Core data set para la generación de datos de la vida real en esclerosis múltiple: adaptación de una iniciativa global para América Latina / Core data set for real world data in multiple sclerosis: customization for latin america from a global task force recommendation

Introducción: Los objetivos primarios del core data set son reducir la heterogeneidad y promover la armonización entre las fuentes de datos en la esclerosis múltiple (EM), reduciendo así el tiempo necesario para ejecutar esfuerzos en la recolección de datos de vida real. Recientemente, un grupo liderado por la Multiple Sclerosis Data Alliance ha desarrollado un core data set para la recolección de datos del mundo real en EM a nivel global. Nuestro objetivo ha sido adaptar y consensuar este conjunto de datos globales a las necesidades de América Latina para que pueda ser implementado por los registros ya desarrollados y en proceso de desarrollo en la región. Material y métodos. Se conformó un grupo de trabajo regionalmente y se adaptó el core data set creado globalmente (proceso de traducción al español, incorporación de variables regionales y consenso sobre variables que se iban a utilizar). El consenso se obtuvo a través de la metodología Delphi remoto de ronda de cuestionarios y discusión a distancia de las variables del core data set. Resultados: Veinticinco profesionales de América Latina llevaron adelante el proceso de adaptación entre noviembre de 2022 y julio de 2023. Se estableció un acuerdo sobre un core data set de nueve categorías y 45 variables, versión 2023, con la sugerencia de implementarlo en registros desarrollados o en vías de desarrollo y cohortes de EM en la región. Conclusión: El core data set busca armonizar las variables recolectadas por los registros y las cohortes de EM en América Latina con el fin de facilitar dicha recolección y permitir una colaboración entre fuentes. Su implementación facilitará la recolección de datos de vida real y la colaboración en la región.(AU)

Introduction: The primary objective of the core data set is to reduce heterogeneity and promote harmonization among data sources in EM, thereby reducing the time needed to execute real life data collection efforts. Recently, a group led by the Multiple Sclerosis Data Alliance has developed a core data set for collecting real-world data on multiple sclerosis (MS) globally. Our objective was to adapt this global data set to the needs of Latin America, so that it can be implemented by the registries already developed and in the process of development in the region. Material and methods: A working group was formed regionally, the core data set created globally was adapted (translation process into Spanish, incorporation of regional variables and consensus on variables to be used). Consensus was obtained through the remote Delphi methodology of a round of questionnaires and remote discussion of the core data set variables. Results: A total of 25 professionals from Latin America carried out the adaptation process between November 2022 and July 2023. Agreement was established on a core data set of nine categories and 45 variables, version 2023 to suggest its implementation in developed or developing registries, and MS cohorts in the region. Conclusion: The core data set seeks to harmonize the variables collected by registries and cohorts in MS in Latin America in order to facilitate said collection and allow collaboration between sources. Its implementation will facilitate real life data collection and collaboration in the region.(AU)

Influencia de la capacidad manipulativa en la calidad de vida y actividades de la vida diaria en la esclerosis múltiple / Influence of manipulative skills on quality of life and activities of daily living in multiple sclerosis

Introducción: Más de un 50% de los pacientes diagnosticados con esclerosis múltiple (EM) comunican problemas con la función manipulativa e impedimentos en su vida diaria a causa de esta alteración. Por ello, el objetivo del presente estudio es determinar la afectación que la fuerza de pinza, la fuerza de presa y la destreza manipulativa ejercen sobre la calidad de vida y la autonomía personal de las personas diagnosticadas de EM, y estudiar si existe diferencia de estos aspectos entre los distintos tipos de esta enfermedad. Sujetos y métodos: Se contó con una muestra total de 126 participantes, de los cuales 57 fueron controles, y 69, casos. A todos ellos se les evaluó con el Multiple Sclerosis Quality of Life-54, el Nine-Hole Peg Test, la dinamometría de pinza y de presa para la medición de la fuerza, y el índice de Barthel para la evaluación de las actividades básicas de la vida diaria. Resultados: Las personas con EM presentaron peores fuerza de pinza, fuerza de presa, destreza manipulativa, desempeño en actividades básicas de la vida diaria y calidad de vida (p < 0,001). La fuerza de presa es un factor condicionante en el desempeño de actividades básicas y calidad de vida en personas con EM. En cuanto al tipo de EM, el tipo remitente-recurrente presentó mejores valores (p < 0,001).Conclusiones: Los hallazgos de este estudio apuntan a que los pacientes diagnosticados con EM presentan una disminución en la fuerza de pinza, la fuerza de presa, la destreza manipulativa, la calidad de vida y la autonomía en las actividades de la vida diaria en comparación con la población sana.(AU)

Introduction: More than 50% of patients diagnosed with multiple sclerosis report problems with manipulative function and impairments in their daily lives due to this disorder. Therefore, the aim of the present study is to determine how pinch strength, prey strength and manipulative dexterity affect the quality of life and personal autonomy of people diagnosed with multiple sclerosis and to study whether there is a difference in these aspects between different types of multiple sclerosis.Subjects and methods: There was a total sample of 126 participants, of which 57 were controls and 69 cases. All of them were assessed with a Multiple Sclerosis Quality of Life-54 test, Nine-Hole Peg Test and Barthel Index.Results: People with multiple sclerosis have worse pinch strength, prey strenght, manipulative dexterity, performance in basic activities of daily living and quality of life (p < 0.001). Prey strength is a conditioning factor for performance and quality of life in people with multiple sclerosis. As for the type of multiple sclerosis, relapsing-remitting multiple sclerosis presented better values (p < 0.001).Conclusions: The findings of this study point to the fact that patients diagnosed with multiple sclerosis have a decrease in prey strength, pinch strength, manipulative dexterity, quality of life and autonomy in activities of daily living compared to the healthy population.(AU)

Synaptic Protein Loss in Extracellular Vesicles Reflects Brain and Retinal Atrophy in People With Multiple Sclerosis.

OBJECTIVES: To assess whether the rate of change in synaptic proteins isolated from neuronally enriched extracellular vesicles (NEVs) is associated with brain and retinal atrophy in people with multiple sclerosis (MS). METHODS: People with MS were followed with serial blood draws, MRI (MRI), and optical coherence tomography (OCT) scans. NEVs were immunocaptured from plasma, and synaptopodin and synaptophysin proteins were measured using ELISA. Subject-specific rates of change in synaptic proteins, as well as brain and retinal atrophy, were determined and correlated. RESULTS: A total of 50 people with MS were included, 46 of whom had MRI and 45 had OCT serially. The rate of change in NEV synaptopodin was associated with whole brain (rho = 0.31; p = 0.04), cortical gray matter (rho = 0.34; p = 0.03), peripapillary retinal nerve fiber layer (rho = 0.37; p = 0.01), and ganglion cell/inner plexiform layer (rho = 0.41; p = 0.006) atrophy. The rate of change in NEV synaptophysin was also correlated with whole brain (rho = 0.31; p = 0.04) and cortical gray matter (rho = 0.31; p = 0.049) atrophy. DISCUSSION: NEV-derived synaptic proteins likely reflect neurodegeneration and may provide additional circulating biomarkers for disease progression in MS.

Is increased activator protein 1 in cerebrospinal fluid as a potential biomarker that distinguishes idiopathic intracranial hypertension from multiple sclerosis?

