Circulating Biomarkers of Interstitial Lung Disease in Systemic Sclerosis

Abstract

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.

Serum Krebs Von Den Lungen-6 as a Biomarker for Early Detection of Bronchiolitis Obliterans Syndrome in Children Undergoing Allogeneic Stem Cell Transplantation

“…This disruption, along with potential SCT-related lung injury because of chemotherapy and/or radiation, infections in the early post-SCT period, and later donor lymphocytes infiltrating the host's lungs because of infections or as part of acute or chronic GVHD, may together contribute to the sequence of events leading to the damaging and fibrotic result demonstrated at BOS diagnosis. KL-6 as a serum biomarker has been shown to be an important diagnostic and prognostic factor in many pediatric and adult interstitial lung diseases, including connective tissue diseases associated with interstitial lung disease where there is auto-immune mediated inflammation [25][26][27][28]. Lung inflammation post-SCT is somewhat similar; however, it is an allo-immune rather than auto-immune event.…”

The Ambitious Goal of Validating Prognostic Biomarkers for Systemic Sclerosis-related Interstitial Lung Disease

“…An ideal biomarker should be noninvasive, reliable, and cheap. Many attempts have been made to find such a candidate biomarker for SSc-ILD, but data have come mostly from retrospective single-center studies 10 . We know now that there are a number of candidate serum proteins that correlate with the presence or severity of ILD in the context of SSc.…”

“…The final step for the validation of a biomarker requires prospective, well-designed multicenter studies in heterogeneous populations. One major problem in the validation process is the identification of factors that influence the basal levels of these biomarkers, such as covariates, genetic assets, and baseline disease severity 10 .…”

“…Hirata, et al confirmed in a Japanese cohort that the MBDA score reflects current clinical disease activity and can track changes in disease activity over time 14 . Although this recent model is encouraging, to date, the panel of investigated biomarkers for SSc-ILD is limited, compared with the panel of investigated biomarkers in idiopathic pulmonary fibrosis 10 . Evidence has been provided for the ability of serum KL-6, surfactant protein-D (SP-D), and CC-chemokine ligand 18 (CCL18) to correlate with the likelihood of progression of SSc-ILD and for monitoring treatment response 10 .…”

“…This allowed the authors to include all data points and account for dependence between longitudinal FVC and survival, reducing the bias resulting from the fact that patients with more rapid decline in FVC are more likely to die. Although autoantibody subsets such as antitopoisomerase I (ATA) and anti-RNP subtypes 10 have been found to be associated with fibrosis in SSc, the investigators chose serum CCL18 and SP-D for their lung specificity and the evidence coming from studies on idiopathic interstitial pneumonias 10 . While serum level of SP-D correlated with FVC obtained at the same time, and CCL18 was a predictor of short-term decline in FVC, the main finding of the study was that neither SP-D nor CCL18 was a longterm predictor of the course of FVC in patients with early SSc.…”