Immunotherapy Of Multiple Sclerosis Research Articles

Trajectories of self-reported fatigue following initiation of multiple sclerosis disease-modifying therapy

BackgroundWe analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing–remitting multiple sclerosis (RRMS), to identify trajectories of fatigue and their association with...

Adverse effects of immunotherapies for multiple sclerosis: a network meta-analysis.

Adverse effects of immunotherapies for multiple sclerosis: a network meta-analysis.

Exploring the Dynamic Role of Gamma-Delta T Cells in Clinical Pathology: A Systematic Review of Current Knowledge and Future Perspectives

Gamma-delta [γδ] T cells are a significant subset of T cells with ability to recognize many antigens without the guidance of major histocompatibility complex (MHC) molecules. A lot of studies have been conducted on them ever since they were discovered 36 years ago. Advances have been made about their structure and function. Thus, there is a need for an up-to-date review about their significance as well as their roles in Multiple Sclerosis. The study aimed to provide an up-to-date knowledge concerning gamma delta T cells in pathogenesis of Multiple Sclerosis (MS). A systematic review methodology was used to scope information from recent studies about gamma delta T cells. The review was carried out in PubMed database and it followed the PRISMA guidelines. The computerized review yielded 60 peer-reviewed articles published between 2011 and 2020. The results showed that gamma delta cells play a critical role in protection against infections and the fight against malignant cells. Most of the reviewed studies highlighted recent advances in research. It was noted that the subset of T cells plays a role in pathogenesis of MS. Several studies have highlighted the protective and detrimental effects of γδ T cells. On the one hand, the cells contribute to the pathogenesis of MS, while, on the other hand, they also help in immunoregulation. However, there is a dearth of literature on their specific role and their mechanism of action. Therefore, further studies are needed about γδ T cells in both human and animal model studies. Based on the findings of the reviewed studies, there is great promise in the use of γδ T cells for MS immunotherapy

Trajectories of cognitive processing speed and physical disability over 11 years following initiation of a first multiple sclerosis disease-modulating therapy

BackgroundWe analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability...

Fasudil-modified macrophages reduce inflammation and regulate the immune response in experimental autoimmune encephalomyelitis.

Multiple sclerosis is characterized by demyelination and neuronal loss caused by inflammatory cell activation and infiltration into the central nervous system. Macrophage polarization plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis, a traditional experimental model of multiple sclerosis. This study investigated the effect of Fasudil on macrophages and examined the therapeutic potential of Fasudil-modified macrophages in experimental autoimmune encephalomyelitis. We found that Fasudil induced the conversion of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type, as shown by reduced expression of inducible nitric oxide synthase/nitric oxide, interleukin-12, and CD16/32 and increased expression of arginase-1, interleukin-10, CD14, and CD206, which was linked to inhibition of Rho kinase activity, decreased expression of toll-like receptors, nuclear factor-κB, and components of the mitogen-activated protein kinase signaling pathway, and generation of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6. Crucially, Fasudil-modified macrophages effectively decreased the impact of experimental autoimmune encephalomyelitis, resulting in later onset of disease, lower symptom scores, less weight loss, and reduced demyelination compared with unmodified macrophages. In addition, Fasudil-modified macrophages decreased interleukin-17 expression on CD4+ T cells and CD16/32, inducible nitric oxide synthase, and interleukin-12 expression on F4/80+ macrophages, as well as increasing interleukin-10 expression on CD4+ T cells and arginase-1, CD206, and interleukin-10 expression on F4/80+ macrophages, which improved immune regulation and reduced inflammation. These findings suggest that Fasudil-modified macrophages may help treat experimental autoimmune encephalomyelitis by inducing M2 macrophage polarization and inhibiting the inflammatory response, thereby providing new insight into cell immunotherapy for multiple sclerosis.

