MiRNA-based therapeutic potential in multiple sclerosis.

This review will briefly introduce microRNAs (miRNAs) and dissect their contribution to multiple sclerosis (MS) and its clinical outcomes. For this purpose, we provide a concise overview of the present knowledge of MS pathophysiology, biomarkers and treatment options, delving into the role of selectively expressed miRNAs in clinical forms of this disease, as measured in several biofluids such as serum, plasma or cerebrospinal fluid (CSF). Additionally, up-to-date information on current strategies applied to miRNA-based therapeutics will be provided, including miRNA restoration therapy (lentivirus expressing a specific type of miRNA and miRNA mimic) and miRNA inhibition therapy such as antisense oligonucleotides, small molecules inhibitors, locked nucleic acids (LNAs), anti-miRNAs, and antagomirs. Finally, it will highlight future directions and potential limitations associated with their application in MS therapy, emphasizing the need for improved delivery methods and validation of therapeutic efficacy.

Cytomegalovirus immune responses are associated with lower serum NfL and disability accumulation risk at multiple sclerosis onset.

BACKGROUND: Infection by cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) play a prognostic role in multiple sclerosis (MS). OBJECTIVES: To explore whether humoral immune responses to HCMV and EBV at disease onset were associated with changes in serum and cerebrospinal fluid (CSF) levels of inflammatory and neurodegeneration biomarkers. METHODS: Ninety-eight MS patients with a median follow-up of 20 years were included in the study. The levels of a panel of nine biomarkers were measured in serum (N = 60) and CSF (N = 61) samples of patients at the time of the first demyelinating event. RESULTS: Immune responses to HCMV inversely correlated with serum neurofilament light chain (sNfL) levels (rho = -0.367; p = 0.039). sNfL levels were reduced in patients with high immune responses to HCMV (p = 0.006). Elevated sNfL levels were associated with higher risk of Expanded Disability Status Scale (EDSS) 3.0 (p = 0.016), 4.0 (p = 0.009) and 6.0 (p = 0.003), and with higher risk of developing secondary progressive MS (p = 0.003) and to receive treatment (p = 0.032). Serum soluble CD21 levels were increased in patients with high immune responses to EBV nuclear antigen 1 (p = 0.020). CONCLUSIONS: High immune responses to HCMV are associated with limited disease progression and central nervous system (CNS) injury in MS patients. These findings reinforce the protective role of HCMV infection in MS.

Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

BACKGROUND: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. METHODS: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). FINDINGS: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. INTERPRETATION: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. FUNDING: Merck.

Serum biomarkers at disease onset for personalized therapy in multiple sclerosis.

The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.

The global patient-reported outcomes for multiple sclerosis initiative: bridging the gap between clinical research and care - updates at the 2023 plenary event.

Significant advancements have been achieved in delineating the progress of the Global PROMS (PROMS) Initiative. The PROMS Initiative, a collaborative endeavor by the European Charcot Foundation and the Multiple Sclerosis International Federation, strives to amplify the influence of patient input on MS care and establish a cohesive perspective on Patient-Reported Outcomes (PROs) for diverse stakeholders. This initiative has established an expansive, participatory governance framework launching four dedicated working groups that have made substantive contributions to research, clinical management, eHealth, and healthcare system reform. The initiative prioritizes the global integration of patient (For the purposes of the Global PROMS Initiative, the term "patient" refers to the people with the disease (aka People with Multiple Sclerosis - pwMS): any individual with lived experience of the disease. People affected by the disease/Multiple Sclerosis: any individual or group that is affected by the disease: E.g., family members, caregivers will be also engaged as the other stakeholders in the initiative). insights into the management of MS care. It merges subjective PROs with objective clinical metrics, thereby addressing the complex variability of disease presentation and progression. Following the completion of its second phase, the initiative aims to help increasing the uptake of eHealth tools and passive PROs within research and clinical settings, affirming its unwavering dedication to the progressive refinement of MS care. Looking forward, the initiative is poised to continue enhancing global surveys, rethinking to the relevant statistical approaches in clinical trials, and cultivating a unified stance among 'industry', regulatory bodies and health policy making regarding the application of PROs in MS healthcare strategies.

Value of Optic Nerve MRI in Multiple Sclerosis Clinical Management: A MAGNIMS Position Paper and Future Perspectives.

