The contribution of tumor necrosis factor to multiple sclerosis: a possible role in progression independent of relapse?

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients.

Evaluation of ovarian reserve and the assisted reproductive technology (ART) cycles' outcome as well as the relapse rate within one year after ART in women with multiple sclerosis: a case-control study.

OBJECTIVE: To compare the ovarian reserve and the results of infertility treatment, as well as to investigate the relapse rate in the first year after the assisted reproductive technology (ART) cycle in patients with multiple sclerosis (MS) referred to Royan Institute. MATERIALS AND METHODS: This retrospective study was carried out to evaluate all women diagnosed with MS and referred to Royan Institute for assessment and treatment of possible infertility between 2011 and 2022. The control group consisted of randomly selected healthy women with tubal factor infertility who were referred for treatment during the same time period and matched in terms of age. A comparison was made between groups in terms of ovarian reserve and infertility treatment outcomes. Additionally, patients with MS who met the criteria were monitored via telephone to evaluate the symptoms, disability and relapse rate both pre- and post-ART. RESULTS: Over the course of a decade, the database documented a total of 60 cases diagnosed with MS. Upon examination of the records, it was found that in 27 patients only admission was done without any hormonal assessment or infertility treatment cycle and 5 patients proceeded with the intrauterine insemination cycle. Eventually, 28 women with MS underwent the ART cycle and all of them were treated with interferon beta, glatiramer acetate, or some oral disease modifying therapies. No statistically significant difference in terms of the basal levels of luteinizing hormone, follicle-stimulating hormone and anti-Müllerian hormone was found between the MS and control groups (P > 0.05). Two groups were comparable in terms of menstrual status. The study revealed that both groups exhibited similarities in terms of the controlled ovarian stimulation protocol and duration, the dosage of gonadotropin administered, as well as the ovarian response type, clinical pregnancy rate, and live birth rate (P > 0.05). After follow up, only 2 patients (9.5%) reported relapse of symptoms within one year after ART. CONCLUSION: The ovarian reserve and ovarian stimulation cycle and pregnancy outcomes following the ART cycle in MS patients were similar to the age-matched control group. The relapse rate of multiple sclerosis did not show a significant increase within a year following the ART cycle.

Early Adversity and Socioeconomic Factors in Pediatric Multiple Sclerosis: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS: This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS: MS cases (64% female, mean age 15.4 years, SD 2.8) were demographically similar to controls (60% female, mean age 14.9 years, SD 3.9). Cases were less likely to have a mother with a bachelor's degree or higher (OR 0.42, 95% CI 0.22-0.80, p = 0.009) and were more likely to experience childhood neighborhood disadvantage (OR 1.04 for each additional point on the neighborhood socioeconomic disadvantage score, 95% CI 1.00-1.07; p = 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION: Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.

[Optimal patient profile for ofatumumab treatment: analysis of Russian data from the Phase 3 study]. / Optimal'nyi profil' patsienta dlya lecheniya ofatumumabom: analiz rossiiskikh dannykh iz issledovaniya 3-i fazy.

The article provides an analysis of the features of the action of ofatumumab in subgroups of patients with multiple sclerosis (MS) who participated in phase 3 ASCLEPIOS I and II studies both in the general subgroup of 1882 patients and among 352 patients from the Russian Federation who participated in these studies. The results of the influence of age, gender, body weight of patients, as well as the basic level of disability on the EDSS scale, the presence of active foci on MRI and previously received therapy with drugs that alter the course of MS (PITRS) are presented. In a total group of 1.882 patients, a more positive effect of ofatumumab compared with teriflunomide was noted on the average annual incidence of exacerbations in men, younger people and with a mild baseline disability level - with a baseline EDSS level less than or equal to 3. In a subgroup of 352 patients from Russia, the same trends were noted, but dependencies were also revealed from the number of previously taken PITRS: a more significant difference was noted in patients with the lowest number of PITRS in the anamnesis. This feature was also confirmed by analyzing the secondary endpoints of the study: the number of active foci on MRI and the confirmed progression of disability according to the EDSS scale. Analysis in clinical subgroups makes it possible to clarify the profile of patients in whom the greatest clinical effect can be expected when using this new drug for the treatment of MS.

[Posterior reversible encephalopathy syndrome in autoimmune disorders]. / Sindrom zadnei obratimoi entsefalopatii pri autoimmunnykh narusheniyakh.