Chapter 17 - Lessons from immunotherapies in multiple sclerosis

The improved understanding of multiple sclerosis (MS) neurobiology alongside the development of novel markers of disease will allow precision medicine to be applied to MS patients, bringing the promise of improved care. Combinations of clinical and paraclinical data are currently used for diagnosis and prognosis. The addition of advanced magnetic resonance imaging and biofluid markers has been strongly encouraged, since classifying patients according to the underlying biology will improve monitoring and treatment strategies. For example, silent progression seems to contribute significantly more than relapses to overall disability accumulation, but currently approved treatments for MS act mainly on neuroinflammation and offer only a partial protection against neurodegeneration. Further research, involving traditional and adaptive trial designs, should strive to halt, repair or protect against central nervous system damage. To personalize new treatments, their selectivity, tolerability, ease of administration, and safety must be considered, while to personalize treatment approaches, patient preferences, risk-aversion, and lifestyle must be factored in, and patient feedback used to indicate real-world treatment efficacy. The use of biosensors and machine-learning approaches to integrate biological, anatomical, and physiological parameters will take personalized medicine a step closer toward the patient's virtual twin, in which treatments can be tried before they are applied.

Repurposing MS immunotherapies for CIDP and other autoimmune neuropathies: unfulfilled promise or efficient strategy?

Despite advances in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other common autoimmune neuropathies (AN), still-many patients with these diseases do not respond satisfactorily to the available treatments. Repurposing of disease-modifying therapies (DMTs) from other autoimmune conditions, particularly multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), is a promising strategy that may accelerate the establishment of novel treatment choices for AN. This approach appears attractive due to homologies in the pathogenesis of these diseases and the extensive post-marketing experience that has been gathered from treating MS and NMOSD patients. The idea is also strengthened by a number of studies that explored the efficacy of DMTs in animal models of AN but also in some CIDP patients. We here review the available preclinical and clinical data of approved MS therapeutics in terms of their applicability to AN, especially CIDP. Promising therapeutic approaches appear to be B cell-directed and complement-targeting strategies, such as anti-CD20/anti-CD19 agents, Bruton's tyrosine kinase inhibitors and anti-C5 agents, as they exert their effects in the periphery. This is a major advantage because, in contrast to MS, their action in the periphery is sufficient to exert significant immunomodulation.

Specific Aspects of Immunotherapy for Multiple Sclerosis in Switzerland—A Structured Commentary, Update 2022

Multiple sclerosis (MS), particularly relapsing MS (RMS), has become a treatable disease in recent decades, and immunotherapies are now able to influence long-term disease course. A wide range of disease-modifying drugs are available, which makes the choice of therapy in individual cases considerably more complex. Due to specific regulatory aspects (partly diverging approvals by Swissmedic compared to the European Medicines Agency (EMA), and an independent evaluation process for the Federal Office of Public Health (FOPH) specialities list (SL)), we issued a consensus recommendation regarding specific aspects of immunotherapy for MS in Switzerland in 2019. Here, we present revised recommendations with an update on newly approved drugs and new safety aspects, also in reference to the risk of COVID-19 infection and vaccination.

Leptomeningeal enhancement under different MS immunotherapies: A monocentric retrospective cohort study of 214 patients

Background: Leptomeningeal inflammation in patients with multiple sclerosis (MS) mainly affects meningeal B-cell follicle-like structures linked to cortical and subpial lesions and can be visualized as leptomeningeal enhancement (LME). Objective: To evaluate the evolution of LME under different MS immunotherapies. Methods: A total of 214 MS patients treated with anti-CD20 therapies or fingolimod at the university hospital Bern were screened for LME. Magnetic resonance imaging (MRI) and medical records were retrospectively evaluated, and comparative statistics were applied. Results: We compared MS patients treated with anti-CD20 therapies (128 patients (59.8%)) or fingolimod (86 patients (40.2%)). Of 128 anti-CD20-treated patients, 108 (84.4%) had no LME, 11 (8.6%) had persistent LME, and 9 (7.0%) showed resolution of LME. Of 86 fingolimod-treated MS patients, 81 (94.2%) had no LME and 5 (5.8%) persistent LME. Patients with LME persistence were older than those without or resolution of LME (p = 0.039). Resolution of LME was more frequent during anti-CD20 compared with fingolimod treatment (p = 0.019). Conclusion: We observed LME resolution under treatment with anti-CD20 therapies. As LME might play an important role in cerebral gray matter pathology in MS, further investigations including extensions to higher field strengths, correlation with clinical phenotypes, and comparison with other immunotherapies are needed.

Sphingosine-1-phosphate receptor modulators in stroke treatment.

Sphingosine-1-phosphate (S1P) is a bioactive lysophospholipid that can influence a broad range of biological processes through its binding to five distinct G-protein-coupled receptors. S1P receptor modulators are a new group of immunosuppressive agents currently used in the immunotherapy of multiple sclerosis. Inflammation following stroke can exacerbate neuronal injury. Given that S1P signaling is linked to multiple immune processes, therapies targeting the S1P axis may be suitable for treating stroke. In this review, we outline S1P metabolism and S1P receptors, discuss the mechanisms of action of S1P receptor modulators in lymphocyte migration and their direct action on cells of the central nervous system, and provide a concise summary of the efficacy of S1P receptor modulators in animal studies and clinical trials on treatments for stroke.

Anti-CD20 therapy for multiple sclerosis-associated uveitis: Acase series.

Approximately 1% of patients with multiple sclerosis (MS) have uveitis, but data on the effects of immunotherapies for MS on MS-associated uveitis are scarce. The aim of this study was to investigate the ophthalmological outcomes in patients with MS-associated uveitis treated with anti-CD20 therapy. A retrospective study of 12 eyes of six patients with MS-associated uveitis, refractory to previous immunotherapies, was conducted. Uveitis activity was assessed before initiation of anti-CD20 therapy and at regular follow-up visits. Primary outcome measures were: vitreous haze score; retinal vasculitis score, determined on fluorescein angiography images; macular edema, as quantified by central retinal thickness (CRT) on optical coherence tomography; and visual acuity (VA). Secondary outcomes included number of annualized uveitis or MS relapses, disease activity on cerebral magnetic resonance imaging (cMRI) and Expanded Disability Status Scale (EDSS) score. After a median (interquartile range [IQR]) treatment time of 28.5 (8-43) months, anti-CD20 therapy was associated with an improvement of vitreous haze score (p= 0.002), retinal vasculitis score (p= 0.001), CRT (p= 0.002), and VA (p= 0.007). The median (IQR) annualized uveitis relapse rate declined from 0.59 (0.56-0.94) before to 0 (0-0.49) after the start of anti-CD20 therapy. The median (IQR) annualized MS relapse rate declined from 0.62 (0.26-2.84) before to 0 (0-0) after the start of anti-CD20 therapy. After initiation of anti-CD20 therapy, there was no disease activity on cMRI, and EDSS score improved (n= 2) or remained stable (n= 4). No severe adverse events were observed. These findings suggest that anti-CD20 therapy may be a valuable treatment option for MS-associated uveitis.

Early Reduction of MRI Activity During 6 Months of Treatment With Cladribine Tablets for Highly Active Relapsing Multiple Sclerosis: MAGNIFY-MS.