The optic nerve is frequently involved in multiple sclerosis (MS). However, MRI of the optic nerve is considered optional in the differential diagnosis of optic neuropathy symptoms either at presentation or in established MS. In addition, unlike spinal cord imaging in comparable scenarios, no role is currently recommended for optic nerve MRI in patients presenting with optic neuritis for its confirmation, to plan therapeutic strategy, within the MS diagnostic framework, nor for the detection of subclinical activity in established MS. In this article, evidence related to these 3 aspects will be summarized and gaps in knowledge will be highlighted, including (1) the acquisition challenges and novel sequences that assess pathologic changes within the anterior visual pathways; (2) the clinical implications of quantitative magnetic resonance studies of the optic nerve, focusing on atrophy measures, magnetization transfer, and diffusion tensor imaging; and (3) the relevant clinical studies performed to date. Finally, an algorithm for the application of optic nerve MRI will be proposed to guide future studies aimed at addressing our knowledge gaps.

Association of Complement Factors With Disability Progression in Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS). METHODS: Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up). RESULTS: In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025). DISCUSSION: Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.

IL-6 Inhibition as a Therapeutic Target in Aged Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) onset at an advanced age is associated with a higher risk of developing progressive forms and a greater accumulation of disability for which there are currently no effective disease-modifying treatments. Immunosenescence is associated with the production of the senescence-associated secretory phenotype (SASP), with IL-6 being one of the most prominent cytokines. IL-6 is a determinant for the development of autoimmunity and neuroinflammation and is involved in the pathogenesis of MS. Herein, we aimed to preclinically test the therapeutic inhibition of IL-6 signaling in experimental autoimmune encephalomyelitis (EAE) as a potential age-specific treatment for elderly MS patients. Young and aged mice were immunized with myelin oligodendrocyte protein (MOG)35-55 and examined daily for neurological signs. Mice were randomized and treated with anti-IL-6 antibody. Inflammatory infiltration was evaluated in the spinal cord and the peripheral immune response was studied. The blockade of IL-6 signaling did not improve the clinical course of EAE in an aging context. However, IL-6 inhibition was associated with an increase in the peripheral immunosuppressive response as follows: a higher frequency of CD4 T cells producing IL-10, and increased frequency of inhibitory immune check points PD-1 and Tim-3 on CD4+ T cells and Lag-3 and Tim-3 on CD8+ T cells. Our results open the window to further studies aimed to adjust the anti-IL-6 treatment conditions to tailor an effective age-specific therapy for elderly MS patients.

Artificial intelligence applied to MRI data to tackle key challenges in multiple sclerosis.

Artificial intelligence (AI) is the branch of science aiming at creating algorithms able to carry out tasks that typically require human intelligence. In medicine, there has been a tremendous increase in AI applications thanks to increasingly powerful computers and the emergence of big data repositories. Multiple sclerosis (MS) is a chronic autoimmune condition affecting the central nervous system with a complex pathogenesis, a challenging diagnostic process strongly relying on magnetic resonance imaging (MRI) and a high and largely unexplained variability across patients. Therefore, AI applications in MS have the great potential of helping us better support the diagnosis, find markers for prognosis to eventually design more powerful randomised clinical trials and improve patient management in clinical practice and eventually understand the mechanisms of the disease. This topical review aims to summarise the recent advances in AI applied to MRI data in MS to illustrate its achievements, limitations and future directions.

Long-term clinical outcomes in patients with CIS treated with interferon beta-1b: results from the 15-year follow up of the BENEFIT trial.

Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b.

Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab.

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay. Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment. Design, Setting, and Participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023. Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year). Main Outcomes and Measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed. Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment. Conclusions and Relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.

Prediction of disease activity and treatment failure in relapsing-remitting MS patients initiating daily oral DMTs.

BACKGROUND: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS). OBJECTIVES: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing-remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials. METHODS: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis. RESULTS: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [0.7-5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder. CONCLUSION: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully.

