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Brain : a Journal of Neurology Aug 2023Multiple sclerosis is a complex autoimmune disease, and several therapies for multiple sclerosis have been developed and widely used. However, existing medications for...
Multiple sclerosis is a complex autoimmune disease, and several therapies for multiple sclerosis have been developed and widely used. However, existing medications for multiple sclerosis were far from satisfactory due to their failure to suppress relapses and alleviate disease progression. Novel drug targets for multiple sclerosis prevention are still needed. We performed Mendelian randomization to explore potential drug targets for multiple sclerosis using summary statistics from the International Multiple Sclerosis Genetics Consortium (nCase = 47 429, nControl = 68 374) and further replicated in UK Biobank (nCase = 1356, nControl = 395 209) and FinnGen cohorts (nCase = 1326, nControl = 359 815). Genetic instruments for 734 plasma and 154 CSF proteins were obtained from recently published genome-wide association studies. The reverse causality detection using bidirectional Mendelian randomization analysis and Steiger filtering, Bayesian co-localization, and phenotype scanning that searched previously reported genetic variant-trait associations were implemented to consolidate the Mendelian randomization findings further. In addition, the protein-protein interaction network was performed to reveal potential associations among proteins and/or present multiple sclerosis medications. At Bonferroni significance (P < 5.63 × 10-5), Mendelian randomization analysis revealed six protein-multiple sclerosis pairs. In plasma, per standard deviation increase in FCRL3, TYMP and AHSG had a protective effect. Odds ratios for the proteins above were 0.83 (95% CI, 0.79-0.89), 0.59 (95% CI, 0.48-0.71) and 0.88 (95% CI, 0.83-0.94), respectively. In CSF, per 10-fold increase in MMEL1 (OR, 5.03; 95% CI, 3.42-7.41) increased the risk of multiple sclerosis, while SLAMF7 (OR, 0.42; 95% CI, 0.29-0.60) and CD5L (OR, 0.30; 95%CI, 0.18-0.52) decreased the risk. None of the six proteins had reverse causality. Bayesian co-localization suggested that FCRL3 [coloc.abf-posterior probability of hypothesis 4 (PPH4) = 0.889], TYMP (coloc.susie-PPH4 = 0.896), AHSG (coloc.abf-PPH4 = 0.957, coloc.susie-PPH4 = 0.973), MMEL1 (coloc.abf-PPH4 = 0.930) and SLAMF7 (coloc.abf-PPH4 = 0.947) shared the same variant with multiple sclerosis. FCRL3, TYMP and SLAMF7 interacted with target proteins of current multiple sclerosis medications. MMEL1 was replicated in both UK Biobank and FinnGen cohorts. Our integrative analysis suggested that genetically determined levels of circulating FCRL3, TYMP, AHSG, CSF MMEL1 and SLAMF7 had causal effects on multiple sclerosis risk. These findings suggested those five proteins might be promising drug targets for multiple sclerosis and warrant further clinical investigation, especially FCRL3 and SLAMF7.
Topics: Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Multiple Sclerosis; Bayes Theorem; Phenotype; Polymorphism, Single Nucleotide
PubMed: 36864689
DOI: 10.1093/brain/awad070 -
Multiple Sclerosis and Related Disorders Mar 2024With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need... (Review)
Review
With evolving diagnostic criteria and the advent of new oral and parenteral therapies for Multiple Sclerosis (MS), most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and time and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of MS therapies is critical to maximize patient benefit. The current guidelines review the current diagnostic criteria for MS and the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, progressive MS, pediatric cases and pregnant women. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.
Topics: Pregnancy; Female; Humans; Child; Multiple Sclerosis; Consensus; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive; Recurrence
PubMed: 38245998
DOI: 10.1016/j.msard.2024.105435 -
Lancet (London, England) Jan 2024Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18-40 years). Novel pathophysiological findings... (Review)
Review
Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18-40 years). Novel pathophysiological findings underline the importance of the interaction between genetics and environment. Improvements in diagnostic criteria, harmonised guidelines for MRI, and globalised treatment recommendations have led to more accurate diagnosis and an earlier start of effective immunomodulatory treatment than previously. Understanding and capturing the long prodromal multiple sclerosis period would further improve diagnostic abilities and thus treatment initiation, eventually improving long-term disease outcomes. The large portfolio of currently available medications paved the way for personalised therapeutic strategies that will balance safety and effectiveness. Incorporation of cognitive interventions, lifestyle recommendations, and management of non-neurological comorbidities could further improve quality of life and outcomes. Future challenges include the development of medications that successfully target the neurodegenerative aspect of the disease and creation of sensitive imaging and fluid biomarkers that can effectively predict and monitor disease changes.
