Monash University
Department of Neuroscience, Central Clinical School

Author Of 1 Presentation

Observational Studies Oral Presentation

PS05.04 - Ongoing disease modifying treatment associated with mis-classification of secondary progressive as relapsing-remitting multiple sclerosis

Abstract

Background

Until recently, disease modifying treatment options for MS patients with a secondary progressive course (SPMS) were limited, leading to the common practice of off-label treatment with drugs approved for relapsing-remitting MS. We previously showed that applying objective algorithms tend to increase the proportion of SPMS in MS registries, suggesting that SPMS is under-diagnosed in clinical practice, possibly related to available treatment options.

Objectives

To compare characteristics of patients clinically assigned an RRMS course that are re-classified when an algorithm-based SPMS assignment method is applied.

Methods

Data from MS registries in the Czech Republic (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (5,086 patients) were used. Inclusion criteria were patients with relapsing remitting (RR)MS or SPMS with age ≥ 18 years at the beginning of the study period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS a data-driven assignment method was applied in the form of a decision tree classifier based on age and last EDSS (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).

Results

Across the five registries 8,372 RRMS patients were re-assigned as SPMS (Denmark: n=1,566, Czech Republic: n=1,958, Germany: n=2,906, Sweden: n=648, United Kingdom: n=1,294) increasing the overall SPMS proportion from 17% to 31%. Re-assigned patients tended be younger, were older at onset and had experienced a quicker progression to SPMS. The overall proportion of clinically assigned SPMS patients on disease modifying treatments (DMTs) was 36% but varied greatly between registries (Czech Republic: 18%, Denmark: 35%, Germany: 50%, Sweden: 40%, and the United Kingdom: 12%) whereas a higher proportion of 69% (OR=4.0, P<0.00004) were on DMTs among RRMS patients re-assigned as SPMS (Czech Republic: 71%, Denmark: 68%, Germany: 78%, Sweden: 80%, and the United Kingdom 40%).

Conclusions

SPMS patients on DMTs may be clinically mis-classified as RRMS, most likely by not being re-assigned to SPMS after conversion has occurred. This challenges the use of time to SPMS conversion as an outcome in comparative effectiveness studies using real world evidence data and argues for the use of objective classification tools in the analysis of MS patient populations.

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Author Of 12 Presentations

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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Epidemiology Poster Presentation

P0482 - Objective classification methods result in an increased proportion of secondary progressive multiple sclerosis in five patient registries (ID 1120)

Abstract

Background

Secondary progressive MS (SPMS) is a research area that is attracting more attention as better treatment options are still needed for this patient group. The assignment of SPMS by clinicians can differ between countries and may be influenced by drug prescription guidelines, reimbursement issues and other societal limitations.

Objectives

To compare the clinically assigned SPMS proportion to three objective SPMS classification methods in five MS registries.

Methods

Data from MS registries in the Czech Republic (CR) (11,336 patients), Denmark (10,255 patients), Germany (23,185 patients), Sweden (11,247 patients) and the United Kingdom (UK) (5,086 patients) were used. Inclusion criteria were patients with relapsing remitting (RR)MS or SPMS with age ≥ 18 years at the beginning of the index period (1 January 2017 – 31 December 2019). In addition to clinically assigned SPMS three different classification methods were applied; method 1: modified real world EXPAND criteria (Kappos et al, Lancet 2018:391; 1263-1273), method 2: the data-derived definition from Melbourne University without the pyramidal Functional Systems Score (Lorscheider et al, Brain 2016:139; 2395-2405) and method 3: the decision tree classifier from Karolinska Institutet (Ramanujam, R. et al., 2020. medRxiv, 2020.07.09.20149674).

Results

The SPMS proportions per registry, when comparing the clinically assigned SPMS with the results of the three classification methods, were CR: 8.8%, 21.3%, 22.1%, 25.0%; Denmark: 15.5%, 27.5%, 25.4%, 28.0%; Germany: 15.6%, 15.4%, 16.7%, 25.4%; Sweden: 23.7%, 20.8%, 23.2%, 24.6% and UK: 34.3%, 21.7%, 38.4%, 58.3% for clinical SPMS and methods 1, 2 and 3, respectively.

