ARTHRITIS & RHEUMATISM Vol. 63, No. 11, November 2011, pp 3199–3203 DOI 10.1002/art.30545 © 2011, American College of Rheumatology EDITORIAL Tyrosine Kinase Inhibitor Therapy for Systemic Sclerosis: Quo Vadis? Fabian A. Mendoza and Sergio A. Jime ´nez Systemic sclerosis (SSc) is a complex auto- immune disorder that causes extensive multiorgan dam- age with serious, and often fatal, consequences (1). Despite numerous and intense efforts to develop effec- tive therapies, SSc remains the autoimmune disease with the highest case-specific mortality rates, and there is the generally accepted perception that there are no clinically effective therapeutic approaches for SSc. Although ex- tensive investigations have examined the complex patho- genesis of SSc, the exact mechanisms involved are not well understood (2–6). However, it is apparent that its most severe clinical manifestations and high mor- tality result from a progressive and uncontrolled fibrotic process. Remarkable recent progress in understanding the molecular events involved in the development of SSc tissue fibrosis has allowed the identification of key molecules and key intracellular signaling cascades that mediate the initiation and progression of fibrosis in this disorder (2–5). The results of these studies have pro- vided novel options for the treatment and correction of the molecular alterations involved in the fibrotic com- ponent of SSc. The most promising appear to include modifiers of transforming growth factor 1 (TGF1) activation and signaling, tyrosine kinase inhibitors, and inhibitors of other growth factors involved in the fibrotic process (7–11). Many of these approaches have received support from the findings of extensive clinical and pre- clinical studies. Furthermore, it is expected that given the strong molecular rationale for their antifibrotic effects, these novel therapies may prove to be highly ef- fective in controlling and reversing the severe clinical manifestations of fibrosis in SSc. The fibrotic process in SSc is caused by over- production of extracellular matrix (ECM) proteins by an expanded population of activated fibroblasts. A hall- mark of the activation of fibroblasts is their conversion into myofibroblasts, a process by which quiescent or resting fibroblasts acquire unique phenotype character- istics, including the expression of smooth muscle actin, the development of contractile and migratory proper- ties, and a marked increase in their biosynthetic activi- ties (12,13). The origin of the activated myofibroblasts in SSc and other fibrotic diseases has not been completely elucidated, although numerous recent studies have dem- onstrated that an important source is the transdifferen- tiation of either epithelial cells or endothelial cells into myofibroblasts, through epithelial to mesenchymal (14,15) or endothelial to mesenchymal (16,17) cell tran- sitions. Although the exact pathways and mediators of these transdifferentiation processes have not been to- tally elucidated, there is clear evidence that TGF plays a major role (18–20). Furthermore, TGF is capable of inducing a potent stimulation of the expression of nu- merous genes that encode ECM proteins and, at the same time, inhibiting the production of ECM-degrading metalloproteinases and stimulating the production of protease inhibitors, such as tissue inhibitor of metallo- proteinases 1 (TIMP-1). Thus, there are several distinct processes and pathways modulated by TGF that mark- edly increase the production and accumulation of fi- brotic tissue, rendering this pleiotropic polypeptide one of the most potent profibrogenic mediators produced by human cells and, therefore, a prime target of antifibrotic therapeutics (9). The profibrotic effects of TGF involve complex, and often redundant, intracellular pathways mediated by the sequential phosphorylation of various intracellular targets through activation of receptor and nonreceptor tyrosine kinases (21–23). The best-characterized profi- brotic effects of TGF involve the canonical Smad pathway, although numerous other important effects are mediated through non-Smad pathways. One of the most relevant non-Smad pathways in SSc involves the partic- Fabian A. Mendoza, MD, Sergio A. Jime ´nez, MD: Thomas Jefferson University, Philadelphia, Pennsylvania. Address correspondence to Sergio A. Jime ´nez, MD, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Suite 509, Bluemle Life Sciences Building, 233 South 10th Street, Philadel- phia, PA 19107. E-mail: Sergio.Jimenez@jefferson.edu. Submitted for publication June 13, 2011; accepted in revised form July 7, 2011. 3199