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Background: Mitochondrial DNA (mtDNA) is a pro-inflammatory damage-associated molecular pattern molecule and could be an early indicator for inflammation and disease activity in MS. Autologous hematopoietic stem cell transplantation (aHSCT) is a potent treatment for MS, but its impact on mtDNA levels in cerebrospinal fluid (CSF) remains unexplored., Objectives: To verify elevated CSF mtDNA concentrations in MS patients and assess the impact of aHSCT on mtDNA concentrations., Methods: Multiplex droplet digital PCR (ddPCR) was used to quantify mtDNA and nuclear DNA in 182 CSF samples. These samples were collected from 48 MS patients, both pre- and post-aHSCT, over annual follow-ups, and from 32 healthy controls., Results: CSF ccf-mtDNA levels were higher in patients with MS, correlated to multiple clinical and analytical factors and were normalized after intervention with aHSCT. Differences before aHSCT were observed with regard to MRI-lesions, prior treatment and number of relapses in the last year prior to aHSCT., Conclusion: Our findings demonstrate elevated CSF mtDNA levels in MS patients, which correlate with disease activity and normalize following aHSCT. These results position mtDNA as a potential biomarker for monitoring inflammatory activity and response to treatment in MS., Competing Interests: Declaration of competing interest The authors have no disclosures to report., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To investigate the effect of autologous hematopoietic stem cell transplantation (AHSCT) on functional aspects of the nervous system assessed by visual (VEP), somatosensory (SEP), and motor (MEP) evoked potentials in patients with relapsing-remitting multiple sclerosis., Background: Several studies have demonstrated the efficacy of AHSCT on inflammatory activity and disability progression in patients with multiple sclerosis. However, the impact of AHSCT on evoked potentials has not been evaluated before., Methods: Twelve AHSCT-treated patients from Uppsala University Hospital were consecutively recruited. Evoked potentials (EP) were collected at baseline and two follow-up visits, 3 and 12 months post-AHSCT. We calculated a composite EP score for each participant and compared it between different time points., Results: The median total EP score decreased from 5 at baseline, to 2.5 at 12 months post-ASHCT (p = 0.008). A significant improvement in tibial SEP (tSEP) latencies was observed (42.7 vs 41.5 ms, p < 0.001), with a similar trend for MEP latencies 12 months post-ASHCT. No significant changes in median SEP or VEP latencies were observed., Conclusions: Treatment with AHSCT was associated with improved transmission in some central nervous system pathways in multiple sclerosis patients., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT., Methods and Findings: To exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results., Conclusions: The results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tolf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: A growing evidence base supports the use of autologous haematopoietic stem cell transplantation (aHSCT) for treatment of relapsing-remitting multiple sclerosis (RRMS), but it has not yet been integrated into most national clinical guidelines. The objective of this study was to assess efficacy and safety when aHSCT is implemented in routine healthcare., Methods: We assessed 231 patients and the final analysis included 174 RRMS patients who were treated with aHSCT in Sweden before 1 January 2020. Efficacy was evaluated by performing a retrospective analysis of prospectively collected data from the Swedish MS registry. Procedure-related safety was assessed by analysing data from electronic patient records covering a period of 100 days following aHSCT., Results: With a median follow-up time of 5.5 (IQR: 3.4-7.5) years, the Kaplan-Meier estimate for no evidence of disease activity was 73% (95% CI 66% to 81%) at 5 years and 65% (95% CI 57% to 75%) at 10 years. Out of the 149 patients with baseline disability, 80 (54%) improved, 55 (37%) were stable and 14 (9%) deteriorated. The mean number of adverse events per patient was 1.7 (±SD: 1.5) for grade 3 events and 0.06 (±SD: 0.3) for grade 4 events. Febrile neutropenia was the most common adverse event, affecting 68% of patients. There was no treatment-related mortality., Conclusions: Treatment with aHSCT for RRMS is associated with freedom from disease activity in a majority of patients, with acceptable adverse events. This procedure should be considered a standard of care for patients with highly active RRMS., Competing Interests: Competing interests: EI has received speakers fee from Merck and honoraria from advisory boards for Sanofi-Aventis, Biogen and Merck. FP previously received research grants from Merck KGaA, Janssen and UCB outside this study. FP has received payment for expert testimony from Novartis. FP has participated in Data Monitoring Committee for clinical trials from Chugai, Lundbeck and Roche. JM has received lecture honorarium from Merck. NL has received honoraria from Sanofi. All other individual authors declare that there is