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Results for “multiple sclerosis”

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PubMed2026

Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.

Humans↗

PubMed2026

Multiancestry genome-wide association and multiomics analyses elucidate spatiocellular features of multiple sclerosis genetics.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination disseminated in space and time. Here we performed a genome-wide association study (GWAS) using 688 MS cases and 205,199 controls from the Japanese population and identified significant associations in the major histocompatibility complex region and a population-specific risk variant in 11q24. Through cross-population GWAS meta-analyses using a total of 29,374 cases and 1,843,563 controls from 4 ancestral populations, we identified 22 novel susceptibility loci. Integration of GWAS and single-cell and single-nucleus RNA sequencing of peripheral blood mononuclear cells and subcortical lesions from patients with MS revealed enrichment of genetic risk factors for MS in CD4+ T helper cell lineage and regulatory T cells, as well as in endothelial cells. Furthermore, spatial transcriptomics of subcortical lesions demonstrated spatial and temporal heterogeneity in associations with MS genetic risk. Our study demonstrates the value of investigation of spatiocellular features of disease genetics across diverse populations and omics modalities.

Humans↗

PubMed2025

GWAS highlights the neuronal contribution to multiple sclerosis susceptibility.

Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease affecting the brain and spinal cord. Genetic studies have identified many risk loci, that were thought to primarily impact immune cells and microglia. Here, we performed a multi-ancestry genome-wide association study with 20,831 MS and 729,220 control participants, identifying 236 susceptibility variants outside the Major Histocompatibility Complex, including four novel loci. We derived a polygenic score for MS and, optimized for European ancestry, it is informative for African-American and Latino participants. Integrating single-cell data from blood and brain tissue, we identified 76 genes affected by MS risk variants. Notably, while T cells showed the strongest enrichment, inhibitory neurons emerged as a key cell type. The expression of IL7 and STAT3 are affected only in inhibitory neurons, highlighting the importance of neuronal and glial dysfunction in MS susceptibility.

Journal Article↗

PubMed2025

Entertainment activities and the risk of multiple sclerosis: A Mendelian randomization analysis.

Modifying environmental and lifestyle factors may have the potential to prevent and ameliorate multiple sclerosis. Further elucidating the etiology of multiple sclerosis and proposing actionable prevention measures are of significant importance, but establishing causality in epidemiological data can be challenging. This study employed a two-sample Mendelian randomization analysis to evaluate the causal effect of entertainment activity factors on the risk of multiple sclerosis. Publicly accessible summary statistics derived from genome-wide association studies were utilized to assess 14 modifiable forms of entertainment activities. The inverse variance weighted random effects method was used as the primary analytical approach to estimate causal effects. Additionally, MR-Egger, weighted median, and weighted mode methods were applied to assess robustness. Systematic sensitivity analyses and heterogeneity tests were conducted to verify the reliability of our findings. We found that spending time outdoors in the summer may prevent the development of multiple sclerosis (odds ratio = 0.995; 95% confidence interval 0.991-0.999; P = .010). In contrast, the other entertainment activities studied showed no significant causal relationship with multiple sclerosis. Our results suggest that spending time outdoors in the summer may protect against the development of multiple sclerosis, providing implications for preventive measures against the disease.

Humans↗

PubMed2026

Nimodipine in animal models of demyelination relevant to multiple sclerosis: a systematic review.

BACKGROUND: Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in which axonal injury, neuronal death, and demyelination occur. Treatment for MS relapses remains limited, which alleviates acute loss of function but has no impact on long-term disability. This study aimed to perform a systematic review of the effects of nimodipine on experimental demyelination models, including experimental autoimmune encephalomyelitis (EAE) and Cuprizone models in rodents. METHODS: This study was conducted following the PRISMA statement. A systematic search was performed in PubMed, Scopus, the Cochrane Library, and Google Scholar. The primary outcome was EAE clinical disease severity (peak clinical score and/or cumulative disease burden). Secondary outcomes included relapse activity (when reported), histological myelin outcomes, oligodendrocyte lineage markers, neuroaxonal injury markers, and inflammatory readouts. Risk of bias was assessed using the SYRCLE tool. RESULTS: Out of 4660 results, 5 studies were included in the systematic review (four EAE studies and one cuprizone model). Nimodipine was administered using heterogeneous regimens (oral, intravenous, intraperitoneal, subcutaneous, or osmotic pump delivery; 1-30 mg/kg/day). The included studies reported the variable effects of nimodipine on relapse-related outcomes, myelination, inflammatory processes, and neuroprotection in the EAE model of MS. Across EAE studies, nimodipine generally reduced clinical disease severity or cumulative burden, although relapse-related outcomes were inconsistent. CONCLUSIONS: Preclinical evidence suggests that nimodipine may attenuate disease severity and demyelination and may promote repair-related processes in rodent models relevant to MS. However, to evaluate the clinical applicability of nimodipine in MS patients, well-powered, transparently reported preclinical replication and early-phase clinical studies are required before clinical translation.

