Search Results (3,691)

Background: Multiple Sclerosis (MS) is a chronic, autoimmune, multifactorial, and complex disorder of the central nervous system (CNS), affecting more than 2 million individuals globally. Genome-wide association studies (GWAS) have explained only a small fraction of its high heritability, highlighting the need for alternative approaches to identify rare genetic variants that contribute to its etiology. To address this, we performed whole-exome sequencing (WES) in a multi-affected family. Methods: WES was performed in a MS multigenerational family comprising two affected sisters, their two healthy brothers, and one affected son. Results: Bioinformatics analysis identified 47 co-segregating rare variants. Three missense variants in genes involved in inflammation, autoimmunity, and demyelinization were identified as the most promising candidates: c.443 C>T, p.Pro148Leu in the RTN4 gene, c.1678 T>G, p.Phe560Val in the JAK2 gene, and c.3449 A>G, p.Tyr1150Cys in the DUOX2 gene. Protein modeling and in silico tools suggest that the three selected variants may have a significant impact on protein function. Conclusions: We identified novel candidate genes for MS in a multiplex family, providing evidence for an oligogenic model of disease susceptibility. Further replication and functional studies are required to validate these preliminary results. Full article

Background: Amyloid positron emission tomography (PET) has been proposed as a tool to monitor myelination in multiple sclerosis (MS). We present baseline results from an ongoing prospective study, which is the first to include both early and standard phases of amyloid PET in patients with newly diagnosed MS. Methods: The prospective study includes patients with newly diagnosed MS (January 2023–February 2024). Clinical evaluation includes neurological disability (EDSS) and neuropsychological assessment. Brain MRI, early [¹⁸F]florbetaben (FBB) PET (eFBB; 0–5, 0–10 min post-injection), and standard FBB PET (sFBB; 90 min post-injection) were acquired. Normal-appearing white matter (NAWM) and damaged white matter (DWM) in MRI were segmented and co-registered with PET images. Results are presented as standardized uptake values (SUV), with the ratio using cerebellum as the reference region (SUVR) and the percentage of change between the DWM and NAWM. Results: Twenty patients were included (35.05 ± 10.72 years; 75% women). Both eFBB and sFBB acquisitions showed significantly lower SUVRmax and SUVRmean, and higher SUVRmin in the DWM compared to NAWM (p < 0.001) in all patients. SUV parameters in both DWM and NAWM from eFBB and sFBB PET correlated with the number of relapses and EDSS (r = −0.454 and r = −0.446, respectively; p < 0.05). Additionally, SUVR values in the DWM during eFBB correlated with cognitive impairment (SDMT; r = −0.516, p < 0.01), fatigue (MFIS-5; r = −0.450, p < 0.05), and quality of life (EQ-5D; r = −0.490, p < 0.05). Conclusions: Quantitative analysis of dual-phase FBB PET demonstrates differential uptake between DWM and NAWM, which is probably associated with demyelination and neurodegeneration. These preliminary findings suggest that amyloid PET may have predictive value for disease activity and progression, supporting its potential as a biomarker in MS. Follow-up data from this study are needed to support the baseline results. Full article

