Clinical Challenges: PML in Multiple Sclerosis

Clinical Challenges: PML in Multiple Sclerosis

Publication date: May 17, 2019

As Joseph Berger, MD, chief of the multiple sclerosis division in the University of Pennsylvania’s Perelman School of Medicine in Philadelphia, pointed out, it’s not MS per se that puts a patient at risk for PML, the rare but often fatal inflammatory viral disease — characterized by progressive damage or inflammation of the white matter of the brain.

“Although they weren’t used widely in great numbers, they were still used, and we never had a case of PML reported as associated with MS, despite the fact that we gave people cyclophosphamide and azathioprine, and large doses of steroids, and a large variety of other drugs when they had aggressive disease that, in theory, would have put them at risk for developing PML. “

Instead, in MS, PML has been associated with a few disease-modifying drugs, the first being natalizumab (Tysabri).

According to the National Multiple Sclerosis Society, while the vast majority of PML cases in MS involve patients taking natalizumab, cases of PML have since been reported in individuals treated with other agents including dimethyl fumarate (Tecfidera) and fingolimod (Gilenya).

In a 2017 article in Multiple Sclerosis and Related Disorders, Berger divided MS disease-modifying therapies into three classes, depending on the degree of PML risk: As he put it in his article, “natalizumab occupied a place of its own with respect to PML risk,” and was the only drug he assigned to class I. PML is caused by activation of the JC (John Cunningham) virus that, according to estimates, is eventually acquired by more than 70% of the population.

As described by the drug’s manufacturer, a patient’s risk of developing PML is higher if that patient has been infected by the JC virus, has taken natalizumab for a prolonged period of time (especially beyond 2 years), and was previously treated (before natalizumab) with an immunosuppressant.

Researchers have toyed with longer intervals between natalizumab infusions as a means of reducing PML risk while maintaining the drug’s efficacy.

As for the risks associated with class II drug fingolimod, “there is no risk mitigation strategy right now,” said Berger, who added that the risk with fingolimod is “very low” (about one case per 18,000 patients).

“Whether PML will be observed with other [disease-modifying therapies] in use for MS .. . remains uncertain,” wrote Berger in his article.

Berger noted that Spanish researchers have proposed that one such marker — lipid-specific IgM bands in spinal fluid — are associated with a reduced risk of developing PML during treatment with natalizumab.

Concepts Keywords
Alemtuzumab Dimethyl fumarate
Antibody Fingolimod
Autoimmune Biogen
Autoimmune Diseases Rituximab
Azathioprine Multiple sclerosis
Bad Disease Human polyomavirus 2
Baltimore Progressive multifocal leukoencephalopathy
Biogen Natalizumab
Biomarkers Immunosuppressants
Brain Medicine
Cellular Adhesion Drugs
Central Nervous System Medical specialties
Cyclophosphamide Plasmapheresis
Division Autoimmune diseases
DMF Drug therapy
Drug Therapy Inflammatory
England High barriers disease
FDA Immunocompromised primary diseases
Fingolimod Regard disease
Gilenya MS PML disease
IgM What bad disease
Immune Function DMF sustained lymphopenia
Immunity Damage inflammation
Immunocompromised
Immunosuppressant
Incidence
Infection
Inflammation
Inhibitor
Integrin
IRIS
John Cunningham
Johns Hopkins Hospital
Lipid
Lymphocyte
Lymphopenia
Mitoxantrone
Multiple Sclerosis
Natalizumab
Newsome
NOVA
Opportunistic Infection
Opportunistic Infections
Pennsylvania
Phase III
Philadelphia
Plasmapheresis
PML
Progressive
Progressive Multifocal Leukoencephalopathy
Rare Disease
Rituximab
Serology
Spanish
Spinal Fluid
Steroids
Texas
Tysabri
Viral
Virus
White Matter

Semantics

Type Source Name
disease MESH multiple
disease MESH development
gene UNIPROT BRCA1
disease MESH immune reconstitution inflammatory syndrome
gene UNIPROT BAD
disease MESH infection
gene UNIPROT OXCT2
drug DRUGBANK Mitoxantrone
drug DRUGBANK Daclizumab
drug DRUGBANK Teriflunomide
gene UNIPROT MAP6
disease MESH lymphopenia
disease DOID lymphopenia
drug DRUGBANK Alemtuzumab
drug DRUGBANK Rituximab
disease MESH opportunistic infection
disease MESH viral disease
disease MESH community
disease MESH progressive multifocal leukoencephalopathy
disease DOID Multiple Sclerosis
gene UNIPROT PML
disease MESH Multiple Sclerosis
disease DOID PML
disease MESH Stroke
disease MESH Cancer
disease DOID Cancer
gene UNIPROT RPL17
gene UNIPROT PDCD1
drug DRUGBANK Pembrolizumab
gene UNIPROT SMIM10L2B
gene UNIPROT SMIM10L2A
disease MESH autoimmune diseases
disease MESH autoimmune responses
disease MESH Neurological Disorders
disease DOID Stroke
drug DRUGBANK Nonoxynol-9
disease DOID autoimmune disease
gene UNIPROT CD274
gene UNIPROT CD40LG
disease MESH rare disease
drug DRUGBANK Fingolimod
drug DRUGBANK Dimethyl fumarate
gene UNIPROT ALG3
gene UNIPROT NR4A2
drug DRUGBANK Natalizumab
gene UNIPROT LARGE1
drug DRUGBANK Azathioprine
drug DRUGBANK Cyclophosphamide
gene UNIPROT SSRP1
disease DOID viral disease
gene UNIPROT MAGEE1
disease MESH inflammation
gene UNIPROT RXFP2

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