Baseline Expanded Disability Status Scale Research Articles

Effectiveness of ocrelizumab on clinical and MRI outcome measures in multiple sclerosis across black and white cohorts: A single-center retrospective study.

To examine differences in the therapeutic response to ocrelizumab in multiple sclerosis (MS) patients who self-identified as either White or Black, assessed longitudinally by expanded disability status scale (EDSS) progression and MRI brain volume loss. MS subjects treated with ocrelizumab were retrospectively identified. Clinical data were available for 229 subjects (White 146; Black 83) and MRI data from for 48 subjects (White 31; Black 17). Outcome measures were changes in the EDSS and brain volume over time. EDSS were analyzed as raw scores, ambulatory (EDSS <5.0) vs. ambulatory with assistance (5.5 ≤ EDSS ≤ 6.5) status, and EDSS severity (< 3.0, 3.0-5.0, and > 5.5 ≤ 6.5). General linear mixed model was used for statistical analysis. FreeSurfer was used for volumetric analysis. The Black cohort had overrepresentation of females (78% vs. 62%, p=0.013), lower age (median, 45 (IQR 39-51) vs. 49 (38-58), p=0.08), lower Vitamin D levels (33 (21-45) vs. 40 (29-52), p=0.002), and higher EDSS (4 (2-6) vs. 2.5 (1-6), p=0.019). There was no progression of EDSS scores over the 2-year observation period. The covariates with significant influence on the baseline EDSS scores were older age, race, longer disease duration, prior MS treatment, and lower vitamin D levels. No differences were observed between the racial groups over time in the cortical, thalamic, caudate, putamen, and brainstem gray matter volumes nor in the cortical thickness or total lesion volume. In this real-world clinical and radiological study, ocrelizumab treatment was highly effective in stabilizing clinical and MRI measures of disease progression in Blacks and Whites, despite higher baseline disability in the Black cohort.

Ratio of lymphocyte to monocyte area under the curve as a novel predictive factor for severe infection in multiple sclerosis.

Individuals with multiple sclerosis (MS) are vulnerable to all types of infection, because MS itself involves immunodeficiency, in addition to involving treatment with immunosuppressants. Simple predictive variables for infection that are easily assessed in daily examinations are warranted. Lymphocyte area under the curve (L_AUC), defined as the sum of serial absolute lymphocyte counts under the lymphocyte count-time curve, has been established as a predictive factor for several infections after allogenic hematopoietic stem cell transplantation. We assessed whether L_AUC could also be a useful factor for predicting severe infection in MS patients. From October 2010 to January 2022, MS patients, diagnosed based on the 2017 McDonald criteria, were retrospectively reviewed. We extracted patients with infection requiring hospitalization (IRH) from medical records and matched with controls in a 1:2 ratio. Variables including clinical severity and laboratory data were compared between the infection group and controls. L_AUC was calculated along with the AUC of total white blood cells (W_AUC), neutrophils (N_AUC), lymphocytes (L_AUC), and monocytes (M_AUC). To correct for different times of blood examination and extract mean values of AUC per time point, we divided the AUC by follow-up duration. For example, in evaluating lymphocyte counts, we defined the ratio of [L_AUC] to [follow-up duration] as [L_AUC/t]. Multivariate regression analysis was conducted to extract predictive factors associated with IRH. Also, discriminative analysis was conducted using candidate variables from multivariate analysis. The total case-control sample included 177 patients of MS with IRH (n=59) and non-IRH (controls) (n=118). Adjusted odds ratios (OR) for the risk of serious infection in patients with MS with higher baseline expanded disability status scale (EDSS) (OR 1.340, 95% confidence interval [CI] 1.070-1.670, p = 0.010) and lower ratio of L_AUC/t to M_AUC/t (OR 0.766, 95%CI 0.591-0.993, p = 0.046) were significant. Notably, the kind of treatment, including glucocorticoids (GCs), disease-modifying drugs (DMDs) and other immunosuppressants agents, and dose of GCs were not significantly associated with serious infection after correlated with EDSS and ratio of L_AUC/t to M_AUC/t. In discriminative analysis, sensitivity was 88.1% (95%CI 76.5-94.7%) and specificity was 35.6% (95%CI 27.1-45.0%), using EDSS ≥ 6.0 or ratio of L_AUC/t to M_AUC/t ≤ 3.699, while sensitivity was 55.9% (95%CI 42.5-68.6%) and specificity was 83.9% (95%CI 75.7-89.8%), using both EDSS ≥ 6.0 and ratio of L_AUC/t to M_AUC/t ≤ 3.699. Our study revealed the impact of the ratio L_AUC/t to M_AUC/t as a novel prognostic factor for IRH. Clinicians should pay more attention to laboratory data such as lymphocyte or monocyte counts itself, directly presenting individual immunodeficiency, rather than the kind of drug to prevent infection as a clinical manifestation.