Background: Chimeric Antigen Receptor T-cell (CAR-T) cell therapy has revolutionized cancer treatment and is now being explored as a novel approach to treat refractory autoimmune diseases by targeting autoreactive immune components, especially B cells. Objective: Our aim was to provide a narrative review of the current evidence, mechanisms, efficacy, safety, and future directions of CAR-T cell therapy in autoimmune diseases. Methods: A structured literature search was conducted in MEDLINE via PubMed using keywords such as “CAR-T”, “chimeric antigen receptor T-cell”, “autoimmune diseases”, “lupus”, “rheumatoid arthritis”, “multiple sclerosis”, and “vasculitis”. Studies on CAR-T mechanisms, efficacy, safety, and clinical outcomes were included. Results: CAR-T cell therapies, especially CD19-directed constructs, demonstrated sustained drug-free remission in all patients across early SLE case series (n = 5–7), with normalization of serological markers and improved renal outcomes. Emerging preclinical and early clinical data in rheumatoid arthritis, multiple sclerosis, ANCA-associated vasculitis, juvenile autoimmune diseases, and idiopathic inflammatory myopathies also report clinical improvement and biomarker normalization. Reported adverse events in autoimmune cohorts were limited to mild cytokine release syndrome in a minority of cases, with no severe neurotoxicity or life-threatening infections, suggesting a more favorable safety profile compared to oncology settings. In parallel, next-generation innovations—including dual-target CARs, CAR-Tregs, and molecular safety switches—are advancing toward clinical translation. Conclusions: CAR-T cell therapy is emerging as a transformative strategy for autoimmune disease management, especially in refractory cases. Although initial outcomes are promising, long-term safety, cost-effectiveness, and broader accessibility remain key challenges. Future research should focus on optimizing cell targets, minimizing off-target effects, and improving affordability. Full article

Multiple sclerosis (MS) is a complex disease marked by chronic neuroinflammation and reactive oxygen species (ROS) toxicity in the central nervous system (CNS). Based on this ROS-driven mechanism, we tested whether PrC-210—a new aminothiol ROS scavenger—could lessen MS symptoms in mice with experimental autoimmune encephalomyelitis (EAE)-induced MS. Our goals were to assess the role of ROS in MS and evaluate the potential benefits of PrC-210 for managing MS. Mice with EAE received varying doses of PrC-210 under preventive and therapeutic protocols. Disease progression was measured using clinical scores and spinal cord histology. Safety was assessed by comparing the gastrointestinal and hematological toxicity between PrC-210 and dimethyl fumarate (DMF, Tecfidera’s active agent). PrC-210 reduced MS severity by up to 62% in paralysis scores versus those in the controls (p = 0.0001), whether used preventively or at the onset of paralysis. The group with the greatest decrease also showed the best spinal cord preservation and least demyelination. DMF caused toxicity at a dose that was ineffective, while PrC-210 showed no toxicity at effective levels. These findings suggest that the systemic administration of PrC-210 may offer a safe, effective MS treatment when started at symptom onset. Full article

Multiple Sclerosis (MS) is an autoimmune and neurodegenerative disorder of the central nervous system (CNS), characterized by demyelination, neuronal loss and physical disability. To date, the exact causes of MS remain unknown. Lifestyle factors, in particular diet, have received growing attention due to their impact on human health, their role in modulating disease pathogenesis, and their influence on gut microbiota composition and activity. As a result, numerous studies have been conducted to examine how specific nutrients, and thereby distinct dietary patterns, may affect the onset and progression of MS. In this narrative review, we aim to explore the most recent and updated evidence concerning the role of fatty acids, carbohydrates, proteins and fibers macronutrients in MS development and progression by evaluating the most relevant literature findings from preclinical models, and clinical trials on people with MS. Dietary macronutrients influence MS pathology through immune and gut–brain axis modulation. Diets rich in saturated fats and refined carbohydrates exacerbate neuroinflammation, promote Th1/Th17 polarization, and worsen disease severity. Conversely, monounsaturated and omega-3 polyunsaturated fatty acids, dietary fibers, and adequate tryptophan metabolism exert anti-inflammatory effects, enhance regulatory T cell (Treg) activity, and improve clinical outcomes. Fiber-derived short-chain fatty acids (SCFAs) and omega-3 metabolites also support gut barrier integrity and suppress astrocyte activation. Evidence on dairy, meat and gluten remains inconclusive, though certain milk proteins and certain components of red/processed meat and of wheat may promote inflammation. Overall, anti-inflammatory and fiber-rich diets, such as those emphasizing unsaturated fats and low sugar intake, appear to confer protective effects in MS. The clarification of the role of dietary components in relation to the disease could help to guide patients toward a healthy and balanced diet, with positive effects on their overall health. Full article

