Tyrosine kinase inhibitors in the treatment of systemic sclerosis: from animal models to clinical trials.
Efficient antifibrotic therapies are not available for patients with systemic sclerosis (SSc). This review summarizes the current preclinical and clinical evidence for imatinib and related tyrosine kinase inhibitors as potential antifibrotic therapies for SSc and other fibrotic diseases. In experimental models of SSc, imatinib, nilotinib, and dasatinib demonstrated strong antifibrotic effects. Imatinib not only prevented fibrosis in the bleomycin-induced model of dermal fibrosis and the tight skin mouse-1 model but also reduced established fibrosis in a modified bleomycin model. Open-label, proof-of-concept trials in SSc showed moderate effects on skin fibrosis, biological measures of skin fibrosis, and lung fibrosis compared with baseline measures. However, whether this reflects the natural course of the disease or is a result of treatment effects is unclear and needs to be analyzed in larger, multicenter, randomized, placebo-controlled trials. Toxicity is expected from cancer trials with frequent mild to moderate adverse events.
Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Gloriastr. 25, 8091 Zürich, Switzerland.
Naoki
N
Iwamoto
Jörg H W
JH
Distler
Oliver
O
Distler
D000818:Animals; D001549:Benzamides; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000188:drug therapy*
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases