Background

NMOSD is an autoimmune disorder characterized by acute, unpredictable relapses that result in accumulating disability. Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced relapse frequency and had a favourable safety profile vs placebo in two randomized, phase 3 clinical trials: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To assess the impact of satralizumab on relapse severity in patients with NMOSD.

Methods

Patients in the SAkura studies received satralizumab 120mg or placebo at Weeks 0, 2, 4, and Q4W thereafter. This analysis was performed using data from the pooled intention-to-treat population across the double-blind periods of both studies. We assessed the severity of protocol-defined relapses (PDRs) by comparing patients’ Expanded Disability Status Scale (EDSS) score at PDR vs their score prior to relapse (last scheduled study visit). A similar analysis on optic neuritis PDRs was performed using visual Functional Systems Score (FSS). A PDR was categorised as severe if it resulted in a change of ≥2 points on the EDSS or visual FSS (optic neuritis analysis). Kaplan-Meier analyses were performed to assess time to first severe PDR. Additionally, the number of patients receiving acute therapy for any relapse was compared between treatment groups.

Results

Overall, 178 patients were included in the analyses. In the satralizumab group, 27 of 104 patients (26%) experienced a PDR vs 34 of 74 patients (46%) in the placebo group. The proportion of PDRs that were severe was lower in patients receiving satralizumab vs placebo (5 of 27 events [19%] vs 12 of 34 events [35%]). Similarly, the proportion of optic neuritis PDRs that were severe was lower in patients receiving satralizumab vs placebo (2 of 8 events [25%] vs 5 of 13 events [39%]). Across all patients, there was a 79% reduction in severe PDR risk with satralizumab vs placebo (hazard ratio [95% CI]; 0.21 [0.07–0.61]; p=0.002). A lower proportion of patients receiving satralizumab were prescribed acute relapse therapy vs placebo (38% vs 58%; odds ratio [95% CI] 0.46 [0.25–0.86], p=0.015).

Conclusions

Patients treated with satralizumab had a lower risk of severe relapse, and were less likely to receive acute relapse therapy compared with placebo. The number of patients with severe PDRs was low, so results should be interpreted with caution.

Background

In multiple sclerosis (MS), thalamic integrity is affected both directly by demyelination, neuronal loss and increasing iron concentration, and indirectly by remote gray and white matter lesions affecting neural projections into and out of the thalamus. Thalamic atrophy may therefore reflect a large fraction of MS-related brain damage and thus represent a useful marker of overall damage and therapeutic efficacy.

Objectives

To assess the efficacy of ocrelizumab (OCR) in patients switching to or maintaining OCR therapy on thalamic atrophy in patients with relapsing MS (RMS) and primary progressive MS (PPMS), participating in the OPERA I/II (NCT01247324/NCT01412333) and ORATORIO (NCT01194570) Phase III trials, respectively.

Methods

At the end of the double-blind controlled treatment period in OPERA I/II, patients entered the open‑label extension (OLE), and either continued to receive OCR (OCR-OCR) or switched from interferon β-1a (IFN β-1a) to OCR (IFN β-1a-OCR). In ORATORIO, patients entered the OLE ~3–9 months after the double-blind period cut-off and either continued OCR (OCR-OCR) or switched from placebo (PBO) to OCR (PBO-OCR). Changes in thalamic volume from the core trial baseline were computed using Jacobian integration and analyzed using a mixed-effect repeated measurement model, adjusted for baseline volume, age, baseline gadolinium-enhancing lesions (presence/absence), baseline T2 lesion volume, region (US vs rest of the world), Expanded Disability Status Scale category (<4, ≥4), week, treatment, treatment and time interaction, and treatment and baseline volume interaction.

Results

In the OLE of OPERA I/II, changes (%) in thalamic volume from baseline at OLE Week 46, 94, 142, 190, and 238, were: –2.88/–2.12 (p<0.001), –3.31/–2.36 (p<0.001), –3.61/–2.78 (p<0.001), –3.68/–3.03 (p<0.001), and –4.07/–3.41 (p<0.001), for IFN β-1a-OCR/OCR-OCR patients, respectively. During the OLE of ORATORIO, changes in thalamic volume at OLE Day 1, Week 48, 96, and 144, were: –3.46/–2.44 (p<0.001), –3.93/–2.61 (p<0.001), –4.30/–3.25 (p<0.001), and –4.86/–3.62 (p<0.001), for PBO-OCR/OCR-OCR patients, respectively.

