Search Results (70)

Background/Objectives: Multiple Sclerosis (MS) is a chronic disease with significant clinical and radiological heterogeneity. This fact, together with the increased number of disease-modifying treatments available, poses challenges in the therapeutic decisions and for the overall management of the disease. In this study, an expert panel on MS from Greece aimed to formulate a consensus, in order to provide recommendation on disease-modifying treatment (DMT) initiation and switching, as well as de-escalation strategies in Relapsing MS (RMS). Methods: The study followed two-round voting based on a modified Delphi setting. A questionnaire was constructed by a subgroup of five experts (core group) and was subsequently administered in a printed form to a group of 12 MS experts in total (panel) in a face-to-face meeting. Consensus required at least 80% agreement within the panel in order to signify strong consensus. Results: The panel agreed that the overall therapeutic plan (DMT choice) must take into consideration the degree of disease activity (low/moderate/high). In certain cases with suboptimal response to a moderate-efficacy DMT, a horizontal switch to another moderate-efficacy DMT may be a valid strategy. However, in cases exhibiting disability accumulation, therapy escalation should be preferred. The concept of de-escalation was suggested as an alternative strategy for cases with stable disease receiving a high-efficacy long-term DMT in the long term. Due to the possibility of rebound phenomena with certain medications (such as fingolimod and natalizumab), a bridging strategy could be applied in cases of family planning and drug-related adverse events (such as lymphopenia and hepatotoxicity), especially in PwMS with recent inflammatory activity. Conclusions: Although novel biomarkers may soon help clinicians predict future disability accumulation, currently, regular and detailed patient monitoring seems to be the optimal way to guide clinicians’ decisions on treatment changes. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system whose heterogeneous clinical, radiological, and biological course has long resisted precise individual-level prediction. The recent convergence of large longitudinal datasets, advanced computational methods, and increasingly informative biomarkers has created conditions in which artificial intelligence (AI) and machine learning (ML) can begin to address that problem substantively. This review surveys the current evidence for AI/ML applications across the MS care continuum, with particular focus on the literature from 2022 through early 2026. Nine domains are examined: automated MRI lesion segmentation and quantification, fluid biomarker interpretation, unsupervised disease subtyping, disability progression prediction, treatment response stratification, drug repurposing and molecular discovery, digital biomarker monitoring, mechanistic interpretability, and integrated clinical management protocols. Notable recent contributions include the SuStaIn-based identification of two biologically distinct MS trajectories distinguished by early versus late serum neurofilament light chain elevation, the MindGlide deep learning platform enabling longitudinal analysis of archived routine clinical MRI data, the T-cell morphological classifier predicting natalizumab treatment response before drug initiation, and the fenebrutinib Phase III program that produced the first Bruton’s tyrosine kinase inhibitor results meeting primary endpoints in both relapsing and primary progressive MS. A proposed AI-Enhanced Management Protocol (AMP-26) reflecting 2026 clinical standards is included as an appendix. Throughout, emphasis is placed on mechanistic interpretability: the distinction between models that correlate features with outcomes and models whose decision logic reflects established MS pathobiology is considered a prerequisite for clinical credibility and regulatory readiness. Full article

Background/Objectives: Multiple sclerosis (MS) constitutes a chronic autoimmune, inflammatory, and neurodegenerative disease, with dissemination in space and time, warranting diagnosis. Epstein–Barr virus (EBV) is increasingly recognized as a key contributor to MS pathogenesis. This review summarizes evidence on EBV-related mechanisms of currently approved disease-modifying therapies (DMTs) and emerging EBV-directed therapeutic strategies in MS. Methods: A systematic search of PubMed, Embase, Cochrane, and Web of Science was performed. Original English-language studies addressing EBV-related therapeutic mechanisms or EBV-targeted interventions in MS were included; 23 studies met the inclusion criteria. Results: Current DMTs may influence EBV-related immunity through diverse mechanisms, including modulation of B-cell subsets, altered lymphocyte trafficking, reduction in EBV-specific humoral responses, and restoration of T-cell surveillance. Monoclonal antibody-based therapies, particularly anti-CD20 agents and natalizumab, appear to affect the EBV–B-cell–immune axis through distinct but complementary mechanisms. Other interventions, including interferons, glatiramer acetate, dimethyl fumarate, autologous hematopoietic stem cell transplantation, and vitamin D supplementation, may also modulate EBV-specific cellular or humoral responses, although the magnitude and durability of these effects vary. Emerging EBV-directed approaches, including EBV-specific T-cell therapy, inhibition of specific proteins, modulation of autophagy, and cholesterol-dependent viral latency, provide additional support for targeting EBV-related pathways in MS. Conclusions: The therapeutic efficacy of DMTs in MS may extend beyond nonspecific immunomodulation and involve partial disruption of EBV-driven immune persistence. Further controlled studies are required to validate EBV-related biomarkers and determine whether direct EBV-targeted therapies can provide sustained clinical benefit. Full article

