Systemic sclerosisTherapeutic Inhibition of Tyrosine Kinases in Systemic Sclerosis: A Review of Published Experience on the First 108 Patients Treated with Imatinib
Section snippets
Materials and Methods
We conducted a careful search for primary articles in MEDLINE/PubMed between January 2008 and February 2012 as well as for abstracts presented in 2008, 2009, 2010, and 2011 European League Against Rheumatism and American College of Rheumatology (ACR) conferences reporting on the therapeutic use of imatinib in SSc. Search terms included “imatinib” in combination with “systemic sclerosis”, “scleroderma”, “pulmonary hypertension”, “pulmonary fibrosis”, “interstitial lung disease”, “graft versus
Results
Our search retrieved a total of 100 primary articles. Among these there were 6 case reports and 1 case series describing the use of imatinib in SSc, comprising in all 13 patients, as well as 3 clinical studies, including 30, 20, and 10 subjects, respectively. In addition, 2 small clinical trials presented in the 2010 ACR conference and involving 27 and 9 SSc patients treated with imatinib, respectively, were also considered. A sixth pilot study of imatinib in SSc patients with lung involvement,
Discussion
The currently available data on the safety and efficacy of imatinib in the treatment of SSc come from case reports and 5 small, observational trials (39, 40, 41, 42), of which only 1 had a comparison arm (39). Despite the fact that positive experiences are published more frequently than negative experiences, a negative outcome was reported in 6 of 15 patients described in case reports and case series. Along this line, the first 2 studies by Spiera et al. (42) and Khanna et al. (40) and the
Acknowledgments
KE is supported by the European Commission research program INFLA-CARE (ECContract Number 223151).
References (77)
- et al.
Bcr-abl tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review
Leuk Res
(2010) - et al.
Immunohistological demonstration of transforming growth factor-beta isoforms in the skin of patients with systemic sclerosis
Clin Immunol Immunopathol
(1993) - et al.
Anti-sclerotic effect of transforming growth factor-beta antibody in a mouse model of bleomycin-induced scleroderma
Clin Immunol
(1999) - et al.
Immunoelectron microscopy of type III collagen in normal and scleroderma skin
J Invest Dermatol
(1980) - et al.
Treatment with imatinib results in reduced IL-4-producing T cells, but increased CD4(+) T cells in the broncho-alveolar lavage of patients with systemic sclerosis
Clin Immunol
(2011) Is IL-4 a potential therapeutic target in systemic sclerosis-associated pulmonary fibrosis?
Clin Immunol
(2011)- et al.
[Experience with imatinib to treat pulmonary arterial hypertension]
Arch Bronconeumol
(2008) - et al.
Imatinib mesylate as salvage therapy for refractory sclerotic chronic graft-versus-host disease
Blood
(2009) - et al.
Imatinib for refractory chronic graft-versus-host disease with fibrotic features
Blood
(2009) - et al.