Conclusions

In the OLE, patients with RMS and PPMS who were initially randomized to ocrelizumab experienced less thalamic volume loss compared with those initiating ocrelizumab later.

Background

Background: An improved understanding of the impact of demyelination on multiple sclerosis (MS) related cognitive impairment is crucial for targeting and testing therapies with the potential to slow cognitive decline. Demyelination can be assessed using myelin water imaging, a quantitative magnetic resonance imaging (MRI) technique that measures signal from water in the myelin bilayers, providing a specific measure of myelin (myelin water fraction, MWF).

Objectives

Objective: To determine if there is an anatomical-functional relationship between myelin content and location with cognitive performance.

Methods

Methods: 76 MS participants (mean (SD) age:50.4y(10.6y), 51F) underwent T2 relaxation imaging to calculate MWF maps and cognitive testing (Symbol Digit Modalities Test (SDMT); Selective Reminding Test (SRT); Controlled Oral Word Association Test (COWAT); Brief Visuospatial Memory Test-Revised (BVMT-R)). Nonparametric permutation testing with FSL Randomise was used to determine which white matter (WM) MWF voxels were associated with cognitive test performance for each test (p<0.01, after multiple comparisons correction), creating test-specific maps of associated WM areas. Pearson ́s correlations assessed relationships between mean MWF in the cognitive test-specific WM areas and respective test scores. MS patients were categorized into cognitively impaired, mildly impaired and cognitively preserved groups based on published norms. Kruskal Wallis ANOVA with post hoc pairwise comparisons investigated mean MWF differences between cognitive groups.

Results

Results: MWF in several WM areas was significantly associated with SDMT, SRT and BVMT-R scores but not the COWAT. All tests found voxels within the corona radiata, posterior thalamic radiation and parts of the corpus callosum significant. Unique WM areas were the inferior longitudinal fasciculus and anterior cingulum for SDMT and the retrolenticular part of the internal capsule for the BVMT-R. Mean MWF in the test-specific WM areas correlated significantly with performance on the SDMT (r=0.58, p= 4.11 x 10^-8), SRT (r=0.56, p= 4.14 x 10^-7) and BVMT-R (r=0.56, p= 1.0 x 10^-6). Mean MWF in the test-specific WM areas was significantly lower in the cognitively impaired group relative to the cognitively preserved group (p<0.01).

Conclusions

Conclusions: There is an anatomical-functional relationship between myelin damage and cognitive performance in MS with unique WM patterns for different cognitive domains.

Background

Limiting MS progression requires characterization of the pathological processes that distinguish disease subtypes that progress from those that do not. CD5 antigen-like (CD5L) protein is predominantly macrophage-secreted with roles in modulating inflammation, lipid metabolism, and inhibiting cell apoptosis. Previous studies have found serum CD5L levels tend to decrease with age in healthy individuals yet are elevated in inflammatory conditions including chronic infections, psoriatic arthritis, and systemic lupus erythematosus.

Objectives

To compare serum CD5L levels in healthy controls (HC) to individuals with relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and clinically isolated syndrome (CIS).

Methods

The study cohort included 35 HC, 20 CIS, and 83 clinically definite MS (CDMS: 33 RRMS, 30 SPMS, 20 PPMS) participants recruited at the University of British Columbia MS clinic. Serum CD5L levels were assessed with a commercial enzyme-linked immunosorbent assay. Correlation, univariate and multivariate linear regression analyses were used to determine the relationship between CD5L levels and age, sex, disease duration (DD), and expanded disability status scale (EDSS).

