Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges.
The Lancet. Neurology
Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis.
10.1016/S1474-4422(24)00027-9
Treatment with Rituximab in the Acute Phase of Relapsing Remitting Multiple Sclerosis.
Shima Ayano,Hamaguchi Tsuyoshi,Tada Yasutake,Yamada Masahito
Internal medicine (Tokyo, Japan)
There have been a few reports on the administration of rituximab for relapsing-remitting multiple sclerosis (RRMS) in the acute phase. We report the case of a 62-year-old woman with an acute lesion of RRMS. Although corticosteroid therapy and plasmapheresis were not effective, the lesion improved with the administration of rituximab. We believe that the B cells were promptly depleted after the infusion of rituximab, and that the inflammatory reactions related to the B cells were suppressed. We suggest that the administration of rituximab can be considered as a treatment option for acute-phase RRMS when conventional therapies are not effective.
10.2169/internalmedicine.3408-19
Elsberg syndrome following acute immunosuppressive treatment for multiple sclerosis relapse.
Choudhury Natasha A,Castrodad-Molina Rhaisa M,Hutton George J,Cuascut Fernando X
Multiple sclerosis and related disorders
First described more than 80 years ago, Elsberg Syndrome (ES) continues to be an under-recognized cause of cauda equina syndrome (CES). ES is an infectious disorder that presents with lower thoracic and/or lumbosacral myelitis in conjunction with CES, and most often occurs in the setting of herpes simplex virus 2 (HSV-2) reactivation (Savoldi et al., 2017; Eberhardt et al., 2004; Whalen et al., 2019). Comorbid neurologic diseases like multiple sclerosis (MS) can become a detrimental confounding factor leading to delayed diagnosis and management of ES due to pre-existing diagnostic bias. We present a case of relapsing-remitting MS (RRMS) complicated by ES, likely due to reactivation of a latent HSV infection following high immunosuppression for presumed refractory MS relapses.
10.1016/j.msard.2022.103498
A Phase 1 randomized study on the safety and pharmacokinetics of OCS-05, a neuroprotective disease modifying treatment for Acute Optic Neuritis and Multiple Sclerosis.
Scientific reports
OCS-05 (aka BN201) is a peptidomimetic that binds to serum glucocorticoid kinase-2 (SGK2), displaying neuroprotective activity. The objective of this randomized, double-blind 2-part study was to test safety and pharmacokinetics of OCS-05 administered by intravenous (i.v.) infusion in healthy volunteers. Subjects (n = 48) were assigned to receive placebo (n = 12) or OCS-05 (n = 36). , Doses tested were 0.05, 0.2, 0.4, 0.8, 1.6, 2.4 and 3.2 mg/kg in the single ascending dose (SAD) part. In the multiple ascending dose (MAD) part, 2.4 and 3.0 mg/kg doses were administered with 2 h i.v. infusion for 5 consecutive days. Safety assessments included adverse events, blood tests, ECG, Holter monitoring, brain MRI and EEG. No serious adverse events were reported in the OCS-05 group (there was one serious adverse event in the placebo group). Adverse events reported in the MAD part were not clinically significant, and no changes on the ECG, EEG or brain MRI were observed. Single-dose (0.05-3.2 mg/kg) exposure (C and AUC) increased in a dose-proportional manner. Steady state was reached by Day 4 and no accumulation was observed. Elimination half-life ranged from 3.35 to 8.23 h (SAD) and 8.63 to 12.2 h (MAD). Mean individual C concentrations in the MAD part were well below the safety thresholds. OCS-05 administered as 2-h i.v. infusions of multiple doses up to 3.0 mg/Kg daily for up to 5 consecutive days was safe and well tolerated. Based on this safety profile, OCS-05 is currently being tested in a phase 2 trial in patient with acute optic neuritis (NCT04762017, date registration 21/02/2021).
10.1038/s41598-023-32278-0
Acute Effects of Ocrelizumab Infusion in Multiple Sclerosis Patients.
