[Basic mechanisms of action of fingolimod in relation to multiple sclerosis]
Unidad y Laboratorio de Neuroinmunología, Servicio de Neurología, Hospital Universitario Puerta de Hierro-Majadahonda, 28035 Majadahonda, Espana. Revista de neurologia
(Impact Factor: 0.83).
Fingolimod has recently been approved for the therapy of relapsing multiple sclerosis. This drug binds to different sphingosine-1-phosphate receptors.
To analyze basic mechanisms of action that can account for the efficacy of this drug in multiple sclerosis.
Fingolimod acts as an inverse agonist on sphingosine-1-phosphate receptors, inducing degradation of receptors. On lymphoid circulation, this effect causes retention in lymph nodes of naive and central memory T cells, including Th17 T lymphocytes, bearing CCR7 and CD62L receptors. As a result, the level of circulating T cells is markedly decreased. B ell circulation is impaired and complex effects on other immune cells are also induced. Fingolimod enters the central nervous system and binds to receptors on glial cells and neurons. In experimental autoimmune encephalomyelitis, the therapeutic efficacy of fingolimod is not only associated with a reduced entry of inflammatory cells into the nervous system, but also with a direct effect mostly on astroglial cells.
In multiple sclerosis patients, the available evidence indicates that fingolimod efficacy is directly associated with impairment of circulation of several T cell subsets and possibly B cells. Animal studies raise the possibility that an additional effect on glial cells might also contribute to the clinical efficacy.
Available from: Pedro Miguel Abreu
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ABSTRACT: The scientific advances regarding the ethiopathogenesis and physiopathology of multiple sclerosis are so fast that periodic update of concepts is awaited. Moreover, new epidemiological data and criteria improving differential diagnosis have been described. The objective of this review is to update concepts about epidemiology, ethiopathogenesis, physiopathology and differential diagnosis of multiple sclerosis. Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system more frequent in young ages and in the female sex, the incidence of which increases with latitude. Recent studies indicate an increase in the incidence and earlier onset in women. Although the cause of the disease is unknown, genetic and environmental risk factors have been identified. The HLA allele HLA-DRB1*15 is the genetic factor more strongly associated with the risk of developing multiple sclerosis; the better established environmental factors are the exposition to the Epstein-Barr virus, smoking and vitamin D levels. The combination of environmental factors with a certain individual genetic predisposition, discloses an immunological dysregulation. Multiple sclerosis is considered to be mediated by T cells and its physiopathology is complex, intervening various immunological factors. From adaptive immunity, it must be emphasized the role of Th17 populations, with secretion of proinflammatory cytokines, cytotoxic T CD8+ and B lymphocytes. The innate immunity also participates in multiple sclerosis immunopathogenesis, mainly through microglia activation. The action of humoral and cellular changes induces focal inflammation with demyelination and axonal damage pointing to a dual face - inflammatory and degenerative - of the disease. Despite the natural repair mechanisms leading to remyelination and axonal recovery, in later stages this ability becomes exhausted and disease progresses. The absence of specific diagnostic biomarkers for multiple sclerosis imposes the exclusion of other inflammatory diseases with neurological involvement, especially when a first demyelinating event occurs - clinically isolated syndrome. The main neurological manifestations appearing in that condition that allow to support or reject the diagnosis of multiple sclerosis are described. The characteristic clinical and paraclinical data of other idiopathic demyelinating (neuromyelitis optica, acute disseminated encephalomyelitis, acute transverse myelitis, optic neuritis) and systemic inflammatory disorders with neurological involvement (systemic erythematous lupus, Behçet's disease, Sjögren'disease) are presented. In conclusion, the knowledge of the factors that contribute to the development of multiple sclerosis and the pathological processes taking place in the nervous system favours a better understanding of the disease and the discovery of new immunotherapeutic targets. The precise diagnosis of multiple sclerosis requires a rigorous systematization of differential diagnoses.
Sinapse 01/2012; 12(2):5-14.
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ABSTRACT: Fingolimod is the first approved drug with oral availability for the treatment of relapsing multiple sclerosis.
To review the mechanism of action of fingolimod and its relationship with the development of infections. To propose preventive measures for those patients who are receiving the drug or will initiate a new treatment. In addition, the role of fingolimod in the development of progressive multifocal leukoencephalopathy on the basis of recent knowledge of its pathophysiology will be discussed.
The mechanism of action of fingolimod is based on an antagonic effect on the sphingosine 1-phospate receptors that will generate an inhibition of the egress of naive and central memory lymphocytes into the bloodstream, allowing the free recirculation of memory effectors T lymphocytes. This effect will produce lymphopenia. Fingolimod-associated lymphopenia is a consequence of lymphocyte redistribution, and it is selective and reversible. There is no evidence of higher number of opportunistic and non-opportunistic infections in comparison to placebo or interferon beta-1a in patients receiving fingolimod. However, two patients developed severe herpetic infections under fingolimod.
Fingolimod induce a selective and reversible lymphopenia that, taking into account the most recent available data, does not seem to be associated with higher risk of opportunistic infections due to a preservation of immuno-surveillance. The risk of herpesvirus infection should be taken into consideration and more studies are warranted to confirm if an association of these infections with the use of fingolimod exists.
Revista de neurologia 08/2012; 55(4):227-37. · 0.83 Impact Factor
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ABSTRACT: This study outlines the design of an electronic register of patients with multiple sclerosis who began treatment with fingolimod in Spain. The system is intended to serve as a tool to monitor its utilisation in daily clinical practice and thus allow optimisation of the way it is used.
To establish the profile of patients with multiple sclerosis undergoing treatment with fingolimod and to determine the effectiveness and safety of this treatment in daily clinical practice.
An observation-based, retrospective and prospective, multi-centre registry is set up, which will be active for five years. Forty neurologists working in Spain will participate in the project. Patients treated with fingolimod who fulfil the selection criteria will be included in the study. The effectiveness variables that will be evaluated are: disability measured by means of the Expanded Disability Status Scale, the rate of attacks, T1 gadolinium-enhancing lesions and new lesions in T2, and the percentage of patients who were free of activity and those who require concomitant treatments. The tolerability variables that will be evaluated are: the rate of patients who present events and adverse reactions, respectively, with a separate analysis of those presenting after the first dose or that are related to the fingolimod risk management plan and the treatment dropout rate.
New pharmaceuticals that have only recently been commercialised require more information about their effectiveness and safety, beyond the controlled environment of a clinical trial. Initiatives involving electronic registries such as the Gilenya register are a solution that can respond to such needs by providing information in the shortest possible time about the most suitable management in order to be able to make the best and most efficient use of it.
Revista de neurologia 01/2014; 58(2):77-83. · 0.83 Impact Factor
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