Background/Objectives: Magnetisation Transfer (MT) MRI is used for neuro-degenerative disorders, including Multiple Sclerosis (MS), providing an indirect measure of large biomolecular MR signal sources which cannot be observed directly because their typical T2 is usually much shorter than the echo time (TE) of conventional MR sequences. We investigated a 3D-radial Zero Time of Echo (ZTE) MT-weighted sequence with potentially enhanced sensitivity to short-T2 MR signals indirectly (via MT weighting) and directly (due to the short TE). Methods: The sequence runs on a human 7T MR scanner, producing whole-brain MT-weighted images with isotropic 0.8 mm resolution in 6.5 minutes. One RF pulse is used to suppress the fat signal and generate MT weighting, reducing RF power deposition to moderate levels. The small excitation pulses and the “quasi-adiabatic” MT pulse mitigate the negative effects of inhomogeneous transmit RF fields observed at 7T in the human head, facilitating the generation of uniform Magnetisation Transfer Ratio (MTR) maps. Results: Results from a biologic phantom, a healthy volunteer, and an MS patient illustrate important imaging features of the “SilentMT” sequence. When the MS patient images were compared with Fluid Attenuated Inversion Recovery (FLAIR) images taken on the same patient at 1.5T and 7T, SilentMT was able to detect all the MS lesions observed on the “reference truth” 1.5T FLAIR; 7T FLAIR, however, failed to detect some lesions in the temporal lobe and brain stem. SilentMT detected a lesion which was not immediately apparent on either FLAIR image. Increased MTR was observed in some regions of the brain of the MS patient, notably the left temporal lobe. Conclusions: This initial investigation of an MT-weighted ZTE sequence shows evidence that it may be more sensitive to pathology in a patient with MS. 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

Background: Uveitis, although a rare complication of multiple sclerosis (MS), poses a significant challenge in clinical management. Traditional treatments like corticosteroids, immunosuppressants, and surgical interventions often provide limited efficacy. Treatment for MS-associated uveitis involves a combination of traditional and emerging therapies, with a growing emphasis on monoclonal antibodies (mAbs). While there is an increasing use of disease-modifying therapies for MS such as interferon-beta (IFN-β), mAbs are gaining attention for their potential to address both neurological and ophthalmological symptoms. Methods: We conducted a systematic review of the existing literature and analyzed the clinical effect of IFN-β and mAb therapies in the context of MS-associated uveitis, assessing their efficacy in reducing inflammation, maintaining visual acuity (VA), and minimizing steroid dependency. Results: MS-associated uveitis had improved or maintained VA in 95% (35/37) of eyes (21 patients) after an average of 34.7 months (range of 7.9 to 78.7 months) of IFN-β treatment. One hundred percent (10/10) of patients (19/19 eyes) had improved or maintained VA after a mean of 25 months (range 8 to 43 months) of mAb treatment. We also found that IFN-β effect on MS-associated uveitis is comparable to mAbs. Conclusions: We outline the need for further research through human data to strengthen current findings and guide evidence-based clinical practice. Full article

Introduction: Biological systems inherently exhibit metabolic variability that functions within optimal ranges, as described by the Constrained Disorder Principle (CDP). Deviations from these ranges, whether excessive or insufficient, are linked to adverse health outcomes. This review examines how signatures of metabolic variability can enhance GLP-1 receptor agonist therapy using artificial intelligence platforms. Methods: We conducted a comprehensive literature review examining metabolic variability across various parameters, including heart rate, blood pressure, lipid levels, glucose control, body weight, and metabolic rate. We focused on studies investigating the relationship between variability patterns and treatment responses, particularly in the context of GLP-1 receptor agonist therapy and the use of CDP-based AI systems. Results: Increased variability in metabolic parameters consistently predicts adverse outcomes, such as cardiovascular events, mortality, and disease progression. Heart rate variability shows a U-shaped association with outcomes, while blood pressure, lipid, and glucose variability demonstrate predominantly linear relationships with risk. Body weight variability is associated with cognitive decline and an increased risk of cardiovascular complications. Additionally, genetic polymorphisms and baseline metabolic profiles can influence responses to GLP-1 receptor agonists. CDP-based AI platforms have successfully enhanced therapeutic outcomes in conditions like heart failure, cancer, and multiple sclerosis by leveraging biological variability rather than suppressing it. Summary: The identification of metabolic variability signatures offers valuable predictive insights for personalizing therapy with GLP-1 receptor agonists. Artificial intelligence systems based on clinical data patterns that include these variabilities represent a significant shift toward dynamic and individualized treatment approaches. This can enhance therapeutic efficacy and help counteract drug resistance in chronic metabolic disorders, potentially improving the response to GLP-1-based therapies. Full article