OBJECTIVES: To distinguish whether idiopathic intracranial hypertension (IIH) is a condition predisposing to multiple sclerosis (MS) or an isolated disease, the current gene transcription factor Activator Protein-1 (AP-1) was evaluated with its potential to differentiate both diseases. BACKGROUND: The aim of this study was to investigate the use of AP-1 as biomarkers for the discrimination of IIH and MS. METHODS: AP-1, TNF-α, and IL-6 protein values in the CSF of the cases were evaluated by the ELISA method. The numerical measures of the groups and the ability of AP-1 to distinguish the groups were analyzed with the ROC curve. RESULTS: There was no difference between the groups in CSF TNF-α, IL-6, CSF, and serum biochemistry analyses. However, it was determined that the AP-1 concentration (pg/ml) was significantly higher in the IIH group, the sensitivity of AP-1 in separating those with IIH was 75%, and the specificity in separating those with MS was 60% in those with an AP-1 concentration of 606.5 and above. CONCLUSION: According to our results, the fact that CSF TNF-α and IL-6 values did not differ in IIH compared to MS revealed that IIH could not methodologically control MS, and AP-1 was a supportive parameter in differentiating both diseases (Tab. 2, Fig. 1, Ref. 31).

Evaluation of optical coherence tomography findings in patients with multiple sclerosis and glaucoma.

PURPOSE: Glaucoma and multiple sclerosis (MS) can cause optic disc pathology and, in this way, affect optical coherence tomography (OCT) data. In this context, the objective of this study is to investigate the changes in the mean, quadrant, and sector data measured by OCT in glaucoma and MS patients. METHODS: The sample of this prospective cohort study consisted of 42 MS patients (84 eyes), 34 Primary open-angle glaucomas patients (67 eyes), and 24 healthy control subjects (48 eyes). The MS group was divided into two groups according to the presence of a history of optic neuritis. Accordingly, those with a history of optic neuritis were included in the MS ON group, and those without a history of optic neuritis were included in the MS NON group. The differences between these groups in the mean, quadrant, and sector data related to the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) were evaluated. RESULTS: Superior nasal (SN), superior temporal (ST), inferior nasal (IN), and superior quadrant (SUP) values were significantly lower in the glaucoma group than in the MS group (p < 0.05). The mean superior GCC (GCC SUP) value was significantly lower in the MS ON group than in the glaucoma group (p < 0.05). On the other hand, SN, ST, inferior temporal (IT), IN, average RNFL (AVE RNFL), semi-average superior RNFL (SUP AVE RNFL), semi-average inferior RNFL (INF AVE RNFL), SUP, and inferior quadrant RNFL (INF) values were significantly lower in the glaucoma group than in the MS NON group (p < 0.05). CONCLUSION: RNFL and GCC parameters get thinner in MS and glaucoma patients. While the inferior and superior RNFL quadrants are more frequently affected in glaucoma patients, the affected quadrants vary according to the presence of a history of optic neuritis in MS patients. It is noteworthy that the GCC superior quadrant was thin in MS ON patients. The findings of this study indicate that OCT data may be valuable in the differential diagnosis of glaucoma and MS.

[Optical coherence tomography angiography in the diagnosis of multiple sclerosis]. / Opticheskaya kogerentnaya tomografiya-angiografiya v diagnostike rasseyannogo skleroza.

PURPOSE: This study analyzes the main changes in retinal microcirculation in patients with multiple sclerosis (MS) and their relationship with the type of disease course. MATERIAL AND METHODS: 159 patients (318 eyes) were examined. The groups were formed according to the type of course and duration of MS: group 1 - 37 patients (74 eyes; 23.27%) with relapsing-remitting MS (RRMS) less than 1 year; group 2 - 47 patients (94 eyes; 29.56%) with RRMS from 1 year to 10 years; group 3 - 44 patients (86 eyes; 27.05%) with RRMS >10 years; group 4 - 32 patients (64 eyes; 20.12%) with secondary progressive MS (SPMS). Subgroups A and B were allocated within each group depending on the absence or presence of optic neuritis (ON). Patients underwent standard ophthalmological examination, including optical coherence tomography angiography (OCTA). RESULTS: A decrease in the vessel density (wiVD) and perfusion density (wiPD) in the macular and peripapillary regions was revealed, progressing with the duration of the disease and with its transition to the progressive type. The minimum values were observed in patients with SPMS (group 4), with the most pronounced in the subgroup with ON (wiVD = 16.06±3.65 mm/mm2, wiPD = 39.38±9.46%, ppwiPD = 44.06±3.09%, ppwiF = 0.41±0.05). CONCLUSION: OCTA provides the ability to detect subclinical vascular changes and can be considered a comprehensive, reliable method for early diagnosis and monitoring of MS progression.