Posterior reversible encephalopathy syndrome (PRES) is characterized by nonspecific symptoms, including not only pronounced non-focal and various focal neurological signs but also specific neuroimaging features, including vasogenic edema affecting predominantly the posterior area. PRES usually develops in the setting of acute arterial hypertension. However, it is not uncommon for PRES to develop in non-hypertensive patients, including people with autoimmune disorders (multiple sclerosis, neuromyelitis optica spectrum disorder, etc). PRES could also be due to the toxic effects of drugs or other substances. The pathophysiological mechanisms of PRES include impaired autoregulation of cerebral blood flow due to acute arterial hypertension and toxic endotheliotropic effects of endogenous and exogenous factors.

[Biobanking in clinical trials involving multiple sclerosis patients]. / Biobankirovanie v klinicheskikh issledovaniyakh s uchastiem patsientov s rasseyannym sklerozom.

Investigation of multiple sclerosis (MS) pathogenesis requires sophisticated analytical tools of precision medicine, such as omics research, which include genomics, microbiomics and metabolomics (proteomics, lipidomics and glycomics). Such sensitive methods are based on careful preanalytical work with biomaterials to maintain quality and obtain objective results. Implementation of biobanking as a universal method for working with biomaterials will help to standardize the stages of research, compare different scientific team's results. Collaboration of MS researchers with large biobanks can also help to conduct multicenter and long-term prospective studies, to include a wide number of patients. In this article, we analyze the experience of biobanking practice technologies in studies of MS patients and share the experience of partnership between the Center for MS of the Tomsk Region and the Bank of Biological Material of the Siberian State Medical University.

[Possibilities of magnetic resonance morphometry and laboratory biomarkers in studying the progression of multiple sclerosis]. / Vozmozhnosti magnitno-rezonansnoi morfometrii i laboratornykh biomarkerov v izuchenii progressirovaniya rasseyannogo skleroza.

OBJECTIVE: To show that magnetic resonance morphometry and laboratory biomarkers are promising methods for early detection of progressive forms of multiple sclerosis (MS). MATERIAL AND METHODS: Eighty-one patients with MS were examined, magnetic resonance morphometry was performed in all of them, 60 patients were analyzed for neurofilament light chains (sNFL), phosphorylated neurofilament heavy chains (spNFH) and glial fibrillary protein (sGFAP) in serum by enzyme-linked immunosorbent assay. RESULTS: Brain volumes were negatively correlated with disease duration, EDSS score, 25-foot walk test score and 9-ring test and positively correlated with the Symbol-Numeric Test and the Montreal Cognitive Assessment. Patients with progressive types of MS (PMS) had smaller volumes of brain gray matter, cerebellar white matter, occipital lobes, caudate nucleus, hippocampus, pallidum, thalamus, and contiguous nucleus. A CSF volume greater than 15.06% could suggest progression (CI 54.79-91%) with a sensitivity of 77.78% and specificity of 70.18%. When patients were on DMT, they had larger thalamic volumes (median 1.09% [1.6; 1.16] vs 1.04% [0.95; 1.14]; p=0.02) and smaller CSF volumes (13.86±2.87% vs. 15.55±3.49%; p=0.03). The levels of sNFL and spNFH were not increased in PMS and during exacerbations, and the low obtained values of sNFL suggest poor sensitivity of the method. There were trends (p=0.374) towards higher sGFAP in patients with PRS (median 3.2 ng/mL [1.85; 4.6] compared to remitting MS (2.05 ng/mL [1.29; 4.52]). CONCLUSION: The results demonstrate the differences in brain volumes in patients with different types of MS and emphasize the importance of long-term follow-up to better assess disease progression.

[Adherence to treatment in the management of patients with multiple sclerosis]. / Priverzhennost' lecheniyu v vedenii patsientov s rasseyannym sklerozom.

Adherence to therapy largely determines the success of treatment interventions: low levels of adherence are associated with reduced treatment effectiveness. For many chronic diseases, the level of adherence to treatment is about 50% or less, which confirms the relevance of this topic and requires its research. The high costs of treatment, the need for long-term continuous use of drugs and the special socio-economic significance of a disease such as multiple sclerosis (MS) determine the importance of maintaining a high level of adherence to its treatment. An analysis of literature data on the concept of treatment adherence, methods of its definition and influencing factors was carried out, the values of the level of adherence in the treatment of MS, as well as measures to maintain it during the COVID-19 pandemic were considered. Increasing awareness of healthcare professionals about the problem of treatment adherence and ways to improve it helps to improve the efficiency of managing patients with MS. The paper considers the primary stage of the strategy to improve treatment adherence among patients with MS, namely the formation of expanded knowledge of the problem by specialists of a multidisciplinary team involved in the diagnosis and treatment of patients with MS.