no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start., Methods: Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories., Results: We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories., Conclusions: In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start., Competing Interests: Competing interests: AF-H has received unrestricted funding from Biogen Idec, Pfizer, Orion Pharma and Celltrion, speaking honoraria from Merck and consulting fee from Roche and AstraZeneca. KF has received honoraria for serving on advisory boards for Biogen and Merck KGaA, and speaker’s fees from Biogen, Novartis and Merck KGaA. JH has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis and Sandoz, and speaker’s fees from Biogen, Novartis, Merck, KGaA, Teva and Sanofi-Genzyme, and he has served as PI for projects, or received unrestricted research support from, Biogen, Celgene, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. AML-G receives grant support and awards from the Patient Centered Outcomes Research Institute and the National MS Society; she currently serves as a voting member on the California Technology Assessment Forum, a core program of the Institute for Clinical and Economic Review (ICER); she has received sponsored and reimbursed travel from ICER and the National Institutes of Health. PN has received travel support from Bayer Schering Pharma, Merck Serono, Biogen and Genzyme a Sanofi Company, honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis and Roche, lectures for Biogen and has received unrestricted grants from Biogen. JL has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, BMS, Celgene, Janssen and Sanofi Genzyme; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis, Merck, Roche, Sanofi Genzyme and BMS; serves on the editorial board of the Acta Neurologica Scandinavica; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator-initiated study. JS has received consultancy fees paid to the institution by Mabion S.A. FP has received research grants from Janssen, Merck KGaA and UCB, and fees for serving as Chair of DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of witness statement for Novartis. TO has received compensation for advisory boards/lectures and unrestricted MS research grants from Biogen, Merck, Novartis and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: The common inflammatory disease multiple sclerosis (MS) is a disease of the central nervous system. For more than 25 years autologous hematopoietic stem cell transplantation (AHSCT) has been used to treat MS. It has been shown to be highly effective in suppressing inflammatory activity in relapsing-remitting MS (RRMS) patients. This treatment is thought to lead to an immune system reset, inducing a new, more tolerant system; however, the precise mechanism behind the treatment effect in MS patients is unknown. In this study, the effect of AHSCT on the metabolome and lipidome in peripheral blood from RRMS patients was investigated., Methods: Peripheral blood samples were collected from 16 patients with RRMS at ten-time points over the five months course of AHSCT and 16 MS patients not treated with AHSCT. Metabolomics and lipidomics analysis were performed using liquid-chromatography high-resolution mass spectrometry. Mixed linear models, differential expression analysis, and cluster analysis were used to identify differentially expressed features and groups of features that could be of interest. Finally, in-house and in-silico libraries were used for feature identification, and enrichment analysis was performed., Results: Differential expression analysis found 657 features in the lipidomics dataset and 34 in the metabolomics dataset to be differentially expressed throughout AHSCT. The administration of cyclophosphamide during mobilization and conditioning was associated with decreased concentrations in glycerophosphoinositol species. Thymoglobuline administration was associated with an increase in ceramide and glycerophosphoethanolamine species. After the conditioning regimen, a decrease in glycerosphingoidlipids concentration was observed, and following hematopoietic stem cell reinfusion glycerophosphocholine concentrations decreased for a short period of time. Ceramide concentrations were strongly associated with leukocyte levels during the procedure. The ceramides Cer(d19:1/14:0) and Cer(d20:1/12:0) were found to be increased (P < .05) in concentration at the three-month follow-up compared to baseline. C16 ceramide, Cer(D18:2/16:0), and CerPE(d16:2(4E,6E)/22:0) were found to be significantly increased in concentration after AHSCT compared to prior to treatment as well as compared to newly diagnosed RRMS patients., Conclusion: AHSCT had a larger impact on the lipids in peripheral blood compared to metabolites. The variation in lipid concentration reflects the transient changes in the peripheral blood milieu during the treatment, rather than the changes in the immune system that are assumed to be the cause of clinical improvement within RRMS patients treated with AHSCT. Ceramide concentrations were affected by AHSCT and associated with leukocyte counts and were altered three months after treatment, suggesting a long-lasting effect., (© 2023. The Author(s).)