Results

Compared to HC (median [IQR], 4.2 [2.8-6.3] μg/ml), SPMS had elevated serum CD5L (7.0 [4.6-8.5] μg/ml, p=0.0006). There were no differences between HC and RRMS (4.8 [3.5-5.8] μg/ml) or PPMS (4.3 [3.3-5.8] μg/ml), and CIS tended to have higher CD5L (5.1 [4.0-7.5] μg/ml, p=0.45). PPMS CD5L levels were low compared to SPMS (p=0.02), but this was not due to differences in age between subtypes. CD5L levels tended to correlate negatively with age in HC (p=0.06), but not in RRMS, SPMS, and PPMS. In contrast, CD5L levels correlated positively with age in the CIS group (p=0.03). Multivariate (p=0.009) and univariate (p=0.002) analyses showed increased CD5L in CDMS was associated with longer DD rather than differences in age, sex, or EDSS. Univariate analysis showed the pattern of increased CD5L in CDMS with longer DD seems to be driven mostly by SPMS (p=0.16).

Conclusions

Our studies suggest that CD5L titers could reflect differences underlying neurological mechanisms in PPMS and SPMS. The positive relationship between CD5L and DD in SPMS points to a distinct and chronic peripheral inflammatory profile compared to other subtypes. Further studies are needed to characterize the processes driving CD5L expression in MS and its potential utility as a biomarker of MS progression.

Background

Susac’s Syndrome (SuS) is a rare autoimmune endotheliopathy of the brain, retina and cochlea that mimics multiple sclerosis (MS). Lesions presumed to be microinfarcts classically involve the corpus callosum (CC). While one brain biopsy reported demyelination, and MRI studies have shown reduced fractional anisotropy in the CC, the specific processes underlying SuS pathology are not yet clear. Myelin water imaging (MWI) and diffusion basis spectrum imaging (DBSI) can provide information about microstructural changes occurring in SuS. MWI provides a quantitative measurement of myelin, termed the myelin water fraction (MWF). DBSI yields various physiologically relevant metrics characterized by water diffusion: the apparent diffusion coefficient (ADC) which relates to overall tissue damage; fractional anisotropy (FA), which decreases with white matter (WM) damage; and radial diffusivity (RD) which increases with myelin loss.

Objectives

Determine in vivo WM microstructural changes in Susac Syndrome compared to MS and healthy controls (HC) using MWI and DBSI.

Methods

Participants included 7 SuS patients following the proposed European Susac Consortium diagnostic criteria (mean age 43.3y (30-78y), 6F), 10 MS patients (mean age 43.2y (26-70y), 9F) and 10 HC (MWI: 44y (27-64y), 9F, DBSI: 35.9y (22-47y), 5F). 3T MRI included MWI (48-echo 3D GRASE sequence), DBSI (9 b-values, 0-1500 s/mm², 99 directions) and a 3DT1 for anatomical reference. The CC and global WM (non-lesional tissue) were segmented and registered using FSL and the JHU atlas. One-way ANOVA with Tukey correction compared CC and global WM between groups.

Results

CC: SuS MWF (0.09±0.01) was lower than MS (0.11±0.02, p=0.03) and trending lower than HC (0.11±0.02, p=0.07). SuS ADC (0.84 ± 0.08 x 10^-3μm²/ms) was higher than MS (0.73±0.04 x 10^-3μm²/ms, p<0.001) and controls (0.71±0.04 x 10^-3μm²/ms, p<0.001). SuS FA (0.82±0.02) was lower than HC (0.86±0.02, p= 0.02). SuS RD was higher (0.27±0.03 x 10^-3μm²/ms) than HC (0.21±0.01 x 10^-3μm²/ms, p=0.004) and trending higher than MS (0.23±0.05 x 10^-3μm²/ms, p=0.05).

Global WM: ADC and RD findings in the Global WM were similar to CC, i.e. ADC and RD were significantly higher in SuS compared to MS and HC (all p<=0.03). However, MWF and FA was insignificantly different between the groups.

Conclusions

We report the first use of MWI in SuS. Both CC and the global WM showed non-lesional myelin damage, which was more severe than MS.

Background

Deep grey matter (DGM) atrophy is a feature in all multiple sclerosis (MS) phenotypes. Studies have shown a strong relationship between DGM atrophy and clinical worsening but the utility of DGM volumes for predicting disease activity is largely unexplored, especially in early disease. Machine learning (ML) is a computational approach that can identify patterns that predict disease outcomes. In ML, the study dataset is divided into training and test subsets. The training set contains known outcomes, which the ML algorithm uses to form a prediction model, which is then evaluated on the test set.

