Time-Domain and Spectral-Domain Optical Coherence Tomography of Retinal Nerve Fiber Layer in MS Patients and Healthy Controls

Objective. The aim of this study was to compare retinal nerve fiber layer thickness (RNFLT) between spectral-domain (SD-) and time-domain optical coherence tomography (TD-OCT) in MS patients and healthy controls (HC). Furthermore, RNFLT between MS eyes with and without optic neuritis (ON) and HC should be explored. Finally, the relationship between RNFLT, disease duration, EDSS, and disease modifying therapy (DMT) should be established. Design. Prospective, cross-sectional study. Participants. 28 MS patients and 35 HC. Methods. Both groups underwent TD- and SD-OCT measurements. RFNLT was correlated between the two machines and between MS eyes with and without ON and HC. Furthermore, RNFLT was correlated to disease duration, EDSS and DMT. Results. A strong correlation (Pearson's r = 0.921, P < 0.001), but a statistically significant difference of 2 μm (P < 0.001), was found between the two devices. RNFLT was significantly different between MS eyes with history of ON (mean RFNLT (SD) 72.21 μm (15.83 μm)), MS eyes without history of ON 93.03 μm (14.25 μm), and HC 99.07 μm (7.23 μm) (P < 0.001). Conclusions. The measurements between different generation of OCT machines are not interchangeable, which should be taken into account if comparing results between different machines and switching OCT machine in longitudinal studies

No evidence of disease activity (NEDA) analysis by epochs in patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta-1a.

BackgroundNo evidence of disease activity (NEDA; defined as no 12-week confirmed disability progression, no protocol-defined relapses, no new/enlarging T2 lesions and no T1 gadolinium-enhancing lesions) using a fixed-study entry baseline is commonly used as a treatment outcome in multiple sclerosis (MS).ObjectiveThe objective of this paper is to assess the effect of ocrelizumab on NEDA using re-baselining analysis, and the predictive value of NEDA status.MethodsNEDA was assessed in a modified intent-to-treat population (n = 1520) from the pooled OPERA I and OPERA II studies over various epochs in patients with relapsing MS receiving ocrelizumab (600 mg) or interferon beta-1a (IFN β-1a; 44 μg).ResultsNEDA was increased with ocrelizumab vs IFN β-1a over 96 weeks by 75% (p &lt; 0.001), from Week 0‒24 by 33% (p &lt; 0.001) and from Week 24‒96 by 72% (p &lt; 0.001). Among patients with disease activity during Weeks 0‒24, 66.4% vs 24.3% achieved NEDA during Weeks 24‒96 in the ocrelizumab and IFN β-1a groups (relative increase: 177%; p &lt; 0.001).ConclusionSuperior efficacy with ocrelizumab compared with IFN β-1a was consistently seen in maintaining NEDA status in all epochs evaluated. By contrast with IFN β-1a, the majority of patients with disease activity early in the study subsequently attained NEDA status with ocrelizumab

Prognostic factors for long-term outcomes in relapsing-remitting multiple sclerosis

Objective: The objective of this article is to investigate potential clinical and MRI predictors of long-term outcomes in multiple sclerosis (MS). Methods: This was a post hoc analysis using data from all 382 patients in the PRISMS long-term follow-up (LTFU) study collected up to eight years after randomisation. An additional analysis was performed including only those patients originally randomised to receive early subcutaneous interferon (IFN) β-1a (n = 259). Baseline/prestudy variables, indicators of early clinical and MRI activity (baseline to month 24), and indicators of IFN β-1a treatment exposure (including medication possession ratio (MPR)) were investigated as candidate prognostic factors for outcomes measured from baseline and from month 24 to LTFU. Explanatory variables identified from univariate regression models (p ≤ 0.15) were selected for inclusion in stepwise multiple regression models. Results: Candidate prognostic factors selected by the univariate analysis (p ≤ 0.15) included age, MS duration, baseline brain volume, EDSS score, and log(T2 burden of disease (BOD)). In most of the multivariate regression models applied, higher baseline brain volume and MPR predicted better long-term clinical outcomes, while higher baseline and greater early increase in EDSS score predicted worse outcomes. Conclusion: Identification of markers that may be prognostic for long-term disability could help identify MS patients at higher risk of disability progression

Five years of ocrelizumab in relapsing multiple sclerosis : OPERA studies open-label extension

Objective: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis. Methods:After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 g 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed. Results:Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; p = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (-1.87% vs-2.15% at year 5; p < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.ConclusionCompared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.Classification of evidenceThis study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.Clinical trial identifiersNCT01247324/NCT01412333

Common variation near IRF6 is associated with IFN-β-induced liver injury in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms of drug-induced liver injury4,5, we aimed to identify biomarkers of IFN-β-induced liver injury using a two-stage genome-wide association study. The rs2205986 variant, previously linked to differential expression of IRF6, surpassed genome-wide significance in the combined two-stage analysis (P = 2.3 × 10-8, odds ratio = 8.3, 95% confidence interval = 3.6-19.2). Analysis of an independent cohort of IFN-β-treated MS patients identified via electronic medical records showed that rs2205986 was also associated with increased peak levels of aspartate aminotransferase (P = 7.6 × 10-5) and alkaline phosphatase (P = 4.9 × 10-4). We show that these findings may be applicable to predicting IFN-β-induced liver injury, offering insight into its safer use

Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings.