International journal of molecular sciences
B cell-depleting therapies such as ocrelizumab (OCR) are highly effective in people with multiple sclerosis (MS). Especially at treatment start and initial infusion, infusion-related reactions (IRR) are a common adverse event. The relevance of acute changes of cell-depleting therapies on peripheral immune compartments and routine lab testing is important for clinical practice. We systematically analyzed routine blood parameters, detailed blood immunophenotyping and serum cytokine profiles in 45 MS patients starting on OCR. Blood samples were collected before and after corticosteroid premedication and directly after each OCR infusion of the first three ocrelizumab infusions. Blood B cells were rapidly depleted and accompanied only by a mild cytokine release at the first OCR infusion. Cytokine release was not significantly detectable from a third application in line with decreasing IRRs. B cell depletion was accompanied by short-lived changes in other immune cell populations in number, activation and cytokine secretion after each OCR infusion. Standard lab parameters did not show any clinically relevant changes. Our data demonstrate only mild changes during the first OCR infusion, which are not present any more during long-term treatment.
10.3390/ijms232213759
Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology.
Therapeutics and clinical risk management
The success of selective B-cells depleting therapies, as the anti-CD20 antibodies, in patients with multiple sclerosis (MS) has confirmed that B-cells are critical in the immune pathogenesis of the disease. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20+ B-cells, profoundly suppresses acute inflammatory disease activity, representing a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS). It is also the first proven therapy able to slow disability progression in primary progressive multiple sclerosis (PPMS), particularly in patients with signs of acute radiological activity before being enrolled. Effectiveness has widely been demonstrated in randomized clinical trials (RCTs), and recently confirmed in open-label extension trials. Here, we review the role of B-cells in MS, the mechanism of action of ocrelizumab, its pharmacokinetics and pharmacodynamics, and the clinical data supporting its use, as well as safety data. We focus on issues related to the maintenance of immunocompetence, essential to ensure an immune response to either a primary infection or a vaccination. Lastly, we discuss about the possible role of ocrelizumab as an exit strategy from natalizumab-treated patients at risk of developing multifocal progressive leukoencephalopathy. In view of using ocrelizumab chronically, collecting long-term safety data and finding strategies to minimize adverse events will be extremely relevant.
10.2147/TCRM.S282390
Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.
The Lancet. Neurology
BACKGROUND:Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis. METHODS:We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed. FINDINGS:Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred. INTERPRETATION:12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis. FUNDING:Sanofi.
10.1016/S1474-4422(21)00237-4
Vitamin D increases glucocorticoid efficacy via inhibition of mTORC1 in experimental models of multiple sclerosis.
Hoepner Robert,Bagnoud Maud,Pistor Maximilian,Salmen Anke,Briner Myriam,Synn Helen,Schrewe Lisa,Guse Kirsten,Ahmadi Farhad,Demir Seray,Laverick Louis,Gresle Melissa,Worley Paul,Reichardt Holger Michael,Butzkueven Helmut,Gold Ralf,Metz Imke,Lühder Fred,Chan Andrew
Acta neuropathologica
The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)D (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8 T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8 T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy.
10.1007/s00401-019-02018-8
Pathogenesis and management of multiple sclerosis revisited.
