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Advanced Neurology BTKi in brain diseases

(DMTs) have been created, most of which concentrate using ultra-high-field contrast-enhanced magnetic
on controlling inflammation and lowering the overall resonance imaging. These reported findings are in favor
pathogenic immune response. of corroborating the role of BTK inhibitors as a promising
Some treatments (e.g., fingolimod, natalizumab) therapeutic approach for MS through modulating the
nonspecifically affect the immune system by modifying above-mentioned pathways.
the trafficking of immune cells, or by influencing a range Several clinical studies of BTK inhibitors in MS are still
of immune effects, including anti-inflammatory helper T2 ongoing (Table 1). One of these studies is a double-blind,
cell functions (glatiramer acetate). 47,48 In addition, some randomized phase 2 clinical trial (i.e., NCT02975349)
tactics rely on the depletion of immunological cells. One investigating evobrutinib, in which 267 RMS patients were
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approach is the removal of B cells. The efficient removal divided into five groups. The results of the trial showed that
of B cells can be achieved through agents that either patients who received evobrutinib, 75 mg once daily, had
disrupt nucleotide or DNA/RNA synthesis (teriflunomide, considerably fewer new lesions over the course of 24 weeks
mitoxantrone, cladribine) or use depleting antibodies than those who received a placebo. 17
(rituximab, ocrelizumab, ofatumumab). Currently, fenebrutinib is being tested in three clinical
B cells have drawn increasing attention as MS mediators trials on MS. In FENtrepid, the effects of BTK inhibitors in
in recent years. It has been shown that the surface molecule comparison with ocrelizumab and placebo are being assessed
CD20 can be particularly effective in depleting B cells. in patients with PPMS. There are two identical trials on RMS
On the other hand, the persistent absence of an essential named FENhance and FENopta, analyzing the therapeutic
immune system component (i.e., B cells) may eventually effects of fenebrutinib versus teriflunomide. Furthermore,
raise security issues. The increased risk of infections orelabrutinib is being assessed in a randomized, double-
in patients with low B-cell counts is one of the effects. blind phase 2 clinical trial for patients with RRMS.
Patients frequently experience lengthier and more severe Remibrutinib and teriflunomide are being compared in a
episodes of these diseases, 50-54 along with the increased randomized, double-blind, double-dummy, parallel-group
risk of infections. Another concern is the effectiveness of phase 3 study on approximately 800 participants with RMS.
vaccinations in patients who are continuously suffering Tolebrutinib is being used in a few ongoing MS trials, with
from the depletion of B cells. A recent study demonstrated a phase 2b dose-finding study on tolebrutinib in RMS
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that patients with MS treated with ocrelizumab showed reporting a reduction in new active brain lesions. However,
attenuated humoral immune responses following clinically due to reports of drug-induced liver damage, in June 2022,
relevant vaccinations or a neoantigen challenge. 55 the U.S. FDA suspended all clinical trials with tolebrutinib.
As a result, innovative B cell-directed MS treatments In summary, B-cell-targeted therapies, especially BTK
are being established, including the inhibitors that target inhibitors, are promising in the treatment of MS. Although
BTK. The current research on the long-term effects of the efficacy and safety of these inhibitors need to be further
immunosuppressive medications emphasize the urgent evaluated, the current results are still encouraging.
need for long-term and quickly reversible methods to
control pathogenic B cells that drive MS. Inhibition of 4.2. Neuromyelitis optica spectrum disorders
the BTK for therapeutic purposes could be one of the Neuromyelitis optica spectrum disorders (NMOSDs) are
effective methods for reaching this objective. It has been CNS autoimmune inflammatory demyelinating diseases.
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demonstrated that evobrutinib effectively reduces the Astrocytic aquaporin-4 (AQP4), a specific antibody for
B cells’ ability to serve as antigen-presenting cells for astrocytes and a key characteristic that sets NMOSD apart
the growth of encephalitogenic T cells, dramatically from MS, is found in 60–80% of NMOSD patients. This
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lessening the severity of the disease. Using BIIB091, autoantibody attaches to the AQP4 receptor and initiates
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scientists showed that the B cell’s ability to behave as an inflammatory pathways that facilitate the necrosis of
antigen-presenting cell type for T cells was diminished, astrocytes. By initiating cell cascade reactions via the
as was the B cell’s ability to be activated. 57,58 In a different BCR on the cell membrane and downstream signaling
investigation, Rijvers et al. discovered more significant levels pathways, which promote cell proliferation and antibody
of BTK activity in T-bet memory B cells from patients with production, peripheral blood B lymphocytes can produce
+
RRMS and SPMS and showed that BTK inhibition altered AQP4 antibody. According to a study by Qiao et al., the
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the expression of T-bet and T-bet-associated molecules. important kinase BTK and the NF-κB signaling pathway
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Bhargava et al. also demonstrated that therapy with a BTK related to B lymphocytes were significantly activated
inhibitor reduced meningeal inflammation, determined during the acute phase of NMOSDs, and the expression
with the measurement of meningeal inflammation of chemokines, specifically CXCL2 and CXCL12,
Volume 3 Issue 1 (2024) 4 https://doi.org/10.36922/an.2184