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS)., Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials., Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics., Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab., Main Outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement., Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%)., Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Background and Objectives: In the past decade, autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a treatment for relapsing-remitting multiple sclerosis (RRMS). How this procedure affects biomarkers of B- and T-cell activation is currently unknown. The objective of this study was to investigate CXCL13 and sCD27 concentrations in CSF before and after AHSCT., Methods: This prospective cohort study was conducted at a specialized MS clinic in a university hospital. Patients with a diagnosis of RRMS, treated with AHSCT between January 1, 2011, and December 31, 2018, were evaluated for participation. Patients were included if CSF samples from baseline plus at least 1 follow-up were available on June 30, 2020. A control group of volunteers without neurologic disease was included as a reference. CSF concentrations of CXCL13 and sCD27 were measured with ELISA., Results: The study comprised 29 women and 16 men with RRMS, aged 19-46 years at baseline, and 15 women and 17 men, aged 18-48 years, in the control group. At baseline, patients had higher CXCL13 and sCD27 concentrations than controls, with a median (IQR) of 4 (4-19) vs 4 (4-4) pg/mL ( p < 0.0001) for CXCL13 and 352 (118-530) vs 63 (63-63) pg/mL ( p < 0.0001) for sCD27. After AHSCT, the CSF concentrations of CXCL13 were considerably lower at the first follow-up at 1 year than at baseline, with a median (IQR) of 4 (4-4) vs 4 (4-19) pg/mL ( p < 0.0001), and then stable throughout follow-up. The CSF concentrations of sCD27 were also lower at 1 year than at baseline, with a median (IQR) of 143 (63-269) vs 354 (114-536) pg/mL ( p < 0.0001). Thereafter, sCD27 concentrations continued to decrease and were lower at 2 years than at 1 year, with a median (IQR) of 120 (63-231) vs 183 (63-290) pg/mL ( p = 0.017)., Discussion: After AHSCT for RRMS, CSF concentrations of CXCL13 were rapidly normalized, whereas sCD27 decreased gradually over the course of 2 years. Thereafter, the concentrations remained stable throughout follow-up, indicating that AHSCT induced long-lasting biological changes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Autologous hematopoietic stem cell transplantation (AHSCT) has been approved for multiple sclerosis (MS) in many European countries. A large proportion of patients are women of child-bearing age. For them, AHSCT may have negative consequences for reproductive health, since the ovaries are particularly susceptible to alkylating agents. Anti-Müllerian hormone (AMH) reflects the ovarian reserve and has been suggested as a potential biomarker of fertility in women. The aim of this study was to investigate AMH levels in relation to age and reproductive potential in MS patients treated with AHSCT. The study cohort comprised 38 female patients, aged 20-44 years, who underwent AHSCT for MS using a cyclophosphamide (200 mg/kg)/rabbit-anti-thymocyte globulin (6 mg/kg) conditioning regimen between 2013-2020. Clinal follow-up visits were made 3 months after AHSCT and then yearly. AMH was analysed in blood samples. The median age at transplantation was 28 years (interquartile range, IQR 25-33). The median AMH concentration was 23 pmol/l at baseline (IQR 6.0-30), 0.5 pmol/l at 3 months (IQR 0-1.5) and 1.1 pmol/l at 2 years (IQR 0-2.9). A multiple linear regression model was used to determine if age and/or AHSCT influenced AMH values; both significantly did (age, -0.21 per year, p = 0.018; AHSCT -19, p <0.0001). Seven women became pregnant, six spontaneously and one both spontaneously and with IVF. One patient underwent an abortion, all other pregnancies led to live births. Six of the women became pregnant despite low or very low post-AHSCT serum concentrations of AMH, suggesting that low serum AMH concentrations do not necessarily reflect impaired fertility in patients treated with high-dose cyclophosphamide., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zafeiri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort., Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing- remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors., Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS ≥6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4)., Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments., Competing Interests: Declaration of Competing Interest Simon Englund declare that there is no conflict of interest; Marie Kierkegaard has received honoraria for lectures from Sanofi, Genzyme Roche and Novartis; Joachim Burman declare that there is no conflict of interest; Katharina Fink has received lecture honoraria from Biogen and Merck, has served on scientific advisory boards for Biogen, Roche, Merck and Alexion, has received a research grant from Amicus; Anna Fogdell-Hahn has received unrestricted funding from Biogen Idec, Pfizer, Orion Pharma and Celltrion, speaking honoraria from Merck, and consulting fee from Roche; Martin Gunnarsson declare that there is no conflict of interest; Jan Hillert has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis and Sandoz and speaker's fees from Biogen, Novartis, Merck KGaA, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Celgene, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. His MS research was funded by the Swedish Research Council and the Swedish Brain foundation; Annette Langer-Gould receives grant support and awards from the Patient Centered Outcomes Research Institute and the National MS Society; she currently serves as a voting member on the California Technology Assessment Forum, a core program of the Institute for Clinical and Economic Review (ICER). She has received sponsored and reimbursed travel from ICER and the National Institutes of Health; Jan Lycke has received travel support and/or lecture