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.

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.

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.

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. METHODS: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. RESULTS: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). DISCUSSION: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.

BACKGROUND: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. OBJECTIVES: To compare diagnostic performances of two different data-driven SPMS definitions. METHODS: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). RESULTS: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). CONCLUSION: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

Disease-Modifying Treatments and Time to Loss of Ambulatory Function in Patients With Primary Progressive Multiple Sclerosis.

Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking. Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS. Design, Setting, and Participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up. Main Outcomes and Measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models. Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective). Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data. Conclusions and Relevance: Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.

Inter-Laboratory Concordance of Cerebrospinal Fluid and Serum Kappa Free Light Chain Measurements.

The kappa index (K-Index), calculated by dividing the cerebrospinal fluid (CSF)/serum kappa free light chain (KFLC) ratio by the CSF/serum albumin ratio, is gaining increasing interest as a marker of intrathecal immunoglobulin synthesis. However, data on inter-laboratory agreement of these measures is lacking. The aim was to assess the concordance of CSF and serum KFLC measurements, and of K-index values, across different laboratories. KFLC and albumin of 15 paired CSF and serum samples were analyzed by eight participating laboratories. Four centers used Binding Site instruments and assays (B), three used Siemens instruments and assays (S), and one center used a Siemens instrument with a Binding Site assay (mixed). Absolute individual agreement was calculated using a two-way mixed effects intraclass correlation coefficient (ICC). Cohen's kappa coefficient (k) was used to measure agreement on positive (≥5.8) K-index values. There was an excellent agreement in CSF KFLC measurements across all laboratories (ICC (95% confidence interval): 0.93 (0.87-0.97)) and of serum KFLC across B and S laboratories (ICC: 0.91 (0.73-0.97)), while ICC decreased (to 0.81 (0.53-0.93)) when including the mixed laboratory in the analysis. Concordance for a positive K-Index was substantial across all laboratories (k = 0.77) and within S laboratories (k = 0.71), and very good (k = 0.89) within B laboratories, meaning that patients rarely get discordant results on K-index positivity notwithstanding the testing in different laboratories and the use of different platforms/assays.

Confirmed disability progression as a marker of permanent disability in multiple sclerosis.

BACKGROUND AND PURPOSE: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. METHODS: In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. RESULTS: The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5). CONCLUSIONS: Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.

Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS.

BACKGROUND: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. OBJECTIVE: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. RESULTS: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. CONCLUSION: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis: An International Registry Study.

BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (ß = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (ß = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (ß = - 0.5, 95% CI -0.6 to 0.4) and 18 years (ß = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (ß = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.

Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study.

Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up ≥5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.

Comparing Natural History of Early and Late Onset Pediatric Multiple Sclerosis.

OBJECTIVE: This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset pediatric multiple sclerosis. METHODS: Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease-modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated. RESULTS: A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all disability milestones. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease, and disease-modifying treatment exposure were independent predictors for long-term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms, and progressive course at disease onset were additional predictors for long-term disability. INTERPRETATION: These findings point toward the existence of a different natural history in early versus late onset pediatric multiple sclerosis patients. ANN NEUROL 2022;91:483-495.

Risk of Getting COVID-19 in People With Multiple Sclerosis: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Several studies have assessed risk factors associated with the severity of COVID-19 outcomes in people with multiple sclerosis (PwMS). The potential role of disease-modifying therapies (DMTs) and demographic and clinical factors on the risk of acquiring SARS-CoV-2 infection has not been evaluated so far. The objective of this study was to assess risk factors of contracting SARS-CoV-2 infection in PwMS by using data collected in the Italian MS Register (IMSR). METHODS: A case-control (1:2) study was set up. Cases included PwMS with a confirmed diagnosis of COVID-19, and controls included PwMS without a confirmed diagnosis of COVID-19. Both groups were propensity score-matched by the date of COVID-19 diagnosis, the date of last visit, and the region of residence. No healthy controls were included in this study. COVID-19 risk was estimated by multivariable logistic regression models including demographic and clinical covariates. The impact of DMTs was assessed in 3 independent logistic regression models including one of the following covariates: last administered DMT, previous DMT sequences, or the place where the last treatment was administered. RESULTS: A total of 779 PwMS with confirmed COVID-19 (cases) were matched to 1,558 PwMS without COVID-19 (controls). In all 3 models, comorbidities, female sex, and a younger age were significantly associated (p < 0.02) with a higher risk of contracting COVID-19. Patients receiving natalizumab as last DMT (OR [95% CI]: 2.38 [1.66-3.42], p < 0.0001) and those who underwent an escalation treatment strategy (1.57 [1.16-2.13], p = 0.003) were at significantly higher COVID-19 risk. Moreover, PwMS receiving their last DMT requiring hospital access (1.65 [1.34-2.04], p < 0.0001) showed a significant higher risk than those taking self-administered DMTs at home. DISCUSSION: This case-control study embedded in the IMSR showed that PwMS at higher COVID-19 risk are younger, more frequently female individuals, and with comorbidities. Long-lasting escalation approach and last therapies that expose patients to the hospital environment seem to significantly increase the risk of SARS-CoV2 infection in PwMS. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that among patients with MS, younger age, being female individuals, having more comorbidities, receiving natalizumab, undergoing an escalating treatment strategy, or receiving treatment at a hospital were associated with being infected with COVID-19. Among patients with MS who were infected with COVID-19, a severe course was associated with increasing age and having a progressive form of MS, whereas not being on treatment or receiving an interferon beta agent was protective.

PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study.