Animals↗

PubMed2024

Multiple sclerosis and abnormal spermatozoa: A bidirectional two-sample mendelian randomization study.

OBJECTIVE: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and previous observational epidemiological studies have suggested an association between MS and male infertility; male infertility due to sperm abnormalities may result from a number of aetiological factors, such as genetics, autoimmune factors, etc., and there are currently no studies to assess whether MS is associated with sperm abnormalities in men. Therefore, we performed a Mendelian randomization (MR) analysis to assess the causal relationship between MS and abnormal spermatozoa. METHODS: In this study, independent single nucleotide polymorphisms (SNPs) strongly associated with multiple sclerosis (MS) were identified by mining public genome-wide association study repositories and used as instrumental variables to explore causality. The causal effect of MS on sperm abnormalities was systematically assessed using two-sample Mendelian randomization (MR) techniques, and various analytical models such as inverse variance weighting (IVW), MR-Egger and MR-PRESSO were implemented to dissect the association. In addition, a wide range of sensitivity tests, including Cochran's Q test to detect heterogeneity, MR-Egger intercept analysis to assess bias, leave-one-out to test model robustness, and funnel plot analysis to detect potential publication bias, were implemented to ensure the robustness and reliability of the causal inference results. RESULTS: There was a significant causal relationship between MS and abnormal sperm (OR 1.090, 95% CI [1.017-1.168], p = 0.014); The accuracy and robustness of the results were confirmed by sensitivity analysis. CONCLUSION: Here we show that there appears to be a causal relationship between multiple sclerosis and abnormal spermatozoa. MS as a chronic disease has a higher risk of concomitant sperm abnormalities in its male patients, and reproductive and fertility issues in men with MS should receive special attention from clinicians.

Humans↗

PubMed2026

Maternal disease control and pregnancy outcomes with anti-CD20 therapy versus natalizumab in multiple sclerosis: a systematic review.

BACKGROUND: Management of multiple sclerosis (MS) during pregnancy requires balancing maternal disease control with fetal safety. Among high-efficacy disease-modifying therapies, anti-CD20 monoclonal antibodies and natalizumab are commonly used in women with active disease, yet their comparative effectiveness and safety during pregnancy remain incompletely defined. This systematic review evaluated maternal disease activity and pregnancy-related outcomes associated with anti-CD20 exposure compared with natalizumab in pregnant women with MS. METHODS: PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane Library were searched from inception through February 2026. Eligible studies included pregnant women with MS exposed to anti-CD20 before or during pregnancy and reporting maternal disease activity compared to natalizumab. RESULTS: Seven studies were included, comprising six observational cohort studies and one pharmacovigilance disproportionality analysis. Across studies, anti-CD20 exposure was consistently associated with lower relapse activity than natalizumab, particularly in the postpartum period. Anti-CD20 strategies were also associated with markedly lower postpartum MRI activity and more favorable disability-related outcomes where reported. Meta-analysis of three studies demonstrated a significant reduction in postpartum MRI activity with anti-CD20 therapy compared with natalizumab (RR 0.06, 95% CI 0.02-0.24; I² = 0%). No clear increase in major congenital anomalies was identified, although some data suggested higher odds of small for gestational age and maternal antibiotic use with anti-CD20 exposure. CONCLUSIONS: Anti-CD20 therapy was associated with lower maternal disease activity than natalizumab during pregnancy, especially for relapse prevention and postpartum MRI suppression. However, evidence regarding fetal and neonatal safety remains limited, warranting cautious individualized treatment decisions and further comparative research.