Blood–brain barrier (BBB) breakdown is a hallmark of several neurological disorders, including multiple sclerosis (MS). NX210c, a novel therapeutic peptide, has shown promise in restoring BBB integrity, in both preclinical and clinical settings, offering potential for use in MS populations and across various central nervous system conditions with overlapping mechanisms. In this study, we evaluated the therapeutic potential of NX210c in patients with relapsing–remitting MS (RRMS) using a previous quantitative systems pharmacology (QSP) model currently redesigned to capture the dynamic interplay between BBB integrity and immune system activity. We validated the QSP model using both preclinical and clinical datasets, and generated virtual populations representing healthy individuals and RRMS patients for in silico testing. NX210c was assessed as both a monotherapy and in combination with established MS treatments. Simulations predicted time course changes in key BBB integrity markers, including tight junction protein (TJP) expression and transendothelial electrical resistance (TEER), under various dosing regimens. NX210c treatment was associated with a significant attenuation of BBB degradation compared to untreated controls (~7–8% higher TJP expression and BBB electrical resistance). Furthermore, we investigated the long-term impact of NX210c on clinical outcomes such as relapse rates. Both 5 and 10 mg/kg doses (single cycle [thrice-weekly for 4 weeks]) induced improvement in disease activity in RRMS patients, as well as a 10 mg/kg dose (single or repeated 4-week cycles every 6 months) in highly active patients. Particularly when administered alongside one of five commonly used MS therapies (interferon β-1a, teriflunomide, cladribine, natalizumab, ocrelizumab), in the highly active subpopulation, the model on average predicted a reduction in relapse frequency in the 10 mg NX210c-treated group versus untreated group from four to no relapses over two years. These findings suggest that NX210c may enhance therapeutic efficacy in RRMS by promoting BBB restoration and modulating immune responses, offering a promising avenue for combination treatment strategies. Full article

Background/Objectives: Very early pediatric-onset multiple sclerosis (POMS) is rare; clinical studies using disease-modifying treatments (DMTs) have not been performed. Clinicians rely on studies performed at older ages. This review resulted from difficulties faced by clinicians and the off-label use of DMTs at this age. Methods: A literature review of studies dated between 1982 and 2025 on very early POMS, specifically with onset before age 5, has been performed, searching for outcomes without or with DMTs. The curated database of the selected patients was analyzed using computed descriptive and integrated cohort-level estimates. The clinical, paraclinical, treatment, and outcome characteristics were analyzed. Statistical analysis used JASP, with GenAI-assisted verification. The treatment outcome of a 16-year-old patient with very early POMS starting at 2 years 4 months that consecutively received interferon, immunoglobulin, and Natalizumab is presented. Results: A total of 101 patients with very early POMS presented, at onset, with ataxic syndrome (57.4%), pyramidal syndrome (41.4%), ophthalmoplegia (10.3%), and optic neuritis (6.9%). In evolution, 22.7% had seizures. Half of the patients were not treated. Among those treated, acute steroid therapy was administered; 11 received the DMTs interferon, Glatiramer acetate, Dimethyl fumarate, and Azathioprine (three), with only two high-efficacy therapies (Natalizumab and Rituximab). Our patient had partial remission under interferon, relapses when stopped and replaced by immunoglobulin and 9 years relapse-free interval when Natalizumab was introduced. Conclusions: Early treatment with high-efficiency DMTs should be considered in very early POMS; association with known increased neuroplasticity at this age may improve prognosis, allowing good recovery of acquired disability. Full article

