Advances in the treatment of relapsing - Remitting multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS). Pathologic hallmarks of MS lesions are inflammation, demyelination, axonal degeneration, neuronal loss, and gliosis. [1,2] MS is the most common neurological non-traumatic cause of disability in young people in the western world. MS initially presents in most patients as a relapsing-remitting condition (RRMS), but the majority of RRMS individuals develop a secondary progressive course (SPMS) later. [3] In fewer cases, the disease progresses from the beginning without superimposed relapses [primary progressive MS (PPMS)] or with rare superimposed relapses [progressive relapsing MS (PRMS)]. [4] The clinical signs in MS can occur in isolation or in combination, and can include motor and sensory deficits, partial or complete visual loss, diplopia, impaired coordination, and gait dysfunction. The diagnosis specifically integrates magnetic resonance imaging (MRI) with clinical attacks and paraclinical methods, and implies the dissemination of inflammatory activity in time and space. [5] MS treatments tackle separately the acute exacerbations and their prevention. Pharmacological management of relapses involves the use of corticosteroids, while approved long-term treatments [disease-modifying treatments (DMTs)] aim to decrease the clinical relapse rate and concomitant inflammation within the CNS.MS therapeutic landscape is changing rapidly. After several years in which first-line DMTs -glatiramer acetate (GA) and interferon β (IFNβ) -constituted the principal treatment options, a variety of new agents for MS treatment are now approved by regulatory authorities or in phase II and III clinical trials.[6] In 2010, fingolimod, the first oral agent, Special EditionThis article reviews and discusses the approved and emerging therapies for multiple sclerosis (MS). MS is a chronic and disabling immune-mediated disease of the central nervous system (CNS) that affects mainly young adults. MS imposes a huge economic burden on healthcare systems and the society. Although the last 20 years have brought a continuous expansion in therapeutic options, there are still unmet needs in MS management. Available MS drugs have varying degrees of efficacy in reducing relapse risk. The long-term term effects of these treatments are incompletely known. New therapies, along with variations of currently available treatments, may prove more effective and tolerable than the available drugs. Treatments for MS differ with respect to the mode of administration, tolerability and likelihood of treatment adherence, side effects, and risk of major toxicity. The armamentarium of approved disease-modifying therapies in MS and those in development include: (1) the first approved, moderately effective, injectable interferon-β and glatiramer acetate; (2) oral drugs (fingolimod, laquinimod, teriflunomide, dimethyl fumarate); (3) monoclonal antibodies (rituximab, ocrelizumab, ofatumumab, daclizumab, alemtuzumab); and (4) immunosuppressive agents (e.g. mitoxantrone)...

Sphingosine-1-phosphate receptor inhibition prevents denervation-induced dendritic atrophy

“…FTY720 is an orally active drug used in clinical medicine for the treatment of MS [ 8 – 10 ]. It is believed to act primarily on circulating lymphocytes and lymphnodes, i.e., immune cells outside the CNS [ 55 ] (for review see [ 16 , 56 ]).…”

“…The role of structural and functional disconnection is of particular interest in Multiple Sclerosis (MS), since some of the cognitive deficits and other symptoms seen in patients have been attributed to perturbations of network function [ 5 , 6 ]. Current pharmacological treatment focuses on the primary mechanism of injury and aims at modulating the immune system in order to prevent axonal damage and cell loss [ 8 – 10 ]. Secondary changes, triggered by denervation-induced transneuronal alterations, have so far not been considered a target.…”

Using Twitter to investigate opinions about multiple sclerosis treatments: a descriptive, exploratory study

“…When looking at frequency of words, notably ‘flu’ and ‘injection’ were in the 50 most common words in tweets about Rebif and Avonex and ‘infusion’ and ‘pml’ in the 50 most common words in tweets about Tysabri. Flu-like symptoms are well known side-effects of the injectible treatments Rebif and Avonex and progressive multifocal leukoencephalopathy or ‘pml’, is a well-known risk for patients taking the intravenously infused Tysabri 5 . This provides some sort of face validity for our results reflecting real specific tweets about MS treatments.…”

Autoreactive lymphocytes in multiple sclerosis: Pathogenesis and treatment target

“…DMTs such as IFN-b and glatiramer acetate, were amongst the first agents commonly prescribed to MS patients (248). Their therapeutic effects were explained by decreasing proinflammatory cytokine production, reducing formation of MRI lesions, inhibiting immune cell activation, and lowering matrix metalloproteinase activity (249)(250)(251). Three major IFN-b products were approved as the first line MS treatment based on the phase III clinical trial results (252).…”

“…S1P is a sphingolipid that regulates lymphocyte migration and enhances T cell survival (258)(259)(260). Fingolimod was the first oral S1P1 modulator approved by the FDA in 2010 for the treatment of MS (248,251). It is an anti-inflammatory drug with the mechanism of action based on degrading the sphingosine-1phosphate (S1P) receptor on lymphocytes (250, 251), which is required for their migration to the CNS (248).…”