Multiple Sclerosis Therapy Research Articles

Neurologic Outcomes in People With Multiple Sclerosis Treated With Immune Checkpoint Inhibitors for Oncologic Indications.

Immune checkpoint inhibitors (ICIs) are increasingly used against various cancers but are associated with immune-related adverse events (irAEs). Risk of irAEs may be higher in patients with certain preexisting autoimmune diseases, and these patients may also experience exacerbation of the underlying autoimmune disease following ICI initiation. People with multiple sclerosis (MS) have mostly been excluded from clinical trials of ICIs, so data on the safety of ICIs in MS are limited. This study aims to assess the rate of MS activity, as well as neurologic and nonneurologic irAEs in persons with MS treated with ICIs for cancer. Participating sites were invited to this retrospective observational study through the Medical Partnership 4 MS+ listserv. Seven large academic centers participated in the study, each conducting a systematic search of their electronic medical record system for patients with MS and history of ICI treatment. The participating neurologist reviewed each chart individually to ensure the inclusion criteria were met. Demographics and data on MS and cancer history, treatments, and outcomes were abstracted from patient charts using a structured instrument. We identified 66 people with MS (median age 66 years, 73% female, 68% not on disease-modifying therapy for MS) who were treated with ICIs for lung cancer (35%), melanoma (21%), or another oncologic indication. During post-ICI follow-up (median: 11.7 months, range 0.2-106.3 months), 2 patients (3%) had relapse or MRI activity, 3 (5%) had neurologic irAEs, and 21 (32%) had nonneurologic irAEs. At the last follow-up, 25 (38%) participants had partial or complete remission of their cancer, while 35 (53%) were deceased. In this multi-institutional systematic retrospective study of predominantly older patients with MS, most of whom were not on disease-modifying therapy, MS activity and neurologic irAEs following ICI treatment were rare. These data suggest that preexisting MS should not preclude the use of ICIs for cancer in older patients, but the results may not be generalizable to younger patients with active MS. Prospective studies of ICI safety that enroll younger patients with MS are needed.

Dimethyl Fumarate Reduces Methylglyoxal-derived Carbonyl Stress Through Nrf2/GSH Activation in SH-SY5Y Cells.

Carbonyl stress refers to the excessive accumulation of advanced glycation end products (AGEs) in mammalian tissues. This phenomenon plays a significant role in the pathogenesis of various diseases, including diabetes, chronic renal failure, arteriosclerosis, and central nervous system (CNS) disorders. We have previously demonstrated that an increase in glutathione concentration, dependent on the nuclear factor erythroid 2-related factor 2 (Nrf2) system, provides a potent cytoprotective effect against Methylglyoxal (MGO)-induced carbonyl stress. Meanwhile, dimethyl fumarate (DMF), known for its Nrf2-activating effects, was recently approved as a treatment for multiple sclerosis (MS), a neurodegenerative disease. DMF is a first line therapy for relapsing-remitting MS and may also be effective for other neurodegenerative conditions. However, the detailed mechanisms by which DMF mitigates neurodegenerative pathologies remain unclear. This study investigates the impact of DMF on anticarbonyl activity and its underlying mechanism focusing on the accumulation of carbonyl protein in the cell. MGO, a glucose metabolite, was used to induce carbonylation in the neuronal cell line. MGO is a typical carbonyl compound that readily reacts with arginine and lysine residues to form AGE-modified proteins. Methylglyoxal-derived hydroimidazolone 1 (MG-H1) often forms uncharged, hydrophobic residues on the protein surface, which can affect protein distribution and lead to misfolding. Our findings indicate that DMF increases levels of glutathione (GSH), glutamate cysteine ligase modifier subunit (GCLM), and nuclear Nrf2 in SH-SY5Y cells. Importantly, DMF pretreatment significantly reduced the accumulation of MG-H1-modified proteins. Furthermore, this effect of DMF was diminished when Nrf2 expression was suppressed and when GCL, a rate-limiting enzyme in GSH synthesis, was inhibited. Thus, the increase in GSH levels, leading to the activation of the Nrf2 pathway, a key factor in DMF's ability to suppress the accumulation of MG-H1-modified proteins. This study is the first to demonstrate that DMF possesses strong anticarbonyl stress activity in neuronal cells. Therefore, future research may extend the application of DMF to other CNS diseases associated with carbonyl stress, such as Alzheimer's and Parkinson's disease.

IL-37 suppresses CNS autoimmunity by increasing the frequency of Treg cells and reducing CD4 + T cell-derived IL-10 production.

Interleukin-37 (IL-37) has anti-inflammatory properties in innate and adaptive immunity. Patients with multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), have increased serum levels of IL-37. However, it is unknown whether IL-37 has an inhibitory effect on ongoing autoimmune neuroinflammation, thus offering a potential MS therapy. Here, we examined the effect of IL-37 in an experimental autoimmune encephalomyelitis (EAE) model after disease onset to determine if it was protective. IL-37-treated mice developed a less severe disease than control mice, with reduced demyelination as determined by increased expression of myelin basic protein. IL-37 suppressed inflammation by decreasing infiltration of CD4 + T cells into the CNS and increasing the frequency of regulatory T cells, while IL-10 expression by CD4 + T cells decreased over time in the CNS. Our findings confirm the immunomodulatory role of IL-37 in CNS inflammation during ongoing disease, thus indicating the potential of IL-37 as an inhibitory reagent for MS therapy.

Impact of symptomatic multiple sclerosis therapy on pregnancy outcome.

Information on symptomatic therapy (ST) use in women of childbearing age with multiple sclerosis is sparse, and data on the impact of ST pregnancy exposure on pregnancy outcome are lacking. To investigate (1) ST use patterns pre-conception, during pregnancy and postpartum and (2) pregnancy outcomes. Pregnancy data from the German Multiple Sclerosis and Pregnancy Registry were analyzed for the ST use from pre-conception to postpartum. Pregnancy outcomes were compared between ST-exposed (n = 282) and matched (disease modifying therapy and age) ST-naive (n = 536) pregnancies. Of 2,449 pregnancies, 1,053 (43.0%) received ST anytime between pre-conception and postpartum, 282 (11.5%) at pre-conception and during pregnancy. The most commonly used drug classes were antidepressants (24.8%), analgetics (31.0%), and anticonvulsives (8.7%). Exposure to ST during pregnancy did not result in an increased incidence of adverse pregnancy outcomes, major congenital abnormalities, or pregnancy complications. Nearly 50% of women used ST between pre-conception and postpartum, but only 12% pre-conception and during pregnancy. ST use during pregnancy did not adversely affect pregnancy outcomes in our cohort. More data are needed to analyze the effect of ST on pregnancy and fetal outcomes stratified by drug to improve recommendations for ST use in family planning.

The role of disease modifying therapies in late-onset multiple sclerosis: A Portuguese multicentric characterization study

IntroductionKnowledge about the effect of disease modifying treatment (DMT) in late-onset multiple sclerosis (LOMS, onset ≥50 years-old) is scarce. This study aims to evaluate the association between DMT use and multiple sclerosis (MS) evolution in a LOMS cohort. MethodsThis multicentre, retrospective and observational study included LOMS patients with ≥2 years of follow-up. Data on demographics, clinical/paraclinical (baseline and follow-up), DMT and adverse events were collected. Primary outcomes were irreversible EDSS 4.0 and 6.0 achievement and first year ARR. Univariate and multivariate regression models were conducted, with treated and/or relapsing phenotypes (RMS) subgroups analyses. ResultsWe included 232 patients (53.4 % with RRMS phenotype; 84.9 % submitted to DMT; median follow-up time of 141.5 (IQR 92.7–193.1) months). Treatment versus non-treatment did not affect EDSS milestones in multivariate analysis (adjusted to phenotype, baseline EDSS, age, and ARR), but initially receiving monoclonal antibodies (MAbs) was associated with lower odds of EDSS 4.0 (OR 0.13). In treated patients, starting with high efficacy DMT (HE-DMT) was related to a lower chance of EDSS 4.0 (OR 0.05) and 6.0 (OR 0.26) compared with being exclusively treated with moderate efficacy DMT (ME-DMT), with similar results when analysing the subgroup of RMS treated patients. In multivariate models, initial treatment with MAbs (vs. non-treatment) and with HE-DMT (vs. ME-DMT) were related to a lower first year ARR; when considering only RMS patients, every DMT class analysed reduced first year ARR vs. non-treatment. During DMT, we documented a rate of 0.6 % serious infections, 0.07 % opportunistic infections and 0.7 % neoplasm diagnosis per patient year. ConclusionDMT type and therapeutic strategy influenced LOMS disability accumulation and relapses in our cohort. Our findings support the importance of investment in LOMS treatment optimization.