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis

There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab). Patients received standard immunotherapies or were untreated. In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study.

Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation). Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course. NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Biomarkers of demyelination and axonal damage are decreased after autologous hematopoietic stem cell transplantation for multiple sclerosis

BackgroundAutologous hematopoietic stem cell transplantation (aHSCT) has seen increased use for relapsing-remitting multiple sclerosis (RRMS) in recent years. It is considered one of the most effective treatments for RRMS and has been associated with improvement in disability and prolonged remission. This suggests that the tissue-injuring disease process may have been altered by aHSCT. To assess whether this hypothesis is correct, we performed a study of three commonly used cerebrospinal fluid biomarkers of tissue damage. MethodsIn this single center study, 63 patients treated with aHSCT at Uppsala University Hospital between January 1st 2012 and January 31st 2019 were screened for participation. A control group consisting of volunteers without neurologic disease were included as a reference. Cerebrospinal fluid concentrations of neurofilament light (NFL), myelin basic protein (MBP) and glial acidic fibrillary protein (GFAp) were determined using ELISA and a multiplex proteomics platform from Meso Scale Discovery. ResultsForty-three patients with a mean age of 31 and a median follow-up time of 3.9 years were included. Their median baseline expanded disability status scale (EDSS) score was 3.5 and the annualized relapse rate in the year preceding aHSCT was 1.6. At baseline the proportion of patients with values above the upper limit of normal was 67% for NFL, 63% for MBP and 16% for GFAp. At 5-year follow-up, the proportion of patients with values above the upper limit of normal was 12% for NFL, 12% for MBP and 25% for GFAp. The mean concentration of NFL decreased from 920 pg/mL at baseline to 270 pg/mL at 5-year follow-up (p < 0.001); MBP decreased from 1500 to 680 pg/mL (p < 0.001); whereas the mean concentration of GFAp was unchanged. ConclusionIn a majority of patients, biomarkers of demyelination and axonal damage reached normal values within five years from treatment with aHSCT.

Effect of Dimethyl Fumarate vs Interferon β-1a in Patients With Pediatric-Onset Multiple Sclerosis

With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS). To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS. The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021. Patients were randomized to DMF or IFNβ-1a. The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group. Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a. This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated. ClinicalTrials.gov Identifier: NCT02283853.

Spinal cord lesions and brain grey matter atrophy independently predict clinical worsening in definite multiple sclerosis: a 5-year, multicentre study

ObjectivesTo evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients.MethodsBaseline 3.0T brain and cervical...

Improvements in Cognitive Processing Speed, Disability, and Patient-Reported Outcomes in Patients with Early Relapsing-Remitting Multiple Sclerosis Treated with Natalizumab: Results of a 4-year, Real-World, Open-Label Study.

STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. GOV: NCT01485003 (5 December 2011).

015 Reduced risk of secondary progressive multiple sclerosis by treatment with clad- ribine tablets: CLARITY study analysis

BackgroundCladribine tablets 10mg, cumulative dose 3.5mg/kg (CT3.5) over 2 years, showed efficacy vs placebo in patients with relapsing multiple sclerosis. This post-hoc analysis explored the relationship between baseline Expanded Disability Status Scale (EDSS) and risk of progression to secondary progres- sive (SPMS, EDSS ≥6.0) in CLARITY.MethodsThis analysis used a proxy composite definition of SPMS. Patients progressing to EDSS ≥6.0 were defined as ≥1 post-baseline EDSS ≥6.0 with 3- or 6-month confirmed disability progression (CDP).ResultsProxy SPMS progression was lower for CT3.5 vs placebo: overall (6.7% vs 13.5% [OR 0.46; 95%CI: 0.28–0.76]; P=0.0024); baseline EDSS ≤3.0 subgroup (3.5% vs 7.7% [OR 0.44; 95%CI: 0.19–0.99]; P=0.047]); baseline EDSS ≥3.5 subgroup (12.2% vs 22.4% [OR 0.48; 95%CI: 0.26–0.9]; P=0.0212). Patients with 3-month CDP with EDSS ≥6.0: 3.5% vs 8.0% (OR 0.42 [95%CI: 0.22–0.82]; P=0.0114); 6-month CDP with EDSS ≥6.0: 2.8% vs 5.8% (OR 0.48 [95%CI: 0.22–1.02]; P=0.0566).ConclusionsRisk of progressing to proxy SPMS within 2 years of treatment or experiencing EDSS ≥6.0 was sig- nificantly reduced with CT3.5 compared to placebo, regardless of baseline EDSS. CLARITY:NCT00213135g.giovannoni@qmul.ac.uk