Objectives

To develop an ML model for predicting new disease activity (clinical or MRI) within 2 years of a first clinical demyelinating event, using baseline DGM volumes. The motivation is to identify individuals at higher risk of new disease activity.

Methods

3D T1-weighted MRIs acquired within 90 days of a first clinical event in 140 subjects from a completed placebo-controlled trial of minocycline were used. Eighty subjects had new disease activity within 2 years, 28 were stable, and 32 withdrew early (unknown outcome). The stable and unknown groups were combined into 1 for ML training. Advanced Normalization Tools and FMRIB Software Library were used to segment the thalami, putamina, globi pallidi, and caudate nuclei. A random forest ML model was trained to predict new disease activity with feature vectors composed of individual DGM nuclei volumes and several other variables (e.g., minocycline vs. placebo, mono-focal vs. multi-focal CIS, normalized brain volume, and sex). Model performance was evaluated using 3-fold cross-validation, with 80% of the data used for training, and the rest for testing.

Results

Sequential elimination of variables ranked the least important by the trained model resulted in improved classification accuracy. Therefore, the less predictive variables were pruned from the feature vector. The best model used DGM volumes alone and achieved 82.1% accuracy, 87% precision, 81% recall and F1-score of 0.84 with area under the curve (AUC) of 0.76.

Conclusions

ML can learn patterns predictive of new disease activity within 2 years after a first clinical demyelinating event from baseline DGM volumes. This approach can potentially augment the many other clinical and demographic variables used in a typical MS clinical work up. Further investigation with larger data sets is warranted to determine generalizability of the approach.

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.

Background

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines.

Objectives

The goal is to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination and implementation.

Methods

The CMSC convened an expert panel in October 2019 to update the standardized MRI protocol. Conference attendees included neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Representatives from CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocol, gadolinium, diffusion weighted imaging, and the central vein sign.

Results

95 neurologists completed the survey. 34% use the CMSC protocol. 48% use a standardized MRI protocol but are uncertain if it is similar to CMSC guidelines. 51% continue to use gadolinium for routine imaging. 58% wanted the central vein sign to be included in the diagnostic work up of MS. 87% were interested in monitoring brain volume and 10% were doing it routinely. The panel worked to harmonize CMSC and MAGNIMS MRI protocols so the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences and exam cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use.

Conclusions

The international expert group developed revised clinical MRI guidelines with the vision and action plans for them to be universally useful and useable and become the standard of care for patients with MS.

Background

Myelin water imaging can isolate the magnetic resonance imaging (MRI) signal from myelin water, providing a quantitative measure associated with myelin, termed the myelin water fraction (MWF), which has been validated in histopathologic studies. The amyloid tracer ¹¹C Pittsburg compound B (PiB) also has an affinity for myelin and its binding can be reduced in MS lesions compared to normal-appearing white matter (NAWM). We sought to determine whether these myelin-sensitive techniques provide overlapping or complementary information in MS.

Objectives

To determine (1) whether MWF and PiB binding are decreased in lesions compared to NAWM and (2) if there is a correlation between MWF andPiB binding.

Methods

Eleven participants (5 relapsing-remitting MS, 3 secondary progressive MS, 3 primary progressive MS) were scanned on a 3T Philips MRI scanner, and on a Siemens HRRT PET scanner with an injection of 18 mCi ¹¹C PiB. Two RRMS participants were treated with glatiramer acetate 40 mg subcutaneously three times per week. MRI scans included structural scans for tissue segmentation and a myelin water sequence for MWF calculation. PIB binding was quantified with the Logan method-derived non-displaceable binding potential (BP_ND) using healthy grey matter from cerebellum as reference region. Lesion masks included all lesions within the imaging volume. Regional mean values of MWF and BP_ND were determined for NAWM and lesions.

Results

Lesions showed a 38% decreased MWF and a 23% decreased BP_ND compared to NAWM (MWF: lesions=0.08±0.01 vs NAWM=0.13±0.02, p<0.0001; BP_ND: lesions=0.91±0.08 vs NAWM=1.18±0.07, p<0.0001). A correlation was found between MWF and BP_ND when including both NAWM and lesions (r=0.73, p=0.0001). However, there was no correlation when fitting for NAWM or lesions alone (NAWM: r=-0.51, p=0.06; lesions: r=0.39, p=0.23).

