Displaying One Session

Poster Fri, Sep 11, 2020
Session Type
Poster
Date
Fri, Sep 11, 2020
Biostatistical Methods Poster Presentation

P0001 - A new software and analysis suite for experimental autoimmune encephalomyelitis (ID 831)

Speakers
Presentation Number
P0001
Presentation Topic
Biostatistical Methods

Abstract

Background

Experimental Autoimmune Encephalomyelitis (EAE) is the most widely used multiple sclerosis animal model. In this model, animals develop an autoimmune inflammatory immune response to myelin protein leading to the development of ascending paralysis. The degree of motor dysfunction is scored daily and used as a metric of disease progression referred to as EAE disease score. Despite the common use of EAE animal models, there is still a large degree of heterogeneity in the field on EAE disease score data presentation and statistical assessment, making it challenging to compare results across studies.

Objectives

In an effort to standardize EAE disease score assessment, our objective was to develop an easy to use web-based application and associated package that provides researchers with a user interface for graphing and conducting statistical analysis of their data.

Methods

Using the programming language R, a shiny based application was developed to provide users with an interface to process their EAE data. For statistical testing, the application was flexibly designed to allow for parametric and non-parametric testing paradigms in addition to a number of different p-value correction methods.

Results

Our application uses a multifaceted analysis including EAE score curves (graphing EAE disease scores by group over time), area under the curve, Poisson modeling of frequency of days over a score threshold, and hierarchical clustering with a unique option of aligning animals by the day of disease onset. With this tool, researchers can quickly analyze their EAE data without code from the user while still maintaining a wide degree of flexibility in graphic and models parameters.

Conclusions

We have developed an application and an accompanying package that can be used quickly and easily to generate results for EAE disease score analysis. In the application, a user-friendly interface designed specifically for EAE models helps researchers assess their data by auto-generating graphs and statistical tests in a fast reproducible manner. We hope that this application and its analyses will assist researchers while initiating discussion and moving towards a field standard of EAE data presentation and analysis.

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Machine Learning/Network Science Poster Presentation

P0002 - Applying machine learning to multimodal neuroimaging data to predict visual episodic memory performance in multiple sclerosis  (ID 1530)

Speakers
Presentation Number
P0002
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Episodic memory (EM) impairment is common in MS. The thalamus, hippocampus, fornix and cingulum are important hubs in the Papez circuit involved in EM processing. The extent to which MS-related early structural and functional changes in these regions relate to visual EM is not known.

Objectives

To build a brain model which represents multimodal MRI measures mostly associated with visual EM processing in early MS using a machine learning approach (Elastic Net-EN).

Methods

A computerized nonverbal test of visual episodic memory (CANTAB Paired Associate Learning-PAL) was administered to 180 MS patients (RADIEMS cohort: 162 relapsing remitting, 18 clinically isolated syndrome, 123 female, mean age = 34.4 ± 7.5, mean years since diagnosis = 2.1 ± 1.4, mean premorbid intelligence = 108.3 ± 8.8). Raw scores of first trial memory were selected for statistical assessment. Neuroimaging data were acquired via a 3T MRI scanner. Lesion load over 12 regions across the brain, volume of bilateral 12 hippocampal subfields, 25 thalamic nuclei, functional and structural connectivity (assessed by fractional anisotropy and mean diffusivity) between bilateral subiculum of hippocampus and anterior thalamic nuclei and structural connectivity of fornix and cingulum were used to build a model predicting EM. Age, sex, IQ and EDSS scores were also included in the model. Five-fold cross-validation was used to train and test the model with 50 repetitions. Pearson’s correlation (r) was used to assess the univariate relationships between the continuous variables and model’s prediction accuracy.

Results

PAL test score was positively correlated with IQ (r = 0.24, p < 0.05), and negatively correlated with age and EDSS score (r = -0.25 and r = -0.23, p < 0.05). The correlation between the model’s predicted memory and actual memory scores was 0.26 ± 0.14, indicating moderate performance similar to pevious literature predicting cognitive scores from imaging variables. The most important MRI predictors of better memory were right hippocampus molecular layer and right thalamus parataenial nucleus volume, functional connectivity between left thalamus anteroventral nuclei and left hippocampus subiculum, left thalamus medial pulvinar and right hippocampus CA4 volume and lesion load in medulla and limbic lobe.

Conclusions

Atrophy and lesions in select regions of Papez Circuit are important imaging predictors of memory in early MS. A next essential step to understanding disease-specificity of these findings is comparison to matched health controls.

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Machine Learning/Network Science Poster Presentation

P0003 - Combinatorial Genetic Interaction Analysis of Multiple Sclerosis Risk Variants (ID 1040)

Speakers
Authors
Presentation Number
P0003
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Common genetic variation within the major histocompatibility complex (MHC), primarily HLA-DRB1*15:01 and HLA-A*02:01, and 200 non-MHC variants contribute to MS risk. It is unknown if specific combinations of these risk variants disproportionately confer elevated risk, as interactions between risk variants have not been extensively studied.

Objectives

To identify if there are specific combinations of risk variants that disproportionately confer increased MS risk using a novel machine learning approach.

Methods

We applied association rule mining (ARM), a combinatorial rule-based machine learning algorithm, to data from non-Hispanic white MS cases (N=207) and controls (N=179). The genetic data consisted of HLA-DRB1*15:01, HLA-A*02:01, and 200 non-MHC risk variants assuming a dominant model. We identified patterns (rules) of 2 to 5 risk variants that were enriched in MS cases compared to controls. Probabilistic measures (confidence and support) evaluated the strength of rules. Odds ratios (ORs), 95% bias corrected confidence intervals (CIs), and permutation p-values obtained from bootstrapped logistic regression models adjusted for genetic ancestry. A Bonferroni approach adjusted for multiple testing. Hahsler and Karpienko’s grouped matrix method identified rules with similar characteristics.

Results

122 rules met minimum requirements of 80% confidence and 5% support. 3 rules met the Bonferroni threshold for significance, and all consisted of 3 variants. The top 3 rules were: 1. HLA-DRB1*15:01, SLC30A7-rs56678847 and rs6880909– carriers of these variants had 20.2-fold increased odds of MS (95% CI: (8.5, 37.5); p=4x10-9); 2. HLA-DRB1*15:01, ADCY3-rs11125803, and rs13327021 (OR: 6.8, 95% CI: (3.1, 20.9); p=0.0001); and 3. HLA-DRB1*15:01, rs13327021, and LOC105375752-rs735542 (OR: 4.9, 95% CI: (2.4, 12.0); p=0.0002). Interestingly, several variants were shared across several of the 122 rules. In particular, INTS8-rs78727559 was present in 34% of top rules and TNIP3-rs17051321 was present in 32% of top rules. HLA-DRB1*15:01, rs35486093, and SLC30A7-rs56678847 were present in 21% of top rules.

Conclusions

In summary, we identified strong evidence suggesting specific combinations of MS risk variants confer elevated risk by applying a robust and novel analytical framework to a modestly sized study population. Replication analyses are underway. These results have the potential to significantly inform efforts aimed at developing risk prediction models for MS.

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Machine Learning/Network Science Poster Presentation

P0004 - Convolutional neural network framework for predicting progression in early MS (ID 1679)

Speakers
Presentation Number
P0004
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Brain tissue damage is closely linked to disability in multiple sclerosis (MS). The localization of white matter (WM) lesions influences the course of the disease.

Objectives

However, the interrelation between lesions topography and cortical atrophy distribution for predicting the clinical disability remains unclear. Use a deep learning neural network framework with the purpose to identify critical co-varying patterns for individualized disease prediction.

Methods

Clinical disability was measured using the Expanded Disability Status Score at baseline and at a one-year follow-up in a cohort of 119 patients with early relapsing-remitting MS and in a replication cohort of 81 patients. Co-varying patterns of cortical atrophy and baseline lesion distribution were extracted by parallel ICA and used as features for constructing a deep learning convolutional neural network. The prediction was conducted for each identified lesion pattern separately using 50% as training cohort and 50% as testing cohort.

Results

In the study cohort, we identified three distinct distribution types of WM lesions (“cerebellar”, “bihemispheric” and “left-lateralized”). The “cerebellar” and “left-lateralized” patterns were reproducibly detected in the second cohort. Each of the patterns predicted to different extents, short-term disability progression, while the “cerebellar” pattern predicting individual disability progression with an 10-fold cross-validation accuracy of above 90% for the Study cohort (95% CI: 88%-94%) and above 85% for the replication cohort (95% CI: 81%-88%) respectively.

Conclusions

These findings highlight that role of distinct spatial distribution of cortical atrophy and WM lesions predicting disability. The cerebellar involvement is shown as a key feature in the CNN framework for prediction of rapid clinical deterioration.

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Machine Learning/Network Science Poster Presentation

P0005 - Decoding the EDSS Scores of Multiple Sclerosis Patients from MRI Biomarkers (ID 1620)

Speakers
Presentation Number
P0005
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Treatment response in multiple sclerosis (MS) is frequently suboptimal and, in many cases, different disease-modifying therapies need to be tested. The expanded disability status scale (EDSS) score and other markers of disease activity (such as relapses, new lesions, brain atrophy, etc.) are crucial for treatment decision making. However, EDSS suffers from poor reliability, repeatability, and high inter-rater variability. Therefore, automatic and objective disability scoring using MRI information could help to monitor disease progression reliably and optimize treatment.

Objectives

Develop a machine-learning model that learns relations between MRI-based brain volumes and clinical disability measured by EDSS.

Methods

Multi-center FLAIR and T1 MRI data from 325 MS patients were used. Individuals were rated in each center using EDSS within 0-89 days before or after the MRI scan. Automated image analysis was performed using icobrain, providing volumetric quantification of gray matter, white matter, whole brain, lateral ventricles, T1 hypointense and FLAIR hyperintense lesions. Moreover, other features, such as age, sex, and center, were available. A machine-learning model based on random forest regression was built for estimating EDSS automatically from these features. The model’s performance was assessed by means of mean squared error (MSE) and mean absolute error (MAE) evaluated overall, and on two EDSS subgroups, <=4 and >4,in a 100 repetition 10-fold-cross-validation fashion. Subsequently, the percentage of cases for which the automatic EDSS was within 1.5, 1 or 0.5 points, respectively, from the clinically reported EDSS was computed.

Results

The proposed automatic EDSS estimation model obtained MSE=2.36±0.03, MAE=1.24±0.89 for the overall interval, with MSE=1.83±0.04, MAE=1.11±0.76 for EDSS<=4 (N=200) and MSE=3.26±0.06, MAE=1.46±1.05 for EDSS>4 (N=118). The percentage of cases with absolute error strictly below 1.5, 1 and 0.5 EDSS points was 67%, 46% and 24%, respectively.

Conclusions

A good match between the automatic EDSS and the measured EDSS is only possible up to a certain extent, suggesting that the MRI-based EDSS score might also capture complementary information on disease activity compared to the clinically measured EDSS. Understanding such differences is a prerequisite for predicting future disability progression in MS.

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Machine Learning/Network Science Poster Presentation

P0006 - Detecting treatment response on T1 gadolinium enhancing lesion burden in clinical trials of multiple sclerosis with deep learning (ID 998)

Speakers
Presentation Number
P0006
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Ocrelizumab (OCR) is a humanized anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of multiple sclerosis (MS). It suppresses the development of new areas of inflammation as shown by the reduction in the number of T1 gadolinium (Gd) enhancing lesions. Deep learning (DL) based segmentation of lesions has the potential to automate these manual reads; enabling faster and more reproducible quantification.

Objectives

To evaluate a DL model’s ability to detect OCR treatment response on the number of T1 Gd enhancing lesions in clinical trials of relapsing remitting MS (RRMS).

Methods

We used images from Opera I trials (NCT01247324, n=898), to train a Unet model to segment both unenhancing and Gd-enhancing T1 lesions. T1 Gd- enhancing lesions in ground truth (GT) masks were present in ~44% of patients at baseline and ~15% across all time points. We created a dataset with an equal number of imaging volumes with and without enhancing lesions and used 70%-30% data splits for training and validation. The model was tested on images from Opera II trials (NCT01412333, n=905). To detect significant differences between treatment and control arms, we performed a negative binomial regression on the number of T1 Gd-enhancing lesions with baseline imaging and clinical covariates.

Results

The DL model achieved a mean dice coefficient (DC) of 0.72, lesion true positive rate of 0.92 (LTPR), lesion false positive rate (LFPR) of 0.06 and a volume correlation coefficient (CC) of 0.97 for Gd-enhancing lesion segmentation. For unenhancing lesion segmentation, the mean DC was 0.68, LTPR 0.78, LFPR 0.18 and volume CC of 0.97. The model had the highest false positives for lesions smaller than 10 voxels (voxel size: 1x1x3 mm3). For Gd-enhancing lesion segmentation a significant OCR treatment effect (p<0.001) in reducing the mean number of Gd-enhancing lesions at 24, 48 and 96 weeks (92%, 96%, 97% reduction from GT manual reads vs 67%, 71%, 78% from model predictions) was detected.

Conclusions

Our DL model performed Gd-enhancing lesion segmentation comparably to similar DL models in the literature and showed a high correlation to GT manual reads. Our model also had sufficiently high sensitivity to detect an OCR treatment response consistent with neuro-radiologist assessments. To our knowledge, this is the first study to report that a DL model has the sensitivity to detect treatment response on Gd-enhancing lesions.

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Machine Learning/Network Science Poster Presentation

P0007 - Detecting treatment response on T2 lesion burden in multiple sclerosis clinical trials with deep learning (ID 1171)

Speakers
Presentation Number
P0007
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Deep Learning (DL) methods are promising to automate or assist the radiologist in many of the measurements currently made manually during clinical trial drug development; thereby reducing inter/intra rater variability and reading time. T2 lesion burden is a routine imaging endpoint in Multiple Sclerosis (MS) clinical trials. Ocrelizumab (OCR) is a humanized anti-CD20+ monoclonal antibody approved for the treatment of relapsing and primary progressive forms of MS. It has been shown to strongly suppress the number of new and enlarging T2 lesions (compared to control treatment) in the relapsing remitting MS (RRMS) based on manual neuro-radiologist assessments.

Objectives

Evaluate DL models to quantify T2 lesion burden and detect the therapeutic response identified by manual neuro-radiologist assessments.

Methods

We evaluated three DL models using multimodal brain MRI (T2w, FLAIR and T1w; voxel size of 1x1x3 mm3): a stack model with three consecutive slices as input; a patch model with 3D sub volumes as input; and a novel model architecture. Models were trained on Opera I (NCT01247324, n=898) datasets (baseline) and tested on Opera II (NCT01412333, n=905) datasets (baseline, 24, 48 and 96 weeks). Number of new and enlarging T2 lesions were estimated heuristically from serial lesion masks predicted by the model.

Results

Lesion size distributions were heavily skewed toward small lesions (~40% < 10 voxels, ~80% < 50 voxels with a minimum lesion size threshold of 3 voxels). All models achieved similar mean dice coefficient (0.7), mean lesion true positive rate (LTPR) of 0.87, 0.85, 0.82 and mean lesion false positive rate (LFPR) of 0.23, 0.24, 0.18. Generally, the models overestimated the number of new and enlarging T2 lesions when compared to the ground truth (GT) masks. This was driven by a high number of false positives (FP) for small lesions. All three models were able to detect a significant treatment response in favor of OCR at weeks 48 (p<0.01) and 96 (p<0.001). Only the novel model showed a significant treatment effect at week 24 (p<0.01).

Conclusions

The cross-sectional performance metrics of all 3 models were comparable to those reported in literature. All models successfully reproduced the treatment response from GT manual reads at 48 and 96 weeks, but only the novel model detected the early response at 24 weeks seen in the GT assessments. To further improve the model’s reliability, future work will be aimed to reduce the number of FPs for small size lesions.

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Machine Learning/Network Science Poster Presentation

P0008 - Divergent patterns of ventral attention network centrality relate to cognitive conversion in MS (ID 473)

Speakers
Presentation Number
P0008
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Cognitive impairment (CI) is common in multiple sclerosis (MS), but due to a lack of longitudinal data it remains unclear which mechanisms relate to conversion to mild or even severe CI. Previous cross-sectional work has suggested the importance of cognition-related resting-state networks, such as the default-mode and attention networks.

Objectives

To characterize the functional network changes related to conversion to CI in a large sample of MS patients over a period of 5 years.

Methods

A total of 233 MS patients and 59 healthy controls (HC), all part of the Amsterdam MS cohort, underwent extensive neuropsychological testing and resting-state fMRI at baseline and follow-up (mean time-interval 4.9±0.9 years). At baseline, MS patients were categorized as being cognitively impaired (scoring ≤-2 SD on ≥2 domains, N=74), mildly impaired (MCI, being impaired on 1 domain or scoring between -1.5 and -2SD on ≥2 domains, N=33) or preserved (CP, not fulfilling the CI or MCI criteria, N=126). In addition, these groups were categorized according to the group to which they converted at follow-up (e.g. CP to CI). Network function was quantified using eigenvector centrality, a measure of network importance, which was averaged over established resting-state networks at both time-points. Correlations with brain volumes were calculated.

Results

Over time, 26.2% of CP patients deteriorated and developed MCI (66.7%) or CI (33.3%) and 73.8% remained CP. 23.5% of MCI patients, progressed to CI. Centrality analysis showed that patients who were CI at baseline demonstrated a higher cross-sectional DMN centrality compared to controls (P=.05). Longitudinally, patients who remained CP and CP-to-MCI converters showed increasing ventral attention network (VAN) centrality over time time (P=.017 and .008, respectively), , whereas in the MCI and CI converter groups this increase was absent. Patients with less severe deep gray matter atrophy at baseline showed stronger increases in VAN centrality over time.

Conclusions

We showed that conversion from intact cognition to impairment in MS is related to an increase in centrality of the VAN, which is absent when overt impairment has manifested, then shifting towards DMN dysfunction. As the ventral attention network is known to normally relay information to the DMN, our results suggest that developing cognitive impairment is related to a progressive loss of control over the DMN by means of VAN dysfunction.

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Biostatistical Methods Poster Presentation

P0009 - ENTIMOS: a discrete event simulation model for maximizing efficiency of infusion suites in centres treating multiple sclerosis patients (ID 1630)

Speakers
Presentation Number
P0009
Presentation Topic
Biostatistical Methods

Abstract

Background

Multiple sclerosis patients are treated with intravenous (IV) disease modifying treatments (DMTs). Infusion suite resources are thus vital components of MS patient care. Infusion suites may be dedicated to MS patients, or shared with patients with other neurological conditions, or other patients requiring infusion. Here, we describe a resource utilization model for the infusion suites of Charing Cross (UK), which serves patients with different neurological conditions.

Objectives

To maximize the clinical efficiency of the infusion suite based on three resource constraints: percentage of patients IV MS DMTs, number of infusion chairs, and number of nurses. Efficiency gains in the infusion suite may benefit both patients and the healthcare system.

Methods

ENTIMOS, a discrete event simulation (DES) model, was created using SIMUL8 based on qualitative information from infusion centers and populated with data specific to the Charing Cross hospital neurology infusion suite. Posology, administration information, and rates of immune related-reactions (IRRs) were applied from published data sources from both MS and non-MS DMTs of interest.

The infusion suite model assumes 75 MS and 21 non-MS patients weekly, including up to seven MS patients initiating IV treatment; is equipped with 12 infusion chairs and six beds; and is staffed with a total of six nurses. We simulated the effects of changing the three resource constraints described on the number of patients waiting for an appointment (queue size), the time for patients to get an appointment for their first or subsequent IV treatments (waiting times), and general resource utilization.

Results

Changing the number of chairs, moving a subset of patients from IV to any non-IV alternative treatments, moving patients between MS IV treatments, or changing the allocation of nurse resources may all have an impact on the queue size and waiting times. Once the changes are implemented in the model, existing resources optimised and the queue size reduced, the effective centre throughput can be increased.

Conclusions

ENTIMOS allows users to optimize their use of constrained resources in an infusion suite to improve patient experience and infusion suite efficiency.

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Machine Learning/Network Science Poster Presentation

P0010 - Integration of the Extreme Gradient Boosting model with clinical data to enable the early diagnosis of multiple sclerosis (ID 715)

Speakers
Presentation Number
P0010
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Delayed multiple sclerosis (MS) diagnoses are not uncommon, especially in Asia, where MS is relatively rare. Therefore, an early MS diagnostic tool is urgently warranted.

Objectives

We aimed to develop an effective tool through machine learning techniques for the early diagnosis of MS in Chinese people.

Methods

Two case sets were established. The first MS cohort had 239 cases and 1142 controls (the training set), and the second MS cohort had 23 cases and 92 controls (the test set). The Extreme Gradient Boosting (XGBoost), Random Forest (RF), Naive Bayes, K-nearest-neighbor (KNN), Support Vector Machine (SVM) algorithms were fitted using Bayesian optimization, and the best parameter sets were assessed using the F1 scores of 5-fold cross-validations. The utility of machine learning algorithms in MS early diagnosis was evaluated by precision, recall, specificity, accuracy and F1 score through 5-fold cross validation.

Results

The XGBoost algorithm performed better than the other algorithms in 5-fold cross-validation. Thirty-four variables were set for the XGBoost algorithm, and their relative importance with MS were ranked. The training set recall was 0.632, with a specificity of 0.903, and the test set recall was 0.609, with a specificity of 0.902. Our study found that 61%, 51%, and 49% of the patients could be diagnosed with MS, 1, 2, and 3 years earlier than their real diagnostic time point, respectively.

Conclusions

A diagnostic tool for early MS recognition based on the XGBoost model and medical record data were developed to help reduce diagnostic delays in MS patients.

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Machine Learning/Network Science Poster Presentation

P0011 - Lesion disconnectomics using atlas-based tractography (ID 1293)

Speakers
Presentation Number
P0011
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Recent studies have described Multiple Sclerosis (MS) as a disconnection syndrome (Rocca et al. 2015). Modelling disconnectomes using brain networks enables to quantify connectivity loss using graph analysis. To build structural connectomes, high-quality diffusion Magnetic Resonance Imaging (dMRI) and robust tractography algorithms are typically required. However, high-quality dMRI is rarely acquired in clinical workups due to time constraints.

Objectives

We propose to use a tractography atlas to extract brain connectivity loss in response to lesions without requiring dMRI, and to model structural disconnectomes with brain graphs. Topological graph features are proposed as new radiological biomarkers and their relation with Total Lesion Volume (TLV) and Expanded Disability Status Scale (EDSS) are studied.

Methods

589 MS patients (159 males, age 28±8yo, EDSS 2.40±1.22, TLV 13.0±14.6mL) underwent MRI at 3T (MAGNETOM Skyra, Siemens Healthcare, Erlangen, Germany). Acquisition protocols included T1-weighted magnetization-prepared rapid gradient echo (MPRAGE) and fluid-attenuated inversion recovery (FLAIR).

Lesions were segmented using LeMan-PV, a prototype lesion segmentation algorithm (Fartaria et al. 2016). The lesion masks were registered to standard MNI space and overlapped with the HCP842 tractography atlas (Yeh et al. 2018). Streamlines passing through lesions were isolated to define the affected connectivity.

The disconnectome graph was built using brain regions from the Brainnetome atlas (Fan et al. 2016) as nodes, whilst edges were weighted by the percent of unaffected streamlines connecting two nodes relative to the atlas connectivity. Topological features were extracted from the disconnectome graph and their Spearman’s correlations with TLV and EDSS were computed.

Results

Transitivity (T) and global efficiency (GE) decreased for larger TLV (R=-0.42 and R=-0.78), whereas the average shortest path length (PL) increased (R=0.78). When looking at correlations with EDSS, T (R=-0.17), GE (R=-0.24) and PL (R=0.23) showed stronger associations than lesion count (R=0.14) but were comparable to TLV (R=0.23). All correlations were significant (p<0.001).

Conclusions

We proposed an atlas-based disconnectome model which allowed to study connectivity loss in MS patients without requiring dMRI. Overall, patients showed a lower small-worldness and efficiency for larger TLV and worse disability. These observations were consistent with previous studies on diffusion-based connectomes and open new avenues of research for routine clinical data.

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Machine Learning/Network Science Poster Presentation

P0012 - Machine-learning optimized Combinatorial MRI scale (COMRISv2) correlates highly with MS disability (ID 1438)

Speakers
Presentation Number
P0012
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Volumetric biomarkers derived from brain MRI correlate only mildly to moderately with disability scales in multiple sclerosis (MS) patients. We previously addressed this issue by employing machine learning (ML) to select semi-quantitative MRI (semi-qMRI) features and their weights in the Combinatorial MRI Scale (COMRISv1). COMRISv1 correlated strongly with physical and cognitive disability in an independent validation cohort.

Objectives

Building on this work, we aimed to test the hypothesis that more powerful ML algorithm (i.e., Random Forests; RF) to both fully quantitative (qMRI) and semi-qMRI biomarkers in COMRISv2 will outperform COMRISv1 in the ability to predict physical and cognitive disability in an independent cohort of MS patients.

Methods

The prospectively acquired MS patients (n=283, divided 2:1 into training and validation cohorts) underwent brain MRI imaging within days of clinical evaluation. Neurological examination was transcribed to NeurEx app that automatically computes disability scales. Semi-qMRI features were determined weekly by consensus of MS-trained neurologists, while qMRI features were computed by lesion-TOADS algorithm implemented to QMENTA platform. All measurements were acquired as part of an IRB-approved clinical protocol, and support was provided by the National Institute of Allergy and Infectious Disease Division of Intramural Research.

Results

All RF-based COMRISv2 models validated (p<0.0001 for all) in the independent cohort. The predictions were stronger for models of physical disability, from which the model based on granular CombiWISE scale achieved the highest correlation (Spearman Rho = 0.855; Linh’s concordance coefficient that reflects 1:1 concordance between predicted and measured outcome; CCC = 0.824). COMRISv2 model of cognitive disability predicted measured symbol digit modalities tests (SDMT) with Rho = 0.493. Unexpectedly, formal comparison of the models consisting only from qMRI or semi-qMRI features demonstrated stronger predictive power of the latter.

Conclusions

COMRISv2 predicts clinical outcomes with strong accuracy but models of physical disability favor qMRI biomarkers reflecting disease burden in the infratentorial compartment, which is currently not measurable as qMRI biomarkers with sufficient accuracy. Addition of qMRI biomarkers of telencephalon damage only strengthened the performance of cognitive disability COMRISv2 model.

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Biostatistical Methods Poster Presentation

P0013 - Modeling a long-term virtual placebo arm for SPMS population in the EXPAND study: Comparing different statistical methods (ID 1774)

Speakers
Presentation Number
P0013
Presentation Topic
Biostatistical Methods

Abstract

Background

Siponimod significantly reduced the risk of 3-/6-month confirmed disability progression (3m/6mCDP) versus placebo by 21% and 26%, respectively in patients with secondary progressive multiple sclerosis (SPMS), during the core part of the EXPAND study. At the end of EXPAND-Core, patients were offered a switch to open-label siponimod in the ongoing EXPAND-Extension allowing follow-up for up to an additional 7 years; therefore, a long-term comparison between siponimod and placebo was not possible and a modeling for the placebo long-term trajectory was proposed using different statistical methodology.

Objectives

To estimate the long-term effect of siponimod versus placebo by modeling placebo treatment corrected for switch at the end of EXPAND-Core.

Methods

In the EXPAND-Extension part, 6mCDP was analyzed to assess disability. Time to 6mCDP to account for the switch to siponimod in placebo-treated patients was modeled by 3 methods: 1) Rank Preserving Structural Failure Time (RPSFT) model that uses the actual time to 6mCDP for switchers to compute a hypothetical time to 6mCDP as if they had never switched; 2) simulating the hypothetical time from the switch to 6mCDP based on core part data as if patients had never switched (Two-stage method); and 3) a parametrical model (Weibull distribution) to extrapolate a placebo survival curve.

Results

As of 6 April 2019, 878 patients (siponimod, n=593; placebo-siponimod switch, n=285) were still ongoing in the EXPAND-Extension. All 3 methods confirmed the long-term effect of siponimod versus placebo in the EXPAND population. The RPSFT model seems to provide the more accurate estimate for time to 6mCDP (hazard ratio [95% confidence interval]: 0.69 [0.53; 0.90]) vs the Two-stage (0.76 [0.64; 0.92]) and Weibull modeling methods (0.58 [0.49; 0.67]). The RPSFT results were indicative of a persistent treatment effect over 5 years with a ~50–60% increase in the time to 6mCDP in siponimod versus placebo-corrected switch (median time to 6mCDP: 42.5 months for placebo-corrected switch as opposed to 51.7 months for uncorrected placebo; median not reached with siponimod). Accuracy of RPSFT is supported by simulations conducted under conditions similar to the EXPAND study, which included waning and increasing treatment effects, that found very low difference between the true hazard ratio and the hazard ratio obtained with RPSFT.

Conclusions

The results support the reliability of RPSFT to model a virtual placebo arm in the long-term in a SPMS population. RPSFT results confirmed a long-term benefit of siponimod over placebo with a preserved hazard ratio on 6mCDP and ~50‒60% prolongation of time to 6mCDP.

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Biostatistical Methods Poster Presentation

P0014 - Personalized and dynamic prognostic model from the Barcelona CIS cohot (ID 1607)

Abstract

Background

In the constantly evolving field of MS, personalized medicine is still one of the most important unmet need that requires further attention

Objectives

We aimed to develop a dynamic risk calculator to predict the long-term prognosis of MS in the context of a large MS Centre in Catalonia

Methods

This is an observational study based on data prospectively acquired from a deeply phenotyped CIS cohort from Barcelona. We first built a natural history baseline risk score (BRS) for predicting moderate disability, integrating baseline prognostic factors: Sex, age at CIS, CIS topography, number of T2 lesions, contrast-enhancing lesions (CEL) and oligoclonal bands. This BRS was designed as follows: For untreated patients, we built a Weibull model to estimate the median time to confirmed EDSS 3.0 and with these estimates we identified risk groups based on the median of the cut-offs of 2000 survival trees. Then we obtained the BRS of the full cohort. In patients with more than ten years of follow-up, we performed an inverse probability weighting to balance patients during their follow up for the propensity of being treated or lost to follow-up. The weights were estimated via a proportional hazards (PH) Cox model considering both baseline information (CIS year, BRS) and time-dependent (diagnosis status, new T2 lesions, CEL and cumulative number of relapses). Finally, a weighted PH Cox model was built to estimate the time to confirmed EDSS 3.0 considering the BRS and time-dependent events (new T2 lesions, cumulative number of relapses and first or second-line treatment use). Sensitivity analyses using other disability outcomes and different follow-ups were conducted.

Results

Of 956 patients, 577 (60.4%) were untreated before confirmed EDSS 3.0. Two BRS were obtained: low and high-BRS. Of 400 patients followed for more than ten years, 226 (56.5%) were low-BRS and 174 (43.5%) were high-BRS. High-BRS showed a HR=2.16 95%CI (1.16,4.02). Each new T2 lesion presented HR=1.04 95%CI (1.00,1.08) and each new relapse HR=1.46 95%CI (1.23,1.74). Being on second-line treatment showed a protective effect (HR=0.23 95%CI (0.06,0.94)) but no association was found for first-line treatments (HR=1.32 95%CI (0.67,2.60). Sensitivity analyses confirmed the association between BRS, new T2 lesions and the accumulation of relapses with the prognosis. However, treatment results were inconclusive.

Conclusions

Presenting a high-BRS doubles the risk of reaching moderate disability. Each new lesion and new relapse increses the risk by 4% and 46%, respectively; and second-line treatments seem to be protective. If validated, this risk calculator could be a crucial step to personalized medicine.

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Machine Learning/Network Science Poster Presentation

P0015 - Predicted brain age as a cognitive biomarker in Multiple Sclerosis (ID 1388)

Speakers
Presentation Number
P0015
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Brain-predicted age difference (BPAD) is the difference between chronological and brain age, the latter being decoded from brain MR images by a machine learning model. BPAD has been established as a biomarker for physical deterioration in multiple sclerosis (MS).

Objectives

The objective was to examine the value of brain-predicted age difference as a biomarker for cognitive deterioration in MS.

Methods

In the first phase we used supervised machine learning (ridge regression, 7-fold cross-validation) to predict chronological age from brain volumes. This was achieved on a sample of 1743 healthy controls (HC) with T1-weighted MR images from a range of public collections, using the icobrain software to compute normalized brain volumes (whole brain, white matter, (cortical) grey matter and lateral ventricles). The age range of this sample was 8 to 94 years. In the second phase we applied this algorithm to decode brain age in 231 T1-weighted MR images from MS patients from two clinical centers. The age range of this sample was 14 to 77 years. BPAD computed for HC (BPADHC) and MS (BPADMS) were compared with an independent student t-test. Cognitive functioning was assessed through the symbol digit modalities test (SDMT), available for all 231 included MS patients, the brief visuospatial memory test revised (BVMT-R) and California verbal learning test II (CVLT-II), the latter two being available for a subset of 97 patients from one center. Pearson correlation was computed between the BPAD values and scores on each cognitive test. P-values were corrected for multiple comparisons by the Benjamini/Hochberg method.

Results

After training, the mean (SD) BPADHC in the best-performing of seven folds was -0.5 (9.2) years, opposed to 9.7 (12.0) years for BPADMS. This difference was statistically significant (p < 0.001). Correlations between BPADMS and SDMT, BVMT-R and CVLT-II were -0.19 (p = 0.005), -0.14 (p = 0.157) and -0.30 (p = 0.005) respectively.

Conclusions

Our results showed a significant association between BPADMS and two cognitive measures in MS, information processing speed and verbal memory. These findings support a potential role for BPADMS as a cognitive biomarker in MS.

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Machine Learning/Network Science Poster Presentation

P0016 - Progressive multifocal leukoencephalopathy lesion and brain parenchymal segmentation from MRI using serial deep convolutional neural networks (ID 1531)

Speakers
Presentation Number
P0016
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the JC virus associated with significant morbidity and mortality, which can occur in the context of certain MS disease modifying therapies. There are currently no validated automatic methods for quantification of PML lesion burden or brain atrophy on MRI.

Objectives

We assessed whether deep learning techniques can be employed for automated brain parenchymal and lesion segmentation in PML using an approach dubbed “JCnet,” named after the causative viral agent.

Methods

We performed a retrospective analysis of PML patients who were evaluated at the NIH Neuroimmunology Clinic. MRI scans were acquired on either a Siemens Skyra or a Philips 3T MRI scanners. For PML brain and lesion segmentation, we implement a 3D patch-based approach with two consecutive fully convolutional neural networks (CNNs) with a feature pyramid architecture. The first network performs brain extraction as foreground, with meninges and cerebrospinal fluid spaces as background , while the second segments the underlying PML lesion(s). We measured the segmentation accuracy using Dice similarity coefficient (DSC) and absolute volume differences (AVD). We evaluated JCnet against methods designed for normal-appearing brain segmentation, FSL/FMRIB's Automated Segmentation Tool (FAST) and FreeSurfer, as well as MS lesion segmentation, Lesion Segmentation Toolbox (LST) and Lesion-TOpology-preserving Anatomical Segmentation (LTOADS). Comparisons were performed using Wilcoxon matched-pairs signed-ranks test.

Results

A total of 41 PML patients (mean age 55 years, SD 13; 44% female) were included in the analysis. The cohort was empirically divided into 31 training and 10 testing cases sampled at random. The mean time between PML onset and MRI acquisition was 4.5 months (range 0.6 – 44.5 months). JCnet resulted in a 4% and 64cm3 absolute improvement in DSC and AVD compared to FAST (p=0.005 and 0.01), and a 6% and 41cm3 absolute improvement compared to FreeSurfer respectively (p=0.005 and p=0.02). This was driven in part by improved segmentation of brain tissue within T1-hypointense PML lesions. For PML lesion segmentation, there was an absolute improvement of 42% and 14cm3 in DSC and AVD respectively compared to LST, and 53% and 19cm3 absolute improvements compared to LTOADS respectively (p=0.005 for all lesion comparisons). This was driven by improved sensitivity of supra- and infratentorial PML lesion identification and segmentation.

Conclusions

We employ an end-to-end deep learning-based method for automated segmentation of lesion and brain parenchymal volume in PML. By tracking quantitative measurements of PML-related MRI changes, this approach provides a window for clinicians and scientists to accurately monitor PML radiographically and its response to experimental therapies.

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Machine Learning/Network Science Poster Presentation

P0017 - Translating MPRAGE to MP2RAGE improves the automatic tissue and lesion segmentation in Multiple Sclerosis patients (ID 766)

Speakers
Presentation Number
P0017
Presentation Topic
Machine Learning/Network Science

Abstract

Background

Compared to the conventional magnetization-prepared rapid gradient-echo imaging (MPRAGE) MRI, magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE) (Marques, J. P., 2010) shows a higher brain tissue and lesion contrast in multiple sclerosis (MS) patients. This specialized sequence is, however, mainly limited to research settings and not widely acquired in clinical routine.

