The limited number of paper-pencil tests were used for assessment, and nevertheless, some significant changes were found. Unlike the paper-pencil tests, computerized batteries and tests are more sensitive and highly standardized, produce instant scoring and can minimize the learning and practice effects on follow-up. We investigated the cognition during MS relapse with the Cambridge Neuropsychological Test Automated Battery (CANTAB), which has shown sensitivity to cognitive dysfunction across different clinical groups, including patients with MS. Objective: The objective of the study was to assess the cognitive functions with CANTAB battery in MS patients during relapse, in stable MS patients, and healthy controls, and to establish the timing and pattern of cognitive recovery after relapse. Methods: Sixty relapsing, thirty stable MS patients, and thirty controls were assessed with CANTAB. The relapse group was assessed during multiple sclerosis relapse and 1 and 3 months after the first assessment. Results: The score of the difficult task of spatial planning was worse in MS relapse group than in MS stable group ( p < 0.05). The scores of medium difficulty tasks of spatial planning, episodic visual recall and working memory were worse in the relapse group than in the control group ( p < 0.05), while in stable MS and control groups, the scores of these tasks didn't differ. The most significant improvement of speed of response, spatial planning, episodic visual recall memory and spatial working memory, was established at 1 month after the first assessment, additional improvement of spatial planning and working memory was observed at 3 months after the first assessment. Conclusions: The results of this study indicate that cognitive function is affected during MS relapse. The difficult task of CANTAB battery, which assesses the spatial planning, showed MS relapse related cognitive dysfunction. The changes in scores of episodic visual recall and working memory may be related to MS relapse. A significant improvement in the speed of response, spatial planning, episodic visual recall and working memory was established at 1 month after MS relapse. The additional improvement in spatial planning for the most difficult task and working memory was observed at 3 months after MS relapse. It may be possible that the practice effect had the impact on the improvement of cognitive scores that was noted in relapsing MS patients.

There is some evidence that cognition may be impaired during multiple sclerosis (MS) relapse. The aims of this study were to assess the cognitive status with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in MS patients during relapse, in stable patients, and in healthy controls; to evaluate cognitive changes up to 3 months after relapse; and to estimate the impact of different factors on cognition after relapse. BICAMS was performed in 60 relapsing, 30 stable patients and 30 controls. Relapsing MS patients were assessed during relapse and one and three months after relapse. SDMT score was lower in relapsing than in stable patients. The mean scores of all BICAMS tests were higher one month after relapse than during relapse (p < 0.001). SDMT score after relapse improved in younger patients, who had more severe relapse (p < 0.05). BVMT-R score improved more in men, in patients with biologically active interferon-beta, in patients treated with methylprednisolone and in patients who were rehabilitated (p < 0.05). CVLT-II score improved in women and in patients with shorter relapse (p < 0.05). A neuropsychological assessment, like the evaluation of physical disability, is important during relapse. BICAMS may be suitable for a quick and effective assessment of cognition during relapse.

Background: Neutralizing antibodies (NAb) to interferon-beta (IFN-β) are associated with reduced bioactivity and efficacy of IFN-β in multiple sclerosis (MS). The myxovirus resistance protein A (MxA) gene expression is one of the most appropriate markers of biological activity of exogenous IFN-β. We hypothesized that therapeutic plasma exchange (TPE) can restore the ability of IFN-β to induce the MxA mRNA expression and that maintenance plasmapheresis can sustain the bioavailability of IFN-β., Material and Methods: Eligible patients underwent 4 primary separate plasma exchange sessions. After the induction TPE sessions, they were transferred to maintenance plasmapheresis. Bioactivity of IFN-β was expressed as in vivo MxA mRNA induction in whole blood using RT-qPCR., Results: Six patients with low IFN-β bioavailability detected by the MxA mRNA response were included. Four patients became biological responders after induction plasmapheresis. In 2 patients an increase of MxA mRNA expression was found, but the values persisted below the cut-off and the patients remained as "poor biological responders". The effect of maintenance plasmapheresis was transient: MxA mRNA expression values reverted to the baseline levels after 1-2 months., Conclusions: Therapeutic plasma exchange is able to restore the bioavailability of IFN-β in the majority of studied patients, but the effect of TPE on the IFN-β bioavailability was transient.