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

Advances in the treatment of relapsing-remitting multiple sclerosis - Critical appraisal of fingolimod

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, traditionally considered to be an autoimmune, demyelinating disease. Based on this understanding, initial therapeutic strategies were directed at immune modulation and inflammation control. At present, there are five licensed first-line disease-modifying drugs for MS in Europe, and two second-line treatments. Currently available MS therapies have shown significant efficacy throughout many trials, but they produce different side effects. Despite disease-modifying drugs being well known and safe, they require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Therefore, the development of new therapeutic strategies is warranted. Several oral compounds are in late stages of development for treating MS. fingolimod is an oral sphingosine-1-phosphate receptor modulator that has demonstrated superior efficacy compared with placebo and interferon β-1a in phase III studies. It has already been approved in the treatment of MS. This review focuses on advances in current and novel oral treatment approaches in MS. We summarily review the oral compounds in this study, focusing on the recent development, approval, and the clinical experience with fingolimod

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

Dysregulated homeostasis of acetylcholine levels in immune cells of RR-multiple sclerosis patients

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNF alpha, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNF alpha, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis

Estimate of Anemia with New Non-Invasive Systems—A Moment of Reflection

Anemia is a global public health problem with major consequences for human health. About a quarter of the world population shows a hemoglobin concentration that is below the recommended thresholds. Non-invasive methods for monitoring and identifying potential risk of anemia and smartphone-based devices to perform this task are promising in addressing this pathology. We have considered some well-known studies carried out on this topic since the main purpose of this work was not to produce a review. The first group of papers describes the approaches for the clinical evaluation of anemia focused on different human exposed tissues, while we used a second group to overview some technologies, basic methods, and principles of operation of some devices and highlight some technical problems. Results extracted from the second group of papers examined were aggregated in two comparison tables. A growing interest in this topic is demonstrated by the increasing number of papers published recently. We believe we have identified several critical issues in the published studies, including those published by us. Just as an example, in many papers the dataset used is not described. With this paper we wish to open a discussion on these issues. Few papers have been sufficient to highlight differences in the experimental conditions and this makes the comparison of the results difficult. Differences are also found in the identification of the regions of interest in the tissue, descriptions of the datasets, and other boundary conditions. These critical issues are discussed together with open problems and common mistakes that probably we are making. We propose the definition of a road-map and a common agenda for research on this topic. In this sense, we want to highlight here some issues that seem worthy of common discussion and the subject of synergistic agreements. This paper, and in particular, the discussion could be the starting point for an open debate about the dissemination of our experiments and pave the way for further updates and improvements of what we have outlined

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