Humans↗

PubMed2026

Perspectives of participating neurologists and study nurses - Mixed-methods process evaluation of a web-based program for relapse management in multiple sclerosis (POWER@M2).

BACKGROUND: Relapsing-remitting multiple sclerosis is a chronic inflammatory disease of the central nervous system and the leading cause of disability in young adults. In Germany, 90% of relapses are treated with high-dose intravenous glucocorticoids, despite limited evidence for long-term benefit and international preference for oral administration. Time constraints often hinder informed decision-making. The multicentre Randomized Controlled Trial (RCT) POWER@MS2 (N = 160, 2020-2023), conducted at 18 German MS-centres, aimed to promote self-determined relapse management through a complex intervention (dialogue-based decision aid, nurse-led webinar, online-chat). OBJECTIVE: While RCTs demonstrate effectiveness, process evaluations are essential to understand implementation, mechanisms of impact and contextual factors. This study explored healthcare professionals' experiences and attitudes toward implementing relapse self-management and self-medication in clinical practice. METHODS: A mixed-methods process evaluation followed the UK Medical Research Council- framework. Quantitative data were collected via validated questionnaires at up to three time points and analysed descriptively. Interview guides were developed based on these results. Qualitative data from neurologist and study nurse interviews were thematically analysed. Results were triangulated using a joint display. RESULTS: Data were collected from 55 neurologists and 17 study nurses (quantitative) and from 7 neurologists and 4 nurses (qualitative) (2020-2024). Most neurologists opposed routine steroid use, reserving it for severe relapses. Some voiced concerns about self-management, but informed patients were generally viewed as capable of safe self-medication. Study nurses gave mixed feedback on the intervention, citing overload and improved guidance. CONCLUSION: Clinicians showed openness toward implementing the intervention. Enhancing accessibility and addressing specific concerns may support broader adoption.

Humans↗

PubMed2023

Rare and low-frequency coding genetic variants contribute to pediatric-onset multiple sclerosis.

BACKGROUND: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. OBJECTIVE: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. METHODS: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk. RESULTS: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. CONCLUSION: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Child↗

PubMed2026

DNA methylation landscape of cerebrospinal fluid cells in multiple sclerosis: an epigenome-wide association study.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which DNA methylation may link genetic and environmental risk factors. METHODS: We profiled genome-wide DNA methylation in cerebrospinal fluid (CSF) cells from people with MS (pwMS) and matched controls. Differentially methylated positions (DMPs) and regions (DMRs) were integrated with transcriptomic data, T-cell chromatin annotations, and pathway analyses. Protocadherin gamma (PCDHγ) expression was assessed in primary CD4+ T-cell subsets and confirmed by flow cytometry. FINDINGS: We identified 2710 DMPs and 4330 DMRs associating with genes that were enriched in immune signalling, adhesion and migration processes, and were accompanied by corresponding RNA changes. MS-associated methylation changes enriched in the cohesin chromatin-regulation pathway localised to T-cell regulatory regions, and this pathway included multiple protocadherin (PCDH) genes, which displayed consistent methylation and expression changes in CSF cells of pwMS compared to controls. PCDHγ cluster gene expression was detected in CD4+ T-cell subsets, and flow cytometry confirmed PCDHγ protein expression in peripheral blood T cells. Moreover, co-expression analysis suggests a role of PCDH genes in aryl hydrocarbon receptor (AHR) signalling. Protein-level validation showed fewer PCDHγ-positive CD4+ T cells in pwMS and activation-induced PCDHγ upregulation after T-cell stimulation. INTERPRETATION: DNA methylation changes in CSF resident cells reflect dysregulated T cell activation and migration in pwMS and suggest involvement of protocadherin molecules in MS pathogenesis. FUNDING: European Research Council, Swedish Research Council, Swedish Brain Foundation, Swedish MS Foundation, Knut and Alice Wallenberg Foundation, European Union and others.

Humans↗

PubMed2026

Heterogeneity in Teriflunomide Treatment Arms: A Systematic Review and Meta‑Regression of Randomised Multiple Sclerosis Trials.

