Exploiting a unified vascular framework to predict organ-specific complications and accomplish disease modification in systemic sclerosis

Immune-mediated vascular endothelial injury is considered one of the earliest pathological features in systemic sclerosis and is thought to occur simultaneously within a broad range of organs, although typically clinically manifesting only as Raynaud’s phenomenon in the early stages. Overt vascular systemic sclerosis manifestations include Raynaud’s phenomenon, abnormal nailfold capillary morphology, digital ulcers, pulmonary arterial hypertension, cardiovascular disease (primary and coronary), telangiectasia, renal crisis, and gastric antral vascular ectasia. Tissue ischaemia might also contribute to aberrant tissue remodelling, resulting in calcinosis and fibrosis. Recognition of the substantial inter-relationship between these vascular complications is growing; examples of vascular treatment interventions targeting digital vasculopathy having off-target vascular benefits in other organs have been reported. In general, treatment of life-threatening vascular complications, such as pulmonary arterial hypertension, is not commenced until classifiable organ disease has occurred; however, the identification of robust prognostic biomarkers might allow such complications to be averted with preventative disease modification. In this Personal View, we describe the inter-relationship between vascular features of systemic sclerosis. We consider how these features might be exploited to establish a unified vascular conceptual framework that can inform the development of both predictive composite indices to guide preventative intervention, and a unified vascular composite endpoint model that can effectively capture clinically meaningful disease modification in future clinical trials of vasoactive treatments in systemic sclerosis.