Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Rheumatology Reports
Published in: Current Rheumatology Reports 1/2011

01-02-2011

Imatinib and the Treatment of Fibrosis: Recent Trials and Tribulations

Authors: Jessica Gordon, Robert Spiera

Published in: Current Rheumatology Reports | Issue 1/2011

Login to get access

Abstract

Imatinib mesylate has become a therapy of interest for the treatment of systemic sclerosis because of its ability to inhibit c-Abl and platelet-derived growth factor receptor, tyrosine kinases involved in profibrotic pathways. Preclinical data using in vitro and murine models of fibrosis have demonstrated the antifibrotic properties of imatinib. Imatinib is currently used widely in the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors, and other conditions, and a large amount of information is available regarding the safety of the medication in these patient populations. Whether imatinib will be tolerable or effective in the treatment of systemic sclerosis is the subject of several investigations. The aim of this review is to summarize this body of research to date.
Literature
1.
Varga J, Abraham D: Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest 2007, 117:557–567.CrossRefPubMed
2.
Tyndall AJ, Bannert B, Vonk M, et al.: Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database. Ann Rheum Dis 2010, 69:1809–1815.CrossRefPubMed
3.
Quillinan NP, Denton CP: Disease-modifying treatment in systemic sclerosis: current status. Curr Opin Rheumatol 2009, 21:636–641.CrossRefPubMed
4.
Nihtyanova SI, Tang EC, Coghlan JG, et al.: Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM 2010, 103:109–115.CrossRefPubMed
5.
Clements PJ, Lachenbruch PA, Seibold JR, et al.: Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993, 20:1892―1896.PubMed
6.
Medsger TA: Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Rheum Dis Clin North Am 2003, 29:255–273.CrossRefPubMed
7.
• Amjadi S, Maranian P, Furst DE, et al.: Course of the modified Rodnan skin thickness score in systemic sclerosis clinical trials: analysis of three large multicenter, double-blind, randomized controlled trials. Arthritis Rheum 2009, 60:2490–2498. In a pooled analysis of three randomized controlled trials, the authors demonstrated that SSc patients in clinical trials tend to demonstrate improvement in mRSS whether treated with placebo or drug. CrossRefPubMed
8.
• Herrick AL, Lunt M, Whidby N, et al.: Observational study of treatment outcome in early diffuse cutaneous systemic sclerosis. J Rheumatol 2010, 37:116–124. Improvements in mRSS in patients with less than 3 years’ disease duration on a variety of different treatment regimens are described. CrossRefPubMed
9.
• Varga JA, Trojanowska M: Fibrosis in systemic sclerosis. Rheum Dis Clin North Am 2008, 34:115–143. This is a comprehensive review of the pathophysiology of fibrosis in SSc. CrossRefPubMed
10.
• Rosenbloom J, Castro SV, Jimenez SA: Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med 2010, 152:159–166. This is a review of the molecular mechanisms of TGF-β and fibrosis. PubMed
11.
Higley H, Persichitte K, Chu S, et al.: Immunocytochemical localization and serologic detection of transforming growth factor beta 1: association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud’s phenomenon. Arthritis Rheum 1994, 37:278–288.CrossRefPubMed
12.
Ludwicka A, Ohba T, Trojanowska M, et al.: Elevated levels of platelet derived growth factor and transforming growth factor-beta 1 in bronchoalveolar lavage fluid from patients with scleroderma. J Rheumatol 1995, 22:1876–1883.PubMed
13.
Klareskog L, Gustafsson R, Scheynius A, et al.: Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis. Arthritis Rheum 1990, 33:1534–1541.CrossRefPubMed
14.
Baroni SS, Santillo M, Bevilacqua F, et al.: Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 2006, 354:2667–2676.CrossRefPubMed
15.
Dragun D, Distler JH, Riemekasten G, Distler O: Stimulatory autoantibodies to platelet-derived growth factor receptors in systemic sclerosis: what functional autoimmunity could learn from receptor biology. Arthritis Rheum 2009, 60:907–911.CrossRefPubMed
16.
17.
Massague J, Seoane J, Wotton D: Smad transcription factors. Genes Dev 2005, 19:2783–2810.
18.
