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?

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.

Interleukin-1 receptor antagonist: An exploratory plasma biomarker that correlates with disability and provides pathophysiological insights in relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disorder. Interleukin-1 receptor antagonist (IL-1RA) is an endogenous soluble antagonist of the IL-1 receptor and blocks the pro-inflammatory effects of IL-1ß known to contribute to MS pathology. The objectives of this study were to determine whether IL-1RA is associated with disability in MS and how this correlates with neurofilament light (NfL) levels in cerebrospinal fluid (CSF). METHODS: Peripheral blood and CSF were collected from consenting MS patients. Patient demographic and clinical variables, including past relapse activity, were also collected. Circulating levels of IL-1RA, IL-18, and IL-1ß were measured in plasma; IL-1RA and NfL were measured in the CSF via Bio-plex multiplex immunoassay kits and ELISA, respectively. IL-1RA expression was investigated in vitro using primary human macrophages and microglia, and in situ using post-mortem MS tissue. RESULTS: Following a multiple regression analysis, IL-1RA levels in plasma correlated with expanded disability status scale score independent of all other variables. In a separate cohort, CSF IL-1RA significantly correlated with NfL. In vitro, induction of the NLRP3 inflammasome, a pathological hallmark within MS lesions, led to increased release of IL-1RA from primary human microglia and macrophages. In the CNS, IL-1RA+ macrophages/microglia were present at the rim of mixed active/inactive MS lesions. CONCLUSIONS: Results presented in this study demonstrate that IL-1RA is a novel exploratory biomarker in relapsing-remitting MS, which correlates with disability and provides mechanistic insights into the regulatory inflammatory responses within the demyelinated CNS.