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November 2021; 8 (6) Views & ReviewsOpen Access

Balancing Potential Benefits and Risks of Bruton Tyrosine Kinase Inhibitor Therapies in Multiple Sclerosis During the COVID-19 Pandemic

Martin S. Weber, Jacqueline A. Nicholas, View ORCID ProfileMichael R. Yeaman
First published September 8, 2021, DOI: https://doi.org/10.1212/NXI.0000000000001067
Martin S. Weber
From the Institute of Neuropathology (M.S.W.), University Medical Center; Department of Neurology (M.S.W.), University Medical Center, Göttingen, Germany; OhioHealth Multiple Sclerosis Center (J.A.N.), Riverside Methodist Hospital, Columbus, OH; David Geffen School of Medicine (M.R.Y.), University of California, Los Angeles (UCLA); Divisions of Molecular Medicine and Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance, CA.
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Jacqueline A. Nicholas
From the Institute of Neuropathology (M.S.W.), University Medical Center; Department of Neurology (M.S.W.), University Medical Center, Göttingen, Germany; OhioHealth Multiple Sclerosis Center (J.A.N.), Riverside Methodist Hospital, Columbus, OH; David Geffen School of Medicine (M.R.Y.), University of California, Los Angeles (UCLA); Divisions of Molecular Medicine and Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance, CA.
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Michael R. Yeaman
From the Institute of Neuropathology (M.S.W.), University Medical Center; Department of Neurology (M.S.W.), University Medical Center, Göttingen, Germany; OhioHealth Multiple Sclerosis Center (J.A.N.), Riverside Methodist Hospital, Columbus, OH; David Geffen School of Medicine (M.R.Y.), University of California, Los Angeles (UCLA); Divisions of Molecular Medicine and Infectious Diseases (M.R.Y.), Harbor-UCLA Medical Center; and Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center (M.R.Y.), Torrance, CA.
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Balancing Potential Benefits and Risks of Bruton Tyrosine Kinase Inhibitor Therapies in Multiple Sclerosis During the COVID-19 Pandemic
Martin S. Weber, Jacqueline A. Nicholas, Michael R. Yeaman
Neurol Neuroimmunol Neuroinflamm Nov 2021, 8 (6) e1067; DOI: 10.1212/NXI.0000000000001067

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Abstract

Bruton tyrosine kinase inhibitors (BTKis) encompass a new class of therapeutics currently being evaluated for the treatment of multiple sclerosis (MS). Whether BTKis affect COVID-19 risk or severity or reduce vaccine efficacy are important but unanswered questions. Here, we provide an overview on BTKi mechanisms relevant to COVID-19 infection and vaccination and review preliminary data on BTKi use in patients with COVID-19. BTKis block B-cell receptor– and myeloid fragment crystallizable receptor–mediated signaling, thereby dampening B-cell activation, antibody class-switching, expansion, and cytokine production. Beyond antibodies, COVID-19 severity and vaccine efficacy appear largely linked to T-cell responses and interferon induction, processes not directly affected by BTKis. Given that B cells have clear roles in antigen presentation to T cells, however, it is possible that BTKis may indirectly interfere with beneficial or detrimental T-cell responses during COVID-19 infection or vaccination. In addition to these possible effects on generating a protective immune response, BTKis may attenuate the hyperinflammatory dysregulation often seen in severe cases of COVID-19 that evolves as a key risk factor in this disease. Currently available outcomes from BTKi-treated patients with COVID-19 are discussed. Clinical trials are currently underway to evaluate the safety and efficacy of BTKis in individuals with MS. Although limited data suggest a potential benefit of BTKis on outcomes for some COVID-19 patients, data from adequately powered, prospective and randomized clinical trials are lacking. Likewise, the specific effect of BTKis on the safety and efficacy of COVID-19 vaccines remains to be determined. Any potential unknown risks that BTKi therapy may present to the patient relative to COVID-19 infection, severity, and vaccine efficacy must be balanced with the importance of timely intervention to prevent or minimize MS progression.

Glossary

BTK=
Bruton tyrosine kinase;
BTKi=
Bruton tyrosine kinase inhibitor;
CLL=
chronic lymphocytic leukemia;
DMT=
disease-modifying therapy;
Fc=
fragment crystallizable;
IFN=
interferon;
IL=
interleukin;
MS=
multiple sclerosis;
SARS-CoV-2=
severe acute respiratory syndrome coronavirus 2;
TLR=
Toll-like receptor;
XLA=
X-linked agammaglobulinemia

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • ↵* These authors contributed equally to this work.

  • The Article Processing Charge was funded by Genentech, Inc.

  • Received May 4, 2021.
  • Accepted in final form July 15, 2021.
  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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  • Article
    • Abstract
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    • BTKis in the Treatment of MS
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    • COVID-19 Pathogenesis and Risk of Severe Infection
    • BTKi Mechanisms of Action and COVID-19 Pathology
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