Disease-a-month : DM
BACKGROUND:Multiple sclerosis is an autoimmune chronic inflammatory disease characterized by selective destruction of myelin in the CNS neurons (including optic nerve). It was first described in the 19 century and remained elusive owing to the disease's unique relapsing and remitting course. The widespread and debilitating prevalence of multiple sclerosis (MS) has prompted the development of various treatment modalities for its effective management. METHODS AND OBJECTIVES:A literature review was conducted using the electronic databases PubMed and Google Scholar. The main objective of the review was to compile the advances in pathogenesis, classifications, and evolving treatment modalities for MS. RESULTS:The understanding of the pathogenesis of MS and the potential drug targets for its precise treatment has evolved significantly over the past decade. The experimental developments are also motivating and present a big change coming up in the next 5 years. Numerous disease-modifying therapies (DMTs) have revolutionized the management of MS: interferon (IFN) preparations, monoclonal antibodies-natalizumab and ocrelizumab, immunomodulatory agents-glatiramer acetate, sphingosine 1-phosphate receptor 1 (S1PR1) modulators (Siponimod) and teriflunomide. The traditional parenteral drugs are now available as oral formulations improving patient acceptability. Repurposing various agents used for related diseases may reinforce the drug reserve to manage MS and are under trials. Although at a nascent phase, strategies to enhance re-myelination by stimulating oligodendrocytes are fascinating and hold promise for better outcomes in patients with MS. CONCLUSIONS:The recent past has seen staggering inclusions to the management of multiple sclerosis catalyzing a significant turnabout in our approach to diagnosis, treatment, and prognosis. Since the advent of DMTs various other oral and injectable agents have been approved. The advances in MS therapeutics and diagnostics have laid the ground for further research and development to enhance the quality of life of afflicted patients.
10.1016/j.disamonth.2022.101497
Multiple sclerosis: time for early treatment with high-efficacy drugs.
Journal of neurology
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.
10.1007/s00415-023-11969-8
Immunoswitch Nanomodulators Enable Active Targeting and Selective Proliferation of Regulatory T Cells for Multiple Sclerosis Therapy.
ACS nano
Interleukin-2 (IL-2) used in multiple sclerosis (MS) therapy modulates the balance between regulatory T (Treg) cells and effector T (Teff) cells. However, the off-target activation of Teff cells by IL-2 limits its clinical application. Therefore, a rapidly prepared immunoswitch nanomodulator termed aT-IL2C NPs was developed, which specifically recognized Treg cells with high TIGIT expression thanks to the presence of an anti-TIGIT and an IL-2/JES6-1 complex (IL2C) being delivered to Treg cells but not to Teff cells with low TIGIT expression. Then, IL2C released IL-2 due to the specific expression of the high-affinity IL-2 receptor on Treg cells, thus enabling the active targeting and selective proliferation of Treg cells. Moreover, the anti-TIGIT of aT-IL2C NPs selectively inhibited the proliferation of Teff cells while leaving the proliferation of Treg cells unaffected. In addition, since the IL-2 receptor on Teff cells had medium-affinity, the IL2C hardly released IL-2 to Teff cells, thus enabling the inhibition of Teff cell proliferation. The treatment of experimental autoimmune encephalomyelitis (EAE) mice with aT-IL2C NPs ameliorated the severity of the EAE and restored white matter integrity. Collectively, this work described a potential promising agent for effective MS therapy.
10.1021/acsnano.3c09225
A workflow for the development of template-assisted membrane crystallization downstream processing for monoclonal antibody purification.
Nature protocols
Monoclonal antibodies (mAbs) are commonly used biologic drugs for the treatment of diseases such as rheumatoid arthritis, multiple sclerosis, COVID-19 and various cancers. They are produced in Chinese hamster ovary cell lines and are purified via a number of complex and expensive chromatography-based steps, operated in batch mode, that rely heavily on protein A resin. The major drawback of conventional procedures is the high cost of the adsorption media and the extensive use of chemicals for the regeneration of the chromatographic columns, with an environmental cost. We have shown that conventional protein A chromatography can be replaced with a single crystallization step and gram-scale production can be achieved in continuous flow using the template-assisted membrane crystallization process. The templates are embedded in a membrane (e.g., porous polyvinylidene fluoride with a layer of polymerized polyvinyl alcohol) and serve as nucleants for crystallization. mAbs are flexible proteins that are difficult to crystallize, so it can be challenging to determine the optimal conditions for crystallization. The objective of this protocol is to establish a systematic and flexible approach for the design of a robust, economic and sustainable mAb purification platform to replace at least the protein A affinity stage in traditional chromatography-based purification platforms. The procedure provides details on how to establish the optimal parameters for separation (crystallization conditions, choice of templates, choice of membrane) and advice on analytical and characterization methods.
10.1038/s41596-023-00869-w
CAR T-cell therapy in autoimmune diseases.