036 Ocrelizumab real-world effectiveness in patients with relapsing and primary progressive multiple sclerosis: MuSicalE baseline data

BackgroundMuSicalE (NCT03593590) is an ongoing, observational study assessing ocrelizumab effec- tiveness/safety in patients with relapsing or primary progressive multiple sclerosis (MS) treated with ocre- lizumab in routine care.MethodsPatients with relapsing-remitting MS (RRMS), relapsing secondary progressive MS (rSPMS) or primary progressive MS (PPMS) initiating ocrelizumab per local label/guidelines are included. The primary endpoint is change in SymptoMScreen score (measures 12 common MS symptoms [range, 0–6]; higher scores indicate greater impairment).ResultsAs of 5 August 2019, 324 patients were eligible for analyses. Overall, patients with rSPMS (n=25) had a longer mean disease duration (16.7 years) versus patients with RRMS (8.6 years; n=243) or PPMS (9.2 years; n=54). Mean [SD] baseline Expanded Disability Status Scale score was higher in patients with rSPMS (5.2 [1.7]) or PPMS (5.0 [1.5]), versus RRMS (3.3 [1.7]). Baseline mean (SD) total SymptoMScreen scores in patients with RRMS, rSPMS and PPMS were 23.0 (13.3), 26.8 (11.9) and 28.7 (11.2), respectively. UK-specific baseline data, including other patient-reported outcomes from secondary end points, will also be presented.ConclusionsBaseline demographics and disease characteristics show expected differences in relapsing and progressive patients. MuSicalE will inform the real-world effectiveness/safety of ocrelizumab in a broad MS population. Recruitment is ongoing.jeremy.hobart@plymouth.ac.uk

004 Physical activity monitoring to assess disability progression in multiple sclerosis

To monitor multiple sclerosis (MS) disability, scales like the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) are commonly used. Both rely on a single clinical assess- ment in time which may not reflect the patient’s performance in their living environment. They also require training and are time consuming. The SenseWear armband incorporates a triaxial accelerometer sensitive to upper and lower limb motion. A proprietary algorithm computes several physical activity variables, such as total energy expenditure, physical activity duration, metabolic equivalents (METs) and average daily steps. Here we assess the SenseWear armband for its ability to monitor disease progression, alongside the EDSS and MSFC. Progressive MS patients (n=50) wore the device for one week, every 6 months for2.5 years. MSFC and EDSS were performed at the end of each week. The armband was agreeable and easy to use. Patients showed progression across all three disability measures (p&lt;0.01). Baseline physical activity, EDSS and MSFC values correlated well between each other. The change in the three measures with time correlated poorly, suggesting that they measure functional aspects which have different pro- gression trajectories. In summary, physical activity monitoring is a user-friendly and ecological method to measure MS disability progression.c.stuart@soton.ac.uk

016 Long-term disease stability in patients treated with cladribine tablets in CLARITY and CLARITY extension

BackgroundThis post-hoc analysis evaluated long-term disease stability of relapsing-remitting multiple sclerosis (RRMS) patients, according to Expanded Disability Status Scale (EDSS), after treatment with clad- ribine tablets 10mg (cumulative dose 3.5mg/kg [CT3.5] over 2 years) in CLARITY and CLARITY Extension.MethodsPatients randomised to CT3.5 in CLARITY then placebo in CLARITY Extension, with ≥1 post- baseline EDSS measurement, were included (CP3.5, n=98). EDSS score over time (CLARITY randomisation to end of follow-up in CLARITY Extension, including the bridging interval between studies) was assessed at 6-month intervals, and separately at time to 3- and 6-month confirmed EDSS score progression from CLARITY baseline.ResultsFive years after CLARITY baseline, median EDSS remained stable compared with baseline. Median EDSS score (95%CI) for CP3.5 was 2.5(2.0–3.5) vs 3.0(2.5–3.5) at baseline. In each 12-month period, EDSS score was stable in &gt;50% of patients, 21–30% improved and 0–25% worsened. During Year 5, EDSS was stable in 53.9% of patients, 21.3% improved and 24.7% worsened; &lt;30% of patients reached 3- or 6-month confirmed EDSS progression.ConclusionsEDSS score was stable up to 5 years post-CLARITY baseline for CP3.5 patients. Between 20–30% of patients demonstrated improvement in EDSS score vs baseline each year. CLARITY:NCT00213135.CLARITY ExtensionNCT00641537g.giovannoni@qmul.ac.uk

Innate Immune Cell-Related Pathology in the Thalamus Signals a Risk for Disability Progression in Multiple Sclerosis.