Objectives

To synthesize realistic-looking MP2RAGE images from MPRAGE acquisitions via generative adversarial network (GAN) and verify if these improve the performance of automatic MS lesion and brain tissue segmentation tools.

Methods

We propose a GAN inspired by the pix2pix framework (Isola, P., 2018) which takes as input 2D slices of 3D MPRAGE images and generates a synthetic MP2RAGE (synMP2RAGE). Differently from pix2pix, the generator of the GAN combines three loss functions: a pixel-wise L1 loss, an adversarial loss, and a perceptual loss. Our framework is trained on 12 healthy controls and 8 MS patients and tested on 36 MS patients, for which an expert manually delineated cortical and white matter lesions. Imaging was performed with a 3T MRI scanner (Siemens Healthcare, Erlangen, Germany) with a 1x1x1.2 mm resolution. Evaluation is performed with reference-based metrics and through automatic segmentation of MS lesions (La Rosa, F., 2020) and brain tissue (Avants, B.B., 2011).

Results

Considering as reference the acquired MP2RAGE, synMP2RAGE achieves a peak signal-to-noise ratio of 31.39, normalized root mean square error of 0.13, and structural similarity index of 0.98, overperforming the MPRAGE (29.49, 0.17, 0.97, respectively) for all metrics. Compared to the initial MPRAGE it also significantly improves the lesion and tissue segmentation masks in terms of the Dice coefficient and volume difference (p-values < 0.001). On the contrary, no significant differences between the real and synMP2RAGE are found in the patient-wise comparison of the lesions’ segmentation (p-values > 0.05), whereas they are significant between MPRAGE and MP2RAGE (p-value < 0.001).

Conclusions

Our proposed framework successfully translates MPRAGE to MP2RAGE, synthesizing realistic-looking images which improve the performance of automatic segmentation tools tested on MS patients. In accordance with previous claims (Finck, T., 2020), these results confirm that GANs can be helpful in the automatic analysis of MRI images.

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Biostatistical Methods Poster Presentation

P0018 - Variability of the response to immunotherapy among sub-groups of patients with multiple sclerosis (ID 1239)

Abstract

Background

Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited.

Objectives

To assess whether patients’ response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype.

Methods

Using the international MSBase registry, we selected patients with MS followed for ≥1 year, with ≥3 visits, ≥1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity.

Results

Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively].

Conclusions

DMTs are associated with reduction in relapse frequency, progression of disability, and increased chance of recovery from disability. In general, the effectiveness of DMTs was most pronounced in subgroups with shorter MS duration, lower EDSS, lower relapse rate and relapsing MS phenotype.

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Biosensors Poster Presentation

P0019 - A Comparison of Digital Gait Technologies in a Population of People with MS –When the Same Isn’t Always Exactly the Same (ID 1944)

Speakers
Presentation Number
P0019
Presentation Topic
Biosensors

Abstract

Background

Multiple Sclerosis (MS), a disease characterized both by relapses and progression, commonly impacts ambulation. Impaired ambulation results in loss of independence. Current approaches to document disease impact/progression on ambulation including EDSS/T25FW are insufficiently sensitive to quantify subtle but critical change. Patient Reported Outcomes (PRO) for gait relate to several critical elements of the gait cycle beyond velocity. Earlier recognition of critical change might improve disease modifying therapy choice and timing of change. Objective multi-dimensional analytics have included digital devices of varying types utilizing different technologies (e.g. foot pressure, accelerometer, 3D video capture). Comparing different technologies in people with MS (PwMS) along a spectrum of disability would be important to optimal technology choice. Simultaneous comparisons of similar outcome measures of gait components would enhance technology choice.

Objectives

To compare and contrast quantified outcome measures of the gait cycle as measured by the use of three different validated and digital ambulatory devices.

Methods

PwMS performed one pass (20 feet) while ambulating at a preferred walking speed along the Zeno™ walkway (ZW, ProtoKinetics), while wearing Opal sensors (OS, APDM), and captured using VSTBalance (VB, VirtuSense) simultaneously. Relevant gait parameters (GP) captured: velocity, stride length, total double support, and cadence. Univariate regression modeling and T-tests were used for statistical analysis for each GP.

Results

9 PwMS (69% female, average age =53.1±11.8 years). Regression modeling showed the following relationships: velocity: ZWvsVB (r2 =0.93, p=1.2E-25), ZWvsOS (r2 =0.99, p=6.9E-40), VBvsOS (r2 =0.96, p=1.8E-25) Stride Length: ZWvsVB (r2 =0.32, p=7.8E-25), ZWvsOS (r2 =0.9, p=1.02E-16), VBvsOS (r2 =0.30, p=1.3E-4). Total double support %: ZWvsVB (r2 =0.22, p=1.6E-3), ZWvsOS (r2 =0.87, p=3.2E-20), VBvsOS (r2 =0.27, p=3.9E-4). Cadence: ZWvsVB (r2 =0.18, p=5.3E-3), ZWvsOS (r2 =0.92, p=1.2E-23), VBvsOS (r2 =0.19, p=4.2E-3). T-tests showed the following relationships: velocity: ZWvsVB (p=0.47), ZWvsOS (p=0.21), VBvsOS (p=0.63). Stride Length: ZWvsVB (p=7.25E-6), ZWvsOS (p=0.08), VBvsOS (p=0.001). Total Double Support %: ZWvsVB (p=0.91), ZWvsOS (p=0.01), VBvsOS (p=0.02). Cadence: ZWvsVB (p=5.6E-5), ZWvsOS (p=0.92), VBvsOS (p=6.3E-5).

Conclusions

Gait velocity had the strongest concordant relationship between all three technologies. Despite this concordance, there was still ~10% variability of this important measure. Other elements of the gait cycle had sub-optimal cross-device relationships. There was considerable discordance with stride length and cadence (ZWvsVB and OSvsVB), and double support (ZWvsOS and VBvsOS). Inconsistent relationships demonstrate the need to carefully select digital gait outcome measurement devices for PwMS.

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Biomarkers and Bioinformatics Poster Presentation

P0020 - A down-regulation of the type I interferon signaling pathway is associated with the response to teriflunomide in multiple sclerosis. (ID 1584)

Abstract

Background

Teriflunomide is an oral first-line treatment of patients with relapsing-remitting multiple sclerosis (RRMS) that has been shown to decrease clinical relapses, reduce brain magnetic resonance imaging (MRI) activity, and slow progression of disability. However, the drug exhibits only limited effectiveness and does not produce clinical benefits in a proportion of MS patients.

Objectives

We aimed to identify differentially expressed genes and cellular pathways associated with the responder and non-responder status in RRMS patients treated with teriflunomide by means of RNA sequencing (RNA-seq).

Methods

RRMS patients treated with teriflunomide were classified into those with No evidence of disease activity (NEDA 3) and those with EDA after 12 months of treatment. Eleven responders [8 females; mean age (standard deviation): 45.8 years (4.5)] and 10 non-responders [8 females; 41.8 years (10.3)] were included in the study. RNA-seq was performed in RNA samples isolated from peripheral blood mononuclear cells before and after 12 months of teriflunomide treatment. 100 bp, paired-end RNA sequencing was performed by using DNAseqTM Technology. Comparative analysis of differentially expressed genes between responders and non-responders was performed at baseline and after 12 months of treatment. Pathway analysis was based on KEGG database using statistically significant genes.

Results

Pathway analysis revealed the type I interferon (IFN) signaling pathway as the most significantly associated with the responder phenotype after 12 months of teriflunomide treatment (p<0.0001). In this context, expression levels for genes known to be predominantly or selectively induced by type I IFNs such as SP100, ZBP1, IFI27, ISG20, IFITM1, IFITM2, MX1, STAT1, PARP9, IFI35, RGS1, RSAD2, IFI44L, IRF1, DDX58, IFI6, IFIT1 and IFIT5 were significantly reduced by the effect of teriflunomide after 12 months of treatment in responders compared to non-responders. At baseline, expression levels for type I IFN genes were similar between responders and non-responders.

Conclusions

Type I IFNs are known to activate dendritic cells, enhance humoral immunity, and favor Th1 immune responses. A down-regulation of type I IFN genes after 12 months of treatment may explain the beneficial effect of teriflunomide in responders. Mechanistic studies are currently underway to investigate the functional implication of the type I interferon signaling pathway in the response to teriflunomide.

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Clinical Outcome Measures Poster Presentation

P0021 - A propensity-matched comparison of long-term disability progression in MS patients treated with dimethyl fumarate or fingolimod (ID 709)

Speakers
Presentation Number
P0021
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Previous comparative effectiveness studies in multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY) on measures of inflammatory disease activity but most studies did not assess long-term disability.

Objectives

To compare long-term disability progression over 5 years (yrs), as assessed by Patient-Determined Disease Steps (PDDS), in NARCOMS registry participants (pts) treated with DMF or FTY.

Methods

The NARCOMS registry is a voluntary self-report registry of people with MS. Pts provide health-related information at enrollment and every 6 months thereafter. We identified pts with RRMS; living in the US; and initiating index DMT (DMF or FTY) from Spring 2011 through Spring 2018. Pts were included if they had ≥1 yr follow-up on index DMT. DMF pts treated with prior FTY, and FTY pts treated with prior DMF, were excluded. We used 1:1 propensity-score matching (PSM) to match FTY to DMF pts. Baseline factors (at time of index DMT initiation) used for PSM were age, disease duration, sex, number of prior DMTs, education, PDDS, cognition score, depression score, relapses in last 6 months, and cardiovascular comorbidities. Time to 6-month confirmed disability progression (≥1-point increase on PDDS sustained for ≥6 months) was estimated using the Kaplan-Meier method and compared using a Cox proportional hazards regression model with robust sandwich estimators. Pts were censored at last follow-up or at the time of DMT discontinuation.

Results

Overall, 689 DMF and 565 FTY pts were included. After PSM, 468 DMF pts were matched with 468 FTY pts. The survey compliance was high in both groups, with >93% of pts in both groups completing ≥50% of surveys while on treatment. Baseline characteristics were well-balanced after PSM, with standardized differences <0.1 for each covariate. Median treatment duration was 3.0 yrs for DMF and 4.0 yrs for FTY. At 5 yrs, 68.3% (95% CI: 62.4-73.5) of DMF pts and 63.3% (95% CI: 59.6-70.1) of FTY pts were free from 6-month confirmed PDDS progression (hazard ratio: 1.01 [95% CI: 0.79-1.28]; p=0.95).

Conclusions

In this propensity-matched analysis of MS pts from the NARCOMS registry, there was no significant difference between DMF and FTY on confirmed disability (PDDS) progression over 5 yrs. These results are consistent with previous studies that have shown similar effectiveness between DMF and FTY on relapse and MRI outcomes.

Supported by: Biogen; NARCOMS is a project of the CMSC

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Clinical Outcome Measures Poster Presentation

P0022 - A systematic literature review and meta-analysis of the efficacy and effectiveness of PR-fampridine in patients with multiple sclerosis (ID 1316)

Speakers
Presentation Number
P0022
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Prolonged release (PR) fampridine is indicated for the improvement of walking in adult multiple sclerosis (MS) patients. Several studies have supported that PR-fampridine improves walking ability in this population; however, reported effects have varied widely across studies and study design.

Objectives

To conduct a systematic literature review (SLR) and meta-analysis (MA) to summarize the evidence on the efficacy and effectiveness of PR-fampridine in MS patients.

Methods

Following PRISMA guidelines, a systematic search of PubMed, EMBASE, YORK and Cochrane Library was conducted from January 1, 2006-April 1, 2019 to identify publications comparing the efficacy and effectiveness of PR-fampridine from Randomized Controlled Trials (RCTs) and observational studies (OBS). For RCTs, outcome measures include Timed 25-Foot Walk (T25FW) and 12-item Multiple Sclerosis Walking Scale (MSWS-12) responders and MSWS-12 scores; for OBS, T25FW walking time and MSWS-12 scores. In the MA, pooled estimates were derived using odds ratios (OR) and standardized mean differences (SMD) of both endpoints. Results from RCTs and OBS were reported separately using a random effects model.

Results

Of a total of 897 unique citations, 27 studies met all criteria for inclusion in the MA, 9 RCTs and 18 single-arm OBS. A pooled estimate based on T25FW responder data from 4 RCTs showed statistically significant improvements in walking ability in the PR-fampridine vs. placebo group; OR (95% CI): 4.8 (2.9-7.9), p<0.0005. Also, findings based on MSWS-12 responder data from 2 RCTs showed significant improvements in walking ability in the PR-fampridine group vs. placebo; OR (95% CI): 1.7 (1.1-2.5); p=0.011. A pooled estimate of mean MSWS-12 scores from 4 RCTs also showed significant improvements in the PR-fampridine vs. placebo group; OR (95% CI): 1.5 (1.2-1.9); p<0.0005. Summary estimates from OBS suggest a significant improvement vs. baseline on T25FW time derived from 9 studies showing that walking time was significantly improved vs. baseline; with SMD (95% CI): –0.31 (-0.479 to -0.146); p<0.0005. Also, the pooled estimate from MSWS-12 endpoint in 6 studies showed that walking ability was statistically improved vs. baseline; SMD (95% CI): -0.98 (-0.892 to -1.058); p<0.0005.

Conclusions

Across randomized and observational data, the use of PR-fampridine is consistently associated with significantly improved walking ability in MS patients measured by MSWS-12 or T25FW endpoints.

This study is funded by Biogen. Biogen funded the analyses for this abstract.

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Clinical Outcome Measures Poster Presentation

P0023 - Alemtuzumab Real World Evidence in a Private Practice Setting (ID 1858)

Speakers
Presentation Number
P0023
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Alemtuzumab significantly improved clinical, MRI, and disability outcomes compared to sub-cutaneous interferon β-1a in MS patients in two phase 3 clinical trials and provided efficacy and safety rationale for treating relapsing multiple sclerosis (RMS) patients in a clinical trial setting. The need for additional data illustrating the efficacy and safety of alemtuzumab use in MS patients outside the clinical trial setting and in the real world exists.

Objectives

To describe patient characteristics and clinical outcomes in RMS patients who have received alemtuzumab in a single neurology center in the United States.

Methods

This retrospective, observational study included patients treated with alemtuzumab and had at least 24 months of follow-up. Patient characteristics and clinical outcomes [annualized relapse rate; disability progression, magnetic resonance imaging (MRI)] were analyzed. Patient data for at least 1 year prior and for up to 2 years after initiation of alemtuzumab was collected via chart reviews for all patients.

Results

A total of 250 patients were included in the study. Mean (standard deviation) age at baseline was 49.7 (10.5). 85% of patients switched from natalizumab during the pre-index period primarily due to JCV positive status (57%). Annualized relapse rate was reduced from 0.088 (2-year pre-) to 0.004 (2-year post) index date (p<0.0001) and 0.164 (1-year pre-) to 0.004 (1-year post) index date (p<0.0003). At 2 years, more patients were stable on brain MRI (98.3% vs. 85.0%) and less patients demonstrated brain MRI worsening (1.27% vs. 14.2%) compared to index date (p <0.0001). Mean (95% Confidence Interval) observed EDSS was 3.58 (3.37, 3.79) at baseline and decreased to 3.03 (2.78, 3.28) and 2.82 (2.53, 3.11) at year 1 and year 2, respectively. The average follow-up time for EDSS was 3.72 years (range: 0 - 4.58 years). At 2 years, 84% of patients did not require ambulatory aid.

Conclusions

This study further supports clinical and radiological efficacy of alemtuzumab in RMS patients. After treatment with alemtuzumab, there was a significant reduction in annualized relapse rate, a significant increase in the proportion of patients with stable brain MRI, improvement in disability, and reduced usage of ambulatory aid. Long term follow-up of this cohort will help assess clinical efficacy in a real-world setting.

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Clinical Outcome Measures Poster Presentation

P0024 - Alemtuzumab slowed brain atrophy over 6 years in patients without relapse and MRI disease activity: post hoc analysis of the pooled CARE-MS studies (ID 784)

Abstract

Background

Over 2 years in the CARE-MS trials (NCT00530348; NCT00548405), alemtuzumab (12 mg/day; baseline (BL): 5 days; 12 months later: 3 days) significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Alemtuzumab efficacy was maintained through a 4-year extension study (NCT00930553), wherein patients could receive additional 3-day courses (≥12 months apart, as needed for disease activity) or receive other disease-modifying therapy per investigator’s discretion.

Objectives

To evaluate post hoc the effects of alemtuzumab on brain atrophy over 6 years in CARE-MS patients without relapses and MRI disease activity.

Methods

Analysis included pooled CARE-MS patients with or without disease activity between BL and Year 1 or BL and Year 2. Absence of disease activity was defined as no BL gadolinium (Gd)-enhancing T1 lesions and no clinical relapses or MRI disease activity (new Gd-enhancing or new/enlarging T2 lesions) from Years 0-1 or Years 0-2 (Definition 1). A second definition had the additional criterion of no relapse within 60 days before BL (Definition 2). Brain atrophy was measured by brain parenchymal fraction (BPF); differences in the median annualized percent change in BPF were assessed using ranked ANCOVA adjusted for region and BL BPF.

Results

Compared with SC IFNB-1a, alemtuzumab reduced median annualized percent change in BPF in patients free of disease activity during Years 0-1 (Definition 1: -0.37% vs -0.61%, P=0.006; Definition 2: -0.36% vs -0.54%, P=0.024) or Years 0-2 (Definition 1: -0.27% vs -0.44%, P=0.014; Definition 2: -0.28% vs -0.41%, P=0.045). Median annualized percent change in BPF was reduced with alemtuzumab versus SC IFNB-1a in patients with disease activity in Years 0-1 (-0.61% vs -0.79%, P=0.005) or Years 0-2 (-0.40% vs -0.56%, P<0.0001). Over 6 years, brain volume loss (BVL) was slower in patients without disease activity who initiated alemtuzumab at core study BL (-1.66%) than in those who received SC IFNB-1a in the core studies and initiated alemtuzumab in the extension (-2.05%).

Conclusions

Brain atrophy was reduced with alemtuzumab compared with SC IFNB-1a in patients without disease activity over 2 years. A slower rate of BVL was maintained through Year 6 in patients without disease activity who received alemtuzumab in the core study compared with SC IFNB-1a, suggesting alemtuzumab may slow neurodegeneration associated with BVL.

STUDY SUPPORT: Sanofi.

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Clinical Outcome Measures Poster Presentation

P0025 - Analysis fo the results of the establishment of a SARS-CoV-2 safety protocol for Multiple Sclerosis patients  (ID 1512)

Speakers
Presentation Number
P0025
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The SARS-CoV-2 infection has spread worlwide becoming a pandemic never before seen. Immunosuppressive (IS) treatments used in Multiple Sclerosis (MS) patients could activate the infection in asymptomatic carriers or reactivate COVID-19 in apparently recovered cases. Our similar experience in some MS patients during the pandemic lead us to design a safety protocol at our MS Unit. It was based on epidemiological data and testing for PCR in nasopharyngeal swabs and serology before administration of monoclonal antibodies, doses of pulsed disease modifying therapies (DMTs), new starts of oral DMTs and methylprednisolone pulses.

Objectives

To describe our experience in the establishment of a SARS-CoV-2 safety protocol in MS patients. We analyze its utility to prevent COVID-19 complications

Methods

Observational, prospective and clinical practice study in the establishment of a multidisciplinary safety protocol (MS Unit – Neurology/Microbiology/Preventive Medicine). Sequential protocol over time adapted to the different pandemic phases and levels of available resources.

Results

152 PCR and 140 serology tests were performed in 90 patients over 3 months. They were performed preceding the treatment with Natalizumab (96 tests), Ocrelizumab (36 tests), Rituximab (3 tests), Methylprednisolone (7 tests), Cladribine (4 tests) and Dimethyl Fumarate (3 tests). 7 asymptomatic carriers were diagnosed (7,8%), 5 of them with positive IgM+IgG serology (5,6%). 5 patients with positive IgM+IgG serology post-infection were confirmed. No COVID-19 reactivation was detected after the establishment of the protocol.

Conclusions

The combined analysis of PCR and serology increased the sensitivity of the SARS-CoV-2 infection diagnosis during the pandemic peak of cases phase. However, this does not happen at pandemic phases with less daily cases, when testing PCR alone detected the same number of cases than testing combined PCR and serology. The safety protocol reaches its objective of avoiding disease reactivation and clinical activation in asymptomatic carriers.

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Clinical Outcome Measures Poster Presentation

P0026 - Analysis of association between expanded disability status scale and patient determined disease steps (ID 421)

Speakers
Presentation Number
P0026
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The Expanded Disability Status Scale (EDSS) is a commonly used measure of disability based on a clinician administered neurological exam in patients with Multiple Sclerosis (pwMS). Ordinal scores range from 0 (no disability) to 10 (death) in 0.5-point increments. The Patient Determined Disease Steps (PDDS) is a patient-reported measure of disability in pwMS, with ordinal scores ranging from 0 (no disability) to 8 (bedridden) in 1-point increments. Few studies have characterized the association between EDSS and PDDS. Those that have are limited by small sample sizes (n=96 to 103) and inconsistent and sometimes unrealistic correlations for patients with mild disability. For example, one of the studies reported a PDDS of 0 corresponds to an EDDS of 2.9.

Objectives

To characterize the association between EDSS and PDDS in a large sample of pwMS, which can help in the better application of PDDS in practice.

Methods

A total of 406 subjects participating in a US-based prospective cohort study were used for the analyses. All subjects had EDSS and PDDS assessments at baseline and approximately 12-months post-baseline, providing a total of 812 assessments. Mixed effect regression models using cubic splines, growth curve models and quadratic polynomials were employed to characterize the association between EDSS and PDDS and compared with models available in literature.

Results

The mean (standard deviation) age was 48.6 (10.35) years and 72.9% were female. Based on the Akaike’s Information Criterion, the quadratic polynomial regression was found to be the best fitting model. The equation predicting EDSS had the following form: EDSS = 1.4359 + 0.0830 * PDDS + 0.0999 * PDDS2, which was modestly convex in shape. Patients with a PDDS of zero were predicted to have an EDSS of 1.4 and patients with a PDDS of 8 were predicted to have an EDSS of 8.4.

Conclusions

The fitted relationship between EDSS and PDDS in this large sample of pwMS showed generally similar scores across the ranges of the scales. The equation predicting EDSS as a function of PDDS revealed a more realistic fit when compared against other published equations. This study successfully developed a user-friendly crosswalk between EDSS and PDDS scores, using repeat measurements over a large sample. This crosswalk can aid in the better application and interpretation of PDDS.

Sponsored by: Biogen

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Biomarkers and Bioinformatics Poster Presentation

P0027 - Are we ready for precision medicine in Multiple Sclerosis? A web-based survey across Europe   (ID 1411)

Presentation Number
P0027
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

We designed a web-based survey to assess the willingness and interest of European neurologists working with MS to implement precision medicine in their routine clinical practice. This study is a part of the EU-funded MULTIPLEMS grant.

Objectives

1) To assess how neurologists across European countries view the role of body-fluid biomarkers in clinical practice; 2) To survey clinical practices of diagnostic work up, therapy selection and monitoring, and frequency of data collection and clinical and paraclinical measurements.

Methods

The survey had three parts: a) demographics of respondents; b) opinion of the role of predictive, diagnostic, disease-activity biomarkers and treatment-response body-fluid biomarkers in clinical practice; c) survey of clinical practice and management of MS cases (including therapy choice and use of biomarkers) by evaluating 5 clinical cases with different characteristics (therapeutic management in drug naive patients and in patients displaying different forms of remaining disease activity, as well as stopping threapy in stable diasease since long).

Results

194 neurologists across 11 European countries responded to the survey, with a mean response rate of 45%. 57.7% were male and the mean age was 49.8 years. The importance of biomarkers in clinical practice was rated from 1 (low) to 7 (high), and it was generally high: 4.1 for predictive and disease-activity biomarkers, 5.2 for treatment-response and 5.7 for diagnostic biomarkers, with neurologists in Belgium, Denmark, Spain, Sweden and UK being the most positive. Determination of cerebrospinal fluid (CSF) oligoclonal bands was considered the most established biomarker for diagnosis (98.5% of neurologists), prediction (56.7%) and disease activity (36.5%), trailed by anti-aquaporin 4 (90.7%) and anti-myelin oligodendrocyte antibodies (85.1%) for diagnosis. Anti-JC (93.8%) and varicella virus (61.9%) and anti-drug (natalizumab (74.7%) and interferon-beta (68.6%)) were considered useful in context of therapy selection and monitoring by most neurologists, while neurofilament levels in CSF and serum and vitamin D levels were less established. Therapeutic management in the five case examples varied widely, likely as a result of differences in local and national guidelines.

Conclusions

European MS neurologists express a positive opinion on the role of body-fluid biomarkers to manage MS in clinical practice, however, these seem still to have had a limited impact on therapeutic management and selection, which also varied markedly across countries. This underscores the need for further research in this area.

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Biomarkers and Bioinformatics Poster Presentation

P0028 - Assessing the temporal relationship of serum neurofilament light and subclinical disease activity: Findings from APLIOS trial (ID 1641)

Speakers
Presentation Number
P0028
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Several studies showed prognostic value of serum neurofilament light chain (sNfL) in relapsing multiple sclerosis (RMS). For the first time, we explored the association of sNfL and subclinical disease activity using data from the APLIOS trial.

Objectives

To evaluate the potential of sNfL as a patient-level biomarker for monitoring subclinical disease activity in RMS patients.

Methods

In the APLIOS open-label study of ofatumumab 20 mg s.c in RMS (n=284), frequent (14 time points over 12 weeks) sNfL measurements were performed (Siemens sNfL RUO assay on ADVIA Centaur®). MRI scans were done every 4 weeks. The potential monitoring value of sNfL was examined in 3 ways: 1) Age-adjusted geometric mean sNfL over time was estimated in 3 subgroups: patients who had on-study clinical relapses (r+), patients with presence of gadolinium-enhancing T1 (GdT1) lesions at or post-baseline but no clinical relapses (GdT1+r) and patients with neither lesions nor clinical relapses (GdT1r); 2) As high-frequency sampling permitted an estimation of daily sNfL levels, every report of GdT1 lesion was linked to the estimated sNfL level at the time of the scan (using a recurrent-events analysis); and 3) Patient-level predictions of GdT1 lesion were done using the last sNfL value before the corresponding scan and compared with MRI-based predictions (in terms of across-scan average area under the receiver operating characteristics curve [AUC]).

Results

Over the study course, the age-adjusted geometric mean sNfL levels in the GdT1rgroup (n=153) were low compared to other two subgroups, with 95% CIs below those of the r+ (n=15) and GdT1+r(n=116) groups. After adjusting for baseline age and MRI covariates, a between-patient difference of 50% higher sNfL at the time of GdT1 scan was associated with a 29% higher risk of persistent GdT1 lesion (p<0.0001). At the individual patient level, the predictive power of the last sNfL value (AUC=0.76) before scan for presence of GdT1 lesion was similar to that of baseline GdT1-count (AUC=0.77).

Conclusions

This study suggests sNfL may have utility for monitoring of subclinical disease activity in RMS patients as shown by its predictive value of GdT1 lesion activity. Assessments of sNfL could complement regular MRIs, and may provide an alternative in cases where standard MRI monitoring is infeasible.

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Clinical Outcome Measures Poster Presentation

P0029 - Assessment of Multiple Sclerosis Severity Score and Age-Related Multiple Sclerosis Severity Score as health indicators in a population-based cohort (ID 447)

Speakers
Presentation Number
P0029
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Persons with multiple sclerosis (MS) present varying degrees of disability throughout the course of the disease. The Multiple Sclerosis Severity Score (MSSS) and the Age-Related Multiple Sclerosis Severity Score (ARMSSS) adjust the score obtained in the Expanded Disability Status Scale (EDSS) according to disease duration and age, respectively. These measures could be useful as health outcome indicators.

Objectives

The aim of this study was to describe the severity of MS in our health district and assess MSSS and ARMSSS consistency over time.

Methods

Patients diagnosed with MS according to 2010 McDonald criteria, with at least one year of disease duration and followed up in our MS unit within the previous 18 months were selected. Sex, age at onset, disease duration, clinical course, age and irreversible EDSS at last follow-up visit were collected. MSSS and ARMSSS were calculated. Our cohort was studied twice, in 2017 and 2020 to assess the consistency of both instruments.

Results

One hundred and seventy-seven patients were included in 2017, and 208 in 2020. Prevalence of MS in our health district was 90 and 105 per 100,000 inhabitants, respectively, in line with the expected prevalence. Median MSSS and ARMSSS were similar in both study years. In 2017, median MSSS was 1.77 (IQR 0.76-4.28) and ARMSSS was 2.9 (IQR 1.47-5.72). In 2020, median MSSS was 2.03 (IQR 0.82-4.36) and ARMSSS was 2.93 (IQR 1.51-5.56).

Conclusions

According to MSSS and ARMSSS, our cohort presented mild disease, and the results were consistent at both time points. MSSS and ARMSSS may be reliable health outcome measures.

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Biomarkers and Bioinformatics Poster Presentation

P0030 - Association of average blood cell telomere length with the clinical course of MS over a 10-year period (ID 352)

Speakers
Presentation Number
P0030
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Aging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS.

Objectives

The aim of this study was to evaluate the length of telomeric DNA sequences in peripheral blood in relation to clinical MS phenotypes and disease progression.

Methods

We measured the average leukocyte telomere length (LTL) in biobanked samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS) and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistics and regression models adjusted for age and sex.

Results

The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up period.

Conclusions

Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between age- and disease-related immune system alterations and blood cell telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained by exploring the distribution of telomere lengths in specific cell populations.

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Clinical Outcome Measures Poster Presentation

P0031 - Asymptomatic anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes (ID 1838)

Speakers
Presentation Number
P0031
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Optical coherence tomography is gaining increasing relevance in the assessment of people with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS.

Objectives

The present study aims at exploring the usefulness of optical coherence tomography as a marker of inflammation and disease burden in the earliest phases of the disease.

Methods

a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder. For the present study, patients also received a visual pathway assessment - including OCT, VEP, visual acuity testing –, measurement of CSF inflammatory markers – a set of 17 cytokines-chemokines and, count of extracellular vesicles of myeloid origin –, and dosage of serum neurofilaments.

Results

19.2% of clinically isolated syndromes had abnormal visual evoked potentials in eyes without optic neuritis. Similarly, optical coherence tomography identified neuro-retinal thinning in 17.8% of patients without prior visual symptoms. The presence of asymptomatic involvement of the anterior optic pathway tested with either techniques was associated with a greater disease burden.

A thinner ganglion cell layer in eyes without prior optic neuritis or instrumental evidences of it was correlated with higher EDSS, lower low contrast visual acuity, longer disease duration, higher brain lesion load, presence of gadolinium enhancing lesions, more severe abnormalities along motor and somatosensory evoked potentials, and higher frequency of CSF-specific oligoclonal bands.

We also found that inner nuclear layer thickens in a post-acute (1.1 – 3.7 months) phase after a relapse, particularly in those who did not receive steroid treatment. Likewise, a longitudinal analysis on 65 patients, showed that this swelling is transient and returns to normal values after one year of follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study were strictly associated with one-another but none of them was associated with inner nuclear layer volume.

Conclusions

The present findings suggest that instrumental evidence of asymptomatic optic nerve involvement is associated with a greater disease burden in early MS and clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.

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Biomarkers and Bioinformatics Poster Presentation

P0032 - Baseline serum Neurofilament light chain levels predict conversion to McDonald 2005 MS within 2 yrs of a first clinical demyelinating event in REFLEX (ID 1096)

Speakers
Presentation Number
P0032
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum Neurofilament light chain (sNfL) is a biomarker of neuronal damage, reflecting disease activity, drug response, and is predictive of future disability in established multiple sclerosis (MS).

Objectives

Post hoc analysis to assess whether baseline (Month [M] 0) sNfL concentration can predict conversion to McDonald (McD) 2005 MS in patients (pts) with a first clinical demyelinating event (FCDE) receiving subcutaneous interferon β-1a (scIFNβ-1a) once (qw) or three (tiw) times weekly, or placebo (PBO) in the phase 3 trial REFLEX.

Methods

Pts randomized to scIFNβ-1a tiw (n=171) or qw (n=175), or PBO (n=171) were followed-up over 2 yrs; converters to 'clinically definite MS' switched to open label scIFNβ-1a tiw. High and low M0 sNfL subgroups were defined by median sNfL concentration (26.1 pg/ml at M0). Median (95% confidence intervals [CI]) time to McD MS (days) by treatment group and M0 sNfL subgroup was calculated by Kaplan Meier. Hazard ratios (HR; 95% CI) to determine factors influencing risk of conversion to McD MS were calculated using a univariate Cox’s proportional hazard model. A stepwise multivariate Cox’s proportional hazard model was performed using factors selected from the univariate model (threshold P<0.15). For both models, variable selection was based on a two-sided Wald test.

Results

High sNfL levels at baseline correlated with the likelihood for conversion to McD MS (low vs high M0 sNfL, HR [95% CI]: 0.58 [0.47; 0.72], P<0.001). Other baseline factors that reduced the risk of conversion to McD MS (univariate model) included: classification of FCDE (mono- vs multifocal: 0.68 [0.55; 0.83], P<0.001) and low numbers of MRI lesions (number of T2 lesions: 1.02 [1.02; 1.03], P<0.001; number of T1 gadolinium-enhancing [Gd+] lesions: 1.14 [1.11; 1.17], P<0.001; number of T1 hypointense lesions: 1.04 [1.02; 1.05]; P<0.001). Furthermore, treatment with scIFNβ-1a tiw (vs PBO: 0.53 [0.41; 0.69], P<0.001) or qw (0.71 [0.56; 0.91], P=0.006) reduced the risk of conversion to McD MS. These findings were confirmed by multivariate models for baseline sNfL subgroup (P=0.024), classification of FCDE (P<0.001), most baseline imaging findings (number of T2 lesions, number of T1 Gd+ lesions; (P≤0.001), and on-study treatment (both P<0.001).

Conclusions

Among other factors, baseline sNfL concentration was identified as a predictor of conversion to McD MS in patients with a FCDE.

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Biomarkers and Bioinformatics Poster Presentation

P0033 - Baseline serum neurofilament light levels have prognostic value for on-study MRI activity: Results from ASCLEPIOS trials (ID 1669)

Speakers
Presentation Number
P0033
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In the ASCLEPIOS I/II trials, ofatumumab significantly lowered serum neurofilament light (sNfL) levels, a marker of disease activity and treatment response, in the first assessment at month 3 and at all subsequent visits versus teriflunomide.

Objectives

To investigate the prognostic value of baseline sNfL for on-study disease activity and worsening in patients with relapsing MS, particularly in newly diagnosed, treatment-naïve patients.

Methods

Patients (pooled N=1882) were randomized to ofatumumab or teriflunomide, receiving treatment for up to 30 months. Patients were stratified by median baseline sNfL levels. We assessed annual on-study T2 lesion formation and brain volume loss (BVL, Jacobian integration) by sNfL category in all patients and in the subgroup of newly diagnosed within 3 year of screening without prior disease-modifying treatment (representing natural course of sNfL and disease at baseline) at month 24 or end of study. The annualized rate of new or enlarging T2 (neT2) lesions in year-2 versus year-1 was assessed in all patients by sNfL category (negative binomial model with time [in year] as offset).

Results

Patients with high sNfL (>median) levels at baseline developed more neT2 lesions per year on study than patients with low (≤median) sNfL levels (adjusted mean rate: ofatumumab: 0.95 vs 0.39, relative increase 143%, p<0.001; teriflunomide 5.28 vs 3.02, relative increase 74.5%, p<0.001). The prognostic value of baseline sNfL persists for year-2 (high vs low, ofatumumab: 0.09 vs 0.06, 64.5%, p=0.124; teriflunomide 4.53 vs 3.12, 45.6%, p=0.003. A single sNfL assessment at baseline had no prognostic value for on-study relapses and disability worsening. Patients with high baseline sNfL had higher annualized rate of BVL than patients with low sNfL (ofatumumab: 0.32% vs 0.23%, relative difference 37.3%, p=0.045; teriflunomide: 0.43% vs 0.29%, relative difference 49.4%, p<0.001). The results were consistent in the subgroup of newly diagnosed, treatment-naïve patients. The relative treatment effect of ofatumumab versus teriflunomide was similar across all measures in both the high and low sNfL groups.

Conclusions

Baseline sNfL levels were prognostic for on-study lesion formation and BVL for at least 2 years, in all patients and in the subgroup of newly diagnosed, treatment-naïve patients. sNfL levels can supplement clinical assessments and help identify patients at high risk for future disease activity.