Conclusions

The proportion of clinically assigned SPMS patients varies between MS registries. When applying other classification methods, the SPMS proportion generally increases but remains variable between registries. As some of the classification methods have extensive requirements regarding data density, the number of unclassifiable samples created are considerable for some of the registries, which will influence the results. Providing a classification method that depends on objective information could prove useful when attempting to estimate the proportion of SPMS patients in MS populations but the choice of method may depend on the data characteristics of the individual MS registry.

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Imaging Poster Presentation

P0572 - Evaluation of cerebellar function scores in relation to cerebellar axonal loss in multiple sclerosis. (ID 933)

Speakers
Presentation Number
P0572
Presentation Topic
Imaging

Abstract

Background

Damage to the cerebellum is common in people with multiple sclerosis (pwMS) and associated with a worse prognosis and, cerebellar relapses are associated with poorer recovery and earlier onset of progressive disease. Studies examining the importance of the cerebellum are hampered by incomplete characterisation of cerebellar damage and its relation to cerebellar function.

Objectives

We aim to examine axonal loss in the cerebellum using diffusion imaging and compare the degree of cerebellar axonal loss with cerebellar dysfunction in pwMS.

Methods

We prospectively recruited 55 pwMS and 14 healthy controls (HC). Clinical assessments included scale for the assessment and rating of ataxia (SARA) and Bain tremor ratings. Subjects underwent 3-tesla volumetric, lesion and diffusion magnetic resonance imaging. Cerebellar axonal loss was examined with fibre-specific markers. Fibre density and cross-section (FDC) accounts for microscopic and macroscopic changes in a fibre bundle.

Results

Significant loss of cerebellar FDC was found in pwMS compared to HC (p=0.03). Lower FDC was associated with increased SARA (r=-0.42, p<0.01) and tremor severity (rho=-0.35, p=0.01). Cerebellar lesion volume correlated with SARA (r=0.49, p<0.01) and tremor severity (rho=0.41, p=0.01). Cerebellar volume showed no correlation with cerebellar clinical assessments.

Conclusions

Fibre-specific measures of cerebellar pathology could provide a functionally relevant marker of cerebellar damage in pwMS. Future trials using fibre-specific markers are needed to further characterise cerebellar pathology and understand its significance in disease progression.

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Imaging Poster Presentation

P0582 - High resolution functional mapping of upper and lower limb sensorimotor function in minimally disabled people with multiple sclerosis using 7T MRI (ID 1050)

Speakers
Presentation Number
P0582
Presentation Topic
Imaging

Abstract

Background

In multiple sclerosis (MS) upper and lower limbs can be affected, but impairments only moderately relate to each other. Previous motor task studies have focussed predominantly on imaging hand function at clinical field strengths, preventing the detection of subtle changes and differentiation of mechanisms underlying subtle motor impairment.

Objectives

To investigate functional brain changes related to upper and/or lower limb motor task performance in minimally disabled MS patients using ultra-high field MRI.

Methods

Twenty-eight MS patients and seventeen healthy controls underwent visually-guided force-matching fMRI tasks using either hand or foot. Task performance (force error and lag) and activation level during upper and lower limb movements were compared between groups. Correlations were assessed between task activation and behavioural performance.

Results

During lower limb force tracking, MS patients showed significantly (p<0.01) longer lag, higher force error, higher primary motor and premotor cortex activation and lower cerebellar Crus I/II activation, compared to controls. No differences were seen in upper limb performance or activation. Upper and lower limb task performance was related to the level of activation in cerebellar, visual and motor areas in MS patients.

Conclusions

Altered lower limb movements and brain activation with preserved upper limb function and activation in minimally disabled patients suggests partially divergent functional mechanisms underlying upper and lower limb disability.