Background: Current disease-modifying therapies (DMTs) for multiple sclerosis (MS) attenuate pathogenic immune responses but are limited by safety and tolerability concerns. Antigen-specific tolerance approaches provide targeted immunomodulation yet remain constrained by their dependence on known autoantigens. LPX-TI641, an orally bioavailable, clinical-stage small-molecule agonist of Tim-3/4, represents an antigen-independent strategy to restore immune tolerance by expanding regulatory T cells (Tregs). Methods: LPX-TI641 was evaluated in vitro for its ability to induce Treg populations in murine splenocytes. Therapeutic efficacy was assessed in vivo using MOG_35–55- and PLP_139–151-induced experimental autoimmune encephalomyelitis (EAE) mouse models. Ex vivo, peripheral blood mononuclear cells (PBMCs) from people with MS (PwMS) were analyzed for Treg phenotype and function in response to LPX-TI641. Results: LPX-TI641 induced dose-dependent expansion of CD4⁺Foxp3⁺ and CD4⁺Foxp3⁺Tim-3⁺ Tregs in vitro. In EAE models, treatment significantly reduced disease severity, prevented relapses, and maintained clinical benefit after discontinuation. In PBMCs from patients with MS, LPX-TI641 restored diminished Tim-3⁺ Treg populations and reversed Treg dysfunction in recall assays. Efficacy in animal models was comparable to or exceeded that of high-efficacy DMTs, including natalizumab. Conclusions: LPX-TI641 promotes antigen-independent immune tolerance through Tim receptor agonism and Treg expansion. These findings support its potential as a novel therapeutic candidate for MS, addressing the limitations of current DMTs. Full article

Objectives: The purpose of this study was to analyze the effect of daily intake of cladribine tablets on the course of multiple sclerosis (MS) while monitoring for 1–4 years during and after the course in several neurological clinics from different regions of the Russian Federation. Materials and Methods: Information was collected on 235 patients from 12 neurological clinics and regional centers for MS, who were observed for an average of 3.4 years after starting treatment with cladribine. Results: An independent analysis of cases of prescription of cladribine in tablets showed that the reason for prescription of cladribine was highly active MS (HAMS) in 159 patients (67.7%), rapidly progressive MS (RPMS) in 20 patients (8.5%), active remitting MS in 50 patients (21.3%) and secondary progressive MS (SPMS) with exacerbations in 6 (2.5%). Among them, only 12 patients (5.1%) had not previously received DMTs, i.e., in these cases, the drug was prescribed as the first DMT. In total, 22 patients had previously received natalizumab, 5—ocrelizumab, and in 1 case—fingolimod. The remaining 207 patients were crossed over from the first-line DMTs. In all cases, there was a decrease in the frequency of exacerbations during and after the completion of the course of cladribine. Exacerbations between the first and second courses of cladribine were noted in 36 patients (15.3% of all treated), almost half of the cases—those who previously received natalizumab (17 exacerbations, or 47.2% of all exacerbations between the 1st and 2nd courses of cladribine), and in 3 cases—from ocrelizumab (in 60% of all patients crossed over from ocrelizumab). During 4 years of follow-up after a full course of cladribine, exacerbations were in 14 patients (6% of all patients included in the analysis), of which in 6 cases—after crossover from natalizumab. Discussion and Conclusions: The data obtained are generally consistent with the results of meta-analyses and reviews published recently, but high probability of exacerbations in patients who were crossed over from second-line drugs such as natalizumab and ocrelizumab were seen. The crossover from natalizumab is carried out more often due to the increased risk of developing progressive multifocal encephalopathy (PML). It is likely that the restoration of MS activity after the withdrawal of natalizumab is quite frequent, cladribine tablets were not able to fully prevent this. Such a crossover does not seem to be optimal, unlike the crossover from first-line DMTs. If such a crossover is still planned, it could be performed within 4 weeks after stopping natalizumab. Full article