BACKGROUND: Teriflunomide is widely used as an active comparator in Phase 3 randomised trials for relapsing multiple sclerosis (RMS). Temporal changes in disease activity within teriflunomide-treated cohorts have not been systematically examined. OBJECTIVES: To assess temporal trends in relapse and disability outcomes across teriflunomide arms of Phase 3 multiple sclerosis (MS) trials and identify predictors of between-trial heterogeneity. METHODS: We performed a systematic review and meta-analysis of Phase 3 randomised controlled trials including a teriflunomide arm. PubMed, Scopus, and ClinicalTrials.gov were searched up to October 2025. Annualised relapse rate (ARR) and 12- and 24-week confirmed disability worsening (CDW) were extracted together with baseline characteristics. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analyses, meta-regression, and sensitivity analyses were performed. RESULTS: Twelve teriflunomide cohorts from eight trials involving 4,900 adults with RMS were included. ARR ranged from 0.11 to 0.37 with substantial heterogeneity (I2 = 94%). Trial start year was inversely associated with ARR and explained a large proportion of between-study variability in exploratory meta-regression analyses. Confirmed disability worsening outcomes also showed substantial heterogeneity with a weaker trend toward lower event rates in more recent trials. CONCLUSION: Teriflunomide-treated trial populations have shifted toward lower relapse activity over time, and trial start year was the principal predictor of between-trial heterogeneity in ARR in exploratory analyses. These findings most plausibly reflect evolving recruitment and diagnostic practices rather than changes in drug efficacy. Accounting for these temporal dynamics is essential when interpreting outcomes from RMS trial using teriflunomide as comparator.

Humans↗

PubMed2025

Exploring proteomic immunoprofiles: common neurological and immunological pathways in multiple sclerosis and type 1 diabetes mellitus.

BACKGROUND: Interest in the study of type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) has increased because of their significant negative impact on the patient quality of life and the profound implications for the health care system. Although the clinical symptoms of T1DM differ from those of MS, such as pancreatic β-cell failure in T1DM and demyelination in the central nervous system (CNS) in MS, both pathologies are considered as autoimmune-related diseases with shared pathogenic pathways, which include autophagy, inflammation and degeneration, among others. Considering the challenges in obtaining pancreatic β-cells and CNS tissue from patients with T1DM and MS, respectively, it is fundamental to explore alternative methods for evaluating disease status. Proteomic analysis of peripheral blood mononuclear cells (PBMCs) is an ideal approach for identifying novel and potential biomarkers for both autoimmune diseases. METHODS: We conducted a proteomic analysis of PBMCs from patients with T1DM and relapsing remitting Multiple Sclerosis (herein forth MS) patients (n = 9 per condition), using a label-free quantitative proteomics approach. The patients were diagnosed following the American Diabetes Association (ADA) criteria for T1DM and McDonald criteria for MS respectively, and were aged over 18 years and more than 2 years from the onset respectively. RESULTS: A total of 2476 proteins were differentially expressed in PBMCs from patients with T1DM and MS patients compared with those form healthy controls (H). Predictive analysis highlighted 15 common proteins, up- or downregulated in PBMCs from patients with T1DM and MS patients vs. healthy controls, involved in the immune system activity (BTF3, TTR, CD59, CSTB), diseases of the neuronal system (TTR), signal transduction (STMN1, LAMTOR5), metabolism of nucleotides (RPS21), proteins (TTR, ENAM, CD59, RPS21, SRP9) and RNA (SRSF10, RPS21). In addition, this study revealed both shared and distinct molecular patterns between the two conditions. CONCLUSIONS: Compared with H, patients with T1DM and MS presented a specific expression pattern of common proteins has been identified. This pattern underscores the shared mechanisms involved in their immune responses and neurological complications, alongside dysregulation of the autophagy pathway. Notably, CSTB has emerged as a differential biomarker, distinguishing between these two autoimmune diseases.

Humans↗

PubMed2026

Big data in multiple sclerosis.

