Molecular stratification and precision medicine in systemic sclerosis from genomic and proteomic data

Abstract

Purpose of review: The goal of this review is to summarize recent advances into the pathogenesis and treatment of systemic sclerosis (SSc) from genomic and proteomic studies.

Recent findings: Intrinsic gene expression-driven molecular subtypes of SSc are reproducible across three independent datasets. These subsets are a consistent feature of SSc and are found in multiple end-target tissues, such as skin and esophagus. Intrinsic subsets as well as baseline levels of molecular target pathways are potentially predictive of clinical response to specific therapeutics, based on three recent clinical trials. A gene expression-based biomarker of modified Rodnan skin score, a measure of SSc skin severity, can be used as a surrogate outcome metric and has been validated in a recent trial. Proteome analyses have identified novel biomarkers of SSc that correlate with SSc clinical phenotypes.

Summary: Integrating intrinsic gene expression subset data, baseline molecular pathway information, and serum biomarkers along with surrogate measures of modified Rodnan skin score provides molecular context in SSc clinical trials. With validation, these approaches could be used to match patients with the therapies from which they are most likely to benefit and thus increase the likelihood of clinical improvement.

Figure 1. Relationships between the SSc molecular networks in skin

Shown is a summary of core, conserved molecular processes in SSc skin. This includes an inflammatory subnetwork that contains both interferon and M2 macrophage modules that interact via Ras-Rac signaling. ECM module appears to represent a transition state between inflammatory and fibroproliferative subnetworks and is connected to M2 macrophages via chemokine signaling and to proliferation module via TGF-β signaling. The proliferation module is connected to the M2 macrophage module via fatty acid signaling and to the interferon module via negative regulation by ERK/MAPK pathway. Adapted with permission from Figure 7 in [3*]. ERK – extracellular-signal-regulated kinases, MAPK – mitogen-activated protein kinases.