Accelerated remyelination and immune modulation by the EBI2 agonist 7α,25-dihydroxycholesterol analogue in the cuprizone model

SummaryResearch indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF3-7α,25OHC, in the cuprizone model. The data showed that extending the bioavailability of 7α,25OHC is sufficient to accelerate remyelination in vivo. Moreover, the analogue, in contrast to the endogenous ligand, upregulated brain expression of Ebi2 and the synthesis of 15 lipids in the mouse corpus callosum. Mechanistically, the increased concentration of oxysterol likely disrupted its gradient in demyelinated areas of the brain, leading to the dispersion of infiltrating EBI2-expressing immune cells rather than their accumulation in demyelinated regions. Remarkably, the analogue CF3-7α,25OHC markedly decreased the lymphocyte and monocyte counts mimicking the key mechanism of action of some of the most effective disease-modifying therapies for multiple sclerosis. Furthermore, the Cd4+ transcripts in the cerebellum and CD4+ cell number in the corpus callosum were reduced compared to vehicle-treated mice. These findings suggest a mechanism by which EBI2/7α,25OHC signalling modulates the immune response and accelerates remyelination in vivo.

Multiple Sclerosis Disease-Modifying Therapy Use in the Department of Veteran Affairs and Medicare: A Comparative Analysis

BackgroundHigh-cost disease-modifying therapies (DMT) for multiple sclerosis (MS) have created affordability challenges for people with MS (PwMS) and payers. The Department of Veterans Affairs (VA) is the largest integrated healthcare system in the US and uses a variety of approaches to manage utilization and cost of MS DMT. The objective of this paper is to compare national utilization trends in the VA to the US Medicare program, another large federal public healthcare program. MethodsCounts of PwMS prescribed DMT from 2012 to 2021 in the VA and Medicare programs were used to estimate changes utilization over this period. For each DMT, we estimated the proportion of all DMT users treated in each year. Trends in utilization were compared to identify differences in how these systems manage DMT use. We compared demographics and DMT use between PwMS in the VA to previously published estimates from a Medicare cohort of PwMS. ResultsDMT use in PwMS was comparable in VA and Medicare programs (65.9% vs 69.7%). In younger (<50 years) PwMS, DMT use was more prevalent in the VA compared to Medicare (85.8% vs 76.9%). Between 2012 and 2021, the proportion of patients on DMT using a lower-efficacy agent (interferon beta and glatiramer) declined in both the VA (90% to 32%) and Medicare (81% to 38%). Oral DMT use (primarily fumarates and sphingosine 1-phosphate [S1P] modulators) increased to a similar degree such that by 2021, 39% of patients in both systems were receiving oral DMT. Use of high-efficacy B cell depleting DMT (ocrelizumab, ofatumumab, and rituximab) was consistently higher in the VA than in Medicare. Despite the approval of generic glatiramer and dimethyl fumarate in 2015 and 2020 respectively, 49% of glatiramer and 58% of fumarate utilization in the Medicare program continued to be for a branded product in 2021. ConclusionsGreater DMT use among younger PwMS along with more frequent use of high-efficacy B cell depleting DMT in VA has the potential to reduce disability and attendant healthcare system costs. Generic DMT adoption in the Medicare program was lower than might be expected. Future studies should evaluate the relationship between DMT utilization, costs, and health outcomes in these populations.

Drug Repurposing and Screening for Multiple Sclerosis Targeting Microglia and Macrophages.

Microglia/macrophages (MG/Mφ) play a central role in the pathogenesis of multiple sclerosis (MS). However, the intricacies of the immunomodulatory microenvironment in MS, particularly the heterogeneity and regulatory mechanisms of MG/Mφ subpopulations, remain elusive. The commonly used treatment options for MS have several drawbacks, such as significant side effects and uncertain efficacy. The exploration of developing new drugs targeting MG/Mφ for the treatment of MS remains to be investigated. We identified three distinct subpopulations of MG/Mφ, among which MG/Mφ_3 significantly increased as the experimental autoimmune encephalomyelitis (EAE) progressed. Ifenprodil and RO-25-6981 demonstrated notable inhibition of inflammatory factor expression, accompanied by reduced cytotoxicity. The interaction modes of these compounds with the common binding pocket in the GluN1b-GluN2B amino terminal domain heterodimer were elucidated. Virtual docking, based on the N-methyl-D-aspartate (NMDA) receptor, showed that homo-skeleton compounds of ifenprodil potentially exhibit low binding free energy with the receptor, including eliprodil and volinanserin. In vitro cell models corroborated the effective inhibition of inflammatory factor expression and minimal cytotoxicity of eliprodil and volinanserin. CoMFA (standard error of estimate = 0.378, R2 = 0.928, F values = 241.255, Prob. of R2 = 0) and topomer CoMFA (q2 = 0.553, q2 stderr = 0.77, intercept = - 1.48, r2 = 0.908, r2 stderr = 0.35) were established based on the inhibitors of NMDA receptor. The contour maps of CoMFA and topomer CoMFA models give structural information to improve the inhibitory function. This study underscores the involvement of MG/Mφ in inflammatory pathways during MS progression and offers promising compound candidates for MS therapy targeting MG/Mφ.