[Experience in the management of pregnant patients with highly active multiple sclerosis in the Moscow region]. / Opyt vedeniya beremennykh patsientok s vysokoaktivnym rasseyannym sklerozom v Moskovskoi oblasti.

OBJECTIVE: To evaluate the effect of discontinuation or prolongation of DMT on the activity of the disease during pregnancy and in the postpartum period in patients with aggressive MS from the Moscow region. MATERIAL AND METHODS: The study included female patients with an aggressive course of MS receiving DMT at the time of pregnancy. The patients were followed-up for the period 2016 to February 2024. RESULTS: There were 17 cases of pregnancy during natalizumab (NZ) therapy; discontinuation of therapy in the first trimester of pregnancy provoked a resumption of disease activity in half of the patients. There were no exacerbations in patients whose therapy was prolonged until the 34th week of pregnancy. In 5 patients receiving fingolimod (FGL), therapy was discontinued upon the establishment of pregnancy, which caused the resumption of disease activity in three out of 5 cases. In 3 patients receiving anti-B-cell therapy, pregnancy occurred within a few months after the next infusion, there were no exacerbations during pregnancy. CONCLUSION: The cancellation of NS therapy in the early stages of pregnancy in most cases leads to the resumption of disease activity during pregnancy. Exacerbations in the postpartum period also correlated with early discontinuation of therapy and with a long period before the restart of infusions. Prolongation of infusions to 30-34 weeks of pregnancy contributed to stabilization of the condition throughout the perinatal period. Discontinuation of FGL therapy at the onset of pregnancy increased the risk of repeated relapses of the disease, up to the development of inflammatory immune restoration syndrome during pregnancy and contributed to the increase in disability in the postpartum period.

[The effect of pregnancy on multiple sclerosis]. / Vliyanie beremennosti na rasseyannyi skleroz.

Planning for pregnancy and possibility of disease modifying treatment (DMTs) is an important question in female patients of reproductive age who suffer from multiple sclerosis (MS). The frequency of refusals to plan pregnancy is 14%. This is due to numerous concerns about the course of pregnancy, its outcomes, as well as the possible effect of DMTs on the fetus and the probability of disease transmission to a child. The article discusses immunological reactions taking place in MS patients during pregnancy, which are protective in its nature. Data for all groups of DMTs regarding pregnancy planning, possible risks of their impact on fertility and teratogenicity is presented.

[The central vein sign in the differential diagnosis of multiple sclerosis]. / Simptom tsentral'noi veny v differentsial'noi diagnostike rasseyannogo skleroza.

OBJECTIVE: To carry out a clinical and radiological assessment of the central vein sign (CVS) as a diagnostic marker for multiple sclerosis (MS) and other demyelinating and non-demyelinating diseases with focal brain damage, using clinical and laboratory examination data, as well as MRI. MATERIAL AND METHODS: The results of clinical and neuroradiological examination of 107 patients diagnosed with MS or with other diseases accompanied by focal brain damage according to MRI data were analyzed. RESULTS: CVS is a sensitive but low-specific diagnostic marker of MS. According to our data, the sensitivity and specificity of 40 and 50% of the threshold of perivenular lesions in the diagnosis of MS are the same and amount to 100% and 39.4%, respectively. Neither the type of MS course, nor the severity of the course, nor the intake of DMT (disease modifying treatment), affect the proportion of foci with CVS. The spread of the proportion of foci with CVS in patients with MS was 60-100%. The proportion of foci with CVS is below 40 and 50% of the threshold in patients with demyelinating and non-demyelinating diseases (NMOSD, migraine, systemic lupus erythematosus, Susak disease, CLIPPERS), which allows for differential diagnosis with MS. The proportion of foci with CVS comparable to MS in patients with acute disseminated encephalomyelitis, small vessel disease, as well as in patients with radiologically isolated syndrome does not allow using this symptom in the differential diagnosis of these conditions. CONCLUSION: The use of CVS as a diagnostic marker of MS is possible only in combination with the already existing diagnostic criteria of MS.

[Mistakes in the diagnosis of neuromyelitis optic spectrum diseases lead to wrong therapy and deterioration of patients' condition]. / Oshibki v diagnostike zabolevanii spektra optikoneiromielita privodyat k nepravil'noi terapii i ukhudsheniyu sostoyaniya patsientov.