Background: There is varied practice with Disease-Modifying Treatment (DMT) for Multiple Sclerosis worldwide. We evaluated early DMT initiation within a real-world population for long-term outcomes. Method: The Scottish Multiple Sclerosis Register (SMSR) identified participants diagnosed with Relapsing Remitting Multiple Sclerosis (RRMS) in 2010/2011. We compared two groups of propensity-matched participants at diagnosis, who went on to receive either early treatment (<12 months from diagnosis) or late/never treated. Participants underwent detailed clinicoradiological evaluation and patient-reported outcome measures 11–13 years post-diagnosis. The primary outcome was mean Expanded Disability Status Scale (EDSS). Results: The SMSR identified 298 participants. A total of 141 had complete retrospective clinical data and 81 agreed to participate, with 32 successfully matched (16 pairs). Median time on DMT was 10.8 years (range 0.4–12.5) for those treated early and 4.0 (0–11.5) years for the late/never-treated group. A total of 7/16 (44%) never received a DMT of those not treated early. All early-treated participants commenced first-line DMT (5/16 subsequently escalated to second-line DMTs). Of those treated later (9/16), 7/9 participants (78%) commenced first-line and 2/9 s-line DMT. There were no serious adverse events identified with any DMT. There was no significant difference in the primary outcome, with mean EDSS 3.93 in the late/never-treated group vs. 4.53 in the early-treated group at 11–13 years post-diagnosis (p = 0.57). There was no significant difference in median change in EDSS from the time of diagnosis to prospective assessment between early and late/never-treated groups. Patient Reported Outcome Measurement Information System (PROMIS) scores for cognition favoured no early treatment (p = 0.02), whilst satisfaction with treatment choice favoured early treatment (p = 0.03). Conclusions: Our cohort did not show clear benefit with early DMT in RRMS, contrasting with other larger studies, with no significant differences between early and late/never-treated patients on clinicoradiological outcomes. Possible explanations include confounding by variables not included in matching and group allocation based on diagnosis date rather than first clinical symptom. Most participants were treated with injectable DMTs, not in keeping with current practice. A prospective, long-term follow-up deep phenotyping study would help characterise benefits of early DMT use, but this is clearly challenging in practice. Full article

