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Background: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon β-1a (IFN) using observational data., Methods: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression., Results: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51)., Conclusions: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research., Competing Interests: Competing interests: MP, SO, BY, RK, AYS have nothing to disclose; AS received speaker’s honoraria from Chiesi and grant from MSBase outside from this work. TK served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Minsitry of Education [project Progres Q27/LF1]. EKH received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars, and Sanofi Genzyme; has been supported by the Czech Ministry of Educaon research project PROGRES Q27/LF1. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. JK received speaker fees, research support, travel support, and/or advisory boards Swiss Multiple Sclerosis Society, SNSF, University of Basel, Progressive Multiple Sclerosis Alliance, Bayer, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi. FP served an advisory board Alexion, Almirall, Bayer, Biogen, Bristol Meyers&Squibb, Merck, Novartis and Roche; he also received personal fee for speaking activities; he also received research grants by Biogen, Merck, Roche, FISM, Reload Onlus and MIUR Ministero Italiano della Ricerca e della Università. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. SJK received compensation for scientific advisory board activity from Merck and Roche and for serving on IDMC for Biogen. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. PG has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. HB has received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. AV served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia. MPS received consulting fees from Roche, Biogen, Merck, Novartis, Sanofi, Celgene, Immunic, Geneuro, GSK, Medday; received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Biogen Merck, Novartis, Sanofi, Celgene; participated on a Data Safety Monitoring Board or Advisory Board for Roche, Sanofi, Novartis, Merck., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and time and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of MS therapies is critical to maximize patient benefit. The current guidelines review the current diagnostic criteria for MS and the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, progressive MS, pediatric cases and pregnant women. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience., Competing Interests: Declaration of competing interest The authors received honoraria from Biologix (the distributor for Biogen Idec across the Middle East and North Africa region) for serving on their advisory board and from other pharmaceutical companies including Novartis, GSK, Bayer, Merck, Sanofi and Roche. The manuscript represents the views and opinions of the members involved in the development of the guidelines. There is no industrial or pharmaceutical support or bias in the selection of the members or the recommendations reached. This effort was sponsored and carried out under the supervision of MENACTRIMS (The Middle East and North Africa Committee for Treatment and Research In Multiple Sclerosis)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

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

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: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear., Objective: To determine whether early non-disabling relapses predict disability accumulation in RRMS., Methods: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up., Results: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n  = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs ( n  = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs ( n  = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically., Conclusion: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Background: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS)., Objective: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East., Methods: We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously., Results: The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%-96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%-91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%., Conclusion: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.

Background: To compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing-remitting multiple sclerosis switching from fingolimod., Methods: Using data from MSBase registry, this multicentre cohort study included subjects who had used fingolimod for ≥6 months and then switched to ocrelizumab, cladribine or natalizumab within 3 months after fingolimod discontinuation. We analysed relapse and disability outcomes after balancing covariates using an inverse-probability-treatment-weighting method. Propensity scores for the three treatments were obtained using multinomial-logistic regression. Due to the smaller number of cladribine users, comparisons of disability outcomes were limited to natalizumab and ocrelizumab., Results: Overall, 1045 patients switched to ocrelizumab (n=445), cladribine (n=76) or natalizumab (n=524) after fingolimod. The annualised relapse rate (ARR) for ocrelizumab was 0.07, natalizumab 0.11 and cladribine 0.25. Compared with natalizumab, the ARR ratio (95% confidence interval [CI]) was 0.67 (0.47 to 0.96) for ocrelizumab and 2.31 (1.30 to 4.10) for cladribine; the hazard ratio (95% CI) for time to first relapse was 0.57 (0.40 to 0.83) for ocrelizumab and 1.18 (0.47 to 2.93) for cladribine. Ocrelizumab users had an 89% lower discontinuation rate (95% CI, 0.07 to 0.20) than natalizumab, but also a 51% lower probability of confirmed disability improvement (95% CI, 0.32 to 0.73). There was no difference in disability accumulation., Conclusion: After fingolimod cessation, ocrelizumab and natalizumab were more effective in reducing relapses than cladribine. Due to the low ARRs in all three treatment groups, additional observation time is required to determine if statistical difference in ARRs results in long-term disability differences., Competing Interests: Competing interests: CZ, OS, RM, AP, JK, MO, RK, SO, DM, IR and ZZ report no disclosures. VJ received conference travel support from Merck and Roche and speaker’s honoraria from Biogen and Roche outside of the submitted work. She receives research support from the Australian National Health and Medical Research Grant and MS Research Australia. MB received conference travel support from Biogen and Novartis. His institution has received research support from Biogen, Merck and Novartis. TK received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. JL-S received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment and research grants from Biogen, Merck, Roche, TEVA and Novartis. SJK received compensation for scientific advisory board activity from Merck and Roche. SH received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. MS participated in, but not received honoraria for, advisory board activity for Biogen, Merck, Bayer Schering, Sanofi Aventis and Novartis. AvdW served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche. She has received speaker’s honoraria and travel support from Novartis, Roche and Merck. She also received grant support from the National Health and Medical Research Council of Australia and MS Research Australia. VVP has received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall and Novartis Pharma. JP received travel compensation from Novartis, Biogen, Genzyme and Teva, and speaking honoraria from Biogen, Novartis, Genzyme and Teva. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme and Novartis, as well as support for research activities from Biogen and Czech Ministry of Education. EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. FP received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. CB received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva; he participated in Sanofi Aventis, Roche and Novartis clinical trials. MM has served on advisory board for Merck, has received speaker honoraria from Merck and Biogen. Her institution receives funding from Merck, Australian National Health Medical Research Council, Brain Foundation, Charles and Sylvia Viertel Foundation, Bethlehem Griffith Foundation and MS Research Australia. HB has received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy., Methods: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation., Results: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80)., Discussion: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod)., Classification of Evidence: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy., (© 2022 American Academy of Neurology.)