Neuromyelitis optic spectrum diseases (NMOSD) are a group of rare neuroimmunological diseases involving mainly the optic nerves and spinal cord, to a lesser extent the brain, and causing severe exacerbations that lead to persistent disability of patients. For many years, opticoneuromyelitis was considered a prognostically unfavorable variant of the course of multiple sclerosis (MS), however, in 2004, specific autoantibodies to aquaporin-4 were found in such patients, which made it possible to isolate NMOSD into a separate group of demyelinating diseases other than MS. Due to similar clinical signs and the predominantly remitting course of diseases, it is often difficult to make a correct diagnosis and, accordingly, prescribe effective therapy, which often leads to incorrectly selected therapy with incorrect diagnosis. In some cases, this leads to a worsening of the course of NMOSD. We present a case of late diagnosis of NMOSD that confirms the development of exacerbation in the patient 2 months after the first course of therapy with alemtuzumab prescribed as a highly effective therapy for highly active remitting MS. Timely diagnosis of NMOSD makes it possible to exclude such cases.

[The first experience with the use of divozilimab in the treatment of multiple sclerosis patients in daily clinical practice]. / Pervyi opyt primeneniya divozilimaba dlya lecheniya patsientov s rasseyannym sklerozom v povsednevnoi klinicheskoi praktike.

OBJECTIVE: The aim of this study is to assess the efficacy and safety of divozilimab in patients who have received post-marketing treatment and participants of clinical trials BCD-132-2 and BCD-132-4 were conducted at the IHB RAS. Additionally, we will present a case report of divozilimab therapy in a patient with highly active multiple sclerosis (MS). MATERIAL AND METHODS: The study included 27 patients with MS. We assessed the dynamics of neurological status, magnetic resonance imaging (MRI) findings, and disability level during divozilimab treatment. We also analyzed the incidence and severity of adverse events (AE), including infusion reactions. RESULTS: During treatment with divozilimab, no exacerbations or radiological disease activity were observed after the first six months. Complete clinical remission was achieved in 25 patients. All 12 patients who received the drug as part of post-marketing use met the NEDA-3 criteria, and five of them showed improvement. Most AE were mild, none exceeding grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE). Laboratory parameter changes were also mild and did not exceed I-II grade according to CTCAE. There were no instances of therapy discontinuation due to intolerance. CONCLUSION: The data from post-registration use of divozilimab confirm the results of clinical trials, showing high efficacy of the drug with a predictable and favorable safety profile.

Challenges Implementing Patient and Public Involvement in a Digital Health Agile Project Which Includes Research, Business and Software Development.

Patient and public involvement (PPI) is a practice for involving future users in the design, development, and research of health technologies. There is increasing interest and demand for PPI, but little evidence based methodological support for integrating PPI in agile development processes. Multiple sclerosis (MS) is a chronic condition that severely impacts the lives of patients and requires active patient involvement. In this paper, we present the results of a case study, examining the adoption and integration of PPI into the development of a digital therapeutics solution for MS. The results highlight five critical phases that proved to be challenging: selecting patient participants, onboarding of patient participants and employees, framing tasks for patient participants, communication between patient participants and the rest of the development team, and reimbursements. The results are useful in creating evidence-based guidelines and methods for supporting the adoption of PPI.

Development of a Concourse for Two Q-Method Studies Exploring Perspectives of Patients with Multiple Sclerosis and Healthcare Professionals on the Use of Wearable Technology-Lessons Learnt.

This paper presents the generation of a Q-set for two Q studies investigating the perspectives of (1) patients with multiple sclerosis and (2) their healthcare professionals on the use of wearable technology. It describes the adopted Q methodology and how it was applied in different phases. The concourse is derived from the relevant literature, based on the unified theory of acceptance and use of technology (UTAUT2) model, with privacy as a moderator, and Hofstede's "Cultural Dimensions" framework, incorporates statements drawn from the concourse following review by experts This is followed by a pilot study involving 4 stakeholders to improve the relevance and quality of the research. A 43-statement Q-sample was developed for the first Q study, and a 32-statement Q-sample was developed for the second Q study. This preliminary study reported the development of a legitimate and reliable concourse in a transparent and comprehensive manner. The lessons learnt from developing the concourse in this study could be beneficial for future research when conducted in a similar digital healthcare context and in the context of MS where individuals often experience symptoms related to vision, sensation, coordination, and movement.

A 73-Year-Old Woman With Confusion, Visual Field Disturbances, and Edematous White Matter Lesions: From the National Multiple Sclerosis Society Case Conference Proceedings.

We describe the case of a 73-year-old woman presenting with headaches, confusion, and vision disturbances. Brain MRI showed a large T2-hyperintense lesion in the right temporo-occipital region with vasogenic edema and leptomeningeal enhancement. A leptomeningeal biopsy was performed, which led to a definitive diagnosis.

