Targeting Multiple End Organs in Lupus and Other Systemic Rheumatic Diseases by Inhibiting Bruton’s Tyrosine Kinase

Abstract

Bruton tyrosine kinase (Btk) plays a vital role in activating and differentiating B-cells and regulating signaling in myeloid cells. Indeed, the potential use of Btk inhibitors in preventing lupus has been reported. Here, we extend these observations to 4 additional models of end-organ inflammation: (a) BWF1 lupus nephritis mice, (b) anti-GBM nephritis, (c) bleomycin-induced systemic sclerosis like skin disease, and (d) bleomycin-induced lung disease. In agreement with the previous studies, BTK inhibitor (BTKB66) treatment was effective in treating lupus nephritis in terms of reducing renal damage both functionally and histologically, accompanied by significant decrease in proteinuria. Both low-dose and high-dose BTKB66 profoundly blocked renal disease in the anti-GBM nephritis model, with efficacy that was comparable to that seen with dexamethasone. This study provides the first evidence that BTK inhibition has both therapeutic and preventative effects in bleomycin-induced SSc-like disease, in terms of reducing skin thickness, fibrosis, collagen deposition, and inflammation. Likewise, significantly lower lung inflammatory cell infiltration was observed after treatment with BTKB66. Therapeutic benefit was associated with lower numbers of macrophages, proliferating macrophages and activated T-cells in the respective injured organs. The observation that these immune cells play key roles in driving end organ inflammation in multiple systemic rheumatic diseases have broad implications for the use of BTKB66 in managing patients with systemic rheumatic diseases where multiple end organs are afflicted, including lupus and systemic sclerosis.

FASlprgene dosage tunes the extent of lymphoproliferation and T cell differentiation in lupus

“…FFPE tissue slides were prepared and stained with Hematoxylin and Eosin (H&E). Sections were analyzed using a light microscope and scored for evidence of glomerulonephritis, and tubulo-interstitial disease, as detailed previously [17]. Kidneys were critically analyzed for any signs of cell proliferation and infiltration, thickening, and fibrous changes.…”

“…FFPE tissue slides were prepared and stained with Hematoxylin and Eosin (H&E). Sections were analyzed using a light microscope and scored for evidence of glomerulonephritis, and tubulo-interstitial disease, as detailed previously [17].…”

NETosis: an emerging therapeutic target in renal diseases

“…Neutrophil Bruton's tyrosine kinase (Btk) mediates reactive oxygen species generation via TLR4-signals, and integrinmediated recruitment and activation (147)(148)(149). Btk inhibitors reduced proteinuria and improved glomerular histopathology in lupus-prone animal models (150)(151)(152)(153). Elsubrutinib is currently under the scope for efficacy in SLE patients including lupus nephritis alone or in combination with upadacitinib compared to placebo (NCT03978520).…”

Novel Therapeutic Strategies in the Treatment of Systemic Sclerosis

“…In a murine model of systemic sclerosis, BTKB66 (a new BTK inhibitor) treatment resulted in a reduction in skin fibrosis, collagen deposition, and decreased inflammatory cell infiltration in the skin [ 133 ]. In another ex vivo study testing the influence of Ibrutinib, a first-in-class, irreversible inhibitor of BTK, it was able to reduce the release of proinflammatory IL-6 and TNF-α.…”