Objective: To explore prospectively through OCT the rate of retinal layer changes in relapsing-remitting multiple sclerosis patients followed up on fingolimod or interferon, as well as the treatments' differential effects on cognitive tests scores., Methods: This prospective observational study enrolled 128 stable RRMS patients treated either with fingolimod (n = 71) or interferon (n = 56). Symbol-Digit Modality Test and retinal OCT scans were obtained at baseline and every 6 to 12 months. A subgroup of patients underwent expanded cognitive tests annually (Brief visual-spatial memory-total recall, BVMT-delayed recall, and Montreal Cognitive Assessment). Retinal-OCT scans were also obtained from 22 age- and sex-matched healthy controls. Mixed effects regression was used to study annualized changes in retinal layers and cognitive function, including differences between treatment groups. Correlations between annualized changes in retinal measurements and cognitive scores were also explored., Results: Fingolimod treated patients showed no significant difference in the rate of thinning of all retinal layers when compared to healthy controls and had significantly less GCIPL thinning when compared to interferons. SDMT scores improved similarly among both RRMS treatment groups. However, interferon but not fingolimod treated patients had significant decline in MOCA and total recall scores. We also found correlations between the annualized change in GCIPL thickness and annualized change in MOCA scores, and similar correlations with annualized change in total recall scores., Conclusion: Fingolimod has a potential role in reducing retinal neurodegeneration in RRMS. Longitudinal OCT measures appear to be sensitive to changes in cognitive function and may be useful for monitoring neuroprotective therapies., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To investigate in a cross-sectional study the effect of serum-derived exosomes on primary human blood monocyte-derived macrophages (MDMs) comparing exosomes from healthy donors vs patients with relapsing-remitting multiple sclerosis in remission and in relapse and to assess whether the response correlates with exosomal Epstein-Barr virus (EBV) protein expression., Methods: A total of 45 serum-derived exosome preparations were isolated from patients and healthy controls and verified for the expression of exosomal and EBV markers. MDMs were differentiated from monocytes for 7 days and incubated for 24 hours with exosomes, and then, cell supernatants were collected for cytokine measurement by cytometric bead array. Cells were immunophenotyped before and after differentiation., Results: Serum-derived exosomes of patients with multiple sclerosis (MS) expressed higher levels of EBV proteins than healthy controls. Of interest, expression of EBV nuclear antigen EBNA1 and latent membrane proteins LMP1 and 2A was higher on exosomes derived from patients with active RRMS compared with healthy controls and stable patients. After data normalization, we observed that incubation with EBV(+) exosomes induced CXCL10 and CCL2 secretion by MDMs. MDMs differentiated from patients with active disease were better secretors of CXCL10 and other interferon-γ-inducible chemokines, including CCL2 and CXCL9, than MDMs from healthy and stable MS groups. MDMs from active patients had a higher frequency of a CD14(++) subset that correlated with the secreted CXCL10., Conclusion: Exosomes expressing EBV proteins correlate with disease activity and induce an inflammatory response in MDMs that is compounded by the origin of the responder cells., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Prevention of long-term disability is the goal of therapeutic intervention in Relapsing Remitting MS (RRMS). The Bayesian Risk Estimate for MS at Onset (BREMSO) gives an individual risk score predicting disease evolution into Secondary Progressive MS (SPMS). We investigated whether BREMSO correlates with physical disability, cognitive dysfunction, and regional brain atrophy early in MS., Methods: One hundred RRMS patients with at least two years of follow-up were enrolled. BREMSO score as well as Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Severity Score (MSSS), Timed 25-Foot Walk Test (T25-FW) and 9-Hole Peg Test (9-HPT), were assessed. Intracranial volume (ICV), subcortical gray matter structures and corpus callosum (CC) were automatically segmented on MRI images and their volumes measured., Results: BREMSO score correlated negatively with SDMT at visit1 (β = -0.33, p = 0.019), visit2 (β = -0.34, p = 0.017) and visit3 (β = -0.34, p = 0.014), and positively with MSSS at visit1 (r = 0.38, p = 0.006), visit2 (r = 0.47, p < 0.0001) and visit3 (r = 0.42, p = 0.002), but not with T25-FW and 9-HPT. BREMSO negatively correlated with CC volume at baseline (p < 0.03). No correlations were found with ICV and subcortical gray matter., Conclusions: BREMSO score at onset correlated with physical disability (MSSS), cognitive function (SDMT) and CC volume measurements in patients with early MS., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We aimed to investigate the immunologic effects of vitamin D replacement in RRMS patients. In a controlled single center study, patients deficient in 25-hydroxyvitamin D (serum level<25ng/ml) received 10,000IU/week cholecalciferol for 3months. Sufficient vitamin D patients (serum level>35ng/ml) were followed for the same period. Assessments were performed at baseline and at 3months. 25-hydroxyvitamin D levels increased significantly from baseline to month-3 in the deficient group after treatment and remained stable in the sufficient group. We observed a decreased interferon-γ (IFNγ) secretion by CD4 + T cells in vitamin D deficient group but not in the sufficient group, and a negative correlation between baseline serum vitamin D and IFNγ production. There was no change in the frequency of T helper or regulatory T cell subsets in either group. Increasing serum levels of 25-hydroxyvitamin D are associated with decreased production of IFNγ by CD4 + T cells., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Costimulatory blockade of T lymphocytes with the CTLA4-Ig fusion protein abatacept could be an effective treatment for the immune-mediated neuroinflammatory disease relapsing-remitting multiple sclerosis (RRMS)., Objective: To evaluate efficacy and safety of abatacept in RRMS., Methods: ACCLAIM (A Cooperative Clinical Study of Abatacept in Multiple Sclerosis) was a Phase II, randomized, double-blind, placebo-controlled, multi-center trial. In all, 65 of 123 planned participants with RRMS were randomized to monthly intravenous infusions of abatacept or placebo for 24 weeks in a 2:1 ratio, switched to the opposite treatment at 28 weeks, and received their final dose of study medication at 52 weeks. Enrollment was closed early due to slow accrual. The primary endpoint was the mean number of new gadolinium-enhancing (Gd+) lesions obtained on magnetic resonance imaging (MRI) scans performed every 4 weeks., Results: No statistically significant differences were observed in mean number of new Gd+ MRI lesions between the abatacept and placebo groups. No statistically significant differences were observed in other MRI and clinical parameters of RRMS disease activity. Abatacept was well tolerated., Conclusion: The ACCLAIM study did not demonstrate efficacy of abatacept in reducing the number of new Gd+ MRI lesions, or clinical measures of disease activity in RRMS.