Background and ObjectivesOur aim was to investigate whether 18-kDa translocator protein (TSPO) radioligand binding in gray matter (GM) predicts later disability progression in multiple sclerosis (MS).MethodsIn this prospective imaging study, innate immune cells were investigated in the MS patient brain using PET imaging. The distribution volume ratio (DVR) of the TSPO-binding radioligand [11C]PK11195 was determined in 5 GM regions: thalamus, caudate, putamen, pallidum, and cortical GM. Volumetric brain MRI parameters were obtained for comparison. The Expanded Disability Status Scale (EDSS) score was assessed at baseline and after follow-up of 3.0 ± 0.3 (mean ± SD) years. Disability progression was defined as an EDSS score increase of 1.0 point or 0.5 point if the baseline EDSS score was ≥6.0. A forward-type stepwise logistic regression model was constructed to compare multiple imaging and clinical variables in their ability to predict later disability progression.ResultsThe cohort consisted of 66 patients with MS and 18 healthy controls. Patients with later disability progression (n = 17) had more advanced atrophy in the thalamus, caudate, and putamen at baseline compared with patients with no subsequent worsening. TSPO binding was significantly higher in the thalamus among the patients with later worsening. The thalamic DVR was the only measured imaging variable that remained a significant predictor of disability progression in the regression model. The final model predicted disability progression with 52.9% sensitivity and 93.9% specificity with an area under the curve value of 0.82 (receiver operating characteristic curve).DiscussionIncreased TSPO radioligand binding in the thalamus has potential in predicting short-term disability progression in MS and seems to be more sensitive for this than GM atrophy measures.

The timed 25-foot walk is a more sensitive outcome measure than the EDSS for PPMS trials: an analysis of the PROMISE clinical trial dataset.

Clinical trials in primary progressive MS (PPMS) generally use the Expanded Disability Status Scale (EDSS) as their primary outcome measure, although different clinical outcomes may be more useful. Disability worsening in PPMS trials may be influenced by baseline factors, such as age, sex, and contrast-enhancing lesions. We used the dataset of PROMISE, a large randomized controlled trial of glatiramer acetate (GA) versus placebo, to compare the clinical outcomes EDSS, timed 25-foot walk (T25FW), and nine-hole peg test (NHPT). We used Cox regression analyses to investigate the association of the baseline factors age, sex, treatment arm, contrast-enhancing lesions (CELs), and EDSS on the time to 3-month confirmed disability worsening (3MCDW) on the EDSS and the T25FW. PROMISE included 943 participants. Worsening on the T25FW or EDSS or occurred much more frequently than on the NHPT. Having CELs at baseline was associated with a shorter time to 3MCDW on both the EDSS and T25FW. An additional resampling experiment using the PROMISE dataset showed that increasing representation of participants with CELs at baseline increases the likelihood of having a positive trial result in favor of GA treatment. Our investigation suggests that the T25FW may be a more useful primary outcome measure than the EDSS in PPMS trials, and that its use may shorten clinical trials. Our findings on the impact of CELs at baseline on disability outcomes inform the critical appraisal of clinical trials in PPMS.

Effects of disease-modifying treatments discontinuation in patients with relapsing-remitting multiple sclerosis: A 5 year prospective cohort study

