Oral High-Dose Atorvastatin Treatment in Relapsing-Remitting Multiple Sclerosis

Paul, Friedemann; Waiczies, Sonia; Wuerfel, Jens; Bellmann‐Strobl, Judith; Dörr, Jan R.; Waiczies, Helmar; Haertle, Mareile; Wernecke, Klaus D.; Volk, Hans‐Dieter; Aktaş, Orhan; Zipp, Frauke

doi:10.1371/journal.pone.0001928

Cited by 113 publications

(83 citation statements)

References 19 publications

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“…However, results of recent studies with combined therapy with IFN-b and statins are controversial. Both beneficial and harmful results of combined therapy were reported (Birnbaum et al 2008;Paul et al 2008;Rudick et al 2009). …”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Effects of IFN-β and Lovastatin on Immunophenotype of Monocyte-Derived Dendritic Cells in Multiple Sclerosis

Bartosik-Psujek

Tabarkiewicz

Pocinska

et al. 2010

Arch. Immunol. Ther. Exp.

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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system and current MS treatment is only partially effective. Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate their role in MS, we analyzed the in vitro effects of interferon (IFN)-beta and lovastatin on the differentiation and maturation of monocyte-derived dendritic cells (DCs) of MS patients. Twenty-seven patients with relapsing-remitting MS were recruited for the study. DC differentiation and maturation were evaluated based on surface phenotypic changes and the expressions of CD14, CD83, CD1a, CD80, CD86, CD206, and C209 were analyzed by flow cytometry. The results showed that IFN-beta and lovastatin affect DC phenotype. Both agents decrease the expression of CD1a, which indicates a weakened presentation of glycolipid antigens. IFN-beta causes up-regulated and lovastatin down-regulated expression of CD86, which results in a biased Th-cell responses in MS. Furthermore, high doses of lovastatin cause a decrease in CD209 expression on the surface of DCs and can limit their migration to various tissues. One of the mechanisms of the beneficial action of IFN-beta and statins may be associated with their influence on DCs.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory Effects of IFN-β and Lovastatin on Immunophenotype of Monocyte-Derived Dendritic Cells in Multiple Sclerosis

Bartosik-Psujek

Tabarkiewicz

Pocinska

et al. 2010

Arch. Immunol. Ther. Exp.

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“…Encouraging results from studies on the effect of statins in the experimental animal models for MS have instigated the evaluation of statins as (co)therapy in MS (Paintlia et al, 2008;Paintlia et al, 2009;Stanislaus et al, 1999;Youssef et al, 2002). Although initial studies have indicated that statins are safe for use in MS (Lanzillo et al, 2010;Paul et al, 2008;Togha et al, 2010;Vollmer et al, 2004), the effects on the disease course are still unclear. Preliminary studies have reported positive effects of statins in relapsing remitting (RR)MS when administered as monotherapy, as well as cotherapy in combination with IFN-b (Paul et al, 2008;Togha et al, 2010;Vollmer et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Although initial studies have indicated that statins are safe for use in MS (Lanzillo et al, 2010;Paul et al, 2008;Togha et al, 2010;Vollmer et al, 2004), the effects on the disease course are still unclear. Preliminary studies have reported positive effects of statins in relapsing remitting (RR)MS when administered as monotherapy, as well as cotherapy in combination with IFN-b (Paul et al, 2008;Togha et al, 2010;Vollmer et al, 2004). By contrast, the use of high doses of ATOR in combination with IFN-b has been shown to negatively influence disease course in RRMS patients, resulting in new and enhanced lesions (Birnbaum et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Statins amplify TLR‐induced responses in microglia via inhibition of cholesterol biosynthesis