Recurrent late-onset neutropenia following treatment with different B cell-depleting strategies in multiple sclerosis.

As B cell-depleting therapies in multiple sclerosis (MS) have gained significant importance in the last several years, their long-term safety profile is of considerable clinical interest. Late-onset neutropenia (LON) is a rare, but potentially severe, adverse event that was first described in patients with rheumatic disorders under therapy with rituximab. Ofatumumab was approved in 2021 for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neutropenia occurred in 0.2% of patients in clinical phase 3 trials, and to date, no cases of LON have been reported under ofatumumab treatment. Here, we report a case of repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment. Additionally, we review the literature on rare occurrences of LON in patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) undergoing B cell-depleting therapies, including rituximab, ocrelizumab, ofatumumab, inebilizumab, and ublituximab. In our case, the patient presented with repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment leading to febrile infections, subsequent use of antibiotics, and application of granulocyte-colony-stimulating factor. After repetitive episodes of LON under both B cell-depleting strategies, cladribine was subsequently initiated. A nine-month follow-up showed a normal neutrophil count and no evidence of disease activity. This case highlights the significance of symptomatic late-onset blood count changes under both ocrelizumab and ofatumumab and emphasizes the importance of continuous monitoring of the differential blood count under B cell-depleting treatment. This study was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB CRC-TR-128 to F.Z., V.F., and S.B..; SFB 1080 and SFB CRC-1292 to F.Z..; and SFB/TRR 355 to S.B.) and the Hermann and Lilly Schilling Foundation (to S.B.).

Guideline-recommended standardized instruments in multiple sclerosis : Acomparative content analysis based on the International Classification of Functioning, Disability and Health (ICF)

Guidelines serve as practice-based decision support and recommend the use of standardized instruments to measure functional capacity in individuals with multiple sclerosis (MS). However, the extent to which aperson's functioning is captured by these instruments is unclear. The aim of this study is to link the content of the MS disease guideline with the International Classification of Functioning, Disability and Health (ICF) in order to capture the distribution of the content on the functional domains and contextual factors and to uncover existing gaps. Instruments of the S2k guideline "Diagnosis and therapy of multiple sclerosis, neuromyelitis optica spectrum diseases and MOG-IgG-associated diseases", which were available free of charge in German or English and designed for adult people, were included. The instruments were classified into their meaningful concepts (meaningful concepts = MCs) and subsequently coded using standardized ICF rules by two raters. The 23 included instruments contained 351 items and 718 MCs. Of these, 663 MCs could be linked to the ICF according to the coding rules. Of these, 51% (340 MCs) related to body functions, 44% (291 MCs) to the activity and participation component, and 5% (32MCs) to environmental factors. The most frequently coded chapter was mobility (d4) with 201 MCs. Interrater agreement was k = 0.79. The linking of the guideline-recommended instruments to the ICF shows that the instruments cover different themes. The area of environmental factors is underrepresented. The ICF linkage reveals abroad spectrum of functioning covered by the guideline-recommended instruments and facilitates the selection of appropriate instruments for the affected persons.

Multiple Sclerosis and Subcutaneous Panniculitis-like T Cell Lymphoma with Hemophagocytic Syndrome: The Role of Treatment Sequencing in the Pathogenetic Mechanism

Introduction: Although panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) have been described as complications following immunosuppressive treatments, there are no reported cases of concomitant SPTCL/HSP and multiple sclerosis (MS). Materials and Methods: We describe the case of a patient affected by an aggressive phenotype of relapsing remitting MS, characterized by consecutive severe relapses with no complete remission. He developed panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) after receiving multiple immunosuppressive treatments in sequence. Despite the aggressive nature of these complications, the patient responded well to a combination of Gemcitabine and Cisplatin. Discussion and Conclusions: With this case, we suggest that physicians always consider blood diseases as possible MS therapy complications, especially in the sequencing setting, and also consider uncommon treatments in those with autoimmune predispositions.

