SP0177 New approaches by targeting soluble mediators

Although the aetiopathogenesis of systemic sclerosis (SSc) remains incompletely understood there is now sufficient knowledge about the pathobiology of the disease and mechanisms underlying development of fibrosis, autoimmunity and vasculopathy to permit informed selection of candidate soluble mediators that may be important drivers of the disease. This has permitted testing of potential targeting approaches in preclinical models and in vitro tissue culture systems. The data from these studies has informed understanding of the disease and has started to be translated into clinical trials that test hypotheses in vivo in patients. This approach has in turn fueled the concepts of reverse translation that are being applied to further understand SSc mechanisms in model systems and observational cohort studies. Soluble mediators that have emerged as strong targets for therapeutic intervention include TGFbeta superfamily members, connective tissue growth factor, IL13, IL4 and IL6. Studies of agents that target these proteins have been proposed or undertaken. Targeting TGF-beta appears to have benefit for skin thickening and attenuate some of the characteristic TGF-beta regulated genes and proteins in skin. However, the most encouraging data have emerged from targeting the IL6 axis using anti-IL6R neutralizing antibodies. This approach was promising in a Phase II study and further trials are ongoing. Interestingly this approach appears to attenuate macrophage gene expression signatures in the skin, may prevent worsening of lung fibrosis and showed significant benefit in the skin by biomarker analysis and a strong trend of benefit over 48 weeks for skin sclerosis score. Other small clinical trials testing TNF-alpha blockade have been more disappointing. Finally, it is possible that soluble mediators may be identified that directly attenuate the fibroproliferative mechanism of SSc. Experimental studies have suggested that increasing alpha-MSH may have benefit for skin fibrosis in a small controlled clinical trial. Clinical trial design is critical to the success and interpretation of studies targeting soluble mediators to define target engagement, mechanism of action, and possible clinical benefit. Advances in trial design are facilitating progress and it seems likely that, as in other rheumatic diseases, targeting key soluble mediators will become a therapeutic reality of the next few years. Defining the place of such approaches compared to other emerging treatment strategies will remain challenging. Disclosure of Interest C. Denton Grant/research support from: Inventiva, CSL Behring, GSK, Bayer, Consultant for: GSK, Actelion, Inventiva, Roche