Natalizumab was the first FDA-approved monoclonal antibody for the treatment of multiple sclerosis (MS). We report on 3 natalizumab-treated patients who developed herpes zoster infections. In addition to progressive multifocal leukoencephelopathy, other opportunistic infections have been rarely reported during Natalizumab treatment. We believe that clinicians need heightened awareness of these infections in view of the risks of serious complications., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Oral fingolimod is a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Fingolimod reduces relapse rate and delays disability progression in patients with relapsing forms of multiple sclerosis (MS). Elevation of liver function tests (LFTs) and reduction in peripheral-blood lymphocyte counts were among the most common adverse events reported in phase II, phase III, and extension studies., Objective: To describe eight patients in whom fingolimod dose was reduced to every other day (n=6) or every third day (n=2) due to increased LFTs more than 3 times the upper limit of normal (ULN) (n=2) or decreased lymphocyte count by ≤0.2×10(9)/L (n=6)., Results: Fingolimod dose reduction resulted in reversal of laboratory abnormalities. Clinically, none of the 8 patients developed clinical relapses, but five patients had new lesions on magnetic resonance imaging (MRI), one of whom with disability progression, and one patient converted to secondary progressive MS (SPMS)., Conclusion: Reducing the frequency of fingolimod administration can reverse laboratory abnormalities but may have a negative impact on drug efficacy., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is an inflammatory demyelination of the central nervous system. We investigated the prevalence of EBV seropositivity and other known risk factors for MS (age, smoking, low vitamin D) and their effect on anti-EBV antibody titers. We retrospectively studied 249 MS patients receiving care at the American University of Beirut Medical Center and 230 controls, during 2010-2014. EBV seropositivity was higher in MS patients compared to controls for both anti-VCA (99.5%; 97.2%) and anti-EBNA-1 (96.3%; 89.4%), and the titers were significantly higher in MS patients. MS patients had a significantly lower vitamin D level (15.5 ± 8.3 ng/ml) compared to controls (20.4 ± 11.3 ng/ml). The proportion of heavy smokers and overweight individuals was significantly higher in MS patients. Lebanese MS patients have risk factors similar to those in western countries. Older age and female gender were associated with a higher anti-VCA titer and male gender with a higher anti-EBNA-1., (Copyright © 2015. Published by Elsevier Inc.)

Background and Purpose: VBM has been widely used to study GM atrophy in MS. MS lesions lead to segmentation and registration errors that may affect the reliability of VBM results. Improved segmentation and registration have been demonstrated by WM LI before segmentation. DARTEL appears to improve registration versus the USM. Our aim was to compare the performance of VBM-DARTEL versus VBM-USM and the effect of LI in the regional analysis of GM atrophy in MS., Materials and Methods: 3T T1 MR imaging scans were acquired from 26 patients with RRMS and 28 age-matched NC. LI replaced WM lesions with normal-appearing WM intensities before image segmentation. VBM analysis was performed in SPM8 by using DARTEL and USM with and without LI, allowing the comparison of 4 VBM methods (DARTEL + LI, DARTEL - LI, USM + LI, and USM - LI). Accuracy of VBM was assessed by using NMI, CC, and a simulation analysis., Results: Overall, DARTEL + LI yielded the most accurate GM maps among the 4 methods (highest NMI and CC, P < .001). DARTEL + LI showed significant GM loss in the bilateral thalami and caudate nuclei in patients with RRMS versus NC. The other 3 methods overestimated the number of regions of GM loss in RRMS versus NC. LI improved the accuracy of both VBM methods. Simulated data suggested the accuracy of the results provided from patient MR imaging analysis., Conclusions: We introduce a pipeline that shows promise in limiting segmentation and registration errors in VBM analysis in MS.