Risk of cancer development associated with disease-modifying therapies for multiple sclerosis: study protocol for a systematic review and meta-analysis of randomised and non-randomised studies

BackgroundThe association between cancer and multiple sclerosis has long been investigated. Several studies and reviews have examined the risk of cancer among patients with multiple sclerosis treated with disease-modifying therapies (DMTs) but with conflicting results. This study will aim to investigate the association between DMTs for multiple sclerosis and subsequent cancer risk using research synthesis methods.Methods/designWe designed and registered a study protocol for a systematic review and meta-analysis. We will include randomised and non-randomised trials, prospective or retrospective cohort studies, and case–control studies of treatment with DMTs compared with placebo, no treatment, or another active agent. The primary outcome will be the risk of cancer (all-malignant neoplasms) in association with the exposure of DMTs. Secondary outcomes will include site-specific cancers (e.g. breast cancer). Literature searches will be conducted in multiple electronic databases (from their inception onwards), including the following: PubMed/MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). Two researchers will screen all citations, full-text articles, and abstract data independently. The risk of bias (quality) of individual studies will be appraised using an appropriate tool. If feasible, we will use a two-stage approach to evidence synthesis: (1) Peto’s method for meta-analysis of data from randomised trials alone; and (2) Random-effects model for meta-analysis adding data from non-randomised studies. We will calculate odds ratios and their associated 95% confidence intervals. Potential sources of heterogeneity will be explored in additional analyses (e.g. subgroups considering different DMTs individually, mechanism of action, type of control, length of follow-up, mode of treatment).DiscussionThis systematic review and meta-analysis of randomised and non-randomised studies will provide an updated synthesis of the risk of cancer associated with DMTs for adult patients with multiple sclerosis. This study will also examine some factors that may explain potential variations across studies. The findings will be published in a peer-reviewed journal.Systematic review registrationOpen Science Framework (https://osf.io/v4sez).

Higher effect sizes for the detection of accelerated brain volume loss and disability progression in multiple sclerosis using deep-learning

PurposeClinical validation of “BrainLossNet”, a deep learning-based method for fast and robust estimation of brain volume loss (BVL) from longitudinal T1-weighted MRI, for the detection of accelerated BVL in multiple sclerosis (MS) and for the discrimination between MS patients with versus without disability progression. Materials and methodsA longitudinal normative database of healthy controls (n = 563), two mono-scanner MS cohorts (n = 414, 156) and a mixed-scanner cohort acquired for various indications (n = 216) were included retrospectively. Mean observation period from the baseline (BL) to the last follow-up (FU) MRI scan was 2–3 years. Expanded Disability Status Scale (EDSS) at BL and FU was available in 149 MS patients. Annual BVL was computed using BrainLossNet and Siena and then adjusted for age. Repeated-measures ANOVA and Cohen's effect size were used to compare BrainLossNet and Siena regarding the detection of accelerated BVL and the differentiation between MS patients with versus without EDSS progression. ResultsCohen's effect size for the differentiation of patients from healthy controls based on the age-adjusted annual BVL was larger with BrainLossNet than with Siena (MS cohort 1: 0.927 versus 0.495, MS cohort 2: 0.671 versus 0.456, mixed-scanner cohort: 0.918 versus 0.730, all p < 0.001). Cohen's effect size for the discrimination between MS patients with (n = 51) versus without (n = 98) EDSS progression was larger with BrainLossNet (0.503 versus 0.400, p = 0.048). ConclusionBrainLossNet can provide added value in clinical routine and MS therapy trials regarding the detection of accelerated BVL in MS and the differentiation between MS patients with versus without disability progression.

Exploring the underlying mechanisms of exercise as therapy for multiple sclerosis: insights from preclinical studies.