honoraria from Biogen, BMS, Novartis, Sanofi, Roche and Alexion, has served on scientific advisory boards for Biogen, BMS, Novartis, Sanofi, Roche and Alexion, serves on the editorial board of the Acta Neurologica Scandinavica, and has received unconditional research grants from Biogen and Novartis. Petra Nilsson has received travel support from Bayer Schering Pharma, Merck Serono, Biogen and Genzyme a Sanofi Company, honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis and Roche, lectures for Biogen and has received unrestricted grants from Biogen. Jonatan Salzer has received institutional fees from Mabion S.A. for serving as a consultant in a clinical trial. Anders Svenningsson declare that there is no conflict of interest; Johan Mellergård has received honoraria for Advisory boards for Sanofi Genzyme and Merck and lecture honoraria from Merck; Tomas Olsson has received honoraria for lectures/advisory boards, and unrestricted MS research grants from Biogen, Novartis, Sanofi, Merck and Roche; Elisa Longinetti declare that there is no conflict of interest; Thomas Frisell declare that there is no conflict of interest; Fredrik Piehl has received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis. There is no commercial entity relevant for potential conflicts., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden., Methods: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups., Results: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups., Conclusion: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate., Competing Interests: Declaration of Competing Interest Helen Tedeholm received a research grant from the Swedish MS Society in 2018. Funds for research time were granted by the Western Swedish Region. Fredrik Piehl has received research grants from Genzyme, Merck KGaA, and UCB, and fees for serving as chair of DMC in clinical trials with Parexel. Jan Lycke has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, Roche, and SanofiGenzyme; has served on scientific advisory boards for Biogen, Novartis, Merck, Roche, BSM, and SanofiGenzyme; serves on the editorial board of Acta Neurologica Scandinavica; and has received unconditional research grants from Biogen and Novartis. Jenny Link has nothing to declare. Leszek Stawiarz has nothing to declare. Joachim Burman has nothing to declare. Pierre de Flon has nothing to declare. Katarina Fink has received honoraria for lectures and advisory boards from Merck, Novartis, Roche, Biogen, and Aktelion. Martin Gunnarsson has nothing to declare. Johan Mellergård has received honoraria for advisory boards from Biogen, Sanofi Genzyme and Merck and lecture honoraria from Merck. Petra Nilsson has received travel support from Bayer Schering Pharma, Merck Serono, Biogen, and Genzyme a Sanofi Company; honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company; serves on advisory boards for Novartis and Roche; lectures for Biogen; and has received unrestricted grants from Biogen. Peter Sundström has nothing to declare. Anders Svenningsson has nothing to declare. Helena Johansson has nothing to declare. Oluf Andersen serves on the editorial board of Acta Neurologica Scandinavica., (Copyright © 2022. Published by Elsevier B.V.)

Background: Autologous hematopoietic stem cell transplantation (aHSCT) has seen increased use for relapsing-remitting multiple sclerosis (RRMS) in recent years. It is considered one of the most effective treatments for RRMS and has been associated with improvement in disability and prolonged remission. This suggests that the tissue-injuring disease process may have been altered by aHSCT. To assess whether this hypothesis is correct, we performed a study of three commonly used cerebrospinal fluid biomarkers of tissue damage., Methods: In this single center study, 63 patients treated with aHSCT at Uppsala University Hospital between January 1st 2012 and January 31st 2019 were screened for participation. A control group consisting of volunteers without neurologic disease were included as a reference. Cerebrospinal fluid concentrations of neurofilament light (NFL), myelin basic protein (MBP) and glial acidic fibrillary protein (GFAp) were determined using ELISA and a multiplex proteomics platform from Meso Scale Discovery., Results: Forty-three patients with a mean age of 31 and a median follow-up time of 3.9 years were included. Their median baseline expanded disability status scale (EDSS) score was 3.5 and the annualized relapse rate in the year preceding aHSCT was 1.6. At baseline the proportion of patients with values above the upper limit of normal was 67% for NFL, 63% for MBP and 16% for GFAp. At 5-year follow-up, the proportion of patients with values above the upper limit of normal was 12% for NFL, 12% for MBP and 25% for GFAp. The mean concentration of NFL decreased from 920 pg/mL at baseline to 270 pg/mL at 5-year follow-up (p < 0.001); MBP decreased from 1500 to 680 pg/mL (p < 0.001); whereas the mean concentration of GFAp was unchanged., Conclusion: In a majority of patients, biomarkers of demyelination and axonal damage reached normal values within five years from treatment with aHSCT., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Epilepsy is associated with advanced multiple sclerosis (MS). We aimed to investigate whether the incidence of epilepsy in MS has been affected by the introduction of disease-modifying treatments (DMT) for MS., Materials and Methods: This retrospective study included 14,557 patients from the Swedish MS register with MS onset between 1991 and 2018. Incident diagnoses of epilepsy or any seizure were identified through cross-linkage with the National Patient Register. Next, yearly prevalence of epilepsy as well as 5- and 10 years incidence of epilepsy or any seizure for consecutive years of MS onset were estimated, the latter with Kaplan-Meier analysis. Cox regression was used to adjust the association between the year of MS onset and incidence of epilepsy for baseline variables., Results: Prevalence of epilepsy in the MS cohort increased from 0.34% in 1991 to 2.54% in 2018 (yearly odds: 1.26 [1.22, 1.29]). The 5 years incidence