• Bhattacharyya S, Ishida W, Wu M, et al.: A non-Smad mechanism of fibroblast activation by transforming growth factor-b via c-Abl and Egr-1: selective modulation by imatinib mesylate. Oncogene 2009, 28:1285–1297. These results position c-Abl downstream of TGF-β signaling and in turn position early growth response factor 1 downstream of this. Delineation of these pathways may demonstrate new areas for additional future therapeutic targets. CrossRefPubMed
19.
Pannu J, Asano Y, Nakerakanti S, et al.: Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate. Arthritis Rheum 2008, 58:2528–2537.CrossRefPubMed
20.
Jimenez SA, Gaidarova S, Saitta B, et al.: Role of protein kinase S-delta in the regulation of collagen gene expression in scleroderma fibroblasts. J Clin Invest 2001, 108:1395–1403.PubMed
21.
Chen Y, Leask A, Abraham DJ, et al.: Heparan sulfate-dependent ERK activation contributes to the overexpression of fibrotic proteins and enhanced contraction by scleroderma fibroblasts. Arthritis Rheum 2008, 58:577–585.CrossRefPubMed
22.
Distler JH, Jungel A, Huber LC, et al.: Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007, 56:311–322.CrossRefPubMed
23.
• Akhmetshina A, Venalis P, Dees C, et al.: Treatment with imatinib prevents fibrosis in different preclinical models of systemic sclerosis and induces regression of established fibrosis. Arthritis Rheum 2009, 60:219–224. The authors used the Tsk1 murine and bleomycin-induced dermal fibrosis murine model to show that in models approximating established stages of fibrosis, imatinib inhibition of PDGF receptor and TGF-β signaling led to decreased dermal thickening. CrossRefPubMed
24.
• Akhmetshina A, Dees C, Pileckyte M, et al.: Dual inhibition of c-Abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J 2008, 22:2214–2222. TKIs dasatinib and nilotinib exhibited similar effects to what was seen with imatinib. CrossRefPubMed
25.
Li M, Abdollahi A, Grone HJ, et al.: Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model. Radiat Oncol 2009, 4:66.CrossRefPubMed
26.
Yoshiji H, Noguchi R, Kuriyama S, et al.: Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats. Am J Physiol Gastrointest Liver Physiol 2005, 288:G907–G913.CrossRefPubMed
27.
Wang S, Wilkes MC, Leof EB, et al.: Noncanonical TGF-beta pathways, mTORC1 and Abl, in renal interstitial fibrogenesis. Am J Physiol Renal Physiol 2010, 298:F142–F149.CrossRefPubMed
28.
Maurer B, Stanczyk J, Jüngel A, et al.: MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum 2010, 62:1733–1743.CrossRefPubMed
29.
• Kay J, High W: Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 2008, 58:2543–2548. This case series of two patients with NSF treated with imatinib showed clinical and histologic improvement in the skin. CrossRefPubMed
30.
• Olivieri A, Locatelli F, Zecco M, et al.: Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood 2009, 114:709–718. In 19 patients with cGVHD, an overall response rate of 79% was seen with imatinib treatment, providing evidence for the efficacy of PDGF receptor inhibition in this fibrotic disease. CrossRefPubMed
31.
Daniels CE, Wilkes MW, Edens M, et al.: Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin mediated lung fibrosis. J Clin Invest 2004, 114:1308–1316.PubMed
32.
•• Daniels CE, Lasky JA, Limper AH, et al.: Imatinib treatment for IPF: randomized placebo controlled trial results. Am J Respir Crit Care Med 2010, 181:604–610. This was an investigator-initiated, multicenter, multinational, double-blind clinical trial in which 119 patients with IPF were randomly assigned to receive imatinib or placebo for 96 weeks. Treatment with imatinib did not improve survival or lung function. CrossRefPubMed
33.
Cohen MH, Williams G, Johnson JR, et al.: Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002, 8:935–942.PubMed
34.
Dagher R, Cohen M, Williams G, et al.: Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 2002, 8:3034–3038.PubMed
35.
Kerkelä R, Grazette L, Yacobi R, et al.: Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006, 12:908–916.CrossRefPubMed
36.
Atallah E, Durand JB, Kantarjian H, et al.: Congestive heart failure is a rare event in patients receiving imatinib therapy. Blood 2007, 110:1233–1237.CrossRefPubMed
37.
Berman E, Nicolaides M, Maki RG, et al.: Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med 2006, 354:2006–2013.CrossRefPubMed