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Biomarkers and Bioinformatics Poster Presentation

P0034 - Can Digital Biomarkers Acquired on a Smarphone Distinguish Healthy Controls from Radiologically Isolated Syndrome Subjects? (ID 238)

Speakers
Presentation Number
P0034
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Radiologically isolated syndrome (RIS) is defined by the incidental finding of MRI lesions suggestive of multiple sclerosis in subjects with a normal neurological examination. Some studies suggested that the use of wearables could unveil infra-clinical differences between RIS subjects and healthy controls (HC).

Objectives

To demonstrate that digital biomarkers collected by a smartphone application can distinguish healthy controls (HC) from subjects with radiologically isolated syndrome (RIS).

Methods

We created a mobile app called MS Screen Test (MSST) that contains:

- Finger tapping speed test: during this task, we measure the mean tapping speed for the dominant hand and the non dominant hand

- Level test: the subject is asked to tilt the phone to move a ball inside a target, then maintain it inside the target for 10 seconds. We measure the required time to bring the ball to the target, then the proportion of time during which the ball is maintained inside the target

- Low contrast vision (LCV) test: letters with varying contrast randomly appearing on the screen. The subject has to tap on the screen each time a letter is seen. The number of good answers is collected

- Cognition test: letters or digits randomly appear on the screen. The subject has to tap on the screen only if a letter is seen. The mean tap latency in milliseconds is collected as well as bad answers

A cohort of HC and RIS subjects were evaluated to compare performances on MSST.

Results

60 HC and 16 RIS subjects were prospectively included (F/M 3.15, mean age 41.6 yrs)

Compared to HC, RIS subjects had a lower tapping speed on both dominant (5.6 Hz vs 6.5 Hz, p=0.001) and non dominant hand (5.1 Hz vs 5.6 Hz, p=0.04), fewer detected letters on the LCV test (10 vs 13, p=0.001) and a higher latency of response on the cognitive test (731 ms vs 599 ms, p<0.0001).

On the level test, the time during which the ball was maintained is the target was shorter for RIS subjects (3 sec vs 4.9 sec, p=0.05).

Conclusions

Our study confirms that digital biomarkers collected by a smartphone can unveil differences between HC and subjects at a presymptomatic stage of MS.

It would be relevant to evaluate whether those biomarkers could predict the risk of conversion to multiple sclerosis, as well as to evaluate their potential predictive value in early diagnosed MS patients

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Biomarkers and Bioinformatics Poster Presentation

P0035 - Can gait modelling predict disease progression in MS? A study using small body worn sensors in a clincial setting.  (ID 1377)

Speakers
Presentation Number
P0035
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Accurate assessment of mobility is critical for the clinical management of people with MS (pwMS), and as a biomarker in clinical trials. Small, body worn sensors hold the possibility to provide greater reliability and accuracy than existing clinical tools. Since these sensors can provide a variety of metrics, they have the potential to provide a richer and more holistic assessment of gait impairment than existing clinical tools. Paradoxically however, the sheer number and partial overlap between the metrics provided by these sensors has led to confusion and impeded their clinical translation and acceptability.

Objectives

This study in the first to establish a data driven conceptual model of factors contributing to gait disturbance in pwMS using data obtained from body worn sensors. We then tested the model for its ability to quantify gait differences across different levels of disability and clinical courses of MS.

Methods

We studied 114 pwMS, divided in three groups according to their Expanded Disability Status Scale (EDSS) score. (mild, EDSS ≤ 3.5, moderate, 4.0 ≤ EDSS ≤ 5.5, and severe EDSS ≥ 6), as well as the clinical course of their illness (relapsing remitting or progressive), and 24 healthy controls. Gait was assessed with inertial sensors (OPAL, APDM), located on the lower shanks and on the lower back while they walked for 6 minutes at their self-selected speed along a 10-m path in a hospital corridor.

Results

Thirty-six metrics were initially computed from the sensor data. Twenty of these met quality criteria for exploratory factor analysis, which revealed a gait model consisting of five factors: rhythm/variability, pace, asymmetry, and forward and lateral dynamic balance. After confirming overall goodness with a confirmatory factor analysis, the model was used to investigate differences in gait features across pwMS with different levels of disability. We found significant alterations in rhythm/variability, asymmetry, and pace domains in the mild disability group, which further progressed in the moderate and severe disability group. Dynamic balance, conversely, appeared to be conserved in mild and moderate disability groups, only deteriorating in the severe disability group.

Conclusions

This model of gait in pwMS highlights clinically relevant and differential gait impairment across different clinical disease course and disability levels. The data can be obtained from small body worn sensors in a clinical setting. This approach has potential as an accurate and responsive clinical biomarker in clinical trials and more widely in clinical practise.

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Biomarkers and Bioinformatics Poster Presentation

P0036 - Cerebral hypometabolism is a marker of disease severity in multiple sclerosis: a non-invasive imaging study using T2-Relaxation-Under-Spin-Tagging MRI (ID 1856)

Speakers
Presentation Number
P0036
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Metabolic dysfunction at a cellular level is a crucial element of progressive neuronal dysfunction, and ultimately neurodegeneration in multiple sclerosis (MS). Changes in retinal superficial vascular plexus (SVP) density, which is known to be reduced in MS, may in part reflect metabolic demand in the neuronal layers of the retina, and could accordingly provide insight regarding concurrent metabolic alterations in the brain.

Objectives

To compare cerebral metabolism in people with MS (PwMS) to healthy controls (HCs) using T2-Relaxation-Under-Spin-Tagging (TRUST) and phase-contrast (PC) MRI, and assess whether cerebral hypometabolism is related to reduced SVP density measured using optical coherence tomography angiography (OCTA).

Methods

In this cross-sectional study, PwMS and HC underwent TRUST and PC MRI to derive the oxygen extraction fraction (OEF; a measure of the efficiency of cerebral tissue in extracting oxygen from circulating blood) and cerebral metabolic rate of oxygen consumption (CMRO2; a volume-adjusted measure of cerebral tissue metabolism). A subset of PwMS underwent OCTA, with quantification of retinal SVP density using a deep neural network based-algorithm. Statistical analyses were adjusted for age and intra-subject inter-eye correlations, where relevant.

Results

We included 49 PwMS and 80 HCs. Overall, OEF was lower, and CMRO2 trended towards being lower, in PwMS as compared to HCs (OEF: 35.9% [SD 5.1] vs. 40.9%, [SD 5.1], p=0.04; CMRO2: 156.3 umol/mL/min [SD 23.9] vs. 158.7 umol/mL/min [SD 19.9], p=0.08). Lower CMRO2 was associated with longer MS disease duration (p=0.02), higher expanded disability status scale score (p=0.01) and lower subcortical gray matter volume fraction (p=0.04). Additionally, lower CMRO2 was associated with higher age in PwMS (p=0.02), but not in HCs (p=0.19), in whom effective neurovascular coupling is expected to maintain a fairly constant rate with aging. Lower OEF correlated with lower retinal SVP density in PwMS (r=0.32, p=0.02).

Conclusions

Cerebral hypometabolism is evident in PwMS compared to HCs, and is associated with longer disease duration and greater disability. Furthermore, alterations in cerebral metabolism are mirrored by alterations in retinal SVP density, supporting the utility of these non-invasive imaging techniques to measure inter-linked pathobiological processes. The ability to detect metabolic dysfunction in-vivo in PwMS may help facilitate the identification of new therapeutic targets and outcome measures for clinical trials.

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Biomarkers and Bioinformatics Poster Presentation

P0037 - Change in serum neurofilament light chain levels: ENSEMBLE 1-year interim results (ID 945)

Speakers
Presentation Number
P0037
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Early treatment of multiple sclerosis (MS) provides significant long-term benefits. The aim of the Phase IIIb ENSEMBLE study (NCT03085810) is to evaluate the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Neurofilament light chain (NfL) is a marker of neuroaxonal injury. OCR reduced elevated NfL levels in patients with relapsing MS and primary progressive MS to those of healthy donors in the OPERA and ORATORIO studies over 96 weeks. NfL levels are assessed yearly in ENSEMBLE.

Objectives

To report 1-year NfL analyses from ENSEMBLE.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; Expanded Disability Status Scale [EDSS] score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients will receive OCR 600 mg every 24 weeks (first dose, 2×300 mg separated by 14 days) for the 192-week treatment period (maximum 8 doses). Serum NfL levels are measured via the Simoa Quanterix Advantage kit.

Results

A total of 582 patients were included in the NfL evaluation (female, 64.3%; mean [SD]: age, 32.4 [9.2] years; baseline EDSS, 1.70 [0.96]; time since MS symptom onset, 1.08 [0.84] years) with characteristics comparable with the overall population (N=678). The median serum NfL level at baseline was 13.20 pg/mL; 81.8% of patients had levels greater than healthy donors (HDs; 7.1 pg/mL). Median NfL levels at baseline in patients stratified by age, gender and EDSS score were consistent with those of the overall population. The highest median NfL levels at baseline were observed in patients with T1-weighted contrast-enhancing lesions (CELs) at screening (18.71 pg/mL; n=260) and relapses within 3 months of enrollment (14.91 pg/mL; n=217). At Week 48 the median serum NfL level was reduced to 6.35 pg/mL; 60.8% of patients had levels comparable to or lower than the HD level. Decreases in median serum NfL levels were observed, independent of the baseline demographics and disease characteristics of age, gender, EDSS score, CELs, relapses and reason for enrollment.

Conclusions

NfL levels at baseline and patterns of change over 48 weeks were in line with previous evaluations and decreased considerably after 1 year of treatment with ocrelizumab.

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Biomarkers and Bioinformatics Poster Presentation

P0038 - CHIT1 at Diagnosis Reflects Long-Term Multiple Sclerosis Disease Activity (ID 783)

Speakers
Presentation Number
P0038
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Evidence for a role of innate immune cells such as the CNS-resident macrophages or microglia in MS pathogenesis is growing, and the heterogeneity of microglial subsets is increasingly recognized. Several biomarkers directly reflect the neurodegenerative and inflammatory processes in MS. Macrophage and microglia-related biomarkers in CSF have been reported in other neurological diseases.

Objectives

We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity
(relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.

Methods

In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia-related proteins, chitotriosidase (CHIT1), chitinase-3–like protein 1 (CHI3L1 or YKL-40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme-linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia-related markers in publicly available RNA expression data from postmortem brain tissue.

Results

CHIT1 levels at diagnostic LP correlated with 2 aspects of long-term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E-04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E-04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL.

Conclusions

CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity.

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Biomarkers and Bioinformatics Poster Presentation

P0039 - Circulating microRNAs as potential inflammatory biomarkers of acute exacerbation in relapsing-remitting multiple sclerosis (ID 938)

Abstract

Background

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory-degenerative disease of the central nervous system. MicroRNAs (miRNAs) are short sequences of 19-25 non-coding single-stranded RNA nucleotides that regulate transcriptional gene expression by inhibiting the translation of specific messenger RNA targets and protein expression respectively. miRNAs are involved in various physiological and pathological processes, in particular contribute to the activation of the Th1 and Th17 pathways that regulate the immune response. Many studies show that the miRNAs are involved in MS epigenetic mechanisms affecting both the expression of inflammatory cells and myelination factors.

Objectives

This study aimed to compare the serum miRNAs in relapsing MS patients compared to remitting ones and to healthy controls for better understanding of MS pathogenesis.

Methods

We evaluated 3 groups of subjects: 16 relapsing-remitting (RR)MS patients in relapse (Group I); 12 RRMS patients in remission (Group II) and 12 sex- and age-matched healthy controls (Group III). Total extraction of RNA from sera was performed with a column-based method that includes small RNAs and minimizes the carryover of enzyme inhibitors typically contained in biofluids (miRNEeasy serum/plasma kit, QIAGEN). Total RNA was labeled and hybridized with Human miRNA Microarray Release 21 (Agilent) containing probes for 2549 human microRNAs from the Sanger database. Arrays were verified for quality control and extracted by Agilent Feature Extraction 10.7.3.1 software and entirely processed by MATLAB (The MathWorks Inc.) in house-built routines. Deregulated miRNAs were established by permutation test and a false discovery procedure used for multiple comparisons. Unsupervised hierarchical clustering was performed to individuate specific pattern of expression among samples and clusters of miRNAs. The results obtained were validated by Real-Time PCR.

Results

We analyzed 2549 miRNA that were expressed in at least 50% of the samples. After eliminating 10 samples that expressed only a few of these miRNAs, we found 66 expressed miRNAs in the half of remained samples. Microarray analysis identified a signature of 8 deregulated miRNAs in relapsing MS patients compared to controls and remitting MS patients. In particular, among these eight miRNAs, two were up-regulated (miR-2861 and miR-6821-5p) while six were down-regulated (miR-4281, miR-5196-5p, miR-6076, miR-642a -3p, miR-671-5p, miR-6879-5p).

Conclusions

We have found several upregulated or downregulated miRNA to be correlated with disease exacerbation in RRMS patients. Previous studies have reported five of these miRNAs to be involved in other inflammatory disorders. We hypothesize that the miRNA could be useful biomarkers not only to improve diagnosis and disease control, but also to predict the phase of acute exacerbation in MS.

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Clinical Outcome Measures Poster Presentation

P0040 - Cladribine tablets versus other DMT in achieving disability improvement in relapsing remitting multiple sclerosis patients – network meta-analysis (ID 573)

Presentation Number
P0040
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple sclerosis is a chronic disease of the central nervous system, most often with relapsing-remitting (RRMS) course.

Cladribine tablets was tested against placebo in randomized controlled trials (RCT) in RRMS.

As there is lack of head-to-head trials directly comparing CT to other highly active DMTs, an indirect comparison via network meta-analysis (NMA) was performed with placebo as a common comparator.

Objectives

To compare probabilities of sustained disability improvement (SDI) on the EDSS, in patients with relapsing-remitting multiple sclerosis (RRMS), treated with cladribine tablets (CT) or fingolimod (FIN), natalizumab (NAT), alemtuzumab (ALE) and ocrelizumab (OCR).

Methods

In compliance with the Polish HTA guidelines, a systematic review was conducted in Pubmed, Embase and Cochrane to identify clinical trials (RCT or non-RCT) evaluating 6-month SDI. An indirect comparison via network meta-analysis (NMA) was performed. Bayesian inference with Markov chains Monte Carlo methods were applied, using the WinBUGS© software.

Results

Finally, 6 trials presenting SDI results and applicable for NMA were included: 5 non-RCTs, with control groups selected by propensity score matching (Kalincik 2018, Kalincik 2015, Kalincik 2017, Barnocini 2016, Guger 2018) and 1 RCT (CARE MS II), allowing for comparison of CT vs FIN, NAT, ALE. Due to the lack of proper data, comparison with OCR was not possible. Additionally, there were only 37 patients treated with CT with SDI data available (Kalincik 2018). NMA results revealed that Hazard Ratios (95% CrI) for achieving 6-month SDI with CT was statistically significantly higher in comparison with all other high efficacy disease modifying treatments studied in this analysis: CT vs FIN – 5,17 (1,81; 15,01), CT vs NAT – 3,06 (1,06; 8,62), CT vs ALE – 9,45 (2,79; 31,94).

Conclusions

Cladribine tablets treatment was associated with higher probability of sustained recovery from disability compared to fingolimod, natalizumab and alemtuzumab in RRMS patients with highly active disease. The conclusion is based on limited quality of identified clinical data.

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Clinical Outcome Measures Poster Presentation

P0041 - Clinical characteristics and outcome of late onset Multiple Sclerosis (ID 1467)

Speakers
Presentation Number
P0041
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Clinical characteristics and disability progression in late onset MS (LOMS) (> 50 years at symptom onset) compared to adult onset MS (AOMS) (> 18- 50 years at symptom onset) is less well studied.

Objectives

To describe clinical characteristics and risk for disability progression in LOMS and AOMS within the Swedish MS population.

Methods

Data were collected from the nationwide Swedish MS registry (SMSreg). Patients with a diagnosis of MS, symptom onset > 18 years and ≥ 2 expanded disability status scale (EDSS) scores recorded were included. Clinical and demographic factors in LOMS and AOMS were compared. The risk for disease progression was assessed by analyzing time to reach sustained EDSS of 4,0 and 6,0 after disease onset, using Cox proportional hazard regression models adjusted for age, sex, disease course at onset.

Results

A total of 13,040 eligible AOMS were included of which 1,120 (8,6%) had LOMS. Median age (inter quartile range, IQR) at symptom onset was 54.0 (51.0-57.0) years in LOMS and 31.0 (26.0-39.0) yeas in EOMS. Diagnostic delay (time from symptom onset to diagnosis; median (IQR)) in LOMS; 1,21 years (0.41-3.35) and EOMS; 1,38 years (0.36-5.0) and sex distribution (female; 68,0 % vs 70,1%) were comparable in both groups. Close to one third of LOMS patients (29,2%) presented with primary progressive MS (PPMS) compared to 5,9% of AOMS. A relapsing onset was observed in 40.0% of LOMS and 65.4% of AOMS. Exposure to first line treatment was documented in 34.9% of LOMS and 59.6% had been exposed to a second line treatment (defined as fingolimod, natalizumab, rituximab or alemtuzumab). The risks to reach EDSS 4.0 (HR 1.96; 95% CI 1.72-2.24) and 6.0 (HR 2.42; 95% CI 2.13-2.75) were increased in LOMS compared to AOMS.

Conclusions

LOMS is characterized by a significantly higher incidence of PPMS as initial disease course and increased risk of disability progression compared to AOMS even after adjustment for age, sex and course, and even though more than half of the LOMS patients had been treated with a second line DMT.

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Clinical Outcome Measures Poster Presentation

P0042 - Clinical evolution of spasticity in adults with multiple sclerosis: systematic review (ID 1615)

Speakers
Presentation Number
P0042
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Spasticity is a common symptom for people with multiple sclerosis (MS), occurring in >80% of MS patients and increasing in prevalence and severity throughout the disease course. Worsening spasticity is associated with pain, sleep disorders, further impaired mobility, bladder dysfunction and other symptoms, impacting negatively on quality of life and increasing health resource utilization and costs. Data showing evolution of spasticity over time appear limited and, when reported, often use non-validated categorical scales.

Objectives

To conduct a systematic review of published evidence on the prevalence and clinical evolution of MS-related spasticity.

Methods

Searches were conducted in bibliographic databases. Two reviewers selected articles according to pre-defined inclusion criteria. Data were extracted to describe the frequency of spasticity, and progression of spasticity severity.

Results

Four studies were eligible for inclusion including a total of 29,196 patients. Study design was either retrospective (n=3), or longitudinal (n=1). Study duration ranged from approximately three to 30 years. Study population, timeframe for evaluation and method of assessment of spasticity within the included studies were heterogeneous which precluded meta-analysis. Two studies reported symptom prevalence and severity (measured using categorical mild/moderate/severe scales) over time. Results demonstrated an increased proportion of patients with severe symptoms, despite treatment. A continuous decrease in the proportion of participants with milder severity was also reported. The remaining two studies reported the clinical evolution of spasticity over time. Both studies used the 0–10 numeric rating scale (NRS) (0 no spasticity to 10 worst possible spasticity) to measure change in spasticity: one compared symptoms pre- vs post-MS diagnosis split by relapse- and progressive-onset disease, and the other in patients with treatment-resistant (≤1 prior therapy) MS-related spasticity, indicated a deterioration in spasticity over time (1 to 3 years [mean 2.1 years], mean NRS 5.7 [1.9] to 5.9 [2.1]).

Conclusions

Few studies consider the evolution of MS spasticity over the longer term. While there was a high degree of variation between the included studies, all indicated a deterioration in MS spasticity symptoms over time despite available treatments. Tracking MS spasticity seems necessary in MS to inform clinical management.

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Clinical Outcome Measures Poster Presentation

P0043 - Clinical practice experience with Cladribine in Multiple Sclerosis (ID 1499)

Speakers
Presentation Number
P0043
Presentation Topic
Clinical Outcome Measures

Abstract

Background

There are different disease-modifying therapies (DMTs) for treating patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Oral Cladribine was commercialized in 2018.

Objectives

To analyze the first year of treatment with Cladribine in RRMS patients: tolerability, security and initial approach to its effectiveness.

Methods

Retrospective, longitudinal and unicenter study in RRMS patients treated with Cladribine. We analyzed its security measuring overall lymphocyte count by Friedman Test and time to appearance of lymphopenia by Kaplan-Meier. We studied its effectiveness by comparing the following variables with the Wilcoxon Test: relapses, Expanded Disability Status Scale (EDSS) score and gadolinium enhancing lesions before and one year after starting Cladribine (statistically significant p<0’05).

Results

53 patients were studied. 88,7% were women with a mean age of 44,8 years old (DS10,25). 56,6% of the patients had a RRMS evolution of less than 10 years, 32,1% between 10 and 20 years, and 9,4% between 20 and 30 years. 64,1% had been previously treated with one or two DMTs. Patients were exposed to Cladribine for 8 months as a median (percentiles P15=2 months, P85=15 months): 36,4% patients for 6 months, 34,1% between 6-12 months and 29,5% for more than 12 months. The overall lymphocyte count reduction regarding the basal level after starting the drug was statistically significant (p<0’05). The lymphocyte count reduction rate was 52,89% during the first year of treatment and 58,99% during the second one. Tolerability was good in 93,02% of the patients. We observed significant reduction of the relapses rate after one year of treatment.

Conclusions

Cladribine seems to be a secure treatment. The most common adverse effect was lymphopenia (81,8%) but it was severe only in 9,09% of the patients and not associated with severe infections. Its tolerability was very good. Effectiveness results are positive, but, to date, they are preliminary.

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Clinical Outcome Measures Poster Presentation

P0044 - CogEval in the Real World: Feasibility, Implementation, and Real World Implications (ID 1295)

Speakers
Authors
Presentation Number
P0044
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive dysfunction in multiple sclerosis (MS) patients is common, and routine/efficient screening for cognitive dysfunction is commonly not feasible in a real-world setting for a variety of reasons.

Objectives

To determine patient satisfaction with the CogEval app using the Processing Speed Test (PST), a validated analog of the Symbol Digit Modalities Test (SDMT) as well as time it takes to complete the PST, and clinical decision making as a result of PST testing.

Methods

30 established or new MS patients in our clinic were followed over a period of 64 weeks, and at each visit, PST was administered. Upon consent, patients were administered a single seven-question satisfaction survey using a 5-point Likert scale (1-strongly disagree, 2-disagree, 3-neutral, 4-agree, 5-strongly agree) during one of these visits. Time to complete practice test and PST was captured. Retrospective chart review was performed to determine clinical decision making as a result of performing the PST.

Results

The average time to complete PST was 4 minutes 23 seconds. Likert scale scores were as follows: I liked using the app (4.6/5), The directions on the app were easy to understand (4.8/5), I was familiar with the risk of cognitive dysfunction in MS before using the app (4.5/5), I like the fact that my provider is testing my cognitive status (4.9/5), Because of this app, I’ll be more motivated to learn about the potential effects of MS on my cognition (4.6/5), The app did not take too long to complete (4.8/5), I am willing to repeat cognitive testing at future visits (4.7/5).

Retrospective chart review regarding medical decision making as a result of performing PST are as follows: Discussion about cognitive dysfunction in MS-30 patients, MRI brain-11 patients, labs to rule out other potential causes of cognitive dysfunction-9 patients, initiate high efficacy therapy-9 patients, switch to high efficacy therapy-4 patients.

Conclusions

Based on Likert Scale scores, patient satisfaction with PST testing was high, instructions were easy for patients to understand, patients appreciated the fact that routine cognitive screening was performed at their clinic visits, and the time to complete PST testing was not burdensome. The average time for PST practice test/test completion was 4 minutes 23 seconds. The PST is an efficient, rapid, and repeatable tool to assess for cognitive dysfunction in MS patients longitudinally.

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Clinical Outcome Measures Poster Presentation

P0045 - Comorbidities present before the MS diagnosis are not predictors for progression (ID 1539)

Speakers
Presentation Number
P0045
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Comorbidities are common in multiple sclerosis (MS) population and have been associated with the course of the disease, delays and greater disability in diagnosis, the progression of disability, higher risk of hospitalization, and shorter life expectancy. Predicting functional status and identifying potentially modifiable risk factors early in the course of the disease can help to guide the patient’s treatment.

Objectives

This study evaluated the association between the presence of comorbidities before MS diagnosis and the progression of the disease.

Methods

A retrospective cohort was performed in a reference center for MS care located in Porto Alegre – RS, Brazil. The patients were included between January 1, 2016, and December 30, 2019. A review was conducted on medical records accessing clinical and demographic data regarding age, gender, initial EDSS (EDSSi), current EDSS (EDSSc), and comorbidities before MS onset. The correlation between EDSSi, EDSSc, and the Charlston Comorbidity Index (CCI) and the Elixhauser Comorbidity Measure (ECM) was assessed.

Results

The study included 213 relapsing-remitting MS patients, 77% were females. At the time of diagnosis, 99 patients (46%) presented at least one comorbidity. Throughout the follow-up 128 patients (60%) had progression of EDSS, from whom 59 (46%) had some comorbidity prior to diagnosis, and 69 (54%) were healthy. There was no significant difference between patients with and without comorbidities in the distributions by gender (χ2 = .52; p = .46), but patients with comorbidities were significantly older (Mann-Whitney test z-score = - 3.09, p = .002). There was no significant difference between the groups in EDSSi (z-score = - 1.44, p = .14), EDSSc (z-score = - 0.02, p = .98), and in the progression of EDSS during follow-up (z-score = 0.37, p = .71). The correlation of CCI with EDSSi and EDSSc were not significant (rs = -0.02, p = 0.79 and rs= - 0.149, p = 0.14), as well as that of ECM (rs = 0.07, p = 0.45, and rs = 0.16, p = 0.10).

Conclusions

The presence of comorbidities before the MS diagnosis did not influence the disease's progression in the studied sample. The scores of the tools for measuring comorbidities have no significant association with the disability at the time of diagnosis of MS and also do not impact the worsening of EDSS. Other factors, possibly genetic and environmental, must be evaluated as causal for the progression of MS in the local population.

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Clinical Outcome Measures Poster Presentation

P0046 - Comparative Effectiveness of Ozanimod Versus Dimethyl Fumarate: Results of a Matching-Adjusted Indirect Comparison (ID 492)

Speakers
Presentation Number
P0046
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Ozanimod is a selective S1P1-5 modulator recently approved in the US for the treatment of relapsing-remitting multiple sclerosis (RRMS). In the absence of head-to-head studies, a matching-adjusted indirect comparison (MAIC) can be used to compare ozanimod with other oral disease-modifying therapies in patients with MS.

Objectives

The objective of this study was to conduct a MAIC of the relative efficacy and safety of ozanimod 1.0 mg with dimethyl fumarate (DMF) 240 mg.

Methods

A systematic literature review was performed to identify clinical studies evaluating the efficacy and safety of ozanimod vs DMF. Individual patient data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate level data for DMF were obtained from CONFIRM and DEFINE. A MAIC was conducted while adjusting for imbalances between studies by reweighting IPD from ozanimod trials to match the mean baseline characteristics reported in the DMF trials. In the absence of a common comparator between ozanimod and DMF, an unanchored comparison was used. Thus, potential treatment effect modifiers and prognostic factors were included in matching.

Results

After matching, baseline patient characteristics were balanced between ozanimod and DMF patients. Compared with DMF, ozanimod demonstrated improved annualized relapse rate (ARR; rate ratio [RR]: 0.80; 95% CI: 0.67–0.97), proportion of patients relapsed (odds ratio [OR]: 0.66; 95% CI: 0.52–0.83), overall adverse events (AEs; OR: 0.11; 95% CI: 0.08–0.16), serious AEs (OR: 0.27; 95% CI: 0.19–0.39), and discontinuations (OR: 0.11; 95% CI: 0.07–0.17) as well as nonsignificant differences for confirmed disability progression (CDP) at weeks 12 (RR: 0.79; 95% CI: 0.58–1.07) and 24 (RR: 0.89; 95% CI: 0.62–1.26).

Conclusions

After adjustment of baseline patient characteristics, ozanimod demonstrated improved relapse outcomes, lower risks of adverse outcomes, and low discontinuations compared with DMF. There were no significant differences in CDP.

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Clinical Outcome Measures Poster Presentation

P0047 - Comparative Efficacy and Safety of Ozanimod Versus Teriflunomide for Relapsing-Remitting Multiple Sclerosis: a Matching-Adjusted Indirect Comparison (ID 569)

Speakers
Presentation Number
P0047
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Ozanimod is a selective S1P1-5 modulator recently approved in the US for the treatment of relapsing-remitting multiple sclerosis (RRMS). In the absence of head-to-head studies, a matching-adjusted indirect comparison (MAIC) can be used to compare ozanimod with other oral disease-modifying therapies in patients with MS.

Objectives

The objective of this study was to compare the relative efficacy and safety of ozanimod 1.0 mg and teriflunomide (TEF) 14 mg.

Methods

A systematic literature review was performed to identify clinical trials that evaluated the efficacy and safety of ozanimod and TEF. Individual patient data (IPD) for ozanimod were obtained from the SUNBEAM and RADIANCE Part B trials, and aggregate level data for TEF were obtained from 6 clinical trials. Heterogeneity was observed between the ozanimod and TEF trials with respect to Expanded Disability Status Scale score, gadolinium-enhanced lesions, disease duration from symptom onset, prior relapse and DMT use, age, sex, region, and weight. An unanchored (no common comparator) MAIC was conducted while adjusting for imbalances between studies by weighting IPD from the ozanimod trials to match the mean baseline characteristics reported in the TEF trials. The following outcomes of interest were assessed: annualized relapse rate (ARR), proportion of patients relapsed, confirmed disability progression (CDP) sustained for 12 and 24 weeks, overall adverse events (AEs), serious AEs (SAEs), and discontinuations due to AEs.

Results

After matching, baseline patient characteristics were balanced between ozanimod and TEF. Compared with TEF, ozanimod demonstrated improvements in ARR (rate ratio [RR]: 0.73; 95% CI: 0.62–0.84), proportion of patients relapsed (odds ratio [OR]: 0.56; 95% CI: 0.44–0.70), overall AEs (OR: 0.35; 95% CI: 0.29–0.43), SAEs (OR: 0.53; 95% CI: 0.37–0.77), and discontinuations due to AEs (OR: 0.14; 95% CI: 0.09–0.21) and similar CDP at 12 (RR: 0.80; 95% CI: 0.61–1.05) and 24 (RR: 0.80; 95% CI: 0.59–1.08) weeks.

Conclusions

Ozanimod was associated with improved relapse outcomes and lower risks of AEs over 1–2 years of follow-up compared with TEF, with no differences in CDP.

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Clinical Outcome Measures Poster Presentation

P0048 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Longitudinal Model-Based Meta-Analysis for Confirmed Disability Accumulation (ID 1257)

Speakers
Presentation Number
P0048
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple sclerosis (MS) is an inflammatory autoimmune disorder and causes progressive neurological disability in young adults. Ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator, is under development for treatment of relapsing multiple sclerosis (RMS).

Objectives

To assess the effect of ponesimod on confirmed disability accumulation (CDA) relative to placebo and other disease-modifying therapies (DMTs) in treating RMS.

Methods

A literature review was performed and a database of 154 unique trials with 58 MS treatments was developed. The database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Results for CDA were reported with Kaplan-Meier plots; thus, extensive data were available to develop a longitudinal model for probability of a 12-week CDA event. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time. Arm-level variables explored as effect modifiers included: percent of patients with remitting RMS, trial start year, mean duration of disease, percent of patients who received DMT within past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.

Results

This model utilized longitudinal data from 26 RCTs in RMS (18 unique treatments [including placebo], 69 treatment arms, and 417 timepoints in 31,160 patients). HRs were estimated for 12-week CDA for 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (6 treatments). Relative treatment effect was found to be significantly smaller in trials with higher pDMT. Results favored ponesimod in comparison to placebo (HR: 0.61; 95% CI: 0.44–0.83), glatiramer acetate (0.65; 0.44–0.94), and interferon β-1b (0.51; 0.33–0.77) in delaying 12-week CDA. Ponesimod was estimated to have numerical improvement to S1P receptor modulators fingolimod, ozanimod, laquinimod, as well as teriflunomide, interferon β-1a (intramuscular and subcutaneous), peginterferon β-1a, cladribine, daclizumab, and dimethyl fumarate (HR range: 0.77–0.94).

Conclusions

Ponesimod was statistically superior compared to placebo and a range of other DMTs suggesting robust efficacy in the treatment of MS.

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Clinical Outcome Measures Poster Presentation

P0049 - Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: A Model-Based Meta-Analysis for Annual Relapse Rate (ID 1256)

Speakers
Presentation Number
P0049
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple sclerosis (MS), an inflammatory autoimmune disorder, is responsible for progressive neurological disability among young adults. Ponesimod is a selective sphingosine-1-phosphate (S1P) receptor 1 immunomodulator under development for relapsing multiple sclerosis (RMS).

Objectives

To assess the effect of ponesimod on the annual relapse rate (ARR) relative to other disease-modifying therapies (DMTs) for treatment of RMS.

Methods

A literature review was performed and a database with 154 unique clinical trials with 58 MS treatments was created. This database was filtered to include randomized controlled trials (RCTs) with >30 patients receiving monotherapy to treat RMS for at least 48 weeks. Mean ARR for each treatment arm was modeled and rate ratios (RRs) between treatments were assumed constant from 48 to 156 weeks. Multiple arm-level variables were explored as modifiers of relative treatment effect: percent of patients with remitting RMS, trial start year, mean disease duration, percent of patients with history of DMT use in past 2 years (pDMT), mean relapses in prior year, mean age, and mean baseline EDSS score.

Results

The model utilized mean ARR data from 41 RCTs in RMS (18 unique treatments [including placebo], 106 treatment arms, 33,904 patients). Rate ratios were estimated for all 17 treatments vs. placebo. A dose-response relationship was included if data at multiple doses were available and results indicated a potential dose-dependent effect (8 treatments). Relative treatment effect was smaller in trials with higher pDMT. In addition to superiority of ponesimod vs. teriflunomide, results suggested that ponesimod reduced ARR significantly compared to placebo (RR: 0.47; 95% CI: 0.32–0.68), interferon β-1a (intramuscular, 0.57; 0.39–0.85), laquinimod (0.58; 0.38–0.88), and interferon β-1b (0.65; 0.44–0.97). Results suggested that ponesimod had numerically superior ARR benefits compared to interferon β-1a (subcutaneous), peginterferon β-1a, glatiramer acetate, and dimethyl fumarate (RR range: 0.68–0.94). Ponesimod had similar ARR benefits to S1P receptor modulators ozanimod, fingolimod, cladribine, and daclizumab (RR range: 1.00–1.04).

Conclusions

Ponesimod reduced ARR in patients with RMS, and was statistically superior as compared with placebo and a range of other DMTs.

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Biomarkers and Bioinformatics Poster Presentation

P0050 - Comparative transcriptomics of multiple sclerosis vs. viral infections, including SARS-CoV-2 (ID 1045)

Speakers
Presentation Number
P0050
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

There are accumulating evidence in the literature that viral infections provide an environmental trigger for the onset of multiple sclerosis (MS) in genetically susceptible individuals. Furthermore, viral infections may contribute to the progression of disability in MS, triggering relapses and promoting neurodgeneration. There are multiple studies assessing the effect of viral infections both in vitro and ex vivo. No study to date has performed a head to head comparison of transcriptomic modulations between MS and viral infections. Furthermore, no study to date has performed these comparisons with the novel coronavirus, SARS-CoV-2, whose neurotropism potential is still under scrutiny.

Objectives

The purpose of this study is to discover common pathways between multiple sclerosis and viral infections, including SARS-CoV-2, on a transcriptomic and functional level.

Methods

The Gene Expression Omnibus (GEO) database was inquired using a query containing the keywords “Virus”, “Multiple Sclerosis”, “Infection”. Included studies involved ex vivo samples of peripheral blood mononuclear cells (PBMCs) following a case – control design. For SARS-CoV-2, a gene signature extracted from a recent infection translatomics experiment (Bojkova et al, 2020) was used in over-representation analyses, and subsequently comapred with the signatures extracted from the MS datasets.

Results

The initial search retrieved 35 studies. Applying the predetermined inclusion criteria, 2 MS vs Healthy Controls (HC) studies and 3 studies of viral infection vs. HC (Dengue, SARS Coronavirus and Rotavirus infections). Multiple common, differentially expressed genes (DEGs) and associated significantly enriched pathways emerged between the MS vs viral infection subgroups. The “Epstein Barr infection” pathway was salient among MS-related viral infection pathways (False Discovery Rate (FDR) <0.05). Furthermore, comparative transcriptomics revealed 4 common gene signatures of 80 to 150 genes, associated with nuclear transport, neuroactive peptide binding and the spliceosome (FDR<0.0001). Comparisons between the MS datasets and the SARS-CoV-2 - host interactome revealed overlapping perturbations in pathways associated with neurodegeneration and mRNA surveillance pathways (FDR<0.05). Notably, a confirmatory analysis of the SARS-CoV-2 interactome with Enrichr, comapring said interactome with disease-control experiments in the Gene Expression Omnibus (GEO) databases revealed relapsing remitting MS among diseases with overlapping gene signatures (FDR<0.05).

