BTK inhibitors and autoimmun diseases

Last updated on: 28.08.2021

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Bruton tyrosine kinase (BTK) was discovered due to its crucial role in B-cell development. Thus, several BTKi have been developed in the context of B cell-mediated diseases, particularly B cell malignancies. BTK is not normally expressed in T cells, but some of the currently available BTKi have considerable off-target effects on signaling molecules expressed in T cells, including TEC, ITK, Janus kinase 3 (JAK3) or lymphocyte-specific protein tyrosine kinase (Estupiñán et al. 2021).

Thus, interest has also been directed towards autoinflammatory diseases (AIDs), where Bruton's tyrosine kinase plays an important role in proinflammatory activation pathways both. BTKi shows potential not only in AIDs, but also in other diseases that exhibit hyperinflammation, such as COVID-19.

Clinical picture
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Outlook for the use of BTKi in inflammatory and autoimmunological diseases:

Rheumatoid arthritis: Bruton tyrosine kinase deficiency is protective in animals in several experimental autoimmune arthritis models (Nyhoff et al. 2016). The protection appears to be largely due to its role in B cells, although BTK may also contribute to disease via macrophages and osteoclasts/osteoblasts (Ni Gabhann et al. 2014). In human rheuamtoid arthritis, dysregulated BCR signaling may lead to abnormal B cell activation and loss of tolerance. pBTK expression was increased in peripheral B cells from RA patients with antibodies to citrullinated proteins. The pBTK expression also correlated with rheumatoid factor levels in the circulation (Corneth et al. 2017). Furthermore, RA synovial tissue cultured with BTKi showed decreased production of proinflammatory cytokines (Hartkamp et al. 2015). These data suggest that BTKi may be a useful therapeutic option in RA. Indeed, at higher doses, fenebrutinib showed efficacy comparable to the tumor necrosis factor (TNF)α inhibitor adalimumab, reducing levels of proinflammatory cytokines and autoantibodies (Cohen et al., 2020). However, other studies with BTKi (spebrutinib, evobrutinib, evobrutinib) showed little effect on disease severity (Neys FH 2021).

Primary Sjögren's syndrome: Studies of B cell deletion in pSS have yielded conflicting results, possibly due to the persistence of pathogenic B cells in salivary glands associated with high BAFF levels (Neys FH 2021).

Systemic lupus erythematosus: Bruton tyrosine kinase-deficient mice and BTKi-treated mice are protected in a variety of experimental models of systemic SLE (Rip et al. 2018). The efficacy of BTK inhibition has been attributed not only to inhibition of BCR signaling - and thus reduction of autoantibody levels - but also to TLR and FcR signaling in monocytes and macrophages, which are important drivers of renal injury in SLE. In SLE patients, increased BTK expression in peripheral B cells was associated with lupus nephritis and correlated with disease severity (Kong et al. 2018). BTKi in SLE are currently being tested in several clinical trials (NCT02537028, NCT04305197, NCT03878303 and NCT02829541).

Systemic sclerosis: Systemic sclerosis (SSc) is a very heterogeneous disease of unknown etiology. However, since more than 90% of patients have autoantibodies, it is likely that B cells play an important role in SSc. Furthermore, disturbances in BCR signaling seem to play a role in the pathogenesis of the disease. In vitro treatment of SSc B cells with ibrutinib reduced the production of IL-6, TNFα, and SSc-specific autoantibodies after TLR stimulation. Although further research is needed, these results suggest that BTKi may be a therapeutic option in SSc (Neys FH 2021).

Multiple sclerosis: Multiple sclerosis (MS) is a demyelinating AID of the central nervous system (CNS). B cells are thought to play an important role in the pathogenesis of MS, as demonstrated by the clinical success of rituximab treatment. In experimental autoimmune encephalitis, a mouse model of MS, BTKi ameliorated the disease (Torke et al. 2020). Compared to other AID and healthy controls, MS B cells did not exhibit increased BTK protein expression or pBTK levels upon BCR stimulation (Torke et al., 2020). A phase II clinical trial with evobrutinib showed promising clinical results at the highest dose (Montalban et al. 2019).