PURPOSE OF REVIEW: This review summarizes recent key advancements in multiple sclerosis (MS) achieved through the utilization of big data from diverse sources and advanced analytical techniques. RECENT FINDINGS: Real-world evidence (RWE) derived from MS big data has significantly enhanced treatment strategies, redefined the concept of disease progression, refined prognostic models, and facilitated personalized medicine. RWE has highlighted the long-term benefits of early intensive treatment compared to escalation strategies, the unfavorable risk profile associated with treatment de-escalation and the importance of managing treatments during pregnancy. Additionally, it has revealed similarities and differences in the effectiveness and safety of specific high-efficacy therapies, as well as key predictors for switching treatments. RWE has also emphasized the central role of progression independent of relapse activity as a significant driver of disability and predictor of unfavorable long-term outcomes in both adult and pediatric onset MS. A data-driven approach utilizing artificial intelligence and big data has established a comprehensive framework for understanding the disease's evolution. Multimodal big data frameworks - encompassing clinical data, MRI, genomics, biomarkers, and app-based metrics - have demonstrated their ability to enhance diagnostic performance and risk stratification in MS. SUMMARY: Big data approaches are transforming MS research and clinical practice by providing stronger RWE to guide therapeutic decision-making, refining models of disease progression, and developing more precise prognostic tools.

Humans↗

PubMed2025

Genomewide association study of a homogeneous multiple sclerosis cohort: Tumefactive demyelination.

BACKGROUND: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. OBJECTIVE: A GWAS was performed to identify variants associated with TD. METHODS: The case-control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p-value threshold of 5 × 10-8 was GWAS significant and 5 × 10-6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. RESULTS: Variants on chromosome 14 (rs117797734, p = 2.06 × 10-11, odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10-7, OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. CONCLUSION: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.

Humans↗

PubMed2026

The Impact of Upper Extremity Rehabilitation on Fatigue in Individuals With Multiple Sclerosis: A Systematic Review.

BACKGROUND: Although numerous interventions have been investigated to alleviate fatigue in people with multiple sclerosis (PwMS), evidence regarding the effects of upper extremity rehabilitation on fatigue remains limited. OBJECTIVE: The objective of this review was to evaluate and synthesize the available evidence on the effects of upper extremity rehabilitation interventions on fatigue in PwMS. METHODS: This review was conducted in accordance with the PRISMA guidelines and was prospectively registered in the PROSPERO database. A systematic search of PubMed, Web of Science, and Scopus was performed up to August 2026. Studies were eligible if they investigated the effects of upper extremity rehabilitation interventions on fatigue in PwMS. The risk of bias of randomized controlled trials was assessed using the Risk of Bias 2 (RoB 2), and the certainty of the evidence was appraised using the GRADE methodology. RESULTS: Nine studies including 250 participants (136 intervention, 114 control) met the inclusion criteria. The included studies evaluated a range of technology-assisted, exercise-based, home-based, and task-oriented upper extremity rehabilitation approaches, with some interventions incorporating more than one therapeutic or technological component. Fatigue outcomes were measured using the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS). Risk of bias was low in three randomized controlled trials, with some concerns in two and high in two; among the two crossover studies, one was rated as low risk and one as high risk. GRADE assessment showed low certainty of evidence for studies using the FSS and very low certainty for those using the MFIS, indicating an overall low certainty of the available evidence. CONCLUSIONS: The available evidence is insufficient to draw definitive conclusions regarding the effects of upper extremity rehabilitation on fatigue in PwMS. Further high-quality randomized controlled trials are required.

Humans↗

PubMed2026

Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

BACKGROUND: Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. METHODS: We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we performed heterogeneity, pleiotropy, MR-Egger, weighted median, mode-based, and MR-PRESSO sensitivity analyses. We also conducted phenome-wide association analyses and queried DrugBank to annotate candidate compounds targeting prioritized genes. RESULTS: We prioritized 43 immune-cell-specific candidate eGenes with convergent genetic support, including 6 for the EBV-related phenotype and 37 for MS. SERPINB1 in NK cells was associated with increased risk of the EBV-related phenotype, whereas HLA-G was associated with decreased risk. For MS, APOM and MSH5 showed protective associations, while AHI1 showed cell-type-dependent, bidirectional associations across immune lineages. Colocalization and independent cohort evaluation supported these findings. Among FDR-significant multi-SNP associations, MR-Egger intercept tests did not indicate directional pleiotropy, although a small subset showed heterogeneity or MR-PRESSO signals. Phenome-wide analyses identified no significant adverse phenotypic associations among evaluable genes at the prespecified threshold. DrugBank annotation nominated sodium nitroprusside, fasudil, artenimol, and choline as hypothesis-generating compounds for experimental follow-up. CONCLUSIONS: This study provides a single-cell genetic framework for prioritizing immune-cell-specific candidate targets for EBV-related phenotypes and MS, and nominates genetically supported targets and pharmacologic hypotheses for experimental investigation.