Trans-Synaptic Degeneration in the Visual Pathway in Patients With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

BACKGROUND AND OBJECTIVES: We aimed to assess the presence of retinal neurodegeneration independent of optic neuritis (ON) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to investigate the development of trans-synaptic anterograde degeneration in these patients after ON. METHODS: Cross-sectional, retrospective study of 34 adult patients with MOGAD and 23 healthy controls (HC). Clinical, optical coherence tomography (OCT), and MRI data were collected. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell inner plexiform layer (GCIPL) were obtained using Heidelberg Spectralis. FreeSurfer7 was used to obtain the lateral geniculate nucleus (LGN), occipital volume fractions (to total estimated intracranial volume), and occipital cortical thickness. For the anterior visual pathway, the analysis was conducted using eyes, classified based on the history of ON (Eye-ON and Eye-NON) and compared with Eye-HC. The analysis of OCT and brain volumetric measures was conducted comparing MOGAD-ON, MOGAD-NON, and HC groups. The analysis of covariance with a Bonferroni-adjusted post hoc test was used to test differences between groups and linear regression analysis to evaluate OCT/MRI associations; age and sex were considered as covariates. RESULTS: 24 (70.5%) patients had a prior ON. Median pRNFL and GCIPL thickness (um) was significantly reduced in Eye-ON vs EyeNON and HC (pRNFL: 69.4 (17.3), 89.6 (13.7), 98.2 (11.7), p < 0.001; GCIPL: 55.8 (8.7), 67.39 (8.7), 72.6 (4.5), p < 0.001). pRNFL and GCIPL thickness had a negative correlation with the number of ON episodes (p = 0.025 and p = 0.031, respectively). LGN volume fraction was significantly lower in patients with MOGAD-ON than in HC (0.33 (0.05) vs 0.39 (0.04), p = 0.002). The occipital cortical thickness was lower in MOGAD-ON compared with MOGAD-NON and HC (p = 0.010). In patients with MOGAD-ON, pRNFL correlated with LGN volume (p = 0.006), occipital thickness (p = 0.002), and the medial occipital cortex (p = 0.002), but not the lateral occipital lobe. DISCUSSION: Compared with HC, MOGAD-ON exhibits reduced retinal thickness, primarily influenced by the presence and the number of prior ON episodes. Moreover, MOGAD-ON demonstrates significant atrophy in the retinal, subcortical, and cortical regions of the visual pathway, distinguishing them from MOGAD-NON and HC. These findings suggest that in patients with MOGAD neurodegeneration is tightly correlated with damage to the involved pathway.

Efficacy and safety results after >3.5 years of treatment with the Bruton's tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study.

BACKGROUND: Evobrutinib - an oral, central nervous system (CNS)-penetrant, and highly selective Bruton's tyrosine kinase inhibitor - has shown efficacy in a 48-week, double-blind, Phase II trial in patients with relapsing MS. OBJECTIVE: Report results of the Phase II open-label extension (OLE; up to week 192 from randomisation) and a cerebrospinal fluid (CSF) sub-study. METHODS: In the 48-week double-blind period (DBP), patients received evobrutinib 25 mg once-daily, 75 mg once-daily, 75 mg twice-daily or placebo (switched to evobrutinib 25 mg once-daily after week 24). Patients could then enter the OLE, receiving evobrutinib 75 mg once-daily (mean (± standard deviation (SD)) duration = 50.6 weeks (±6.0)) before switching to 75 mg twice-daily. RESULTS: Of 164 evobrutinib-treated patients who entered the OLE, 128 (78.0%) completed ⩾192 weeks of treatment. Patients receiving DBP evobrutinib 75 mg twice-daily: annualised relapse rate at week 48 (0.11 (95% confidence interval (CI) = 0.04-0.25)) was maintained with the OLE twice-daily dose up to week 192 (0.11 (0.05-0.22)); Expanded Disability Status Scale score remained stable; serum neurofilament light chain fell to levels like a non-MS population (Z-scores); T1 gadolinium-enhancing lesion numbers remained low. No new safety signals were identified. In the OLE, evobrutinib was detected in the CSF of all sub-study patients. CONCLUSION: Long-term evobrutinib treatment was well tolerated and associated with a sustained low level of disease activity. Evobrutinib was present in CSF at concentrations similar to plasma.

Effect of Evobrutinib on Slowly Expanding Lesion Volume in Relapsing Multiple Sclerosis: A Post Hoc Analysis of a Phase 2 Trial.