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Imaging Poster Presentation

P0626 - Quantitative Susceptibility Mapping at 7 Tesla detects ongoing active lesions in relapse-free RRMS patients (ID 1540)

Abstract

Background

Microglia are iron-rich cells, found surrounding multiple sclerosis (MS) lesions in areas of active inflammation. Quantitative Susceptibility Mapping (QSM) can detect this increased iron and thus could be a novel MRI biomarker for microglia-associated inflammation in the brain. The proportion of patients with active inflammation is currently unknown, as is the proportion of MS lesions seen on conventional MRI sequences that are active across patients. Ultra-high field MRI (7 Tesla +) provides superior signal to noise and susceptibility contrast making it the optimal method for detecting iron in MS lesions and tracking active inflammation.

Objectives

To compare the number of lesions with positive QSM signal indicating active inflammation with lesion size and number in patients with relapsing-remitting MS (RRMS) using 7T MRI.

Methods

21 people with RRMS (mean ± SD age = 42 ± 11 yrs; sex: 2m/19f; mean ± SD disease duration = 5.5 ± 3.2 yrs; all EDSS < 4; no relapses in previous 12 months) were scanned using MP2RAGE anatomical and multi-echo gradient echo sequences on a Siemens 7T MAGNETOM MRI scanner. MP2RAGE was used to identify lesions and then co-registered to QSM (calculated from gradient echo phase images using an in-house pipeline). The number of lesions with an average QSM value over 0 (QSM+), indicating the presence of iron associated with active inflammation, were compared to the total number and total volume (log10 transformed) of lesions across patients using linear regression.

Results

The number of lesions in patients ranged from 3 to 92 (mean ± SD = 33 ± 25) and volumes ranged from 26 to 14505 mm3 (mean ± SD = 2554 ± 3445 mm3). Across all patients, the average proportion of QSM+ lesions was 0.61 (95% CI = 0.50-0.72, R2=0.87, p<0.0001), and for each log10 cubic millimeter change in the lesion volume, there were an additional 15 QSM+ lesions (95% CI = 7.0-24, R2=0.43, p=0.0012). There were no associations between the proportion of QSM+ lesions and any disease or demographic variables.

Conclusions

Irrespective of disease severity or duration, the proportion of QSM+ lesions was highly consistent. Based on the assumption that QSM+ lesions are undergoing active inflammation, our results indicate that around ~60% of lesions in RRMS patients could be active.

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Imaging Poster Presentation

P0636 - Relationship of real-world brain atrophy to MS disability using icobrain: 4 centre pilot study (ID 716)

Abstract

Background

To date, no studies have explored the relationship between brain atrophy and MS disability using differing MRI protocols and scanners at multiple sites.

Objectives

To assess the association between brain atrophy and MS disability, as measured by EDSS and 6-month confirmed disability progression (CDP).

Methods

In this retrospective study at 4 MS centres, a total of 1300 patients had brain MRI imaging assessed by icobrain. Relapse-onset MS patients were included if they had two clinical MRIs 12 (±3) months apart and ≥2 EDSS scores post MRI-2, the first ≤3 months from MRI-2, with ≥6 months between first and last EDSS. Volumetric data were analysed if the alignment similarity between two images was as good as that of same-scanner scan-rescan images (normalised mutual information ≥0.2). The percentage brain volume change (PBVC), percentage grey matter change (PGMC), FLAIR lesion volume change, whole brain volume, grey matter volume, FLAIR lesion volume and T1 hypointense lesion volume at MRI-2 were calculated. Ordinal mixed effect models were used to determine the association between these volumetric MRI measures and all EDSS scores post MRI-2. Cox proportional hazards models were used for the 6-month CDP outcome, using a subset of patients with ≥3 EDSS. Models were adjusted for proportion of time spent on disease-modifying therapy during MRIs ± whole brain/grey matter volume at baseline MRI.