rate of epilepsy, ranging from 0.4% (95% CI 0.008-0.79%) to 1.3% (95% CI 0.71-1.89%), and the 10 years incidence rate of epilepsy, ranging from 1.1% (95% CI 0.31-1.88%) to 2.6% (95% CI 1.22-3.97%) showed no significant trends (p = .147 and p = .418, respectively). Similarly, no significant trends were found for the incidences of any seizure. The incidence trends of epilepsy remained not significant after adjusting for sex, MS onset type (relapsing or progressive onset), or age at MS onset., Conclusions: Our findings do not support the hypothesis that the introduction of novel DMT for MS has reduced the incidence of epilepsy among MS patients., (© 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Objective: To estimate risks for all-cause mortality and for severe COVID-19 in multiple sclerosis patients and across relapsing-remitting multiple sclerosis patients exposed to disease-modifying therapies., Methods: We conducted a Swedish nationwide population-based multi-register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age-, sex-, and region-matched to five population-based controls (n = 86,176 in March 2020) during March 2020-June 2021. We compared annual all-cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID-19 in relation to disease-modifying therapy use, using Cox regression., Results: Absolute all-cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population-based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID-19 remained in line with those for all-cause hospitalization, intensive care admission, and mortality. Among relapsing-remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID-19 remained in the demographics-, socioeconomic status-, comorbidity-, and multiple sclerosis severity-adjusted model., Interpretation: Risks of severe COVID-19-related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non-COVID-19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre-pandemic years. The risk conveyed by disease-modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective treatment for multiple sclerosis (MS). The impact of previous long-lasting disease-modifying treatments (DMT) for safety and efficacy of AHSCT is unknown., Objective: To explore whether previous DMTs with long-lasting effects on the immune system (anti-CD20 therapy, alemtuzumab and cladribine) affect treatment-related complications, long-term outcome and risk of new MS disease activity in patients treated with AHSCT., Methods: Retrospective observational study of 104 relapsing remitting patients with MS treated by AHSCT in Sweden and Norway from 2011 to 2021, grouped according to the last DMT used ≤6 months prior to AHSCT. The primary outcomes were early AHSCT-related complications (mortality, neutropenic fever and hospitalisation length), long-term complications (secondary autoimmunity) and proportion of patients with No Evidence of Disease Activity (NEDA-3 status): no new relapses, no MRI activity and no disease progression during the follow-up., Results: The mean follow-up time was 39.5 months (range 1-95). Neutropenic fever was a common AHSCT-related complication affecting 69 (66%) patients. There was no treatment-related mortality. During the follow-up period, 20 patients (19%) were diagnosed with autoimmunity. Occurrence of neutropenic fever, hospitalisation length or secondary autoimmunity did not vary dependent on the last DMT used prior to AHSCT. A total of 84 patients (81%) achieved NEDA-3 status, including all patients (100%) using rituximab, alemtuzumab or cladribine before AHSCT., Conclusion: This study provides level 4 evidence that AHSCT in patients previously treated with alemtuzumab, cladribine or rituximab is safe and efficacious., Competing Interests: Competing interests: SASK has received unrestricted grants from Novartis and Biogen Idec. LB has received speaker honoraria from Novartis. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, Sanofi-Aventis, Merck and Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines., Methods: RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744., Findings: Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns., Interpretation: RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed., Funding: Swedish Research Council., Competing Interests: Declaration of interests AS has served on the data safety monitoring board of GeNeuro. JS has received institutional consultancy fees from Mabion SA. MA has received compensation for lectures or advisory boards from Biogen, Novartis, and Genzyme. JM has received honoraria for advisory boards from Sanofi Genzyme and Merck and lecture honoraria from Merck. FP has received research grants from Janssen, Merck, and UCB, and fees for serving on data monitoring committees in clinical trials with Chugai, Lundbeck, and Roche. JL has received travel support or lecture honoraria from Biogen, Novartis, Merck, Roche, Axelion, Sanofi, and BMS; has served on scientific advisory boards for Almirall, Biogen, Novartis, Merck, Roche, BMS, and Sanofi; serves on the editorial board of the Acta Neurologica Scandinavica; and has received unconditional research grants from Biogen and Novartis. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Importance: B-cell-depleting monoclonal antibodies are widely used for treatment of multiple sclerosis but are associated with an impaired response to vaccines., Objective: To identify factors associated with a favorable vaccine response to tozinameran., Design, Setting, and Participants: This prospective cohort study was conducted in a specialized multiple sclerosis clinic at a university hospital from January 21 to December 1, 2021. Of 75 patients evaluated for participation who received a diagnosis of multiple sclerosis with planned or ongoing treatment with rituximab, 69 were included in the study, and data from 67 were analyzed., Exposures: Sex, age, number of previous rituximab infusions, accumulated dose of rituximab, previous COVID-19 infection, time since last rituximab treatment, CD19+ B-cell count before vaccination, CD4+ T-cell count, and CD8+ T-cell count were considered potential factors associated with the main