Background and Purpose: The pathological differences underlying the clinical disease phases in multiple sclerosis (MS) are poorly characterized. We sought to explore the relationship between the distribution of white matter (WM) lesions in relapsing-remitting (RR) and secondary progressive (SP) MS and the normal regional variability of cerebral perfusion., Methods: WM lesions were identified and quantified on a single magnetic resonance imaging scan from 1,249 patients with MS. The spatial distribution of lesions was compared between early RR, late RR, and SP MS in the context of normal cerebral perfusion patterns provided by a single-photon emission-computed tomography atlas of healthy individuals., Results: Patients with SP MS had more distinct and larger lesions than patients with RR MS. Across all subjects, lesions were present in regions of relatively lower normal perfusion than normal appearing WM. Further, lesions in SP MS were more common in areas of lower perfusion as compared to the lesion distribution in early and late RR MS., Conclusion: Chronic plaques were more prevalent in WM regions with lower relative perfusion. Lesions in more highly perfused regions were more commonly observed in early RR MS and therefore, may be more likely to successfully remyelinate and resolve., (Copyright © 2011 by the American Society of Neuroimaging.)

Objective: To investigate the predictive value of 1 year subtraction MRI (sMRI) on activity and progression over the next 4 years in early phase multiple sclerosis (MS). To compare sensitivity of sMRI and contrast enhanced MRI towards disease activity., Methods: The study was performed on 127 MS patients with brain MRI within 5 years of symptom onset (y0), after 1 year (y1) and after 5 years (y5). Measures of clinical (Expanded Disability Status Scale, relapse rate) and conventional MRI outcomes (brain parenchyma fraction (BPF); T2 lesion volume (T2LV); contrast enhancing lesions (CEL)) were available at all time points. sMRI was obtained from y1-y0, y5-y1 and y5-y0 image pairs and the number of new, enlarged, resolved and regressed lesions was counted., Results: One year lesion change measured by sMRI predicted sMRI lesion change (p<0.0001), BPF and T2LV (p<0.05) changes, as well as clinical relapse rate (p<0.02) in the subsequent 4 years. sMRI measures were retained in stepwise predictive models that included other candidate MRI predictors. Active lesions on sMRI over a 1, 4 or 5 year interval provided a more sensitive assessment of disease activity than number of CEL at y0, y1 and/or y5: 83%, 93% and 90% of patients without CEL showed sMRI activity during the y1-y0, y5-y1, and y5-y0 intervals., Conclusions: sMRI is a feasible and sensitive tool for detecting MS activity and may provide an alternative to contrast enhanced MRI in clinical practice, particularly in cases where CEL are not available or inconclusive. Furthermore, sMRI metrics combined with conventional MRI outcomes (CEL, T2LV, BPF) can increase the prediction of longer term MRI activity and progression.

Background: Interleukin 12 (IL-12), a cytokine that promotes generation of helper T cells subtype 1, is increased in multiple sclerosis. Albuterol sulfate, a β2-adrenergic agonist, reduces IL-12 expression, so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy., Objectives: To investigate the clinical and immunologic effects of albuterol treatment as an add-on therapy in patients starting glatiramer acetate treatment., Design: Single-center double-masked clinical trial., Setting: Academic research. Patients Subjects with relapsing-remitting multiple sclerosis., Main Outcome Measures: In this single-center double-masked clinical trial, subjects with relapsing-remitting multiple sclerosis were randomized to receive a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of placebo daily for 2 years or a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of albuterol daily for 2 years. The primary clinical efficacy measurement was the change in Multiple Sclerosis Functional Composite at 2 years, and the primary immunologic end point was the change in expression of IL-13 and interferon γ at each study time point. The classification level of evidence from this trial is C for each question, as this is the first class II clinical trial addressing the efficacy of glatiramer acetate plus albuterol., Results: Forty-four subjects were randomized to receive glatiramer acetate plus albuterol or glatiramer acetate plus placebo, and 39 subjects contributed to the analysis. Improvement in the Multiple Sclerosis Functional Composite was observed in the glatiramer acetate plus albuterol group at the 6-month (P = .005) and 12-month (P = .04) time points but not at the 24-month time point. A delay in the time to first relapse was also observed in the glatiramer acetate plus albuterol group (P = .03). Immunologically, IL-13 and interferon-γ production decreased in both treatment groups, and a treatment effect on IL-13 production was observed at the 12-month time point (P < .05). Adverse events were generally mild, and only 3 moderate or severe events were considered related to the treatment., Conclusion: Treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis., Trial Registration: clinicaltrials.gov Identifier: NCT00039988.