Humans↗

PubMed2026

Disease-modifying therapy uptake in a pediatric-onset multiple sclerosis population, British Columbia, Canada.

BACKGROUND: The treatment of pediatric-onset multiple sclerosis (POMS) is evolving as disease-modifying therapies (DMTs) undergo pediatric clinical trials. However, most DMTs remain off-label in children resulting in barriers to access and variability in treatment patterns across jurisdictions. The aim of this study was to describe trends in DMT uptake in POMS in British Columbia, Canada. METHODS: We utilized linked clinical and administrative datasets to identify MS with onset <18 years-of-age and assess DMT uptake from dispensed prescriptions between January 1, 1996 and March 1, 2020 in British Columbia, Canada. RESULTS: Of 173 POMS cases (median follow-up = 11.5 years), 32 (18%) filled a DMT prescription <18 years-of-age; 76 (44%) did so at any age. Moderate-efficacy therapies (beta-interferons/glatiramer acetate/teriflunomide/dimethyl fumarate) were the initial DMT in 60 cases (79%) overall, however by the end of follow-up a high-efficacy therapy was the most recent DMT dispensed for 52/76 cases (68%). After 2016, anti-CD20 monoclonal antibodies became the most common DMT class dispensed. CONCLUSIONS: Moderate-efficacy therapies were the more common initial DMT dispensed for individuals with POMS, but more than two-thirds eventually received a high-efficacy therapy. Only a minority of POMS cases were first dispensed a DMT under age 18 years.

Disease modifying therapies↗

PubMed2026

Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID (LC19), post-traumatic stress disorder (PTSD), rheumatoid arthritis (RA), and multiple sclerosis (MS) are clinically distinct disorders that share substantial symptom overlap, including persistent fatigue, cognitive impairment, autonomic dysfunction, and immune dysregulation. Although these conditions differ in diagnosis and clinical presentation, their underlying biological mechanisms remain poorly understood and may involve convergent regulatory pathways. METHODS: The EpiSwitch® 3D genomics platform and Orion knowledgebase were used to integrate chromosome conformation signatures with genome-wide association study (GWAS)-derived datasets across ME/CFS, LC19, PTSD, RA, and MS. Three-dimensional genomic anchors were mapped to coding genes and analysed using STRING protein-protein interaction networks and Cytoscape-based systems biology approaches. Disease-specific anchor datasets were generated and compared at both gene and network levels to identify shared biological processes and regulatory mechanisms. RESULTS: Analysis of the ME/CFS dataset identified 552 unique 3D genomic anchors mapped to 567 genes, with analogous disease-specific anchor sets generated for LC19, PTSD, RA, and MS. Direct overlap between disease-associated genes was limited; however, higher-order network analyses revealed substantial interconnectivity and convergence across conditions. Shared biological pathways included immune and cytokine signalling, interferon responses, mitochondrial function, metabolic regulation, and neuroendocrine processes. Highly connected hub genes included immune regulatory nodes such as LAG3 and components of the mTOR signalling pathway, implicating T-cell exhaustion, chronic immune activation, and immunometabolic dysregulation as common mechanisms underlying these disorders. CONCLUSIONS: These findings support a systems-level model in which clinically overlapping fatigue-associated syndromes arise from perturbations of interconnected regulatory networks rather than discrete disease-specific pathways. Despite limited genetic overlap, substantial convergence at the network level suggests shared biological architecture across ME/CFS, LC19, PTSD, RA, and MS. The identification of common regulatory pathways provides a mechanistic framework for the development of cross-disease diagnostic and therapeutic strategies. By capturing dynamic regulatory states, 3D genomic biomarkers offer significant potential for objective blood-based diagnostics, patient stratification, and the identification of shared therapeutic targets across complex chronic disorders. These findings support the application of precision medicine approaches and may accelerate the development of novel interventions for fatigue-associated multisystem diseases.

Humans↗