Results

Of the 260 relapse-onset MS patients included, 204 (78%) MRI pairs were performed in the same scanner and 56 (22%) pairs were from different scanners. During the follow-up period (median 3.8 years, range 1.3-8.9), 29 of 244 (12%) patients experienced 6-month CDP. There was no evidence for association between annualised PBVC or PGMC and CDP or EDSS (p>0.05). Cross-sectional whole brain and grey matter volume (at MRI-2) tended to associate with CDP (HR 0.99, 95% CI 0.98-1.00, p=0.06). Every 1ml of whole brain or grey matter volume lost represented a 1% higher chance of reaching 6-month CDP. Only whole brain volume (at MRI-2) was associated with EDSS score (β -0.03, SE 0.01, p<0.001) and the slope of EDSS change over time (β -0.001, SE 0.0003, p=0.02). On average, every 33ml reduction of brain volume was associated with a 1 step increase in EDSS.

Conclusions

In this real-world clinical setting where a fifth of the brain atrophy analysis were performed on different scanners, we found no association between individual brain atrophy and MS disability. However, there was an association between cross-sectional whole brain volume with EDSS and slope of EDSS change.

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Neuropsychology and Cognition Poster Presentation

P0803 - Discriminating Spatialised Speech in Complex Environments in Multiple Sclerosis (ID 1538)

Speakers
Presentation Number
P0803
Presentation Topic
Neuropsychology and Cognition

Abstract

Background

Multiple Sclerosis (MS) is a multi-component disease where inflammatory and neurodegenerative processes disrupt wide-ranging cerebral systems, including auditory networks. Although cochlear hearing loss is uncommon, people with MS (pwMS) frequently report deficits in binaural hearing, which involves integration of sound inputs to both ears, for using acoustic spatial localization and disambiguating important signals from competing sounds. Spatial processing deficits have been described in pwMS using localization tasks of simple tones presented in silence but have yet to be evaluated in realistic listening situations, such as speech emanating from various spatial locations within a noisy environment.

Objectives

To investigate how pwMS discriminate speech appearing to emanate from different spatial positions, in background competing conversation.

Methods

Pre-recorded everyday sentences from a standard list (Bamford-Kowal-Bench sentences) were presented via headphones with virtual acoustic techniques used to simulate as if they originated from 0⁰, 20⁰ and 50⁰ on the azimuth plane around the listener. Simultaneous eight talker babble was presented as if emanating from 0⁰. Controls (n=20) and age-matched pwMS with mild (Expanded Disability Status Scale (EDSS) score < 2; n = 23), moderate (EDSS 2.5 – 4.5; n = 16) and advanced disability (EDSS 5 – 7; n = 8) were required to repeat the target sentence. Mild pwMS also completed the Paced Serial Addition Test (PASAT) and a basic three alternative forced-choice spatial task of detecting interaural time differences (a binaural spatial cue) in noise bursts. All participants passed a standard hearing evaluation.

Results

Sentence intelligibility increased for all listeners when speech was spatially separated from noise at 20⁰ and 50⁰ azimuth compared to when stimuli was colocalized at 0⁰ with the noise. A mixed-effects model confirmed that a one-unit increase in spatial separation increased the odds of discriminating the correct sentence for controls by 5%, but only 3% for moderate and advanced pwMS. Spatial processing in mild pwMS was comparable to controls in both the complex babble environment and the basic three-alternative noise burst task. PASAT scores moderately correlated with discrimination scores in colocalized conditions (0⁰) (r = 0.5, p < 0.01) and strongly in the largest separated condition (50⁰) (r = 0.7, p < 0.0001).

Conclusions

Knowing the spatial location of a sound is particularly critical in a complex noisy environment, as spatial cues help to group ambiguous sound elements into coherent streams. Although pwMS were able to use spatial cues, those with moderate and advanced disability did not receive the same spatial release from noise as controls. As spatial perception has largely been studied only in the visual domain, this is the first study to investigate how pwMS navigate their acoustic surroundings and communicate in noisy social environments.

