Abstract

Systemic sclerosis (SSc) is a complex multisystem disease that links autoimmunity, inflammation, vascular damage to development of fibrosis or scarring in target organs. The pathogenesis of the disease involves reciprocal interaction between the immunological, vascular and mesenchymal compartments and involves processes that are central to connective tissue growth and repair. However in the context of SSc this process is dysfunctional in that the amount of tissue damage is excessive or the repair process is dysregulated. Thus it seems likely that perturbation of the cross talk between cells and pathways that regulate the cell types involved are important in pathogenesis and represent appropriate targets for therapeutic intervention. It is likely that some emerging therapies can attenuate the pathogenesis of SSc by acting on multiple cell type sand this is perhaps especially relevant to an approach such as autologous haematopoietic stem cell transplant. However it is likely that individual pathways or mediators can be modified in a less extreme manner and have benefit as potential disease modifying therapy. A number of key mediators and pathways are emerging including IL6, TGFbeta and intracellular pathways linked to nuclear hormone receptors. These are being targeted experimentally. Another strategy for treatment would be targeting the initiating cells such as monocytes, especially those with a profibrotic phenotype, or the effector cells in fibrosis such as myofibroblasts. Evidence supporting these strategies is emerging and it is likely that restoration of a more balanced interaction between vessels, extracellular matrix and fibroblasts would underpin effective therapies for the fibrotic and vascular components of SSc.