Conclusions

In this pilot study, lesions showed a decrease in both myelin water and PiB binding as expected in demyelinated tissue. The partial correlation between MWF and PIB BP_ND suggests that each technique might have different sensitivity for detecting the severity of demyelination in heterogeneously affected tissue. PIB BP_ND values in NAWM were relatively homogenous. PIB BP_ND was good at discriminating between NAWM and lesions. MWF showed more subtle differences in myelination in NAWM and lesions. PET-PiB imaging and MWF appear to provide reliable measures of myelin abnormality in MS lesions. MWF may be able to provide additional information on the heterogeneity of demyelination in lesions and NAWM.

Background

Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced patients’ risk of NMOSD relapse in the double-blind (DB) periods of two randomized, phase 3 clinical trials in NMOSD: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To assess the efficacy of satralizumab over a longer period of treatment, using data from the SAkura studies’ open-label extension (OLE) periods.

Methods

Patients entering SAkuraSky/Star were randomized to receive satralizumab 120mg or placebo at Weeks 0, 2, 4, and Q4W thereafter. After completing the DB period or experiencing a relapse, patients could enter the OLE period (same satralizumab dosing as DB period). The primary endpoint of both studies was time to first protocol-defined relapse (PDR) in the DB period, adjudicated by a Clinical Endpoint Committee (CEC). In this analysis, which includes OLE data (CEC adjudication unavailable), we assessed time to first investigator-reported PDR (any relapse considered by the investigator to meet PDR criteria) in the combined DB+OLE periods, using a pooled population from both studies.

Results

Overall, 179 patients were randomized to treatment (satralizumab n=105; placebo n=74), of whom 166 received ≥1 dose of satralizumab in the combined DB+OLE period. The median (range) satralizumab exposure in the DB period was 96.1 (8–224) weeks, and in the combined DB+OLE was 131.9 (13–276) weeks.

In the combined DB+OLE, patients originally randomized to satralizumab had a 51% lower risk of investigator-reported PDR vs those originally randomized to placebo (HR [95% CI] 0.49 [0.31–0.79]; P=0.002); the risk reduction was more pronounced in AQP4-IgG seropositive patients (66% risk reduction; HR [95% CI] 0.34 [0.19–0.62]; P<0.001). Patients who switched from placebo to satralizumab upon entry into the OLE period were included in the placebo group for this analysis, which likely reduced the observed treatment difference between satralizumab and placebo compared with the DB period.

No patients randomized to satralizumab withdrew from the OLE period due to a relapse, vs four patients who were originally randomized to placebo. The safety profile of satralizumab in the OLE was consistent with the DB period.

Conclusions

Across the DB and OLE periods of the SAkura studies, patients randomized to satralizumab had a significantly reduced risk of relapse vs placebo.

Background

People with antibodies to myelin oligodendrocyte glycoprotein (MOG) using reliable cell-based assays have heterogeneous course. Best management practices and outcome predictors are still uncertain.

Objectives

This study aimed to assess the treatment experience in a relapsing MOG positive cohort and the impact on disability accrual.

Methods

Retrospective chart review of (aquaporin4 negative) MOG antibody positive patients at University of British Columbia Multiple Sclerosis Clinic with relapsing disease, and minimum 1year follow-up.

Results

Of 49 MOG positive patients, 37(64.8% female) met inclusion criteria. Median age was 26 years (range 3-62; 10 pediatric cases) with median follow-up of 6years(range 1-36). Median time to second disease episode from first was 12 months (range 1-228); and to third (n=27) was 25 months (range 3-312). Median number total disease episodes was 3 (range 2-10).

For some, management decisions were initiated prior to MOG diagnosis. At first disease presentation 35/37 patients received acute therapy but only 1 started chronic therapy. First-line chronic therapies were later started in another 30 patients; in 35%(13/37) after second disease episode, and at the third in 27%(10/37). Most common were azathioprine(61%) and rituximab(19%). Sixteen patients(52%) required second line therapy, mostly due to adverse effects(62.5%) or disease activity(31%). Most common second line therapies were mycophenolate mofetil (MMF) or rituximab. Three patients required third line therapy.

