The role of Bruton's tyrosine kinase in pathogenesis of chronic spontaneous urticaria and the prospects for the use of new treatment

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Abstract

Chronic spontaneous urticaria is a fairly common disease with an unpredictable course, burdensome symptoms and a significant negative impact on patients` quality of life. Despite the established stepwise approach to treatment with antihistamines in standard and increased dosages, anti-IgE therapy, there remains a portion of patients with unsatisfactory control of urticaria symptoms, with the need to develop drugs that target new therapeutic targets. Mast cells, basophils and B cells are key cells involved in the pathogenesis of urticaria; activation, differentiation, proliferation, cytokine secretion and degranulation in all three types of cells is regulated via Bruton's tyrosine kinase signalling pathway through FcεRI and BCR receptors respectively. Inhibition of Bruton's tyrosine kinase is being developed as a new therapeutic strategy for chronic spontaneous urticaria.

Here we present overview of the current understanding of chronic spontaneous urticarial`s pathogenesis, the role of Bruton's tyrosine kinase, the history of medical use of Bruton's tyrosine kinase inhibitors, as well as clinical data on the use of new Bruton's tyrosine kinase inhibitors in patients with chronic spontaneous urticaria who have not achieved adequate disease control with antihistamines.

About the authors

Elena S. Fedenko

National Research Center--Institute of Immunology Federal Medical-Biological Agency of Russia

Email: efedks@gmail.com
ORCID iD: 0000-0003-3358-5087
SPIN-code: 5012-7242

MD, Dr. Sci. (Med), Professor

Russian Federation, Moscow

Olga G. Elisyutina

National Research Center--Institute of Immunology Federal Medical-Biological Agency of Russia; Peoples’ Friendship University of Russia

Author for correspondence.
Email: el-olga@yandex.ru
ORCID iD: 0000-0002-4609-2591
SPIN-code: 9567-1894

MD, Dr. Sci. (Med)

Russian Federation, Moscow; Moscow

Natalia I. Ilina

National Research Center--Institute of Immunology Federal Medical-Biological Agency of Russia

Email: instimmun@yandex.ru
ORCID iD: 0000-0002-3556-969X
SPIN-code: 6715-5650

MD, Dr. Sci. (Med.), Professor

Russian Federation, Moscow

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2. Fig. 1. Cells and cell receptors involved in chronic spontaneous urticaria pathogenesis ([11], adapted [85]). AR ― alarmin receptor; C3aR ― complement 3a receptor; C5aR ― complement 5a receptor; CCR3 ― C-C motif chemokine receptor 3; CRTh2 ― chemoattractant receptor-homologous molecule expressed on Th2 cells; CysLTR ― cysteinyl leukotriene receptor 1; HR ― histamine receptor; MRGPRX2 ― mas-related G protein-coupled receptor X2; PAFR ― platelet-activating factor receptor; PGD2 ― prostaglandin D2; Siglec 8 ― sialic acid-binding immunoglobulin-like lectin 8; TSLP ― thymic stromal lymphopoietin; VEGF ― vascular endothelial growth factor; VEGFR ― vascular endothelial growth factor receptor.

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3. Fig. 2. Signalling pathway through BCR receptors in B cells and FcεRI receptors in mast cells and basophils (adapted [85]). BCR ― B-cell receptor; FcεRI ― high-affinity IgE receptor; BLNK ― B-cell linker protein; Ca ― calcium; ДАГ ― diacylglycerol; IKK ― IkB kinase; ИФ3 ― inositol-3,4,5-phosphate; MAPK ― mitogen-activated protein kinase; NFAT ― nuclear factor of activated T cells; NF‑kB ― nuclear factor-kB; P ― phosphorylation; PIP2 ― phosphatidylinositol-4,5-bisphosphate; PKCb ― protein kinase Cb; PLCg2 ― phospholipase C-g2.

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4. Fig. 3. Proportion of patients achieving well-controlled urticaria and complete response with remibrutinib in REMIX 1 and REMIX-2 studies [86].

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