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Neuropsychology and Cognition Poster Presentation

P0831 - Validation of longitudinal reaction time trajectories in multiple sclerosis using the MSReactor computerized battery and latent class analysis. (ID 1660)

Speakers
Presentation Number
P0831
Presentation Topic
Neuropsychology and Cognition

Abstract

Background

Longitudinal cognitive trajectories in MS are heterogenous and difficult to measure. Computerised tests designed to screen broad cognitive domains may be a reliable method to detect discrete trajectories of cognitive performance

Objectives

To validate a latent class model to identify trajectories of reaction time change in people with relapsing remitting MS (pwRRMS).

Methods

The MSReactor computerised cognitive battery is a self-administered, online set of reaction time tasks assessing psychomotor function (PsychoM), visual attention (VisAtt) and working memory (WorkingM). Participants completed both 6-monthly in-clinic testing and additional remote testing. Latent class analysis was used to model the longitudinal reaction times and identify discrete cognitive trajectories within the heterogeneous data. We applied a cross validation method to confirm the optimal models for all three reaction time tasks. Briefly, the cohort was split into training and test sets (50:50) and the mean root mean square error (RMSE) calculated for the difference between training and test trajectories calculated at each day of follow up, over 100 repetitions. To determine the minimum number of tests required to reliably classify an individual into a longitudinal trajectory the dataset for each task was reduced to 3, 4 and 5 tests per participant and classification compared to the complete dataset.

Results

We included 478 pwRRMS who had completed at least 3 MSReactor tests over a minimum of 30 days follow up. In total, 3846 individual tests were included in each model (median tests/participant=5 (range 3-332), mean follow up of 774 +- 359.5 days). Three latent classes were identified for each task, with the PsychoM task identifying a group of pwRRMS with a mean predicted trajectory of slowing reaction times. In validation, the PsychoM task was the most consistent with the smallest RMSE for each of the 3 classes (68 milliseconds (ms), 95%CI 59-77ms; 61ms, 95% CI 50-72ms and 16ms, 95% CI 14-18ms) followed by the VisAtt task (RMSE = 114ms, 95ms and 29ms) and WorkingM task (RMSE = 137ms, 138ms and 46ms). Reduced datasets of 3, 4 and 5 tests per participant in the PsychoM task were able to classify participants into the trajectories identified in the full dataset model, with 83%, 86% and 90% accuracy respectively.

Conclusions

Latent class modelling of longitudinal reaction times collected with MSReactor was able to detect discrete trajectories of cognitive performance. The PsychoM task latent class model identified a group of RRMS with a mean predicted slowing of reaction times and was the most consistent model in cross validation. Performing the modelling on just 3, 4 or 5 tests per participant was highly accurate in defining latent trajectories, giving the battery clinical utility where multiple years of follow up may not be realistic.

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Observational Studies Poster Presentation

P0862 - Disability accrual in primary-progressive & secondary-progressive multiple sclerosis (ID 1232)

Abstract

Background

Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS.

Objectives

We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016).

Methods

Inclusion required adult-onset progressive MS; ≥ 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS ≤ 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if ≥ 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over ≥ 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS ≥ 7 (wheelchair required) was assessed (Kaplan-Meier).

Results

5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 ± 10.2, vs. 41.5 ± 10.7 [mean ± SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78–0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98–0.99); and higher in males (1.18; 1.12–1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71–0.87) but similar for PPMS-A (1.01; 0.93–1.10) and SPMS-N (0.94; 0.85–1.05). Sensitivity analyses corroborated these results. However, patients with SPMS-A reached EDSS ≥ 7 at younger ages (cumulative probability 30% by 57, vs. 64–66 for SPMS-N, PPMS-A, PPMS-N).