BackgroundOne of the most challenging issues in patients with multiple sclerosis is the discontinuation of Disease-Modifying Treatments (DMTs) and subsequent complications. ObjectiveWe aimed to investigate the extent of adherence to DMTs in naïve multiple sclerosis patients, outcomes of non-adherence to treatments, and the risk factors that lead to drug discontinuation. Materials and MethodsIn this prospective cohort study, 288 naïve cases of Relapsing-Remitting Multiple Sclerosis (RRMS) with the age of 18 years and older were included. Their baseline EDSS (Expanded Disability Status Scale) amounts were < 2, and they were followed from 2015 for the duration of 5 years. Patients underwent clinical examination every 3 months and MRI once a year and all information was recorded. Moreover, patients that experienced pregnancy during the study period, were excluded from the main study population and evaluated separately. At the end of the 5-year period, DMT adherence rate, factors affecting treatment continuity, and the effect of treatment continuity on developed disabilities based on the EDSS were measured and analyzed by statistical software SPSS-26, CMA-3.7, and STATA-17. ResultsThe mean age of patients was 30.01 ± 7.21 years. 12.2% of them were male and 87.8% were female. The treatment adherence rate was 82.5%, and tiredness of treatment prolongation (42.5%) was the most important reason for non-adherence to treatment. Additionally, There was a significant relationship between treatment adherence rate and the higher education level (P value = 0.016), being married (P value = 0.006), and the type of DMTs (Glatiramer Acetate (Adjusted OR = 7.7), Rituximab (Adjusted OR = 3.83), and Fingolimod (Adjusted OR = 3.81) had the highest adherence rates.). However, treatment adherence had no significant relationship with age, gender, employment, and patients' familial histories. The mean EDSS of patients with and without drug continuity after 5 years were 0.92 ± 1.09 & 1.76 ± 1.17, respectively, which showed a significant difference (P value < 0.001) in developed disabilities. Furthermore, the survival estimate of patients with drug adherence was higher than the other group. ConclusionApproximately one in five patients with RRMS does not have treatment adherence during the first 5 years of treatment. Type of DMT, level of education, and marital status are factors that affect treatment adherence. Poor treatment adherence is associated with EDSS progression in multiple sclerosis patients.

Anti-CD20 immunotherapy in progressive multiple sclerosis: 2-year real-world follow-up of 108 patients.

Anti-CD20 monoclonal antibodies are recently introduced treatments in progressive MS and real-world data are lacking. The aim of this study is to describe a cohort of progressive MS patients treated with ocrelizumab or rituximab in a real-world setting. This monocentric prospective cohort study at the University Hospital of Strasbourg included patients with primary progressive or secondary progressive MS that started treatment with anti-CD20 antibodies before June 2019. Every six months, patients were assessed using the following standardized clinical evaluations: Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9-HPT) and Symbol Digit Modalities Test (SDMT). The primary analysis considered EDSS progression (of at least 1.0 if EDSS ≤ 5.5 and at least 0.5 if EDSS ≥ 6.0). We included 108 patients, with a median age upon inclusion of 53years [48.0-58.0]. 72% were classified as primary progressive forms. Median baseline EDSS was 6.0 [4.0-6.5]. EDSS was significantly correlated with T25FW, SDMT and 9-HPT. Following 2years of treatment, 38.9% of patients presented EDSS progression compared to baseline. Our large cohort confirms tolerance of these treatments in a real-world setting. Standardized clinical assessments could improve detection of deteriorating patients. Further studies are needed to establish predictive factors.

Treatment regimens for neuromyelitis optica spectrum disorder attacks: a retrospective cohort study

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) attacks require an urgent probabilistic anti-inflammatory therapeutic strategy. As inadequately treated attacks result in disability, there is a need to identify the optimal attack-treatment regimen. Our study aimed to identify predictors of outcome after a first attack in patients with an NMOSD presentation and propose the best treatment strategy.MethodsWe performed a retrospective cohort study on the French national NMOSD registry (NOMADMUS), a nested cohort of the French multiple sclerosis observatory (OFSEP) recruiting patients with NMOSD presentations in France. We studied the first attack for any independent locations of clinical core characteristic of NMOSD, in treatment-naïve patients. The primary outcome was the evolution of the Expanded Disability Status Scale (EDSS) score at 6 months, stratified in two ways to account for recovery (return to baseline EDSS score) and treatment response (classified as “good” if the EDSS score decreased by ≥ 1 point after a nadir EDSS score ≤ 3, or by ≥ 2 points after a nadir EDSS score > 3). We used ordinal logistic regression to infer statistical associations with the outcome.ResultsWe included 211 attacks among 183 patients (104 with anti-AQP4 antibodies, 60 with anti-MOG antibodies, and 19 double seronegative). Attack treatment regimens comprised corticosteroids (n = 196), plasma exchanges (PE; n = 72) and intravenous immunoglobulins (n = 6). Complete recovery was reached in 40 attacks (19%) at 6 months. The treatment response was “good” in 134 attacks (63.5%). There was no improvement in EDSS score in 50 attacks (23.7%). MOG-antibody seropositivity and short delays to PE were significantly and independently associated with better recovery and treatment response.ConclusionsWe identified two prognostic factors: serostatus (with better outcomes among MOG-Ab-positive patients) and the delay to PE. We, therefore, argue for a more aggressive anti-inflammatory management of the first attacks suggesting an NMOSD presentation, with the early combination of PE with corticosteroids.