Objective: To determine the rate of treatment failure in patients outside of a controlled treatment trial and to ascertain the factors physicians used to make this decision., Methods: One hundred and thirty four patients with the diagnosis of relapsing-remitting (RR) multiple sclerosis (MS) or clinically isolated symptom (CIS) enrolled in the CLIMB study (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital) were treated with either interferon beta or glatiramer acetate as their initial treatment for MS., Results: The probability of failing initial treatment within 3 years was 30%. Clinical activity, defined as relapses and/or progression in disability, determined treatment failure in 35.7% (n=10) of nonresponders. New T2 hyperintense or gadolinium-enhancing lesions on MRI was used to define treatment failure in 28.6% (n=8) and new MRI lesions were used in combination with clinical activity in 35.7% (n=10). Treatment failures had a higher T2 hyperintense lesion volume (p=0.015) and number of gadolinium-enhancing lesions (p=0.0001) on the enrollment MRI than responders., Conclusions: These observations demonstrate that treating physicians use both clinical and MRI parameters to define a response to treatment and initiation of a treatment change and that baseline MRI identified those with increased risk of treatment failure.

Background: Natalizumab is an antibody directed against integrin alpha4 that reduces disease activity in patients with multiple sclerosis (MS) by blocking migration of T and B cells into the CNS. The goal of this study was to characterize the effects of natalizumab treatment on cytokine production and expression of activation markers, costimulatory molecules, and trafficking determinants on CD4+ and CD8+ T cells., Methods: In a longitudinal study, we investigated the expression of surface makers and cytokine expression on peripheral blood lymphocytes from 28 patients with MS who started natalizumab treatment and were followed for 1 year. A mixed effects model was used to compare pretreatment to on-treatment measurements., Results: The frequency of CD4+ T cells producing interferon-gamma, tumor necrosis factor, and interleukin (IL)-17 upon anti-CD3 stimulation increased 6 months after initiation of natalizumab treatment and remained elevated throughout the follow-up. The frequency of CD4+ T cells expressing CD25, HLA-DR, and CCR6 ex vivo was increased at one or more time points during treatment. Among CD8+ T cells, the frequency of cells producing IL-2 and IL-17 after stimulation was increased during natalizumab treatment, as was the frequency of CD8+ T cells expressing CD58 and CCR5 ex vivo. The increase in the frequency of activated cells could not be replicated by in vitro exposure to natalizumab., Conclusion: Natalizumab treatment increases the percentage of activated leukocytes producing proinflammatory cytokines in blood, presumably due to sequestration of activated cells in the peripheral circulation.

Background: Daclizumab is a humanized monoclonal antibody (mAb) that blocks the interleukin-2 receptor alpha subunit (IL-2R-alpha chain; CD25) expressed on activated T cells leading to the inhibition of T-cell expansion, thus strongly reduces brain inflammation in patients with multiple sclerosis (MS). Another mechanism is significant expansion of CD56 (bright) natural killer (NK) cells that in turn inhibit T-cell survival., Objective: At the Partners MS center, we have been using Daclizumab in an open-label fashion in patients who fail first line therapy or non-standard immunosuppressive treatment. Our aim was to assess its safety and tolerability in our patient population.