[Treatment of multiple sclerosis]. / Behandelmogelijkheden bij multiple sclerose.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, caused by an autoimmune reaction. Treatment options have largely increased over the years. In this article, we present two clinical cases. Patient A has a classic relapsing remitting course of multiple sclerosis with satisfactory effect on second line therapy. Patient B had a stable disease course until a new relapse occurred after the initiation of TNF-alpha blocking therapy because of Crohn's disease. The co-occurrence of multiple auto-immune diseases creates challenges, but also opportunities in choosing the right treatment strategy.

The landscape of real-world evidence of rituximab utilization and clinical outcomes in patients with cancer, rheumatoid arthritis, and multiple sclerosis: A scoping review.

BACKGROUND: Rituximab (RTX) is an anti-CD20 monoclonal antibody that is used to treat various conditions in cancer, rheumatoid arthritis (RA), and multiple sclerosis (MS). Although RTX has been used in the United States for almost 3 decades, questions remain regarding its real-world utilization and effectiveness. OBJECTIVE: To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS. METHODS: A broad search was conducted in MEDLINE, Embase, and CINAHL covering the period of January 2010 to June 2022. Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. Data were extracted and summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state. RESULTS: A total of 260 studies met eligibility criteria, with 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Across all disease cohorts, most studies (n = 189; 72.7%) were retrospective. 171 (65.8%) studies used hospital or electronic health record data as their data source and 65 (23.2%) used registry databases. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Conclusive statements on RTX's benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug's positive benefit. There were limited studies assessing RTX use, associated economic burden, and biosimilar switching. CONCLUSIONS: The findings underscore the need for health care providers to better understand the treatment landscape and utilization of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence can help support health care decisions and treatment using rituximab.

Astroglial connexin 43 is a novel therapeutic target for chronic multiple sclerosis model.

In chronic stages of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalitis (EAE), connexin (Cx)43 gap junction channel proteins are overexpressed because of astrogliosis. To elucidate the role of increased Cx43, the central nervous system (CNS)-permeable Cx blocker INI-0602 was therapeutically administered. C57BL6 mice with chronic EAE initiated by MOG35-55 received INI-0602 (40 mg/kg) or saline intraperitoneally every other day from days post-immunization (dpi) 17-50. Primary astroglia were employed to observe calcein efflux responses. In INI-0602-treated mice, EAE clinical signs improved significantly in the chronic phase, with reduced demyelination and decreased CD3+ T cells, Iba-1+ and F4/80+ microglia/macrophages, and C3+GFAP+ reactive astroglia infiltration in spinal cord lesions. Flow cytometry analysis of CD4+ T cells from CNS tissues revealed significantly reduced Th17 and Th17/Th1 cells (dpi 24) and Th1 cells (dpi 50). Multiplex array of cerebrospinal fluid showed significantly suppressed IL-6 and significantly increased IL-10 on dpi 24 in INI-0602-treated mice, and significantly suppressed IFN-γ and MCP-1 on dpi 50 in the same group. In vitro INI-0602 treatment inhibited ATP-induced calcium propagations of Cx43+/+ astroglial cells to similar levels of those of Cx43-/- cells. Astroglial Cx43 hemichannels represent a novel therapeutic target for chronic EAE and MS.

Gas6/TAM system as potential biomarker for multiple sclerosis prognosis.