Background/Objectives: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease characterized by immune dysregulation, vasculopathy, and fibrosis. Objectives: To evaluate the genetic architecture and autoantibody profile in a Kazakh cohort of patients with SSc. Methods: A total of 26 Kazakh patients with diffuse SSc were examined for disease activity and organ impairment using EScSG and the modified Rodnan skin score (mRSS). Eighteen healthy volunteers were enrolled in the control group. Antinuclear factor (ANF) was estimated on HEp-2 cells, while antibodies to Scl-70, CENP-B, U1-snRNP, SS-A/Ro52, SS-A/Ro60, Sm/RNP, Sm, SS-B, Rib-P0, and nucleosomes were determined by immunoblotting. The level of IL-6 cytokine was detected using ELISA. To investigate the genetic basis of SSc in Kazakh patients, a custom AmpliSeq panel including targeting immune/fibrosis pathways and 120 genes was used on the Ion Proton sequencer. The statistical analysis of categorical variables was conducted using Fisher’s exact test and Chi-square (χ²) test. Results: The examination of SSc patients (mRSS 16 ± 7.2; EScSG 3.54 ± 2.18) revealed a broad range of antibodies to Scl-70, CENP-B, SS-A/Ro60, SS-A/Ro52, U1-snRNP, and RNP/Sm, which were undetectable in the control group. Genetic analysis identified multiple variants across immune regulatory genes, including likely pathogenic changes in SAMD9L, REL, IL6ST, TNFAIP3, ITGA2, ABCC2, AIRE, IL6R, AFF3, and TREX1. Variants of uncertain clinical significance were detected in LY96, IRAK1, RBPJ, IL6ST, ITGA2, AIRE, IL6R, JAZF1, IKZF3, IL18, IL12B, PRKCQ, PXK, and DNASE1L3. Novel variants at the following genomic coordinates were identified and have not been previously reported in association with SSc: LY96 (chr8:74922341 CT/C), PTPN22 (chr1:114381166 CT/C), IRAK1 (indels at chrX:153278833), and SAMD9L (chr7:92761606 GT/G; chr7:92764981 T/TT). Conclusions: The first immunogenetic investigation of SSc in Kazakhstan revealed a polygenic architecture involving immune signalling pathways that partially overlap with international cohorts while exhibiting region-specific variation. Although the limited sample size and lack of functional validation constrain the interpretability of the findings, the results provide a framework for larger research to confirm the pathogenic mechanisms and establish clinical relevance. Full article

Background/Objectives: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) and chronic obstructive pulmonary disease (COPD) are linked to multi-organ vulnerability involving the lungs, heart, and kidneys. This study aimed to compare the annual changes in pulmonary, cardiac, and renal parameters in patients with SSc-ILD and COPD across three consecutive years, using both individual biomarkers and integrated composite profiles. Methods: This observational longitudinal study included repeated assessments in 2023, 2024, and 2025. Functional, laboratory, and imaging parameters were collected: 6-min walk test (6MWT), SpO₂ (pre-/post-exercise), spirometry/CT lung volumes, gas exchange (pO₂/pCO₂/lactate), echocardiography [left ventricular ejection fraction (LVEF), estimated systolic pulmonary artery pressure (sPAP)], cardiac biomarkers (NT-proBNP, MR-proANP, hsTnT), renal markers [eGFR, creatinine, albuminuria, albumin-to-creatinine ratio (ACR)], heart rate variability (HRV), and renal CT densitometry. All markers were standardized (z-scores, higher values = worse). Subprofiles were generated and aggregated into three integrated profiles (cardiac, renal, pulmonary). Within-group dynamics were analyzed using the Wilcoxon signed-rank test (year-to-year deltas), between-group comparisons with the Mann–Whitney U test, effect sizes via Cliff’s delta, and multiple testing correction with the Benjamini–Hochberg false discovery rate (FDR). Results: Exercise tolerance declined in both groups: by 2025, 6MWT distance decreased by −10 m in SSc-ILD (p = 0.006; q = 0.010) and −20 m in COPD (p = 0.002; q = 0.004); post-exercise SpO₂ fell in both cohorts (both p < 0.001; q < 0.001). MR-proANP remained consistently higher in SSc-ILD across all years (p ≤ 0.005; q ≤ 0.028). sPAP increased in both groups, reaching higher values in COPD by 2025 (p = 0.007; q = 0.033). NT-proBNP and hsTnT increased over time, while eGFR declined, and ACR rose in both cohorts (both p < 0.001; q < 0.001). HRV (HF/total power) decreased by 2025. Composite profiles showed: in 2023, the cardiac profile was worse in SSc-ILD (δ ≈ 0.27; p = 0.011; q = 0.048), but differences diminished by 2025; the renal profile was initially worse in SSc-ILD but later shifted unfavorably in COPD; the pulmonary profile showed no consistent between-group differences. Conclusions: Over three years, patients with SSc-ILD and COPD exhibited concordant deterioration in pulmonary, cardiac, and renal function. Distinct leading markers emerged: desaturation during exercise and neurohormonal activation (MR-proANP) in SSc-ILD, versus reduced 6MWT and higher sPAP in COPD. These findings support the need for integrated monitoring of the cardio–pulmo–renal continuum. Limitations include the observational design, multiple comparisons, and absence of advanced repeated-measures modeling. Full article

