Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

Permanent tissue damage in multiple sclerosis lesions is associated with reduced pre-lesion myelin and axon volume fractions.

BACKGROUND: The use of advanced magnetic resonance imaging (MRI) techniques in MS research has led to new insights in lesion evolution and disease outcomes. It has not yet been determined if, or how, pre-lesional abnormalities in normal-appearing white matter (NAWM) relate to the long-term evolution of new lesions. OBJECTIVE: To investigate the relationship between abnormalities in MRI measures of axonal and myelin volume fractions (AVF and MVF) in NAWM preceding development of black-hole (BH) and non-BH lesions in people with MS. METHODS: We obtained magnetization transfer and diffusion MRI at 6-month intervals in patients with MS to estimate MVF and AVF during lesion evolution. Lesions were classified as either BH or non-BH on the final imaging visit using T1 maps. RESULTS: Longitudinal data from 97 new T2 lesions from 9 participants were analyzed; 25 lesions in 8 participants were classified as BH 6-12 months after initial appearance. Pre-lesion MVF, AVF, and MVF/AVF were significantly lower, and T1 was significantly higher, in the lesions that later became BHs (p < 0.001) compared to those that did not. No significant pre-lesion abnormalities were found in non-BH lesions (p > 0.05). CONCLUSION: The present work demonstrated that pre-lesion abnormalities are associated with worse long-term lesion-level outcome.

Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years.

BACKGROUND: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile. OBJECTIVE: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years. METHODS: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide. RESULTS: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections. CONCLUSION: In patients with up to 3.5 years' exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.

Brain volume loss in individuals over time: Source of variance and limits of detectability.

BACKGROUND: Brain volume loss measured from magnetic resonance imaging (MRI) is a marker of neurodegeneration and predictor of disability progression in MS, and is commonly used to assess drug efficacy at the group level in clinical trials. Whether measures of brain volume loss could be useful to help guide management of individual patients depends on the relative magnitude of the changes over a given interval to physiological and technical sources of variability. GOAL: To understand the relative contributions of neurodegeneration vs. physiological and technical sources of variability to measurements of brain volume loss in individuals. MATERIAL AND METHODS: Multiple T1-weighted 3D MPRAGE images were acquired from a healthy volunteer and MS patient over varying time intervals: 7 times on the first day (before breakfast at 7:30AM and then every 2 â€‹h for 12 â€‹h), each day for the next 6 working days, and 6 times over the remainder of the year, on 2 â€‹Siemens MRI scanners: 1.5T Sonata (S1) and 3.0T TIM Trio (S2). Scan-reposition-rescan data were acquired on S2 for daily, monthly and 1-year visits. Percent brain volume change (PBVC) was measured from baseline to each follow-up scan using FSL/SIENA. We estimated the effect of physiologic fluctuations on brain volume using linear regression of the PBVC values over hourly and daily intervals. The magnitude of the physiological effect was estimated by comparing the root-mean-square error (RMSE) of the regression of all the data points relative to the regression line, for the hourly scans vs the daily scans. Variance due to technical sources was assessed as the RMSE of the regression over time using the intracranial volume as a reference. RESULTS: The RMSE of PBVC over 12 â€‹h, for both scanners combined, ("Hours", 0.15%), was similar to the day-to-day variation over 1 week ("Days", 0.14%), and both were smaller than the RMS error over the year (0.21%). All of these variations, however, were smaller than the scan-reposition-rescan RMSE (0.32%). The variability of PBVC for the individual scanners followed the same trend. The standard error of the mean (SEM) for PBVC was 0.26 for S1, and 0.22 for S2. From these values, we computed the minimum detectable change (MDC) to be 0.7% on S1 and 0.6% on S2. The location of the brain along the z-axis of the magnet inversely correlated with brain volume change for hourly and daily brain volume fluctuations (p â€‹< â€‹0.01). CONCLUSION: Consistent diurnal brain volume fluctuations attributable to physiological shifts were not detectable in this small study. Technical sources of variation dominate measured changes in brain volume in individuals until the volume loss exceeds around 0.6-0.7%. Reliable interpretation of measured brain volume changes as pathological (greater than normal aging) in individuals over 1 year requires changes in excess of about 1.1% (depending on the scanner). Reliable brain atrophy detection in an individual may be feasible if the rate of brain volume loss is large, or if the measurement interval is sufficiently long.

Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations.

The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.

Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis.

The therapeutic mode of action of dimethyl fumarate (DMF), approved for treating patients with relapsing-remitting multiple sclerosis, is not fully understood. Recently, we and others demonstrated that Ab-independent functions of distinct B cell subsets are important in mediating multiple sclerosis (MS) relapsing disease activity. Our objective was to test whether and how DMF influences both the phenotype and functional responses of disease-implicated B cell subsets in patients with MS. High-quality PBMC were obtained from relapsing-remitting MS patients prior to and serially after initiation of DMF treatment. Multiparametric flow cytometry was used to monitor the phenotype and functional response-profiles of distinct B cell subsets. Total B cell counts decreased following DMF treatment, largely reflecting losses of circulating mature/differentiated (but not of immature transitional) B cells. Within the mature B cell pool, DMF had a greater impact on memory than naive B cells. In keeping with these in vivo effects, DMF treatment in vitro remarkably diminished mature (but not transitional B cell) survival, mediated by inducing apoptotic cell death. Although DMF treatment (both in vivo and in vitro) minimally impacted B cell IL-10 expression, it strongly reduced B cell expression of GM-CSF, IL-6, and TNF-α, resulting in a significant anti-inflammatory shift of B cell response profiles. The DMF-mediated decrease in B cell proinflammatory cytokine responses was further associated with reduced phosphorylation of STAT5/6 and NF-κB in surviving B cells. Together, these data implicate novel mechanisms by which DMF may modulate MS disease activity through shifting the balance between pro- and anti-inflammatory B cell responses.

Managing Multiple Sclerosis: Treatment Initiation, Modification, and Sequencing.

Recent therapeutic advances in the management of multiple sclerosis (MS) have raised questions about the selection of appropriate patient candidates for various treatments and, if the plan is to move from one treatment to another, the appropriate sequencing of these therapies. The selected approach should provide optimal disease management without limiting future therapeutic options based on safety concerns, and recognize potential future treatments and the possibility of combination therapies. Additional challenges include incorporation of patient needs and preferences into the overall therapeutic approach, in order to ensure optimal outcomes in the short and long term. The objective of this manuscript is to provide an overview of what is currently known regarding the impact of various therapies for MS on future therapeutic choices (sequencing). In this context, we reviewed the available evidence in support of various treatments and, based on the presence of disease activity, suggested a scheme for switching or escalating therapy with the main focus on sequencing of therapeutic approaches.

Toward a Shared-Care Model of Relapsing-Remitting Multiple Sclerosis: Role of the Primary Care Practitioner.