Background: Neurodegeneration is present from the earliest stages of multiple sclerosis [MS], and oxidative stress together with mitochondrial dysfunction are key contributors to neuronal injury and disease progression. Objective: To investigate the role of the antioxidant enzyme paraoxonase 1 (PON1) and serum asymmetric dimethylarginine (ADMA) levels in MS across different disease subtypes and immunomodulatory treatments. Methods: Serum lipid levels and PON1 activity were measured and compared by disease subtype and treatment in a single-center MS cohort (N = 262; CIS = 10, RRMS = 208, PPMS = 19, SPMS = 25; 110 untreated, 152 treated) and in 91 healthy controls. ADMA levels were assessed in sera from 79 MS patients (19 untreated, 60 treated) and 31 age-matched controls. Results: Median serum paraoxonase (PON) and arylesterase (ARE) activity levels were 83.8 and 127.2 IU/L in MS patients versus 85.9 and 136.9 IU/L in controls, with no significant difference for PON (p = 0.191) but a significant reduction in ARE [p = 0.003]. PON activity differed significantly among disease subtypes (p = 0.023), with the highest levels in CIS. PON and ARE activity also varied across treatment groups (p = 0.038 and p = 0.034, respectively), with longitudinal analysis indicating a measurable effect of immunomodulatory therapy on PON activity at 10 years (p = 0.0136). Significant differences in enzyme activity were observed between untreated and interferon-treated patients (PON p = 0.0055, ARE p = 0.0001), with trends toward differences in ARE under natalizumab and fingolimod. ADMA levels were lower in MS patients than controls (p < 0.0001) and differed among treatment subgroups (natalizumab, dimethyl fumarate, glatiramer acetate, untreated RRMS). Conclusions: PON1 activity and ADMA levels differ between MS subgroups and under immunomodulatory treatments. Long-term therapy was associated with increased PON1 activity, while highly effective immunomodulators reduced ADMA levels. These changes may contribute to the treatment-related reduction in disease activity and attenuation of neurodegenerative processes in MS. Full article

Adipocytokines are involved in the pathogenesis of multiple sclerosis by modulating inflammation, blood–brain barrier function and immune responses, which may affect disease course and treatment outcomes. Our study assessed serum levels of visfatin, adiponectin and resistin in patients with relapsing–remitting multiple sclerosis treated with fingolimod or natalizumab. We examined 49 patients with relapsing–remitting multiple sclerosis and 38 healthy controls. Participants were divided into three groups: patients treated with fingolimod, those treated with natalizumab and the controls. Serum levels of visfatin, adiponectin and resistin were measured. We analyzed correlations with disease duration, treatment duration and body mass index. Adiponectin levels were significantly higher in patients treated with natalizumab compared to those receiving fingolimod and healthy controls (p < 0.05). In the fingolimod group, visfatin levels increased with treatment duration. The mean level was 51.27 pg/mL for treatment shorter than eighteen months and 59.12 pg/mL for longer treatment (p < 0.05). In the same group, resistin levels correlated positively with body mass index (p < 0.05), while visfatin levels showed a negative correlation (p < 0.05). Fingolimod may affect adipocytokine levels, which could support patient monitoring. Increased adiponectin in natalizumab-treated patients suggests its possible role in the therapeutic mechanism of the treatment. Full article