Conclusions

Ours is the first study to directly compare viral infection mechanisms with the molecular pathophysiology of MS in a transcriptomic level. Our results indicate a “response to infection” phenotype in MS PBMCs, associated with alternative splicing and disruptions of transcriptional surveillance.

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Biomarkers and Bioinformatics Poster Presentation

P0051 - Comparison of serum and CSF fluid biomarkers for predicting long term disease progression in MS
  (ID 1448)

Speakers
Presentation Number
P0051
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

With the availability of more powerful treatments for multiple sclerosis (MS), prognostic biomarkers are badly needed.

Objectives

Our objective was to evaluate the long-term prognostic value of 4 protiens in paired serum and CSF samples obtained early-on following MS diagnosis.

Methods

In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) and more than 15 years of routine clinical follow-up. Neurofilament light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Tau and UCHL-1 were quantified in paired serum (s) and CSF (c) samples from patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Outcomes of biomarker performance included conversion to progressive MS phenotype and reaching an EDSS ≥4.

Results

67 patients had a median follow-up of 17.4 years (range:15.1-26.1), by which time 10/67 had been classified as PPMS, 16 SPMS and 41 RRMS. 29 had developed EDSS ≥4. Baseline CSF levels 3 of the candidate markers were higher than MS patients compared to controls: cNfL (Mann Whitney p=0.0001, median 624 vs. 277pg/mL), cGFAP (p<0.0001, 6900 vs. 694pg/mL) and cTau (p=0.0001, 15.4 vs. 8.12pg/mL) but not UCH-L1. Patient-control differences were less marked in serum: sNfL (p= 0.0037, 10.1 vs. 7.3pg/mL), sGFAP (p=0.0011, 68 vs 51pg/mL), no difference in sTau and sUCH-L1. Positive correlations existed between paired serum and CSF samples only for NfL (Spearman r=0.71, p<0.0001) and GFAP (r=0,4, p=0.003). ROC curve analysis showed cUCH-L1 was most predictive of developing EDSS ≥4 after 15 years of follow-up (AUC 0.72, p=0.003) followed by sNfL (AUC 0.70, p=0.012) and cGFAP (AUC 0.66, p=0.03). Similarly, cUCH-L1 was most predictive of developing a progressive phenotype (PP/SPMS, AUC 0.69, p=0.0097), followed by cGFAP (AUC 0.66, p=0.024) and barely by sNfL (AUC 0.64,p=0.057). cNfL (AUC 0.60,p=0.17), sGFAP, sTau, cTau and sUCH-L1 were not predictive of either reaching EDSS ≥4 or converting to a progressive phenotype (PP/SPMS).

Conclusions

This is the first study to report and association of baseline CSF UCH-L1 levels with long term clinical outcomes in MS. This marker was more predictive of EDSS worsening and conversion to a progressive phenotype than well-established markers NfL and GFAP. More generally, CSF biomarker levels better segregating MS patients from controls at baseline compaired to levels in paired serum samples.

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Clinical Outcome Measures Poster Presentation

P0052 - Completion rates by clinicians in global MS studies for the electronic EDSS compared to paper (ID 1904)

Speakers
Authors
Presentation Number
P0052
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The Expanded Disability Status Scale (EDSS) is a widely used assessment in multiple sclerosis (MS) clinical trials and often used as primary or secondary endpoints, contributing to labeling claims. However, inter- and intra-rater variability is high, which can lead to decreased power to detect treatment effects. Electronic implementations of the EDSS have been shown to reduce inconsistencies and improved inter-rater reliability. Yet, clinician acceptance of electronic implementations of the EDSS has rarely been examined.

Objectives

The aim of this study is to determine clinicians’ acceptance of the electronic EDSS by comparing the completion rates of the electronic version of the EDSS versus the pencil-and-paper version.

Methods

Data was collected as part of two phase 3, multicenter global MS trials during a 2-year period. All clinicians were provided ERT’s electronic EDSS, which uses the Neurostatus system of scoring algorithms and feedback including real-time, on-device detection of inconsistencies and post-submission guidance and queries on inconsistencies by expert reviewers. Clinicians had the option to complete the EDSS electronically in real-time or complete the assessment using the pencil-and-paper version prior to entering the scores on the electronic device.

Results

A total of 9142 assessments were completed with 2160 patients, from 357 sites, in 39 countries. 69.1% of the assessments were completed electronically in real-time and 30.8% were completed on paper first and transcribed onto the electronic device. 0.1% of the assessments were completed using neither the electronic nor paper version, but scores were entered electronically from clinicians’ recollection of the assessment. A majority of the sites used the electronic EDSS for more than 50% of their assessments. Sites in Thailand, Taiwan, Norway and Italy used the electronic EDSS for 100% of their assessments. Assessments using the electronic EDSS took an average of 82.1 minutes to complete. It took an average of 43.4 days for assessments completed on paper to be entered on the electronic device.

Conclusions

Overall, the use of the electronic EDSS was widely accepted by clinicians across the majority of the countries. This finding supports the use of an electronic EDSS to reduce inconsistencies, improve inter-rater reliability, and expedite the collection of data.

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Biomarkers and Bioinformatics Poster Presentation

P0053 - Correlation Between Spinal Fluid and Blood Levels of Neurofilament Light, GFAP, Tau, and UCHL1: Do We Need a Correction Factor? (ID 1942)

Speakers
Presentation Number
P0053
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Plasma neurofilament light(pNFL) levels account for 30-60% of the variance in CSF neurofilament light(cNFL) levels depending on the study. Age, disability, relapses, and the presence of contrast enhancing MRI lesions can increase both pNFL and cNFL. Additional nervous system biomarkers can now be studied in plasma. Understanding the factors that increase their variability in blood may be helpful in normalizing levels to better understand what levels are concerning for ongoing disease activity.

Objectives

To evaluate factors contributing to blood and cerebrospinal fluid(CSF) discordance and determine if a correction of blood levels can better estimate what is happening in the CSF compartment.

Methods

Matched plasma and CSF samples were identified in the Rocky Mountain Multiple Sclerosis Center Biorepository at the University of Colorado. Neurofilament Light(NFL), Glial Fibrillary Acidic Protein(GFAP), tau, and Ubiquitin carboxy-terminal hydrolase L1(UCHL1) levels were assessed using Single Molecule Array(SIMOA) in a Quanterix SR-X machine. Analyses were done on log transformed NFL concentrations.

Results

Fifty-seven patients had matched plasma and cerebrospinal fluid samples evaluated for neurofilament light which included 24 patients with multiple sclerosis(MS), 7 with neuromyelitis optica spectrum disorder(NMOSD), and 18 patients with headache whose opening pressures were <20cmH2O. These patients had a mean age of 46.5(+/-11.2) years, 75% female, mean albumin index of 6.3(+/-5.5), and BMI of 27.4(+/-5.8). The CSF and plasma concentrations in pg/ml were for NFL 1059.3(+/-3052.4) and 12.2(+/-32.4), GFAP 7621.5(+/-9713.4) and 52.9(+/-39.7), tau 41.5(+/-41.3) and 1.3(+/-0.8), UCHL1 1356.0(+/-1677.1) and 23.6(+/-32.8). Respectively the CSF vs plasma Spearman correlations (95% confidence intervals, p values) were: 0.79(0.67-0.87,<0.0001), 0.67(0.50-0.79,<0.0001), 0.75(0.61-0.85,<0.0001), and 0.70(0.54-0.81,<0.0001). Adjusting individually for age, BMI, or albumin index did not affect the correlation for NFL.

Conclusions

Blood and CSF levels of NFL, GFAP, tau, and UCHL1 correlated well. Models will be created that explore the relationship between Blood and CSF levels of these biomarkers.

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Clinical Outcome Measures Poster Presentation

P0054 - Cost of a relapse-free patient in relapsing-remitting multiple sclerosis, a reliable result-based health indicator. (ID 461)

Speakers
Presentation Number
P0054
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Nowadays we know the efficacy and safety of disease-modifying therapies (DMTs) in multiple sclerosis (MS) but we lack result-based health indicators to evaluate its cost-effectiveness.

Objectives

The objective of the study is to analyze if the cost per year of a relapse-free patient is a reliable health indicator comparing the cost between 2016 and 2019 of DMTs in a cohort of relapsing-remitting MS (RRMS) treated with DMTs in a representative population cohort.

Methods

Patients followed in our MS unit during 2019, diagnosed with MS and belonging to our sanitary district were evaluated, our center has the only MS unit in the district. From them, patients diagnosed with RRMS were retrospectively selected for this study. Clinical data were collected prospectively on a 6-monthly basis and at the time of any relapse. All patients were visited by a qualified neurologist who performed a neurological examination assessing the disease severity by the Expanded Disease Status Scale (EDSS). Data from magnetic resonance imaging (MRI) were retrospectively retrieved. The proportion of patients with no evidence of disease activity (NEDA) was analysed. The mean cost of DMTs during 2019 had been analyzed as well as the cost of a relapse-free patient. The cost of a relapse-free patient was a ratio between the total cost of DMTs and the number of relapse-free patients. The results of 2019 were compared with the results already obtained in 2016.

Results

A total of 214 patients belonging to our sanitary district diagnosed with MS and followed in our MS unit in 2019, were selected. They indicated an MS prevalence of 105 per 100000 inhabitants, representative of the expected prevalence of MS in epidemiological population-based studies performed in our area. From them, 183 patients were RRMS and were included in our study. They were 67.8% women, their mean age was 48.3 (SD 12.9) years, their mean age at onset was 31.8 (SD 10.8) years, their disease duration was 16.32 (SD 11.7) years and their median irreversible EDSS was 2.0 (range 0-7.5). From those 183, 126 patients (68.9% of the cohort) were treated with DMTs during 2019, 151 patients (82.5% of the cohort) remained free of relapses during 2019, 171 patients did not increase their EDSS (93.4% of the cohort) and 126 of the 144 with Magnetic Resonance Imaging (MRI) in 2019 had neither new T2 lesions nor gadolinium-enhancing lesions (87.5%). The proportion of NEDA (no evidence of disease activity) in those 144 patients was 69.4%. The mean cost of DMTs per patient in 2019 was 6985.4 euros (95% CI: 5986.9-7983.9) when all patients were considered, relapse-free and relapsing patients as well as treated and not treated, in 2016 it was 7414.3 euros (95% CI: 6325.2-8503.4). The cost per year of DMTs of a relapse-free patient was 8465.8 euros in 2019 and 9762.2 euros in 2016.

Conclusions

The cost per year of a relapse-free patient may be a reliable result-based health indicator given its stability in successive measurements in the same population.

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Biomarkers and Bioinformatics Poster Presentation

P0055 - Cross-sectional and longitudinal estimation of radiographic and clinical endpoints to quantify MS disease trajectory with blood serum protein levels. (ID 836)

Speakers
Presentation Number
P0055
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Quantification of the activity and progression of multiple sclerosis (MS) is an important tool for research on MS as well as its clinical treatment. Currently, disease activity and progression assessments rely on qualitative clinical evaluations or the acquisition of radiographic data such as magnetic resonance imaging (MRI).

Objectives

Quantifying MS disease activity (DA) and progression (DP) instead through the use of blood biomarkers would provide a significant reduction in barriers to such testing (e.g. monetary cost, time and specialized personnel requirements, invasiveness, operational difficulty, etc.). The use of an ensemble of proteins representing various biological pathways involved in MS pathophysiology would also provide useful insights into this complex and heterogeneous disease.

Methods

We investigated proteomic biomarkers associated with different levels of MS DA and DP using 205 blood serum samples from 88 patients (University Hospital Basel), extracting protein levels using Proximity Extension Assays (PEA) from OlinkTM. We then conducted a focused statistical analysis on 21 proteins that were selected for a custom MS assay panel development project based on their association with endpoints in previous studies. We corrected these protein levels using clinical data, including: age, sex, disease duration, age of the bio-banked sample, and medication status. We then compared protein levels to five different radiographic and clinical endpoints.

– Primary Endpoint: Gadolinium (Gd) enhanced lesion count

– Secondary Endpoints: T2 lesion volume, Expanded Disability Status Scale (EDSS) score, Clinically Defined Relapse Status, and Annualized Relapse Rate (ARR)

Results

In this report, we examine the univariate performance of selected proteins on the prediction of all five endpoints, comparing it to that of several multivariate machine learning techniques. We draw distinctions between the highest performing models for each endpoint and draw connections to the underlying biology governing MS activity and progression.

Conclusions

We found significant improvements in predictive power from the use of multivariate models in comparison to even the highest performing univariate techniques. The samples analyzed in this study will be re-assayed for validation purposes alongside additional cohorts in the forthcoming 21-plex custom MS proteomic assay panel.

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Biomarkers and Bioinformatics Poster Presentation

P0056 - CSF inflammatory profile of primary progressive multiple sclerosis (ID 1657)

Speakers
Presentation Number
P0056
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Background: So far, no specific biomarkers that help to stratify primary progressive multiple sclerosis (PPMS) from relapsing remitting multiple sclerosis (RRMS) patients are still unknown. In the diagnosis of PPMS, among with clinical and imaging assessment, the analysis of cerebrospinal fluid with regard to evidence of oligoclonal bands and/or elevated IgG index is helpful.

Objectives

Objectives: To evaluate the levels of 69 pro and anti-inflammatory cytokines and chemochines as well as Nf-L in the CSF of PPMS at the diagnosis.

Methods

Methods: Levels of 69 inflammatory mediators and of NF-L has been evaluated in the CSF obtained at the diagnosis from 16 patients with PPMS, 80 patients with RRMS and 12 patients with central nervous system non-inflammatory neurological disorders by mean of immune-assay multiplex techniques based on the Luminex technology and Human NF-light enzyme-linked immunosorbentassays. Clinical assessment including EDSS and white and grey matter (WM and GM) lesion volume and numbers were collected by using 3-T MRI analysis.

Results

Results: No significant differences were noticed in IgG index, CSF lymphocyte count, NF-L levels, WM and GM lesion volume and number were not significantly different between PPMS and RRMS. PPMS patients had higher EDSS when compared to RRMS group (median[IQR] 3 [3-4] vs 2[1-2.375]) and older age (mean54.5±9.6y vs 36.8 ± 11.9, p<0.001). Among selected molecules that appeared increased in both PPMS and RRMS groups respect to controls, a multivariate logistic regression analysis showed that at diagnosis altered levels of some B-cell related cytokines such as IL-10 (OR=0.28, CI95%[0.09-0.96]) and CXCL12 (OR=3.97, CI95%[1.34-11.7]) and the monocyte-related osteopontin (OR=2.24, CI95%[1.01-4.99]) were predictive for a primary progressive course of the disease instead of a relapsing one. Kegg pathway analysis confirmed that most of molecules characterizing PPMS CSF profile are involved in chronic immune inflammatory diseases.

Conclusions

Conclusions: At the diagnosis, CSF of PPMS patients appeared characterized by high levels of inflammatory mediators. A detailed CSF profiling obtained at the diagnosis could help to differentiate progressive forms of MS, providing new insights into its pathogenesis and useful tools in clinical practice.

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Biomarkers and Bioinformatics Poster Presentation

P0057 - Decline in serum neurofilament is associated with decreased clinical and radiological disease activity over two years of dimethyl fumarate treatment (ID 1294)

Speakers
Presentation Number
P0057
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Dimethyl fumarate (DMF) treatment is associated with a decrease in serum neurofilament light chain (sNfL) in patients with relapsing-remitting multiple sclerosis (RRMS). sNfL is an exploratory biomarker of MS disease activity. Additional data describing the association between sNfL and disease activity are needed to further investigate this biomarker as a potential predictor of treatment response, which could enable a more holistic disease monitoring approach to treatment.

Objectives

To describe variation in sNfL levels with respect to clinical and radiological disease activity in DMF-treated patients.

Methods

DMF-treated patients with RRMS and complete 2Y follow-up data were analyzed. Serum samples were collected, and routine clinical and radiological assessments were conducted at baseline (BL) and at regular intervals. sNfL concentrations were measured by Single Molecule Array (SiMoA). Normative sNfL data from a cohort of 135 healthy adult controls (age range 21-82 years) were used as a comparator. Age-normative sNfL cutoffs were defined based on the 95th percentile of sNfL levels.

Results

Forty-one patients with 2Y follow-up data were included. Mean (SD) age and disease duration were 37.5 (10.1) and 6.0 (6.5) years, respectively, with mean (SD) time on DMF treatment 43.8 (9.15) months. Twenty-nine (70.7%) patients were treated with a previous MS therapy. Nineteen (46.3%) and 22 (53.7%) patients were below and above age-normative sNfL level at BL, respectively. Over 2Y, mean (95% CI) sNfL level decreased from 8.5 (7.1, 10.2) to 3.4 (2.0, 4.0) pg/ml, representing a 36.6% annual decrease, and 60% decrease over 2Y. Patients experienced a 71.1% (95% CI: 38.8%, 86.3%) reduction in ARR from 1Y prior to BL (0.463, 95% CI [0.279, 0.724]) to 2Y (0.134 [0.067, 0.24]), and 75.6% (59.4%, 87.1%) patients were free of new T2 lesions at 2Y. sNfL was below age-normative level in 53.7% (37.6%, 69%) of patients at BL vs 97.6% (85.6%, 99.9%) at 2Y. Patients with sNfL below age-normative level at BL generally remained below this threshold. At 2Y, patients both above and below age-normative sNfL level at BL experienced low cumulative ARR (95% CI) of 0.132 (0.043, 0.307) and 0.136 (0.05, 0.297), respectively, representing reductions of 75% and 66.7%.

Conclusions

DMF-treated patients reached NfL levels approaching that of healthy controls over 2Y with a reduction in disease activity, regardless of sNfL level at BL in this real-world setting. These data support a correlation between reductions in sNfL levels and decreased disease activity over 2Y of treatment, and potential of sNfL as a biomarker of treatment response that could be assessed during treatment in addition to standard of care monitoring.

Supported by: Biogen.

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Biomarkers and Bioinformatics Poster Presentation

P0058 - Decrease of peripheral CD19+ IgG+ B-cells with age and immunotherapy in patients with relapsing remitting Multiple sclerosis. (ID 1459)

Speakers
Presentation Number
P0058
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Little is known about the impact of aging, long term immunotherapy and the combination of both on the immune system in MS.

Objectives

Identification of age and treatment dependent peripheral immune cell changes in MS patients that are distinct from people with other neurological conditions or healthy controls.

Methods

We performed flow cytometric immunophenotyping on whole blood samples of 133 patients with relapsing-remitting MS (range: 17-66 years; median: 39). A cohort of 95 patients with other neurological diseases as well as 13 healthy people served as controls (range: 17-85 years; median: 45). The focus was on characterizing subsets of CD3+ T cells and CD19+ B cells. We used 22 different fluorochromes, split into two panels, labelling well-established surface markers. We observed 20 identifiable subsets in the T cell panel and 15 subsets in the B cell panel. Relative abundance of each identified subset in a sample was plotted against patient age. Linear regression was performed to determine age-related trends. Trend lines of MS and control group were then compared and an F-test used to determine whether slopes significantly differed from one another. As this was an exploratory study, we decided to also compare overall mean values for each parameter between MS and control group, irrespective of age, with a T-test.

Results

We observed a significant age-related decrease in eight subsets and increases in two subsets of the MS-patients. Controls showed a significant decrease in nine subsets and an increase in three. When comparing slopes, all but one were not different between MS patients and controls (p < 0.05). Only the relative abundance of CD19+ IgG+ cells decreased significantly with increasing age in MS patients (p = 0.0007), whereas there was no obvious trend in the control group (p = 0.5887), suggesting the change was specific to the MS group. Comparing slopes of these trend lines with an F-test, significant difference was achieved (p = 0.0261). Omitting age as a factor in the comparison of MS and control patients, we found differences in mean abundance of CD19+ CD27- IgD+ cells (p = 0.0014), CD19+ IgG+ cells (p = 0.0455), CD19+ CD27+ cells (p = 0.0152) and central memory CD3+ CD4+ cells (p = 0.0003). A subgroup analysis comparing CD19+ IgG+ cells in therapy naive (n = 22) and treated (n = 103) patients showed lower mean values in the latter (p = 0.0062), although the treated group did not contain patients that were on B-cell depleting therapy.

Conclusions

Our results show an age-dependent decrease of CD19+ IgG+ B lymphocytes in MS patients which is likely explained by previous immunotherapies. The identified CD19+ IgG+ subgroup represents terminally differentiated populations of B cells. Further studies will focus on their relation to clinical phenotypes, disease trajectories and the impact of different immunotherapies on this subset.

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Clinical Outcome Measures Poster Presentation

P0059 - Defining predictors of disease activity and worsening in multiple sclerosis: an analysis of the CombiRx trial (ID 828)

Speakers
Presentation Number
P0059
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Disease activity in multiple sclerosis (MS) is highly variable, and there are limited prospective studies on predictors of disease outcomes.

Objectives

The aim of the study is to identify and assess clinical characteristics in MS that predict disease activity and progression.

Methods

The study population consisted of a prospective cohort of 1,008 patients with relapsing-remitting (RR) onset MS enrolled in the CombiRx trial. Cox regression analysis was used to determine hazard ratio (HR) associations between baseline (BL) demographics (age <38 vs. ≥38, sex, race), clinical history (number of relapses in prior year <3 vs. ≥3, disease duration, Expanded Disability Status Scale (EDSS)), and MRI metrics (presence or absence of gadolinium (Gd) and number of T2 lesions), and treatment (glatiramer acetate (GA), interferon-beta 1a (IFN), or combination therapy); with outcomes of time to first new disease activity over 7-years of follow-up including relapse, MRI activity defined by new combined unique active lesion, and disease worsening as defined by confirmed 6-month increase in EDSS.

Results

1,008 participants were randomized, with 959 eligible for assessment of disease worsening and activity on follow-up MRI. Participants were median 38 (range 18, 61) years of age at baseline, 72.7% female, 88.3% Caucasian, 7.1% black/African American, mean 1.2 years since diagnosis, with median 2 relapses in the prior 12 months and median EDSS 2 (IQR 1, 2.5). Risk of relapse was higher in patients younger than 38 at BL vs. older (HR 1.36, 95% CI: 1.12,1.65) and with BL EDSS ≥3.5 vs. <3.5 (HR 1.66, 95% CI: 1.27, 2.14). Presence of Gd+ lesions at baseline was also associated with increased risk of relapse (HR 1.37, 95%CI: 1.14, 1.66). Risk of new MRI activity was higher in younger participants (HR 1.56, 95%CI: 1.34, 1.86) and those taking either single agent arms compared to the combination (GA: HR 1.48, 95%CI 1.22, 1.80; IFN: HR 1.43, 95%CI 1.18, 1.74). Similarly, higher preexisting lesion burden greater than the median lesion count with ≥71 T2 hyperintense lesions vs. <71 (HR 1.50, 95%CI 1.27, 1.78) and presence of BL Gd+ lesions (HR 1.75, 95%CI: 1.49, 2.06) were also associated with a higher risk of developing new MRI activity. Risk of disease worsening was higher for those with BL EDSS < 2 (HR 2.79, 95%CI 2.14, 3.67). There were no associations between sex and disease duration on clinical or radiological disease activity or worsening.

Conclusions

Both clinical and radiological disease activity are predicted by younger age and presence of Gd+ lesions. Additionally, relapses are also predicted by higher EDSS, and there is some protective evidence of the combination therapy in lowering risk of new MRI activity. Only baseline EDSS level was associated with disease worsening.

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Clinical Outcome Measures Poster Presentation

P0060 - Descriptive study on recruitment effort for a remote monitoring study in Multiple Sclerosis: RADAR study (ID 1529)

Abstract

Background

There is a growing body of literature highlighting the role that wearable and mobile remote monitoring technology (RMT) can play in the assessment of Multiple Sclerosis (MS) and how it could improve clinical care and improve efficiency of research.

The Remote Assessment of Disease and Relapse in the Central Nervous System (RADAR-CNS) study is a pan-European consortium aimed to improve the management of different CNS disorders such as MS, Epilepsy or Major Depression using smartphones and wearable devices.

Most of the available data are based in small monocentric studies, however the full validation of these digital devices requires multicenter, well designed studies providing information on feasibility and acceptability.

Objectives

We aimed to describe the outcomes of the recruitment process in the Multiple Sclerosis (MS) RADAR-CNS disability and fatigue study (D&F).

Methods

The study was run in three European centers. Main eligibility criteria for D&F study were patients with relapsing-reminting or secondary progressive MS with an EDSS score between 2.0 and 6.0. Passive and active data were continuously collected through wearables (FitBit) and mobile phones (Android) and compared to the on-site visit every 3 months. The study duration is 2 years. The study sample size was 400 patients.

Results

The enrolment of the D&F study extended for a period of 18 months. We identified 4094 potential candidates (min-max 885-1789). At the end of the recruitment period, 678 (16.6%; min-max 0-24.2%) remained in the pre-screening phase. 3416 (min-max 885-1454) patients were assessed for eligibility. Out of those, 2372 (69.4%; min-max 53.3-87.1%) were excluded for not fulfilling the eligibility criteria: 1520 (64.1%; 15.0-87.1%) did not meet the EDSS score, 254 (10.7%; 0.2-49.6%) would not be suitable in the investigators opinion and 598 (25.2%; 3.0-60.3) did not have an Android. Out of the 1044 (30.6%; 12.9-46.7) eligible candidates, 644 (61.7%; 13.8-79.7%) declined to participate. A total of 400 (90-162) patients, 9.8% of the potential candidates, were enrolled into the study.

Conclusions

Our study illustrates the primary challenges in recruiting MS patients in RMT studies related to eligibility, both clinical and technological criteria, followed by reasons related to patients preferences. There is variability in the recruitment approach between centers. In future studies, developing technology for all types of phones and more attractive assessment for patients should be considered.

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Biomarkers and Bioinformatics Poster Presentation

P0061 - Determining the effect of blood anticoagulants on the detection level of neurobiomarkers in headache and control patients on the SIMOA platform (ID 1833)

Speakers
Presentation Number
P0061
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In the development of the sensitive single molecule array (SIMOA) technology, serum and blood plasma from EDTA collection tubes were used to verify and validate blood levels of NFL, GFAP, Tau and UCHL1 across healthy controls[1]. As the need arises to establish extensive baseline levels of these neurobiomarkers in order to better evaluate neurodegeneration in a wide variety of patients including multiple sclerosis (MS) patients, a validation study across a variety of blood collection anticoagulants is necessary to ensure there are no significant differences in blood levels due to the additives themselves.

Objectives

To determine whether SIMOA results are reliable and comparable within patients and between cohorts, we measured blood levels of the neurobiomarkers neurofilament (NFL), glial fibrillary acidic protein (GFAP), tau and ubiquitin C-terminal hydrolase L1 (UCHL1) in samples collected with different blood collection additives.

Methods

Serum and blood plasma were collected voluntarily from either headache or healthy control patients in one of four different blood collection tubes representing the 4 most common types of anticoagulant: none (serum), EDTA, sodium heparin (hep) and sodium citrate (NaC). Plasma and serum were isolated from whole blood by centrifugation at 1500 x g for 20 minutes. Plasma was centrifuged at 400 x g for 10 minutes to further deplete cells. Biomarker levels of NFL, GFAP, Tau and UCHL1 were measured via SIMOA with the Neuro4Plex A Advantage kit in the Quanterix SR-X machine according to manufacturer instructions. Statistical comparisons were made using GraphPad Prism analysis software.

Results

No statistically significant differences in blood concentrations were found between the anticoagulants for the NFL, GFAP or UCHL1 biomarkers in either the headache patients or the healthy control patients. However, Tau levels were significantly lower in all serum samples (p value <0.0001) from both patient cohorts with average levels 65-80% lower than plasma.

Conclusions

Use of serum should be avoided when establishing baseline blood levels of the neurobiomarker Tau on the SIMOA platform.

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Clinical Outcome Measures Poster Presentation

P0062 - Developing standard data of cognitive function using Processing Speed Test in Japanese healthy volunteers and comparison to the US normative data (ID 1616)

Speakers
Presentation Number
P0062
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive dysfunction can be observed early in the disease course of multiple sclerosis (MS) patients and has important consequences for daily activities. International guidelines recommend annual screening with the Symbol Digit Modalities Test (SDMT) and use of electronic administration to increase clinical adoption. The Processing Speed Test (PST) is a self-administered, iPad®-based validated adaptation of the SDMT in MS. The PST is not yet widely used in Japan, and there are few reports of its usage in Japanese subjects.

Objectives

To develop normative data of the PST score on Japanese healthy volunteers (HVs) in order to utilize it as a cognitive function test on Japanese patients with MS, and to characterize the PST score distribution between Japanese HVs and United States (US) HVs.

Methods

A single arm, cross-sectional study was conducted in Japanese HVs. The primary endpoint was the distribution of PST score. The secondary endpoints were distribution of PST scores stratified by age, educational status, and gender. Comparison of the PST scores between Japanese and US HVs collected in a previously reported study was evaluated using an age, gender, and education matched analysis.

Results

Of 254 subjects who participated in this study, 242 subjects with a Mini Mental State Examination score ≥ 27 were analyzed. The mean age was 44.1 years, 51.2% were male and 60.7% were educated over 13 years (vocational school, university, or more educated). Mean PST score (±SD) was 61.8±10.0, median of 62.0 (min 37, max 88). The mean PST score (±SD) significantly decreased with age, with scores of 69.6±8.8 (20-29 years, n=52), 64.9±10.9 (30-39 years, n=45), 63.5±6.1 (40-49 years, n=46), 57.1±8.7 (50-59 years, n=44) and 54.3±6.7 (60-65 years, n=55). The mean score (±SD) with education over 13 years (63.9±9.8) was significantly higher than with education 12 years or less (58.7±9.7) (p<0.0001). There was no significant difference in PST score between males (61.6±10.9) and females (62.0±9.1) (p=0.75). Mean (95% CI) difference between Japanese and US HV PST scores from the matched analysis was 10.2 (8.2, 12.2) (p<.0001), with Japanese > US.

Conclusions

The PST score in healthy Japanese subjects significantly decreased with age and was significantly higher in subjects with higher educational background. The average PST score was higher in Japanese HVs compared to US HVs. Use of country specific normative data may contribute to more accurate cognitive screening in Japanese MS patients.

Study supported by: Biogen

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Biomarkers and Bioinformatics Poster Presentation

P0063 - Development of a Custom Multivariate Proteomic Serum Based Assay for Association with Radiographic and Clinical Endpoints in MS (ID 833)

Abstract

Background

Multiple Sclerosis (MS) is a complex and heterogeneous disease. Investigating the biological pathways and cell types involved in MS pathophysiology as represented by protein biomarker expression can help inform the development of tools to monitor disease activity, disease progression, identify early evidence of relapse, and monitor treatment response.

Objectives

To develop a blood based multiplex proteomic assay that associates with clinical and radiographic endpoints in patients with MS. These endpoints include the presence of gadolinium-enhanced (Gd+) lesions, Annualized Relapse Rate (ARR) and clinically defined relapse status (active versus stable).

Methods

Serum samples (n=690 in total) from multiple deeply-phenotyped cohorts (ACP, CLIMB and EPIC) were tested in immunoassays for the measurement of 1196 proteins using Proximity Extension Assays (PEA) from OlinkTM and for 215 proteins using xMAPTM immunoassays from Myriad RBM, Inc. (RBM). Associated radiographic and clinical endpoints at the time of the blood draw were correlated with the protein levels. Twenty-one proteins were selected for inclusion in a custom assay based on their performance in univariate and multivariate statistical models, and replication across independent cohorts. Biological pathway modeling and network analysis were performed to ensure comprehensive representation of MS neurophysiology. Area under the curve (AUC) was selected as the key metric for model performance evaluation.

Results

Multivariate statistical ensembles restricted to the expression levels of the biomarkers selected for the custom assay achieved AUC performance of 0.827 for classification of the presence of Gd+ lesions, 0.802 for classification of clinically defined relapse status, and 0.930 for the classification of patients with Low ARR (≤0.2 relapses) vs High ARR (≥1.0 relapses). A multivariate model utilizing shifts in biomarker expression in longitudinally paired samples achieved the highest observed performance of 0.950 for classification of Gd+ lesion presence. In each case, the multivariate models significantly outperformed (p-value <0.05) the AUC of the highest performing univariate biomarker.

Conclusions

Multivariate models restricted to the 21 selected proteins effectively classified several radiographic and clinical endpoints with stronger performance than any single biomarker. A 21-plex custom assay panel is being developed for further investigation and validation using additional cohorts.

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Clinical Outcome Measures Poster Presentation

P0064 - Development of the international, multidisciplinary, patient-relevant standard outcome set for Multiple Sclerosis: the S.O.S.MS project (ID 1106)

Speakers
Authors
Presentation Number
P0064
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Currently, there is no consensus on which treatment outcomes need to be measured in Multiple Sclerosis (MS) care. Consequently, it is difficult to monitor and (inter)nationally compare real-world treatment outcomes of MS care. To encourage the shift towards value-based healthcare, there is need for a standard set of outcomes for MS.

Objectives

The aim of this study was to develop an international, multidisciplinary, patient-relevant standard outcome set for MS (S.O.S.MS).

Methods

A mixed method design including a systematic literature review, four patient focus groups (n=30) and consensus-driven RAND- modified Delphi process with an international, multidisciplinary MS expert panel. The expert panel consisted of seventeen MS experts of five different disciplines from seven high-prevalent MS countries. The consensus process consisted of four online consensus meetings plus three online voting rounds.

Results

A standard outcome set for MS was defined, consisting of fourteen outcome indicators divided in three domains: disease activity (3), physical functioning (5) and quality of life (6). Patient focus groups showed that outcome indicators in the quality of life domain were most important to patients. For each outcome indicator, a measurement tool was selected and the frequency of measurement was defined. Both clinical measurement tools as well as patient reported outcome measures (PROMs) were included. In addition to the fourteen outcome indicators, seven case-mix variables were selected.

Conclusions

This international, multidisciplinary standard outcome set for MS enables (inter)national measurement and comparison of patient-relevant outcomes of MS care. Results on the standard outcome set can be used for benchmarking, quality improvement, scientific research, patient information, shared-decision making and contracting care.

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Biomarkers and Bioinformatics Poster Presentation

P0065 - Differential neuroinflammation genes expression in benign and highly active multiple sclerosis (ID 1452)

Speakers
Presentation Number
P0065
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple sclerosis (MS) is a highly heterogenous disease. Its progression rates and inflammatory activity vary from benign course with rare relapses and expanded disability scale (EDSS) scores 3 or less after more than 10 years after disease onset to highly active disease with rapid progression, high disability scores and poor response to disease modifying treatments (DMTs). Despite extensive research there are currently no biomarkers that could precisely predict MS course.

Objectives

We aimed to investigate differences in the expression of multiple genes associated with neuroinflammation in patients with benign and highly active MS.

Methods

The study included 25 patients with MS (12 with highly active disease and 13 with benign MS) and 12 healthy controls (HCs). Gene expression was analyzed in subjects peripheral blood mononuclear cells (PBMC) RNA using the Neuroinflammation gene expression panel consisting of 770 genes for the Nanostring nCounter platform. Data was processed with the nSolver Analysis Software 4.0 and IBM SPSS and Statistics 23. Gene expression levels were compared with clinical features.

Results

We identified differences in the expression of 89 genes in PBMCs of benign, highly active MS patients and HCs using ANOVA. Genes related to innate immunity, autophagy, microglia function and apoptosis were the most widely represented. Heatmap analysis showed a subset of genes that were differentially expressed in patients with benign and highly active MS. Pairwise comparison of gene expression in patients with benign and highly active MS in the post-hoc analysis revealed 28 genes with significantly different expression in the two subgroups, mostly genes related to microglia function, innate immune response and apoptosis.

Conclusions

The study identified differential expression of genes related to neuroinflammation in benign and highly active MS. The results could have potential implications for prognosis and treatment planning.

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Biomarkers and Bioinformatics Poster Presentation

P0066 - Dimethyl fumarate decreases serum neurofilament light chain in relapsing-remitting multiple sclerosis patients. (ID 924)

Presentation Number
P0066
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) levels are associated with disease activity and prognosis in relapsing-remitting multiple sclerosis (RRMS) patients. Treatment with second-line disease modifying therapies (DMTs) leads to a reduction of sNfL, but little is known regarding first-line DMTs as dimethyl fumarate (DMF).

Objectives

To explore changes of sNfL levels in RRMS patients during treatment with DMF. To evaluate the potential role of sNfL measurement to predict an optimal treatment response.