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

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. 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. 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. 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.

Slowly Expanding Lesions Predict 9-Year Multiple Sclerosis Disease Progression.

Background and ObjectivesChronic active lesions contribute to multiple sclerosis (MS) severity, but their association with long-term disease progression has not been evaluated yet. White matter (WM) lesions showing linear expansion over time on serial T1- and T2-weighted scans (i.e., slowly expanding lesions [SELs]) have been proposed as a marker of chronic inflammation. In this study, we assessed whether SEL burden and microstructural abnormalities were associated with Expanded Disability Status Scale (EDSS) score worsening and secondary progressive (SP) conversion at 9.1-year follow-up in patients with relapsing-remitting (RR) MS.MethodsIn 52 patients with RRMS, SELs were identified among WM lesions by linearly fitting the Jacobian of the nonlinear deformation field between time points obtained combining 3T brain T1- and T2-weighted scans acquired at baseline and months 6, 12, and 24. Logistic regression analysis was applied to investigate the associations of SEL number, volume, magnetization transfer ratio (MTR), and T1-weighted signal intensity with disability worsening (i.e., EDSS score increase) and SP conversion after a median follow-up of 9.1 years.ResultsAt follow-up, 20/52 (38%) patients with MS showed EDSS score worsening; 13/52 (25%) showed SP conversion. A higher baseline EDSS score (for each point higher: OR = 3.15 [95% CI = 1.61; 8.38], p = 0.003), a higher proportion of SELs among baseline lesions (for each % increase: OR = 1.22 [1.04; 1.58], p = 0.04), and lower baseline MTR values of SELs (for each % higher: OR = 0.66 [0.41; 0.92], p = 0.033) were significant independent predictors of EDSS score worsening at follow-up (C-index = 0.892). A higher baseline EDSS score (for each point higher: OR = 6.37 [1.98; 20.53], p = 0.002) and lower baseline MTR values of SELs (for each % higher: OR = 0.48 [0.25; 0.89], p = 0.02) independently predicted SPMS conversion (C-index = 0.947).DiscussionThe proportion of SELs is associated with MS progression after 9 years. More severe SEL microstructural abnormalities independently predict EDSS score worsening and SPMS conversion. The quantification of SEL burden and damage using T1-, T2-weighted, and MTR sequences may identify patients with RRMS at a higher risk of long-term disability progression and SPMS conversion.Classification of EvidenceThis study provides Class III evidence that in patients with RRMS starting treatment with natalizumab or fingolimod, the proportion of SELs on brain MRI was associated with EDSS score worsening and SPMS conversion at 9-year follow-up.

Automatic deep learning multicontrast corpus callosum segmentation in multiple sclerosis.

Background and PurposeCorpus callosum (CC) atrophy is predictive of future disability in multiple sclerosis (MS). However, current segmentation methods are either labor‐ or computationally intensive. We therefore developed an automated deep learning‐based CC segmentation tool and hypothesized that its output would correlate with disability.MethodsA cohort of 631 MS patients (449 females, baseline age 41 ± 11 years) with both 3‐dimensional T1‐weighted and T2‐weighted fluid‐attenuated inversion recovery (FLAIR) MRI was used for the development. Data from 204 patients were manually segmented to train convolutional neural networks in extracting the midsagittal intracranial and CC areas. Remaining data were used to compare segmentations with FreeSurfer and benchmark the outputs with regard to clinical correlations. A 1.5 and 3 Tesla reproducibility cohort of 9 MS patients evaluated the segmentation robustness.ResultsThe deep learning‐based tool was accurate in selecting the appropriate slice for segmentation (98% accuracy within 3 mm of the manual ground truth) and segmenting the CC (Dice coefficient .88‐.91) and intracranial areas (.97‐.98). The accuracy was lower with higher atrophy. Reproducibility was excellent (intraclass correlation coefficient > .90) for T1‐weighted scans and moderate‐good for FLAIR (.74‐.75). Segmentations were associated with baseline and future (average follow‐up time 6‐7 years) Expanded Disability Status Scale (ρ = –.13 to –.24) and Symbol Digit Modalities Test (r = .18‐.29) scores.ConclusionsWe present a fully automatic deep learning‐based CC segmentation tool optimized to modern imaging in MS with clinical correlations on par with computationally expensive alternatives.