The objective of this study was to develop a shared-care model to enable primary-care physicians to participate more fully in meeting the complex, multidisciplinary healthcare needs of patients with multiple sclerosis (MS). DESIGN: The design consisted of development of consensus recommendations and a shared-care algorithm. PARTICIPANTS: A working group of 11 Canadian neurologists involved in the management of patients with MS were included in this study. MAIN MESSAGE: The clinical management of patients with multiple sclerosis is increasing in complexity as new disease-modifying therapies (DMTs) become available, and ongoing safety monitoring is required. A shared-care model that includes primary care physicians is needed. Primary care physicians can assist in the early detection of MS of individuals presenting with neurological symptoms. Additional key roles for family physicians are health promotion, symptom management, and safety and relapse monitoring of DMT-treated patients. General principles of health promotion include counseling MS patients on maintaining a healthy lifestyle; performing standard screening measures; and identifying and treating comorbidities. Of particular importance are depression and anxiety, which occur in >20% of MS patients. Standard work-ups and treatments are needed for common MS-related symptoms, such as fatigue, pain, bladder dysfunction, sexual dysfunction, spasticity, and sleep disorders. Ongoing safety monitoring is required for patients receiving specific DMTs. Multiple sclerosis medications are generally contraindicated during pregnancy, and patients should be counseled to practice effective contraception. CONCLUSIONS: Multiple sclerosis is a complex, disabling illness, which, similar to other chronic diseases, requires ongoing multidisciplinary care to meet the evolving needs of patients throughout the clinical course. Family physicians can play an invaluable role in maintaining general health, managing MS-related symptoms and comorbidities, monitoring for treatment-related adverse effects and MS relapses, and coordinating allied health services to ensure continuity of care to meet the complex and evolving needs of MS patients through the disease course. RÉSUMÉ: Élaborer un modèle de soins partagés dans les cas de sclérose en plaques récurrente-rémittente. Objectif: Élaborer un modèle de soins partagés afin de permettre aux médecins de première ligne de mieux répondre aux besoins complexes et multidisciplinaires de patients atteints de la sclérose en plaques (SP). Conception : Recommandations résultant d'un consensus et élaboration d'un algorithme en matière de soins partagés. PARTICIPANTS: Un groupe de travail formé de onze neurologues canadiens impliqués dans la prise en charge de patients atteints de la SP. Message-clé : La prise en charge clinique de patients atteints de la SP est de plus en plus complexe dans la mesure où des médicaments modificateurs de l'évolution de la maladie (MMSP) deviennent accessibles et où un suivi permanent en matière de sécurité est nécessaire. Soulignons aussi qu'un modèle de soins partagés incluant les médecins de première ligne est nécessaire. Ces professionnels peuvent permettre un dépistage plus rapide de la SP chez des individus présentant des symptômes neurologiques. Ils peuvent aussi jouer un rôle de premier plan en matière de promotion de la santé, de soulagement des symptômes et de suivi de patients traités avec des MMSP en ce qui a trait à leur sécurité et à de possibles rechutes. Parmi les principes généraux de promotion de la santé, on peut inclure les suivants : offrir aux patients atteints de la SP des conseils leur permettant de maintenir de saines habitudes de vie ; adopter des mesures de dépistage standards ; identifier et traiter les comorbidités. À cet égard, l'anxiété et la dépression sont d'une importance particulière et sont fréquemment signalées (> 20 %) chez les patients atteints de SP. Des démarches d'investigation et des traitements standards sont nécessaires dans le cas des symptômes courants reliés à la SP, par exemple de la fatigue, des douleurs, une dysfonction vésicale, des dysfonctions sexuelles, de la spasticité et des troubles du sommeil. On l'a dit, un suivi permanent s'impose dans le cas de patients bénéficiant d'un traitement spécifique avec des MMSP. Les médicaments associés à la SP sont généralement contre-indiqués durant la grossesse de sorte qu'on devrait conseiller aux patients d'adopter des méthodes de contraception efficaces. CONCLUSIONS: La SP est une maladie complexe et invalidante qui, à l'instar d'autres maladies chroniques, exige des soins multidisciplinaires continus afin de répondre, en lien avec un tableau clinique précis, aux besoins en constante évolution des patients. Les médecins de première ligne peuvent jouer un rôle irremplaçable à plusieurs égards : dans le maintien d'une bonne santé ; le suivi et le soulagement des symptômes et des comorbidités reliés à la SP ; le suivi des rechutes et des effets indésirables associés aux traitements. N'oublions pas non plus la coordination des services paramédicaux afin d'assurer, durant l'évolution de la SP, une continuité des soins répondant aux besoins complexes et en constante évolution des patients atteints de cette maladie.

