Interstitial lung disease (ILD) is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). Although a large proportion of SSc patients have only limited interstitial involvement with an indolent course, in a significant minority ILD is progressive, requiring prompt treatment and careful monitoring. One of the main challenges for the clinician treating this highly variable disease is the early identification of patients at risk of progressive ILD, while avoiding potentially toxic treatments in those whose disease is inherently stable. Easily available and repeatable biomarkers that allow estimation of the risk of ILD progression and early response to treatment are highly desirable. In this paper, we review the evidence for circulating biomarkers with potential roles in diagnosis, monitoring of disease activity, or determining prognosis. Peripheral blood biomarkers offer the advantages of being readily obtained, non-invasive, and serially monitored. Several possible candidates have emerged from studies performed so far, including SP-D, KL-6, and CCL18. Presently however, there are few prospective studies evaluating the predictive ability of prospective biomarkers after adjustment for disease severity. Future carefully designed, prospective studies of well characterised patients with ILD, with optimal definition of disease severity and outcome measures are needed. 1. Introduction Systemic sclerosis (SSc) is a multisystem, autoimmune connective tissue disease, characterised by excessive extracellular matrix deposition, with remarkable heterogeneity in organ involvement pattern and prognosis. Pulmonary involvement, due to pulmonary fibrosis or pulmonary hypertension, is the leading cause of mortality [1, 2]. The pathogenesis of pulmonary fibrosis in SSc involves a complex combination of epithelial and endothelial cell injury with inflammatory and immune activation. Occurring in response to unknown initiating factors, the interaction between vascular, epithelial, and immune dysfunction leads to dysregulated fibroblast activation and increased extracellular matrix production [3]. This paper will focus on the circulating biomarkers for SSc-associated interstitial lung disease (SSc-ILD), as summarised in Figure 1. Figure 1: Potential biomarkers in SSc-ILD. A degree of interstitial involvement is present in the majority of patients with SSc, although severity of lung disease at presentation and subsequent longitudinal behaviour are highly variable. In view of the marked variability in the natural history of SSc-ILD, markers of the
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