outcome., Main Outcomes and Measures: Serological vaccine responses were measured by quantitation of anti-spike immunoglobulin G (IgG) antibodies, anti-receptor-binding domain (RBD) IgG antibodies, and their neutralizing capacities. Cellular responses to spike protein-derived SARS-CoV-2 peptide pools were assessed by counting interferon gamma spot-forming units in a FluoroSpot assay., Results: Among 60 patients with ongoing rituximab treatment (49 women [82%]; mean (SD) age, 43 [10] years), the median (range) disease duration was 9 (1-29) years, and the median (range) dose of rituximab was 2750 (500-10 000) mg during a median (range) time of 2.8 (0.5-8.3) years. The median (range) follow-up from the first vaccination dose was 7.3 (4.3-10.0) months. Vaccine responses were determined before vaccination with tozinameran and 6 weeks after vaccination. By using established cutoff values for anti-spike IgG (264 binding antibody units/mL) and anti-RBD IgG (506 binding antibody units/mL), the proportion of patients with a positive response increased with the number of B cells, which was the only factor associated with these outcomes. A cutoff for the B-cell count of at least 40/μL was associated with an optimal serological response. At this cutoff, 26 of 29 patients (90%) had positive test results for anti-spike IgG and 21 of 29 patients (72%) for anti-RBD IgG, and 27 of 29 patients (93%) developed antibodies with greater than 90% inhibition of angiotensin-converting enzyme 2. No factor associated with the cellular response was identified. Depending on the peptide pool, 21 of 25 patients (84%) to 22 of 25 patients (88%) developed a T-cell response with interferon gamma production at the B-cell count cutoff of at least 40/μL., Conclusions and Relevance: This cohort study found that for an optimal vaccine response from tozinameran, rituximab-treated patients with multiple sclerosis may be vaccinated as soon as possible, with rituximab treatment delayed until B-cell counts have reached at least 40/μL. An additional vaccination with tozinameran should be considered at that point.

Purpose: Epilepsy in multiple sclerosis (MS) is rare, and longitudinal clinical studies evaluating treatment with antiseizure medications (ASMs) are difficult to conduct. We instead designed a nationwide register study to estimate retention rates of ASMs prescribed as initial monotherapy for epilepsy in MS and investigated factors influencing their retention., Methods: multiple sclerosis patients with a first prescription of ASM for epilepsy were identified by cross-referencing the Swedish MS register with comprehensive national registers. One and five-year retention rates of ASMs were estimated using Kaplan-Meier analysis. Cox proportional regression was employed to estimate hazard ratios (HR) of discontinuation for different ASMs as well as for baseline predictors., Results: One hundred and twenty-nine MS patients were included. The most commonly prescribed ASMs were: carbamazepine (n = 38, 29.5%), lamotrigine (n = 33, 25.6%) and levetiracetam (n = 19, 14.7%). One-year retention rates (95% CI) were: lamotrigine 87.5% [76, 98.9], carbamazepine 60.5% [45, 76], levetiracetam 60.2% [37.2, 83.2], valproate 51.3% [23, 79.6] and phenytoin 44.4% [11.8, 77]. Fiveyear retention rates (95% CI) were: lamotrigine 74.4% [57.3, 91.5], carbamazepine 52.2% [34.9, 69.4], valproate 51.3% [23.1, 79.5] and phenytoin 14.8% [0, 40.9]. With carbamazepine as reference, lamotrigine was the only ASM that displayed a lower hazard of discontinuation, HR 0.41 [0.17, 0.99]. We could not identify any baseline factors that influenced the risk of discontinuation., Conclusion: Lamotrigine displayed the lowest risk of discontinuation when prescribed as initial monotherapy for epilepsy in MS. Newer ASMs generally compared well to older ones, at least suggesting non-inferiority., Competing Interests: Declaration of Competing Interest J. Zelano reports consultancy fee from the Swedish medical products agency, the National Board of Health and Welfare and speaker honoraria from UCB and Eisai for non-branded educational events. As an employee of Sahlgrenska university hospital (no personal compensation) he is/has been investigator in clinical trials sponsored by GW pharma, Bial, SK life science, and UCB. The other authors have no disclosures to report., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established., Objectives: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS., Methods: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated., Results: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p  < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans., Conclusion: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.

Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Background: Oligoclonal bands (OCB) are widely believed to be stable over time and rarely affected by disease-modifying treatment in MS. It is presently unknown how intrathecal immunoglobulin production and other cerebrospinal fluid (CSF) biomarkers are impacted by a highly efficacious procedure such as autologous haematopoietic stem cell transplantation (aHSCT)., Objective: To describe the evolution of intrathecal immunoglobulin and neurofilament light (NFL) over time in MS patients treated with aHSCT., Methods: In this retrospective study, available data from previously made CSF investigations in 46 patients treated with aHSCT were analysed., Results: After a median follow-up time of 745 days, immunoglobulin G (IgG) OCB remained detectable in 74% of patients, the proportion of patients with a pathological IgG index went down from 70% to 46%, and the proportion of patients with a pathological NFL went down from 72% to 24%. In patients with follow-up time >1500 days, IgG OCB were detectable in 50% of patients, 14% had a pathological IgG index and none a pathological NFL., Conclusions: Intrathecal immunoglobulin production and NFL were lower after treatment with aHSCT, decreased over time and were normalised in a significant portion of patients. This challenges the notion that OCB are unaffected by therapeutic intervention in MS.