Lancet (London, England)
Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.
10.1016/S0140-6736(23)01126-1
Multiple sclerosis.
Lancet (London, England)
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.
10.1016/S0140-6736(23)01473-3
CNS therapeutics: Immune cells break the barriers.
Science translational medicine
Peripheral immune cells can be seen as attractive vectors and drug carriers for central nervous system therapeutics because these cells have unique properties that allow them to migrate across the blood-brain barrier, enabling drug delivery to brain regions that are inaccessible to free drugs.
10.1126/scitranslmed.adh1150
Diagnosis and Treatment of Multiple Sclerosis: A Review.
McGinley Marisa P,Goldschmidt Carolyn H,Rae-Grant Alexander D
JAMA
Importance:Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease of the central nervous system characterized by inflammatory demyelination with axonal transection. MS affects an estimated 900 000 people in the US. MS typically presents in young adults (mean age of onset, 20-30 years) and can lead to physical disability, cognitive impairment, and decreased quality of life. This review summarizes current evidence regarding diagnosis and treatment of MS. Observations:MS typically presents in young adults aged 20 to 30 years with unilateral optic neuritis, partial myelitis, sensory disturbances, or brainstem syndromes such as internuclear ophthalmoplegia developing over several days. The prevalence of MS worldwide ranges from 5 to 300 per 100 000 people and increases at higher latitudes. Overall life expectancy is less than in the general population (75.9 vs 83.4 years), and MS more commonly affects women (female to male sex distribution of nearly 3:1). Diagnosis is made based on a combination of signs and symptoms, radiographic findings (eg, magnetic resonance imaging [MRI] T2 lesions), and laboratory findings (eg, cerebrospinal fluid-specific oligoclonal bands), which are components of the 2017 McDonald Criteria. Nine classes of disease-modifying therapies (DMTs), with varying mechanisms of action and routes of administration, are available for relapsing-remitting MS, defined as relapses at onset with stable neurologic disability between episodes, and secondary progressive MS with activity, defined as steadily increasing neurologic disability following a relapsing course with evidence of ongoing inflammatory activity. These drugs include interferons, glatiramer acetate, teriflunomide, sphingosine 1-phosphate receptor modulators, fumarates, cladribine, and 3 types of monoclonal antibodies. One additional DMT, ocrelizumab, is approved for primary progressive MS. These DMTs reduce clinical relapses and MRI lesions (new T2 lesions, gadolinium-enhancing lesions). Efficacy rates of current DMTs, defined by reduction in annualized relapse rates compared with placebo or active comparators, range from 29%-68%. Adverse effects include infections, bradycardia, heart blocks, macular edema, infusion reactions, injection-site reactions, and secondary autoimmune adverse effects, such as autoimmune thyroid disease. Conclusions and Relevance:MS is characterized by physical disability, cognitive impairment, and other symptoms that affect quality of life. Treatment with DMT can reduce the annual relapse rate by 29% to 68% compared with placebo or active comparator.
10.1001/jama.2020.26858
Targeting the gut to treat multiple sclerosis.
The Journal of clinical investigation
The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.
10.1172/JCI143774
Thinking outside the box: non-canonical targets in multiple sclerosis.
Nature reviews. Drug discovery
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the need for new and exceptional therapeutic options beyond the established immunological landscape. In this Review, we highlight such non-canonical targets in preclinical MS research with a focus on five highly promising areas: oligodendrocytes; the blood-brain barrier; metabolites and cellular metabolism; the coagulation system; and tolerance induction. Recent findings in these areas may guide the field towards novel targets for future therapeutic approaches in MS.
10.1038/s41573-022-00477-5
Epstein-Barr virus and multiple sclerosis.