Balancing Early Aggression Against Risk of Progression in Multiple Sclerosis.

Multiple sclerosis is a chronic demyelinating disease characterized by focal and diffuse inflammation of the central nervous system resulting in significant physical and cognitive disabilities. Disease-modifying therapies targeting the dysfunctional immune response are most effective in the first few years after disease onset, indicating that there is a limited time window for therapy to influence the disease course. No evidence of disease activity is emerging as a new standard for treatment response and may be associated with improved long-term disability outcomes. An aggressive management strategy, including earlier use of more potent immunomodulatory agents and close monitoring of the clinical and radiologic response to treatment, is recommended to minimize early brain volume loss and slow the progression of physical and cognitive impairments in patients with relapsing-remitting multiple sclerosis.

From progression to progress: The future of multiple sclerosis.

Significant advances have been made in the diagnosis and treatment of multiple sclerosis in recent years yet challenges remain. The current classification of MS phenotypes according to disease activity and progression, for example, does not adequately reflect the underlying pathophysiological mechanisms that may be acting in an individual with MS at different time points. Thus, there is a need for clinicians to transition to a management approach based on the underlying pathophysiological mechanisms that drive disability in MS. A Canadian expert panel convened in January 2023 to discuss priorities for clinical discovery and scientific exploration that would help advance the field. Five key areas of focus included: identifying a mechanism-based disease classification system; developing biomarkers (imaging, fluid, digital) to identify pathologic processes; implementing a data-driven approach to integrate genetic/environmental risk factors, clinical findings, imaging and biomarker data, and patient-reported outcomes to better characterize the many factors associated with disability progression; utilizing precision-based treatment strategies to target different disease processes; and potentially preventing disease through Epstein-Barr virus (EBV) vaccination, counselling about environmental risk factors (e.g. obesity, exercise, vitamin D/sun exposure, smoking) and other measures. Many of the tools needed to meet these needs are currently available. Further work is required to validate emerging biomarkers and tailor treatment strategies to the needs of individual patients. The hope is that a more complete view of the individual's pathobiology will enable clinicians to usher in an era of truly personalized medicine, in which more informed treatment decisions throughout the disease course achieve better long-term outcomes.

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis.

Importance: Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective: To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants: This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures: Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures: Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results: The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance: In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software.

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.

Laquinimod in multiple sclerosis.

Laquinimod is a novel, orally administered immune-modulatory molecule in advanced phase clinical trials in relapsing-remitting multiple sclerosis. Experimental evidence to date, derived mostly from animal models of multiple sclerosis, suggests that laquinimod may mediate its effects via modulating pro-inflammatory immune responses and interfering with cell trafficking, as well as potentially acting directly in the central nervous system to limit demyelination and axonal injury. The clinical trial results to date have established efficacy on imaging markers of disease activity and have shown a favorable safety and tolerability profile. If phase III studies confirm clinical efficacy and safety, laquinimod would represent a welcome new option in the treatment of multiple sclerosis.

Safety of Fingolimod in Patients with Multiple Sclerosis Switched from Natalizumab: Results from TRANSITION-A 2-Year, Multicenter, Observational, Cohort Study.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs). We assessed effectiveness by recording relapses, Expanded Disability Status Scale (EDSS) scores, and MRI activity. Of 637 patients enrolled, 505 completed the study (mean age, 42 years). Overall, 72.8% and 12.7% experienced AEs and SAEs respectively. The most common AEs were fatigue, headache, and urinary tract infection; no cases of PML were observed. Fingolimod treatment resulted in low disease activity. Patients with ≤8 weeks washout period had a markedly lower risk of relapses (4.5%) than those with >8 weeks (51.4%). In patients switching from natalizumab to fingolimod, no new safety signals with overall low relapse activity were observed in patients with washout latencies of ≤8 weeks before fingolimod initiation. Fingolimod was found to be safe and effective in patients transitioning from natalizumab.