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking., Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer., Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84)., Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. ANN NEUROL 2020;87:688-699., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Introduction: Standardized commercial kits enable targeted metabolomics analysis and may thus provide an attractive complement to the more explorative approaches. The kits are typically developed for triple quadrupole mass spectrometers using serum and plasma., Objectives: Here we measure the concentrations of preselected metabolites in cerebrospinal fluid (CSF) using a kit developed for high-resolution mass spectrometry (HRMS). Secondarily, the study aimed to investigate metabolite alterations in patients with secondary progressive multiple sclerosis (SPMS) compared to controls., Methods: We performed targeted metabolomics in human CSF on twelve SPMS patients and twelve age and sex-matched healthy controls using the Absolute IDQ-p400 kit (Biocrates Life Sciences AG) developed for HRMS. The extracts were analysed using two methods; liquid chromatography-mass spectrometry (LC-HRMS) and flow injection analysis-MS (FIA-HRMS)., Results: Out of 408 targeted metabolites, 196 (48%) were detected above limit of detection and 35 were absolutely quantified. Metabolites analyzed using LC-HRMS had a median coefficient of variation (CV) of 3% and 2.5% between reinjections the same day and after prolonged storage, respectively. The corresponding results for the FIA-HRMS were a median CV of 27% and 21%, respectively. We found significantly (p < 0.05) elevated levels of glycine, asymmetric dimethylarginine (ADMA), glycerophospholipid PC-O (34:0) and sum of hexoses in SPMS patients compared to controls., Conclusion: The Absolute IDQ-p400 kit could successfully be used for quantifying targeted metabolites in the CSF. Metabolites quantified using LC-HRMS showed superior reproducibility compared to FIA-HRMS.

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.

Little is known about the inflammatory milieu in the blood during autologous hematopoietic stem cell transplantation (AHSCT) and how it is affected by the stem cell mobilization, collection, and reinfusion and conditioning regimen. In this study, we analyzed 92 proteins connected to inflammation at 10 time points during and after AHSCT in 16 patients with multiple sclerosis (MS). Serum from 29 patients with newly diagnosed MS and 15 healthy controls were included for comparative analysis. There were no significant differences in inflammatory serum protein levels between patients with newly diagnosed MS and healthy controls, but 29 out of 73 detectable proteins were significantly altered between at least 2 adjacent sampling time points during AHSCT. The predominant changes occurred after the conditioning regimen had been administered, whereas stem cell mobilization, collection, and reinfusion appeared to have less impact. Two distinct response patterns could be discerned, likely representing loss of basal cytokine production and homeostasis. The analyzed serum proteins gradually returned to baseline levels after treatment, with no remaining differences at 3 months after AHSCT. We conclude that treatment with AHSCT has a major but transient impact on the inflammatory milieu of peripheral blood., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objectives: Off-label use of rituximab to treat MS patients in Sweden is high, and the need for long-term safety data may not be met. Our objectives were to assess the rate of rituximab prescription in patients with multiple sclerosis in Sweden and, in addition, to evaluate the safety of rituximab in a single centre for patients with multiple sclerosis., Material and Methods: Review of the Swedish MS register was performed to study the number of MS patients treated with rituximab during the last 6 years. Investigation also included a retrospective review of medical files in search for possible side effects/adverse events in all adult patients with MS treated with rituximab at Uppsala University Hospital., Results: Presently, in Sweden the rate of rituximab prescriptions in relation to other annually started of disease- modifying drugs in MS is 53.5%., Conclusions: The share of MS patients in Sweden who are treated with rituximab is very high, and also rapidly increasing. Taken into account the off-label use, cases with adverse medical conditions that could possibly be related to rituximab use should be reported thoroughly., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Purpose: The 2014 International League Against Epilepsy clinical definition of epilepsy allows diagnosis after a single unprovoked seizure if the 10-year recurrence risk exceeds 60%. Multiple sclerosis (MS) carries an increased risk of epilepsy, but the risk after a first seizure is unknown. We aimed to investigate the risk of epilepsy in patients with MS who had suffered a first seizure., Methods: We cross-referenced data from the Swedish MS register with the national patient register for 15 810 patients with MS and 43 635 controls and included 289 patients with MS and 222 controls with a first diagnosis of seizure or status epilepticus (SE) without prior epilepsy or presumed symptomatic aetiology. Kaplan-Meier curves were used to estimate the risk of epilepsy., Results: The 10-year risk of epilepsy was 51.4% [95% confidence interval (CI), 44.0-58.9] for patients with MS and 41.3% (95% CI, 33.5-49.1) for controls. The risk was 46.1% (95% CI, 35.3-56.9) for patients with relapsing-remitting MS and 60.7% (95% CI, 46.6-74.8) for patients with secondary progressive MS. For patients with MS with SE, the 10-year risk of epilepsy was 85.9% (95% CI, 67.9-100)., Conclusions: Our data indicate that patients with relapsing-remitting MS have a similar risk as controls of developing epilepsy after a single seizure. Patients with secondary progressive MS could run a greater risk of subsequent epilepsy, but our data do not indicate a risk that, with certainty, exceeds the threshold specified by the International League Against Epilepsy. Patients with SE have a high risk of epilepsy, possibly motivating diagnosis and treatment., (© 2018 EAN.)

