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      Use of Fingolimod in the Management of Relapsing–Remitting Multiple Sclerosis: Experience from Latin America

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          Abstract

          Once-daily fingolimod 0.5 mg (FTY720; Gilenya ®, Novartis Pharma AG, Basel, Switzerland) is a sphingosine 1-phosphate receptor modulator that is approved for the treatment of relapsing multiple sclerosis (MS); currently, this includes approval in 13 Latin American countries. However, despite a well-characterized efficacy and safety profile in a large clinical development program, thus far there has been limited representation of patients from across the Latin American region. Differences in MS disease characteristics have been reported for the Latin American population compared with Caucasians, which may be additional to recent improvements in MS diagnosis. Furthermore, healthcare provision and regional socioeconomic factors exist that are unique to Latin America compared with other regions. Therefore, to optimize MS treatment pathways and improve patient clinical outcomes, it is important to investigate the efficacy and safety profile of fingolimod using ethnically relevant data. Here, we review key data from Hispanic patients enrolled in the fingolimod clinical trial program, summarize recent findings from the FIRST LATAM study, and appraise fingolimod data from real-world patient populations.

          Funding : Novartis Pharma AG, Basel, Switzerland.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s12325-015-0226-0) contains supplementary material, which is available to authorized users.

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          Most cited references 66

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          Sex ratio of multiple sclerosis in Canada: a longitudinal study.

          Incidence of multiple sclerosis is thought to be increasing, but this notion has been difficult to substantiate. In a longitudinal population-based dataset of patients with multiple sclerosis obtained over more than three decades, we did not show a difference in time to diagnosis by sex. We reasoned that if a sex-specific change in incidence was occurring, the female to male sex ratio would serve as a surrogate of incidence change. Since environmental risk factors seem to act early in life, we calculated sex ratios by birth year in 27 074 Canadian patients with multiple sclerosis identified as part of a longitudinal population-based dataset. The female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3.2:1 in Canada. Year of birth was a significant predictor for sex ratio (p<0.0001, chi(2)=124.4; rank correlation r=0.84). The substantial increase in the female to male sex ratio in Canada seems to result from a disproportional increase in incidence of multiple sclerosis in women. This rapid change must have environmental origins even if it is associated with a gene-environment interaction, and implies that a large proportion of multiple sclerosis cases may be preventable in situ. Although the reasons why incidence of the disease is increasing are unknown, there are major implications for health-care provision because lifetime costs of multiple sclerosis exceed pound1 million per case in the UK.
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            Association between parasite infection and immune responses in multiple sclerosis.

            To assess whether parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis (MS). A prospective, double-cohort study was performed to assess the clinical course and radiological findings in 12 MS patients presenting associated eosinophilia. All patients presented parasitic infections with positive stool specimens. In all parasite-infected MS patients, the eosinophilia was not present during the 2 previous years. Eosinophil counts were monitored at 3- to 6-month intervals. When counts became elevated, patients were enrolled in the study. Interleukin (IL)-4, IL-10, IL-12, transforming growth factor (TGF)-beta, and interferon-gamma production by myelin basic protein-specific peripheral blood mononuclear cells were studied using enzyme-linked immunospot (ELISPOT). FoxP3 and Smad7 expression were studied by reverse-transcriptase polymerase chain reaction. During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. Furthermore, myelin basic protein-specific responses in peripheral blood showed a significant increase in IL-10 and TGF-beta and a decrease in IL-12 and interferon-gamma-secreting cells in infected MS patients compared with noninfected patients. Myelin basic protein-specific T cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF-beta secretion, showing a cytokine profile similar to the T-cell subsets Tr1 and Th3. Moreover, cloning frequency of CD4+CD25+ FoxP3+ T cells was substantially increased in infected patients compared with uninfected MS subjects. Finally, Smad7 messenger RNA was not detected in T cells from infected MS patients secreting TGF-beta. Increased production of IL-10 and TGF-beta, together with induction of CD25+CD4+ FoxP3+ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS.
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              Is Open Access

              Environmental Risk Factors for Multiple Sclerosis: A Review with a Focus on Molecular Mechanisms

              Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system commonly affecting young adults. Pathologically, there are patches of inflammation (plaques) with demyelination of axons and oligodendrocyte loss. There is a global latitude gradient in MS prevalence, and incidence of MS is increasing (particularly in females). These changes suggest a major role for environmental factors in causation of disease. We have reviewed the evidence and potential mechanisms of action for three exposures: vitamin D, Epstein Barr virus and cigarette smoking. Recent advances supporting gene-environment interactions are reviewed. Further research is needed to establish mechanisms of causality in humans and to explore preventative strategies.
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                Author and article information

                Contributors
                jcorreale@fleni.org.ar , jorge.correale@gmail.com
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                14 July 2015
                14 July 2015
                2015
                : 32
                : 7
                : 612-625
                Affiliations
                [ ]Department of Neurology, Institute for Neurological Research Raúl Carrea, FLENI, Buenos Aires, Argentina
                [ ]Department of Neurology, National Institute of Neurology and Neurosurgery, and Neurological Center, ABC Hospital Santa Fe, Mexico City, Mexico
                [ ]Servicio de Neurología, Clinica de Marly, and Entidad Prestadora De Servicios de Salud Nogales, Bogota, Colombia
                [ ]Department of Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile
                [ ]Department of Neurology, Universidade Federal de São Paulo, São Paulo, Brazil
                Article
                226
                10.1007/s12325-015-0226-0
                4522024
                26170106
                © The Author(s) 2015
                Categories
                Review
                Custom metadata
                © Springer Healthcare 2015

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