Nature reviews. Microbiology
Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus with a well-established causal role in several cancers. Recent studies have provided compelling epidemiological and mechanistic evidence for a causal role of EBV in multiple sclerosis (MS). MS is the most prevalent chronic inflammatory and neurodegenerative disease of the central nervous system and is thought to be triggered in genetically predisposed individuals by an infectious agent, with EBV as the lead candidate. How a ubiquitous virus that typically leads to benign latent infections can promote cancer and autoimmune disease in at-risk populations is not fully understood. Here we review the evidence that EBV is a causal agent for MS and how various risk factors may affect EBV infection and immune control. We focus on EBV contributing to MS through reprogramming of latently infected B lymphocytes and the chronic presentation of viral antigens as a potential source of autoreactivity through molecular mimicry. We consider how knowledge of EBV-associated cancers may be instructive for understanding the role of EBV in MS and discuss the potential for therapies that target EBV to treat MS.
10.1038/s41579-022-00770-5
Ageing and multiple sclerosis.
The Lancet. Neurology
The factor that is most relevant and strongly associated with the clinical course of multiple sclerosis is chronological age. Very young patients exclusively have relapsing remitting disease, whereas those with later onset disease face a more rapid development of permanent disability. For people with progressive multiple sclerosis, the poor response to current disease modifying therapies might be related to ageing in the immune system and CNS. Ageing is also associated with increased risks of side-effects caused by some multiple sclerosis therapies. Both somatic and reproductive ageing processes might contribute to development of progressive multiple sclerosis. Understanding the role of ageing in immune and neural cell function in patients with multiple sclerosis might be key to halting non-relapse-related progression. The growing literature on potential therapies that target senescent cells and ageing processes might provide effective strategies for remyelination and neuroprotection.
10.1016/S1474-4422(22)00184-3
Epstein-Barr virus as a cause of multiple sclerosis: opportunities for prevention and therapy.
The Lancet. Neurology
Multiple sclerosis is a chronic inflammatory disease of the CNS that results from the interplay between heritable and environmental factors. Mounting evidence from different fields of research supports the pivotal role of the Epstein-Barr virus (EBV) in the development of multiple sclerosis. However, translating this knowledge into clinically actionable information requires a better understanding of the mechanisms linking EBV to pathophysiology. Ongoing research is trying to clarify whether EBV causes neuroinflammation via autoimmunity or antiviral immunity, and if the interaction of EBV with genetic susceptibility to multiple sclerosis can explain why a ubiquitous virus promotes immune dysfunction in susceptible individuals. If EBV also has a role in driving disease activity, the characterisation of this role will help diagnosis, prognosis, and treatment in people with multiple sclerosis. Ongoing clinical trials targeting EBV and new anti-EBV vaccines provide hope for future treatments and preventive interventions.
10.1016/S1474-4422(22)00471-9
Radiologically isolated syndrome.
The Lancet. Neurology
Individuals can be deemed to have radiologically isolated syndrome (RIS) if they have incidental demyelinating-appearing lesions in their brain or spinal cord that are highly suggestive of multiple sclerosis but their clinical history does not include symptoms consistent with multiple sclerosis. Data from international longitudinal cohorts indicate that around half of people with RIS will develop relapsing or progressive symptoms of multiple sclerosis within 10 years, suggesting that in some individuals, RIS is a presymptomatic stage of multiple sclerosis. Risk factors for progression from RIS to clinical multiple sclerosis include younger age (ie, <35 years), male sex, CSF-restricted oligoclonal bands, spinal cord or infratentorial lesions, and gadolinium-enhancing lesions. Other imaging, biological, genetic, and digital biomarkers that might be of value in identifying individuals who are at the highest risk of developing multiple sclerosis need further investigation. Two 2-year randomised clinical trials showed the efficacy of approved multiple sclerosis immunomodulatory medications in preventing the clinical conversion to multiple sclerosis in some individuals with RIS. If substantiated in longer-term studies, these data have the potential to transform our approach to care for the people with RIS who are at the greatest risk of diagnosis with multiple sclerosis.
10.1016/S1474-4422(23)00281-8
Learning CNS immunopathology from therapeutic interventions.