Introduction: The protein growth arrest-specific 6 (Gas6) and its tyrosine kinase receptors Tyro-3, Axl, and Mer (TAM) are ubiquitous proteins involved in regulating inflammation and apoptotic body clearance. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system leading to progressive and irreversible disability if not diagnosed and treated promptly. Gas6 and TAM receptors have been associated with neuronal remyelination and stimulation of oligodendrocyte survival. However, few data are available regarding clinical correlation in MS patients. We aimed to evaluate soluble levels of these molecules in the cerebrospinal fluid (CSF) and serum at MS diagnosis and correlate them with short-term disease severity. Methods: In a prospective cohort study, we enrolled 64 patients with a diagnosis of clinical isolated syndrome (CIS), radiological isolated syndrome (RIS) and relapsing-remitting (RR) MS according to the McDonald 2017 Criteria. Before any treatment initiation, we sampled the serum and CSF, and collected clinical data: disease course, presence of gadolinium-enhancing lesions, and expanded disability status score (EDSS). At the last clinical follow-up, we assessed EDSS and calculated MS severity score (MSSS) and age-related MS severity (ARMSS). Gas6 and TAM receptors were determined using an ELISA kit (R&D Systems) and compared to neurofilament (NFLs) levels evaluated with SimplePlex™ fluorescence-based immunoassay. Results: At diagnosis, serum sAxl was higher in patients receiving none or low-efficacy disease-modifying treatments (DMTs) versus patients with high-efficacy DMTs (p = 0.04). Higher CSF Gas6 and serum sAXL were associated with an EDSS <3 at diagnosis (p = 0.04; p = 0.037). Serum Gas6 correlates to a lower MSSS (r2 = -0.32, p = 0.01). Serum and CSF NFLs were confirmed as disability biomarkers in our cohort according to EDSS (p = 0.005; p = 0.002) and MSSS (r2 = 0.27, p = 0.03; r2 = 0.39, p = 0.001). Results were corroborated using multivariate analysis. Conclusions: Our data suggest a protective role of Gas6 and its receptors in patients with MS and suitable severity disease biomarkers.

Human regulatory memory B cells defined by expression of TIM-1 and TIGIT are dysfunctional in multiple sclerosis.

Background: Regulatory B cells (Bregs) play a pivotal role in suppressing immune responses, yet there is still a lack of cell surface markers that can rigorously identify them. In mouse models for multiple sclerosis (MS), TIM-1 or TIGIT expression on B cells is required for maintaining self-tolerance and regulating autoimmunity to the central nervous system. Here we investigated the activities of human memory B cells that differentially express TIM-1 and TIGIT to determine their potential regulatory function in healthy donors and patients with relapsing-remitting (RR) MS. Methods: FACS-sorted TIM-1+/-TIGIT+/- memory B (memB) cells co-cultured with allogenic CD4+ T cells were analyzed for proliferation and induction of inflammatory markers using flow cytometry and cytokine quantification, to determine Th1/Th17 cell differentiation. Transcriptional differences were assessed by SMARTSeq2 RNA sequencing analysis. Results: TIM-1-TIGIT- double negative (DN) memB cells strongly induce T cell proliferation and pro-inflammatory cytokine expression. The TIM-1+ memB cells enabled low levels of CD4+ T cell activation and gave rise to T cells that co-express IL-10 with IFNγ and IL-17A or FoxP3. T cells cultured with the TIM-1+TIGIT+ double positive (DP) memB cells exhibited reduced proliferation and IFNγ, IL-17A, TNFα, and GM-CSF expression, and exhibited strong regulation in Breg suppression assays. The functional activity suggests the DP memB cells are a bonafide Breg population. However, MS DP memB cells were less inhibitory than HC DP memB cells. A retrospective longitudinal study of anti-CD20 treated patients found that post-treatment DP memB cell frequency and absolute number were associated with response to therapy. Transcriptomic analyses indicated that the dysfunctional MS-derived DP memB/Breg population exhibited increased expression of genes associated with T cell activation and survival (CD80, ZNF10, PIK3CA), and had distinct gene expression compared to the TIGIT+ or TIM-1+ memB cells. Conclusion: These findings demonstrate that TIM-1/TIGIT expressing memory B cell subsets have distinct functionalities. Co-expression of TIM-1 and TIGIT defines a regulatory memory B cell subset that is functionally impaired in MS.