PEER CONNECT: a pragmatic feasibility randomised controlled trial of peer coaching for adults with long-term conditions.

OBJECTIVE: To test the feasibility of a targeted peer coaching intervention on the health and well-being of people with long-term health conditions and low activation attending outpatient clinics at a UK National Health Service (NHS) Trust. DESIGN: Randomised controlled feasibility trial, with embedded qualitative study. SETTING: An NHS integrated health and care organisation in the South West of England, UK, with significant areas of deprivation. PARTICIPANTS: Patients (over 18 year of age) of the Trust's rheumatology, pain or multiple sclerosis services, with a Patient Activation Measure score at level 1 or 2. INTERVENTION: Up to 14 sessions of peer coaching delivered in a stepped-down model delivered over 6 months. MAIN OUTCOMES: Primary feasibility outcomes were recruitment, retention, intervention adherence and peer, coach and staff experience.Secondary outcomes included psychological well-being, resource use, long-term condition management and disease-specific measures. RESULTS: 97 potential coaches were contacted directly. 27 (27.8%) were screened and of those 21 (77.8%) were eligible and recruited into the study. For a range of reasons, only five (23.8%) progressed through training and on to deliver peer coaching. 747 potential peers were invited to take part and 19 (2.5%) were screened. Of those screened, seven (36.8%) were eligible, recruited and randomised, all white females with median age of 50 years (range: 24-82 years). One peer in the intervention group withdrew prior to receiving the intervention, the remaining four received coaching. Peers and coaches reported a range of benefits related to their health and well-being. CONCLUSION: Coach recruitment, training and study procedures were feasible and acceptable. Due to low peer recruitment numbers, it was decided not to progress to a definitive trial. Further research is required to explore how to engage with and recruit people reporting low levels of activation and the acceptability and effectiveness of peer coaching for this group. TRIAL REGISTRATION NUMBER: ISRCTN12623577.

Immunogenicity, clinical efficacy, and safety of the sinopharm (BBIBP-CorV) SARS-CoV-2 vaccine among people with multiple sclerosis receiving disease-modifying therapies: a prospective cohort study.

BACKGROUND: To investigate the safety (adverse events [AEs] and post-vaccination multiple sclerosis [MS] activity within 6 weeks), clinical efficacy (protection against coronavirus disease 2019 [COVID-19]), and vaccine-induced humoral immunogenicity (SARS-CoV-2 neutralizing antibody, anti-nucleocapsid IgG, and anti-spike IgG) of the Sinopharm (BBIBP-CorV) vaccine among people with MS (PwMS) receiving different disease-modifying therapies (DMTs). METHODS: This prospective cohort study was conducted between November 2021 and May 2022. PwMS were followed for six months after the 2nd dose of vaccination. Antibody responses were measured 2-16 weeks after the 2nd dose injection. Multivariate logistic regression was employed to assess the impact of each DMT on dichotomous antibody responses, adjusting for age, sex, MS phenotype, expanded disability status scale, disease duration, and vaccination-antibody titration interval. RESULTS: Among the 261 screened PwMS, 209 (aged 38.23 ± 9.73 years, female: 70.8%; relapsing-remitting MS: 80.4%) were included. The frequencies of experiencing non-serious AEs and post-vaccination MS activity were 66.0% and 4.8%, respectively. Breakthrough COVID-19 infection was observed in 14.8% of the PwMS. A subcohort of 125 PwMS was assessed for antibody responses. Positive neutralizing antibodies, anti-nucleocapsid IgG, and anti-spike IgG were detected in 36.8%, 35.2%, and 52.0% of the PwMS, respectively. Multivariate regression indicated a 96% (OR: 0.04 [95% CI: 0.00, 0.51], P = 0.013), 93% (OR: 0.07 [0.01, 0.64], P = 0.019), and 89% (OR: 0.11 [0.01, 0.96], P = 0.045) reduced odds of positive neutralizing antibody, anti-nucleocapsid IgG, and anti-spike IgG, respectively, among fingolimod-receivers. Additionally, anti-CD20s-receivers had 88% (OR: 0.12 [0.02, 0.85], P = 0.034) lower odds of being positive for anti-nucleocapsid IgG. CONCLUSIONS: BBIBP-CorV appeared to be well tolerated in PwMS, with promising clinical efficacy. However, a suboptimal humoral response was observed in PwMS receiving fingolimod and anti-CD20s. Future research should investigate the relationship between humoral responses and the frequency and severity of COVID-19 infection across various DMTs.

The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis.

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.