Science translational medicine
Modulation of immune cell trafficking across the blood-brain barrier has not only introduced a therapeutic avenue for multiple sclerosis (MS) but also represents an example of reverse translational medicine. Data from clinical trials of drugs such as natalizumab and fingolimod have revealed the involvement of different compartments in relapsing versus non-relapsing MS immune biology, contributed to our understanding of central nervous system (CNS) immune surveillance, and stimulated new fields of research. Here, we discuss the results of these trials, as well as patient biomaterial-based scientific projects, and how both have informed our understanding of CNS immunopathology.
10.1126/scitranslmed.adg7863
Does non-invasive brain stimulation improve spatiotemporal gait parameters in people with multiple sclerosis? A systematic review and meta-analysis.
Journal of bodywork and movement therapies
BACKGROUND:Multiple sclerosis (MS) is a chronic autoimmune disease that causes progressive functional impairment, mainly in walking tasks. Noninvasive brain stimulation (NIBS) could influence the motor function and improving gait ability of patients. OBJECTIVE:The aim was to analyze the effects of NIBS (transcranial direct current stimulation [tDCS] or transcranial magnetic stimulation [TMS] on functional locomotion in people with multiple sclerosis (PwMS). METHODS:A search was conducted for randomized controlled trials published up to November 2023 comparing the application of NIBS versus a sham or control group. The primary outcome were spatiotemporal gait parameters and functional mobility. Two review authors independently assessed the risk of bias in the included studies, and we used the Grading of Recommendations Assessment, Development, and Evaluation methodology to rate the certainty of the evidence for each outcome. A meta-analysis was performed by pooling the appropriate data using RevMan Web. RESULTS:A total of four clinical trials were included for metanalysis. We observed that there is no statistically significant difference in overall effect in gait speed (MD = 0.08; 95% CI: -0.08-0.24; p = 0.32), and cadence (MD = 0.22; 95% CI: -11.54-11.98; p = 0.97%) between groups. But there was a statistically significant difference in overall effect in stride length between groups (MD:0.19; 95% CI: 0.07-0.31; p = 0.002), mainly when the intervention performed by multiple sessions and associated with motor rehabilitation (MD = 0.29; 95% CI: 0.14-0.44; p = 0.0002). CONCLUSIONS:tDCS applied by multiple session and combined with motor rehabilitation (i.e., aerobic and/or resistance training) can improve stride length in PwMS.
10.1016/j.jbmt.2023.11.043
The Efficacy of Fingolimod and Interferons in Controlling Disability and Relapse Rate in Patients with Multiple Sclerosis: A Systematic Review and Meta-Analysis.
International journal of preventive medicine
Background:Fingolimod and interferons are used in the relapse form of multiple sclerosis (MS). The goal of this systematic review and meta-analysis was to evaluate the efficacy of fingolimod versus interferon in patients with MS. The systematic search was done in PubMed, Scopus, Embase, Web of Science, and Google Scholar. Methods:The references of included studies as well as conference abstracts were searched up to July 2021. The literature search revealed 8211 articles, and after deleting duplicates 5594 remained. For the meta-analysis, four studies were included. The standardized mean difference (SMD) of the Expanded Disability Status Scale (EDSS) after treatment (interferon vs fingolimod) was -0.06 (95% CI: -0.28, 0.17) (I = 80.2%, = 0.002). Results:The SMD of the annual relapse rate (ARR) after treatment (interferon - fingolimod) was -0.08 (95% CI: -0.53, 0.36) (I = 95.5%, < 0.001). The SMD of the ARR after treatment and before treatment in the interferon group was - 1.45, (95% CI: -1.55, -1.36) (I = 0, = 0.3). The SMD of ARR after treatment and before treatment in the fingolimod group was - 1.3, (95% CI: -1.94, -0.65) (I = 97.4%, < 0.001). Conclusions: The results of this systematic review show that efficacy of interferon and fingolimod in controlling relapse rate and disability is similar.
10.4103/ijpvm.ijpvm_12_22
Multiple Sclerosis Part 1: Essentials and the McDonald Criteria.