BACKGROUND AND OBJECTIVES: Chronic active lesions (CALs) are demyelinated multiple sclerosis (MS) lesions with ongoing microglia/macrophage activity, resulting in irreversible neuronal damage and axonal loss. Evobrutinib is a highly selective, covalent, CNS-penetrant, Bruton tyrosine kinase inhibitor. This post hoc analysis evaluated the effect of evobrutinib on slowly expanding lesion (SEL) volume, an MRI marker of CALs, assessed baseline-week 48 in a phase 2, double-blind, randomized trial (NCT02975349) in relapsing MS (RMS). METHODS: In the 48-week, double-blind trial, adult patients received evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]), placebo (switched to evobrutinib 25 mg QD after week 24), or open-label dimethyl fumarate (DMF) 240 mg BID. SELs were defined as slowly and consistently radially expanding areas of preexisting T2 lesions of ≥10 contiguous voxels (∼30 mm3) over time. SELs were identified by MRI and assessed by the Jacobian determinant of the nonlinear deformation from baseline to week 48. SEL volume analysis, stratified by baseline T2 lesion volume tertiles, was based on week 48/end-of-treatment status (completers/non-completers). Treatment effect was analyzed using the stratified Hodges-Lehmann estimate of shift in distribution and stratified Wilcoxon rank-sum test. Comparisons of evobrutinib and DMF vs placebo/evobrutinib 25 mg QD were made. Subgroup analyses used pooled treatment groups (evobrutinib high dose [75 mg QD/BID] vs low dose [placebo/evobrutinib 25 mg QD]). RESULTS: The SEL analysis set included 223 patients (mean [SD] age: 42.4 [10.7] years; 69.3% female; 87.4% relapsing/remitting MS). Mean (SD) SEL volume was 2,099 (2,981.0) mm3 with evobrutinib 75 mg BID vs 2,681 (3,624.2) mm3 with placebo/evobrutinib 25 mg QD. Median number of SELs/patient ranged from 7 to 11 across treatments. SEL volume decreased with increasing evobrutinib dose vs placebo/evobrutinib 25 mg QD, and no difference with DMF vs placebo/evobrutinib 25 mg QD was noted. SEL volume significantly decreased with evobrutinib 75 mg BID vs placebo/evobrutinib 25 mg QD (-474.5 mm3 [-1,098.0 to -3.0], p = 0.047) and vs DMF (-711.6 [-1,290.0 to -149.0], p = 0.011). SEL volume was significantly reduced for evobrutinib high vs low dose within baseline Expanded Disability Status Scale ≥3.5 and longer disease duration (≥8.5 years) subgroups. DISCUSSION: Evobrutinib reduced SEL volume in a dose-dependent manner in RMS, with a significant reduction with evobrutinib 75 mg BID. This is evident that evobrutinib affects brain lesions associated with chronic inflammation and tissue loss. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov number: NCT02975349. Submitted to ClinicalTrials.gov on November 29, 2016. First patient enrolled: March 7, 2017. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that evobrutinib reduces the volume of SELs assessed on MRI comparing baseline with week 48, in patients with RMS.

Optic nerve topography in multiple sclerosis diagnostic criteria: Existing knowledge and future directions.

Current diagnostic criteria for multiple sclerosis (MS) do not consider the optic nerve as a typical topography for establishing the diagnosis. Recent studies have proved the utility of optic nerve magnetic resonance imaging, optical coherence tomography and visual evoked potentials in detecting optic nerve lesions during the early stages of MS. In addition, emerging evidence supports the inclusion of optic nerve topography as a fifth region to fulfil the dissemination in space criteria. Anticipating a modification in the McDonald criteria, it is crucial for neurologists to familiarize with the diagnostic properties of each test in detecting optic nerve lesions and understand how to incorporate them into the MS diagnostic process. Therefore, the objective of this article is to review the existing evidence supporting the use of these tests in the diagnostic process of MS and provide a practical algorithm that can serve as a valuable guide for clinical practice.

Use of smartphone-based remote assessments of multiple sclerosis in Floodlight Open, a global, prospective, open-access study.

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a 'bring-your-own-device' solution that remotely measures a user's mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input ('active tests'). Levels of mobility of study participants ('life-space measurement') were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.