Effective Therapy For Multiple Sclerosis Research Articles

Immunoswitch Nanomodulators Enable Active Targeting and Selective Proliferation of Regulatory T Cells for Multiple Sclerosis Therapy.

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.

Gut flora in multiple sclerosis: implications for pathogenesis and treatment.

Multiple sclerosis is an inflammatory disorder characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Although current first-line therapies can help manage symptoms and slow down disease progression, there is no cure for multiple sclerosis. The gut-brain axis refers to complex communications between the gut flora and the immune, nervous, and endocrine systems, which bridges the functions of the gut and the brain. Disruptions in the gut flora, termed dysbiosis, can lead to systemic inflammation, leaky gut syndrome, and increased susceptibility to infections. The pathogenesis of multiple sclerosis involves a combination of genetic and environmental factors, and gut flora may play a pivotal role in regulating immune responses related to multiple sclerosis. To develop more effective therapies for multiple sclerosis, we should further uncover the disease processes involved in multiple sclerosis and gain a better understanding of the gut-brain axis. This review provides an overview of the role of the gut flora in multiple sclerosis.

Lessons learned after 20 years of real-world experience with natalizumab

BackgroundWhile natalizumab (NTZ) is an effective therapy for multiple sclerosis (MS), it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). After 20 years (2002–2022) of experience with NTZ at our center, we observed no cases of PML. ObjectivesWe evaluated the likelihood of experiencing PML in a subset of our treatment cohort, as well as reviewed treatment practices at our center that may mitigate PML risk. MethodsFor this retrospective study, we reviewed patient characteristics, treatment practices, and clinical and MRI findings in patients receiving NTZ from 2006 to 2020. Observation of no PML cases was compared to the global and US PML incidences, and to the expected incidence based on published risk estimates. Results766 patients were evaluated. The number of NTZ infusions received ranged from 1 to 126, with a mean of 28. Patients received neurological examination prior to each infusion, which sometimes resulted in a pause in therapy to rule out PML if clinical worsening occurred. Extended interval dosing (EID) was the overall dosing schedule for 31% of patients. EID did not result in higher rates of radiological disease worsening than standard interval dosing (SID) patients. Depending on the analysis conducted, the finding of 0 PML cases in our cohort ranged from slightly unexpected to slightly expected. ConclusionsThe utilization of EID as well as regular clinical monitoring of patients may have lowered PML risk while still maintaining NTZ efficacy.

Adaptive and innate immune responses in multiple sclerosis with anti-CD20 therapy: Gene expression and protein profiles.

Anti-CD20 is a highly effective therapy for multiple sclerosis (MS), a disease with multiple abnormalities in function of B and T cells and innate immune cells. Anti-CD20 therapy depletes B cells, which alters antibody production and has diverse effects on B cell immunity. These changes potentially affect immunity beyond B cells in MS. Determine if anti-CD20 therapy effects non-B cell, as well as B cell, gene expression, and serum protein levels. Samples were collected from 10 healthy controls and from clinically stable relapsing-remitting MS - 10 untreated, 9 interferon-β-treated, and 15 ocrelizumab-treated patients were studied before, and 2 weeks and 6 months after, the first anti-CD20 infusion. Peripheral blood mononuclear cells (PBMC) were analyzed with sensitive, 135,000-transcript RNA expression microarrays, using stringent criteria. Gene expression was compared to 43 MS-relevant serum immune and neurotrophic proteins, using multiplex protein assays. Anti-CD20 therapy reduced expression of 413 total genes and 185 B-cell-regulated genes at 2 weeks vs. pre-therapy. Expression of 19 (15%) of these B cell genes returned toward baseline by 6 months, including genes for the B cell activation protein, CD79A, and for immunoglobulin A, D, and G heavy chains. Expression pathways for Th17 and CD4 regulatory T-cell (Treg) development, differentiation, and proliferation also quieted. In contrast, expression increased in Th1 and myeloid cell antiviral, pro-inflammatory, and toll-like receptor (TLR) gene pathways. These findings have clinical implications. B cell gene expression diminishes 2 weeks after anti-CD20 antibody infusion, but begins to rebound by 6 months. This suggests that the optimum time for vaccination is soon before reinfusion of anti-CD20 therapy. In addition, at 6 months, there is enhanced Th1 cell gene expression and induction of innate immune response genes and TLR expression, which can enhance anti-viral and anti-tumor immunity. This may compensate for diminished B cell gene expression after therapy. These data suggest that anti-CD20 therapy has dynamic effect on B cells and causes a compensatory rise in Th1 and myeloid immunity.

RADT-42. EFFECTS OF RADIOTHERAPY FOR CNS NEOPLASMS IN PEOPLE WITH MULTIPLE SCLEROSIS

Abstract INTRODUCTION Patients with multiple sclerosis (MS) may be at higher risk of brain tumors (Khalil 2012, London 2020, etc.). However, MS patients have been reported to have adverse effects from radiotherapy, a mainstay of CNS treatment. In the last ten years, radiation techniques have improved. We submit a case report of an MS patient with demyelinating CNS lesions shortly after radiation therapy for an astrocytoma and review the literature. Case description: A 40-year-old woman with a history of MS treated with Siponimod underwent resection of a right frontotemporal grade 2 astrocytoma, IDH mutant. She received adjuvant proton radiotherapy (54 Gy(RBE) over 30 fractions) followed by temozolomide chemotherapy. She tolerated radiotherapy well and only experienced grade 1 dermatitis, fatigue, and hair loss within the field of treatment. 1-month post radiation MRI was stable. 4 months post radiation there was an asymptomatic new typical demyelinating lesion on FLAIR without T1 or contrast changes. This was outside the high dose radiation field (i.e. received ~30 Gy(RBE)). Her Siponimod had been held for concerns of interactions with radiation or chemotherapy. DISCUSSION Cases have been reported of people with MS experiencing adverse effects from radiotherapy. Murphy, et al., reported a 30-year-old woman with MS experiencing an attack of demyelination 2 months after radiotherapy (50 Gy over 25 fractions), and Borges, et al. presents a 28-year-old patient who experienced radiotherapy-induced inflammatory demyelination after receiving whole-ventricular irradiation (24 Gy over 15 fractions). Miller, et al., reported 6 patients without exacerbations of MS but had developed grade 4 neurotoxicity in a median of 1 year; most of those patients were treated with older radiation techniques, however. Radiotherapy effects in people with MS is a topic that should be revisited in the era of more conformal RT techniques, effective MS therapies, and cancer treatment including immunotherapy.

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients

BackgroundAlemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.ObjectivesTo evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients.MethodsIn this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files.ResultsAltogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1–3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented.ConclusionsSAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Initial highly effective therapy for MS: A strong start.

In this issue of Neurology® , Buron et al.1 present an article titled “Initial high-efficacy disease-modifying therapy in multiple sclerosis: A nationwide cohort study.” The goal of this study was to determine the best way to start therapy in patients with multiple sclerosis (MS). The authors examined starting patients on treatment known to be highly effective for MS known as high-efficacy disease-modifying therapies (heDMTs). They wanted to know if this approach is better than beginning with more moderate treatments (known as medium-efficacy disease-modifying therapies [meDMTs]) and intensifying treatment later if needed.

Tardive Reactivation of Progressive Multiple Sclerosis During Treatment with Biotin.

Multiple sclerosis (MS) is a common autoimmune disease of the central nervous system, causing neurological disability in young adults. A growing understanding of its immunopathogenesis has led to an expanding array of therapies. Notable new advances in disease-modifying therapies for relapsing forms of multiple sclerosis that are based on anti-inflammatory activity have recently been developed. Management of progressive MS is still challenging. Data published in 2014 suggested that daily high doses of biotin, a vitamin involved in myelin synthesis, might have a beneficial impact on disability and progression in progressive MS. However, some patients worsened while on biotin without any clear explanation for this effect. We report the case of a 41-year-old patient suffering from primary progressive (PP) MS who presented after 16 months of treatment with high doses of biotin (QIZENDAY) with worsening of his Expanding Disability Status Scale (EDSS) score and the appearance of a symptomatic new T2 pseudo-tumoural lesion on brain magnetic resonance imaging (MRI), suggestive of tardive inflammatory reactivation possibly due to the biotin. The newer and more effective therapies for MS are, however, associated with risks that necessitate an active management strategy and continuous vigilance. Physicians should be aware of iatrogenic neurological complications and the possible paradoxical effects of biotin. Future treatment approaches to progressive MS must include identification of a biomarker of disease activity. The study of neurofilaments in the cerebrospinal fluid (CSF) and the serum could be of interest when determining the optimal treatment strategy.

Autologous Hematopoietic Cell Transplantation in Multiple Sclerosis: Changing Paradigms in the Era of Novel Agents.