BACKGROUND: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients. MATERIALS AND METHODS: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other". RESULTS: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04). CONCLUSIONS: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.

Comparative Effectiveness and Cost-Effectiveness of Natalizumab and Fingolimod in Patients with Inadequate Response to Disease-Modifying Therapies in Relapsing-Remitting Multiple Sclerosis in the United Kingdom.

BACKGROUND: Patients with highly active relapsing-remitting multiple sclerosis inadequately responding to first-line therapies (interferon-based therapies, glatiramer acetate, dimethyl fumarate, and teriflunomide, known collectively as "BRACETD") often switch to natalizumab or fingolimod. OBJECTIVE: The aim was to estimate the comparative effectiveness of switching to natalizumab or fingolimod or within BRACETD using real-world data and to evaluate the cost-effectiveness of switching to natalizumab versus fingolimod using a United Kingdom (UK) third-party payer perspective. METHODS: Real-world data were obtained from MSBase for patients relapsing on BRACETD in the year before switching to natalizumab or fingolimod or within BRACETD. Three-way-multinomial-propensity-score-matched cohorts were identified, and comparisons between treatment groups were conducted for annualised relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M). Results were applied in a cost-effectiveness model over a lifetime horizon using a published Markov structure with health states based on the Expanded Disability Status Scale. Other model parameters were obtained from the UK MS Survey 2015, published literature, and publicly available UK sources. RESULTS: The MSBase analysis found a significant reduction in ARR (rate ratio [RR] = 0.64; 95% confidence interval [CI] 0.57-0.72; p < 0.001) and an increase in CDI6M (hazard ratio [HR] = 1.67; 95% CI 1.30-2.15; p < 0.001) for switching to natalizumab compared with BRACETD. For switching to fingolimod, the reduction in ARR (RR = 0.91; 95% CI 0.81-1.03; p = 0.133) and increase in CDI6M (HR = 1.30; 95% CI 0.99-1.72; p = 0.058) compared with BRACETD were not significant. Switching to natalizumab was associated with a significant reduction in ARR (RR = 0.70; 95% CI 0.62-0.79; p < 0.001) and an increase in CDI6M (HR = 1.28; 95% CI 1.01-1.62; p = 0.040) compared to switching to fingolimod. No evidence of difference in CDW6M was found between treatment groups. Natalizumab dominated (higher quality-adjusted life-years [QALYs] and lower costs) fingolimod in the base-case cost-effectiveness analysis (0.453 higher QALYs and £20,843 lower costs per patient). Results were consistent across sensitivity analyses. CONCLUSIONS: This novel real-world analysis suggests a clinical benefit for therapy escalation to natalizumab versus fingolimod based on comparative effectiveness results, translating to higher QALYs and lower costs for UK patients inadequately responding to BRACETD.

Modulation of Tregs and iNKT by Fingolimod in Multiple Sclerosis Patients.

The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127- cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14-CD19- Vα24-Jα18 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4-CD8- double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY.

Natalizumab Versus Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis: A Subgroup Analysis From Three International Cohorts.

INTRODUCTION: Natalizumab has proved to be more effective than fingolimod in reducing disease activity in relapsing-remitting multiple sclerosis (RRMS). Whether this association is universal for all patient groups remains to be determined. OBJECTIVE: The aim of this study was to compare the relative effectiveness of natalizumab and fingolimod in RRMS subgroups defined by the baseline demographic and clinical characteristics of interest. METHODS: Patients with RRMS who were given natalizumab or fingolimod were identified in a merged cohort from three international registries. Efficacy outcomes were compared across subgroups based on patients' sex, age, disease duration, Expanded Disability Status Scale (EDSS) score, and disease and magnetic resonance imaging (MRI) activity 12 months prior to treatment initiation. Study endpoints were number of relapses (analyzed with weighted negative binomial generalized linear model) and 6-month confirmed disability worsening and improvement events (weighted Cox proportional hazards model), recorded during study therapy. Each patient was weighted using inverse probability of treatment weighting based on propensity score. RESULTS: A total of 5148 patients (natalizumab 1989; fingolimod 3159) were included, with a mean ± standard deviation age at baseline of 38 ± 10 years, and the majority (72%) were women. The median on-treatment follow-up was 25 (quartiles 15-41) months. Natalizumab was associated with fewer relapses than fingolimod (incidence rate ratio [IRR]; 95% confidence interval [CI]) in women (0.76; 0.65-0.88); in those aged ≤ 38 years (0.64; 0.54-0.76); in those with disease duration ≤ 7 years (0.63; 0.53-0.76); in those with EDSS score < 4 (0.75; 0.64-0.88), < 6 (0.80; 0.70-0.91), and ≥ 6 (0.52; 0.31-0.86); and in patients with pre-baseline relapses (0.74; 0.64-0.86). A higher probability of confirmed disability improvement on natalizumab versus fingolimod (hazard ratio [HR]; 95% CI) was observed among women (1.36; 1.10-1.66); those aged > 38 years (1.34; 1.04-1.73); those with disease duration > 7 years (1.33; 1.01-1.74); those with EDSS score < 6 (1.21; 1.01-1.46) and ≥ 6 (1.93; 1.11-3.34); and patients with no new MRI lesion (1.73; 1.19-2.51). CONCLUSIONS: Overall, in women, younger patients, those with shorter disease durations, and patients with pre-treatment relapses, natalizumab was associated with a lower frequency of multiple sclerosis relapses than fingolimod. It was also associated with an increased chance of recovery from disability among most patients, particularly women and those with no recent MRI activity.