OBJECTIVE: To evaluate 5-year efficacy and safety of alemtuzumab in patients with active relapsing-remitting multiple sclerosis and inadequate response to prior therapy. METHODS: In the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) II study (NCT00548405), alemtuzumab-treated patients received 2 courses (baseline and 12 months later). Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or MRI activity. Annualized relapse rate (ARR), 6-month confirmed disability worsening (CDW; ≥1-point Expanded Disability Status Scale [EDSS] score increase [≥1.5 if baseline EDSS = 0]), 6-month confirmed disability improvement (CDI; ≥1-point EDSS decrease [baseline score ≥2.0]), no evidence of disease activity (NEDA), brain volume loss (BVL), and adverse events (AEs) were assessed. RESULTS: Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3-5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1-5: -0.48%, -0.22%, -0.10%, -0.19%, -0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter. CONCLUSIONS: Alemtuzumab provides durable efficacy through 5 years in patients with an inadequate response to prior therapy in the absence of continuous treatment. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab provides efficacy and slowing of brain atrophy through 5 years

Inter-Vendor Reproducibility of Myelin Water Imaging Using a 3D Gradient and Spin Echo Sequence

Myelin water imaging can be achieved using multicomponent T2 relaxation analysis to quantify in vivo measurement of myelin content, termed the myelin water fraction (MWF). Therefore, myelin water imaging can be a valuable tool to better understand the underlying white matter pathology in demyelinating diseases, such as multiple sclerosis. To apply myelin water imaging in multisite studies and clinical applications, it must be acquired in a clinically feasible scan time (less than 15 min) and be reproducible across sites and scanner vendors. Here, we assessed the reproducibility of MWF measurements in regional and global white matter in 10 healthy human brains across two sites with two different 3 T magnetic resonance imaging scanner vendors (Philips and Siemens), using a 32-echo gradient and spin echo (GRASE) sequence. A strong correlation was found between the MWF measurements in the global white matter (Pearson’s r = 0.91; p &lt; 0.001) for all participants across the two sites. The mean intersite MWF coefficient of variation across participants was 2.77% in the global white matter and ranged from 4.47% (splenium of the corpus callosum) to 17.89% (genu of the corpus callosum) in white matter regions of interest. Bland-Altman analysis showed a good agreement in MWF measurements between the two sites with small bias of 0.002. Overall, MWF estimates were in good agreement across the two sites and scanner vendors. Our findings support the use of quantitative multi-echo T2 relaxation metrics, such as the MWF, in multicenter studies and clinical trials to gain deeper understanding about the pathological processes resulting from the underlying disease progression in neurodegenerative diseases

SAkuraBONSAI: Protocol Design of a Novel, Prospective Study to Explore Clinical, Imaging, and Biomarker Outcomes in Patients With AQP4-IgG-Seropositive Neuromyelitis Optica Spectrum Disorder Receiving Open-Label Satralizumab

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune disease of the central nervous system that produces acute, unpredictable relapses causing cumulative neurological disability. Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced NMOSD relapse risk vs. placebo in two Phase 3 trials: SAkuraSky (satralizumab ± immunosuppressive therapy; NCT02028884) and SAkuraStar (satralizumab monotherapy; NCT02073279). Satralizumab is approved to treat aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD. SAkuraBONSAI (NCT05269667) will explore fluid and imaging biomarkers to better understand the mechanism of action of satralizumab and the neuronal and immunological changes following treatment in AQP4-IgG+ NMOSD. Objectives: SAkuraBONSAI will evaluate clinical disease activity measures, patient-reported outcomes (PROs), pharmacokinetics, and safety of satralizumab in AQP4-IgG+ NMOSD. Correlations between imaging markers (magnetic resonance imaging [MRI] and optical coherence tomography [OCT]) and blood and cerebrospinal fluid (CSF) biomarkers will be investigated. Study design: SAkuraBONSAI is a prospective, open-label, multicenter, international, Phase 4 study that will enroll approximately 100 adults (18-74 years) with AQP4-IgG+ NMOSD. This study includes two patient cohorts: newly diagnosed, treatment-naïve patients (Cohort 1; n = 60); and inadequate responders to recent (\u3c6 months) rituximab infusion (Cohort 2; n = 40). Satralizumab monotherapy (120 mg) will be administered subcutaneously at Weeks 0, 2, 4, and Q4W thereafter for a total of 92 weeks. Endpoints: Disease activity related to relapses (proportion relapse-free, annualized relapse rate, time to relapse, and relapse severity), disability progression (Expanded Disability Status Scale), cognition (Symbol Digit Modalities Test), and ophthalmological changes (visual acuity; National Eye Institute Visual Function Questionnaire-25) will all be assessed. Peri-papillary retinal nerve fiber layer and ganglion cell complex thickness will be monitored using advanced OCT (retinal nerve fiber layer and ganglion cell plus inner plexiform layer thickness). Lesion activity and atrophy will be monitored by MRI. Pharmacokinetics, PROs, and blood and CSF mechanistic biomarkers will be assessed regularly. Safety outcomes include the incidence and severity of adverse events. Conclusions: SAkuraBONSAI will incorporate comprehensive imaging, fluid biomarker, and clinical assessments in patients with AQP4-IgG+ NMOSD. SAkuraBONSAI will provide new insights into the mechanism of action of satralizumab in NMOSD, while offering the opportunity to identify clinically relevant neurological, immunological, and imaging markers

Prevalence of Grey Matter Pathology in Early Multiple Sclerosis Assessed by Magnetization Transfer Ratio Imaging

The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject's GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

Supported by F. Hoffmann–La Roche