AB0626 IMATINIB FOR THE TREATMENT OF SYSTEMIC SCLEROSIS: RATIONALE, CLINICAL EVIDENCE AND FUTURE DEVELOPMENT
Authors: A. Waheed, C. Buckingham, G. Brar
Journal: Annals of the Rheumatic Diseases (2020)

Background: Systemic sclerosis (SSc) is a chronic disorder of connective tissue affecting the skin and internal organs. The molecular mechanisms behind SSc are not entirely understood, but recent advances highlight key signalling pathways 1 (see Figure 1). Fibrosis disrupts tissue architecture resulting in organ dysfunction. This causes significant morbidity and mortality 1 , therefore there is a clear need for identifying efficacious antifibrotic treatment. Imatinib is a tyrosine kinase inhibitor with established use in some malignancies, and existing evidence that it can treat SSc 2 . Objectives: The aim of this literature review is to summarise the current evidence and future developments of imatinib as antifibrotic treatment in SSc. Methods: PubMed headings “systemic sclerosis”, “scleroderma”, “imatinib” and synonyms were used. See Figure 2. Results: Lead author and year Study design Population Intervention (imatinib dose given daily ) Results Hinchcliff ME. 2016 Case study 1 female (F) with an 8-month history of diffuse cutaneous systemic sclerosis (dcSSc) 400mg Severe adverse events (AEs) Pope J. 2014 Early phase proof of concept trial 10 with dcSSc. 9 given 400mg, 1 placebo Poor drug tolerability Prey S. 2012 Double blind RCT 28 with SSc 15 given 400mg, 13 placebo No improvement Khanna D. 2011 Phase I/IIa pilot trial 20 with SSc Up to 600mg AEs present Pope J. 2011 Double blind RCT 10 with SSc. 9 given 400mg, 1 placebo No improvement, AEs present Gordon J. 2014 Open label, single arm, extension phase clinical trial 17 with average disease duration of 3.5 years 100-400mg ↓ modified Rodnan skin score (mRSS) Fraticelli P. 2014 Phase II pilot trial 30 with SSc 200mg ↑ lung function Guo L. 2012 Case series 6 F, Chinese pts with SSc 200mg ↓ mRSS and ↑ lung function Divekar AA. 2011 Single centre, open-label study 15 with SSc 100mg up to 600mg/day ↑ lung function Spiera RF. 2011 1-year, phase IIa, single-arm, open-label clinical trial 30 with dcSSc 400mg ↓ mRSS and ↑ lung function Freyhaus H. 2009 Case report 58yo F 400mg ↑ lung function Chung L. 2009 Case report 2 with early dcSSc 200mg ↓ mRSS and ↑ lung function Van Daele PL. 2008 Case report 69yo F 400mg ↓ mRSS and ↑ lung function P. P. Sfikakis. 2008 Case report 24yo F 400mg ↓ mRSS and ↑ lung function 9 studies showed imatinib had positive efficacy in the treatment of SSc. 5 showed no improvement or adverse effects. Conclusion: Overall, current evidence suggests that imatinib can be a useful drug to improve manifestations of SSc, for some. Despite inconclusive evidence, a dose-dependent relationship seems to exist for imatinib toxicities, with more research needed to ascertain a safe dose. Gene expression profiles may distinguish patients that can benefit from imatinib 3 . Also, Notch signalling could be exploited to increase imatinib uptake into fibroblasts, thereby increasing efficacy 4 . References: [1]Pattanaik D et al. Pathogenesis of Systemic Sclerosis. Frontiers in Immunology. 2015;6: 272 [2]Distler JHW et al. Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies. Annals of the Rheumatic Diseases. 2010;69: 48-51 [3]Chung L et al. Molecular framework for response to imatinib mesylate in systemic sclerosis. Arthritis and Rheumatology. 2009 Feb;60(2):584-91 [4]Harrach S et al. Notch Signaling Activity Determines Uptake and Biological Effect of Imatinib in Systemic Sclerosis Dermal Fibroblasts. Journal of Investigative Dermatology. 2019; 139(2):439-4475 Acknowledgments: Skin Research Institute of Singapore Disclosure of Interests: None declared