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Does the use of the Bruton Tyrosine Kinase inhibitors and the c-kit inhibitor masitinib result in clinically significant outcomes among patients with various forms of multiple sclerosis?

  • Shane Arsenault
    Correspondence
    Corresponding author.
    Affiliations
    Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
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  • Rochelle Y. Benoit
    Affiliations
    Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, Newfoundland and Labrador A1B 3V6, Canada
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  • Fraser Clift
    Affiliations
    Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada
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  • Craig S. Moore
    Affiliations
    Discipline of Medicine (Neurology), Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada

    Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John's, Newfoundland and Labrador A1B 3V6, Canada
    Search for articles by this author
Published:September 05, 2022DOI:https://doi.org/10.1016/j.msard.2022.104164

      Highlights

      • Traditionally, MS has been thought of as a T-cell mediated disease, but research over the past decade has demonstrated the importance of B cells in both acute demyelination and disease progression.
      • The highly selective irreversible Bruton Tyrosine Kinase (BTK) inhibitors evobrutinib, tolebrutinib, and orelabrutinib, and the reversible BTK inhibitor fenebrutinib, all target B-cell activation and aspects of innate immunity, including macrophage and microglia biology.
      • The c-KIT inhibitor masitinib mitigates neuroinflammation by controlling the survival, migration, and degranulation of mast cells, leading to the inhibition of proinflammatory and vasoactive molecular cascades that result from mast cell activation.
      • BTKi's are exciting and present novel therapies with a proven mechanism of action against the pathophysiological processes involved in RRMS, relapse-free SPMS, NRSPMS and PPMS.

      Abstract

      Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system accompanied by chronic inflammation, axonal loss, and neurodegeneration. Traditionally, MS has been thought of as a T-cell mediated disease, but research over the past decade has demonstrated the importance of B cells in both acute demyelination and disease progression. The highly selective irreversible Bruton Tyrosine Kinase (BTK) inhibitors evobrutinib, tolebrutinib, and orelabrutinib, and the reversible BTK inhibitor fenebrutinib, all target B-cell activation and aspects of innate immunity, including macrophage and microglia biology. The c-KIT inhibitor masitinib mitigates neuroinflammation by controlling the survival, migration, and degranulation of mast cells, leading to the inhibition of proinflammatory and vasoactive molecular cascades that result from mast cell activation.
      This article will review and critically appraise the ongoing clinical trials of two classes of receptor tyrosine kinase inhibitors that are emerging as potential medical treatments for the varying subtypes of MS: BTK inhibitors and c-KIT inhibitors. Specifically, this review will attempt to answer whether BTK inhibitors have measurable positive clinical effects on patients with RRMS, SPMS with relapses, relapse-free SPMS, and PPMS through their effect on MRI T1 lesions; annualized relapse rate; EDSS scale; MSFC score; and time to onset of composite 12-week confirmed disability progression. Additionally, this review will examine the literature to determine if masitinib has positive clinical effects on patients with PPMS or relapse-free SPMS through its effect on EDSS or MSFC scores.

      Keywords

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