Dasatinib as salvage therapy for steroid refractory and imatinib resistant or intolerant sclerotic chronic graft-versus-host disease
Biol Blood Marrow Transplant
(2012)
Imatinib in the treatment of nephrogenic systemic fibrosis
Am J Kidney Dis
Imatinib treatment of generalized localized scleroderma (morphea)
J Am Acad Dermatol
Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: A European LeukemiaNet study
Blood
Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group
Eur J Cancer
Recent advances in the treatment of systemic sclerosis
Clin Rev Allergy Immunol
Trends in mortality in patients with systemic sclerosis over 40 years: A systematic review and meta-analysis of cohort studies
Rheumatology (Oxford)
Tyrosine kinases as targets for cancer therapy
N Engl J Med
Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis
J Clin Invest
A non-Smad mechanism of fibroblast activation by transforming growth factor-beta via c-Abl and Egr-1: Selective modulation by imatinib mesylate
Oncogene
Pathogenesis of fibrosis: Role of TGF-beta and CTGF
Curr Opin Rheumatol
Transforming growth factor beta as a therapeutic target in systemic sclerosis
Nat Rev Rheumatol
Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma
J Rheumatol
Blockade of endogenous transforming growth factor beta signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: Association with increased expression of transforming growth factor beta receptors
Arthritis Rheum
Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: A model for human scleroderma
J Immunol
Abnormalities in the regulators of angiogenesis in patients with scleroderma
J Rheumatol
Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis
Arthritis Rheum
Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse
Development
Activation of microvascular pericytes in autoimmune Raynaud's phenomenon and systemic sclerosis
Arthritis Rheum
Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension
Am J Respir Crit Care Med
Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension
Eur Respir J
Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis
Arthritis Rheum
Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice
Am J Respir Crit Care Med
Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis
J Exp Med
Imatinib mesylate inhibits fibrogenesis in asbestos-induced interstitial pneumonia
Exp Lung Res
Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis
Arthritis Rheum
Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension
Int J Cardiol
Reversal of experimental pulmonary hypertension by PDGF inhibition
J Clin Invest
Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats
Am J Respir Cell Mol Biol
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Tyrosine kinases in the pathogenesis of tissue fibrosis in systemic sclerosis and potential therapeutic role of their inhibition
2021, Translational ResearchCitation Excerpt :A summary of various clinical studies employing Imatinib for SSc is displayed in Table I. The mechanisms responsible for the variability in the clinical response are not currently apparent and there is great interest in the identification of the molecular events that may be involved as strongly emphasized by Bournia et al.173 One recent study explored the serum proteomic profile of SSc patients more likely to display the greatest probability of beneficial response (responder) compared with patients who failed to improve (clinically nonresponders) in the previously described clinical trial of Spiera et al.168 The results identified a proteomic signature characterized by the presence of PM/Scl-100 autoantibodies, high serum levels of CxC motif ligand 4 (CXCL-4) and CD-40 ligand (CD40L) that was predictive and accurate for a beneficial response.176 Furthermore, recent studies have demonstrated that there is significant variability related to the ability of certain TKIs to be transported intracellularly, and it was recently unveiled that the efficacy of TKIs may depend not only on the dose of drug employed but also by their ability to be transported to the intracellular compartment.
Non-canonical (non-SMAD2/3) TGF-β signaling in fibrosis: Mechanisms and targets
2020, Seminars in Cell and Developmental BiologyCitation Excerpt :These findings prompted clinical trials to test the safety and efficacy of imatinib in the treatment of patients with SSc. Results from clinical trials on the use of imatinib in severe SSc are variable ranging from ineffective or adverse responses to promising clinical improvements in some severely ill patients [101]. It was concluded that imatinib might be considered as an individualized treatment strategy in severe SSc [101]
Notch Signaling Activity Determines Uptake and Biological Effect of Imatinib in Systemic Sclerosis Dermal Fibroblasts
2019, Journal of Investigative DermatologyCitation Excerpt :The TKI imatinib potently inhibits c-Abl at submicromolar concentrations along with other TKs such as c-Fms (half maximal inhibitory concentration = 1.4 μmol/L), and PDGFRα/β (half maximal inhibitory concentration = 0.1 μmol/L) (Paniagua and Robinson, 2007). For these reasons, a therapeutic role of imatinib in SSc treatment has been proposed, but its efficacy as an SSc therapeutic agent is still under investigation (Bournia et al., 2013). Because TKIs are orally administered, most of them are of a hydrophilic nature.
Clinical Features and Treatment of Scleroderma
2016, Kelley and Firestein's Textbook of Rheumatology: Volumes 1-2, Tenth EditionEmerging therapeutic targets for the treatment of hepatic fibrosis
2016, Drug Discovery TodayCitation Excerpt :Imatinib mesylate is a small molecule that inhibits several tyrosine kinases, including c-Abl, PDGFR, and c-kit, by blocking the binding of ATP to the active kinase site. Encouraging results have been reported in clinical studies on patients with severe SSc [55], although imatinib exerted few beneficial effects on survival or lung function improvement in patients with IPF [56]. The novel tyrosine inhibitor BIBF 1120 has recently been approved in Europe for the treatment of IPF [52].
A role of antifibrotics in the treatment of Scleroderma-ILD?
2020, Pulmonology
The authors have no conflicts of interest to disclose.