Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry.

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 ß-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.

Routine CSF parameters as predictors of disease course in multiple sclerosis: an MSBase cohort study.

BACKGROUND: It remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course. METHODS: This large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis. RESULTS: In total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015). CONCLUSIONS: In RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

Prevalence and incidence of multiple sclerosis in Turkey: A nationwide epidemiologic study.

BACKGROUND: Many studies on multiple sclerosis (MS) reveal different prevalence and epidemiologic results. OBJECTIVES: In this study, we aimed to determine the epidemiologic profile of MS using official health records in Turkey. METHODS: Patients diagnosed with MS from the official health data of the Ministry of Health, representing the entire population of Turkey, were included in the study. Prevalence and incidence calculations were performed using the data on gender, age, year of birth, city of residence, and year of diagnosis. RESULTS: As a result of the study, the number of patients with the ICD code G35 was determined as 201,061 and the number of patients with this code entered at least three times was determined as 82,225. The prevalence of MS in Turkey was calculated as 96.4 per 100,000 and the female/male ratio as 2.1/1. The incidence of MS in 2022 was 6.2 per 100,000 and the mean patient age was 43.1 ± 13.3 years (female: 43.0 ± 13.1 vs male: 43.2 ± 13.7) while the mean age at first diagnosis was 34.0 ± 13.0 (female: 33.6 ± 12.6 vs male: 34.9 ± 13.7). CONCLUSION: The research was conducted via Official Database of Turkey, which includes population of 85 million and provides valuable insights into the prevalence and incidence rates of this chronic disease.

Impact of COVID-19 on pregnancy and fetal outcomes in women with multiple sclerosis.

BACKGROUND: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes. OBJECTIVES: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection. METHODS: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders. RESULTS: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations. CONCLUSION: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes.

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

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.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

Disability accrual in primary and secondary progressive multiple sclerosis.

BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

External validation of a clinical prediction model in multiple sclerosis.

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.

Impact of COVID-19 vaccination or infection on disease activity in a radiologically isolated syndrome cohort: The VaxiRIS study.

BACKGROUND: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. OBJECTIVES: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). METHODS: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients' history of COVID-19 infection. RESULTS: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. CONCLUSION: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.

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.

Comparative effectiveness in multiple sclerosis: A methodological comparison.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Sars-CoV2 infection in pregnant women with multiple sclerosis.

BACKGROUND: In the general population, maternal SARS-CoV-2 infection during pregnancy is associated with worse maternal outcomes; however, only one study so far has evaluated COVID-19 clinical outcomes in pregnant and postpartum women with multiple sclerosis, showing no higher risk for poor COVID-19 outcomes in these patients. OBJECTIVE: In this multicenter study, we aimed to evaluate COVID-19 clinical outcomes in pregnant patients with multiple sclerosis. METHODS: We recruited 85 pregnant patients with multiple sclerosis who contracted COVID-19 after conception and were prospectively followed-up in Italian and Turkish Centers, in the period 2020-2022. A control group of 1354 women was extracted from the database of the Multiple Sclerosis and COVID-19 (MuSC-19). Univariate and subsequent logistic regression models were fitted to search for risk factors associated with severe COVID-19 course (at least one outcome among hospitalization, intensive care unit [ICU] admission and death). RESULTS: In the multivariable analysis, independent predictors of severe COVID-19 were age, body mass index ⩾ 30, treatment with anti-CD20 and recent use of methylprednisolone. Vaccination before infection was a protective factor. Vaccination before infection was a protective factor. Pregnancy was not a risk nor a protective factor for severe COVID-19 course. CONCLUSION: Our data show no significant increase of severe COVID-19 outcomes in patients with multiple sclerosis who contracted the infection during pregnancy.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

The comparative effectiveness of fingolimod, natalizumab, and ocrelizumab in relapsing-remitting multiple sclerosis.

BACKGROUND: Fingolimod, natalizumab, and ocrelizumab are commonly used in the second-line treatment of relapsing-remitting multiple sclerosis (RRMS). However, these have only been compared in observational studies, not in controlled trials, with limited and inconclusive results being reported. A comparison of their effect on relapse and disability in a real-world setting is therefore needed. OBJECTIVES: The objective of this study was to compare the efficacy of fingolimod, natalizumab, and ocrelizumab in reducing disease activity in RRMS. METHODS: This multicenter, retrospective observational study was carried out with prospectively collected data from 16 centers. All consecutive RRMS patients treated with fingolimod, natalizumab, and ocrelizumab were included. Data for relapses, Expanded Disability Status Scale (EDSS) scores, and brain magnetic resonance imaging (MRI) scans were collected. Patients were matched using propensity scores. Annualized relapse rates (ARR), time to first relapse, and disability accumulation were compared. RESULTS: Propensity score matching retained 736 patients in the fingolimod versus 370 in the natalizumab groups, 762 in the fingolimod versus 434 in the ocrelizumab groups, and 310 in the natalizumab versus 310 in the ocrelizumab groups for final analyses. Mean ARR decreased markedly from baseline after treatment in all three treatment groups. Mean on-treatment ARR was lower in natalizumab-treated patients (0.09, 95% confidence interval (CI), 0.07-0.12) than in those treated with fingolimod (0.17, 0.15-0.19, p<0.001), ocrelizumab (0.08, 0.06-0.11), and fingolimod (0.14, 0.12-0.16, p=0.001). No significant difference was observed in mean on-treatment ARR between patients treated with natalizumab (0.08, 0.06-0.11) and ocrelizumab (0.09, 0.07-0.12, p=0.54). Compared to fingolimod, the natalizumab and ocrelizumab groups exhibited a higher percentage of relapse-free patients and a lower percentage of MRI-active patients at year 1. No significance differences in disability accumulation were determined between the therapies. CONCLUSION: Natalizumab and ocrelizumab exhibited similar effects on relapse control, and both were associated with better relapse control than fingolimod. The effects of the three therapies on disability outcomes were similar.

Is cancer risk reduced in multiple sclerosis? Results from a tertiary referral center.

BACKGROUND: Multiple sclerosis (MS) patients may be protected against cancer because of increased immune surveillance. However, aberrant T/B cell functioning in MS may increase the risk of cancer. We aimed to compare the frequency of cancer among patients with MS with an appropriate control group matched by the variables such as age, gender, tobacco smoking history, body mass index (BMI), and family history of cancer. METHODS: The MS patients who were registered and followed up at the MS Center in Hacettepe University Hospitals and appropriately matched with controls were included. A self-administered questionnaire with links to the online survey was delivered. RESULTS: Overall, 1037 responses out of 2074 in MS patients and 506 responses out of 1500 control group were included. Fourteen (1.35%) of MS patients and 18 (3.6%) of the controls were diagnosed with cancer. The odds ratio of having cancer in patients with MS compared to the control group was 0.389 (95% CI = 0.161-0.940, p < 0.05). DISCUSSION: There was no statistically significant difference in age, gender, tobacco smoking, and BMI between the groups after propensity score matching. The odds of having cancer were lower in our MS patients compared to the controls. The autoimmune changes responsible for the pathogenesis of MS may be responsible for the decrease in cancer risk.

Retrospective analysis of effectiveness of fingolimod in real life setting in Turkey (REFINE).

BACKGROUND: During multiple sclerosis (MS) treatment different modes of action such as lateral (interferon beta to glatiramer acetate or glatiramer acetate to interferon beta) or vertical (interferon beta/glatiramer acetate to fingolimod) drug switch can be performed. This study aims to investigate the clinical effectiveness of switching from the first-line injectable disease modifying treatments (iDMTs) to fingolimod (FNG) compared to switching between first-line iDMTs. METHODS: This is a multicenter, observational and retrospective study of patients with relapsing-remitting MS who had lateral and vertical switch. The observation period included three key assessment time points (before the switch, at switch, and after the switch). Data were collected from the MS patients' database by neurologists between January 2018 and June 2019. The longest follow-up period of the patients was determined as 24 months after the switch. RESULTS: In 462 MS patients that were included in the study, both treatments significantly decreased the number of relapses during the postswitch 12 months versus preswitch one year while patients in the FNG group experienced significantly fewer relapses compared to iDMT cohort in the postswitch 12 months period. FNG cohort experienced fewer relapses than in the iDMT cohort within the postswitch 2 year. The mean time to first relapse after the switch was significantly longer in the FNG group. DISCUSSION: The present study revealed superior effectiveness of vertical switch over lateral switch regarding the improvement in relapse outcomes. Patients in the FNG cohort experienced sustainably fewer relapses during the follow-up period after the switch compared the iDMT cohort. Importantly, switching to FNG was more effective in delaying time to first relapse when compared with iDMTs.

Comparing switch to ocrelizumab, cladribine or natalizumab after fingolimod treatment cessation in multiple sclerosis.

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.

Prediction of multiple sclerosis outcomes when switching to ocrelizumab.

BACKGROUND: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. OBJECTIVE: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. METHODS: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). RESULTS: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2-6 m compared to <1 m: HR = 9.57, 95% CI = 1.92-47.64, p = 0.006). CONCLUSION: The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.

Post-COVID-19 longitudinally extensive transverse myelitis: is it a new entity?

INTRODUCTION: To the best of our knowledge, here we present two post-COVID19 longitudinally extensive transverse myelitis (LETM) with atypical presentations CASE PRESENTATIONS: A 44-year-old male who did not have any previous medical condition and a 73-year-old male foreigner who did not have any disease other than type 2 diabetes mellitus were admitted to our neurology clinic in the same period with similar clinical presentations of transverse myelitis. Upon admission, paraplegia and urinary-fecal incontinence were observed in their neurological examination. Neurological complaints had started within approximately 3-4 weeks following the resolution of the COVID-19 infection. Thoracic lower segment LETM was observed on spinal magnetic resonance imaging (MRI) in one of the patients, and long segment myelitis extending from the lower thoracic segment to the conus medullaris was observed in the other one. No significant diagnostic positivity was present in their diagnostic evaluation. In both cases, we assume a post-infectious etiology in terms of secondary immunogenic overreaction following COVID-19. CONCLUSION: Our patients improved with multiple treatments such as methylprednisolone, intravenous immunoglobulin, and plasmapheresis. Whether post-infectious myelitis behaves differently from other viral infections after COVID-19 is currently unclear. Long lag times appear to be a post-infectious neurological complication resulting from the host response to the virus.

Early clinical markers of aggressive multiple sclerosis.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.