Background: Individual magnetic resonance imaging (MRI) disease severity measures, such as atrophy or lesions, show weak relationships to clinical status in patients with multiple sclerosis (MS)., Objective: To combine MS-MRI measures of disease severity into a composite score., Design: Retrospective analysis of prospectively collected data., Setting: Community-based and referral subspecialty clinic in an academic hospital., Patients: A total of 103 patients with MS, with a mean (SD) Expanded Disability Status Scale (EDSS) score of 3.3 (2.2), of whom 62 (60.2%) had the relapsing-remitting, 33 (32.0%) the secondary progressive, and 8 (7.8%) the primary progressive form., Main Outcome Measures: Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV (T1:T2) assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1:T2., Results: The MRDSS score averaged 5.1 (SD, 2.6). Baseline MRI and EDSS correlations were moderate for BPF, T1:T2, and MRDSS and weak for T2LV. The MRDSS showed a larger effect size than the individual MRI components in distinguishing patients with the relapsing-remitting form from those with the secondary progressive form. Models containing either T2LV or MRDSS were significantly associated with disability progression during the mean (SD) 3.2 (0.3)-year observation period, when adjusting for baseline EDSS score., Conclusion: Combining brain MRI lesion and atrophy measures can predict MS clinical progression and provides the basis for developing an MRI-based continuous scale as a marker of MS disease severity.

Background: The modulation of costimulatory pathways represents an original therapeutic approach to regulate T cell-mediated autoimmune diseases by preventing or reducing autoantigen-driven T-cell activation in humans. Autoreactive CD4(+) T cells play a critical role in initiating the immune response leading to the chronic inflammation and demyelination characteristic of multiple sclerosis (MS)., Methods: We used IV infusions of CTLA4Ig to block the CD28/B7 T-cell costimulatory pathway in a phase 1 dose-escalation study in MS. Sixteen patients with relapsing-remitting MS received a single CTLA4Ig infusion and were monitored for up to 3 months after treatment. In an extension study, four additional subjects received four doses of CTLA4Ig., Results: CTLA4Ig was well tolerated in patients with MS, and most adverse events were rated as mild. Immunologic assessment of the patients showed a reduction in myelin basic protein (MBP) proliferation within 2 months of infusion and decreased interferon-gamma production by MBP-specific lines., Conclusions: Inhibiting costimulatory molecule interactions by using CTLA4Ig seems safe in multiple sclerosis (MS), and the immunologic effects suggest that it may be a promising approach to regulate the inflammatory process associated with MS.

As part of a biomarker discovery effort in peripheral blood, we acquired an immunological profile of cell-surface markers from healthy control and untreated subjects with relapsing-remitting MS (RRMS). Fresh blood from each subject was screened ex vivo using a panel of 50 fluorescently labelled monoclonal antibodies distributed amongst 56 pools of four antibodies each. From these 56 pools, we derived an immunological profile consisting of 1018 'features' for each subject in our analysis using a systematic gating strategy. These profiles were interrogated in an analysis with a screening phase (23 patients) and an extension phase (15 patients) to identify cell populations in peripheral blood whose frequency is altered in untreated RRMS subjects. A population of CD8(low)CD4(-) cells was identified as being reduced in frequency in untreated RRMS subjects (P = 0.0002), and this observation was confirmed in an independent sample of subjects from the Comprehensive Longitudinal Investigation of MS at the Brigham & Women's Hospital (P = 0.002). This reduction in the frequency of CD8(low)CD4(-) cells is also observed in 38 untreated subjects with a clinically isolated demyelination syndrome (CIS) (P = 0.0006). We also show that these differences may be due to a reduction in the CD8(low)CD56(+)CD3(-)CD4(-) subset of CD8(low) cells, which have a natural killer cell profile. Similarities between untreated CIS and RRMS subjects extend to broader immunological profiles: consensus clustering of our data suggests that there are three distinct populations of untreated RRMS subjects and that these distinct phenotypic categories are already present in our sample of untreated CIS subjects. Thus, our large-scale immunophenotyping approach has yielded robust evidence for a reduction of CD8(low)CD4(-) cells in both CIS and RRMS in the absence of treatment as well as suggestive evidence for the existence of immunologically distinct subsets of subjects with a demyelinating disease.