Magnetic resonance imaging clinics of North America
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by relapsing-remitting or progressive neurologic symptoms and focal white matter lesions. The hallmark of the disease is the dissemination of CNS lesions in space and time, which is defined by the McDonald criteria. MRI is an essential diagnostic and prognostic biomarker for MS which can evaluate the entire CNS. MS mimics must be excluded before a diagnosis of MS is made.
10.1016/j.mric.2023.11.002
Multiple Sclerosis: An Emergency Medicine-Focused Narrative Review.
The Journal of emergency medicine
BACKGROUND:Multiple sclerosis (MS) is a rare but serious condition associated with significant morbidity. OBJECTIVE:This review provides a focused assessment of MS for emergency clinicians, including the presentation, evaluation, and emergency department (ED) management based on current evidence. DISCUSSION:MS is an autoimmune disorder targeting the central nervous system (CNS), characterized by clinical relapses and radiological lesions disseminated in time and location. Patients with MS most commonly present with long tract signs (e.g., myelopathy, asymmetric spastic paraplegia, urinary dysfunction, Lhermitte's sign), optic neuritis, or brainstem syndromes (bilateral internuclear ophthalmoplegia). Cortical syndromes or multifocal presentations are less common. Radiologically isolated syndrome and clinically isolated syndrome (CIS) may or may not progress to chronic forms of MS, including relapsing remitting MS, primary progressive MS, and secondary progressive MS. The foundation of outpatient management involves disease-modifying therapy, which is typically initiated with the first signs of disease onset. Management of CIS and acute flares of MS in the ED includes corticosteroid therapy, ideally after diagnostic testing with imaging and lumbar puncture for cerebrospinal fluid analysis. Emergency clinicians should evaluate whether patients with MS are presenting with new-onset debilitating neurological symptoms to avoid unnecessary testing and admissions, but failure to appropriately diagnose CIS or MS flare is associated with increased morbidity. CONCLUSIONS:An understanding of MS can assist emergency clinicians in better diagnosing and managing this neurologically devastating disease.
10.1016/j.jemermed.2023.12.003
Reaching an evidence-based prognosis for personalized treatment of multiple sclerosis.
Rotstein Dalia,Montalban Xavier
Nature reviews. Neurology
Personalized treatment is ideal for multiple sclerosis (MS) owing to the heterogeneity of clinical features, but current knowledge gaps, including validation of biomarkers and treatment algorithms, limit practical implementation. The contemporary approach to personalized MS therapy depends on evidence-based prognostication, an initial treatment choice and evaluation of early treatment responses to identify the need to switch therapy. Prognostication is directed by baseline clinical, environmental and demographic factors, MRI measures and biomarkers that correlate with long-term disability measures. The initial treatment choice should be a shared decision between the patient and physician. In addition to prognosis, this choice must account for patient-related factors, including comorbidities, pregnancy planning, preferences of the patients and their comfort with risk, and drug-related factors, including safety, cost and implications for treatment sequencing. Treatment response has traditionally been assessed on the basis of relapse rate, MRI lesions and disability progression. Larger longitudinal data sets have enabled development of composite outcome measures and more stringent standards for disease control. Biomarkers, including neurofilament light chain, have potential as early surrogate markers of prognosis and treatment response but require further validation. Overall, attainment of personalized treatment for MS is complex but will be refined as new data become available.
10.1038/s41582-019-0170-8
Pathophysiology, Diagnosis, Treatment and Emerging Neurotherapeutic Targets for Progressive Multiple Sclerosis: The Age of PIRA.
Neurologic clinics
More than one million individuals are impacted by progressive forms of multiple sclerosis. The literature examining the management of MS has focused primarily on relapsing forms of disease, and effective therapies targeting progressive mechanisms in MS remains a significant unmet need. Despite this, there are several encouraging potential therapeutics on the horizon. Improved understanding of mechanisms underlying MS progression, identification and validation of biomarkers, identification of novel therapeutic targets, and improved trial design are needed to further propel progress in the management of individuals with progressive forms of MS.
10.1016/j.ncl.2023.07.002
Updates and advances in multiple sclerosis neurotherapeutics.
