Bruton's Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease

Abstract

Systemic autoimmune disorders are complex heterogeneous chronic diseases involving many different immune cells. A significant proportion of patients respond poorly to therapy. In addition, the high burden of adverse effects caused by "classical" anti-rheumatic or immune modulatory drugs provides a need to develop more specific therapies that are better tolerated. Bruton's tyrosine kinase (BTK) is a crucial signaling protein that directly links B-cell receptor (BCR) signals to B-cell activation, proliferation, and survival. BTK is not only expressed in B cells but also in myeloid cells, and is involved in many different signaling pathways that drive autoimmunity. This makes BTK an interesting therapeutic target in the treatment of autoimmune diseases. The past decade has seen the emergence of first-line BTK small-molecule inhibitors with great efficacy in the treatment of B-cell malignancies, but with unfavorable safety profiles for use in autoimmunity due to off-target effects. The development of second-generation BTK inhibitors with superior BTK specificity has facilitated the investigation of their efficacy in clinical trials with autoimmune patients. In this review, we discuss the role of BTK in key signaling pathways involved in autoimmunity and provide an overview of the different inhibitors that are currently being investigated in clinical trials of systemic autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, as well as available results from completed trials.

Fig. 1

Role of BTK in B-cell signaling. Overview of BCR signaling and other important signaling modules for B cells. Upon BCR engagement, LYN will activate and phosphorylate Ig-α and Ig-β, subsequently activating SYK. Together with CD19-mediated activation of PI3K, this leads to the activation of SLP65, BTK, and PLCγ2. This in turn activates downstream signaling pathways crucial for proliferation and survival, including engagement of ERK, NF-κB, and downstream mediators of AKT like S6, and anti-apoptotic proteins like BCL-2. Signaling downstream of TLRs and BAFFR also involves BTK phosphorylation, leading to activation of these same proliferation and survival factors. Other receptor signaling pathways like chemokine receptor signaling also contribute to migration, proliferation, and survival of B cells. BTK Bruton’s tyrosine kinase, BCR B-cell receptor, Ig immunoglobulin, PTPN22 protein tyrosine phosphatase non-receptor type 22, SYK spleen tyrosine kinase, PI3K phosphoinositide 3-kinase, SLP65 Src homology 2 domain-containing leukocyte adaptor protein of 65 kDa, CIN85 Cbl-interacting protein of 85 kDa, PLCγ2 phospholipase Cγ2, DAG diacylglycerol, IP₃ inositol triphosphate, PKC-β protein kinase C β, TRAF3 TNF receptor-associated factor 3, NIK NF-κB-inducing kinase, IKKα inhibitor of NF-κB kinase, MyD88 myeloid differentiation factor 88, MAL MyD88 adaptor-like, IRAK2 interleukin-1 receptor-associated kinase 2, ERK extracellular signal-related kinase, NFAT nuclear factor of activated T cells, BCAP B-cell adaptor for PI3K, PTEN phosphatase and tensin homolog, SHIP1 SH-2 containing inositol 5' polyphosphatase 1, BCL-2 B-cell lymphoma-2

Fig. 2

The four main pathogenic roles of B cells in the context of systemic autoimmune disease. (I) Initiation or enhancement of autoimmune responses by presenting auto-antigens to T cells and concomitantly providing co-stimulatory signals. (II) B cells can differentiate into autoantibody-producing plasma cells. (III) B cells can produce pro-inflammatory cytokines. (IV) B cells are involved in stimulating the development and maintenance of these tertiary lymphoid structures