Conclusions

Progressive phase onset is later in SPMS than PPMS. Hazard of disability accrual during the progressive phase is lower in SPMS than PPMS. However, patients with SPMS-A reach wheelchair requirement younger than other progressive phenotypes, reflecting earlier progression onset versus SPMS-N, and greater disability at onset versus PPMS

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Observational Studies Poster Presentation

P0907 - Real-world experience with Cladribine Tablets in the MSBase Registry (ID 1587)

Abstract

Background

Cladribine tablets are approved for treatment of multiple sclerosis (MS) in many jurisdictions. Real-world outcomes data is very limited.

Objectives

We analysed the cladribine treatment experience in the MSBase registry. We described baseline characteristics, treatment pathways, and relapse and discontinuation outcomes in patients with ≥6 months follow-up data from cladribine initiation.

Methods

We performed a secondary data analysis using MSBase Registry data of patients with a confirmed diagnosis of MS and newly treated with cladribine tablets after regulatory approval. Descriptive statistics were used to analyze baseline patient characteristics recorded within 3 months prior to cladribine tablets initiation, including demographics, disease course and duration, prior disease modifying drugs (DMD), and Expanded Disability Status Scale (EDSS).

Results

As of the 4th June 2020, MSBase included 660 patients treated with cladribine from 9 countries, mainly from Australia and Europe. A total of 576 met all inclusion criteria. These included 496 relapsing-remitting MS (RRMS) patients. In these, median age at cladribine tablets start was 45 years and median disease duration since clinically isolated syndrome was 12.6 years. Median EDSS at cladribine tablets start was 2.5. Around 13% of all RRMS patients initiated cladribine tablets as first line therapy. Of all RRMS patients switching to cladribine tablets with a treatment gap of <6 months, the most common immediate prior DMDs were fingolimod (17%), followed by natalizumab, teriflunomide and dimethylfumarate (all appx. 10%). Total follow-up time was 340 patient-years. Annualised relapse rate (ARR) on cladribine tablets was 0.12 (95%CI 0.09-0.17), compared to a pre-cladribine ARR of 0.38. Treatment persistence was 95% after 12 months (95%CI 91-98%), and 92% after 24 months (95%CI 87-96%).

Conclusions

This study characterizes RRMS patients treated with cladribine tablets in a real-world clinic setting. First-line use was uncommon. ARR was low, consistent with clinical trial data, and early discontinuations were very rare.

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Observational Studies Poster Presentation

P0909 - Real-world experience with Ocrelizumab in the MSBase Registry (ID 1559)

Abstract

Background

Ocrelizumab (OCR) is a humanised anti-CD20+ monoclonal antibody approved for the treatment of primary progressive multiple sclerosis (PPMS), and relapsing forms of MS, including both relapsing-remitting (RRMS) and secondary progressive MS (SPMS) with relapses.

Objectives

In a real-world setting, to describe 1) baseline characteristics of patients with MS treated with OCR, 2) treatment pathway across lines of therapy up to initiation of OCR, and 3) initial clinical experience in patients with ≥6 months follow-up data from OCR initiation.

Methods

Secondary data analysis using MSBase Registry data including patients with a confirmed diagnosis of MS and started OCR therapy within 3 months prior to or at time of MSBase eligible/initial visit. Descriptive statistics were used to analyze baseline patient characteristics' recorded within 3 months of OCR initiation, including demographics, disease course and duration, prior disease modifying therapies (DMT), and EDSS. Occurrence of relapse was analyzed in patients with ≥6 months follow-up data from OCR initiation.