Background: B-cell-depleting drugs targeting the CD20 antigen have been increasingly implemented as an “exit strategy” from natalizumab for relapsing–remitting multiple sclerosis (RRMS) patients due to the increased risk of progressive multifocal leukoencephalopathy. Data on recently approved anti-CD20 drugs, such as ofatumumab serving as a natalizumab “exit strategy”, are lacking. Furthermore, due to their immunosuppressive mechanism of action, prolonged use of these “highly effective” drugs is associated with the development of hypogammaglobulinemia and, consequently, a higher risk of infections. There are no guidelines for monitoring serum immunoglobulin levels in individuals undergoing “highly effective” multiple sclerosis treatment. Methods: We present a case of a 26-year-old male RRMS patient with selective IgM deficiency and multiple sclerosis initially treated with natalizumab and later ofatumumab. Results: The patient achieved “no evident disease activity “status while undergoing treatment with natalizumab and ofatumumab, but these therapies, especially ofatumumab, greatly impacted further drops in IgM levels. However, no significant decrease in IgG levels was observed, and no infectious events occurred. In addition, the patient did not show signs of disease activity while on ofatumumab, which also offered a more convenient mode of administration. Conclusions: Our experience points to the need to further explore benefit–risk ratios of highly effective treatments, even in cases with low immunoglobulin levels. However, closely monitoring immunoglobulin levels and conducting clinical follow-ups to ensure prompt recognition of potential infectious complications constitute approaches that have been thought of for such patients. Full article

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative autoimmune disorder of the central nervous system characterized by demyelination and neurodegeneration. Traditionally considered a T-cell-mediated disease, the crucial role of B lymphocytes in its pathogenesis, through different mechanisms contributing to inflammation and autoreactivity, is increasingly recognized. The risk of long-term disability in MS patients can be reduced by an early treatment initiation, in particular with high-efficacy therapies. The aim of this review is to provide an overview of the mechanisms of action of high-efficacy therapies for MS, with a focus on their impact on B cells and how this contributes to the drugs’ efficacy and safety profiles. Anti-CD20 monoclonal antibodies, Alemtuzumab, Cladribine and sequestering therapies encompassing Natalizumab and S1P receptors modulators will be discussed and emerging therapies, including Bruton’s Tyrosine Kinase inhibitors, will be presented. Full article

Background and Clinical Significance: In multiple sclerosis (MS), there are many therapeutic options, but most of the available drugs can cause drug-induced liver injury (DILI) after the first infusions. A wide group of other drugs may induce liver injury, from simple anti-pyretic medication like Acetaminophen to various dietary herb supplements like Ashwagandha. Case Presentation: A 39-year-old female patient, diagnosed with MS, has been previously treated with Glatiramer Acetate and interferon-beta, and is currently undergoing immunomodulatory treatment with natalizumab (infusion no. 81). She had a recent history of an airway infection for which she took 4–5 capsules of Acetaminophen per day for 7 days, along with the consumption of dietary supplement with Ashwagandha herb. She presented with jaundice, pruritus, and lower limb ecchymoses. The laboratory results revealed higher aminotransferase levels, total bilirubin, and alkaline phosphatase. The screening for autoimmune and infectious hepatitis was negative. The scenario of toxic hepatitis induced by recently used drugs (Ashwagandha dietary herb supplement and Acetaminophen) was adequate to start therapy with oral cortisone. The clinical and laboratory results gradually improved, with normal levels of liver enzymes and bilirubin, with no further increase after the discontinuation of corticosteroid therapy and dietary herb supplements. Conclusions: This case highlights the challenges in determining the multiple etiologies and managing acute liver injury in an MS patient on natalizumab, an immunomodulatory drug that can induce liver injury after the first infusions, especially in the context of recent ingestion of hepatotoxic drugs. Full article

