Therapeutic Inhibition of Tyrosine Kinases in Systemic Sclerosis: A Review of Published Experience on the First 108 Patients Treated with Imatinib Vasiliki-Kalliopi Bournia, MD,* Konstantinos Evangelou, MD, PhD, † and Petros P. Sfikakis, MD* Objective: Experimental and clinical evidence suggest a therapeutic role for the tyrosine kinase inhibitor imatinib in fibrosing conditions. We evaluated published data on the safety and efficacy of imatinib for patients with systemic sclerosis (SSc), a severe autoimmune disease with significant morbidity and mortality. Methods: A careful search for all original articles and abstracts on the use of imatinib in SSc published in English from 2008 through February 2012 was performed. Two additional patients from our center are also described. Results: Five small observational clinical trials on the use of imatinib in severe SSc have been conducted and case reports and small series of refractory to current approaches patients have been reported, adding to a total of 108 patients having received this drug to date. In most of these patients imatinib was given for skin or pulmonary fibrosis. Encouraging results were reported in 3 of 4 studies, whereas the fifth study was prematurely terminated for safety reasons. Overall, clinical results are highly variable, ranging from ineffective or toxic responses to extremely encouraging clinical improvements in some severely ill patients. These discrepancies could partly reflect imatinib-related safety issues, in particular, SSc pa- tients or idiosyncratic resistance to imatinib, as happens in chronic myelogenous leukemia and gastro- intestinal stromal tumors, the drug’s approved indications. Conclusions: The limited available experience suggests that imatinib could be considered as an individualized treatment approach in severe SSc and underscores the need to identify markers for selecting particular patients, who will safely respond to therapeutic inhibition of tyrosine kinases. © 2013 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 42:377-390 Keywords: scleroderma, imatinib, tyrosine kinase inhibitors, pulmonary arterial hypertension, nephrogenic systemic fibrosis, chronic graft-versus-host disease (cGVHD), morphea S ystemic sclerosis (SSc) is a debilitating autoimmune disease with significant morbidity and mortality. It is characterized by a fibroproliferative vasculopathy, an excessive production of extracellular matrix, and an aberrant autoimmune activation. The underlying patho- physiologic mechanisms remain elusive and, although there are considerable improvements in disease manage- ment (1), these are poorly reflected in patient survival (2). Tyrosine kinases are enzymes that regulate important cellular functions, including survival, proliferation, differ- entiation, and motility, by catalyzing the phosphorylation of tyrosine residues in protein substrates (3). Imatinib mesylate was the first bcr-abl tyrosine kinase inhibitor to be introduced for the management of chronic myeloid leukemia (CML). This drug also blocks the platelet-de- rived growth factor receptor (PDGFR), as well as the Arg, and c-kit kinases (4). In addition to CML, imatinib has received approval for the treatment of systemic mastocy- tosis, hypereosinophilic syndrome, relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia, dermatofibrosarcoma protruberans, gastroin- testinal stromal tumors (GIST), and myelodysplastic or myeloproliferative diseases associated with PDGFR gene rearrangements. *First Department of Propedeutic and Internal Medicine, Laikon Hospital, Athens, Greece. †Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, University of Athens, Athens, Greece. The authors have no conflicts of interest to disclose. Address reprint requests to Petros P. Sfikakis, MD, Athens University Medical School, Laikon Hospital, 17, Ag. Thoma Street, Athens, 11527, Greece. E-mail: psfikakis@med.uoa.gr. SYSTEMIC SCLEROSIS 377 0049-0172/13/$-see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2012.06.001