Putten

Kuipers

Zuiderwijk‐Sick

et al. 2011

Glia

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Statins inhibit the endogenous intracellular mevalonate pathway and exposure to statins affects innate and adaptive immune responses. Different statins are currently under evaluation as (co)therapy in neuro-inflammatory diseases like multiple sclerosis. However, there are important discrepancies in the reported effects of statins on innate immune responses in different cell types. Studies to characterize such responses in clinically relevant primary cells are currently lacking. In this study, we investigated the effect of statins on Toll-like receptor (TLR)-induced responses of microglia, the resident macrophages of the central nervous system (CNS). Exposure of primary microglia from adult rhesus monkeys to different statins strongly amplified proinflammatory cytokine protein and mRNA levels in response to myeloid differentiation primary response gene 88-dependent TLR activation in particular. Rather than affecting nuclear facor-jB activation levels, statin exposure affected stress-activated protein/Jun-amino-terminal and p38 kinase signaling pathways. Mechanistic studies using specific pathway inhibitors and rescue experiments show that statininduced inhibition of cholesterol biosynthesis, rather than inhibition of isoprenylation, was mainly responsible for the amplified TLR responses. Additionally, microglia were more sensitive to statin-mediated effects than bone marrowderived macrophages of the same donor. This correlated to lower intrinsic microglial expression levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the enzyme targeted by statins. Amplification of TLR-induced responses in microglia by statin exposure might contribute to the generation of a more pro-inflammatory CNS microenvironment which can be of relevance for the pathogenesis of neuroinflammatory disorders. V

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“…[41][42][43][44] Overall, further studies regarding adjuvant statin and disease-modifying therapy are needed to better understand their role in MS disease activity and progression.…”

Section: Dyslipidemiamentioning

confidence: 99%

A Review of Vascular Disease Risk Factors and Multiple Sclerosis

Kannan¹,

Yadav²

2017

US Neurology

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Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system and the most common non-traumatic cause of disability in young adults. Recent research shows that vascular disease risk factors (VDRFs) such as obesity, smoking, hyperlipidemia, hypertension, type II diabetes mellitus, and metabolic syndrome, can influence MS on its onset, disease activity, progression, and resultant disability. This review evaluates the current knowledge on the role of VDRFs on outcomes among people with MS (PwMS) and shows that while VDRF prevalence may or may not be higher among PwMS compared with the general population, its presence can influence MS in myriad ways. Management of VDRFs through early detection and treatment may be a promising approach to improving outcomes in PwMS. KeywordsMultiple sclerosis, smoking, obesity, dyslipidemia, hypertension, type II diabetes, metabolic syndrome Compliance with Ethics:This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system and the most common non-traumatic cause of disability in young adults. MS affects nearly 400,000 people in the US and 2.5 million people worldwide. While the precise etiology of MS is unknown, it is suspected that the disease causation is multifactorial, in which exposure to environmental factors triggers an autoimmune response among genetically susceptible individuals.1 Recent research suggests an important plausible role of vascular disease risk factors (VDRFs) such as smoking, obesity, hyperlipidemia, hypertension, diabetes, and metabolic syndrome on MS pathogenesis. It is estimated that nearly 50% of people with MS (PwMS) have at least one VDRF at the time of their MS diagnosis, and are more likely than healthy controls to have more than one VDRF.2,3 The presence of VDRFs among PwMS appears to be associated not only with ongoing radiographic disease activity and progression on magnetic resonance imaging (MRI), but also with increased risk of clinical disability progression.3-5 The purpose of this paper is to examine the current literature on the relationship between these potentially modifiable factors that affect MS onset, activity, progression, and disability, and identify potential targets for improving clinical outcome among PwMS. SmokingThe association between smoking and MS susceptibility has been investigated extensively over...

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Oral High-Dose Atorvastatin Treatment in Relapsing-Remitting Multiple Sclerosis

Cited by 113 publications

References 19 publications

Immunomodulatory Effects of IFN-β and Lovastatin on Immunophenotype of Monocyte-Derived Dendritic Cells in Multiple Sclerosis

Immunomodulatory Effects of IFN-β and Lovastatin on Immunophenotype of Monocyte-Derived Dendritic Cells in Multiple Sclerosis

Statins amplify TLR‐induced responses in microglia via inhibition of cholesterol biosynthesis

A Review of Vascular Disease Risk Factors and Multiple Sclerosis

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