Autologous hematopoietic stem cell transplantation (AHSCT) is established as a standard of care for diseases ranging from hematological malignancies to other neoplastic pathologies and severe immunological deficiencies. In April 1995, our group performed the first AHSCT in progressive multiple sclerosis (MS). Since then, a plethora of studies have been published with encouraging but controversial results. Major challenges in the field include appropriate patient selection, improvements in AHSCT procedure, and timing of this treatment modality. Beyond AHSCT, several new intravenous or oral agents have been developed and approved over the last 20 years in MS. The emergence of multiple effective therapies for MS has created a challenging scenario for both treating physicians and patients. Novel cell-based therapies other than AHSCT are also currently investigated in MS patients with promising results. Our review is aimed at summarizing state-of-the-art knowledge on basic principles and results of AHSCT in MS and its role compared to novel agents.

Severe Exacerbation of Multiple Sclerosis Following Withdrawal of Fingolimod.

Fingolimod is an effective therapy for multiple sclerosis (MS). Isolated reports of very aggressive MS rebound after discontinuation of fingolimod are drawing neurologists' attention to this potentially severe complication of the drug. Our objective was to collect literature data on cases of MS rebound following fingolimod withdrawal. In addition, we report six new cases of this adverse event in Brazil. We carried out a systematic review of published data on cases of MS rebound after fingolimod was discontinued. In addition, the study reports a retrospective data series of Brazilian patients presenting this rebound reaction. Twenty papers have been published reporting on 52 patients with severe MS rebound after fingolimod withdrawal. Six new patients are included in the present paper, all of them with aggressive rebound and accumulated disability sequelae. We recommend gradual discontinuation of fingolimod with replacement by other treatment. The washout period should not exceed 4weeks.

Combination of apoptotic T cell induction and self-peptide administration for therapy of experimental autoimmune encephalomyelitis

BackgroundClinical trials on multiple sclerosis with repeated injections of monoclonal antibodies depleting CD4+ T cells have not resulted in much success as a disease therapy. Here, we developed an immunotherapy for EAE in mice by combining a transient depletion of T cells together with the administration of neuron derived peptides. MethodsEAE was induced in SJL and C57BL/6 mice, by proteolipid protein peptide PLP139–151 (pPLP) and myelin-oligodendrocyte glycoprotein MOG35–55 (pMOG) peptides, respectively. Anti-CD4 and anti-CD8 antibody were injected intraperitoneally before or after peptide immunization. EAE scores were evaluated and histology data from brain and spinal cord were analyzed. Splenocytes were isolated and CD4+, CD4+CD25− and CD4+CD25+ T cells were purified and cultured in the presence of either specific peptides or anti-CD3 antibody and proliferation of T cells as well as cytokines in supernatant were assessed. FindingsThis experimental treatment exhibited therapeutic effects on mice with established EAE in pPLP-susceptible SJL mice and pMOG-susceptible C57BL/6 mice. Mechanistically, we revealed that antibody-induced apoptotic T cells triggered macrophages to produce TGFβ, and together with administered auto-antigenic peptides, generated antigen-specific Foxp3+ regulatory T cells (Treg cells) in vivo. InterpretationWe successfully developed a specific immunotherapy to EAE by generating autoantigen-specific Treg cells. These findings have overcome the drawbacks of long and repeated depletion of CD4+ T cells, but also obtained long-term immune tolerance, which should have clinical implications for the development of a new effective therapy for multiple sclerosis. FundThis research was supported by the Intramural Research Program of the NIH, NIDCR.

B cell depletion with ublituximab reshapes the T cell profile in multiple sclerosis patients

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, thought to be mediated by myelin-specific CD4+ T cells. However, B cell depletion has proven to be an effective therapy for MS, but the mechanism is not well understood. This study was designed to determine how B cell depletion changes lymphocyte profiles. During a phase IIa clinical trial with ublituximab, a novel CD20 antibody, blood was collected from 48 MS patients at 11 time points over 24 weeks and the lymphocyte profiles were analyzed by flow cytometry. The percentage of naïve CD4+ and CD8+ T cells increased, while the percentage of both effector and central memory T cells declined. CD4+ Th1 effector cells decreased, while there was a significant increase in CD4+ regulatory T cells. The depletion of B cells had a favorable shift in the lymphocyte landscape, reducing the number of naïve T cells becoming activated and transitioning to memory T cells. The ratio of Th1 cells to CD4+ regulatory T cells declined, suggesting that immune regulation was being restored. These data suggest that loss of B cells as antigen presenting cells is a major mechanism of action for the beneficial effects of CD20 antibody therapy in MS.

Increased CD74 binding and EAE treatment efficacy of a modified DRα1 molecular construct.

Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system (CNS) with a strong inflammatory component that affects more than 2 million people worldwide (and at least 400,000 in the United States). In MS, macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) enhance the inflammatory event as a result of their interaction with their cognate receptor CD74. Therefore, the search for new agents aimed at blocking this interaction is critical for therapeutic purposes and will be of paramount importance for the treatment of MS. DRα1-MOG-35-55 constructs have been demonstrated to be effective in the treatment of experimental autoimmune encephalomyelitis (EAE) a mouse model for MS. This effect is directly correlated with the binding to its cell surface receptor, CD74, apparently preventing or blocking the binding of two inflammatory factors, MIF and D-DT. Here we report that a single amino acid substitution (L50Q) in the DRα1 domain of the human and mouse DRα1-MOG-35-55 constructs (notated as DRhQ and DRmQ, respectively) possessed increased affinity for CD74, a greater capacity to block MIF binding, the ability to inhibit pERK1/2 signaling and increased therapeutic activity in mice with EAE. These data suggest that binding affinity for CD74 could serve as an in vitro indicator of biological potency of DRhQ and thus support its possible clinical utility as an effective therapy for MS and perhaps other diseases in which there is an inflammatory reaction driven by MIF and D-DT.

Are sigma receptor modulators a weapon against multiple sclerosis disease?

Effective therapies for multiple sclerosis (MS) are still missing. This neurological disease affects more than 2.5million people worldwide. To date, biological immunomodulatory drugs are effective and safe during short-term treatment, but they are suitable only for parenteral administration and they are expensive. Accordingly, academic and industrial environments are still focusing their efforts toward the development of new MS drugs. Considering that neurodegeneration is a contributory factor in the onset of MS, herein we will focus on the crucial role played by sigma 1 receptors (S1Rs) in MS. A pilot study was performed, evaluating the effect of the S1R agonist (R)-RC33 on rat dorsal root ganglia experimental model. The encouraging results support the potential of S1R agonists for MS treatment.

Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod

Background: Neurofilament light chain (NFL) is a cerebrospinal fluid (CSF) marker of neuroaxonal damage in multiple sclerosis (MS). Objective: To determine the correlation of NFL in CSF and serum/plasma, and in plasma after switching from injectable MS therapies to fingolimod. Methods: A first cohort consisted of MS patients (n = 39) and neurological disease controls (n = 27) where CSF and plasma/serum had been collected for diagnostic purposes. A second cohort (n = 243) consisted of patients from a post-marketing study of fingolimod. NFL was determined with Single Molecule Array (Simoa™) technology (detection threshold 1.95 pg/mL). Results: Mean NFL pg/mL (standard deviation (SD)) was 341 (267) and 1475 (2358) in CSF and 8.2 (3.58) and 17.0 (16.94) in serum from controls and MS, respectively. CSF/serum and plasma/serum levels were highly correlated (n = 66, rho = 0.672, p < 0.0001 and n = 16, rho = 0.684, p = 0.009, respectively). In patients starting fingolimod (n = 243), mean NFL pg/mL (SD) in plasma was reduced between baseline (20.4 (10.7)) and at 12 months (13.5 (7.3), p < 3 × 10−6), and levels remained stable at 24 months (13.2 (6.2)). Conclusion: NFL in serum and CSF are highly correlated and plasma NFL levels decrease after switching to highly effective MS therapy. Blood NFL measurement can be considered as a biomarker for MS therapy response.

Natalizumab stabilizes physical, cognitive, MRI, and OCT markers of disease activity: A prospective, non-randomized pilot study.

Natalizumab is an effective therapy for multiple sclerosis (MS). Its effectiveness has been demonstrated in several clinical and imaging studies. The objective of this study was to further demonstrate the efficacy of natalizumab using a comprehensive battery of clinical and imaging markers in the same cohort of patients followed longitudinally, hence capturing the multi-faceted nature of the MS disease process. A prospective, open-label, pilot study of 20 MS patients treated with natalizumab was conducted. High resolution MRI, Symbol-Digit Modalities Test (SDMT), and Optical Coherence Tomography (OCT) scans were obtained at baseline, 48, and 96 weeks. 15 patients completed the study. Natalizumab treatment decreased Expanded Disability Status Scale score (EDSS) and no change in SDMT, Brain Parenchymal Fraction (BPF), or any of the OCT markers of retinal degeneration was observed. Thalamic and whole brain volume as assessed by Percentage Brain Volume Change (PBVC) showed continuous deterioration. Higher baseline T2 lesion load correlated with increased rate of PBVC at 96-weeks (r = 0.566, R2 = 0.320, p = 0.035) and thalamic volume loss (r = -0.586, R2 = 0.344, p = 0.027). Most patients, 93%, achieved no evidence of disease activity (NEDA) at 2 years, likely due to early disease duration and lower initial baseline lesion load. This study further demonstrates stabilization of clinical and imaging markers of disease activity during natalizumab treatment.

The benefit of integrating safety data from the FDA mandated registry with medwatch reports: A Southern Network on Adverse Reactions (SONAR) analysis based on the Tysabri Outreach Commitment to Health Registry (TOUCH).

e18237Background: Natalizumab is an effective therapy for multiple sclerosis. Its most notable toxicity is PML. The FDA mandated registry, TOUCH, focuses on PML cases. We identified an unusual case...

Extended interval dosing of natalizumab in multiple sclerosis

BackgroundNatalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose...

Classification, diagnosis, and differential diagnosis of multiple sclerosis.

The increasing availability of effective therapies for multiple sclerosis as well as research demonstrating the benefits of early treatment highlights the importance of expedient and accurate multiple sclerosis diagnosis. This review will discuss the classification, diagnosis, and differential diagnosis of multiple sclerosis. An international panel of multiple sclerosis experts, the MS Phenotype Group, recently revised the multiple sclerosis phenotypic classifications and published their recommendations in 2014. Recent research developments have helped improve the accuracy of multiple sclerosis diagnosis, especially with regard to differentiating multiple sclerosis from neuromyelitis optica spectrum disorders. Current multiple sclerosis phenotypic classifications include relapsing-remitting multiple sclerosis, clinically isolated syndrome, radiologically isolated syndrome, primary-progressive multiple sclerosis, and secondary-progressive multiple sclerosis. The McDonald 2010 diagnostic criteria provide formal guidelines for the diagnosis of relapsing-remitting multiple sclerosis and primary-progressive multiple sclerosis. These require demonstration of dissemination in space and time, with consideration given to both clinical findings and imaging data. The criteria also require that there exist no better explanation for the patient's presentation. The clinical history, examination, and MRI should be most consistent with multiple sclerosis, including the presence of features typical for the disease as well as the absence of features that suggest an alternative cause, for a diagnosis of multiple sclerosis to be proposed.

Polysialic acid as an antigen for monoclonal antibody HIgM12 to treat multiple sclerosis and other neurodegenerative disorders.

CNS regeneration is a desirable goal for diseases of brain and spinal cord. Current therapeutic strategies for the treatment of multiple sclerosis (MS) aim to eliminate detrimental effects of the immune system, so far without reversing disability or affecting long-term prognosis in patients. Approachable molecular targets that stimulate CNS repair are not part of the clinical praxis or have not been identified yet. The purpose of this study was to identify the molecular target of the human monoclonal antibody HIgM12. HIgM12 reverses motor deficits in chronically demyelinated mice, a model of MS. Here, we identified polysialic acid (PSA) attached to the neural cell adhesion molecule (NCAM) as the antigen for HIgM12 by using different NCAM knockout strains and through PSA removal from the NCAM protein core. Antibody binding to CNS tissue and primary cells, antibody-mediated cell adhesion, and neurite outgrowth on HIgM12-coated nitrocellulose was detected only in the presence of PSA as assessed by western blotting, immunoprecipitation, immunocytochemistry, and histochemistry. We conclude that HIgM12 mediates its in vivo and in vitro effects through binding to PSA and has the potential to be an effective therapy for MS and neurodegenerative diseases. The human antibody HIgM12 stimulates neurite outgrowth in vitro and promotes function in chronically demyelinated mice, a model of multiple sclerosis. The cellular antigen for HIgM12 was undetermined. Here, we identified polysialic acid attached to NCAM (neural cell adhesion molecule) as the cellular target for HIgM12. This includes glial fibrillary acidic protein (GFAP)-positive mouse astrocytes (GFAP, red; HIgM12, green; DAPI, blue) among other cell types of the central nervous system. These findings indicate a new strategy for the treatment of neuro-motor disorders including multiple sclerosis.