Cortical pathology, callosal atrophy and axonal loss are substrates of progression in multiple sclerosis (MS). Here we describe cortical, periventricular subcortical lesions and callosal demyelination in relapsing-remitting experimental autoimmune encephalomyelitis in SJL mice that are similar to lesions found in MS. Unlike the T-cell infiltrates that peak during acute disease, we found that microglia activation persists through the chronic disease phase. Microglia activation correlated with abnormal phosphorylation of neurofilaments in the cortex and stripping of synaptic proteins in cortical callosal projecting neurons. There was significant impairment of retrograde labeling of NeuN-positive callosal projecting neurons and reduction in the labelling of their transcallosal axons. These data demonstrate a novel paradigm of cortical and callosal neuropathology in a mouse model of MS, perpetuated by innate immunity. These features closely mimic the periventricular and cortical pathology described in MS patients and establish a model that could be useful to study mechanisms of progression in MS.

Objective: To determine whether changes in activation markers on peripheral blood T cells correlate with disease activity in patients with multiple sclerosis., Design: In a prospective longitudinal study during 1 year, we analyzed the change in percentage of activated T lymphocytes in the peripheral blood of 40 patients with multiple sclerosis in relation to clinical findings and changes on brain magnetic resonance imaging (MRI) scans. The patients underwent repeated imaging of the brain (mean number of MRIs for each patient, 22) at the time blood samples were obtained as well as at monthly neurological examinations, and at the time of scoring on the Kurtzke Expanded Disability Status Scale (EDSS) and ambulation index scale., Results: A change in the percentage of cells expressing the activation markers interleukin 2 receptor (CD25), class II major histocompatibility complex (MHC) (I3) or surface dipeptidyl peptidase (CD26) correlated significantly with a change in lesion volume or a change in number of gadolinium-enhancing lesions as detected on MRI. Changes in CD25( +) cells and in CD4(+) cells expressing class II MHC also correlated with changes in disability as measured by EDSS in patients with relapsing-remitting disease, and changes in CD4(+)CD25(+) cells correlated with the occurrence of attacks in patients with relapsing-remitting disease. These correlations are dependent on measurement of changes between time points sampled at 1- or 2-week intervals., Conclusion: There is a linkage between peripheral T-lymphocyte activation as measured by cell surface markers and disease activity in patients with multiple sclerosis. Arch Neurol. 2000;57:1183-1189

Background: MS is a chronic inflammatory disease of the CNS postulated to be a Th1 type cell-mediated autoimmune disease. There is increased interferon-gamma (IFNgamma) secretion in MS, and IFNgamma administration induces exacerbations of disease. IFNgamma expression is closely regulated by a number of cytokines produced by different cells of the immune system. Interleukin-12 (IL-12) is a major factor leading to Th1-type responses, including IFNgamma secretion, and there is increased secretion of IL-12 in MS. IL-10 is a potent inhibitor of both IL-12 and IFNgamma expression., Methods: The authors investigated cytokine production and proliferative responses of peripheral blood mononuclear cells stimulated with soluble anti-CD3 in healthy controls and patients with stable relapsing-remitting MS or progressive MS., Results: The authors found that T cell receptor-mediated IFNgamma and IL-10 secretion were increased in progressive MS, whereas IL-4 and IL-2 secretion and lymphocyte proliferative responses were normal. Anti-IL-12 antibody suppressed raised IFNgamma in progressive MS but did not affect raised IL-10. In addition, neutralization of endogenous IL-10 upregulated IFNgamma in controls but not progressive MS. IL-10 was produced by CD4+ cells whereas IFNgamma was produced by both CD4+ and CD8+ cells. There were no differences in IL-10 receptor expression in MS patients., Conclusions: These abnormalities in IL-10 regulation were not seen in the relapsing-remitting form of MS. Thus, the defect in regulation of both IL-12 and IFNgamma production by endogenous IL-10 in progressive MS could be an important factor involved in the transition of MS from the relapsing to the progressive stage and has implications for treating MS patients with exogenous IL-10.