Background and Objectives: Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation and neurodegeneration. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, has shown promise in reducing disease activity in MS patients. This prospective study aims to assess the effectiveness of ocrelizumab in reducing confirmed disability progression in patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) over a two-year period. By evaluating clinical data, and MRI findings, this study seeks to provide comprehensive insights into ocrelizumab’s impact on disease dynamics and disability. Materials and Methods: Ninety-eight patients aged 18 to 65 with confirmed MS were enrolled under ocrelizumab therapy at the Neurology Department of “Pius Brinzeu” Clinical Emergency Hospital in Romania between July 2020 and July 2024. Participants were assessed at baseline and every six months over two years. The key outcomes measured were changes in the Expanded Disability Status Scale (EDSS) as a measure of confirmed disability progression (CDP), annualized relapse rate (ARR), and MRI findings. Results: Over the two-year period, the mean EDSS score significantly decreased from 5.2 ± 1.8 to 4.6 ± 1.7 (mean change = −0.6 ± 0.9; p = 0.032), indicating improved neurological function. The proportion of patients experiencing relapses dropped markedly from 61.2% to 14.3% (p < 0.001). The MRI results showed significant reductions in patients with new or enlarging T2 lesions from 68.4% to 27.6% (p < 0.001) and gadolinium-enhancing lesions from 44.9% to 15.3% (p < 0.001). Patients previously treated with natalizumab exhibited a greater reduction in EDSS scores (−1.0 ± 0.8; p = 0.001) compared to other treatments. Multivariate regression identified the baseline EDSS score (β = 0.65; p < 0.001), previous natalizumab use (β = −0.30; p = 0.013), and age at diagnosis (β = 0.02; p = 0.048) as significant predictors of two-year EDSS scores. While markers of active inflammation decreased, the proportion of patients with brain atrophy increased from 31.6% to 43.9% (not statistically significant; p = 0.105). SPMS patients had higher rates of brain atrophy at baseline (61.1% vs. 25.0%; p = 0.007) and at two years (100.0% vs. 31.3%; p < 0.001) compared to RRMS patients. Conclusions: Ocrelizumab effectively reduced disease activity and improved neurological disability over two years in both RRMS and SPMS patients. Significant reductions in relapse rates and MRI markers of inflammation were observed. Previous natalizumab treatment was associated with greater improvements. Despite these benefits, the progression of neurodegeneration, particularly brain atrophy in SPMS patients, underscores the need for additional strategies targeting neurodegenerative aspects of MS. Full article

Natalizumab is a highly effective therapy for multiple sclerosis (MS). The aim of this study was to evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing–remitting MS treated with Natalizumab. sNfL and sGFAP were analyzed at baseline, 6 and 12 months post treatment using the single-molecule array (SiMoA) technique. We recruited matched healthy controls for comparison. The study included 54 patients, with a median age of 33 years (Interquartile range (IQR), 29–41), with 32 women (60%) and 76 healthy controls. A decrease in sNfL was observed at 6 (67%, p = 0.005) and 12 (72%, p < 0.0001) months compared to baseline. After two years, six patients experienced evidence of disease activity (EDA-3). The remaining ones had no evidence of disease activity (NEDA-3). NEDA-3 presented a remarkable reduction in sNfL (p < 0.0001) and sGFAP (p = 0.01) after 6 months of treatment that continued to be observed after 12 months compared to baseline. EDA-3 only reached a significant decrease in sNfL after 12 months; there were no significant changes in sGFAP values. Natalizumab leads to a decrease in sNfL, which is higher and occurs earlier in NEDA-3 patients. Patients also showed a significant reduction in sGFAP levels, which was not observed in the EDA-3 group. Full article

Background/Objectives: Multiple sclerosis (MS) is a disease characterized by demyelination and axonal damage of the central nervous system. Despite the observed benefits, highly effective treatment (HET)-based therapy has adverse effects, which include an increased risk of developing progressive multifocal leukoencephalopathy (PML). Additionally, the risk grows if the patient has antibodies for the John Cunningham virus (JCV). The appearance of PML is rare, and only one report has been found in Mexico. The objective of this research was to determine and analyze the immunological memory for JCV in a population of Mexican patients with MS under treatment. Methods: All participants underwent a complete medical history and neurological evaluation. Once they signed their informed consent, a blood sample was taken to determine if antibodies against JCV were present in their serum. Results: In total, 121 MS patients were analyzed, and the population consisted of 62.8% women and 37.2% men with an average age of 42.28. The three most common HETs received by the participants were natalizumab (67.76%), followed by teriflunomide and fingolimod. Conclusions: The seropositivity was 62.8%, and in this group, the average duration of disease evolution was 152.33 ± 93.37 months. Natalizumab was the most used HET, and despite this, only a positive association between a positive JCV antibody index with duration of fingolimod and history of depression was found. Also, a positive correlation of the JCV Ab index within the forms of SPMS and PPMS compared to RRMS was observed. No differences were observed between populations, type, and duration of MS. Full article