Background: Therapeutic plasma exchange (TPE) is an established treatment for immune-mediated neurological diseases in adults, but pediatric-specific data remain limited. This retrospective single-center study investigates the safety, complication profile, and clinical outcomes of TPE in children with pediatric neuroimmunological disorders (PNID). Methods: Medical records of pediatric patients who underwent TPE at the Medical University of Vienna between April 2006 and October 2022 were reviewed. Inclusion criteria required TPE initiation before the age of 18 years. Data collected included diagnoses, pre-TPE therapy, TPE characteristics, complications and clinical outcomes based on retrospective documentation. Results: A total of 53 patients (60% female, median age 13 years) were included and underwent 378 TPE procedures. Most common diagnoses were pediatric-onset multiple sclerosis (23%) and autoimmune encephalitis (19%). TPE was preceded by corticosteroids and/or intravenous immunoglobulin in 83% of patients. Complications occurred in 81% of patients and 23% of procedures and were predominantly rated mild to moderate (CTCAE I–II), including nausea, hypotension, and catheter-related issues. Severe complications (CTCAE III–IV) occurred in 11% of patients; no deaths were reported. Clinical improvement was documented in 84% of patients, with 42% showing significant improvement. Conclusions: TPE is a generally well-tolerated and effective treatment in PNID, with a high rate of clinical improvement and predominantly mild complications. The higher reported complication rate compared to other studies likely reflects more comprehensive documentation of minor adverse events. These findings support the use of TPE in PNID, particularly in cases refractory to first-line therapies. Standardized reporting of outcomes and complications is essential to improve comparability across studies and guide future clinical practice. Full article

Life course exposure estimates developed using geospatial datasets must address issues of individual mobility, missing and incorrect data, and incompatible scaling of the datasets. We propose methods to assess and resolve these issues by developing individual exposure histories for an adult cohort of patients with amyotrophic lateral sclerosis (ALS) and matched controls using residence history and PM_2.5, black carbon, NO₂, and traffic intensity estimates. The completeness of the residence histories was substantially improved by adding both date and age questions to the survey and by accounting for the preceding and following residence. Information for the past five residences fully captured a 20-year exposure window for 95% of the cohort. A novel spatial multiple imputation approach dealt with missing or incomplete address data and avoided biases associated with centroid approaches. These steps boosted the time history completion to 99% and the geocoding success to 92%. PM_2.5 and NO₂, but not black carbon, had moderately high agreement with observed data; however, the 1 km resolution of the pollution datasets did not capture fine scale spatial heterogeneity and compressed the range of exposures. This appears to be the first study to examine the mobility of an older cohort for long exposure windows and to utilize spatial imputation methods to estimate exposure. The recommended methods are broadly applicable and can improve the completeness, reliability, and accuracy of life course exposure estimates. Full article

This study explored the use of physical methods, namely X-ray diffraction, atomic force microscopy, and energy-dispersive X-ray spectroscopy, to analyze the structure and composition of tear fluid desiccates. Tear samples were collected from patients with dry eye syndrome, glaucoma, and multiple sclerosis. Our results revealed significant differences in the crystallization patterns, chemical composition, and morphology of tear fluid among the disease groups compared to healthy individuals. XRD analysis identified variations in salt crystallization within tear fluid desiccates. AFM provided nanoscale morphological visualization. EDX determined the presence of key chemical elements. Our findings showed that changes in crystallization and unbalance of ionic composition in tear fluid may serve as potential markers for diagnosing ocular diseases. This study highlights the potential of these techniques for non-invasive diagnostics and contributes to the development of innovative strategies for monitoring structural properties in tear fluid desiccates of analyzed inflammatory, and neurodegenerative diseases. Full article