17/37 patients had good outcome (EDSS<2) at last follow-up despite relapsing course, whilst 20(54%) had residual disability. Onset clinical phenotype distribution was similar between these two outcomes. 5% had persistent disability from disease onset, but mostly this developed from the second(19%) or third(16%) episode. 4/6 untreated patients had good outcome. Only 30% of the pediatric cohort vs 63% of the adult cohort had EDSS ≥2.0.

Conclusions

Chronic therapy was not typically started at disease onset, mostly due to initial absence of diagnosis. Azathioprine, MMF and rituximab were all effective therapies. Azathioprine was associated with high proportion of intolerance. Approximately half of patients recovered well from the initial episode; the rest accrued disability, typically from second or third disease episode, independent of clinical phenotype at onset. Further studies are required to identify factors influencing disability accrual, to enable earlier effective treatment in those at highest risk.

Background

Patients with neuromyelitis optica spectrum disorder (NMOSD) may experience severe disability after their incident (first) attack, with disability accumulating with subsequent relapses. Satralizumab, a humanized monoclonal antibody that inhibits the interleukin-6 receptor, reduced relapse frequency and had a favorable safety profile vs placebo in two randomized, placebo-controlled, phase 3 clinical trials in patients with NMOSD: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To review a case series of treatment-naïve, aquaporin-4-IgG seropositive (AQP4-IgG+) NMOSD patients who enrolled in SAkuraStar following their incident attack.

Methods

All instances of investigator-reported relapse were assessed in six treatment-naïve, AQP4-IgG+ NMOSD patients enrolled in SAkuraStar after their first attack. Relapses that met protocol-defined relapse (PDR) criteria are specified. Patients who experienced a PDR or remained in SAkuraStar when the double-blind period ended were eligible to enter the open-label extension (OLE). Expanded Disability Status Scale (EDSS) scores were recorded at regular intervals and at relapse.

Results

Of the six enrolled patients, two were randomized to placebo, and four to satralizumab. Demographic characteristics in these six patients were generally consistent with the overall SAkuraStar population. One of the two patients who received placebo experienced a PDR on Study Day 21, with a 1.5-point increase in EDSS score, and fully recovered to pre-relapse EDSS score. Two of the four patients who received satralizumab experienced a relapse. The first patient experienced a PDR on Study Day 214, with a 1-point increase in EDSS, and the second patient experienced a relapse (not meeting PDR criteria) on Study Day 458, with a 0.5-point increase in EDSS score. Both patients fully recovered to pre-relapse EDSS score.

Five of six patients continued in the ongoing OLE, and no further relapses were reported (up to March 2020). Safety outcomes were consistent with the overall SAkuraStar safety population.

Conclusions

Treatment-naïve AQP4-IgG+ patients enrolled in SAkuraStar after their incident attack and randomized to placebo experienced a relapse earlier than those randomized to satralizumab. All patients fully recovered to pre-relapse EDSS score. Interpretation is limited due to the small sample size.

Background

Real-world evidence can be used to better characterize the course of multiple sclerosis (MS), care provision and outcomes in clinical practice. Magnetic resonance imaging (MRI) that occurs in the context of usual care is an important source of information that can inform clinical decision-making. Guidelines exist to enhance the clinical impact of routine MRI in MS, but it is unclear whether MRIs acquired as part of routine care in the United States adhere to these guidelines.

Objectives

To describe the clinical routine brain MRIs from patients with MS across different US imaging sites.

Methods

FlywheelMS is a novel patient-centered study that aims to extract and digitize health information not readily available in existing electronic health records of patients with MS. Up to 5,000 consenting adults with a confirmed MS diagnosis will be enrolled. Brain MRI data were retrieved, and summary statistics were computed to describe the sessions, imaging sites, scanner field strengths and slice thickness of T1-weighted and FLAIR (fluid-attenuated inversion recovery) images. Longitudinal acquisition consistency (i.e. MRIs acquired from the same center with the same scanner) was also assessed.

