A link between long-term natalizumab dosing in MS and PML

Major, Eugene O.; Nath, Avindra

doi:10.1212/nxi.0000000000000235

Cited by 29 publications

(23 citation statements)

References 10 publications

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“…PML is a significant complication in AIDS patients and is considered an AIDS defining illness despite advances in anti-retroviral therapy [2]. In the last decade PML has also emerged as a fatal complication in multiple sclerosis patients being treated with powerful immunomodulators [6][7][8][9][10][11]. The mechanisms that contribute to the reactivation and spread of this relatively benign virus from the periphery to the CNS to cause debilitating and often fatal disease are not understood.…”

Section: Introductionmentioning

confidence: 99%

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

et al. 2020

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The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy (PML) in immunosuppressed and immunomodulated patients. Initial infection with JCPyV is common and the virus establishes a long-term persistent infection in the urogenital system of 50-70% of the human population worldwide. A major gap in the field is that we do not know how the virus traffics from the periphery to the brain to cause disease. Our recent discovery that human choroid plexus epithelial cells are fully susceptible to virus infection together with reports of JCPyV infection of choroid plexus in vivo has led us to hypothesize that the choroid plexus plays a fundamental role in this process. The choroid plexus is known to relay information between the blood and the brain by the release of extracellular vesicles. This is particularly important because human macroglia (oligodendrocytes and astrocytes), the major targets of virus infection in the central nervous system (CNS), do not express the known attachment receptors for the virus and do not bind virus in human tissue sections. In this report we show that JCPyV infected choroid plexus epithelial cells produce extracellular vesicles that contain JCPyV and readily transmit the infection to human glial cells. Transmission of the virus by extracellular vesicles is independent of the known virus attachment receptors and is not neutralized by antisera directed at the virus. We also show that extracellular vesicles containing virus are taken into target glial cells by both clathrin dependent endocytosis and macropinocytosis. Our data support the hypothesis that the choroid plexus plays a fundamental role in the dissemination of virus to brain parenchyma.

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Section: Introductionmentioning

confidence: 99%

JC Virus infected choroid plexus epithelial cells produce extracellular vesicles that infect glial cells independently of the virus attachment receptor

et al. 2020

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“…The efficacy of the injectable DMTs (interferon-ß and glatiramer-acetate) is lower than the newer therapies, they often cause local side effects, thus patients often cannot tolerate the long-term use. On the other hand, the higher effectivity of monoclonal antibodies (natalizumab, alemtuzumab, ocrelizumab, daclizumab), which are not taken daily, can lead to serious side effects (progressive multifocal leukoencephalopathy (PML) with natalizumab, daclizumab, which was withdrawn from the market in early 2018 due to severe, potentially lethal side effects, listeriosis following treatment with alemtuzumab) [35][36][37]. The effectivity of per os drugs is similar to the injectable DMTs, but they require regular blood test control, some should be taken more than once a day and in case of missed doses or stopping the treatment, their effect fades away fast.…”

Section: Therapy Of Msmentioning

confidence: 99%

Medicinal Chemistry of Multiple Sclerosis: Focus on Cladribine

Biernacki

Sandi

Bencsik

et al. 2020

MRMC

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Background: In the recent years, many novel Disease-Modifying Drugs (DMD) have been introduced to the market in the treatment of multiple sclerosis. Objectives: To provide the reader with an up to date, compact review on the pharmacokinetic properties, mechanism of action, and clinical attributes of one of the most recently approved drugs in the therapy of multiple sclerosis, cladribine. Conclusion: Cladribine tablets proved to be a highly efficient treatment choice for Relapsing- Remitting Multiple Sclerosis (RRMS), especially for patients with high disease activity. It is the first DMD for MS with a complex mechanism of action, by inhibiting the adenosine-deaminase enzyme it increases the intracellular levels of deoxyadenosine triphosphate, which with relative selectivity depletes both T- and B-cells lines simultaneously. However long term follow-up safety and effectiveness data are still missing, and clear treatment protocols are lacking beyond the first two treatment years cladribine should prove to be a valuable addition to the therapeutic palette of RRMS, and potentially for Clinically Isolated Syndrome (CIS) as well.

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“…Cases of PML due to the use of fingolimod or DMF are fortunately rare [177,178] . However, the overall risk of PML with natalizumab use is high (4 per 1000) [179][180][181] . Patients with MS taking natalizumab should be switched to another DMD with a lower PML risk, if the anti-JC virus antibody index exceeds 0.9 during treatment.…”

Section: Attack Prevention In Msmentioning

confidence: 99%