Topics: Young Adult; Humans; Multiple Sclerosis; Quality of Life; Treatment Outcome; Life Style
PubMed: 37949093
DOI: 10.1016/S0140-6736(23)01473-3 -
Medicine Feb 2024Multiple sclerosis (MS) is a chronic autoimmune disease with demyelination, inflammation, neuronal loss, and gliosis (scarring). Our object to review MS pathophysiology... (Review)
Review
Multiple sclerosis (MS) is a chronic autoimmune disease with demyelination, inflammation, neuronal loss, and gliosis (scarring). Our object to review MS pathophysiology causes and treatment. A Narrative Review article was conducted by searching on Google scholar, PubMed, Research Gate about relevant keywords we exclude any unique cases and case reports. The destruction of myelinated axons in the central nervous system reserves this brunt. This destruction is generated by immunogenic T cells that produce cytokines, copying a proinflammatory T helper cells1-mediated response. Autoreactive cluster of differentiation 4 + cells, particularly the T helper cells1 subtype, are activated outside the system after viral infections. T-helper cells (cluster of differentiation 4+) are the leading initiators of MS myelin destruction. The treatment plan for individuals with MS includes managing acute episodes, using disease-modifying agents to decrease MS biological function of MS, and providing symptom relief. Management of spasticity requires physiotherapy, prescription of initial drugs such as baclofen or gabapentin, secondary drug options such as tizanidine or dantrolene, and third-line treatment such as benzodiazepines. To treat urinary incontinence some options include anticholinergic medications such as oxybutynin hydrochloride, tricyclic antidepressants (such as amitriptyline), and intermittent self-catheterization. When it comes to bowel problems, one can try to implement stool softeners and consume a high roughage diet. The review takes about MS causes Pathophysiology and examines current treatment strategies, emphasizing the advancements in disease-modifying therapies and symptomatic treatments. This comprehensive analysis enhances the understanding of MS and underscores the ongoing need for research to develop more effective treatments.
Topics: Humans; Multiple Sclerosis; Treatment Outcome; Chronic Disease; Muscle Spasticity
PubMed: 38394496
DOI: 10.1097/MD.0000000000037297 -
Seminars in Pediatric Neurology Jul 2023The current diagnostic criteria for pediatric onset multiple sclerosis (POMS) are summarized, as well as the evidence for performance of the most recent iteration of... (Review)
Review
The current diagnostic criteria for pediatric onset multiple sclerosis (POMS) are summarized, as well as the evidence for performance of the most recent iteration of McDonald criteria in the pediatric population. Next, the varied roles of MRI in POMS are reviewed, including diagnostic considerations and research-based utilization. The primary role of bloodwork and cerebrospinal fluid studies in the diagnosis of POMS is to rule out disease mimics. Prognostically, POMS portends a more inflammatory course with higher relapse rate and disability reached at younger ages compared with AOMS counterparts. As such, there is an emerging trend toward the earlier use of highly efficacious disease modifying therapies to target prompt immunomodulatory disease control. Current POMS disease modifying therapies (DMTs) and active clinical POMS trials are detailed.
Topics: Child; Humans; Age of Onset; Magnetic Resonance Imaging; Multiple Sclerosis; Guidelines as Topic
PubMed: 37451754
DOI: 10.1016/j.spen.2023.101054 -
Autoimmunity Reviews Nov 2023Multiple sclerosis (MS) is an autoimmune-mediated degenerative disease of the central nervous system, characterized by inflammatory demyelination. It is primarily found... (Review)
Review
Multiple sclerosis (MS) is an autoimmune-mediated degenerative disease of the central nervous system, characterized by inflammatory demyelination. It is primarily found in women of childbearing age, making pregnancy a significant concern for both patients with MS and clinicians. To assist these patients in achieving their desire for pregnancy, reducing MS relapses during all stages of pregnancy, preventing the progression of MS, mitigating the impact of MS treatment on the course and outcome of pregnancy, and a thorough understanding of the relationship between pregnancy and MS, as well as specific management and the application of relevant medications for MS patients at each stage of pregnancy, are essential. This article provides an update on pregnancy-related issues in women with MS, including the general recommendations for management at each stage of pregnancy.
Topics: Pregnancy; Humans; Female; Multiple Sclerosis; Pregnancy Complications; Recurrence
PubMed: 37741528
DOI: 10.1016/j.autrev.2023.103449 -
Current Allergy and Asthma Reports Sep 2023In this review, we provide a comprehensive update on current scientific advances and emerging therapeutic approaches in the field of multiple sclerosis. (Review)
Review
PURPOSE OF REVIEW
In this review, we provide a comprehensive update on current scientific advances and emerging therapeutic approaches in the field of multiple sclerosis.