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system CNS characterized by demyelination, inflammation, and neurodegenerative changes, making it the most common nontraumatic disabling neurological disease in young adults. While current pharmacological treatments primarily target immunomodulation or immunosuppression, exercise is gaining increasing attention from the scientific community as an adjunctive therapy. This review explores the potential biological mechanisms of exercise in animal models of MS, focusing on its effects on neuroprotection and inflammation. The review examines how exercise inhibits pro-inflammatory microglial reactivity, stabilizes the blood-brain barrier, and enhances neurotrophic factor expression in animal studies. Future research directions are proposed by summarizing the evidence and limitations of existing animal models of MS, emphasizing the need to further validate these mechanisms in humans to better integrate exercise into the comprehensive management of MS. Additionally, investigating exercise-induced biomarkers for MS symptom reduction may provide a scientific basis for new therapeutic strategies.

Relapse-Associated and Relapse-Independent Contribution to Overall Expanded Disability Status Scale Progression in Multiple Sclerosis Patients Diagnosed in Different Eras.

The introduction of disease-modifying therapies for multiple sclerosis (MS) has led to a deceleration of disease course over the years. Although decreased relapse rate constitutes a factor, the role of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in MS course deceleration is still unclear. We retrospectively examined long-term Expanded Disability Status Scale (EDSS) progression in patients referred to the MS Center of Montichiari (Italy) and diagnosed with relapsing-remitting MS from 1980 to 2022. To isolate PIRA, we deducted all EDSS changes associated with relapses from overall EDSS change. We compared the relative contribution of PIRA and RAW to EDSS progression in patients diagnosed in different periods using mixed-effects models. A total of 1,405 patients were included in the study, of whom 231 were diagnosed in 1980-1996 (pre-treatment era), 577 in 1997-2008 (injectable disease-modifying therapy era), and 597 after 2008 (oral drugs, monoclonal antibodies, and anti-CD20 era). Across ages, both PIRA and RAW were reduced in patients diagnosed in more recent periods as compared with earlier periods. The average contribution of PIRA to overall EDSS progression was already predominant in patients diagnosed in 1980-1996 (78%) and in 1997-2008 (76%), but it was significantly increased (p = 0.0009) in patients diagnosed in later years (87%). The deceleration of MS course observed throughout the years is determined not only by fewer RAW events, but also by a reduction in PIRA. However, the shift toward a mostly relapse-independent progression highlights the importance of evaluating new therapies based on their effect on PIRA. ANN NEUROL 2024.

Coeliac disease as a model for understanding multiple sclerosis.

The genetic architecture of multiple sclerosis (MS) is similar to that of coeliac disease, with human leukocyte antigen (HLA) being the greatest genetic determinant in both diseases. Furthermore, similar to the involvement of gluten in coeliac disease, Epstein-Barr virus (EBV) infection is now widely considered to be an important environmental factor in MS. The molecular basis for the HLA association in coeliac disease is well defined, and B cells have a clear role in antigen presentation to gluten-specific CD4+ T cells. By contrast, the mechanisms underlying the HLA association of MS are unknown but accumulating evidence indicates a similar role of B cells acting as antigen-presenting cells. The growing parallels suggest that much could be learned about the mechanisms of MS by using coeliac disease as a model. In this Perspective article, we discuss the insights that could be gained from these parallels and consider the possibility of antiviral treatment against EBV as a therapy for MS that is analogous to the gluten-free diet in coeliac disease.

Age-Related Features of Clinical and Neurological Characteristics and Pathogenetic Therapy in Patients with Multiple Sclerosis

INTRODUCTION: Multiple sclerosis (MS) is a neurological demyelinating disease of the central nervous system manifested by pronounced heterogeneous symptoms. Peculiarities of the onset, progression rate, and severity of syndromes are different in different age groups. An increase in the frequency of exacerbations, high degree of disability of patients in different age groups evidence insufficient effectiveness of the conducted pathogenetic therapy. Due to a wide choice of multiple sclerosis disease modifying drugs (MSDMDs), it is important to study the clinical and neurological characteristics of patients with MS in different age groups with the aim of further developing an individual approach to treatment. AIM: To study clinical and neurological features and effectiveness of pathogenetic therapy of MS in patients of different age groups. MATERIALS AND METHODS: A prospective analysis of the data of neurological examination and results of magnetic resonance imaging of 100 patients of different age groups with relapsing-remitting MS, who received outpatient treatment in Kursk Regional Multidisciplinary Clinical Hospital, was conducted in the period of stable remission. RESULTS: The leading syndromes in patients with relapsing-remitting course of MS were cerebellar (78%) and pyramidal (70%) syndromes, besides, dysfunction of the cranial nerves (71%) was also observed. A quantitative parameter of explicitness of pelvic disorder syndrome predominated in middle-aged and elderly patients compared to young ones (p 0.001). Cognitive disorders were more often (14%) recorded in middle-aged and elderly patients (p 0.001). The use of glatiramer acetate permitted to reduce the degree of disability in young subjects (p 0.05); in patients of the middle age group, the most effective was a timely transition from interferon beta to ocrelizumab (p 0.05). The use of first-line MSDMDs (interferon-beta) in elderly patients demonstrated low effectiveness (p 0.05). CONCLUSION: In middle-aged and elderly patients with equal timing of MS onset, the neurological deficit is more expressed than in young ones. First-line pathogenetic therapy, in particular, glatiramer acetate, is more effective in young patients, while patients of middle age are recommended an early transition to second-line MSDMDs.

