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Progressive multifocal leukoencephalopathy and sphingosine 1-phosphate receptor modulators used in multiple sclerosis: an updated review of literature

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Abstract

Objective

Progressive multifocal leukoencephalopathy (PML) is a serious viral infection associated with disease-modifying therapies (DMT) for multiple sclerosis (MS) including sphingosine 1-phosphate receptor (S1PR) modulators. The objective of this review was to investigate the characteristics of PML in MS patients associated with drugs of the S1PR modulator.

Methods

We conducted a literature review and analysis of 24 patients from 12 publications in PubMed, SCOPUS and EMBASE. This is a descriptive analysis and study of characteristics of PML associated fingolimod and related S1PR modulator group of DMT.

Results

A total of 24 cases of PML in MS patients treated with fingolimod were identified. Of these, 21 cases contained data regarding changes in the expanded disability status scale (EDSS). One case of PML in association with ozanimod treatment in a clinical trial was also identified. In PML cases associated with fingolimod, the mean age at the time of PML diagnosis was 50.91 ± 11.5 years. All patients were treated with fingolimod for more than 24 months. Compared to patients who improved or were stable, in terms of EDSS, after symptomatic management of PML, the non-improved groups were significantly older. There were no fatalities in either group during the reported follow-up period.

Conclusion

The incidence of PML appears to be extremely low in MS patients treated with S1PR modulators. Risk of PML increases with increase in duration of treatment with S1PR modulators like fingolimod, and increased age at the time of PML diagnosis is associated with worse prognosis.

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Fig. 1

Availability of data and materials

Data were extracted from the articles published in PUBMED, Google Scholar, Scopus, Novartis, Bristol Myers, Janssen. This will be provided on request.

Abbreviations

PML:

Progressive multifocal leukoencephalopathy

MS:

Multiple sclerosis

RRMS:

Relapsing remitting multiple sclerosis

PPMS:

Primary progressive multiple sclerosis

EDSS:

Expanded Disability Status Score

IRIS:

Immune reconstitution inflammatory syndrome

DMT:

Disease-modifying therapy

JCV:

JC Polyomavirus

CSF:

Cerebrospinal fluid

PML:

Progressive multifocal leukoencephalopathy

CNS:

Central nervous system

PLEX:

Plasmapheresis

IA:

Immunoadsorption

IVIG:

Intravenous immunoglobulin

AAN:

American Academy of Neurology

S1PR:

Sphingosine 1-phosphate receptor modulators

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Acknowledgements

West Virginia Clinical and Translational Science Institute, Morgantown, WV; SW and SS supported in part by WVCTSI via US National Institute of General Medical Sciences of National Institute of Health under award under 5U54GM104942-05

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Authors and Affiliations

  1. Department of Neurology, Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV, 26506, USA

    Shitiz Sriwastava & Syed Hassan Khalid

  2. West Virginia Clinical and Translational Science Institute, Morgantown, WV, USA

    Shitiz Sriwastava

  3. Neuroscience Institute, Geisinger Medical Center, Danville, PA, USA

    Durgesh Chaudhary

  4. Department of Neurology, Wayne State University, Detroit, MI, USA

    Shitiz Sriwastava, Samiksha Srivastava & Robert P. Lisak

  5. School of Medicine, West Virginia University, Morgantown, WV, USA

    Shitiz Sriwastava & Katherine Beard

  6. Department of Biostatistics, West Virginia University, Morgantown, WV, USA

    Xue Bai & Sijin Wen

  7. Department of Biochemistry, Microbiology and Immunology, Wayne State University, Detroit, MI, USA

    Robert P. Lisak

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  1. Shitiz Sriwastava
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Contributions

Conceptualization: Shitiz Sriwastava; Drafting the manuscript: Shitiz Sriwastava, Samiksha Srivastava, Durgesh Chaudhary, Katherine Beard, Syed Hassan Khalid, Robert Lisak. Data abstraction and data analysis: Samiksha Srivastava, Xue Bai, Sijin Wen. Editing and Final Draft: Shitiz Sriwastava, Robert Lisak.

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Correspondence to Shitiz Sriwastava.

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Conflicts of interest

Disclosures: Shitiz Sriwastava, Samiksha Kayastha, Durgesh Chaudhary, Katherine Beard, Syed Hassan Khalid, Xue Bai, Sijin Wen—Reports no disclosure. In the last 2 years Dr. Lisak has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from: Alexion, Argenx, UCB/Ra Pharmaceuticals, Novartis, Mallinckrodt, Genentech/Roche, Chugai, Janssen, GLG Consulting, Alpha Sites Consulting, Schlesinger Group Consulting, Slingshot Consulting, Health Sources, Adivo Associates, Smart Analyst, Clairview, Clarion and Decision Resources. He served as Chair of the Adjudication Committee for a MS clinical trial for MedDay (Biotin study). He is funded by a R21 grant by NINDS “Molecular Characterization of B Cell Exosomes in Multiple Sclerosis” and as site PI for NINDS funded study “LP4/Agrin Antibodies in Double Seronegative Myasthenia Gravis”. He has received publication royalties from Oxford University Press (Neuroimmunology, 2019) and Blackwell Wiley (International Neurology, 2nd Edition, 2016).

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Sriwastava, S., Chaudhary, D., Srivastava, S. et al. Progressive multifocal leukoencephalopathy and sphingosine 1-phosphate receptor modulators used in multiple sclerosis: an updated review of literature. J Neurol 269, 1678–1687 (2022). https://doi.org/10.1007/s00415-021-10910-1

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