Inter-assay diagnostic accuracy of cerebrospinal fluid kappa free light chains for the diagnosis of multiple sclerosis.

Background: Cerebrospinal fluid (CSF) kappa free light chain (κFLC) measures gained increasing interest as diagnostic markers in multiple sclerosis (MS). However, the lack of studies comparing assay-dependent diagnostic cutoff values hinders their use in clinical practice. Additionally, the optimal κFLC parameter for identifying MS remains a subject of ongoing debate. Objectives: The aim of this study was to compare same-sample diagnostic accuracies of the κFLC index, κIgG index, CSF κFLC/IgG ratio, and isolated CSF κFLC (iCSF-κFLC) between two reference centers using different methods. Methods: Paired serum and CSF samples were analyzed for κFLC and albumin concentrations by Freelite®-Optilite (Sint-Jan Bruges hospital) and N Latex®-BNII (Ghent University hospital). Diagnostic performance to differentiate MS from controls was assessed using ROC curve analysis. Results: A total of 263 participants were included (MS, n = 80). Optimal diagnostic cutoff values for the κFLC index (Freelite®-Optilite: 7.7; N Latex®-BNII: 4.71), κIgG index (Freelite®-Optilite: 14.15, N Latex®-BNII: 12.19), and CSF κFLC/IgG ratio (Freelite®-Optilite: 2.27; N Latex®-BNII: 1.44) differed between the two methods. Sensitivities related to optimal cutoff values were 89.9% (Freelite®-Optilite) versus 94.6% (N Latex®-BNII) for the κFLC index, 91% (Freelite®-Optilite) versus 92.2% (N Latex®-BNII) for the κIgG index, and 81.3% (Freelite®-Optilite) versus 91.4% (N Latex®-BNII) for the CSF κFLC/IgG ratio. However, for iCSF-κFLC, optimal diagnostic cutoff values (0.36 mg/L) and related specificities (81.8%) were identical with a related diagnostic sensitivity of 89.9% for Freelite®-Optilite and 90.5% for N Latex®-BNII. The diagnostic performance of the κFLC index [area under the curve (AUC) Freelite®-Optilite: 0.924; N Latex®-BNII: 0.962] and κIgG index (AUC Freelite®-Optilite: 0.929; N Latex®-BNII: 0.961) was superior compared to CSF oligoclonal bands (AUC: 0.898, sensitivity: 83.8%, specificity: 95.9%). Conclusions: The κFLC index and the κIgG index seem to be excellent markers for identifying MS, irrespective of the method used for κFLC quantification. Based on the AUC, they appear to be the measures of choice. For all measures, optimal cutoff values differed between methods except for iCSF-κFLC. iCSF-κFLC might therefore serve as a method-independent, more cost-efficient, initial screening measure for MS. These findings are particularly relevant for clinical practice given the potential future implementation of intrathecal κFLC synthesis in MS diagnostic criteria and for future multicentre studies pooling data on κFLC measures.

Value contribution of blood-based neurofilament light chain as a biomarker in multiple sclerosis using multi-criteria decision analysis.