Methods

Blood samples from 64 consecutive RRMS patients initiating DMF at Hospital Universitario Ramón y Cajal were collected at baseline and at 3, 6 and 12 months thereafter. sNfL levels were measured using a sensitive Single Molecular Array (SIMOA) assay (Quanterix). Patients were classified into No Evidence of Disease Activity (NEDA) and Ongoing Disease Activity (ODA) according the presence/absence of relapses, EDSS progression and/or MRI activity during the first year.

Results

Age at treatment initiation was 40.6 [33.2-46.3] years (median [25-75%IQR]) and EDSS was 1.5 [1.5-2.5]. Forty eight (75%) patients received other previous DMTs, seven of them were second-line DMTs. 66% of patients had evidence of disease activity at DMF initiation. Baseline sNfL levels were higher in patients who had evidence of disease activity at that time compared with patients who had not (12.2 pg/ml Vs. 8.8 pg/ml, p=0.024). No differences were found in baseline sNfL levels between naïve and previously treated patients, or between patients treated with first and second line DMTs. After 12 months of DMF treatment, 44 (69%) patients were NEDA and 20 (31%) were ODA. Baseline sNfL levels were higher in ODA patients compared to NEDA patients (14.6 pg/ml Vs. 9.2 pg/ml, p=0.016). A cut-off value of 12 pg/ml was established to predict NEDA status (OR=4.7; 95%CI: 1.6–15.7; p=0.008). After one year of DMF, sNfL levels decreased by 34.4% (p<0.0001). Both NEDA and ODA patients experienced a progressive sNfL reduction during the first year of treatment. However, this reduction was observed earlier in NEDA patients (three months after DMF initiation) than in ODA patients (six months).

Conclusions

DMF induced a progressive decrease in sNfL concentration during the first year of treatment. This reduction was delayed in ODA patients. Patients with basal sNFL values ≤ 12 pg/ml showed increased probability to achieve NEDA status at 12 months.

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Clinical Outcome Measures Poster Presentation

P0067 - Disability improvement by Multiple Sclerosis Functional Composite in progressive MS patients and MRI features (ID 1729)

Speakers
Presentation Number
P0067
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Disability improvement is an important functional measure in progressive MS. The MRI features of disability improvement have not been explored.

Objectives

To assess quantitative brain and spinal cord MRI measures, including volumetric features, that correlate with improvement in the T25FW or 9HPT compared to multiple sclerosis (MS) patients with stable or worsening features.

Methods

A nested cohort from the SysteMS substudy of Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) Study was selected to match inclusion criteria for patients enrolling in a phase 2 trial of repeat dose intrathecal Mesenchymal Stem Cells-Neurotrophic Factor (MSC-NTF) cells in patients with progressive MS (NCT03799718). 3T MRIs at baseline and at follow-up timepoint (12-24 months later) underwent brain and lesion volumetric analysis by Icometrix, as well as mean upper cervical cord area (MUCCA) which generated 34 measures. These 34 MRI volumetric measures (ml) were compared in patients with improved versus patients with worsening or stable 9-hole peg test (9HPT) or timed-25-foot-walk (T25FW) scores. Results were not corrected for multiple comparisons due to the exploratory nature of this study.

Results

48 patients met inclusion criteria. 17 patients had improved 9HPT score, while 29 had worsened or had stable 9HPT score from baseline to 12-24 months later. Whole brain volume at baseline for these 3 cohorts (Improved 9HPT:1505±51 vs. stable-worse 9HPT:1471±62;p=0.069;t-test) and follow-up (Improved:1501.555±52.039 vs. stable-worse:1461.304±63.562);p=0.03;t-test) differed between the two groups, as did gray matter volume at follow-up (Improved 1505.059 ±50.961 vs. stable-worse 865.57±41.352); p=0.063:t-test). For T25FW, 18 patients had an improved score, while 27 were worsened or stable over the 12-month period. Deep white matter FLAIR/T2 lesion volume at baseline (Improved:0.43±0.507 vs. stable-worse:0.827±0.561;p=0.03;t-test) and follow-up (Improved:0.429±0.503 vs. stable-worse:0.864±0.603;p=0.02) differed between two T25FW groups. MUCCA was not associated with improvement measures.

Conclusions

Improved 9HPT measures over a 12-month period correlated with baseline brain volume, while T25FW improvements correlated with baseline deep white matter T2 lesion volume. These results will inform analysis of clinical outcomes in the ongoing phase 2 clinical trial of MSC-NTF cells in progressive MS.

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Clinical Outcome Measures Poster Presentation

P0068 - Disability Progression in MS Participants Treated with Delayed-release Dimethyl Fumarate: Age-related Subgroup Analysis of the NARCOMS Registry (ID 397)

Speakers
Presentation Number
P0068
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Dimethyl fumarate (DMF) clinical trials excluded relapsing-remitting multiple sclerosis (RRMS) patients aged >55 years (yrs). The limited data on DMF use in this age group evaluated relapses but not disability. Unlike relapses, which often decrease as MS patients age, disability progression often increases.

Objectives

To characterize long-term disability outcomes over 4.5 yrs of DMF treatment in RRMS participants based on age at time of DMF initiation.

Methods

We identified NARCOMS participants (pts) with RRMS, living in the US, and initiating DMF from Fall 2013–Spring 2018 with ≥1 yr follow-up. We dichotomized age at DMF initiation as <55 (younger) and ≥55 yrs (older). Disability was measured using the Patient Determined Disease Steps (PDDS). Time to 6-month confirmed PDDS progression (≥1-point increase) and conversion to SPMS were estimated using the Kaplan-Meier method and compared using a log rank test. Cox proportional hazards regression models were adjusted for sex and initial PDDS level. Pts were censored at last follow-up or DMF discontinuation, whichever came first. Safety data were not collected.

Results

647 RRMS pts initiated DMF. In the younger subgroup (n=351, 54%), median age was 47 yrs, 88% female, and 24% reported a relapse in the last 6 months. In the older subgroup (n=296, 46%), median age was 60 yrs, 82% female, and 22% reported a relapse in the last 6 months. Compared to the younger subgroup, older pts had longer MS disease duration (11 vs 17 yrs, p<0.001) and significantly greater disability at baseline as measured by PDDS. Median treatment duration was 2.5 yrs in younger pts and 2 yrs in older pts. At last follow-up, 283 (81%) younger pts and 236 (80%) older pts remained on DMF. Most pts in both groups were estimated to remain free of disability progression over 4.5 yrs: 64% (95%CI: 57-71) of younger pts vs 74% (95%CI: 67-80) of older pts (p=0.12). Most pts in both subgroups also were estimated to remain free from conversion to SPMS over 4.5 yrs: 90% (95%CI: 85-94) of younger pts vs 86% (95%CI: 79-91) of older pts (p=0.17).

Conclusions

Conclusions: As expected, older pts (≥55 yrs) had significantly longer MS disease duration and higher baseline disability compared with younger pts (<55 yrs). Despite these baseline differences, most pts in both groups remained free of PDDS progression and free from conversion to SPMS over 4.5 yrs of DMF treatment.

Supported by: Biogen; NARCOMS is a project of the CMSC

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Biosensors Poster Presentation

P0069 - dreams: developing a comprehensive, sensitive and validated set of digital biomarkers for MS (ID 1323)

Speakers
Presentation Number
P0069
Presentation Topic
Biosensors

Abstract

Background

Smartphones and watches and their inbuilt sensors allow for the collection of a near to infinite amount of data about their owners. Taking advantage of these capabilities to improve disease characterisation and monitoring and to support treatment decisions in MS seems obvious but faces a number of challenges: Selection and validation of a comprehensive and meaningful set of tests, managing the immense amount of data and identifying the useful information, data privacy and ascertainment of long-term adherence.

Objectives

To assess systematically the feasibility of a comprehensive smartphone and smartwatch based set of digital biomarkers for disease monitoring in patients with MS (PwMS) and validate this tool against currently available state of the art clinical, imaging and body fluid assessments.

Methods

The dreams App is a software application including multiple biomarkers for each of the domains movement, dexterity, cognition and vision as well as questionnaires for fatigue and other patient reported outcomes. Compliance is enhanced through a gamification-approach. We are currently conducting a feasibility study with a group of PwMS and matched healthy controls to further evaluate the technical reliability of a larger set of digital biomarkers and select those best suited for the validation studies. Early next year, the first of two independent validation studies including 400 PwMS, recruited from participants in the Swiss MS cohort (SMSC) is planned to further validate the digital biomarkers through correlation with established standardized clinical, imaging and body fluid markers already implemented in the SMSC.

Results

Preliminary in-house reliability testing with healthy controls showed intra class correlation coefficients of >60% for the digital biomarkers included in the feasibility study and >80% for at least one in every domain. These results were derived through unguided repetitions over multi-day-timeframes and not optimal laboratory conditions in order to truthfully reflect future use.

Conclusions

With this program, we aim at establishing dreams as a novel smartphone-based comprehensive, modular, validated, independent and broadly accepted digital assessment tool for PwMS. Integrated into a data management and precision medicine based decision support system this assessment tool would improve every day management and allow for better assessment of new therapies in the setting of clinical trials.

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Biomarkers and Bioinformatics Poster Presentation

P0070 - Effect of evobrutinib, a BTK inhibitor, on immune cell and immunoglobulin levels in relapsing MS: an open-label extension to a phase II study (ID 1683)

Speakers
Presentation Number
P0070
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Evobrutinib (EVO), a highly selective Bruton’s tyrosine kinase (BTK) inhibitor, has a dual mode of action on B cells and myeloid cells involved in multiple sclerosis (MS) pathogenesis. A Phase II randomized study (NCT02975349) investigated the effect of EVO on immune cells and immunoglobulins (Ig). After a 48-week randomized, double-blind period (DBP), relapsing MS (RMS) patients treated with EVO showed no evidence of B cell depletion or clinically relevant changes in memory or mature-naïve B cell subsets. IgG levels remained stable and slight elevations and reductions, respectively, in IgA and IgM levels were observed.

Objectives

To investigate the long-term effects of EVO on B cells (total, mature-naïve and memory subsets), T cells (total, helper and cytotoxic subsets), NK cells, and Ig levels after 48 additional weeks in the ongoing open-label extension (OLE).

Methods

Adults with RMS were randomized double-blind to EVO 25 mg QD, 75 mg QD, 75 mg BID, or placebo (PBO). PBO patients switched to EVO 25mg QD at Week 24. At Week 48, all patients were OLE-eligible, and received EVO 75 mg QD (median ≈48 weeks), then 75 mg BID. Safety of EVO, including assessment of total B cell counts and Ig levels, was a secondary endpoint; effects on B cell subsets, T cells, and NK cells were exploratory. Immune cell counts were assessed at OLE Week 48 relative to DBP baseline, and Ig levels at OLE Weeks 24 and 48.

Results

Of 213 patients receiving EVO during the DBP, 164 (77%) entered the OLE and 148 (90%) completed ≥60 additional treatment weeks. Investigation of total CD19+ B cells and B cell subsets revealed a decrease in CD19+ B cells and in mature-naïve B cells in all groups originally randomized to EVO. The decrease in mature-naïve B cells was consistent with that observed for CD19+ B cell counts, however no evidence of a change in the memory B cell levels was observed. No relevant changes in IgG levels relative to DBP baseline were observed. Mean IgA and IgM levels remained increased and decreased, respectively, but mean values were within normal ranges. Furthermore, there was no evidence of a change in T or NK cell parameters. Overall, EVO treatment was not associated with an increased risk of infections.

Conclusions

Immune cell numbers and Ig levels seen in patients receiving EVO for 48 weeks of the OLE were consistent with those in the DBP. The results suggest a gradual decline of B cells over time with consistent BTK inhibition, however the clinical meaningfulness of these changes remains to be determined. The observed changes in B cells, IgA and IgM levels were not associated with an enhanced risk of infections. These findings suggest that the continuous pharmacological inhibition of BTK over 96 weeks with EVO does not lead to substantial B cell reductions or changes in Ig levels.

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Clinical Outcome Measures Poster Presentation

P0071 - Effect of oral ponesimod on clinical disease activity and MRI-based outcomes in patients with relapsing multiple sclerosis: Phase 3 OPTIMUM study (ID 1570)

Abstract

Background

Ponesimod (PON), an orally active, highly selective and reversible modulator of sphingosine-1-phosphate receptor 1, reduces circulating lymphocytes by sequestration in lymphoid organs. In the phase-3 OPTIMUM study (NCT02425644), PON showed superior efficacy vs teriflunomide (TER) in patients with relapsing multiple sclerosis (RMS).

Objectives

To evaluate prespecified MRI-based endpoints and no evidence of disease activity (NEDA) status in patients with RMS.

Methods

Patients (18-55 years) with RMS (expanded disability status scale scores: 0-5.5) were randomized (1:1) to receive PON 20 mg or TER 14 mg for 108 weeks. MRI endpoints included: percentage change from baseline to week 108 in brain volume (SIENA, Structural Image Evaluation, using Normalization of Atrophy), mean number of new gadolinium-enhancing (Gd+) T1 lesions and volume/count of new/enlarging T2-weighted (T2) lesions. NEDA-3 (absence of confirmed relapse, 12-week confirmed disability accumulation, Gd+T1 and new/enlarging T2 lesions on annual MRIs) and NEDA-4 status (NEDA-3 and no average annual brain volume decrease ≥0.4%) were evaluated from baseline to week 108.

Results

985/1133 (86.9%) randomized patients completed the study. MRI findings for PON vs TER from baseline to week 108, respectively, were: least square (LS) mean percent change from baseline in brain volume: −0.91% vs −1.25% (difference: 0.34%, 95% CLs: 0.17;0.50, p<0.0001); LS mean difference (PON−TER) in change from baseline in total T2 lesion load: −399.2 mm3 (95% CLs: −651.5;−146.8, p=0.002); mean number of new/enlarging T2 lesions per year: 1.40 vs 3.16 (rate ratio [RR]: 0.44, 95% CLs: 0.36;0.54, p<0.0001); PON vs TER odds ratio (OR [95% CL]) for absence of new/enlarging T2 lesions: 1.71 (1.30;2.25, p=0.0001); mean number of new Gd+T1 lesions per scan: 0.18 vs 0.43 (RR: 0.42, 95% CLs: 0.31;0.56, p<0.0001); PON vs TER (OR [95% CL]) for absence of new Gd+T1 lesions: 2.18 (1.61;2.95, p<0.0001). At week 108, 28.2% (159/564) PON vs 18.3% (102/558) TER patients (OR: 1.70, 95% CLs: 1.27;2.28, p=0.0004) achieved NEDA-3; 15.0% (79/526) PON vs 8.5% (45/532) TER patients (OR: 1.85, 95% CLs: 1.24;2.76, p=0.0026) achieved NEDA-4. The most common reason for not achieving NEDA-3 or NEDA-4 status was presence of new/enlarging T2 lesions.

Conclusions

PON showed benefit vs TER for all MRI outcomes including brain volume loss and a significantly higher proportion of patients achieved NEDA-3 and NEDA-4 status, supporting the effects observed on clinical endpoints.

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Clinical Outcome Measures Poster Presentation

P0072 - Effect of switching disease modifying drugs on relapse rate in stable relapsing remitting multiple sclerosis patients planning for pregnancy. (ID 580)

Speakers
Presentation Number
P0072
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The decision to have children is complex for multiple sclerosis patients due to the range of aspects that affect it. One of the most important aspects is the use of disease modifying drugs (DMDs) when planning or during pregnancy and how continuing, stopping or switching them may affect the disease course. It is always better to avoid the use of medications during pregnancy but in patients with severe disease stopping their medium or high potency medications imposes high risk of disease recurrence, rebound or Immune Reconstitution Inflammatory Syndrome (IRIS),specifically when stopping Natalizumab (NTZ) or Fingolimod. Switching to another medication that can be used up to conception and even during pregnancy which are either Glatiramer acetate (GA) or Interferons (IFNs) may be an option.

Objectives

To review available evidence on the effect of different switching strategies in stable relapsing remitting MS (RRMS) patients on clinical and radiological disease activity.

Methods

We searched MEDLINE, EMBASE, EMCARE, CINAHL, SCOPUS, Cochrane Library up to March 2020. No limits or restrictions on time or study design were applied, but only papers written in English were included. We used the revised Cochrane risk of bias tool for randomized trials (ROB2), and national heart, lung and blood institute (NIH) quality assessment tool for before-after (pre-post) with no control group cohort studies.

Results

Seven articles that matched the inclusion criteria were included: 4 cohorts, 2 case reports and one RCT. Results were synthesized narratively and Meta-analysis was not possible due to high heterogeneity (limited treatment overlap) between the studies. Four different switching strategies were identified, the first three were considered de-escalation from high to low potency DMDs, (NTZ to GA), (NTZ to monthly methylprednisolone for three months then GA) which is called (bridging) and (NTZ to IFN). All studies measured the mean change in annualized relapse rate after switching as disease activity measure. These switches showed some protection from rebound and IRIS but not from disease recurrence. The fourth strategy IFN to GA (switching between first line injectables), showed disease stability in two case reports.

Conclusions

Evidence on switching strategy effect on disease course in stable RRMS patients is scarce, available data suggests partial activity in case of de-escalation, and stability in case of switching between first line injectables.

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Clinical Outcome Measures Poster Presentation

P0073 - Effectiveness of peginterferon beta-1a versus non-pegylated interferons and glatiramer acetate in a real-world setting using propensity score matching (ID 1659)

Speakers
Presentation Number
P0073
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Peginterferon (pegIFN) beta-1a with a prolonged half-life and increased systemic exposure was developed for the treatment (tx) of relapsing-remitting multiple sclerosis (RRMS) resulting in less frequent dosing intervals without attenuating the biological or pharmacodynamic properties associated with existing IFN treatments. Real-world data with pegIFN beta-1a in clinical practice are limited. NeuroTransData GmbH (NTD) is a Germany-wide network of neurologists and psychiatrists. The NTD MS registry is a database capturing demographic, clinical history, and clinical variables from MS patients in a real-world setting.

Objectives

To compare pegIFN beta-1a populations with populations using the following injectables: SC IFN beta-1a, IM IFN beta-1a, SC IFN beta-1b, glatiramer acetate (GA).

Methods

NTD registry data from adult patients with RRMS who initiated tx no earlier than 2014, had ≥12 months of tx exposure, and ≥1 EDSS measurement or a relapse after index therapy initiation were retrospectively analyzed. Primary endpoints were annualized relapse rate (ARR) and time to first relapse. The secondary endpoint was time to confirmed disability progression (CDP). Patient characteristics between treatment groups were compared using propensity-score matching (PSM).

Results

In total, 175 pegIFN beta-1a patients, 308 from the IFN group (SC IFN beta-1a, IM IFN beta-1a, SC IFN beta-1b), and 287 GA patients were included in the analysis set. Mean tx duration was 2.5, 2.7, and 2.4 years, respectively. After PSM, no difference was found in the ARR and time to relapse between pegIFN beta-1a patients and patients from the IFN group (estimated ARR ratio 1.18; 95% CI 0.72, 1.94; p= 0.5047; relapse hazard ratio [HR] 1.14; 95% CI 0.71, 1.84; p=0.5790) or the GA group (estimated ARR ratio 0.74; 95% CI 0.45, 1.24; p=0.2608; relapse HR 0.76; 95% CI 0.47, 1.25; p=0.2813). For time to CDP, a significantly higher estimated treatment effect in favor of pegIFN beta-1a was found compared to both, the IFN (CDP HR 0.43; 95% CI 0.21, 0.89; p=0.0234) and the GA group (CDP HR 0.46; 95% CI 0.22, 0.97; p=0.0425).

Conclusions

Statistically significant superiority of pegIFN beta-1a was demonstrated for time to CDP. However, the current analysis is limited by small sample sizes and follow-up time. Updated results with larger sample sizes and longer follow-up time will be presented in order to assess if superiority of pegIFN beta-1a in other endpoints can be supported by statistical evidence.

This study was funded by Biogen.

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Clinical Outcome Measures Poster Presentation

P0074 - Effects of Ocrelizumab on Cognition-Real World Evidence Using the CogEval App (ID 504)

Speakers
Authors
Presentation Number
P0074
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive dysfunction in MS patients is common, with up to 65% of patients experiencing cognitive difficulties during the course of the disease. The effects of ocrelizumab on cognition have not been studied in a real-world setting.

Objectives

We sought to determine the effects of ocrelizumab on cognition in patients with relapsing multiple sclerosis (MS) or active secondary progressive multiple sclerosis (aSPMS) using the CogEval app's Processing Speed Test (PST), a validated analogue of the Symbol Digit Modalities Test (SDMT). The PST has three major advantages over the SDMT: 1) PST takes only 2 minutes to complete, and does not require a healthcare professional to be present with the patient during testing, 2) PST has been shown to be more sensitive to T2 lesion volume compared to SDMT, and 3) There is a smaller learning effect with PST compared to SDMT.

Methods

We performed the PST on patients in our clinic currently receiving ocrelizumab or who were started on ocrelizumab from January 2019 to April 2020. Only patients who had received at least two doses of ocrelizumab and had at least 3 PST scores were included in the analysis. 28 patients met these criteria. Based on the average of subsequent PST tests performed (Range: 2-5) we analyzed the proportion of patients who improved on PST (>4 points) were stable (no change >4 points or <4 points) or worsened (< 4 points). We performed univariate regression analyses based on age (>40 and <40), gender, smoking, and educational attainment (four-year college degree vs. no college degree). We also performed a sub-group analysis on nine patients starting ocrelizumab therapy with a PST score prior to initiation of ocrelizumab.

Results

Average time on treatment for the cohort was 430 days. 32.1% of patients showed improvement of their PST scores, 50% of patients had stable PST scores, and 17.9% of patients had a worsening of their PST scores. Univariate regression analyses were performed based on age, gender, smoking, and educational attainment (four-year college degree vs. no college degree) and there were no significant trends with any of these analyses. In the sub-group analysis of nine patients with a PST score prior to initiation of ocrelizumab, three patients showed improvement in their PST scores, four patients were stable, and two patients worsened.

Conclusions

To our knowledge, this is the first real-world analysis of the effects of ocrelizumab on cognition using the PST, a validated analogue of SDMT. A substantial majority of patients showed stability or improvement on PST during the course of their treatment with ocrelizumab. Univariate regression analyses looking at age, gender, smoking and educational attainment showed no significant trends, suggesting baseline demographics/disease characteristics did not affect the outcome of PST scores. Longer-term real-world analyses are necessary to determine the effects of prolonged B cell depletion on cognition in MS patients taking ocrelizumab.

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Clinical Outcome Measures Poster Presentation

P0075 - Efficacy of Rituximab in Adult and Pediatric Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Systematic Review and Meta-analysis (ID 1932)

Speakers
Presentation Number
P0075
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Myelin-oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) is an emerging disease entity related to a broad spectrum of acquired inflammatory demyelination of the central nervous system. Previous studies have demonstrated the efficacy of rituximab (RTX), an anti-CD20 monoclonal antibody, in neuromyelitis optica spectrum disorder, and multiple sclerosis. Although RTX is commonly used in MOGAD as well, the benefit of this therapy is still underinvestigated.

Objectives

To evaluate the effect of RTX in adult and pediatric MOGAD including the change in annualized relapse rate (ARR), and expanded disability status (EDSS), the post-treatment ARR, as well as the prevalence of freedom-from-relapse and EDSS progression.

Methods

A literature search was conducted on MEDLINE, EMBASE, and Cochrane databases. Eligibility criteria included observational studies that evaluated the efficacy of RTX in adult and pediatric MOGAD. We excluded review articles, case reports, studies that included fewer than 2 patients, and unpublished studies. We performed meta-analysis using Comprehensive Meta-analysis version 3.3 software from Biostat, Inc (Eaglewood, NJ, USA). Study results were statistically combined using a random-effect model and displayed with forest plots. The standard mean differences (SMD) with 95% confidence interval (95%CI) of ARR and EDSS, mean post-treatment ARR as well as the prevalence of freedom from relapse and EDSS progression were calculated.

Results

The initial search yield 398 articles. Forty articles underwent full-text review. Twelves cohorts and case series (259 MOGAD patients) were included in the meta-analysis. The SMD of pre- and post-treatment ARR was - 0.629 (95% CI -0.874 to -0.384, p <0.001) for all MOGAD patients, -0.440 (95% CI -0.648 to -0.231, p <0.001) in adults, and -0.957 (95% CI -1.450 to -465, p <0.001) in pediatric population. Post-treatment ARR were 0.893 (95% CI 0.174 to 1.612) in adults, and 0.468 (95% CI 0.181 to 0.754) in children. The prevalence of freedom-from-relapse were 68.8% (95% CI 40.2% to 87.8%) and 59.7% (95%CI 37.0% to 78.8%) in adult and pediatric subgroups, respectively. Although EDSS was not significantly changed, 82.7% (95%CI 63.0% to 93.1%) of MOGAD patients had no increasing in EDSS after RTX therapy

Conclusions

This meta-analysis of the cohorts and case series demonstrated the effects of RTX in adult and pediatric MOGAD patients. Although RTX reduced the relapse rate significantly, a large portion of patients continued to relapse. There was substantial heterogeneity in treatment regimens among studies. Prospective controlled studies are needed to validate these results as well as investigate the safety and tolerability of this treatment.

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Clinical Outcome Measures Poster Presentation

P0076 - Evaluation of diagnosis and treatment practices in patients with Multiple Sclerosis by Brazilian neurologists’ experts in demyelinating disorders. (ID 994)

Abstract

Background

Recent changes in Multiple Sclerosis (MS) diagnostic criteria and new medications promoted a major impact on the way specialists manage the disease.

Objectives

This study aimed to give an insight into the factors considered by Brazilian neurologists in the management of MS, and to identify how these factors contribute to diagnosis and treatment.

Methods

Potential participants were selected by a Steering Committee, which was assembled of MS experts from eleven Brazilian states and was responsible to development the Survey. Only MS specialists were included in the study (neurologists who have completed a neuroimmunology fellowship or who treat more than 30 patients with MS). Links to the online survey were distributed between March 2019 and January 2020. The questionnaire was composed of 11 question sections with hypothetical scenarios, as radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS).

Results

Neurologists from 13 Brazilian states responded to Survey (n=94). In CIS scenario, respondents agreed to treat patients with high risk of MS diagnosis, results that was not founded in RIS case, which half of the respondents opted to not treat, even in high risk patients. In RRMS and high-risk CIS, choice of treatment was distributed among interferon beta, glatiramer acetate and teriflunomide, which were changed to dimethyl fumarate and fingolimod as RRMS severity increased. In PPMS case, almost all respondents agreed to start treatment with ocrelizumab or rituximab. In contrast, the majority of respondents opted to treat SPMS only if there is evidence of disease activity. Reasons for switching medication, in a 12-month period, were appearance of one new or enlarging brain T2 lesion; one gadolinium-enhancing lesion in brain imaging; and one clinical relapse. Almost all specialists perform lumbar puncture for diagnoses, and monitor disease through a 12-months interval neuroimaging. Furthermore, almost all specialists check levels of vitamin D and prescribe supplements for low levels.

Conclusions

This study allowed the identification of areas of agreement among Brazilian neurologists on different scenarios related to patients with MS. These results can be used to promote debate among Brazilian experts, with the goal of helping update future protocols and improve patient management.

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Clinical Outcome Measures Poster Presentation

P0077 - Evaluation of Quality of Life and Fatigue in Patients Followed in Multiple Sclerosis Outpatient Clinic (ID 249)

Speakers
Presentation Number
P0077
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Fatigue in multiple sclerosis (MS) is a common disabling symptom that may have a major impact on quality of life (QoL) of MS patients, however it frequently is overlooked in daily clinical practice. Moreover, the studies exploring the QoL and fatigue have mostly been limited to the MS patients. Currently, we are unaware of any data exploring the QoL and fatigue in the clinical subtypes of MS and other demyelinating diseases. This study aims at bridging this gap.

Objectives

Our objective is to evaluate the quality of life and fatigue in the clinical subtypes of MS patients as well as in patients with other demyelinating diseases.

Methods

The clinical types, quality of life (Multiple Sclerosis Quality of Life-54 - MSQoL-54) and fatigue levels (Fatigue Severity Scale - FSS) of the patients were analyzed retrospectively. Patients were divided into two groups in terms of disability as those with EDSS scores ≥3 and <3. The quality of life of the patients was evaluated according to clinical types and disabilities. The cut‐off score for fatigue was set to be ≥4 in FSS.

Results

The mean age of the patients was 39.59 ± 9.85, and the mean disease duration was 6.30 years. Of all enrolled patients, 1.5% had Radiological Isolated Syndrome (RIS) (n = 1), 10.6% had Clinical Isolated Syndrome (KIS) (n = 7), 68.2% had Relapsing-Remitting MS (RRMS) (n = 45), 9.1% had Secondary Progressive MS (SPMS) (n = 6), 3% had Primary Progressive MS (PPMS) (n = 2), 4.5% had Neuromyelitis Optica Spectrum Disease (NMOSD) (n = 3), and 3% had other demyelinating disease (n = 2). Mean overall MSQoL-54 score was 86.79 ± 8.57, and mean Beck Depression Inventory score was 10.39 in all patients. MSQoL-54 score was 88.36 ± 8.54 in RRMS patients; 81.25 ± 5.78 in SPMS patients; 84.57 ± 10.84 in CIS patients; 82.75 ± 6.71 in PPMS patients; 83.50 ± 7.05 in NMOSD patients; 75.50 in RIS patient; and 90.50 ± 2.12 in patients followed up with the diagnosis of demyelinating disease. Although the QoL scores of the progressive forms were lower; no statistically significant difference between clinical types was found (p = 0.281). The mean MSQoL-54 score was 82.61 ± 5.70 in patients with EDSS scores ≥3 (n = 13) whereas it was 87.82 ± 8.89 in patients with EDSS scores <3 (n = 53) (p = 0.014). The prevalence of fatigue in our cohort was 65.2%. 57.8% of patients with RRMS; 83.3% in SPMS patients; 85.7% in CIS patients; 100% in RIS patients; 50% in PPMS patients; 66.7% in NMOSD patients; and 100% in patients who were followed up with the demyelinating disease reported fatigue (FSS ≥4).

Conclusions

Despite the several limitations including the small number of the patients in subgroups, our results show the higher fatigue levels regardless of clinical types and the association of increased disability and reduced quality of life in MS patients. In addition to medical treatments, periodic evaluation of patients' quality of life with appropriate support programs and taking necessary measures may contribute positively to the course of the disease.

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Clinical Outcome Measures Poster Presentation

P0078 - Evidence for the efficacy of nabiximols oromucosal spray in the management of patients with spasticity: A systematic review (ID 1609)

Speakers
Presentation Number
P0078
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Spasticity is a common symptom for people with multiple sclerosis (MS), and increases in prevalence and severity throughout the disease course. Worsening spasticity is associated with impaired mobility and other symptoms and negatively impacts quality of life, increasing health resource utilization and costs. Nabiximols oromucosal spray, containing mainly tetrahydrocannabinol (THC) and cannabidiol (CBD), and also other CBD and non-CBD components is approved in >25 countries outside of the US as add-on therapy in people with moderate-to-severe MS spasticity who do not respond adequately to other antispasticity medications.

Objectives

To evaluate the efficacy and safety of nabiximols spray as add-on therapy to antispasticity treatment in people with moderate to severe treatment-resistant MS spasticity.

Methods

The review was undertaken following principles published by the Centre for Reviews and Dissemination. A comprehensive search of Medline, Embase, and Cochrane Library databases was conducted. Randomised controlled trials (RCTs) and non-randomised trials investigating the effect of adding nabiximols to standard antispasticity treatment in people with moderate-to-severe MS spasticity were included. Evaluated outcomes included proportion of patients with improvement (30%) in Numeric Rating Scale (NRS) spasticity, mean change in NRS spasticity, quality of life, adverse events. When appropriate data were pooled using meta-analysis.

Results

A total of 7 RCTs with 1,570 participants were eligible for inclusion. Studies scored low risk of bias. Of these studies, data from 4 studies (468 participants) evaluated nabiximols within the approved dose, 1–12 sprays/day: 2 (n=347) were appropriate for pooling (after a 4-week single-blind period, almost half of the enrolled participants met early response criterion [improvement of 20%, label condition] and were randomised). Of these early responders, a greater proportion of patients were clinically relevant responders (30% NRS improvement) with nabiximols than placebo at the end of a 12-week double-blind period (pooled: 75% vs 45%, RR 0.55 [0.33, 0.92]), with a statistically significant reduction in mean NRS spasticity (NRS 0-10) from baseline compared with placebo (pooled: mean difference -1.30 [-2.33, -0.27]). Adverse events were generally mild-to-moderate in severity, transient and rarely required treatment discontinuation. One systematic review of non-randomised studies was identified which reported results in line with those from RCTs.

Conclusions

Add-on nabiximols provides clinically relevant improvement of MS spasticity in patients who do not respond adequately to antispasticity medications both in clinical trial and daily practice settings.
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Clinical Outcome Measures Poster Presentation

P0079 - Experience in Multiple Sclerosis Patients with SARS CoV-2 Infection (ID 1508)

Speakers
Presentation Number
P0079
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The new coronavirus SARS-CoV-2 infection has spread worlwide becoming a pandemic never before seen. Multiple Sclerosis (MS) patients in a state of immunosuppression (IS) may be exposed to a greater risk of COVID-19 complications, although there is increasing evidence postulating a possible protective role of selective IS.

Objectives

To describe the real-world experience in MS patients with SARS-CoV-2 infection at a MS Unit of a hospital in Madrid, Spain. We describe clinical evolution and MS treatment actions

Methods

Observational, prospective and usual clinical practice study in MS patients affected by SARS-CoV-2 infection with clinical diagnosis (at least three of the following: fever, anosmia, cough, diarrhea, myalgia) and/or microbiological diagnosis (PCR in nasopharyngeal swabs and/or serology).

Results

41 SARS-CoV-2 infection cases were registered. 21 were women with a mean age of 39,4 years old (DS10,3). 38 were relapsing-remitting MS patients and 3 had a progressive MS. The mean MS time course was nine years (DS1,4). 39 patients were treated with disease-modifying therapies (DMTs): 46,3% with oral agents, 39% with monoclonal antibodies and 10% with injectable agents. 27 patients were previously treated with other DMTs. The median Expanded Disability Status Scale (EDSS) was 2,5 (DS0,7). 11 patients had clinical activity the previous year. 18 cases were confirmed by PCR and/or serology and 23 were clinically diagnosed. 17% of the patients were admitted to hospital (6 were diagnosed with pneumonia) and none required admission to the intensive care unit. There were no deaths.Three patients had other comorbidities. Admitted patients were older and had higher EDSS score without statistical significance. MS got worse in 7 patients. DMTs were stopped or delayed in 10 patients due to the SARS-CoV-2 infection.

Conclusions

All the MS patients studied had a good outcome of the SARS-CoV-2 infection. Only 17% of them required admission to hospital and 14,6% of the cases were asymptomatic. 95% of the patients were treated with DMTs. From our experience, the SARS-CoV-2 infection does not seem to entail a more aggressive form of the disease in this group of patients. Selective IS may favor the good evolution. Larger clinical registers are needed to establish solid conclusions.

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Biomarkers and Bioinformatics Poster Presentation

P0080 - Exploring neurofilament light in CSF as a biomarker for multiple sclerosis in clinical practice (ID 586)

Speakers
Presentation Number
P0080
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neurofilament light (NFL), a biomarker of axonal damage and disease activity in multiple sclerosis (MS), has been increasingly recognized for prognostic and therapeutic decisions.

Objectives

To assess the sensitivity and specificity of cerebrospinal fluid (CSF) NFL for disease activity and to evaluate its prognostic value in predicting disease severity and conversion from relapsing-remitting (RRMS) to secondary progressive MS (SPMS).

Methods

Patients with a confirmed diagnosis of RRMS (n=769) who had determined NFL in CSF as part of the diagnostic work-up or from assessments as part from regular clinical visits between 2001 and 2018 were retrospectively identified in the Swedish MS registry. Measurements over time of disease activity (clinical relapses and lesion formation on MRI) and disability (EDSS) were retrieved. We assessed NFL levels in relation to concomitant clinical and MRI activity and as outcome for treatment response.