Results

Out of 2,389 patients enrolled, 1555 brain MRI data were retrieved from the first 492 patients (female, 81%; mean age at consent, 49±11 years). The mean number of MRI sessions per patient was 3.2±2.4, and data were captured between 1999 and 2018. Sessions were acquired at 598 different imaging sites, using mainly 1.5T scanners (61.3%), followed by 3T (32.7%) and lower field-strength magnets (3.4%; not available, 2.6%). The mean slice thickness of T1-weighted (3.1±1.7 mm) and FLAIR images (3.1±1.3 mm) was similar. Of the 352 patients (72%) that had more than one MRI session, 85 (24.1%) had consistent acquisition (i.e. same site/scanner), 153 (43.5%) had one site or scanner change, and 114 (32.4%) had more than one site and/or scanner change.

Conclusions

The novel, patient-centered approach of FlywheelMS can successfully extract imaging data from medical records of patients with MS across US imaging sites. These data will help us in describing the clinical routine MRI, determining the compliance to guidelines and understanding which measure (e.g. lesion volume and/or atrophy) could be potentially extracted from MRI data.

Background

Neurological disability progression occurs across the spectrum of people living with multiple sclerosis (PwMS). Currently, no treatments exist that substantially modify the course of clinical progression in MS, one of the greatest unmet needs in clinical practice. Characterizing the determinants of clinical progression is essential for the development of novel therapeutic agents and treatment approaches that target progression in PwMS.

Objectives

The overarching aim of CanProCo is to evaluate a wide spectrum of factors associated with the onset and rate of disease progression in MS, and to describe how these factors interact with one another to influence progression.

Methods

CanProCo is a prospective, observational cohort study aiming to recruit 1000 individuals with radiologically-isolated syndrome (RIS), relapsing-remitting MS (RRMS), and primary-progressive MS (PPMS) within 10-15 years of disease onset, and 50 healthy controls (HCs) from five large academic MS centers in Canada. Participants undergo detailed clinical evaluations annually. A subset of participants enrolled within 5-10 years of disease onset (n=500) also have blood, cerebrospinal fluid, and MRIs collected facilitating study of biological measures (e.g. single-cell RNA-sequencing[scRNASeq]), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and environmental factors as determinants contributing to the differential progression in MS.

Results

Recruitment commenced in April/May 2019 and n=536 patients have been recruited to date (RRMS=457, PPMS=35, RIS=25, HC=19). Baseline age, sex distribution, and Expanded Disability Status Scale (EDSS) scores (median, range) of each subgroup are: RRMS=38 years, 73% female, EDSS=1.5 (0-6.0); PPMS=52 years, 40% female, EDSS=4.0 (1.5-6.5); RIS=41 years, 68% female, EDSS=0 (0-3.0); HC=37 years, 63% female. Recruitment has surpassed the 50% target but has been paused due to the COVID-19 pandemic. scRNASeq on frozen blood samples has been validated.

Conclusions

Halting the progression of MS is a fundamental clinical need to improve the lives of PwMS. Achieving this requires leveraging transdisciplinary approaches to better characterize mechanisms underlying clinical progression. CanProCo is the first prospective cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.

Background

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines.

Objectives

The goal is to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination and implementation.

Methods

The CMSC convened an expert panel in October 2019 to update the standardized MRI protocol. Conference attendees included neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Representatives from CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocol, gadolinium, diffusion weighted imaging, and the central vein sign.

Results

95 neurologists completed the survey. 34% use the CMSC protocol. 48% use a standardized MRI protocol but are uncertain if it is similar to CMSC guidelines. 51% continue to use gadolinium for routine imaging. 58% wanted the central vein sign to be included in the diagnostic work up of MS. 87% were interested in monitoring brain volume and 10% were doing it routinely. The panel worked to harmonize CMSC and MAGNIMS MRI protocols so the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences and exam cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use.

Conclusions

The international expert group developed revised clinical MRI guidelines with the vision and action plans for them to be universally useful and useable and become the standard of care for patients with MS.