Results

As of 4th June 2020, MSBase included 2531 patients newly treated with OCR, of whom 1679 had an EDSS evaluation within 3 months of OCR start. There were 1185 patients with RRMS, 236 with SPMS, and 183 with PPMS. Median age at OCR initiation was 41.9 years, 49.5 years, to 50.1 years in RRMS, SPMS, and PPMS, respectively. Mean disease duration from symptom onset up to OCR initiation was longer in SPMS (19.7 years) than in RRMS (10.6 years) and PPMS (9.7 years). OCR was initiated as first line therapy in 17.5%, 5.5%, and 54.2% of RRMS, SPMS, and PPMS patients respectively. Most frequent previous DMT’s in RRMS were fingolimod (25.7%) and natalizumab (23.5%). 693 patients with RRMS had ≥6 months follow-up during OCR exposure. Of these, 643 remained relapse free (93%; 95% CI 86.0, 100.0) over a mean OCR exposure of 1.23 years. The annualized relapse rate (ARR) was 0.08 (95% CI 0.06-0.10), compared to an ARR of 0.85 in the 24 months pre-OCR start. In the overall cohort, treatment persistence at 12 and 24 months was 98.4% (95% CI: 97.3-9.1%) and 92.5% (95%CI 89-95%), respectively.

Conclusions

This study characterizes an international population of patients with RRMS, PPMS, and SPMS newly treated with OCR in a real-world clinical setting. First-line use was uncommon in RRMS and SPMS. During OCR treatment, ARR was below 0.1, and OCR discontinuations were very rare.

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Reproductive Aspects and Pregnancy Poster Presentation

P1131 - Pregnancy in a modern day multiple sclerosis cohort: Predictors of postpartum relapse and disability progression (ID 1321)

Abstract

Background

Disease activity has been investigated in pregnant women with RRMS treated with low-efficacy or no therapy. How newer, more efficacious therapies affect relapse and disability progression risk after pregnancy remains understudied.

Objectives

To describe disease activity in a modern pregnancy cohort contrasted with historical cohorts. To determine the predictors of postpartum relapse and the predictors of six-month confirmed disability progression events in a contemporary pregnancy cohort.

Methods

Data were obtained from the MSBase Registry. Term/preterm pregnancies conceived from 2011-2019 (modern cohort) were compared with those conceived between 2005-2010 and pre-2005. Annualised relapse rates (ARR) were calculated for each pregnancy trimester and 12 months either side. Predictors of time-to-relapse postpartum (1st 3 months) and time to 6-month confirmed disability progression event were determined with clustered Cox regression analyses. Breastfeeding duration and time to DMT reinitiation were modelled as time-varying covariates.

Results

We included 1640 pregnancies from 1452 women (modern cohort). Disease-modifying therapy (DMT) used in the year before conception included interferon-beta (n=597), natalizumab (n=219) and fingolimod (n=147). Continuation of DMT up to conception increased over time (31% pre-2005 vs 54% modern cohort). Preconception ARR decreased across epochs (pre-2005: 0·58 [95% CI 0·49-0·70]; 2005-2010: 0·40 [95% CI 0·36-0·45]; modern: 0·29 [95% CI 0·27-0·32]). In all epochs, ARR decreased during pregnancy to reach similar troughs in the 3rd trimester, and rebounded in the 1st 3-months postpartum. Preconception use of high-efficacy DMT predicted early postpartum relapse (hazard ratio (HR) 2.1 [1.4-3.1]); although those on no DMT were also at risk of postpartum relapse, relative to women on low-efficacy DMT (HR 2.7 [1.2-5.9]). Conception EDSS 2, higher preconception and in-pregnancy ARR were also risk factors. DMT reinitiation, particularly of high-efficacy DMT (HR 0.17 [0.07-0.38]), was protective against postpartum relapse. Women who breastfed were less likely to relapse (HR 0.63 [0.42-0.94]). 4.5% of modern pregnancies had confirmed disability progression after delivery. This was predicted by higher pregnancy and postpartum ARR, with postpartum ARR remaining independently predictive in multivariable analysis (HR 1.5 [1.2-2.0]).

Conclusions

The early postpartum period remains a period of vulnerability for disease rebound in women with MS in the modern era. Early DMT reinitiation, particularly with high-efficacy treatment, is protective against postpartum relapse. Confirmed disability progression events after pregnnacy are uncommon in the modern era. Relapse activity is the key driver of these events.

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Presenter Of 1 Presentation

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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