38.
Gordon JK, Magid SK, Maki RG, et al.: Elevations in creatine kinase in patients treated with imatinib mesylate (Gleevec). Leuk Res 2010, 34:827–829.CrossRefPubMed
39.
Sfikakis PP, Gorgoulis VG, Katsiari CG, et al.: Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology (Oxford) 2008, 47:735–737.CrossRef
40.
van Daele PLA, Dik WA, Thio HB, et al.: Is imatinib mesylate a promising drug in systemic sclerosis? Arthritis Rheum 2008, 58:2549–2552.CrossRefPubMed
41.
Distler JH, Manger B, Spriewald BM, et al.: Treatment of pulmonary fibrosis for twenty weeks with imatinib mesylate in a patient with mixed connective tissue disease. Arthritis Rheum 2008, 58:2538–2542.CrossRefPubMed
42.
• Chung L, Fiorentino DF, Benbarak MJ, et al.: Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis Rheum 2009, 60:584–591. This hypothesis-generating work posits the existence of an imatinib-responsive gene signature in certain dcSSc patients. CrossRefPubMed
43.
Sabnani I, Zucker MJ, Rosenstein ED, et al.: A novel therapeutic approach to the treatment of scleroderma-associated pulmonary complications: safety and efficacy of combination therapy with imatinib and cyclophosphamide. Rheumatology 2009, 48:49–52.CrossRefPubMed
44.
Hatano M, Yao A, Shiga T, et al.: Imatinib mesylate has the potential to exert its efficacy by down-regulating the plasma concentration of platelet-derived growth factor in patients with pulmonary arterial hypertension. Int Heart J 2010, 51:272–276.CrossRefPubMed
45.
Spiera R, Gordon J, Mersten J, et al.: Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a one year, phase IIa, single arm, open label clinical trial [abstract]. Presented at the American College of Rheumatology Annual Scientific Meeting. Atlanta, GA; November 6–11, 2010.
46.
Pope J, McBain DL, Petrlich L, et al.: A proof of concept trial of Gleevec (imatinib) in active diffuse scleroderma (DSSc) [abstract]. Presented at the American College of Rheumatology Annual Scientific Meeting. Philadelphia, PA; October 17–21, 2009.
47.
Chung L, Ruiz P, Wood T, et al.: Evaluation of an imatinib response gene signature in patients with systemic sclerosis [abstract]. Presented at the American College of Rheumatology Annual Scientific Meeting. Atlanta, GA; November 6–11, 2010.
48.
Saggar R, Khanna D, Mayes M, et al.: Open labeled study of imatinib mesylate (Gleevec) in the treatment of systemic sclerosis-associated active interstitial lung disease (SSc-ILD): preliminary results. Am J Respir Crit Care Med 2010, 181:A3991.
49.
Distler O, Distler JHW, Varga J, et al.: A multi-center, open-label, proof of concept study of imatinib mesylate demonstrates no benefit for the treatment of fibrosis in patients with early, diffuse systemic sclerosis [abstract]. Presented at the American College of Rheumatology Annual Scientific Meeting. Atlanta, GA; November 6–11, 2010.
50.
Denton CP, Nihtyanova SI, Varga J, et al.: Comparative analysis of change in modified Rodnan skin score in patients with diffuse systemic sclerosis receiving imatinib mesylate suggests similar disease course to matched patients receiving standard therapy [abstract]. Presented at the American College of Rheumatology Annual Scientific Meeting. Atlanta, GA; November 6–11, 2010.
Metadata
Title
Imatinib and the Treatment of Fibrosis: Recent Trials and Tribulations
Authors
Jessica Gordon
Robert Spiera
Publication date
01-02-2011
Publisher
Current Science Inc.
Published in
Current Rheumatology Reports / Issue 1/2011
Print ISSN: 1523-3774
Electronic ISSN: 1534-6307
DOI
https://doi.org/10.1007/s11926-010-0146-6

Other articles of this Issue 1/2011

Current Rheumatology Reports 1/2011 Go to the issue

ReviewPaper

Use of Hydroxychloroquine to Prevent Thrombosis in Systemic Lupus Erythematosus and in Antiphospholipid Antibody–Positive Patients

ReviewPaper

Autoantibodies Directed Against Domain I of Beta2-Glycoprotein I

ReviewPaper

The Genetics of Scleroderma

ReviewPaper

New Insights into the Biology and Pathobiology of Beta2-Glycoprotein I

ReviewPaper

Update on Antiphospholipid Syndrome in Children

ReviewPaper

The Scleroderma Kidney: Progress in Risk Factors, Therapy, and Prevention
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits