Pharmacology and clinical efficacy of dimethyl fumarate (BG-12) for treatment of relapsing-remitting multiple sclerosis

The last two decades have seen the introduction of several therapies for multiple sclerosis (MS). These therapies are intended to work at different levels of the disease, typically targeting direct symptom management, brief corticosteroid administration for acute exacerbations, and the regular use of disease-modifying drugs. Nevertheless, in clinical practice, disease-modifying drugs or immunosuppressive treatments are frequently associated with suboptimal response in terms of efficacy and several side effects leading to poor patient adherence, so the proportion of relapsing–remitting MS patients not adequately responding to disease-modifying therapy have been reported to range from 7% to 49%. Natalizumab and fingolimod are the newest US Food and Drug Administration-approved agents that have been added to the MS treatment armamentarium, but their use is limited by a less known safety profile and recognized specific risk. Thus, there is an important need for new therapeutic strategies, especially those that may offer greater patient satisfaction and safer risk profile in order to optimize therapeutic outcomes. A number of potential therapies for MS are now in late-stage development. Effective, safe, and well-tolerated therapies may improve compliance and empower patients with a level of independence not presently possible. To meet these characteristics, most of these therapies are oral compounds. Herein, we review the pharmacology and efficacy of dimethyl fumarate (BG-12) to date and its role in the evolving marketplace

Emerging oral treatments in multiple sclerosis – clinical utility of cladribine tablets

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that represents one of the first causes of neurological disability in young adults. Although the pathogenesis of MS is still unclear, an autoimmune mechanism has been demonstrated. According to this evidence in the last 15 years different treatments acting on the immune system have been developed. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Moreover the clinical efficacy of these disease-modifying drugs is suboptimal. Thus, there is an important need for the development of new therapeutic strategies. Several oral therapies (fingolimod, fumaric acid, teriflunomide, laquinimod) are in development; Among these cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers sustained regulation of the immune system through a preferential lymphocyte depleting action. Cladribine has a well-characterized and well-known safety profile, derived from more than 15 years of use of the parenteral formulation both in the oncology field and in MS. This paper reviews the new oral emerging treatments and presents the available data about the use of cladribine in MS and the future perspective of its clinical use

Induction treatment strategy in multiple sclerosis: a review of past experiences and future perspectives

Abstract The scenario of multiple sclerosis (MS) treatment has changed profoundly in recent decades. In this setting, one of two strategies is usually used: escalation or induction. The first involves a pyramid of possible treatments of increasing efficacy (but also increasing safety risks) that are introduced progressively as needed. The induction strategy, on the other hand, immediately pursues higher efficacy, since drugs with a higher risk profile are used from the outset. Understanding which of these treatment strategies is the more suitable for a given patient is the first step in the therapeutic decision-making process. Prognostic factors evaluated on the basis of the clinical presentation and any disease activity on magnetic resonance imaging (MRI) should guide and help clinicians in making their choices. Even though the pathogenesis of MS is not yet completely understood, specific pathological changes are known to occur in the adaptive and innate immune system over the course of the disease. To date, treatment has been based mainly on two drugs, mitoxantrone and cyclophosphamide, autologous haematopoietic stem cell therapy (within clinical trial setting), but new compounds are now emerging. Among the new treatments, alemtuzumab and cladribine appear to be valid candidates as induction drugs. In this review we provide an overview of induction strategies based on literature evidence and our own past experiences, providing descriptions of clinical cases. We also outline the future perspectives in this field

Resiquimod-Mediated Activation of Plasmacytoid Dendritic Cells Is Amplified in Multiple Sclerosis

Background: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. The cause of multiple sclerosis is unknown but there are several evidences that associate the genetic basis of the disease with environmental causes. An important association between viral infection and development of MS is clearly demonstrated. Viruses have a strong impact on innate immune cells. In particular, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), are able to respond to viruses and to activate the adaptive immune response. Methods: In this study we mimic viral infection using synthetic single-strand RNA, Resiquimod, and we compared the response of both DC subsets derived from healthy donors and MS patients by characterizing the expression of costimulatory molecules on the DC surface. Results: We found that pDCs from MS patients express higher levels of OX40-L, HLA-DR, and CD86 than healthy donors. Moreover, we found that blood cells from MS patients and healthy donors upon Resiquimod-stimulation are enriched in a subpopulation of pDCs, characterized by a high amount of costimulatory molecules. Conclusion: Overall, these results indicate that activation of pDCs is enhanced in MS, likely due to a latent viral infection, and that costimulatory molecules expressed on pDCs could mediate a protective response against the viral trigger of autoimmunity

Butyrylcholinesterase and Acetylcholinesterase polymorphisms in Multiple Sclerosis patients: Implication in peripheral inflammation

Multiple Sclerosis (MS) is an autoimmune disease, having not fully understood aetiology, and both genetic and environmental factors contribute to the pathogenesis of the disease. The cholinergic system has been indicated as a mediator of neuro-immune interactions, as well as an internal regulator of immune responses. The aim of the present research was to assess the associations between BChE and AChE genetic variations and serum cholinergic and inflammatory profiles in 102 Relapsing Remitting-MS patients and 117 healthy controls. An increased frequency of the BChE K-allele in MS patients as compared to controls was found. In addition, data showed that patients had higher BChE enzymatic activity, which is increased by the presence of the polymorphic allele and reduced amounts of circulating ACh. AChE polymorphism was significantly associated to reduced activity in both patients and controls. We propose that serum BChE and AChE activity may be used as a secondary markers to assess the role of non-neuronal cholinergic system in regulating peripheral inflammation via ACh regulation. This pilot study shed light on the role of the non-neuronal cholinergic system in immune cells to better understand MS pathogenesis. The cross-talk between the periphery and the CNS could have a new undescribed crucial role for MS, regarded as a systemic disease

Effects of Shock Wave Therapy on a Patient with Co-Occurring Vascular Congenital Malformation and Buerger's Disease

Background: Intermittent claudication (IC) is a common symptom of Peripheral Artery Disease (PAD) mostly caused by arterial stenosis and/or occlusion in the lower extremities, typically resulting from atherosclerosis. Although less frequent, congenital vascular malformations and thromboangiitis obliterans, also known as Buerger’s disease (BD), can also cause IC, leading to progressively worsening symptoms, especially during walking. Extracorporeal Shock Wave Therapy (ESWT) is a non-invasive treatment that has been studied for its potential to promote neovascularization and vasodilation in PAD. Case Report: We present a man with congenital bilateral deep femoral artery agenesis and concomitant BD who underwent ESWT of the leg muscles. The treatment significantly improved his walking abilities, alleviated pain, and enhanced his quality of life, which persisted even 18 months after treatment. Conclusion: Functional and clinical improvements, in addition to quality of life, suggest that ESWT could represent a promising symptomatic treatment for PAD

The added value of spinal cord lesions to disability accrual in multiple sclerosis

Spinal cord MRI is not routinely performed for multiple sclerosis (MS) monitoring. Here, we explored whether spinal cord MRI activity offers any added value over brain MRI activity for clinical outcomes prediction in MS. This is a retrospective, monocentric study including 830 MS patients who underwent longitudinal brain and spinal cord MRI [median follow-up 7 years (range: < 1–26)]. According to the presence (or absence) of MRI activity defined as at least one new T2 lesion and/or gadolinium (Gd) enhancing lesion, each scan was classified as: (i) brain MRI negative/spinal cord MRI negative; (ii) brain MRI positive/spinal cord MRI negative; (iii) brain MRI negative/spinal cord MRI positive; (iv) brain MRI positive/spinal cord MRI positive. The relationship between such patterns and clinical outcomes was explored by multivariable regression models. When compared with the presence of brain MRI activity alone: (i) Gd + lesions in the spine alone and both in the brain and in the spinal cord were associated with an increased risk of concomitant relapses (OR = 4.1, 95% CI 2.4–7.1, p < 0.001 and OR = 4.9, 95% CI 4.6–9.1, p < 0.001, respectively); (ii) new T2 lesions at both locations were associated with an increased risk of disability worsening (HR = 1.4, 95% CI = 1.0–2.1, p = 0.05). Beyond the presence of brain MRI activity, new spinal cord lesions are associated with increased risk of both relapses and disability worsening. In addition, 16.1% of patients presented asymptomatic, isolated spinal cord activity (Gd + lesions). Monitoring MS with spinal cord MRI may allow a more accurate risk stratification and treatment optimization

Manual and automated tissue segmentation confirm the impact of thalamus atrophy on cognition in multiple sclerosis: A multicenter study

Atrofia; IRM; Esclerosis múltipleAtròfia; IRM; Esclerosi múltipleAtrophy; MRI; Multiple SclerosisBackground and rationale Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining. Methods Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor. Results In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings. Conclusion Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings.The study was funded by the Nauta fonds through a travel grant. The MS Center Amsteram is supported by the Dutch MS Research Foundation through a program grant (current grant 18-358f). D.B. is supported by project PI18/00823 from the “Fondo de Investigación Sanitaria Carlos III”. F.B. and O.C. are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The acquisition of data in London was funded by supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A sincere thank you to Tom Verhoeven for his editing of the figures

Distinct Expression of Inflammatory Features in T Helper 17 Cells from Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). T helper (Th) 17 lymphocytes play a role in the pathogenesis of MS. Indeed, Th17 cells are abundant in the cerebrospinal fluid and peripheral blood of MS patients and promote pathogenesis in the mouse model of MS. To gain insight into the function of Th17 cells in MS, we tested whether Th17 cells polarized from naïve CD4 T cells of healthy donors and MS patients display different features. To this end, we analysed several parameters that typify the Th17 profile during the differentiation process of naïve CD4 T cells obtained from relapsing-remitting (RR)-MS patients (n = 31) and healthy donors (HD) (n = 28). Analysis of an array of cytokines produced by Th17 cells revealed that expression of interleukin (IL)-21, tumour necrosis factor (TNF)-β, IL-2 and IL-1R1 is significantly increased in Th17 cells derived from MS patients compared to healthy donor-derived cells. Interestingly, IL-1R1 expression is also increased in Th17 cells circulating in the blood of MS patients compared to healthy donors. Since IL-2, IL-21, TNF-β, and IL-1R1 play a crucial role in the activation of immune cells, our data indicate that high expression of these molecules in Th17 cells from MS patients could be related to their high inflammatory status

Evaluation of Disability Progression in Multiple Sclerosis via Magnetic-Resonance-Based Deep Learning Techniques

Short-term disability progression was predicted from a baseline evaluation in patients with multiple sclerosis (MS) using their three-dimensional T1-weighted (3DT1) magnetic resonance images (MRI). One-hundred-and-eighty-one subjects diagnosed with MS underwent 3T-MRI and were followed up for two to six years at two sites, with disability progression defined according to the expanded-disability-status-scale (EDSS) increment at the follow-up. The patients' 3DT1 images were bias-corrected, brain-extracted, registered onto MNI space, and divided into slices along coronal, sagittal, and axial projections. Deep learning image classification models were applied on slices and devised as ResNet50 fine-tuned adaptations at first on a large independent dataset and secondly on the study sample. The final classifiers' performance was evaluated via the area under the curve (AUC) of the false versus true positive diagram. Each model was also tested against its null model, obtained by reshuffling patients' labels in the training set. Informative areas were found by intersecting slices corresponding to models fulfilling the disability progression prediction criteria. At follow-up, 34% of patients had disability progression. Five coronal and five sagittal slices had one classifier surviving the AUC evaluation and null test and predicted disability progression (AUC &gt; 0.72 and AUC &gt; 0.81, respectively). Likewise, fifteen combinations of classifiers and axial slices predicted disability progression in patients (AUC &gt; 0.69). Informative areas were the frontal areas, mainly within the grey matter. Briefly, 3DT1 images may give hints on disability progression in MS patients, exploiting the information hidden in the MRI of specific areas of the brain