Results

Patients with a concurrent clinical relapse had significantly higher NFL concentrations (median NFL no relapse 278 ng/L, relapsed 1122 ng/L, p<0.001) and a correlation with relapse severity was observed (p<0.001). Patients with gadolinium-enhancing lesions had higher median NFL levels (1414 ng/L) than those without (426 ng/L, p<0.001) and NFL levels correlated with the number of gadolinium enhancing lesions (p<0.001). CSF NFL showed sensitivity of 93.3% and specificity of 77.4% to disease activity (relapses and/or MRI activity). High NFL at diagnosis (n=414) was independently associated with worsening of disability and predicted progression to EDSS≥3 (n=128, p<0.001, HR 0.566 95% CI 0,413-0,711) and conversion to secondary progressive MS (n=39, p=0.0003, HR=0,380 95% CI 0,225-0,641). In a subset of patients (n=159), NFL was analysed at baseline and at follow-up (median time between LPs 23.7 months). Patients who switched from a first-line to a second-line therapy (n=65) exhibited significant reduction in NFL concentrations (p<0.001). However, patients who did not receive disease modifying therapy (DMT) (n=32), had first-line therapy (n=40), or switched to a third-line treatment (n=22) between baseline and follow-up did not show a significant decrease in their CSF NFL levels (p=0.975, p=0.658, and p=0.059 respectively).

Conclusions

Since 2001 CSF NFL has been part of the clinical assessment at Sahlgrenska University Hospital, Gothenburg. Thus, the results of this study are based on a real-life material and we can confirm the utility of NFL as a biomarker in MS. Our data underline NFL as a sensitive biomarker of disease activity, its usefulness for prediction of disability and clinical course and for monitoring DMT response. Serum/plasma NFL is most likely to show similar properties but probably at a lower precision.

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Biomarkers and Bioinformatics Poster Presentation

P0081 - Exploring the usability and patient satisfaction of a virtual rehabilitation program in multiple sclerosis: The RehabVR study protocol (ID 210)

Speakers
Presentation Number
P0081
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Background: There is an association between motor and cognitive impairment in patients with multiple sclerosis (MS) over their disease course and strong evidence that physical therapy can prevent disability progression in these patients. Virtual reality (VR) has emerged as a promising treatment approach in rehabilitation for patients with MS due to its potential to increase patient motivation and rehabilitation adherence. However, there is a lack of studies about its safety, feasibility and effectiveness in MS patients.

Objectives

Objectives: The objective of this study protocol is to evaluate the feasibility, adherence, safety and effectiveness of a virtual reality rehabilitation (VRR) program in MS patients compared to a conventional rehabilitation (CR) program.

Methods

Methods: A randomized, prospective, open-label, controlled feasibility study will be conducted in a sample of 48 individuals diagnosed with MS. Participants will be allocated 2:1 to the VRR group (32) or CR group (16). Both groups will perform 8 in-hospital physical therapy sessions of 2 hours each, twice a week over 4 weeks. The VRR group will perform half of these sessions with a VRR tool. In addition, both groups will continue rehabilitation at home for 5 months. The VRR program was designed by a multidisciplinary group of healthcare professionals (neurologists, physiatrists, physiotherapists, neuropsychologists) according to a validated CR program. Feasibility will be assessed by the User Satisfaction Evaluation Questionnaire (USEQ). Secondary outcomes include adherence, disability, spasms and spasticity, balance, fatigue, activities of daily living, depression, anxiety, work status, cognition, demographic and clinical characteristics (in the VRR and CR groups), and safety (in the VRR group). Outcome measures will be assessed at baseline and at 1 and 6 months from the start of rehabilitation.

Results

Results: Due to the present comunication is a description of an ongoing study protocol there are stil not results to present.

Conclusions

Conclusions: A better understanding of long-term patient satisfaction with a VRR program specifically designed for MS patients would allow us to optimize the rehabilitation program and to collect valuable information for its implementation in the clinical practice. Additionally, the study will provide information on long-term adherence, changes in motor symptoms, cognitive function and patient-reported outcomes after the rehabilitation program. Altogether, the results from this study will help to gather valuable knowledge on the use of rehabilitation with a new VR tool in MS patients.

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Biomarkers and Bioinformatics Poster Presentation

P0082 - From proteome to interactome: a mechanistic approach to MS biomarker discovery (ID 1215)

Speakers
Presentation Number
P0082
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Multiple sclerosis (MS) is a multifaceted disease with an intricate pathophysiology that lies at the intersection of autoimmunity, inflammation, redox imbalance, demyelination, and neurodegeneration. The varying interplay of distinct and converging mechanistic profiles in MS is believed to contribute to the heterogeneity observed in disease course and outcomes, clinical presentation, and therapeutic response. With this high degree of undeciphered molecular complexity, identifying biomolecular markers that are reproducible as well as specific to even the major subclasses of MS has been problematic. These difficulties have hindered the clinical translation of biomarkers and their use to aid in disease assessment and treatment strategies for individual MS patients.

Objectives

We posit that a biocentric framework can be leveraged to augment the prognostic capacity of MS biomarkers. By coupling machine learning findings with a computational illustration of their dynamical interactions within disease-perturbed networks, we hope to extract biomarkers that convey the full spectrum of MS pathophysiology—from disease activity to worsening and progression. Furthermore, by honing in on biomarkers that reflect the true underlying biology, we may be able to expand on the standard list of MS clinical and surrogate endpoints, further guiding patient stratification and informing targeted therapeutic selection and drug repurposing.

Methods

Using a panel of 21 protein serum biomarkers that were pre-selected per radiographic and clinical endpoints, we ran spatial expression correlation to extract a proteomic signature specific to MS organs and cell types. We modeled the functional connectivity of these proteins and then performed unsupervised clustering and network centrality analysis to identify motifs of interconnected proteins. Network motifs were later annotated using significantly enriched gene ontology terms and pathways in order to contextualize their mechanism-of-action with respect to MS.

Results

Topological mapping of protein functional interactions uncovered 10 major pathological profiles in MS: (1) myelin integrity; (2) lipid metabolism; (3) immune modulation; (4) inflammation; (5) cerebrovascular function; (6) cell-cell communication; (7) cellular energetics; (8) synaptic dynamics; (9) neuroaxonal integrity; and (10) gut microbiota. Their shifting degree of involvement was captured to characterize the different paths to disease activity and progression. A rich repertoire of immune, glial, and neuronal cells was implicated as being critical in orchestrating the synergistically evolving crosstalk between these various disease mechanisms.

Conclusions

Through a complementary integration of data analytics and systems biology, we were able to shift the focus from that of single proteins to disease processes, identifying clinical biomarkers that appear to fully recapitulate hallmarks of MS.

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Biomarkers and Bioinformatics Poster Presentation

P0083 - Gadolinium improves detection of central vein lesions in MS using 3T FLAIR*. (ID 1404)

Abstract

Background

The central vein sign (CVS) is a proposed MRI diagnostic biomarker for multiple sclerosis (MS). Use of gadolinium (Gd) in the CVS literature has been inconsistent, and it is unknown whether Gd improves detection of CVS when using FLAIR*.

Objectives

To determine if, and to what extent, gadolinium injection improves detection of CVS lesions when using FLAIR* imaging.

Methods

A cross-sectional multicenter study recruited adults clinically and/or radiologically suspected of having MS. High-isotropic-resolution, T2*-weighted segmented echo-planar imaging (T2*-EPI) was acquired pre- and post-injection of Gd-based contrast agent at 3T; pre-Gd 3D FLAIR images were also acquired. T2*-EPI and FLAIR images were processed on the QMENTA platform to generate FLAIR* images. FLAIR* pre-Gd and post-Gd scans from this substudy of 30 patients at 5 sites were analyzed. FLAIR images were used to create T2 lesion masks. Subsequently, FLAIR* images were evaluated in a random order. Lesions were categorized as CVS+, CVS-, or excluded based on the North American Imaging in MS (NAIMS) Criteria by two trained raters blinded to clinical data and Gd use. The proportion of CVS+ lesions was calculated for each scan, and differences in CVS detection based on Gd use were assessed by a Wilcoxon rank-sum test. Diagnostic performance was compared against McDonald 2017 Criteria.

Results

The mean participant age was 45 years (SD: 12); 23 (77%) were women. 14 (47%) met McDonald 2017 Criteria for MS, while 16 (53%) did not (“non-MS”). A total of 487 CVS+ lesions and 976 CVS- lesions were evaluated. The percentage of CVS+ lesions post-Gd in the MS group (median 67% [IQR 30%]) was higher than pre-Gd (41% [47%], p<0.001). There was no apparent difference in percentage of CVS+ lesion in the non-MS group (post-Gd: 10% [23%]; pre-Gd: 5% [29%]; p=0.1). In the MS group, 12/14 (86%) had ≥40% CVS+ lesions on post-Gd imaging, whereas only 8/14 (57%) exceeded that threshold on pre-Gd imaging. When evaluating CVS performance using the 40% CVS+ threshold, the sensitivity and specificity of the CVS post-Gd for MS were 86% and 81%, respectively, compared to 54% and 86% pre-Gd.

Conclusions

The detection of the CVS using FLAIR* at 3T is improved when Gd is used. Based on these results, a multicenter prospective CVS diagnostic study, sponsored by NINDS and NAIMS, will use Gd in the study protocol. Future clinical use of the CVS should balance the increased costs and potential risks of Gd use with the risks of misdiagnosis due to missing CVS on non-contrast imaging.

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Biomarkers and Bioinformatics Poster Presentation

P0084 - Gene expression profiling and TCR diversity of ATA188, an off-the-shelf, allogeneic EBV-targeted T-cell immunotherapy for progressive MS (ID 1770)

Speakers
Presentation Number
P0084
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

There is increasing evidence that infection with the Epstein-Barr virus (EBV) plays a role in the development and pathogenesis of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J, et al. Mult Scler 2012]. We have developed a novel allogeneic T cell therapy targeting EBV-encoded antigens, ATA188. Preliminary data from a phase 1 study (NCT03283826) suggests ATA188 is well tolerated and has shown initial efficacy in patients with progressive forms of MS [Pender MP et al. EAN 2020; LB130].

Objectives

The goal of this study was to characterize ATA188 allogeneic EBV-targeted T cells to delineate activated gene sets, molecular signatures and underlying functional pathways associated with effector cell function and therapeutic potential.

Methods

ATA188 T cells were profiled with a curated 326-gene panel using the NanoString nCounter® platform. Total RNA from control and antigen-activated EBV-specific CD8+ T cells were sorted following EBV stimulation, sequenced, and analyzed. Individual genes differentially expressed were identified and further subjected to enrichment analyses. Furthermore, deep TCRβ chain sequencing (TCR-seq) was conducted to define TCR clonal diversity and identity in ATA188 cells.

Results

Despite being derived from unrelated healthy donors, the ATA188 T cells showed considerable concordance in expression profiles (Spearman>0.80; p<E-10) within the control and activated states. Significantly differentially expressed genes (fold change>1.5, p<0.01) were identified, representing a distinct activation signature for ATA188 cells. The activated states were associated with upregulation of IL-2, IFNG, XCL1, CCL4, CSF2, TNFRSF9, and downregulation of KLF2. These patterns were consistent with activation of cytokine-receptor, JAK-STAT, T-cell receptor, and chemokine signaling pathways. Finally, TCR-seq analysis showed that ATA188 cells contain varying EBV-specific TCR clonotypes associated with specific restriction through one or more HLA alleles.

Conclusions

Transcriptional and TCR repertoire profiling of ATA188 revealed T-cell-intrinsic signatures and clonotypes associated with defined EBV-specific TCR repertoire, EBV-specific T-cell activation, and functional signaling pathways. These data are consistent with the proposed mechanism of action of ATA188 targeting EBV infected B cells by recognizing EBV antigens presented by defined TCRs.

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Clinical Outcome Measures Poster Presentation

P0085 - Harmonization of real-world studies in multiple sclerosis: retrospective analysis from the RIReMS group (ID 687)

Abstract

Background

Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies.

Objectives

In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.

Methods

RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ2).

Results

Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ2=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ2=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ2=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ2=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ2=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p=0.02; τ2=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p=0.02; τ2=1.00).

Conclusions

We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.

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Biomarkers and Bioinformatics Poster Presentation

P0086 - Highly sensitive quantitation of CXCL13 as an intrathecal biomarker in optic neuritis (ID 718)

Speakers
Presentation Number
P0086
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

CXCL13 chemokine is a key regulator of B cell chemotaxis and CXCL13 in cerebrospinal fluid (CSF) is of pathophysiological relevance in multiple sclerosis (MS).

Objectives

To assess the potential value of a highly sensitive CXCL13 assay in acute optic neuritis (ON) patients for prediction of MS.

Methods

A Simoa CXCL13 assay was used to measure CXCL13 in CSF and serum of two independent, treatment-naïve ON cohorts: A training cohort (TC) derived from a population-based cohort (n = 33) and a validation cohort (VC) of patients collected consecutively in line with the population study precepts (n = 30). Prospectively, 14/33 patients from the TC and 12/30 patients from the VC showed progression to MS (MS-ON). The remaining 19/33 from TC and 18/30 from VC were considered as isolated ON (ION). A group of healthy controls (HC, n = 11) were used for comparison.

Results

CXCL13 was detectable in all samples. General ON patients had higher CXCL13 than HCs (p = 0.012). In the TC, CXCL13 in MS-ON patient CSF was higher than in ION and HC (p = 0.0001 and p<0.0001, respectively). This was confirmed in the TC, where MS-ON patients too showed increased CSF CXCL13 relative to ION (p = 0.0091). Logistic regression analysis showed area under curve of 0.83 (95% confidence interval: 0.73-0.93) and an odds-ratio of 19.6 at the optimal cutoff.

Conclusions

Increased ability to detect CSF CXCL13 using the Simoa assay allowed identification of ON patients and segregated MS-ON from ION. These data indicate a promising potential of this assay, and further studies are warranted.

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Biomarkers and Bioinformatics Poster Presentation

P0087 - Identification of proteins associated with ageing in patients with progressive multiple sclerosis (ID 1589)

Abstract

Background

Similar to other neurodegenerative disorders, the onset of progressive MS is related to age, a factor known to amplify neurodegeneration. Recent studies have shown that exposure of aged mice to a young blood circulation through parabiosis or administration of young blood plasma (plasma from 3-month-old mice) reverses cognitive deficits observed with normal ageing.

Objectives

We aimed to search for soluble factors in the serum of patients with progressive MS that are affected by age and are differentially decreased in patients compared to healthy controls (HC) of similar age.

Methods

Protein levels were determined in serum samples from a cohort of 30 untreated MS patients (15 patients with secondary progressive MS - SPMS - and 15 with primary progressive MS - PPMS) and 25 HC. Progressive MS patients were classified according to age and clinical characteristics into the following three groups (each group containing 10 patients, 5 with SPMS and 5 with PPMS): (i) 40 ± 3 years old, disease duration <10 years, EDSS <4.5; (ii) 50 ± 3 years old, disease duration between 10-20 years, EDSS between 4.5-6; and (iii) 60 ± 3 years old, disease duration >20 years, EDSS >6.5. HC were classified based on age into the following groups (each group containing 5 individuals): 20, 30, 40, 50, and 60 ± 3 years old. To maximize the breadth and depth of serum proteome coverage, the top 70 abundant proteins in serum were depleted. Afterwards, samples were subjected to mass spectrometry.

Results

After depletion of the most abundant proteins in serum, a total of 2,059 molecules were detected in all 55 samples. The maSigPro package (R Bioconductor) was used to identify proteins with significantly divergent expression profiles as a function of time. A quadratic regression model was fit for each molecule and 823 proteins, among the 2059 analyzed, were found differentially expressed (FDR < 0.05) between the MS group and HC. The serum levels of the following proteins were significantly decreased by ageing in progressive MS patients compared with HC and were selected for further studies: PLXDC2, Neudesin, Myostatin, Myocilin, and EMMPRIN.

Conclusions

Protein expression profiling associated with ageing in progressive MS patients and HC lead to the identification of number of promising candidates associated with neurotrophic functions, myelination, and nervous system development. Results obtained by mass spectrometry need to be validated by targeted immunoassays.

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Biomarkers and Bioinformatics Poster Presentation

P0088 - Identification of putative multiple sclerosis biomarkers in CSF by targeted-mass spectrometry (ID 913)

Speakers
Presentation Number
P0088
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The individual expression of Multiple Sclerosis (MS) is highly heterogeneous. One of the greatest potential benefits of biomarkers is to predict disease severity and guide therapeutic choices.

Objectives

Our objective is to evaluate the predictive value of soluble brain-specific proteins of 10-year MS clinical outcomes.

Methods

This retrospective study analyzed cerebrospinal fluid (CSF) from 35 MS patients (mean age: 42; 79% female) and 23 non-MS controls (mean age: 35.5; 68% female) collected within 5 years of disease onset. We quantified 63 brain-specific proteins in the CSF of these patients using a targeted liquid-chromatography tandem mass spectrometry assay. This assay was previously developed in-house by mining of the Human Protein Atlas database and experimental search of CSF to establish brain-enriched proteins.

Results

Our parallel reaction monitoring assay (PRM) used in this study had high assay reproducibility (median across peptides CV = 5.7%). Twelve proteins significantly differentiated MS from controls (p<0.05). The levels of 6 proteins at baseline were significantly associated with CIS, RRMS or PPMS. We also observed a trend with a number of proteins negatively predicting evolution of CIS to RRMS or SPMS. Finally, we observed an association between 3 proteins and the rate of EDSS progression rate over 10 years (Spearman rank correlation: r=-0.59, r=-0.36, r=-0.44; p=0.0006, p=0.046, p=0.0151 respectively).

Conclusions

We identified 12 CSF brain-specific proteins that are unique to MS patients and 3 proteins that seem to predict disease course over the next decade. These proteins also highlight putative pathways implicated in MS pathogenesis and can be targets for future therapeutic regimes.

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Biomarkers and Bioinformatics Poster Presentation

P0089 - IFP35 as biomolecular marker of neuroinflammation and treatment response in Multiple Sclerosis (ID 196)

Speakers
Presentation Number
P0089
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The innate immunity in clinically isolated syndrome (CIS) and Multiple Sclerosis (MS) is poorly studied, but very important for both initiation and progression of the disease. In a predisposed subject, the activation of damage-associated molecular patterns (DAMPs) mediated by Toll-like receptors provides a micro-chemical inflammatory environment resulting in the self-maintaining neuroinflammation. IFN-beta is one of the most prescribed agents for MS’ treatment. Its heterogeneous response is individual and urges defining biological marker. The Rio Score (RS) provided a clinical assessment tool for predicting the one year-response in IFN-treated MS, but no pharmacodynamic biomarker is available. Interferon induced protein 35 (IFP35) is a zinc-finger factor correlating with the biological IFN activity, also serving as proinflammatory DAMP via the Janus kinase/signal transducers on the transcription of JAK-STAT protein.

Objectives

The primary aim of this study is to profile the IFP35 expression in CIS and clinically defined MS (CDMS) patients; furthermore, to assess the IFP35 differential profile to individuate the responder (RS=0) and non-responder (RS≥1) subjects among the IFN-treated MS group.

Methods

30 CIS-patients, 50 relapsing remitting (RR) MS-patients treated with IFNbeta-1b and IFNbeta-1a, 10 Secondary Progressive (SP) MS-patients along with 20 healthy controls (HCs) were enrolled. All patients underwent the blood sample, clinical and MRI evaluation, obtaining lesion load (LL), white/grey matter fraction (W/GMF) and RS definition over a 30-months observational period. Quantitative assessment of IFP35 was obtained by western-blot technique from peripheral blood mononuclear cells.

Results

IFP35 from the CIS-patients was 2.06-fold up-regulated than HCs (p<0.0001) and 1.67-fold up-regulated than SPMS-patients (p=0.035); IFP35 from IFNbeta-1a-treated patients was higher than IFNbeta-1b (p=0.006). Furthermore, IFP35 from the RS=0 group was 1.88-fold up-regulated than RS ≥ 1 (p<0.0001). IFP35 expression also inversely correlated to RS (r=0.60; p<0.0001), WMF (r=-0.50; p=0.0017) and LL (r =-0.51; p=0.0026). Finally, Kaplan-Meier analysis sorted a cut-off value of IFP35 ≥ 65% for RS=0 (p<0001).

Conclusions

We demonstrated for the first time the IFP35 biological pattern as predictive indicator of drugs efficacy in IFN-treated MS, but also of disease activity, thus reflecting the innate immunity-dependent neuroinflammation.

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Biomarkers and Bioinformatics Poster Presentation

P0090 - Immune cell profiles associated with CIS progression and stability using RNA-seq single-cell analysis (ID 577)

Speakers
Presentation Number
P0090
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Clinically Isolated Syndrome (CIS) can be an initial multiple sclerosis (MS) presentation, but the risk for developing future demyelinating episodes is often uncertain. The singular clinical episode of demyelination is thought to be driven by acute inflammation brought about by proinflammatory macrophages, autoreactive CD8+ and CD4+ T cells, and B cells crossing the blood-brain-barrier.

Objectives

To use single-cell transcriptome analyses to identify immune cell profiles in CIS patients associated with a higher risk of developing an MS relapse or new central nervous system (CNS) disease activity on brain MRI.

Methods

Cryopreserved peripheral blood mononuclear cells (PBMC) were collected at study entry and six months from six CIS participants from the ITN020AI STAyCIS trial of atorvastatin. Three participants met the primary endpoint defined as ≥ 3 new T2 lesions on MRI or an MS relapse within 12 months, while the other three did not. RNA from about 10,000 PBMC per sample were sequenced at the single-cell level using the 10X Genomics Chromium platform and analyzed using Cell Ranger software. Seurat R software package was used for downstream analysis, with cell type annotated both computationally (SingleR) and by matching differentially expressed genes with canonical markers using online genomics databases.

Results

Approximately 30 clusters of differentially expressed transcripts were assigned as specific cell types; baseline frequencies of seven clusters enriched >2-fold for macrophage, NK, NKT, CD4+ T cell, and B cell transcripts were associated with disparate outcomes at six months. Several clusters assigned as B cells, CD4+ and CD8+ T cells were expanded from baseline at six months in participants with CNS disease activity at that time point, while no notable changes were observed in those with stable disease.

Conclusions

An understanding of the immunological changes associated with future disease activity in CIS may be useful for making early treatment decisions. Our preliminary data suggest that participants with disparate clinical outcomes exhibited different frequencies of innate and adaptive leukocyte populations in PBMC, which may represent a predictive biomarker for aggressive early intervention. Also, expanded clusters of CD4+ and CD8+ T cells and B cells in blood at the time of disease activity may identify biomarkers that contribute to acute demyelination. Follow-up studies are underway to increase sample size and incorporate protein expression data to better define cell subtypes and clonality of T and B cells associated with disparate outcomes in the STAyCIS trial.

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Clinical Outcome Measures Poster Presentation

P0091 - Improving patient outcomes through a comprehensive care management platform (MOVING MS) (ID 364)

Speakers
Presentation Number
P0091
Presentation Topic
Clinical Outcome Measures

Abstract

Background

When standard of care neurology visits are 6 months apart, there can often be gaps in care and missed opportunities to improve patient function; the result is poor follow-up for care management or low medication adherence. MS care can be comprehensively approached with a human-tech platform that supports symptom and medication tracking, nursing interventions, laboratory monitoring for subclinical disease activity and curated MRI reports to ensure accurate data at return visits.

Objectives

To test the Octave integrated MS care platform for efficacy in reducing unplanned healthcare utilization (UHU) and improving patient and physician satisfaction.

Methods

This prospective, randomized study with a within-subjects, waitlist-control trial design aims to reduce UHU costs and increase patient and physician satisfaction with their MS care. Secondary endpoints include determining the feasibility of the human-tech service, blood-based disease activity tests and enhanced MRI reports. Approximately 80 participants will be randomized to a case or waitlist group. Case subjects will have access to the platform for all 12 months of enrollment; waitlist subjects will have access for the second 6 months of enrollment. The platform includes medication and symptom tracking, check-ins every 2 weeks with an MS-certified nurse and curated physician/MRI reports. UHU will be qualified by events captured in the EHR and monetary value assigned to these events. Satisfaction will be measured through participant and physician questionnaires. Subject’s blood tests will be correlated to symptomology and MRI findings to assess subclinical disease activity.

Results

UHU was created by Octave and is a composite metric of unplanned office visits and communication by phone or e-message, weighted by expense per interaction as collected in the EHR. Our analysis aims to quantify the UHU difference between 1) case vs. control samples over the first 6 months of the study, and 2) waitlist control patients for the first vs. second 6 months of the study. Satisfaction will be measured between case and control groups using a Likert scale and quantified with a 2-sample t-test.

Conclusions

This trial aims to improve MS disease management, reduce UHU and increase patient/physician satisfaction through a mobile platform intervention, using a waitlist design.

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Clinical Outcome Measures Poster Presentation

P0092 - Incidence of recurrence of disease activity after fingolimod discontinuation in older patients (ID 264)

Speakers
Presentation Number
P0092
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Discontinuing fingolimod (FTY) in older patient is a growing concern with little evidence supporting the decision to pursue treatment and reasonable doubt for disease reactivation after withdrawal.

Objectives

We investigate the incidence of RDA and rebound in MS patients who discontinued fingolimod for any reason, and looked for risk factors influencing this risk. Of particular interest was the subgroup of older patients who discontinued FTY for other reasons than disease progression. Our hypothesis was that these patients, older at treatment discontinuation, previously stable on treatment, would have a statistically lower risk of recurrence of activity given their age.

Methods

Retrospective analysis of 288 MS patients on FTY. Recurrence of disease activity (RDA) was defined as the occurrence of either clinical and/or MRI activity in the 6 months after FTY withdrawal; among these patients with RDA, we considered rebound when the levels of disease activity surpassed pretreatment activity. We defined a subgroup of patients older than ≥ 50 years at FTY discontinuation and with NEDA-3 status during FTY treatment.

Results

128 patients discontinued FTY from 2011 to 2019 mainly for estimated high PML risk (3.6%), inefficacy (26.6%) or pregnancy planning (18%). RDA occurred in 45 patients (35.2 %) within 3.4 months (SD 2). Younger age at disease onset (p=0.008), highly active disease at baseline (p=0.037) and previous treatment with natalizumab (p=0.050) increased the risk of RDA at FTY discontinuation. Sixteen patients (12.5%) experienced rebound with a mean of 9 Gd enhancing lesions. Baseline MRI activity (p=0.008) and longer wash-out period (p=0.001) correlated with rebound. Twenty-two patients were older than 50 years at FTY withdrawal and discontinued FTY for other reasons than disease progression. The incidence of RDA was lower, yet not statistically significant, from younger patients (18.2 % RDA, p=0.068).

Conclusions

RDA occurred in 35.2% of our patients including 12.5% with rebound. Older age at FTY discontinuation may be associated with a lower risk of disease reactivation, although the incidence of RDA remains high, as 1/5 of the older patients, previously stable on treatment, experienced RDA.

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Biomarkers and Bioinformatics Poster Presentation

P0093 - Increased serum GFAP associates with microstructural white matter damage in multiple sclerosis (ID 1066)

Speakers
Presentation Number
P0093
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Astrocytes and microglial cells are now recognized as active players in contributing to the diffuse neuroaxonal damage associated with disease progression of multiple sclerosis (MS). The serum level of glial fibrillary acidic protein (GFAP), a biomarker for astrocytic activation, is increased in MS and associated with the disease progression and disability. Similarly, diffusion tensor imaging (DTI) parameters for microstructural changes in brain, including demyelination and axonal loss, associate with disability. The association between brain DTI parameters and serum GFAP has not been previously explored in MS.

Objectives

To get insights into DTI-measurable pathological correlates of elevated serum GFAP in the normal appearing white matter (NAWM) of MS.

Methods

A total of 62 MS patients with mean age of 49.4 years were included in the study. Study patients underwent DTI-MRI and blood sampling for GFAP determination by single molecule array (Simoa). MS patients were subdivided to GFAP(high) and GFAP(low) groups based on the median value of GFAP (97.7 pg/ml). Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the NAWM and six segmented NAWM regions. The associations between the DTI parameters and GFAP levels were analyzed within the GFAP(high) and GFAP(low) subgroups using Spearman correlation analysis and multiple regression model with sex and disease modifying treatment (no, 1st line or 2nd line) as adjustments performed with the R statistical software (version 4.0.0).

Results

Elevated serum GFAP levels correlated significantly with decreased FA values within the entire, frontal, temporal and cingulate NAWM (R=-0.39, p=0.03; R=-0.42, p=0.02; R=-0.37; p=0.04 and R=-0.38, p=0.03) and increased MD and RD within the frontal NAWM (R=0.36, p=0.046 for both) in the GFAP(high) subgroup. Associations between higher GFAP and lower FA in frontal and cingulate NAWM were sustained in the multiple regression model corrected for confounding variables (standardized regression coefficient r = -0.29, p = 0.045 and r = -0.33, p = 0.025).

Conclusions

Our results give evidence that increased serum GFAP levels are associated with DTI-measurable micro-damage in the NAWM in MS. Our work supports the use of serum GFAP as a biomarker for MS pathology-related astrocytopathy and related diffuse white matter damage.

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Biomarkers and Bioinformatics Poster Presentation

P0094 - Inter-laboratory evaluation of cerebrospinal fluid and serum kappa free light chain measurements (ID 966)

Abstract

Background

The kappa index, calculated by dividing the cerebrospinal (CSF)/serum kappa free light chain (KFLC) ratio by the CSF/serum albumin ratio, is gaining increasing interest as an indirect marker of intrathecal activation of the humoral immune response. The demonstration of intrathecal synthesis is of particular relevance in the diagnostic work-up of suspected Multiple Sclerosis. However, the lack of consistent data on inter-laboratory agreement in CSF and serum KFLC measurements is one of the factors that hamper the use of kappa index in routine practice.

Objectives

Aim of this study was to assess agreement in CSF and serum KFLC measurements and kappa index values across different laboratories.

Methods

Fifteen paired CSF and serum samples were analyzed in all participating laboratories (nr=8). Four centers used Binding Site instruments and assays, 3 centers used Siemens instruments and assays, and one center used a Siemens instrument and a Binding Site assay.

Absolute individual agreement between laboratories was calculated using a two-way mixed effects intraclass correlation coefficient (ICC). Cohen's kappa coefficient was used to measure inter-laboratory agreement on positive (5.8) kappa index values.

Results

Within Binding Site laboratories, ICC for KFLC measurements was 0.96 (95%CI: 0.9-0.98) for CSF, 0.93 (95%CI: 0.63-0.98) for serum and 0.97 (95%CI: 0.94-0.99) for kappa index values. Within Siemens laboratories, ICC for KFLC measurements was 0.99 (95%CI: 0.97-100) for CSF, 0.93 (95%CI: 0.48-0.98) for serum and 0.95 (95%CI: 0.89-0.98) for kappa index values. ICC calculated for all laboratories was 0.93 (95%CI: 0.87-0.97) for CSF KFLC, 0.81 (95%CI: 0.53-0.93) for serum KFLC and 0.65 (95%CI: 0.43-0.84) for kappa index. Cohen's kappa coefficient for a positive kappa index was 0.89 across Binding Site laboratories, 0.70 across Siemens laboratories, and 0.77 across all laboratories.

Conclusions

There was an excellent agreement in CSF KFLC measurements and in kappa index values within laboratories using the same instrument and assay (Binding Site or Siemens), while serum KFLC measurements were less concordant. Agreement across all laboratories was decreased when including the laboratory using a Siemens instrument coupled with a Binding Site assay in the analyses. Concordance for a positive kappa index was substantial across all laboratories and within Siemens laboratories, and very good within Binding Site laboratories.

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Clinical Outcome Measures Poster Presentation

P0095 - Intracortical motor conduction is associated with dexterity in progressive multiple sclerosis (ID 1841)

Speakers
Presentation Number
P0095
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Hand dexterity dysfunction is a key feature of disability in people with progressive multiple sclerosis (PMS). It underlies corticospinal tract (CST) and cerebellar integrity but also disruption of cortical networks, which are hardly assessed by standard techniques. Transcranial magnetic stimulation is a promising tool for evaluating the integrity of intracortical motor pathways.

Objectives

to investigate neurophysiological correlates of motor hand impairment in PMS and assess intracortical motor conduction through the use of a innovative TMS protocol.

Methods

Antero-posterior (AP) stimulation of the primary motor cortex activates the CST indirectly through polysynaptic pathways, while a direct CST activation occurs with latero-medial (LM) directed current. 30 PMS and 15 healthy controls underwent dominant hand motor evoked potentials (MEP) using AP and LM-directed stimulation, and a clinical assessment of dexterity (nine-hole peg test) and strength (MRC scale, grip and pinch).

Results

PMS with AP-LM latency difference 2.5 standard deviation above the mean of controls (33%) showed worse dexterity but no difference in upper limb strength. Accordingly, AP-LM latency shortening predicted dexterity (R2 0.538, p<0.001), but not strength impairment. On the contrary, absolute MEP latencies only correlated with strength (grip: R2 0.381, p=0.014; MRC: R2 0.184, p=0.041).

Conclusions

AP-LM latency shortening may be used to assess the integrity polysynaptic intracortical networks implicated in dexterity impairment.

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Biomarkers and Bioinformatics Poster Presentation

P0096 - Intrathecal immunoglobulin M synthesis is associated with higher disease activity and severity in Multiple Sclerosis (ID 1101)

Abstract

Background

Additional biomarkers reflecting disease activity and predicting severity of multiple sclerosis (MS) are urgently needed.

Objectives

To explore whether intrathecal immunoglobulin (Ig) M synthesis is associated with time from disease onset to first relapse, MS Severity Score (MSSS) and time to first initiation of high efficacy disease modifying treatments (DMT) in patients with relapsing MS in the Swiss Multiple Sclerosis Cohort study.

Methods

487patients were categorized by presence of CSF oligoclonal IgG bands (OCGB) and quantitative intrathecal IgG and IgM production (Intrathecal Fraction, IF). Treatments were classified according to "no therapy", "platform", "oral" and "high efficacy". Multivariable Cox proportional hazard models or a multivariable linear model, adjusted for relevant covariables, were used to assess time from disease onset to described endpoints and associations with the MSSS.

Results

OCGB were present in 89.3%, IgGIF in 66.3%, IgMIF in 26.9% and IgAIF in 11.9% of patients. Patients with IgMIF had a shorter interval from disease onset to first relapse (HR 1.887 [CI 1.181, 3.014], p<0.01) compared to those without OCGB and IgGIF and IgMIF. Quantitatively, patients with IgMIF above versus below the median had a 1.75- fold increased hazard of occurrence of a first relapse (HR 1.746 [CI 1.097, 2.781]; p=0.019). IgMIF positive patients had on average a 1.24 steps higher MSSS compared with those without any intrathecal Ig synthesis (estimate: 1.243 [CI 0.501,1.986], p<0.01), followed by patients with OCGB and quantitative production of IgGIF (estimate: 0.966 [CI 0.283, 1.650], p<0.01) and patients with only OCGB (estimate: 0.716 [CI -0.030, 1.461], p=0.060). Accordingly, patients with IgMIF production had a shorter interval to initiation of high efficacy DMT (HR 2.788 [CI 1.306, 5.951], p<0.01). Quantitatively, above versus below median IgMIF was associated with a 2.36-fold risk of escalation to a high efficacy DMT (HR 2.361 [CI 1.304, 4.277]; p<0.01).

Conclusions

In relapsing MS, presence of intrathecally produced IgM is associated with higher disease activity, more severe disease course and earlier use of high efficacy treatments. Intrathecally produced IgM may qualify as useful prognostic biomarker for therapeutic decision making in early stage of disease.

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Biomarkers and Bioinformatics Poster Presentation

P0097 - Intrathecal immunoglobulin M synthesis is associated with higher serum neurofilament light chain levels and increased MRI disease activity in MS (ID 1089)

Abstract

Background

Intrathecal IgM synthesis was reported to be associated with higher clinical disease activity and severity. We found an association also with earlier use of high efficacy treatments in relapsing MS (RMS).

Objectives

To explore whether patients with intrathecal IgM synthesis show a) higher serum neurofilament light chain levels (sNfL) as a reflection of neuronal damage, or b) signs of increased disease severity in cerebral MRI, in patients with RMS followed in the Swiss MS Cohort Study.

Methods

487 patients were categorized by presence of oligoclonal IgG bands (OCGB) and intrathecally produced IgG/M:

1) OCGB-/IgG-/IgM- (reference [ref]);

2) OCGB+/IgG-/IgM-;

3) OCGB+/IgG+/IgM- and

4) OCGB+/IgG+/IgM+.

sNfL was measured (at baseline and every 6- or 12 months) with the NF-light® assay. Age-dependent sNfL z-scores (sNfLz) were modelled in 8865 healthy control samples to reflect the deviation of a patient sNfL value compared to mean values observed in same age healthy controls. Yearly T2 lesion number and occurrence of new/enlarging T2 lesions were automatically assessed in cerebral MRIs and checked manually. Contrast enhancing lesions (CEL) were manually quantified. Linear or negative binomial mixed models were used to investigate the associations between the four CSF Ig patterns and longitudinal sNfLz and MRI measures, adjusted for DMT and other covariates.

