Investigative approaches to drug therapy

Abstract

Current approaches to disease-modifying therapy in scleroderma together with strategies that are in use to tackle individual complications of the disease are reviewed in other chapters. Here, we will consider some of the novel approaches to therapy that are under evaluation and also the extent to which some established agents may have a broader effect on the disease process than was initially expected. Immunomodulatory strategies are largely covered elsewhere and will not be a major focus of the current chapter. The majority of therapeutic interventions for scleroderma that attempt to modify the disease process are immunomodulatory, and these are discussed in detail in other chapters. However, scleroderma is a multifaceted disease and it is likely that other mechanisms including vascular injury and fibrosis or epithelial damage may also be logically targeted. With this in mind, it is worthwhile to explore the novel mechanisms by which a number of therapies that are already in use may be regarded as potential disease-modifying treatments. In addition, there is an emerging list of therapies that target pivotal pathways or mediators that are emerging from studies of pathogenesis including animal models, in vitro analysis of fibroblasts and from genetic or gene expression studies. Preliminary data from early clinical trials suggest that tyrosine kinase molecules may be potential candidates for therapy especially in the fibrotic phase of the disease. Based on the new insights into the key role of effecter T cells in particular Th-17, T regulatory and follicular helper T subsets have T-cell-directed therapies including halofuginone, basiliximab, alemtuzumab, abatacept and rapamycin have been proposed to be clinically beneficial. HMG-CoA reductase inhibitors, endothelin receptor antagonists and phosphodiesterase type V inhibitor have been shown to be useful to treat the vascular manifestations associated with systemic sclerosis. Table 50.1 summarises some of the targeted approaches to treating scleroderma that fall within the arena of investigative approaches to drug therapy.