Type I diabetes: In non-obese diabetic mice, BTK deficiency ameliorated the disease by increasing BCR editing, thereby reducing the number of autoreactive BCRs and thus the number of pathogenic autoantibodies. Some data suggest that targeting BCR signaling and BTK in particular may be beneficial in diabetic patients (Neys FH 2021).

Granulomatosis with polyangiitis: In this clientele, BTK levels were elevated in peripheral B cells from patients with active disease but not from patients in remission, suggesting an association with disease activity (von Borstel et al. 2019). In vitro incubation of B cells from patients with acalabrutinib reduced cytokine production and plasma cell differentiation, although this reduction was less than in B cells from healthy controls (von Borstel et al., 2019). Nevertheless, targeting BCR signaling with BTKi may represent a new treatment option in GPA.

Pemphigus: Pemphigus and bullous pemphigoid are AIDs characterized by blistering and erosions of the skin or mucous membranes and associated with IgG autoantibodies directed against structural proteins in epithelia. Therapy includes high-dose corticosteroids and rituximab, resulting in remission in a majority of patients. Because of the prominent role of autoantibodies, BTKi have been studied in canine pemphigus foliaceus and provided a good response (Goodale et al. 2020). The efficacy of BTKi is currently being investigated in phase II (NCT02704429) and III (NCT03762265) clinical trials.

Immunethrombocytopenic pur pura: Immune thrombocytopenic purpura (ITP) is an AID characterized by autoantibodies directed against platelets. Animal studies have shown BTKi efficacy in a mouse model and a phase I/II clinical trial is currently underway (NCT03395210) with initial results suggesting clinical activity (Kuter et al. 2020).

Idiopathic pulmonary fibrosis: A proportion of patients with idiopathic pulmonary fibrosis (IPF) were found to have increased BTK expression in circulating B cells (Heukels et al. 2019). However, BTKi showed differential effects in bleomycin mouse models of pulmonary fibrosis, likely due to off-target effects and multi-kinase inhibition (Sun et al. 2020).

BTK and BTKi beyond the B-cell compartment:

Psoriasis: Psoriasis as an autoinflammatory disease of the skin is characterized by epidermal hyperplasia and parakeratosis. In this context, TLR-activated myeloid cells produce cytokines that are crucial for the differentiation of IL-17 and IL-22 producing T cells. The finding that BTKi attenuates TLR7-triggered psoriasiform inflammation in mice, likely by acting on innate immune cells (Nadeem et al. 2020) suggests that BTKi may be a therapeutic option.

Chronic graft-versus-host disease: This serious and life-threatening complication of allogeneic hematopoietic stem cell transplantation is primarily caused by donor T cells. However, B cells are also thought to play an important role in the pathogenesis of the disease. This assumption is confirmed by the clinical benefit of B-cell depletion by rituximab. BTKi by ibrutinib could reverse established GvHD in several T-cell and alloantibody-driven mouse models. A phase Ib/II clinical trial of ibrutinib in active chronic GvHD patients shows a clear clinical response with effects on both B and T cells (Miklos et al. 2017). Based on the observed efficacy and acceptable safety, ibrutinib has been approved by the FDA for the treatment of GvHD patients who have failed prior therapy.

Asthma and chronic obstructive pulmonary disease: Consistent with the critical roles of BTK and IL-2-inducible T-cell kinase (ITK) in mast cell degranulation and of ITK in T-cell activation, ibrutinib suppressed allergic airway inflammation in mice and blocked allergen-induced contraction of human bronchi (Dispenza et al. 2020). Moreover, BTKi suppressed alveolar changes associated with the progression of chronic obstructive pulmonary disease (COPD) in animal experiments, possibly by affecting neutrophils in the airways. Therefore, BTK/ITK inhibition in models of airway inflammation may affect both B, T and myeloid cell activation (Neys FH 2021).

Atherosclerosis: BTKi targeting glycoprotein GPIb and GPVI signal transduction in platelets has been shown to block atherosclerotic plaque-selective platelet aggregation but spare physiological hemostasis (Busygina et al., 2018), suggesting that BTKi has therapeutic potential in atherosclerosis.