Results

IgM+ patients had higher sNfLz vs reference (estimate 0.50 [CI 0.12, 0.89], p=0.011), whereas those with only OCGB+ (0.11 [-0.28, 0.50], p=0.582) or with OCGB+/IgG+ (0.20 [-0.16, 0.56], p=0.270) did not (n=2970 observations). This was confirmed when analyzing only untreated patients adjusting for T2 and CEL numbers (1.16 [0.47, 1.86], p<0.01 vs 0.58 [-0.11, 1.27], p=0.1022 vs 0.51 [-0.11, 1.13], p=0.108 vs ref, respectively) (n=234).

IgM+ patients had 2.28-fold more T2 lesions ([1.51, 3.44], p<0.01) vs ref; for patients with only OCGB+ (1.61 [1.07, 2.43], p=0.0237) or OCGB+/IgG+ (1.58 [CI 1.08, 2.32], p=0.0179) (n=1580) this association was weaker.

IgM+ was associated with a 2.47-fold risk for new/enlarging T2 lesions on yearly follow-up MRIs vs ref (2.47 [1.28, 4.78], p<0.01) but not the two other patient groups (1.84 [CI 0.93; 3.65], p=0.0799 and 1.61 [CI 0.87; 2.95], p=0.1280) (n=861).

Conclusions

Intrathecal IgM synthesis was consistently associated with quantitative measures of neuro-axonal injury and disease severity in RMS. Our findings strongly support the clinical utiliy of this biomarker.

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Biomarkers and Bioinformatics Poster Presentation

P0098 - Investigation of biomarkers in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders (ID 1302)

Speakers
Presentation Number
P0098
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In neuroimmunology; biomarkers have been determined as having a pivotal role. Among them, Neurofilament Light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Interleukin-6 (IL-6), Osteopontin, Growth-associated protein 43 (GAP-43) have been examined for different central nervous system autoimmune disorders. It has been shown that each of them has a potential role for a different immunopathogenesis.

Objectives

In our study, we aimed to evaulate NfL, GFAP, Osteopontin, IL-6, GAP-43 in different subgroups of Multiple Sclerosis(MS). Relapsing-Remitting MS(RRMS)(n=38), Secondary-Progressive MS(SPMS)(n=16), Primary-Progressive MS(PPMS)(n=8), were included in this study. The samples from aquaporin-4(AQP4)-Ab-positive NMOSD(n=7), Myelin Oligodendrocyte Glycoprotein(MOG)-Ab-positive(n=9) patients and healthy controls(HC)(n=20) were also studied. All biomarkers were evaluated both in serum and cerebrospinal fluid (CSF).

Methods

Serum (n=98) and available CSF (n=20)(paired with serum,only MS subtypes) samples have used this cross-sectional study. For measuring NfL and GFAP concentrations in sera and CSF samples, we used SIMOA technology and assays on the Quanterix SIMOA HD-X ANALYZER. IL-6 measurements were performed on the Roche Cobas e-411 analyzer with the electrochemiluminescence method. Osteopontin and GAP-43 levels determined with the ELISA assays. Clinical and radiological data at sampling were collected for each case.

Results

We observed a significant positive correlation between serum NFL,GFAP and CSF NFL,GFAP levels in MS patiens(NfL,p=0,001,rho=0,686; GFAP,p=0,006,rS=0,594). For serum samples, there was a very strong positive correlation between treatment-naive GFAP and treatment-naive NFL levels in MS patients (p<0,001, rS=0,828). Additionaly, we have found negative correlation between serum IL-6 and GFAP levels in MS patients (p<0,01, rS =-0,356). Also there was a negative correlation between serum IL-6 and NfL levels in MS patients (p<0,01, rS =-0,422). When compared with HC, there was a significant incrase in terms of serum IL-6 levels in central neuroimmunological disorders(p<0,001).Mean value of AQP4-Ab-positive NMOSD serum GFAP levels(111,7±29,39 pg/mL) were signififantly higher than MOG-Ab-positive serum GFAP levels(80,39±32,53 pg/mL)(p<0,05). MOG-Ab-positive serum IL-6 mean values(42±52,17 pg/mL) were found to be higher than AQP4-Ab-positive NMOSD group(6,17±4,36 pg/mL)(p<0,05).

Conclusions

NfL and GFAP are certainly promising biomarkers in MS patients. NMOSD and MOG-Ab-positive patients have to be assessed in prospective studies that have a large number of patients. Our study is the first that Single Molecule Array (SIMOA) technology has been used in Turkey to evaluate NfL, GFAP levels both in serum and CSF levels.

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Clinical Outcome Measures Poster Presentation

P0099 - Is disease activity prior to fingolimod initiation in treatment-naive patients predictive of response?  (ID 323)

Speakers
Presentation Number
P0099
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Randomized controled trials, post-hoc analysis and real-world post-marketing studies have confirmed fingolimod (FTY) efficacy over placebo as second-line therapy in case of persistent disease activity and in treatment-naive patients with rapidly evolving highly active RR-MS. In countries where fingolimod is available as first-line therapy without restrictions, we have an opportunity to observe long-term efficacy profile of this drug in treatment-naive patients according to their initial disease activity.

Objectives

To evaluate and compare the incidence of NEDA-3 status at last follow up according to the baseline MS disease activity.

Methods

Retrospective analysis of clinical and radiological data of 54 RR-MS patients treated with FTY. The patients were divided into highly active patients (HΑ) if ≥ 2 relapses in the year before treatment initiation and ≥1 Gd-enhancing T1 lesion or “not highly active” (NHA). NEDA-3 status at endpoint was defined as no relapses, no EDSS progression and no new T2 or Gd-enhancing lesions during the follow-up.

Results

Mean follow-up duration was 48.2, SD 18.4 months. FTY efficiently reduced relapses (NHA 90.3% reduction, p<0.001, HA 84.9%, p<0.001), and new Gd enhancing lesions (NHA 85.4% reduction, p=0.019, HA 92.3%, p=0.043). 53.7% reached NEDA-3 status at endpoint, although the distribution was different in the two subgroups with 62.2%, (n=23/37) of the NHA patients reaching NEDA 3 status compared to 35.3% (n=6/17) of the HA. The proportion of patients reaching NEDA-3 status decreased over time (first line : 80% at 2 years and 66% at 4 years, HA : 58% at 2 years and 38% at 4 years, p=0.042). 63% of patients were still on FTY at last follow-up (n=34/54). Main reason for discontinuation was lack of efficacy (75%, n=15/20).

Conclusions

Chances of reaching NEDA-3 status reduce over time with the highest relative benefit from FTY treatment observed when prescribed as a first line disease-modifying drug in treatment-naïve MS patients, which may favour its indication in that context rather than for HA patients only.

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Clinical Outcome Measures Poster Presentation

P0100 - Italian prospective multicentric observational real-life study of aggressive Relapsing Remitting Multiple Sclerosis treated with alemtuzumab (ID 1730)

Abstract

Background

Alemtuzumab(ALEM) is an anti-CD52 monoclonal antibody approved for the treatment of active Multiple Sclerosis(MS) which showed an overall high efficacy in clinical trials, also in the highly active subgroup of patients.

Objectives

The aim of this multicenter obervational study is to evaluate efficacy and safety of ALEM-treatment in a population of aggressive MS naïve-patients at year 2 and 3 after a complete cycle of treatment.

Methods

We conducted a multicenter prospective observational study in a cohort of ALEM-naïve MS patients. Clinical and neuroradiological parameters were collected from patients’ clinical records in 26 Italian MS Centers from October 2015 to May 2020.

Results

133 naïve patients were treated with ALEM: 60,2% females, mean age 31,4(± 8,9) years, mean disease duration 18,5(± 22,7) months, mean follow-up(FU) 34,2(± 12,1) months, median EDSS 3(0-6,5), ARR in the year preceding treatment 1,8 (± 0,9), mean number of brain T2/FLAIR-hyperintense lesions 29,8 (± 20,8) and mean number of Gd-enhancing lesions 3,4(± 5,1). Regarding ALEM efficacy, we report data obtained after the first complete cycle of treatment (2 ALEM-courses) because the occurrence of disease activity between the first and second course is not indicative of a therapeutic failure. 99 and 61 over 133 patients have at least 24 and 36 months FU respectively: 97% and 82% were relapse-free, ARR was 0,02 and 0,1, 92.9% and 82% were MRI activity-free and 97,7% and 91,8% progression-free with median EDSS of 2,0 and 1,5 (IQR 1 – 2,5) at year 2 and 3. The mean time to first relapse was 27,6(± 6,4) months 89,2% and 69,4% of patients reached NEDA-3 at year 2 and year 3 respectively. 5,3% of patients needed a third cycle of therapy. Overall 74,4% of patients had adverse events. Infusion-reaction and infections occurred respectively in 70,1% and 9,8% of patients; regarding secondary autoimmune disease the most frequent was thyroid dysfunction (15,8%).

Conclusions

In our very active MS-population after ALEM-treatment a strong reduction of both relapse rate and MRI activity was achieved. These results strengthen the assumption that aggressive naïve patient is an ideal candidate for immune system resetting, likely due to young age, short disease duration and low disability. Furthermore, absence of previous immunomodulating/immunosuppressant drugs altering the immune system could play a key role in determining effectiveness of this powerful drug. However, longer FU is needed to confirm our data and evaluate whether an early induction therapy could be worthy in this specific population, balancing benefit-risk ratio.

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Biosensors Poster Presentation

P0101 - Kinematic assessment of upper limb function in progressive multiple sclerosis (ID 201)

Speakers
Presentation Number
P0101
Presentation Topic
Biosensors

Abstract

Background

Upper limb dysfunction is common in progressive forms of multiple sclerosis (MS) leading to increased dependency and reduced quality of life. Clinicians and researchers need tailored outcome measures to quantify upper limb dysfunction, and evaluate potential deterioration or intervention efficacy. Current assessments rely on coarse measures and subjective evaluation. This is particularly disappointing as advances in digital technologies allow precise measurement of upper limb function in well constrained tasks.

Objectives

We will use novel kinematic assessment tools to explore the extent and progression of upper limb dysfunction in patients with progressive MS

Methods

We developed a kinematic assessment system that could accurately track arm movements over time and space and provide precise objective measures of function. The ‘gold-standard’ system allows infrared tracking of arm movements but is integrated with a ‘performance’ system that captures kinematic milestones (e.g. movement duration) alone.

Results

We have successfully built the kinematic assessment systems. Participants reach, grasp and move pre-designed cylindrical objects from one docking station to another on a manufactured board. Reaction times, hand velocity, hand trajectory and grip aperture are measured using a low cost and portable dual infrared camera system, capturing quantifiable trajectories in 3D space. We are now testing our systems with a sample of primary and secondary progressive MS patients (n=40) from the local outpatient population. Performance on our system will be calibrated against: the Expanded disability status scale (EDSS); the nine hole PEG test (9HPT); the ABILHAND; and AMSQ-SF10 questionnaire. The measures are taken over the course of a year (baseline, six months and twelve months).

Conclusions

It is possible to build low cost portable systems capable of providing rich kinematic data that capture upper arm function. Our current study will determine whether a simple performance system (that does not require infrared tracking) might provide rich measures in an even easier to deploy clinical assessment tool. This work will establish the extent to which these detailed kinematic measures map to the current clinical standard assessments. This provides an important first step in the development and evaluation of reach to kinematic analysis in the quantification of upper limb function in progressive MS.

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Clinical Outcome Measures Poster Presentation

P0102 - KonectomTM smartphone-based digital outcome assessment of cognitive and motor function in multiple sclerosis (ID 815)

Speakers
Presentation Number
P0102
Presentation Topic
Clinical Outcome Measures

Abstract

Background

The next generations of MS therapies aim at enhancing remyelination, protecting neurons/axons and altering the slowly progressive course of MS from its inception. To evaluate their efficacy, it is essential to develop novel, patient-centric outcome assessments that can quantify patient’s function with high frequency in their everyday life.

Objectives

To develop a digital solution that enables patients to quantitatively self-assess their function at high frequency in free-living environment in complement to in-clinic supervised administration and derive outcome measures that are able to detect the subtle changes during MS evolution.

Methods

KonectomTM smartphone application was designed and developed with patient-focused user experience insights to assess cognition, upper extremity function, ambulation/mobility and MS-related quality of life. To optimize accuracy and adherence of self-assessments, tutorials, vocal instructions and completion reward features were built into the app. KonectomTM was developed under IEC 62304 / ISO 13485 standards. KonectomTM digital outcome assessments (DOAs) will derive digital features processed from iPhone X accelerometer, gyroscope, touch, force touch, and GPS sensor information. KonectomTM formal usability study was completed in September 2019, in Chicago and in Paris (N=14 participants). KonectomTM is being evaluated in two Phase 2 studies in patients with relapsing MS (NCT04079088, N=300, 72 weeks of treatment period; undisclosed RMS Ph2 study).

Results

KonectomTM DOAs include 9 active test modules (mood/physical state 5-point Likert scale, multiple sclerosis impact scale 29-item questionnaire version 2 [MSIS-29v2], cognitive processing speed test, pinching test, drawing test, grip force test, static balance test, U-turn test and 6-min walk test) and a passive continuous monitoring of mobility behaviour. In the user experience testing, KonectomTM received a system usability scale (SUS, range 0-100, mean [SD]) score of 87.7 [8.7] which is much above the benchmark average of smartphone applications with a likelihood to recommend (LTR, range 0-10, mean [SD]) of 8.1 [2.0]. Results were consistent between French and US participants.

Conclusions

KonectomTM provides a patient-centric modular digital platform for ecological monitoring of neurological disability in MS clinical trials and real-world use with potential to be extended to other neurological disorders affecting cognitive and motor functions

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Biomarkers and Bioinformatics Poster Presentation

P0103 - Liothyronine treatment of MS patients alters proteins in CSF related to angiogenesis and immune function (ID 438)

Speakers
Presentation Number
P0103
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Thyroid hormones have effects on a variety of glial and immune cell populations that appear to be involved in the pathogenesis of multiple sclerosis (MS). Since tri-iodothyronine (T3) is believed to mediate the most important thyroid hormone actions, liothyronine (synthetic T3) may have the potential to induce reparative mechanisms and limit neurodegeneration in MS.

Objectives

To utilize proteomics to assess the effect of liothyronine treatment on the cerebrospinal fluid (CSF) proteome in MS.

Methods

We utilized CSF collected from 18 patients with MS enrolled in a single center trial of oral liothyronine for 24 weeks. Participants received liothyronine according to a standardized dose-titration schedule. Participants continued their maintenance MS immune therapies during the study. Eligibility criteria included euthyroid patients, 18-58 years old, 2010 McDonald MS and Expanded Disability Status Scale (EDSS) score 3.0-7.5. Main exclusion was known thyroid dysfunction. The primary outcome was safety and tolerability of liothyronine. CSF was collected at baseline and end of study (24 weeks) as an exploratory outcome for treatment response. SOMAscan platform (DNA aptamer based detection of proteins) was used to detect and quantify a panel of 1314 proteins in the CSF.

Results

Study participants had a mean age of 45.9 ± 8.8 years, F:M ratio of 7:9, relapsing disease (11/16), mean disease duration of 9 years and median EDSS of 3.5. Of the measured proteins, 46 changed (19 increased and 27 decreased) over the course of the study (p<0.05). These included proteins related to immune function such as TACI, NKp46, IgA and IgD and angiogenesis such as Cadherin-5, sTIE-1 and ANGPT2. Enrichment analyses using PANTHER and STRING databases noted that the biological processes that were over-represented included – angiogenesis and innate and adaptive immune function. Angiogenesis related proteins predominantly demonstrated an increase with liothyronine treatment while the majority of immune related proteins decreased with treatment.

Conclusions

Changes in CSF proteins involved in central nervous system immune cell function and promotion of angiogenesis were seen with a short course of liothyronine treatment in people with MS. A larger clinical trial would help determine whether these observed changes have a biological effect that is clinically meaningful.

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Clinical Outcome Measures Poster Presentation

P0104 - Long term disability trajectories in multiple sclerosis: a group-based trajectory analysis of the AusLong cohort (ID 1920)

Speakers
Presentation Number
P0104
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Understanding progression of disability in multiple sclerosis (MS) is essential to design preventive and therapeutic strategies.

Objectives

We analyzed data from the Ausimmune Longitudinal (AusLong) Study to investigate the existing heterogeneity in long-term disability accumulation in a prospective cohort of People with MS (PwMS) followed over 10 years from the date of their first clinical diagnosis (FCD) and identify clinical and demographic factors associated with these trajectories.

Methods

We used a group-based trajectory model (GBTM) to measure the heterogeneity in the disability trajectories based on Expanded Disability Status Scale (EDSS) in a prospective cohort of 263 participants followed from FCD.

Results

We identified three distinct clinically meaningful disability trajectories: no or mild, moderate and severe disability trajectories. Those in the minimal disability trajectory did not show any appreciable progression of disability (median EDSS ~ 1 at 10-year review), those in moderate and severe disability trajectories experienced disability worsening (median EDSS~ 2.5 and 6, respectively). The relative probability of being in a worsening disability trajectory was higher for older age at onset, those experiencing a higher number of relapses within five-year post FCD and those having a shorter interval between the first two attacks. High annual relapse rate was associated with an upward shift in moderate disability trajectory, whereas non-smoking status was associated with reducing the EDSS score in minimal and severe disability trajectories.

Conclusions

Those at highest risk of rapid disability progression can be identified based on their early clinical information with potential therapeutic implications.

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Biomarkers and Bioinformatics Poster Presentation

P0105 - Longitudinal proteomic analysis of MS patients before and after autologous hematopoietic stem cell transplantation (ID 1549)

Speakers
Presentation Number
P0105
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum markers which reflect MS disease activity could help personalize MS therapeutics. Longitudinal samples from patients undergoing autologous haematopoetic stem cell transplantation (HSCT) for aggressive MS represent a valuable cohort to search for such biomarkers, as these patients had very active disease prior to treatment followed by durable supression of inflammatory disease activity after treatment.

Objectives

To investigate changes in candidate serum proteins in patients with active MS compared to controls as well as before and after HSCT in relation to clinical and MRI outcomes.

Methods

97 proteins of interest were identified including established markers of inflammation and neurodegeneration. Levels were quantified using an in-house antibody colocalization microarray in 24 MS patients with aggressive relapsing MS at baseline compared to 10 controls. Pre-post HSCT changes were analyzed over 10 timepoints pre and up to 36 months post HSCT. We used principal componant analysis for data reduction prior to correlation as well as mixed effects models of individual proteins to compare changes in levels to clinical and MRI covariates of interest (age, EDSS score, relapses, sustained progression, lesional and volumetric MRI measures).

Results

Levels of 19 proteins differed between MS patients at baseline and controls and 17 proteins differed comparing baseline and 12-months post HSCT (simple t tests, p<0.1); we focused on the levels of these proteins for subsequent analyses. 7 proteins were identified in both comparisons including amphiregulin, cathepsin, CRP, GRO, HAI-1 and leptin, which may indicate normalization post HSCT. 8/24 patients developed sustained EDSS progression in the absence of ongoing relapses post HSCT; using mixed effects models, of the 17 candidate proteins, the longitudinal trajectory of CRP levels differed in patients who developed sustained progression compared to those who did not (B=-0.003, p=0.045). Component analysis was used to summarize clusters of proteins into a single value based on internal correlation/discordance. At baseline, one cluster of proteins (CRP, KLK14, PAI-1, IGFBP-7, PDGF) correlated with preceding rapid progression from diagnosis to EDSS 6 (p=0.011, r=0.80) and EDSS worsening in the preceding 24 months (p=0.047, r=0.46). A different cluster of proteins (HAI-1, amhiregulin, FAS, capthespsin B, e-cadherin, GFAP) correlated with the pretreatment rate of brain atrophy. Comparing pre-post changes, one cluster correlated with rate of brain atrophy in the first year post HSCT (p=0.024, r=0.059).

Conclusions

This exploratory analysis of longitudinal serum biomarkers changes pre and post HSCT provides hypothesis generating observations worthy of future investigation.

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Clinical Outcome Measures Poster Presentation

P0106 - Long-term single-centre experience with natalizumab. (ID 365)

Speakers
Presentation Number
P0106
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Natalizumab (NZB) is a disease-modifying treatment (DMT) used in persons with MS (PwMS) with an active relapsing course, either as a first-line, or after previous treatments.

The principal biological effect of NZB is thought to be the blockade of the molecular interaction between α4β1-integrin (also known as very late antigen-4) expressed by mononuclear inflammatory cells, and vascular cell adhesion molecule-1 (CAM-1) expressed by cerebral vascular endothelial cells.

NZB is a potent DMT which must be monitored with caution, its use being hampered by the risk of opportunistic infections, mostly progressive multifocal leukoencephalopathy (PML).

Objectives

To document the efficacy and safety of NZB for the treatment of RRMS in a population of persons with MS (PwMS) followed in a regular MS Clinic setting.

Methods

We report our single-centre experience over a period of 13 years: from JAN 2007 through the end of May 2020.

All PwMS treated with NZB were included, regardless of the treatment duration.

The retainment of patients in our MS Clinic is 95%.

We use the iMed database, an international MS registry. .

Results

We report on 230 PwMS, 159 women, 71 men treated with NZB since 2007, up to 30 April 2020.

We had no PML case. We had 2 PML 'clinical alerts', but CSF search for JC virus (JCV) was negative.

There was no rebound of activity, nor IRIS, after NZB cessation, as we usually quickly switch to an alternative DMT.

Median age at MS onset: 26.3 years. Median age at NZB initiation: 35 years. Median disease duration before treatment: 8.07 years.

First line use: 94. Previous BRACE DMT: 136.

Risk factors: previous immuno-suppression: 7; NZB duration > 24 months: 112; JCV index > 1: 81.

Median treatment duration: 23 months; still active: 71 including 7 after > 6 years.

ARR at NZB onset: 1.5; during NZB: 0.27; current: 0.89.

Median EDSS at NZB start: 3.0. Current median EDSS: 2.8. EDSS stable: 65, worsened: 58; improved: 60.

MRI: stable: 133 (58%) ; improved: 5 (2%); worsened: 35 (25%).

Conversion to SPMS: 48 (20%) 29 W, 19 M.

Reasons for NZB cessation: planned: 27; pregnancy: 3; loss of efficacy: 39; increased JCV index: 62. No blood toxicity (CBC, ALT).

We had 9 pregnancies: 4 planned interruptions; 5 full term, with normal babies.

Treatment after NZB cessation: 48 fingolimod, glatiramer: 17; ocrelizumab: 16; others: 29; none: 32 (no rebound observed).

One patient had COVID 1 year after NZB: complete recovery; needed only nasal O2 during 3 day hospital admission.

Conclusions

NZB, when used with caution, is an effective and safe MS DMT during the RRMS phase, even after extended disease and treatment durations.

NZB is most effective to reduce relapse frequency, less effective against progression, as 20% of PwMS transited to the secondary progressive phase.

Gender, disease duration, and age do not influence outcomes.

We encountered no significant toxicity, in particular no PML.

Clinical, JCV index measures, and MRI monitoring are paramount to maintain safety.

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Clinical Outcome Measures Poster Presentation

P0107 - Lymphocyte response in standard and extended interval dosing of natalizumab (ID 312)

Speakers
Presentation Number
P0107
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Natalizumab (Tysabri) is a humanised monoclonal IgG4 antibody used in the management of severe relapsing remitting multiple sclerosis (RRMS). It is the first in its class of selective adhesion molecules.

The four-weekly standard interval dosing (SID) of natalizumab is based on initial phase 3 trials showing that a4 integrin receptor saturation remains >70% four weeks following a 300mg infusion. Extended interval dosing (EID) e.g. six weekly infusions, can be associated with a lower integrin receptor saturation however this may not result in any clinical difference. A recent study by Yamout et al confirmed that both regimens had similar impact on MRI inflammatory activity and Expanded Disability Status Score (EDSS) outcomes. Additionally EID may be linked with a lower risk of progressive multifocal leucoencephalopathy (PML), the most worrying adverse event in natalizumab use.

Natalizumab use results in elevation of serum levels of lymphocytes, through their sequestration in peripheral blood. The lymphocytosis response has been established as a marker for therapeutic efficacy- patients displaying lower levels of natalizumab induced lymphocytosis are at greater risk for relapse.

Objectives

Given the established evidence of peripheral blood lymphocyte count as a marker of therapeutic efficacy, we sought to establish the lymphocyte response in our cohort of patients on SID, EID and those who transitioned from SID to EID.

Methods

We collected lymphocyte levels on all patients on tysabri (on standard and extended interval dosing). Lymphocyte count was tracked at three monthly intervals during natalizumab use. Lymphocyte levels on ten patients who were switched from standard dosing to extended interval dosing was also analysed.

Results

We had 92 patients using tysabri. Ten of the patients were transitioned from SID to EID.

The average lymphocyte count prior to commencement of natalizumab was 1.89.

Post two infusions at SID, this increased to 2.66, and after five infusions increased to 3.46. There was no significant change after this, with average lymphocyte counts maintained between 3 and 3.5 for the remainder of the therapy.

Of the eight patients who were transitioned from SID to EID:

-Average pre natalizumab lymphocyte level was 1.88.

-Average lymphocyte level on SID was 3.23

-Average level post two infusions on EID was 3.41

Conclusions

Our data confirms that there is no significant difference in lymphocyte count between patients on SID and EID, and similarly between patients who transition between SID and EID.

EID has been shown to be at least as effective as SID in treatment of RRMS while also lowering the risk of progressive multifocal leucoencephalopathy (PML). Studies have shown no increase in relapses. The Expanded Disability Status Scale (EDSS) also shows no difference between patients on SID and EID. Our data contributes to the evidence underlying the safety of EID use in patients with highly active relapsing remitting MS.

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Clinical Outcome Measures Poster Presentation

P0108 - Meta-analysis of randomized controlled trials and real-world evidence comparing natalizumab and fingolimod for relapsing-remitting multiple sclerosis (ID 681)

Speakers
Presentation Number
P0108
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Natalizumab (NTZ) and fingolimod (FTY) are effective treatments for patients with relapsing-remitting multiple sclerosis (RRMS), yet comparative randomised controlled trials (RCTs) of their effectiveness have been limited.

Objectives

To compare the effectiveness of NTZ versus FTY in a network meta-analysis (NMA) of studies in RRMS patients, including indirect evidence from RCTs and direct real-world evidence from non-randomized studies (NRSs).

Methods

RCTs and NRSs were identified in a systematic literature review of studies assessing the effectiveness of NTZ and FTY. An NMA was employed to synthesize the evidence. RCTs indirectly compared treatments via placebo. Outcomes evaluated at 2 years included relapse rate (3 RCTs, 10 NRSs), relapse free patients (3 RCTs, 7 NRSs), 6-month confirmed disability worsening (CDW) (3 RCTs, 3 NRSs), 6-month confirmed disability improvement (CDI) (2 RCTs, 3 NRSs), and no evidence of disease activity (NEDA-3; defined as no relapses, no CDW, and no active magnetic resonance imaging lesions) (2 RCTs, 5 NRSs). Incidence rate ratios (IRRs), odds ratios (ORs) and hazard ratios (HRs) summarised relative effects; values <1 favoured NTZ. Sensitivity analyses employed design-adjusted NMA models; NRSs were down-weighted according to their risk of bias with the ROBINS-I tool.

Results

The relapse rate (IRR [95% confidence interval (CI)]) was lower in patients treated with NTZ than with FTY in RCTs (0.67 [0.51–0.88]), NRSs (0.65 [0.50–0.85]) and the NMA (0.67 [0.55–0.82]). The probability (OR [95% CI]) of remaining relapse free was higher with NTZ than with FTY in RCTs (0.88 [0.62–1.25]), NRSs (0.48 [0.35–0.67]) and the NMA (0.52 [0.39–0.70]). The probability (OR [95% CI]) of CDW was lower with NTZ than with FTY in RCTs (0.66 [0.42–1.05]), NRSs (0.80 [0.54–1.17]) and the NMA (0.74 [0.55–0.99]). The probability (HR [95% CI]) of CDI was similar with NTZ and FTY in RCTs (0.98 [0.53–1.81]) but was higher with NTZ than with FTY in NRSs (0.52 [0.24–1.14]) and the NMA (0.59 [0.33–1.05]). NEDA-3 was more often achieved (OR [95% CI]) with NTZ than with FTY in RCTs (0.55 [0.32–0.93]), NRSs (0.38 [0.29–0.50]) and the NMA (0.41 [0.32–0.52]). Design-adjusted NMAs did not substantially alter the clinical interpretation of results.

Conclusions

NTZ was more effective than FTY across a range of key effectiveness measures. In the absence of head-to-head trials, these results provide evidence about the comparative effectiveness of NTZ and FTY.

This study is funded by Biogen. Biogen funded the analyses and writing support for this abstract. Writing support was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

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Biomarkers and Bioinformatics Poster Presentation

P0109 - microRNA expression and its association with disability and brain atrophy (ID 1255)

Abstract

Background

MicroRNAs (miRNAs) are endogenous, non coding, small RNAs with post-transcriptional regulating functions. They participate in several cellular processes, including inflammation, neurodegeneration and remyelination

Objectives

To correlate serum miRNAs profile expression with disability, cognitive functioning and brain volume in patients with remitting-relapsing multiple sclerosis (RRMS)

Methods

Cross-sectional study in RRMS patients on stable treatment with glatiramer acetate (GA) during at least 6 months.

We selected the 20 best miRNAs candidates for RRMS and cognitive dysfunction through simple topological analysis (Anaxomics ®). MiRNAs profile was determined with LNA-based PCR (Exiqon). Clinical variables were Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT) and brain volume (whole brain volume, grey matter volume, white matter volume, cerebellum volume, basal ganglia volume and T1 lesion load volume) (automatic software NeuroQuant ®). Correlation was analyzed with Spearman correlation coefficient (r) (p<0,05; software: SPSS)

Results

We included 20 patients (13 women), age 38,2 (29,4, 47,8) years, duration of disease: 5,1 (1,5, 8,5) years, and time on GA 2,1 (0,8, 6) years. We found a pathogenic association between miR.146a.5p and has.mir.9.5p with EDSS (r:0,434, p=0,03; r:0,516, p=0,028); miR.146a.5p with SDMT (r:-0,476, p=0,016); has.mir.9.5p with thalamus (r:-0,545, p=0,036), and miR.200c.3p with pallidum and cerebellum (r:-0,675, p=0,002; r:-0,472, p=0,048).

Conclusions

MiRNAs could be useful biomarkers in multiple sclerosis. We would like to highlight the association of proinflammatory has.mir.9.5p with EDSS and thalamus volume. They are needed more studies to confirm this findings.

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Biomarkers and Bioinformatics Poster Presentation

P0110 - Modulation of cerebrospinal fluid immunoglobulins by ocrelizumab treatment (ID 1597)

Abstract

Background

Intrathecal production of immunoglobulin (Ig) and the presence of cerebrospinal fluid (CSF)–specific oligoclonal bands (OCBs) are hallmarks of multiple sclerosis (MS) that persist throughout the disease course and treatment.

Objectives

To describe baseline (BL) correlations of CSF IgM and IgG production with CSF biomarkers and to assess the pharmacodynamic effects of ocrelizumab (OCR) treatment on these parameters in patients with relapsing MS (RMS) from the Ocrelizumab Biomarker Outcome Evaluation (OBOE) study (NCT02688985).

Methods

Seventy-nine of 100 total patients with RMS had available BL CSF samples for assessment of IgG OCBs, IgG and IgM (measured at University Medical Center Göttingen), with demographic, MRI and clinical parameters representative of the total RMS population. CSF samples at either 12 (n=22), 24 (n=24) or 52 (n=17) weeks postdose and from a 12-week reference arm (no OCR; n=16) were assessed for longitudinal changes.

Results

Median (interquartile range [IQR]) CSF levels at BL were as follows: IgG index, 0.79 (0.63–1.28); IgM index, 0.19 (0.11–0.33); CD3+ T cell number, 2.52 (0.80–5.61) cells/µL; CXCL13, 9.89 (3.91–31.50) pg/mL; CCL19, 47.95 (31.09–70.86) pg/mL; neurofilament light chain (NfL) 1280.0 (828.1–2968.9) pg/mL. At BL, IgG index and IgM index correlated moderately with levels of B cells (r=0.65, r=0.4 respectively), T cells (r=0.54, r=0.3 respectively) and CXCL13 (r=0.58, r=0.43 respectively), but not CCL19 or NfL. IgG index tended to decrease with OCR treatment and was significantly reduced by 52 weeks (n=17/79; median [IQR] change from BL −9.5% [−20.4% to −0.1%]; p<0.02) compared with stable levels in the reference arm. While IgG OCBs were detected at BL in all patients, IgG OCBs tended to decrease with OCR treatment, with three of 17 patients having no detectable IgG OCBs at 52 weeks. Reductions in IgM index were not observed with OCR treatment.

Conclusions

Baseline CSF levels of B cells, T cells and CXCL13 correlated with IgG index and to a lesser degree IgM index in patients with RMS from the OBOE study. Significant reductions were observed in IgG index with OCR treatment, along with a trend toward reduced OCBs, with three patients showing no detectable OCBs. These data suggest that OCR impacts CSF Ig production, a hallmark of MS not previously thought to be affected by B-cell depletion therapy. These 1-year observations need to be confirmed with longer-term data and correlated with clinical response.

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Biomarkers and Bioinformatics Poster Presentation

P0111 - Monitoring Multiple Sclerosis Treatment with Plasma Biomarkers: NfL, GFAP, UCH-L1, and Tau (ID 909)

Speakers
Presentation Number
P0111
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Blood neurofilament light (NfL) levels have been linked to multiple sclerosis (MS) activity and progression but are affected by factors such as age and body mass index (BMI). Less is known about what factors affect blood levels of Glial Fibrillary Acid Protein (GFAP), Ubiquitin Carboxy-Terminal Hydrolase L1 (UCH-L1), and Tau. Single Molecule Array (SIMOA) platforms allow multiplex measurement of these biomarkers with high sensitivity.

Objectives

To evaluate factors associated with higher levels of four plasma biomarkers—NfL, GFAP, UCH-L1, and Tau—in individuals with MS on immunotherapy.

Methods

Subjects with MS between 18-65 years taking dimethyl fumarate (n=40), fingolimod (n=37), natalizumab (n=47), or rituximab (n=90) for at least 1 year were identified from Rocky Mountain MS Center Biorepository. Neuro 4-plex A plasma assays were conducted on the Quanterix SR-X SIMOA platform. Biomarker concentrations were log transformed. For each biomarker, summary statistics were generated, and logistic regressions on the probability of having a level in the top quartile, adjusting for age, were performed with different explanatory variables including gender, BMI, disease duration, length on disease modifying therapy (DMT), DMT type, and MS subtype (relapsing MS [RMS] or progressive MS [PMS]). All statistics were generated in SAS.

Results

Included were 214 subjects (194 RMS, 20 PMS; 70.3% female; 86.9% Caucasian) with mean age of 44.1(SD 9.8). Mean disease and treatment durations were 150.7(SD 95.7) and 49.7(SD 33.5) months, respectively. Means (IQR) for NfL, GFAP, UCH-L1 and Tau were 6.6(3.9-7.1), 66.9(45.5-81.4), 11.5(7.1-13.8), and 1.2(0.8-1.5) pg/ml, respectively. NfL, GFAP, and UCH-L1 increased with age. (Remainder of results are given age-adjusted.) PMS was more likely than RMS to be in the top quartile for NfL (OR 3.5,p=0.01), GFAP (OR 2.6,p=0.06), and UCH-L1 (OR 2.8,p=0.04). Longer disease duration (5 years) increased the likelihood of elevated NfL (OR 1.3,p=0.02) and elevated GFAP (OR 1.3,p=0.03). Higher BMI (5 units) decreased the likelihood of elevated NfL (OR 0.6,p=0.0007) and GFAP (OR 0.8,p=0.03) but increased the likelihood of having an elevated Tau (OR 1.4,p=0.002). Ethnicity and treatment duration had no effect, but men were more likely to have elevated UCH-L1 (OR 2.1,p=0.03) and lower Tau (OR 0.2,p=0.0004). Comparing DMTs, no biomarker differences were observed except subjects on rituximab and dimethyl fumarate were less likely to have elevated Tau.

Conclusions

Plasma NfL, GFAP, and UCH-L1 are promising biomarkers to differentiate relapsing from progressive MS. Age and BMI should be incorporated into biomarker models to determine normal thresholds. No differences were observed between treatments for NFL, GFAP, or UCH-L1, but subjects on dimethyl fumarate and rituximab were less likely to have elevated Tau. Lack of randomization or repeated measures limited comparative effectiveness analyses.

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Clinical Outcome Measures Poster Presentation

P0113 - MRI activity as a predictor of suboptimal response to natalizumab treatment: single center prospective cohort trial (ID 850)

Speakers
Presentation Number
P0113
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Second line disease modifying drugs are widely used in clinical practice, the most common is natalizumab. NTZ have usually reduced the annualized rate of relapse and MRI lesion load in clinical trials but sometimes clinical and MRI activity was still present. Defining the predictors of suboptimal response is still needed to decide which second line treatment drug is optimal for patient.