RECENT FINDINGS
Multiple sclerosis (MS) is a common disorder characterized by inflammation and degeneration within the central nervous system (CNS). MS is the leading cause of non-traumatic disability in the young adult population. Through ongoing research, an improved understanding of the disease underlying mechanisms and contributing factors has been achieved. As a result, therapeutic advancements and interventions have been developed specifically targeting the inflammatory components that influence disease outcome. Recently, a new type of immunomodulatory treatment, known as Bruton tyrosine kinase (BTK) inhibitors, has surfaced as a promising tool to combat disease outcomes. Additionally, there is a renewed interested in Epstein-Barr virus (EBV) as a major potentiator of MS. Current research efforts are focused on addressing the gaps in our understanding of the pathogenesis of MS, particularly with respect to non-inflammatory drivers. Significant and compelling evidence suggests that the pathogenesis of MS is complex and requires a comprehensive, multilevel intervention strategy. This review aims to provide an overview of MS pathophysiology and highlights the most recent advances in disease-modifying therapies and other therapeutic interventions.
Topics: Humans; Multiple Sclerosis; Epstein-Barr Virus Infections; Herpesvirus 4, Human
PubMed: 37402064
DOI: 10.1007/s11882-023-01102-0 -
Journal of Neurology Jan 2024This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower... (Review)
Review
This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower treatment efficacy (LETA) at onset with subsequent escalation has been challenged by new data suggesting that MS patients derive greater benefit when therapy is initiated with high-efficacy treatment agents (HETA). Several recent studies compared treatment efficacy and safety of early administration of HETA versus LETA. The results of randomized, double blind, phase III studies with LETA as a control arm and population-based larger and longer studies using propensity scoring, marginal structural modeling and weighted cumulative exposure analysis support the benefit of early treatment with HETA. Patients initiating their treatment with HETA, regardless of prognostic factors and MRI burden at baseline, showed significantly lower annualized relapse rate (ARR) and reduced disability progression in follow-up periods of up to 10-15 years. Moreover, the safety profile of recently approved HETA ameliorates concerns about off-target effects associated with a number of earlier high-efficacy drugs. Patient perception has also changed with an increasing preference for medication profiles that both improve symptoms and prevent disease progression. Accumulating data from randomized studies and the results of large population-based studies demonstrating short-term and longer-term patient benefits support the view that HETA should be more widely used. The adoption of early treatment with HETA capitalizes on a window of opportunity for anti-inflammatory drugs to maximally impact disease pathology and heralds a sea change in clinical practice toward pro-active management and away from a philosophy routed in generating clinical benefit as a consequence of treatment failure.
Topics: Humans; Multiple Sclerosis; Pharmaceutical Preparations; Treatment Outcome; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic
PubMed: 37851189
DOI: 10.1007/s00415-023-11969-8 -
Multiple Sclerosis and Related Disorders Nov 2023Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician... (Review)
Review
Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.
Topics: Humans; Multiple Sclerosis; Antigens, CD20; Agammaglobulinemia; Rituximab; Disease Management
PubMed: 37783194
DOI: 10.1016/j.msard.2023.105009 -
EBioMedicine Mar 2024Neurofilament light chain (NfL) is a long-awaited blood biomarker that can provide clinically useful information about prognosis and therapeutic efficacy in multiple... (Review)
Review
Neurofilament light chain (NfL) is a long-awaited blood biomarker that can provide clinically useful information about prognosis and therapeutic efficacy in multiple sclerosis (MS). There is now substantial evidence for this biomarker to be used alongside magnetic resonance imaging (MRI) and clinical measures of disease progression as a decision-making tool for the management of patients with MS. Serum NfL (sNfL) has certain advantages over traditional measures of MS disease progression such as MRI because it is relatively noninvasive, inexpensive, and can be repeated frequently to monitor activity and treatment efficacy. sNfL levels can be monitored regularly in patients with MS to determine change from baseline and predict subclinical disease activity, relapse risk, and the development of gadolinium-enhancing (Gd+) lesions. sNfL does not replace MRI, which provides information related to spatial localisation and lesion stage. Laboratory platforms are starting to be made available for clinical application of sNfL in several countries. Further work is needed to resolve issues around comparisons across testing platforms (absolute values) and normalisation (reference ranges) in order to guide interpretation of the results.
Topics: Humans; Multiple Sclerosis; Intermediate Filaments; Biomarkers; Prognosis; Disease Progression; Neurofilament Proteins
PubMed: 38354532
DOI: 10.1016/j.ebiom.2024.104970