Introduction: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that represents a leading cause of non-traumatic disability among young and middle-aged adults. MS is characterized by neurodegeneration caused by axonal injury. Current clinical and radiological markers often lack the sensitivity and specificity required to detect inflammatory activity and neurodegeneration, highlighting the need for better approaches. After neuronal injury, neurofilament light chains (NfL) are released into the cerebrospinal fluid, and eventually into blood. Thus, blood-based NfL could be used as a potential biomarker for inflammatory activity, neurodegeneration, and treatment response in MS. The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the Multi-Criteria Decision Analysis (MCDA) methodology. Materials and methods: A literature review was performed, and the results were synthesized in the evidence matrix following the criteria included in the MCDA framework. The study was conducted by a multidisciplinary group of six experts. Participants were trained in MCDA and scored the evidence matrix. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. Results: MS was considered a severe condition as it is associated with significant disability. There are unmet needs in MS as a disease, but also in terms of biomarkers since no blood biomarker is available in clinical practice to determine disease activity, prognostic assessment, and response to treatment. The results of the present study suggest that quantification of blood-based NfL may represent a safe option to determine inflammation, neurodegeneration, and response to treatments in clinical practice, as well as to complement data to improve the sensitivity of the diagnosis. Participants considered that blood-based NfL could result in a lower use of expensive tests such as magnetic resonance imaging scans and could provide cost-savings by avoiding ineffective treatments. Lower indirect costs could also be expected due to a lower impact of disability consequences. Overall, blood-based NfL measurement is supported by high-quality evidence. Conclusion: Based on MCDA methodology and the experience of a multidisciplinary group of six stakeholders, blood-based NfL measurement might represent a high-value-option for the management of MS in Spain.

Risk factors and long-term outcomes of oropharyngeal dysphagia in persons with multiple sclerosis: a systematic review protocol.

BACKGROUND: Oropharyngeal dysphagia (OPD) can be functionally debilitating in persons with multiple sclerosis (pwMS). OPD induces alterations in safety and efficiency of food and/or liquid ingestion and may incur negative sequalae such as aspiration pneumonia or malnutrition/dehydration. Early detection and timely management of OPD in pwMS could prevent such complications and reduce mortality rates. Identifying risk factors of OPD relative to its onset or repeat manifestation will enable the development of care pathways that target early assessment and sustained management. The aims of this systematic review are to compile, evaluate, and summarize the existing literature reporting potential risk factors and associated long-term outcomes (e.g., aspiration pneumonia, malnutrition, dehydration, and/or death) of OPD in pwMS. METHODS: We will undertake a systematic review to identify studies that describe patterns and complications of OPD in pwMS. Variables of interest include predictors of OPD along with long-term outcomes. We will search MEDLINE, Embase, CINAHL, AMED, the Cochrane Library, Web of Science, and Scopus. We will consider studies for inclusion if they involve at least 30 adult participants with MS and report risk factors for OPD and/or its long-term outcomes. Studies will be excluded if they refer to esophageal or oropharyngeal dysphagia induced by causes other than multiple sclerosis. Study selection and data extraction will be performed by two independent assessors for abstract and full article review. We will present study characteristics in tables and document research findings for dysphagia-related risk factors or its complications via a narrative format or meta-analysis if warranted (e.g., mean difference and/or risk ratio measurements). All included studies will undergo risk-of-bias assessment conducted independently by two authors with consensus on quality ratings. DISCUSSION: There is a lacune for systematic reviews involving risk factors and long-term outcomes of dysphagia in pwMS to date. Our systematic review will provide the means to develop accurate and efficient management protocols for careful monitoring and evaluation of dysphagia in pwMS. The results of this systematic review will be published in a peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022340625.

Investigating disparities in smoking cessation treatment for veterans with multiple sclerosis: A national analysis.