Purpose: The prevalence of epilepsy is increased in multiple sclerosis (MS), but information on AED treatment and seizure outcome is scarce. We describe epilepsy characteristics including the use of AEDs and proportion of seizure-free patients at two tertiary hospitals in Sweden., Method: We retrospectively studied electronic medical records of all patients with a diagnosis of MS and seizures at Sahlgrenska university hospital and Uppsala university hospital. Clinical data were reviewed until 2017., Results: We identified a total of 62 MS patients with at least one seizure. Median age at the first seizure (before or after MS) was 41 years (range 0-80). The most common MS disease course at the first seizure was secondary progressive MS, the neurological disability was considerable, and most patients had several MRI lesions at their first seizure. The first EEG demonstrated epileptiform discharges in 38% and unspecific pathology in 40%. Current seizure status could be determined for 37 patients. Out of these, 46% had been seizure free for more than one year at last follow-up. The majority of patients (65%) were on monotherapy at last follow-up. Carbamazepine was the most commonly used first AED, with a retention rate of 52%. No individual AED was associated with a particularly high rate of seizure freedom. The most common reason for discontinuation of the first AED was side-effects., Conclusion: Seizure freedom rates were low, perhaps indicating a need for higher ambitions in management. Side effects of AEDs may be a particular concern when treating epilepsy in patients with MS., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Autologous hematopoietic stem cell transplantation (aHSCT) is a promising therapy for multiple sclerosis (MS), which has mainly been used in adults. The purpose of this study was to investigate efficacy and adverse events of aHSCT in the treatment of children with MS using data from the European Society for Blood and Marrow Transplantation registry. Twenty-one patients with a median follow-up time of 2.8 years could be identified. PFS at 3 years was 100%, 16 patients improved in expanded disability status scale score and only 2 patients experienced a clinical relapse. The procedure was generally well tolerated and only two instances of severe transplant-related toxicity were recorded. There was no treatment-related mortality, although one patient needed intensive care. aHSCT may be a therapeutic option for children with disease that does not respond to standard care.

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.

Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care., (© 2016 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS., Methods: Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months., Results: At 5 years, relapse-free survival was 87%; MRI event-free survival 85%; expanded disability status scale (EDSS) score progression-free survival 77%; and disease-free survival (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free survival 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%)., Conclusions: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS., Materials and Methods: Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted., Results: Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers., Conclusions: Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur., Case: A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term., Conclusions: This is the second known case where natalizumab treatment continued throughout the whole gestational period., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To assess the frequency of bilateral and recurrent optic neuritis (ON) in multiple sclerosis (MS) and to compare these results with epidemiological data of ON in neuromyelitis optica (NMO) and recurrent ON without other signs of disease., Methods: We identified 472 patients with diagnosis of MS from the Swedish Multiple Sclerosis Register. These patients were evaluated for the presence of ON and whether the ON was the presenting symptom of MS; unilateral or bilateral; monophasic or recurrent., Results: Twenty-one percent presented with ON as their first manifestation of MS. The proportion of patients developing a second attack of ON before demonstration of other manifestations of MS was 5.5% and the frequency of recurrent bilateral ON as the presenting symptom was 3.8%. Only two patients presented with simultaneously appearing bilateral ON corresponding to 0.42%., Conclusion: Recurrent ON, whether unilateral or bilateral, is a common presentation of MS. As MS is a much more common disease than NMO, care must be taken when evaluating the work-up of patients with recurrent ON. In some cases repeated MRI and lumbar punctures are warranted to improve diagnostic accuracy, even in the presence of the serological marker NMO-IgG., (© 2010 John Wiley & Sons A/S.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. Objectives: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. Methods: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. Results: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1–20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5–9.5). After a median follow-up of 30 (12–118) months, the median EDSS score improved to 2.0 (0–6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. Conclusion: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS. [ABSTRACT FROM AUTHOR]