Background and ObjectivesThe onset of action for high-efficacy immunotherapies in multiple sclerosis (MS) is an important parameter. This study (MAGNIFY-MS) evaluates the onset of action of cladribine tablets by observing changes in combined unique active (CUA) MRI lesion counts during the first 6 months of treatment in patients with highly active relapsing MS.MethodsMRI was performed at screening, baseline, and at months 1, 2, 3, and 6 after initiating treatment with cladribine tablets 3.5 mg/kg. CUA lesion counts, defined as the sum of T1 gadolinium-enhancing (Gd+) lesions and new or enlarging active T2 lesions (without T1 Gd+), were compared between postbaseline and the baseline period and standardized to the period length and the number of MRIs performed.ResultsIncluded in this analysis were 270 patients who received ≥1 dose of cladribine tablets. After treatment initiation, significant reductions in mean CUA lesion counts were observed from month 1 onward compared with the baseline period (−1.193 between month 1 and month 6, −1.500 between month 2 and month 6, and −1.692 between month 3 and month 6; all p < 0.0001). Mean T1 Gd+ lesion counts were decreased from month 2 onward compared with baseline (−0.857 at month 2, −1.355 at month 3, and −1.449 at month 6; all p < 0.0001), whereas the proportion of patients without any CUA lesions increased from 52.0% between month 1 and month 6 to 80.5% between month 3 and month 6.DiscussionFindings suggest an early onset of action for cladribine tablets, with an increasing reduction in active MRI lesions over time.Trial Registration InformationNCT03364036; Date registered: December 06, 2017.Classification of EvidenceUsing frequent MRI assessments of the brain over the first 6 months of the MAGNIFY-MS study (NCT03364036), we aimed to determine the onset of action of cladribine tablets 3.5 mg/kg in adult patients with highly active relapsing MS. This study provides Class IV evidence that, in such patients, treatment with cladribine tablets is associated with an early onset of action with reductions in active MRI lesion counts from month 2 (day 60) onward, with an increasing reduction in such lesions over time.

Development and evaluation of evidence-based patient information handbooks about multiple sclerosis immunotherapies

BackgroundMultiple sclerosis treatment options are increasing. Evidence-based patient information (EBPI) are therefore crucial to enable patient involvement in decision making. Based on earlier work on decision support, patient information handbooks on 8 MS immunotherapies were developed, piloted and evaluated with support from the German Clinical Competence Network MS and the German MS Society. MethodsHandbooks were structured according to EBPI concepts. Drafts were commented by patient representatives and neurologists with an MS expertise. Executive boards of the German MS Society and the Competence Network as well as pharmaceutical companies’ feedback was included. Handbooks were distributed among MS neurologists by the German MS Society. Evaluation followed applying a mixed methods approach with interviews, focus groups and surveys. One survey addressed persons with MS (pwMS) based on a questionnaire included in each handbook. Neurologists who received printed patient handbooks were invited to give feedback in a second survey. ResultsEight handbooks were developed providing absolute and relative risk information in numbers and figures as well as monitoring needs and drug fact boxes. Despite the high amount of information and the display of low absolute risk reduction rates of treatments, handbooks were overall appreciated by pwMS (n=107) and mostly also by physicians (n=24). For more than 70% of the pwMS the information was new, understandable and supportive for decision making. But patients felt uncomfortable with relative risk information. However, response rates in the evaluation were low, exposing the challenges when implementing EBPI into clinical care. Therefore, conclusions must be considered preliminary. ConclusionEBPI on immunotherapies for MS seem feasible and are appreciated by patients and treating neurologists but more implementation research is needed.

Multiple sclerosis therapies differentially affect SARS-CoV-2 vaccine–induced antibody and T cell immunity and function

BACKGROUNDVaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of the effects of MS DMTs on SARS-CoV-2 vaccine–specific immunity is needed, including quantitative and functional B and T cell responses.METHODSSpike-specific Ab and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 study participants, including healthy controls and patients with MS in 6 DMT groups: untreated and treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 mAbs. Anti–spike-Ab responses were assessed by Luminex assay, VirScan, and pseudovirus neutralization. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker and cytokine expression and tetramer.RESULTSAnti-spike IgG levels were similar between healthy control participants and patients with untreated MS and those receiving GA, DMF, or NTZ but were reduced in anti-CD20 mAb– and S1P-treated patients. Anti-spike seropositivity in anti-CD20 mAb–treated patients was correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization were reduced in anti-CD20 mAb– and S1P-treated patients. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups, except in S1P-treated patients, in whom postvaccine CD4+ T cell responses were attenuated.CONCLUSIONThese findings from a large cohort of patients with MS exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines.FUNDINGNIH grants 1K08NS107619, K08NS096117, R01AI159260, R01NS092835, R01AI131624, and R21NS108159; NMSS grants TA-1903-33713 and RG1701-26628; Westridge Foundation; Chan Zuckerberg Biohub; Maisin Foundation.

Multiple Sclerosis immunotherapies and COVID-19 mortality: an analysis of the FDA Adverse Event Reporting System.

Background:Evidence on mortality risks associated with MS-immunotherapies during the SARS-CoV2 pandemic derived thus far mainly from single country experiences.Objective:In this analysis, we aim to determine the frequency of COVID-19 associated fatality reports of patients receiving an MS-immunotherapy as reported to the international Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from February 2020 to March 2021.Methods:In all, 1071 cases for this cross-sectional analysis were retrieved from FAERS and a multivariable logistic regression was performed. We adjusted for sex, age, region, month of report to FDA, immunotherapy-class and additionally for healthcare-system and pandemic-related metrics.Result:Anti-CD20 therapies (60%) followed by sphingosine-1 phosphate modulators (12%) and dimethylfumarat (10%) were reported most frequently. In 50% of the cases, MS-phenotype is not reported, relapsing MS in 35% and progressive MS in 15%. Besides older age (odds ratio [OR]: 1.1; 95% confidence interval [CI]: 1.07–1.13; p < 0.01), anti-CD20 therapies were significantly associated with a higher risk of death (OR: 4.1; 95% CI: 1.17–14.46; p = 0.03), whereas female sex was associated with a reduced mortality risk (OR: 0.4, 95% CI: 0.22–0.72; p < 0.01).Conclusion:Using international open access data and a multidisciplinary approach for risk prediction, we identified an increased mortality risk associated with anti-CD20 therapies, which is in line with national and multi-national cohort studies.

Myelin Peptide-Mannan Conjugate Multiple Sclerosis Vaccines: Conjugation Efficacy and Stability of Vaccine Ingredient.

Myelin peptide–mannan conjugates have been shown to be potential vaccines in the immunotherapy of multiple sclerosis. The conjugates are comprised from the epitope peptide and the polysaccharide mannan which transfers as a carrier the antigenic peptide to dendritic cells that process and present antigenic peptides at their surface in complex with MHC class I or class II resulting in T-cell stimulation. The conjugation of antigenic peptide with mannan occurs through the linker (Lys–Gly)5, which connects the peptide with the oxidized mannose units of mannan. This study describes novel methods for the quantification of the vaccine ingredient peptide within the conjugate, a prerequisite for approval of clinical trials in the pursuit of multiple sclerosis therapeutics. Myelin peptides, such as MOG35–55, MBP83–99, and PLP131–145 in linear or cyclic form, as altered peptide ligands or conjugated to appropriate carriers, possess immunomodulatory properties in experimental models and are potential candidates for clinical trials.

Novel Approaches in the Immunotherapy of Multiple Sclerosis: Cyclization of Myelin Epitope Peptides and Conjugation with Mannan.

Multiple Sclerosis (MS) is a serious autoimmune disease. The patient in an advanced state of the disease has restrained mobility and remains handicapped. It is therefore understandable that there is a great need for novel drugs and vaccines for the treatment of MS. Herein we summarise two major approaches applied for the treatment of the disease using peptide molecules alone or conjugated with mannan. The first approach focuses on selective myelin epitope peptide or peptide mimetic therapy alone or conjugated with mannan, and the second on immune-therapy by preventing or controlling disease through the release of appropriate cytokines. In both approaches the use of cyclic peptides offers the advantage of increased stability from proteolytic enzymes. In these approaches, the synthesis of myelin epitope peptides conjugated to mannan is of particular interest as this was found to protect mice against experimental autoimmune encephalomyelitis, an animal model of MS, in prophylactic and therapeutic protocols. Protection was peptide-specific and associated with reduced antigen-specific T cell proliferation. The aim of the studies of these peptide epitope analogs is to understand their molecular basis of interactions with human autoimmune T-cell receptor and a MS-associated human leucocyte antigen (HLA)-DR2b. This knowledge will lead the rational design to new beneficial non-peptide mimetic analogs for the treatment of MS. Some issues of the use of nanotechnology will also be addressed as a future trend to tackle the disease. We highlight novel immunomodulation and vaccine-based research against MS based on myelin epitope peptides and strategies developed in our laboratories.

Synthesis and Pharmacological Characterization of Visabron, a Backbone Cyclic Peptide Dual Antagonist of α4β1 (VLA-4)/α9β1 Integrin for Therapy of Multiple Sclerosis.

Integrins α4β1/ α9β1 are important in the pathogenesis and progression of inflammatory and autoimmune diseases by their roles in leukocyte activation and trafficking. Natalizumab, a monoclonal antibody selectively targeting α4β1 integrin and blocking leukocyte trafficking to the central nervous system, is an immunotherapy for multiple sclerosis (MS). However, due to its adverse effects associated with chronic treatment, alternative strategies using small peptide mimetic inhibitors are being sought. In the present study, we synthesized and characterized visabron c (4–4), a backbone cyclic octapeptide based on the sequence TMLD, a non-RGD unique α4β1 integrin recognition sequence motif derived from visabres, a proteinous disintegrin from the viper venom. Visabron c (4–4) was selected from a minilibrary with conformational diversity based on its potency and selectivity in functional adhesion cellular assays. Visabron c (4–4)’s serum stability, pharmacokinetics, and therapeutic effects following ip injection were assessed in an experimental autoimmune encephalomyelitis (EAE) animal model. Furthermore, visabron c (4–4)’s lack of toxic effects in mice was verified by blood analysis, tissue pathology, immunogenicity, and “off-target” effects, indicating its significant tolerability and lack of immunogenicity. Visabron c (4–4) can be delivered systemically. The in vitro and in vivo data justify visabron c (4–4) as a safe alternative peptidomimetic lead compound/drug to monoclonal anti-α4 integrin antibodies, steroids, and other immunosuppressant drugs. Moreover, visabron c (4–4) design may pave the way for developing new therapies for a variety of other inflammatory and/or autoimmune diseases.

Delay from treatment start to full effect of immunotherapies for multiple sclerosis (2679)

Delay from treatment start to full effect of immunotherapies for multiple sclerosis (2679)

Vaccine Hesitancy in Patients With Multiple Sclerosis: Preparing for the SARS-CoV-2 Vaccination Challenge.

ObjectiveVaccine hesitancy is a complex public health issue referring to concerns about safety, efficacy, or need for vaccination. Using pneumococcal vaccination, which is recommend in anti-CD20–treated multiple sclerosis (MS) patients, as a model, we assessed vaccination behavior in patients with MS to prepare for the upcoming SARS-CoV-2 vaccination challenge.MethodsBy a medical chart review, we retrospectively identified patients with MS treated with ocrelizumab at the University Hospital Bern in 2018–2020. Pneumococcal vaccination was discussed with the patients during clinical visits and highlighted in the after-visit summary addressed to the general practitioner before ocrelizumab initiation as part of our clinical standard of care.ResultsPneumococcal vaccination was performed in 71/121 (58.7%) of patients, and 50/121 (41.3%) patients were not vaccinated. Patients who did not get a pneumococcal vaccination were younger (no vaccination vs vaccination; mean [95% CI] 40.1 [36.1–44.1] vs 45.4 [41.9–48.8], p = 0.028) and had more frequently a relapsing remitting disease course (no vaccination vs vaccination, n [%]; 43/50 [86.0%] vs 49/71 [69.0%], p = 0.031). Furthermore, patients who did not get vaccination had more frequently a history of comorbid psychiatric disorder (no vaccination vs vaccination, n (%); 12/50 [24.0] vs 7/71 [9.8], p = 0.035).ConclusionOur study demonstrated that in our single-center cohort, 41.3% of patients with MS do not get the recommended pneumococcal vaccination. Future research should focus on vaccine hesitancy in the vulnerable cohort of patients with MS to improve the safety of MS immunotherapies.