Objectives

To determine the early clinical and MRI predictors of suboptimal treatment responses at one year of natalizumab (NTZ) therapy.

Methods

Clinical assessment (EDSS, relapses) and MRI (T2, T1Gd+) on start, after 6 and 12 months were made. All patients receive NTZ as second line therapy. RRMS patients undergoing treatment with NTZ for at least 12 months were classified as optimal responders if they have no EDSS score increase, no relapses and stable MRI (<3 new T2 and no Gd+(GELs)).Statistical analysis: one-way ANOVA, ROC-curve.

Results

43 patients (34 female) were included in analysis, RRMS, age–35.9-41.6 (95%CI) years, with disease duration of 58-131(95%CI) months;25-31(95%CI) NTZ infusions. On month 12 30.2% have a suboptimal response: 3 patient have a clinical relapse, 4–increasing of EDSS, 13–MRI activity. The comparison of the groups did not reveal statistically significant differences in age, sex, duration of the disease, duration of therapy before starting NTZ, relapse rate on baseline. Patients in suboptimal response group have more severe previous year MRI activity (before NTZ): more severe T2 lesion load (F=6.3,p=0.016) and high number of GELs (F=4.1,p=0.051). Predictors of suboptimal response are: more than 4 new T2 lesions during last year and more than 2 GELs on MRI before NTZ.

Conclusions

High previous year MRI activity is a strong predictor of suboptimal NTZ response. This cohort of patients probably needs more powerful therapy, for example, alemtuzumab or cladribine.

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Biomarkers and Bioinformatics Poster Presentation

P0114 - MS Biomarker Discovery: a multi-modal approach to identify biomarkers of myelin repair by leveraging a preclinical rodent model of MS (ID 485)

Speakers
Presentation Number
P0114
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Analysis of remyelination and repair therapies in preclinical models for Multiple Sclerosis (MS) has historically relied mainly on histological examination, which provides limited clinical translatability. To overcome the challenge, we aimed to set up preclinical models, initiated with the cuprizone demyelination model, and to integrate multi-modal longitudinal biomarker evaluations.

Objectives

Employ multi-modal biomarker approaches to longitudinally and sensitively monitor myelin changes by leveraging the cuprizone mouse model.

Methods

C57BL/6 male mice are fed with cuprizone diet (demyelinating toxin) for either 4 weeks or 12 weeks followed by recovery for 2 weeks and 4 weeks, respectively. During demyelination and remyeination, animals undergo either MRI or evoked potential recording for structural and functional assessment of myelin. All readouts are assessed in conjunction with histological examination to correlate multi-modal biomarkers for measuring remyelination.

Results

Cuprizone preclinical model of MS was successfully established that reproduced histological changes in myelin content during the remyelination and demyelination phases. MRI based imaging measurements (MTR and T1/T2 ratio) and electrophysiology (transhemispheric and sensory evoked potentials) were highly consistent with cellular level changes in myelin content and correlative with each other. Of interest, during de- and re-emyelination, MTR and T1/T2 demonstrated a reduction and trend to rebound respectively, while DTI was increased and stayed high during the measurement timeframe. Ongoing evaluation to further explore and study the correlation between multiple biomarker modalities and serum neurofilament analyses is underway.

Conclusions

A platform to longitudinally monitor multi-modal biomarkers in the context of demyelination/remyelination in a preclinical model of MS has been established by this study. Ultimately this platform willserve to evaluate efficacy of remyelinating therapeutics by implementing translational biomarkers for faster readouts.

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Clinical Outcome Measures Poster Presentation

P0115 - mSteps: A pilot study using a phone application with GPS, accelerometers and Wi-Fi positioning to measure walking distance in MS, indoors and outdoors (ID 1102)

Speakers
Presentation Number
P0115
Presentation Topic
Clinical Outcome Measures

Abstract

Background

There is to our knowledge few validated electronic tool in MS that measures the distance walked by a person with MS (PwMS). Utilising global positioning systems (GPS), WI-FI positioning and an in-built smartphone accelerometer to measure distance walked by a PwMS outdoors or indoors, could alleviate the uncertainty around using pedometers in those with gait disturbances, and is an attractive option.

Objectives

To pilot an accurate measure of distance walked using a smartphone application (mSteps) to facilitate Expanded Disability Status Scale (EDSS) measurement, indoors and outdoors, using both an MS and a control cohort.

Methods

The pilot study recruited 25 PwMS and 10 controls. mSteps utilised the iPhone’s inbuilt accelerometer and GPS functionalities to calculate the distance walked and time taken, indoors and outdoors. Due to unpredictable weather the physician monitored walk took place indoors which was fitted with location beacons to allow for WI-FI indoor positioning. The control cohort did the same walk indoors and outdoors to validate the use of the GPS functionality.

The participant was instructed to walk 25 feet, without rest, whilst the study phone was attached to their arm using a runner’s arm band and study personnel walked alongside them with a trundle wheel. Measurements were taken at 3 separate time points within a 3-month period.

95% levels of agreement between app and trundle wheel (gold standard) were calculated using the Bland-Altman repeated measures analysis. Levels of agreement, app vs trundle, were calculated for indoor measurements on both PwMS and controls with additional app vs trundle outdoor measurements for controls only. The a priori defined clinically acceptable difference was 1.52m.

Results

The 95% levels of agreement for indoor measurements on PwMS were -2.46 to 2.27m; and for controls were -2.02 to 2.71m. The 95% levels of agreement for outdoor measurements on controls were -0.45 to 0.43m.

Conclusions

The outdoor GPS functionality of mSteps is very accurate as shown by the 95% levels of agreements compared to the a priori clinically determined difference. The indoor WI-FI positioning function of mSteps however, was not accurate enough and shows that it is not reliable enough for further use. The control cohort showed the same inaccuracy indoors which eliminates the possibility that an uneven gait pattern in the MS cohort contributed to the error margin. A further validity study is being carried out, looking at a cohort of PwMS walking outdoors using mSteps and a trundle wheel.

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Clinical Outcome Measures Poster Presentation

P0116 - Multiple Sclerosis and Cognitive Impairment: Computerized Cognitive Assessment and PROMIS-Cognitive Function Questionnaire: An Unfulfilled Promis (ID 1873)

Speakers
Presentation Number
P0116
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Cognitive impairment (CI) is common in people with Multiple Sclerosis (PwMS) but often not addressed in routine care. Disease burden/progression in PwMS is traditionally measured by reported relapse, EDSS, and MRI change. CI is a source of significant disability independent of findings on examination. Use of a validated multi-domain screening cognitive assessment battery (NeuroTrax, CAB-NT) provides quantitative patient centric information to track CI longitudinally. Patient self-reported outcome measures (PRO) are also often used to gauge disability progression. PROMIS–Cognitive Function Short Form (CF-SF) is a validated disease agnostic PRO that can be incorporated to evaluate patient perception of disease impact. The relationship of the PROMIS PRO to a multi-domain quantitative cognitive assessment tool has not been explored in PwMS.

Objectives

To examine the cross-sectional relationship between PRO PROMIS-Cognitive Function (CF-SF) scores and CAB-NT scores.

Methods

Retrospective review of consecutive PwMS who completed both the CAB-NT and PROMIS-CF-SF in the course of routine care on the same day. CAB-NT included 7 cognitive domains: memory (Mem), executive function (Exe), attention (Att), information processing speed (Inf), visual spatial (Vis), verbal function (Ver), motor skills (Mot) as well as a global cognitive summary score (GCS). Cognitive domains impaired (CDI, domain score’s <85) are also calculated.

Results

147 PwMS, average age 49+/- 12, 70% female. Significant relationships (p<0.05) were identified through regression analysis with Pearson’s correlation coefficient (r) only for the following Cognitive Domain scores: GCS (r=0.27), Mem (r=0.23), Exe (r=0.27), Att (r=0.27), Inf (r=0.42), and Mot (r=0.27), CDI (r=0.4).

Conclusions

The PROMIS-Cognitive Function Short Form PRO does not provide a meaningful alternative to objective measures of CI in PwMS. Computerized Multi-domain Cognitive Testing provides an accurate tool to evaluate the degree of cognitive impairment across multiple relevant cognitive domains as well as the combination of domain impairment and accumulative cognitive impairment. The promise of the PROMIS-Cognitive Function Short Form to provide an effective PRO to evaluate cognitive impairment in PwMS has not been fulfilled.

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Biomarkers and Bioinformatics Poster Presentation

P0117 - Mystery of MRZ reaction in multiple sclerosis   (ID 1449)

Speakers
Presentation Number
P0117
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Background: Multiple Sclerosis (MS) is an immune mediated disease of the central nervous system (CNS). Epstein-Barr virus (EBV) is among the most well-established environmental risk factors in MS. MS patients also make low affinity antibodies against neurotrophic viruses such as measles (M), rubella (R), and zoster (Z), and they make these intrathecally. This phenomenon is quite specific for MS and it is called MRZ reaction. The pathophysiological role of MRZ reaction currently remains unclear.

Objectives

Objectives: Because EBV induces differentiation of infected B cells in antigen-nonspecific manner, the aim of this project is to test the hypothesis that the extent of MRZ reaction correlates with the amount of EBV infected B cells in the intrathecal compartment of MS patients and with the MS severity.

Methods

Methods: In a pilot cohort of 80 patients with broad range of MS severity, we blindly analyzed MRZ reaction by enzyme-linked immunosorbent assay (ELISA) applied to matched cerebrospinal fluid (CSF) and serum samples. To derive a single measure of the extent of MRZ reaction, we summed antibody indexes (AI) for each reaction component (M, R and Z) to MRZ score.

Results

Results: Upon unblinding the MS severity outcomes and diagnostic subgroups, the MRZ scores did not significantly correlate with B cell/plasma cell biomarkers known to be increased in MS CSF (i.e., B-cell maturation antigen/BCMA and IgG index) and were not significantly different between relapsing remitting, primary progressive and secondary progressive MS. Finally, the MRZ scores did not correlate with clinical outcomes of MS severity (MS disease severity scale: MS-DSS and brain damage severity: principal component of brain parenchymal fraction and the symbol digit modalities test normalized for patient’s age).

Conclusions

Conclusions: The study proved null hypothesis (i.e., MRZ reaction is not associated with intrathecal biomarkers of B cell/plasma cell expansion and with MS severity). The association between MRZ reaction and MS remains a mystery.

Acknowledgments: The research was supported by the Intramural Research Program of the NIH, NIAID.

Notice: This study involved patients and it was approved by NIAID IRB.

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Biomarkers and Bioinformatics Poster Presentation

P0118 - Neurofilament light chain concentration predicts risk of relapse in participants with relapsing multiple sclerosis in phase 3 ozanimod trials (ID 1211)

Speakers
Presentation Number
P0118
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

In patients with multiple sclerosis (MS), neurofilament light chain concentration (NfL-c) is increased in blood and cerebrospinal fluid (CSF). Plasma and CSF NfL-c correlate and may serve as a biomarker for neurologic damage and disease activity in relapsing MS (RMS). Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, reduced annualized relapse rate (ARR) and plasma NfL-c (pNfL-c) vs interferon β-1a (IFN) in phase 3 RMS trials.

Objectives

To expand upon previously reported data showing that baseline (BL) pNfL-c predicts risk of on-treatment relapse, we analyzed the relationship between changes in pNfL-c and on-treatment risk of relapse with ozanimod vs IFN.

Methods

In this exploratory, post hoc analysis, pNfL-c was measured at BL and after 12 and 24 months of treatment with oral ozanimod 0.46 or 0.92 mg/d or intramuscular IFN β-1a 30 µg/wk in the phase 3 SUNBEAM (NCT02294058; ≥12 mo) and RADIANCE (NCT02047734; 24 mo) trials. The effect of treatment on pNfL-c was assessed, as were the relationships between BL pNfL-c and relapse rate and pNfL-c change from BL and ARR. NfL data are reported as median percentage change from BL. Poisson generalized linear models were used to fit the number of relapses as a function of BL pNfL-c and treatment group with an offset for duration. We calculated a predictive model of expected ARR based on median percentage change from BL in pNfL-c.

Results

At end of treatment, median pNfL-c was significantly reduced from BL by 20‒23% (P<0.01) and 23‒27% (P≤0.0001) with ozanimod 0.46 and 0.92 mg, respectively, and by 13‒15% with IFN. Higher BL p-NfL-c was associated with an increase in number of relapses (P<0.0001). Over a 12-month period, participants treated with either dose of ozanimod had significantly fewer relapses than those treated with IFN (P<0.05); the greatest effect was observed with ozanimod 0.92 mg. Further analyses reveal that treatment groups associated with a greater median reduction from BL pNfL-c are also associated with lower ARR. Predictive modeling estimated that a 25% reduction in pNfL-c, similar to that observed with ozanimod 0.92 mg, predicts an ARR (standard error [SE]) of 0.18‒0.23 (0.4); a 13% reduction, which was similar to that observed with IFN, predicts an ARR (SE) of 0.29‒0.37 (0.04).

Conclusions

Our findings further support pNfL-c as a biomarker for RMS disease activity. BL pNfL-c is related to relapse rate, as are changes in pNfL-c during treatment. Ozanimod causes dose-dependent reductions in pNfL-c and ARR compared with IFN.

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Biomarkers and Bioinformatics Poster Presentation

P0119 - Neurofilament light chain levels correlate with lesion activity and axonal damage in MS (ID 902)

Speakers
Presentation Number
P0119
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The level of neurofilament light chain (NfL), a major component of the neuronal cytoskeleton, in plasma or cerebrospinal fluid (CSF) is considered a promising biomarker in multiple sclerosis (MS) for inflammation-mediated axonal damage.

Objectives

The relation between NfL levels and MS specific neuropathological measures is not yet known, and is the subject of this study.

Methods

In this autopsy study (n=105), CSF NfL levels were measured using a Simoa assay and were correlated with hallmarks for acute and chronic damage axonal damage, clinical and pathological donor characteristics, and to proportions and activity of MS white matter lesions determined with myelin and HLA stainings.

Results

CSF NfL levels correlated with presence of acute axonal damage features (APP+ bulbs: p=0.04, APP+ axons: p=0.03) and correlated negatively with axonal density (Bielschowsky+ axons: p=8.3e-3) in the normal appearing pyramid tract. As CSF NfL levels were confounded by stroke (<1 year before death, p=2.0e-3), these donors were excluded from further MS specific clinical and neuropathological analysis. NfL correlated negatively with disease duration (p=6.9e-3), thus with more severe MS. NfL levels positively correlated with the proportion of active MS lesions containing foamy microglia (p=9.85e-10) and not those containing ramified microglia. NfL levels of donors without atrophy at neuropathological examination were positively correlated with the proportion of mixed lesions with foamy microglia (p=1.75e-3), and negatively correlated with the proportion of inactive lesions (p=5.66e-3) and remyelinated lesion presence (p=0.04).

Conclusions

We validated that CSF NfL levels reflect pathological hallmarks of acute disease activity and concomitant axonal degeneration. These observations support the clinical use of NfL to monitor these neuropathological processes in people with MS.

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Clinical Outcome Measures Poster Presentation

P0120 - Neuroperformance test outcomes as predictors of employment in a large, heterogeneous real world MS populations: Results from MS PATHS (ID 1758)

Speakers
Presentation Number
P0120
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Neuro-performance testing has been used extensively in MS clinical trials, resulting in a large literature on processing speed (Symbol Digit Modalities Test [SDMT]), manual dexterity (9-Hole Peg Test [9HPT]), and walking speed (25-foot walk [25FW]). Computer adapted versions were developed and validated, to support widespread use in clinical practice. The Multiple Sclerosis Performance Test (MSPT) includes a self-administered Processing Speed Test (PST), simulating SDMT; Manual Dexterity Test (MDT), simulating 9HPT; and Walking Speed Test (WST), simulating 25FW. MSPT is deployed within the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network. Optimal test thresholds associated with employment status in a real-world population have not been reported.

Objectives

To determine thresholds for standardized test scores of processing speed, manual dexterity, and walking speed as predictors of employment status in a real world MS population.

Methods

Neuroperformance testing was done as part of clinical visits in MS PATHS. Employment status was collected via standardized questionnaire. Patients aged 18 to 60 in the US were divided into a training set (n=3210) and a test set (n=1605). PST, MDT and WST benchmarks predicting unemployment at baseline and employment worsening at 2 years were identified as the test scores with the minimum p-value in logistic regression models adjusting for age, sex and education. Odds ratios representing the risk of unemployment or employment worsening were calculated based on the identified benchmarks.

Results

4815 of 9585 participants (50%) were employed full-time at baseline. In the training set benchmarks for unemployment were: PST ≤44 correct, OR (95% CI) 5.3 (4.7, 6.0); MDT >28.7 seconds, OR 7.2 (6.3, 8.1); and WST >8 seconds, OR 6.7 (5.8, 7.7). For patients employed at baseline, benchmarks for worsening employment status were: PST ≤44 correct, OR 4.3 (3.1, 6.0); MDT >24 seconds, OR 3.3 (2.3, 4.6); and WST >7.6 seconds, OR 6.4 (4.7, 8.8). Benchmarks were confirmed in the validation set.

Conclusions

Clinically relevant neuroperformance test benchmarks for predicting unemployment and employment worsening were identified in a training set and confirmed in a validation set using a large real world MS population. Future research will determine early risk factors for these benchmarks in order to identify potential employment preservation strategies.

Disclosures: MS PATHS is sponsored by Biogen

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Biomarkers and Bioinformatics Poster Presentation

P0121 - Objective measurement of speech correlates with disease status and quality of life in people with MS without dysarthria (ID 1681)

Speakers
Presentation Number
P0121
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Objective measurement of speech has shown promising results to monitor disease state in Multiple Sclerosis (MS). Yet, it is not clear if changes in speech can be detected before overt dysarthria.

Objectives

In this study, we characterize the relationship between disease severity and objective speech metrics exclusively in people with no perceivable dysarthria.

Methods

An acoustic composite score was calculated using regression modelling of speech data from 119 people with MS (pwMS, 75% female), irrespective of dysarthria presence. That score was then tested in pwMS without dysarthria, as determined by blinded perceptual rating, for correlations with the Expanded Disability Status Scale (EDSS), brain volume and lesion load from magnetic resonance imaging, and quality of life scores from the Multiple Sclerosis Impact Scale (MSIS-29) .

Results

PwMS without dysarthria (n=77) were more likely to be female (82% vs 62%, p=0.017), were on average 5.7 years younger (age mean ± standard deviation 53.5±11.4, p=0.009), had MS for 2.5 years shorter (11±8.5 years, p=0.034) and scored EDSS 1.7 step lower (2.7±1.9, p<0.001) than pwMS with dysarthria (n=42). The acoustic composite score correlated with EDSS scores (r=0.45, p<0.001) and quality of life (r=0.4, p=0.01) in pwMS without perceivable dysarthria, but not with brain volume or lesion load.

Conclusions

Acoustic analysis offers a valuable insight into the subclinical development of speech impairment in MS. These results highlight the potential of automated analysis of speech to assist in monitoring disease progression and treatment response.

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Clinical Outcome Measures Poster Presentation

P0122 - Ocrelizumab in patients with multiple sclerosis: A single center experience.  (ID 668)

Speakers
Presentation Number
P0122
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Multiple Sclerosis is a progressive demyelinating autoimmune disorder that can lead to significant morbidity and mortality. It can be either relapsing remitting i.e Relapsing Remitting Multiple Sclerosis (RRMS) or progressive in nature like Primary Progressive Multiple Sclerosis (PPMS). Several Disease Modifying Treatments (DMT) are used to treat this disorder. Ocrelizumab is a humanized CD20 monoclonal antibody which was approved for management of RRMS and PPMS in 2017. Trials such OPERA I and II as well as ORATORIO has shown improved clinical outcomes in patients with RRMS and PPMS respectively.

Objectives

We aim to study the clinical disease progression including disability scores and imaging findings such as volumetric analysis of several central structures in patients being treated with Ocrelizumab at baseline and 12 months.

Methods

We enrolled a total of 124 patients that were seen at our institute, who are currently being treated with Ocrelizumab (92 with RRMS and 32 with PPMS) between August 2017 to July 2020. Clinical data was obtained from their medical records including Expanded Disability Status Scale (EDSS) and Timed 25 Foot Walk (T25FW) at baseline and 12 months. MRI of the brain, which included T1-w, T2-w, T2-FLAIR, post gadolinium T1-MRAGE sequences were also collected. LesionQuant software, developed by CorTechs laboratory will be used to obtain volumes of the cortical gray matter, white matter, hippocampi and white matter lesion load in the periventricular, juxtacortical, infratentorial and deep cerebral white matter areas.

Results

When independent paired t- test was performed there was significant improvement in the T25FW over time (t= 3.19, n=47; p=0.003 Cohen’s d= 0.46) but no such changes were observed with the EDSS scores (t= 1.58, n= 120; p=0.118 Cohen’s d= 0.14). Means of T25FW before and after intervention were 10.98 seconds and 9.49 seconds respectively. Means of EDSS scores before and after interventions were 3.58 and 3.52 respectively. We’re currently in the process of obtaining volumetric measure of the structures mentioned above and correlating them with the clinical scales in the near future.

Conclusions

In 31 participants with PPMS, EDSS score improved in 6 (19%), was stable in 22 (71%), and deteriorated in 3 (10%). In 89 participants with RRMS, EDSS score improved in 3 (3%), was stable in 76 (86%), and deteriorated in 10 (11%). We hope to further explore the effect of medication by computing imaging features in the near future.

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Biomarkers and Bioinformatics Poster Presentation

P0123 - Ocrelizumab reduces thalamic volume loss and clinical progression in PPMS and RMS independent of baseline NfL and other measures of disease severity (ID 1621)

Speakers
Presentation Number
P0123
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS). Thalamic atrophy occurs early and may be a sensitive marker of overall brain damage. Ocrelizumab (OCR) reduced brain atrophy and NfL in patients with relapsing MS (RMS) and those with primary progressive MS (PPMS).

Objectives

To examine the independent impact of OCR and baseline (BL) NfL on thalamic volume (TV) and clinical progression in patients with PPMS and RMS, including those with RMS without acute BL activity (i.e. no gadolinium–enhancing [Gd+] lesions or relapse in the last 3 months).

Methods

Patients were from OPERA I/II (RMS, n=1,421) and ORATORIO (PPMS, n=596). Thalamic atrophy was calculated as annualized percentage TV change (PTVC) from Wk 24 to the end of controlled treatment (ORATORIO, Wk 120; OPERA I/II, Wk 96). OCR treatment (vs IFNβ-1a [RMS] or placebo [PPMS]) and log-transformed BL NfL were examined for associations with PTVC (linear regression) and 24-week confirmed disability progression (Cox regression) adjusting for BL demographic and disease characteristics.

Results

In patients with PPMS and RMS, OCR treatment (PTVC: +0.47% and +0.33%, respectively) and lower BL NfL (+0.20% and +0.33% per 2-fold lower NfL) independently associated with a smaller TV reduction (all p<0.005). Adjusting for BL NfL level, Gd+ lesion count, T2 lesion volume and BL disability, OCR still reduced disability progression on Expanded Disability Status Scale (EDSS) (PPMS, hazard ratio [HR]=0.73; RMS, HR=0.65; both p<0.05]), 9-Hole Peg Test (9HPT) (PPMS, HR=0.53, p=0.002; RMS, HR=0.52, p=0.059), Timed 25-Foot Walk (T25FW) (PPMS, HR=0.79, p=0.063), Symbol Digit Modalities Test (RMS, HR=0.54, p=0.002) and time to EDSS 6 (RMS, HR=0.42, p=0.009). In patients with PPMS, higher BL NfL was associated with worsening on 9HPT (HR=1.34 per 2-fold higher NfL), T25FW (HR=1.19) and time to EDSS 7 (HR=1.78) (all p<0.05). In patients with RMS without acute BL activity, higher BL NfL was associated with EDSS worsening (HR=1.49), progression independent of relapse activity (PIRA) (HR=1.61), 9HPT (HR=2.1) and time to EDSS 6 (HR=2.24) (all p<0.05).

Conclusions

Ocrelizumab treatment remained associated with reduced thalamic atrophy and clinical progression after adjusting for baseline NfL and other factors. Higher BL NfL was associated with increased rates of thalamic atrophy and clinical progression in patients with PPMS and those with RMS without acute disease activity.

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Clinical Outcome Measures Poster Presentation

P0124 - Ocrelizumab treatment in patients with relapsing-remitting multiple sclerosis: a single-center real-world experience (ID 1619)

Speakers
Presentation Number
P0124
Presentation Topic
Clinical Outcome Measures

Abstract

Background

ocrelizumab (OCR) treatment in pivotal trials of patients (pts) with relapsing-remitting multiple sclerosis (RRMS) was associated with high clinical efficacy and safety. However, real word data on efficacy and safety are still scarce

Objectives

To provide first experience on patients with RRMS treated with OCR in a single center real-world setting (MS Center of University of Genoa)

Methods

We collected safety and efficacy data from pts with RRMS treated with OCR. The probability of disability worsening-free survival, relapse-free survival, MRI-activity free-survival and NEDA-3 status was calculated with the Kaplan-Meier estimator and Cox proportional hazards regression analysis.

Results

96 RRMS pts [60 females (62.5%), mean (SD) age 37.3 (10.2) years] with a mean disease duration (DD) of 9.6 (9.3) years, a median (IQR) baseline EDSS of 2.5 (2-4) and a mean ARR of 0.79 (0.73). Median (IQR) number of previous DMTs was 1 (0-2). The mean time from previous DMT discontinuation and OCR start of 209 (661) days. Reasons for previous DMTs discontinuation were (i) lack of efficacy for 45 (67%), (ii) occurrence of adverse events for 7 (10%) and (iii) high JCV titer during natalizumab treatment for 5 (7.5%) pts. 28 pts (29.5%) had not received any DMT prior to OCR. Naïve pts had significantly shorter disease duration (2.6 vs 12.5 years; p<0.0001), had higher ARR (1.1 vs 0.7; p=0.002) and more frequently exhibited inflammatory activity on baseline MRI scan (96.3% vs 74.6%; p=0.019). Mean follow-up (FU) was 1.4 (1.2) years.

At 1-year FU, MRI-inflammatory activity free survival was 75.9%, relapse free survival was 95.9%, progression free survival was 98.7%. 2-years NEDA-3 status was achieved in 73.6% of pts. At multivariate analyses, adjusting for DD, ARR and baseline MRI activity, 2-years NEDA-3 status was significantly higher in naïve compared with treated pts [90.7% versus 60.8% at the end of the observation period; HR (CI 95% ) 0.14 (0.03-0.65); p=0.012]. We recorded 55 adverse events in 39 pts (4 lower respiratory tract infections; 18 upper respiratory tract infections; 7 herpes simplex-1 reactivation; 1 shingles; 8 upper urinary tract infections; 2 breast cancers). No serious infusion-associated reactions were reported

Conclusions

OCR treatment allows complete disease control in a high proportion of real-world RRMS pts, with a manageable safety profile. Although ocrelizumab can control disease activity after failure of highly efficacy DMTs, its efficacy seems to be higher in naïve patients

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Biomarkers and Bioinformatics Poster Presentation

P0125 - Ocrelizumab treatment induces a sustained blood NfL reduction in patients with PPMS and RMS (ID 1865)

Speakers
Presentation Number
P0125
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Blood neurofilament light chain (NfL) is a biomarker of neuroaxonal injury associated with acute disease activity and may be prognostic for disability progression in patients with multiple sclerosis (MS). Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody indicated for relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To assess the impact of OCR on blood NfL distribution in patients with RMS from the OPERA I and II trials and those with PPMS from ORATORIO.

Methods

Pretreatment and posttreatment NfL levels (measured using the SiMOA assay) with OCR vs interferon β-1a (OPERA I and II; n=1,421) or placebo (ORATORIO; n=596) were compared using geometric mean (GM) and GM ratios (GMR). Patients were stratified by presence/absence of acute disease activity at baseline (BL) (T1 gadolinium [Gd]-enhancing lesions and/or relapse in prior 3 months for RMS; T1 Gd-enhancing lesions for PPMS). Age-adjusted NfL distributions (using a linear model for log-NfL and age derived from a healthy donor [HD] cohort) at BL and after OCR were compared with HD using the Kolmogorov-Smirnov test.

Results

Significant reductions in NfL were observed 3 months after OCR initiation (RMS, GMR=0.80; PPMS, GMR=0.89) and sustained through the end of controlled treatment (RMS [96 weeks], GMR=0.56; PPMS [120 weeks], GMR=0.81; all p<0.0001). Age-adjusted BL serum NfL was elevated in patients with RMS disease activity (GM [95% CI]=12.7 [11.9–13.6] pg/mL) vs those without (5.5 [5.3–5.7] pg/mL) and HD (4.1 [3.9–4.4] pg/mL; all p<0.0001). In OCR-treated patients with RMS, GM [95% CI] serum NfL levels after 96 weeks (with activity at BL, 4.4 [4.2–4.6] pg/mL; without activity at BL, 4.1 [4.0–4.3] pg/mL) were comparable to HD (4.1 [3.9–4.4] pg/mL; all p>0.1). Age-adjusted BL plasma NfL was also elevated in PPMS patients with disease activity (GM [95% CI]=8.7 [7.5–10.1] pg/mL) vs those without (4.9 [4.6–5.2] pg/mL) and HD (3.1 [2.9–3.3] pg/mL; all p<0.0001). In OCR-treated patients with PPMS, GM [95% CI] plasma NfL levels after 120 weeks (with activity at BL, 4.6 [4.1–5.1] pg/mL; without activity at BL, 4.2 [4.0–4.4] pg/mL) were reduced from BL (all p<0.005) but remained elevated vs HD (all p<0.001).

Conclusions

NfL is highly elevated in patients with acute MS disease activity, and more subtle elevations are observed in RMS and PPMS patients without detectable disease activity. Ocrelizumab significantly reduces NfL in RMS and PPMS patients with and without detectable disease activity.

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Biomarkers and Bioinformatics Poster Presentation

P0126 - Olfactory threshold as a biomarker predicting treatment response in relapsing multiple sclerosis (ID 296)

Speakers
Presentation Number
P0126
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Olfactory threshold impairment is transiently occurring in patients with active multiple sclerosis (MS) and during acute MS relapse resolving in phases of clinical stability and after initiation of disease-modifying treatment (DMT). Thus, threshold impairment is a marker of short-term inflammatory activity in relapsing multiple sclerosis (RMS).

Objectives

The objective of this study was to investigate the potential of olfactory threshold for prediction of treatment response in RMS.

Methods

In this 4-year prospective observational study on 113 RMS patients, olfactory threshold was measured at DMT initiation (M0) and after 3 (M3) and 12 months (M12) of follow-up by the Sniffin’ Sticks test. Inclusion criteria included adherence to DMT for at least 2 years. Treatment response was defined as absence of relapse during the observation period. Best possible cut-off values of olfactory threshold for predicting treatment response were determined by receiver-operating characteristics (ROC) analyses. Odds ratios (OR) for treatment response were calculated by stepwise multivariate logistic regression models correcting for age, sex, and disease duration at baseline.

Results

A combination of threshold score ≥6.0 at M3 and ≥1.0 points improvement from M0 to M3 sustained to M12 displayed the best prediction of treatment response (OR 5.1; 95% CI: 2.3 – 7.8; p<0.001; specificity 90%, sensitivity 83%) followed by threshold score ≥6.0 at M3 alone (OR 3.6; 95% CI: 1.3 – 7.0; p<0.001; specificity 83%, sensitivity 76%), ≥1.0 points improvement from M0 to M3 sustained to M12 alone (OR 3.5; 95% CI: 1.2 – 6.8; p<0.001; specificity 82%, sensitivity 70%). Threshold score at M12 alone and improvement from M3 to M12 was not significantly predictive. Also, adding threshold score at M12 to the model did not improve predictive accuracy.

Conclusions

Olfactory threshold impairment predicts relapse activity upon DMT initiation. Pending validation, olfactory threshold may be a useful and easily obtainable biomarker of treatment response in RMS.

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Clinical Outcome Measures Poster Presentation

P0127 - Oral therapies for treatment of relapsing-remitting multiple sclerosis in Austria (ID 252)

Speakers
Presentation Number
P0127
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Studies matching the clinical efficacy between fingolimod (FTY), dimethylfumarate (DMF) and teriflunomide (TERI) provided conflicting results. These discrepancies ask for further investigations to confirm or rebut the published findings, especially by real-life experiences.

Objectives

To compare the efficacies, frequencies and reasons for treatment interruption of FTY, DMF or TERI in a nationwide observational cohort.

Methods

Twocohorts of patients with relapsing-remitting multiple sclerosis (RRMS) having started treatment with FTY, DMF or TERI documented in the Austrian MS Treatment Registry (AMSTR) since 2014 and either staying on therapy for at least 24 months (24m cohort) or with at least one follow-up visit after start of treatment (total cohort). The 24m cohort included 629 RRMS patients: 295 in the FTY, 227 in the DMF and 107 in the TERI group. We used multinomial propensity scores for inverse probability weighting in generalized linear and Cox proportional hazards models to correct for the bias of this non-randomised registry study.

Results

Estimated mean annualized relapse rates (ARR) over 24 months were 0.13 for FTY, 0.09 for DMF and 0.11 for TERI treatment. For TERI in comparison with DMF, we observed higher probability for treatment interruption (p=0.023) and reduced sustained EDSS regression for 12 (p=0.016) and 24 weeks (p=0.031) and, for the comparison of DMF versus FTY, a reduced sustained EDSS progression for 12 weeks (p=0.02).

Conclusions

Relapse rates with treatment with FTY, DMF and TERI were similar. Patients treated with DMF showed less sustained disability progression for 12 weeks than FTY treated patients. However, FTY and DMF treatment was associated with more likely EDSS regression for 12 and 24 weeks and a lowerprobability for treatment interruptionas compared to TERI treated patients.

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Clinical Outcome Measures Poster Presentation

P0128 - Outcomes in Alemtuzumab-Treated Patients With Thyroid Adverse Events: 6-Year Pooled CARE-MS Data (ID 736)

Abstract

Background

Over 6 years in the CARE-MS core and extension trials (NCT00530348; NCT00548405; NCT00930553), alemtuzumab improved outcomes in RRMS patients, but many experienced thyroid adverse events (AEs).

Objectives

To characterize thyroid AEs over 6 years in alemtuzumab-treated patients from the CARE-MS core and extension trials.

Methods

Patients received 2 alemtuzumab courses, with as-needed additional alemtuzumab ≥12 months after the most recent course. An expert panel of 3 independent endocrinologists reviewed all reported cases of thyroid-related laboratory abnormalities and AEs to assess diagnosis, start date, and outcome through a consensus approach. Cases for which consensus was not reached, or those that were preexisting or occurred after Y6 were excluded.

Results

Over 6 years, 378/811 (47%) alemtuzumab-treated patients had a thyroid AE or laboratory abnormality (342 [42%] with thyroid AE; 44 serious AEs). After panel review, 292 cases had a consensus diagnosis as a thyroid AE, no consensus diagnosis could be reached in 60 cases, 2 cases were deemed pre-existing, and 24 occurred after Y6. Cases with a consensus diagnosis were adjudicated to Graves’ disease (40%), Hashimoto’s disease (17%), transient thyroiditis (8%), Graves’ disease switching to hypothyroidism (6%), Hashimoto’s disease switching to hyperthyroidism (3%), or uncertain (27%). Oral thyroid medications were given to 245/292 (84%) patients, primarily levothyroxine/levothyroxine sodium (n=187; 64%) or thiamazole (n=126; 43%); 32/292 (11%) patients underwent thyroidectomy and 26/292 (9%) underwent radioiodine therapy. Within 2 years of the last alemtuzumab course, 83% of thyroid AEs appeared (>97% were detected within 4 years). Patients with vs without thyroid AEs received similar numbers of alemtuzumab courses (2 courses: 62% vs 60% of patients; 3 courses: 24% in each group). From baseline to Y6, MS disease outcomes were similar in patients with vs without thyroid AEs (annualized relapse rate: 0.20 vs 0.21; mean EDSS score change: −0.04 vs +0.08; proportion with stable/improved EDSS scores: 81% vs 80%; proportions MRI disease activity-free: 60%-78% per year vs 60%-76% per year; and median cumulative brain volume loss: −1.11% vs −1.27%). Outcomes as of last follow-up were recovered (53%), ongoing (46%), and unknown (0.3%).

Conclusions

Graves’ disease was the most common thyroid AE. Most thyroid AEs were treated with oral medications. No differences in 6-year MS disease outcomes were seen when comparing patients with or without thyroid AEs.

STUDY SUPPORT: Sanofi and Bayer Healthcare Pharmaceuticals.

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Clinical Outcome Measures Poster Presentation