BACKGROUND AND AIMS: Smoking is a risk factor for multiple sclerosis (MS) development, symptom burden, decreased medication efficacy, and increased disease-related mortality. Veterans with MS (VwMS) smoke at critically high rates; however, treatment rates and possible disparities are unknown. To promote equitable treatment, we aim to investigate smoking cessation prescription practices for VwMS across social determinant factors. METHODS: We extracted data from the national Veterans Health Administration electronic health records between October 1, 2017, and September 30, 2018. To derive marginal estimates of the association of MS with receipt of smoking-cessation pharmacotherapy, we used propensity score matching through the extreme gradient boosting machine learning model. VwMS who smoke were matched with veterans without MS who smoke on factors including age, race, depression, and healthcare visits. To assess the marginal association of MS with different cessation treatments, we used logistic regression and conducted stratified analyses by sex, race, and ethnicity. RESULTS: The matched sample achieved a good balance across most covariates, compared to the pre-match sample. VwMS (n = 3320) had decreased odds of receiving prescriptions for nicotine patches ([Odds Ratio]OR = 0.86, p < .01), non-patch nicotine replacement therapy (NRT; OR = 0.81, p < .001), and standard practice dual NRT (OR = 0.77, p < .01), compared to matches without MS (n = 13,280). Men with MS had lower odds of receiving prescriptions for nicotine patches (OR = 0.88, p = .05), non-patch NRT (OR = 0.77, p < .001), and dual NRT (OR = 0.72, p < .001). Similarly, Black VwMS had lower odds of receiving prescriptions for patches (OR = 0.62, p < .001), non-patch NRT (OR = 0.75, p < .05), and dual NRT (OR = 0.52, p < .01). The odds of receiving prescriptions for bupropion or varenicline did not differ between VwMS and matches without MS. CONCLUSION: VwMS received significantly less smoking cessation treatment, compared to matched controls without MS, showing a critical gap in health services as VwMS are not receiving dual NRT as the standard of care. Prescription rates were especially lower for male and Black VwMS, suggesting that under-represented demographic groups outside of the white female category, most often considered as the "traditional MS" group, could be under-treated regarding smoking cessation support. This foundational work will help inform future work to promote equitable treatment and implementation of cessation interventions for people living with MS.

Understanding the meaning of the lived experience "maternal role" in women with multiple sclerosis and planning a supportive program: a combined exploratory study protocol.

BACKGROUND: The maternal role is one of the most challenging yet rewarding roles that women experience in their lives. It begins when a woman becomes pregnant, and as the pregnancy progresses, she prepares to fulfill her role as a mother. A woman's health plays a crucial role in her ability to fulfill the maternal role. Multiple sclerosis (MS), as an autoimmune disease, presents unique challenges in achieving this role. Failing to fulfill the maternal role can have lasting consequences for both the mother and the baby. Given the increasing number of women with MS of reproductive age in Iran and the absence of specific programs for this group during pregnancy and postpartum, researchers have decided to develop a supportive program by exploring the meaning of the maternal role and identifying the needs of these women during this period. METHODS/MATERIALS: This study will be conducted in 3 stages. The first stage involves a qualitative study to explore the meaning of the "maternal role" in women with MS through a descriptive and interpretive phenomenological approach based on Van Manen's method. Data will be collected through semi-structured interviews with pregnant women with MS and mothers with MS who have children under one-year-old, recruited from the Multiple Sclerosis Society of Mashhad, Iran. The second stage will involve designing a support program based on the findings of the phenomenological study, literature review, and exploratory interviews. A logical model will guide the development of the program, and validation will be conducted using the nominal group technique. DISCUSSION: This study is the first of its kind in Iran to explore the meaning of the maternal role and develop a support program for women with MS. It is hoped that the results of this study will help address the challenges of motherhood faced by these women.

The maternal role is considered one of the most significant roles a woman will undertake in her lifetime. It is a process in which a woman, as a mother, attains competency in her role and eventually becomes comfortable with her identity as a mother. However, there are various factors, such as diseases, that can impede a mother from fully embracing her role. Multiple sclerosis (MS), an autoimmune disease that predominantly affects women of reproductive age, is one such condition.Given the lack of research in Iran regarding the experiences of women with MS in their maternal role, a study was developed in three phases. The first phase involves interviewing pregnant women with MS and mothers with MS who have children under one-year-old to explore the meaning of the maternal role. In the second phase, utilizing the findings from the initial interviews and the experts' opinions, a support program will be created to assist women with MS during pregnancy and after giving birth, and in the last stage, this program will be evaluated by nominal group technique.

Oxidative phosphorylation regulates B cell effector cytokines and promotes inflammation in multiple sclerosis.

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.

Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis.

The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.