PML in a Patient Treated with Fumaric Acid

Ermis, Ummehan; Joachim, Weis; Schulz, Jörg B.

doi:10.1056/nejmc1211805

Cited by 172 publications

(108 citation statements)

References 3 publications

(2 reference statements)

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“…Both patients had been on other therapies including topical coal tar, salicylates, and sulfadiazine in one, and retinoic acid, PUVA, fumaric acid, and methotrexate in the other case. Exposure to fumarates was recently associated with PML in 2 patients with psoriasis, both of which had pronounced lymphopenia for presumably more than 2 years (174,175). Although lymphopenia is frequent in patients treated with fumarates and may even be severe, PML seems to be rare given the more than 180 000 patient years of exposure to fumaderm, a fixed combination of oral dimethyl fumarate, and three monoethyl hydrogen fumarate salts (176).…”

Section: Jcpyv Diseasementioning

confidence: 99%

The human JC polyomavirus (JCPyV): virological background and clinical implications

Hirsch

Kardas

Kranz

et al. 2013

APMIS

142

169

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JC polyomavirus (JCPyV) was the first of now 12 PyVs detected in humans, when in 1964, PyV particles were revealed by electron microscopy in progressive multifocal leukoencephalopathy (PML) tissues. JCPyV infection is common in 35–70% of the general population, and the virus thereafter persists in the renourinary tract. One third of healthy adults asymptomatically shed JCPyV at approximately 50 000 copies/mL urine. PML is rare having an incidence of <0.3 per 100 000 person years in the general population. This increased to 2.4 per 1000 person years in HIV‐AIDS patients without combination antiretroviral therapy (cART). Recently, PML emerged in multiple sclerosis patients treated with natalizumab to 2.13 cases per 1000 patients. Natalizumab blocks α4‐integrin‐dependent lymphocyte homing to the brain suggesting that not the overall cellular immunodeficiency but local failure of brain immune surveillance is a pivotal factor for PML. Recovering JCPyV‐specific immune control, e.g., by starting cART or discontinuing natalizumab, significantly improves PML survival, but is challenged by the immune reconstitution inflammatory syndrome. Important steps of PML pathogenesis are undefined, and antiviral therapies are lacking. New clues might come from molecular and functional profiling of JCPyV and PML pathology and comparison with other replicative pathologies such as granule cell neuronopathy and (meningo‐)encephalitis, and non‐replicative JCPyV pathology possibly contributing to some malignancies. Given the increasing number of immunologically vulnerable patients, a critical reappraisal of JCPyV infection, replication and disease seems warranted.

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Section: Jcpyv Diseasementioning

confidence: 99%

The human JC polyomavirus (JCPyV): virological background and clinical implications

Hirsch

Kardas

Kranz

et al. 2013

APMIS

142

169

View full text Add to dashboard Cite

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“…As of December 2014, there had been 517 cases of natalizumab-induced PML, and 23% of these PML patients have died, since the introduction of the drug in 2004 (Biogen Idec, 2014). Newly marketed therapies such as dimethyl fumarate and other fumaric acid ester-containing drugs prescribed for MS and psoriasis have also led to PML (18,19), indicating an urgent need to better understand the disease pathogenesis of JCPyV.…”

mentioning

confidence: 99%

The Greater Affinity of JC Polyomavirus Capsid for α2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity

Stroh

Maginnis

Blaum

et al. 2015

J Virol

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The human JC polyomavirus (JCPyV) establishes an asymptomatic, persistent infection in the kidneys of the majority of the population and is the causative agent of the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals. The Mad-1 strain of JCPyV, a brain isolate, was shown earlier to require ␣2,6-linked sialic acid on the lactoseries tetrasaccharide c (LSTc) glycan for attachment to host cells. In contrast, a JCPyV kidney isolate type 3 strain, WT3, has been reported to interact with sialic acid-containing gangliosides, but the role of these glycans in JCPyV infection has remained unclear. To help rationalize these findings and probe the effects of strain-specific differences on receptor binding, we performed a comprehensive analysis of the glycan receptor specificities of these two representative JCPyV strains using high-resolution X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, and correlated these data with the results of infectivity assays. We show here that capsid proteins of Mad-1 and WT3 JCPyV can both engage LSTc as well as multiple sialylated gangliosides. However, the binding affinities exhibit subtle differences, with the highest affinity observed for LSTc. Engagement of LSTc is a prerequisite for functional receptor engagement, while the more weakly binding gangliosides are not required for productive infection. Our findings highlight the complexity of virus-carbohydrate interactions and demonstrate that subtle differences in binding affinities, rather than the binding event alone, help determine tissue tropism and viral pathogenesis. IMPORTANCEViral infection is initiated by attachment to receptors on host cells, and this event plays an important role in viral disease. We investigated the receptor-binding properties of human JC polyomavirus (JCPyV), a virus that resides in the kidneys of the majority of the population and can cause the fatal demyelinating disease progressive multifocal leukoencephalopathy (PML) in the brains of immunosuppressed individuals. JCPyV has been reported to interact with multiple carbohydrate receptors, and we sought to clarify how the interactions between JCPyV and cellular carbohydrate receptors influenced infection. Here we demonstrate that JCPyV can engage numerous sialylated carbohydrate receptors. However, the virus displays preferential binding to LSTc, and only LSTc mediates a productive infection. Our findings demonstrate that subtle differences in binding affinity, rather than receptor engagement alone, are a key determinant of viral infection. J C polyomavirus (JCPyV) infects ϳ50% of healthy individuals and causes an asymptomatic, lifelong persistent infection in the kidney (1, 2). The form of the virus that resides in the kidney is nonpathogenic and is excreted in the urine (3, 4). In immunosuppressed individuals, JCPyV can spread from the site of persistence to the central nervous system (CNS) (5, 6) and infect the glial cells astrocytes and oligodendroctyes (7,8). Oligod...

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“…The safety profile includes nonsevere, but potentially unpleasant, side effects such as gastrointestinal irritations and flush symptoms, which in the majority of patients tend to diminish and abate over time; however, there are also more severe, though very rare, side effects. Much attention has been paid to the news that fumarates (used in a similar but differing formulation in psoriasis [21,22]) can, in general, be associated with the occurrence of JC virus (JCV)-induced progressive multifocal leukencephalopathy (PML). PML is a relevant issue, especially in natalizumab treatment (see below), but lately also occurred in patients with MS treated with DMF.…”

Section: Dimethyl Fumaratementioning

confidence: 99%

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

2016

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Treatment options in relapsing-remitting multiple sclerosis have increased considerably in recent years; currently, a dozen different preparations of diseasemodifying therapies are available and some more are expected to be marketed soon. For the treating neurologist this broad therapeutic repertoire not only greatly improves individualized management of the disease, but also makes choices more complex and difficult. A number of factors must be considered, including disease activity and severity, safety profile, and patient preference. We here discuss the currently existing options and suggest treatment algorithms for managing relapsing-remitting multiple sclerosis.

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PML in a Patient Treated with Fumaric Acid

Cited by 172 publications

References 3 publications

The human JC polyomavirus (JCPyV): virological background and clinical implications

The human JC polyomavirus (JCPyV): virological background and clinical implications

The Greater Affinity of JC Polyomavirus Capsid for α2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

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