Neurodegenerative disease management
The multiple sclerosis (MS) neurotherapeutic landscape is rapidly evolving. New disease-modifying therapies (DMTs) with improved efficacy and safety, in addition to an expanding pipeline of agents with novel mechanisms, provide more options for patients with MS. While treatment of MS neuroinflammation is well tailored in the existing DMT armamentarium, concerted efforts are currently underway for identifying neuropathological targets and drug discovery for progressive MS. There is also ongoing research to develop agents for remyelination and neuroprotection. Further insights are needed to guide DMT initiation and sequencing as well as to determine the role of autologous stem cell transplantation in relapsing and progressive MS. This review provides a summary of these updates.
10.2217/nmt-2021-0058
Multiple Sclerosis.
Olek Michael J
Annals of internal medicine
Many groundbreaking advances have occurred in the field of multiple sclerosis since this series last reviewed the disorder in 2014. The U.S. Food and Drug Administration has approved 7 new medications for relapsing-remitting multiple sclerosis and approved the first medication for primary progressive multiple sclerosis. The McDonald criteria for diagnosing multiple sclerosis were updated in 2017. New blood tests can now differentiate patients with multiple sclerosis from those with neuromyelitis optica spectrum disorder, and 3 new medications have been approved specifically for the latter disorder. Also, new medications for treating the symptoms of multiple sclerosis have been introduced.
10.7326/AITC202106150
Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis.
Nature reviews. Neurology
In contrast to the multiple disease-modifying therapies that are available for relapsing-remitting multiple sclerosis (MS), the therapeutic options for progressive MS (PMS) are limited. Recent advances in our understanding of the neuroimmunology of PMS, including the mechanisms that drive slowly expanding lesions, have fuelled optimism for improved treatment of this condition. In this Review, we highlight the commonly observed neuropathology of PMS and discuss the associated mechanisms of CNS injury. We then apply this knowledge to formulate criteria for therapeutic efficacy in PMS, beginning with the need for early treatment owing to the substantial neuropathology that is already present at the initial clinical presentation. Other requirements include: antagonism of neuroaxonal injury mediators such as pro-inflammatory microglia and lymphocytes; remediation of oxidative stress resulting from iron deposition and mitochondrial dysfunction; and promotion of neuroprotection through remyelination. We consider whether current disease-modifying therapies for relapsing-remitting MS meet the criteria for successful therapeutics in PMS and suggest that the evidence favours the early introduction of sphingosine 1-phosphate receptor modulators. Finally, we weigh up emerging medications, including repurposed generic medications and Bruton's tyrosine kinase inhibitors, against these fundamental criteria. In this new therapeutic era in PMS, success depends collectively on understanding disease mechanisms, drug characteristics (including brain penetration) and rational use.
10.1038/s41582-021-00581-x
The role of glial cells in multiple sclerosis disease progression.
Nature reviews. Neurology
Despite the development of highly effective treatments for relapsing-remitting multiple sclerosis (MS), limited progress has been made in addressing primary progressive or secondary progressive MS, both of which lead to loss of oligodendrocytes and neurons and axons, and to irreversible accumulation of disability. Neuroinflammation is central to all forms of MS. The current effective therapies for relapsing-remitting MS target the peripheral immune system; these treatments, however, have repeatedly failed in progressive MS. Greater understanding of inflammation driven by CNS-resident cells - including astrocytes and microglia - is, therefore, required to identify novel potential therapeutic opportunities. Advances in imaging, biomarker analysis and genomics suggest that microglia and astrocytes have central roles in the progressive disease process. In this Review, we provide an overview of the involvement of astrocytes and microglia at major sites of pathology in progressive MS. We discuss current and future therapeutic approaches to directly target glial cells, either to inhibit pathogenic functions or to restore homeostatic functions lost during the course of the disease. We also discuss how bidirectional communication between astrocytes and microglia needs to be considered, as therapeutic targeting of one is likely to alter the functions of the other.
10.1038/s41582-022-00624-x