Background

Patients with neuromyelitis optica spectrum disorder (NMOSD) may experience severe disability after their incident (first) attack, with disability accumulating with subsequent relapses. Satralizumab, a humanized monoclonal antibody that inhibits the interleukin-6 receptor, reduced relapse frequency and had a favorable safety profile vs placebo in two randomized, placebo-controlled, phase 3 clinical trials in patients with NMOSD: SAkuraSky (satralizumab in combination with baseline immunosuppressants; NCT02028884), and SAkuraStar (satralizumab monotherapy; NCT02073279).

Objectives

To review a case series of treatment-naïve, aquaporin-4-IgG seropositive (AQP4-IgG+) NMOSD patients who enrolled in SAkuraStar following their incident attack.

Methods

All instances of investigator-reported relapse were assessed in six treatment-naïve, AQP4-IgG+ NMOSD patients enrolled in SAkuraStar after their first attack. Relapses that met protocol-defined relapse (PDR) criteria are specified. Patients who experienced a PDR or remained in SAkuraStar when the double-blind period ended were eligible to enter the open-label extension (OLE). Expanded Disability Status Scale (EDSS) scores were recorded at regular intervals and at relapse.

Results

Of the six enrolled patients, two were randomized to placebo, and four to satralizumab. Demographic characteristics in these six patients were generally consistent with the overall SAkuraStar population. One of the two patients who received placebo experienced a PDR on Study Day 21, with a 1.5-point increase in EDSS score, and fully recovered to pre-relapse EDSS score. Two of the four patients who received satralizumab experienced a relapse. The first patient experienced a PDR on Study Day 214, with a 1-point increase in EDSS, and the second patient experienced a relapse (not meeting PDR criteria) on Study Day 458, with a 0.5-point increase in EDSS score. Both patients fully recovered to pre-relapse EDSS score.

Five of six patients continued in the ongoing OLE, and no further relapses were reported (up to March 2020). Safety outcomes were consistent with the overall SAkuraStar safety population.

Conclusions

Treatment-naïve AQP4-IgG+ patients enrolled in SAkuraStar after their incident attack and randomized to placebo experienced a relapse earlier than those randomized to satralizumab. All patients fully recovered to pre-relapse EDSS score. Interpretation is limited due to the small sample size.

Background

Real-world evidence can be used to better characterize the course of multiple sclerosis (MS), care provision and outcomes in clinical practice. Magnetic resonance imaging (MRI) that occurs in the context of usual care is an important source of information that can inform clinical decision-making. Guidelines exist to enhance the clinical impact of routine MRI in MS, but it is unclear whether MRIs acquired as part of routine care in the United States adhere to these guidelines.

Objectives

To describe the clinical routine brain MRIs from patients with MS across different US imaging sites.

Methods

FlywheelMS is a novel patient-centered study that aims to extract and digitize health information not readily available in existing electronic health records of patients with MS. Up to 5,000 consenting adults with a confirmed MS diagnosis will be enrolled. Brain MRI data were retrieved, and summary statistics were computed to describe the sessions, imaging sites, scanner field strengths and slice thickness of T1-weighted and FLAIR (fluid-attenuated inversion recovery) images. Longitudinal acquisition consistency (i.e. MRIs acquired from the same center with the same scanner) was also assessed.

Results

Out of 2,389 patients enrolled, 1555 brain MRI data were retrieved from the first 492 patients (female, 81%; mean age at consent, 49±11 years). The mean number of MRI sessions per patient was 3.2±2.4, and data were captured between 1999 and 2018. Sessions were acquired at 598 different imaging sites, using mainly 1.5T scanners (61.3%), followed by 3T (32.7%) and lower field-strength magnets (3.4%; not available, 2.6%). The mean slice thickness of T1-weighted (3.1±1.7 mm) and FLAIR images (3.1±1.3 mm) was similar. Of the 352 patients (72%) that had more than one MRI session, 85 (24.1%) had consistent acquisition (i.e. same site/scanner), 153 (43.5%) had one site or scanner change, and 114 (32.4%) had more than one site and/or scanner change.

Conclusions

The novel, patient-centered approach of FlywheelMS can successfully extract imaging data from medical records of patients with MS across US imaging sites. These data will help us in describing the clinical routine MRI, determining the compliance to guidelines and understanding which measure (e.g. lesion volume and/or atrophy) could be potentially extracted from MRI data.