NEDA-state, psychological symptoms and quality of life are stable in natalizumab-treated multiple sclerosis patients: An up to 6-years long follow-up study

IntroductionNatalizumab (NAT), a highly effective disease modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS), was approved for clinical use in Hungary on February 1, 2010. In this study we aimed to assess its effectiveness in view of the concept of “No Evidence of Disease Activity” (NEDA-3), furthermore evaluate its effect on limb function, pathopsychological symptoms (cognition, fatigue, depression) and quality of life (QoL). Patients and methodsFrom February 1, 2010, to December 1, 2022, 121 eligible patients were consecutively enrolled from the MS center of the University of Szeged, Hungary. Here, we report data on 6-years of follow-up. First, we evaluated the proportion of patients reaching the NEDA-3 state and any possible influencing factors. Then, we assessed the change of upper and lower limb functions via the 9-hole-peg test (9HPT) and the 25-feet walk test (TW25F). Finally, we assessed the change of pathopsychological symptoms (cognition, fatigue, depression) and QoL via the BICAMS, FIS, BDI-II and MSQoL-54 questionnaires, and the possible influencing factors behind it. ResultsCumulatively, 97 patients (80.2 %) achieved NEDA-3 throughout the follow-up period. On a year-by-year basis, the proportion changed from 95.9 % in the 1st year to 84.3 %, 81.3 %, 76.4 %, 74.5 % and 78.9 % in the 2nd, 3rd, 4th, 5th and 6th year respectively (p<0.001). Baseline EDSS scores and the type of preceding DMT affected this outcome. Both the upper and the lower limb functions remained stable. Cognitive functions improved (p<0.001), fatigue and depression scores remained stable during the follow-up period. QoL remained stable or improved in all subscales of MSQoL-54 questionnaire. ConclusionOur 6-years long detailed follow-up study demonstrates that NAT not only reduces disease activity and progression. It effectively protects from the worsening of limb function, cognitive and other psychological impairments, and stabilizes the patients’ quality of life in basically every measurable aspect.

Enhancing Quality of Life in Multiple Sclerosis Patients Through Coadministration of FDA-Approved Immunomodulators and Melatonin

Objective: The primary goal of this study was to assess the binding characteristics and affinities of melatonin and certain U.S. Food and Drug Administration (FDA)-approved lipophilic drugs used in the treatment of multiple sclerosis (MS) with the brain and muscle Arnt-like 1 (BMAL1) clock protein. Additionally, the study aimed to investigate their potential as modulators of BMAL1 activity for therapeutic applications in MS.Methods: Molecular docking and simulation studies were conducted to investigate the interactions between the BMAL1 protein and the selected agents as ligands. Docking simulations were performed using AutoDock Vina, and key interactions were analyzed with Biovia Discovery Studio Visualizer. A molecular dynamics simulation was conducted using GROMACS 2020.4 and the binding free energies were calculated using the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The pharmacokinetic properties of the ligands were predicted using the BOILED-Egg model implemented in the SwissADME web tool.Results: Melatonin demonstrated the highest binding affinity (-8.5 kcal/mol) and most favorable binding free energy (-245.26±1.27 kJ/mol) with BMAL1, suggesting its potential synergistic activity with other FDA-approved drugs in MS therapy. The pharmacokinetic analysis indicated that all three ligands were likely to cross the blood-brain barrier and exhibit high gastrointestinal absorption, with teriflunomide and melatonin potentially achieving a better profile.Conclusion: This study highlights the potential of concomitant use of melatonin to modulate BMAL1 activity, providing a foundation for developing targeted chronotherapeutic strategies in MS treatment.

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.