Coronavirus disease: Bruton tyrosine kinase has emerged as a potential therapeutic target to attenuate the hyperinflammatory response in coronavirus disease 2019 (COVID-19). A dysregulated response of macrophages recognizing SARS coronavirus-2 single-stranded RNA via TLRs is thought to be detrimental to the host in severe COVID-19 disease (Merad and Martin, 2020). This likely involves BTK-dependent signaling pathways, including activation of NF-κB and the NLRP3 inflammasome, leading to the release of pro-inflammatory cytokines. Several lines of evidence suggest that BTKi may reduce COVID-19 symptoms.

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  1. Bieber K et al (2021). Milestones in personalized medicine in pemphigus and pemphigoid. Front Immunol 11:3294.
  2. Busygina K et al (2018). Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans. Blood 131: 2605-2616.
  3. Corneth O B J et al (2017). Enhanced Bruton's tyrosine kinase activity in peripheral blood B lymphocytes from patients with autoimmune disease. Arthritis Rheumatol. (Hoboken, N.J.) 69: 1313-1324.
  4. Dispenza M C et al (2020). Bruton's tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis. J Clin Invest 130: 4759-4770.
  5. Estupiñán H Y et al (2021). Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Front Cell Dev Biol 9:630942.
  6. Goodale E C et al. (2020) Open trial of Bruton's tyrosine kinase inhibitor (PRN1008) in the treatment of canine pemphigus foliaceus. Vet. Dermato. 31:410–e110.
  7. Hartkamp L M et al (2015). Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants. Ann Rheum Dis 74: 1603-1611.
  8. Hendriks R W et al (2014). Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer 14: 219-232.
  9. Heukels P et al (2019). Enhanced Bruton's tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis. Respir Re. 20:232.
  10. Kong W et al (2018). Increased expression of Bruton's tyrosine kinase in peripheral blood is associated with lupus nephritis. Clin. Rheumatol 37: 43-49.
  11. Kuter D J et al (2020). Phase I/II, open-label, ongoing study of PRN1008 (rilzabrutinib), an oral bruton tyrosine kinase inhibitor, in patients with severely pretreated immune thrombocytopenia (ITP) [abstract]. Res Pr Thromb Haemost 4
  12. Merad M et al (2020). Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 20: 355-362.
  13. Miklos D et al (2017). Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood 130: 2243-2250.
  14. Montalban X et al (2019). Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med 380: 2406-2417.
  15. Nadeem A et al (2019). Inhibition of Bruton's tyrosine kinase and IL-2 inducible T-cell kinase suppresses both neutrophilic and eosinophilic airway inflammation in a cockroach allergen extract-induced mixed granulocytic mouse model of asthma using preventative and therapeutic. Pharmacol Res 148:104441.
  16. Neys FH (2021) Targeting Bruton's tyrosine kinase in inflammatory and autoimmune pathologies. Front. Cell Dev. Biol., 04 June 2021 |
  17. Ni Gabhann J et al (2014). Btk regulates macrophage polarization in response to lipopolysaccharide. PLoS One 9:e85834.
  18. Nyhoff L E et al (2016). Bruton's tyrosine kinase deficiency inhibits autoimmune arthritis in mice but fails to block immune complex-mediated inflammatory arthritis. Arthritis Rheumatol. 68: 1856-1868.
  19. Pan Z et al. (2007) Discovery of selective irreversible inhibitors for bruton's tyrosine kinase. Chem Med Chem 2: 58-61.
  20. Rip J et al (2018). The role of bruton's tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit Rev Immunol. 38: 17-62.
  21. Sun B et al.( 2020). Novel pyrimidines as multitarget protein tyrosine kinase inhibitors for the treatment of idiopathic pulmonary fibrosis (IPF). ChemMedChem 15: 182-187.
  22. Torke S et al (2020). Inhibition of Bruton's tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol 140: 535-548.
  23. Vetrie D et al (1993). The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361: 226-233.
  24. von Borstel A et al (2019). Evidence for enhanced Bruton's tyrosine kinase activity in transitional and naïve B cells of patients with granulomatosis with polyangiitis. Rheumatology (Oxford). 58: 2230–2239.
  25. Von Hundelshausen P et al (2021). Bleeding by bruton tyrosine kinase inhibitors: dependency on drug type and disease. Cancers 13:1103.
  26. Zhao G et al. (2019) Nanoparticle-delivered siRNA targeting Bruton's tyrosine kinase for rheumatoid arthritis therapy. Biomater Sci 7: 4698-4707.

Last updated on: 28.08.2021