Performance of Candidate Serum Biomarkers for Systemic Sclerosis–Associated Interstitial Lung Disease

Abstract

Objective. Interstitial lung disease (ILD) in systemic sclerosis (SSc) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SSc-associated ILD.Methods. Serum samples from a combined cohort of SSc patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme-linked immunosorbent assay for concentrations of lung epithelial-derived surfactant protein D (SP-D), Krebs von den Lungen 6 glycoprotein (KL-6), CCL18, and OX40 ligand (OX40L). Lung fibrosis was measured by high-resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow-up 3.2 ± 4.4 years) were investigated.Results. In SSc patients at baseline, serum levels of KL-6 correlated with the forced vital capacity (FVC) (r = −0.317, P < 0.001), diffusing capacity for carbon monoxide (r = −0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL-6 and SP-D, but not CCL18 and OX40L, were associated with lung fibrosis (odds ratio [OR] 2.41, 95% confidence interval [95% CI] 1.43-4.07 [P = 0.001] and OR 3.15, 95% CI 1.81-5.48 [P < 0.001], respectively). In SSc patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR] 2.90, 95% CI 1.25-6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02-13.52; P = 0.048). Matrix-based logistic regression models for the diagnosis and prognosis of SSc-associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP-D (for diagnosis) and serum levels of CCL18 (for progression of disease).Conclusion. These results show that SP-D is a relevant diagnostic biomarker for SSc-associated ILD, whereas KL-6 could be used to assess the severity of lung fibrosis. CCL18 appears to be a potential predictive marker for progression of ILD in SSc.

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

“…Increased serum levels of KL-6, a glycoprotein produced by type II pneumocytes, are strongly associated with the presence of ILD in SSc, and could be incorporated into screening algorithms, although not all studies agree on its ability to predict SSc-ILD disease progression. [45][46][47] Other biomarkers, including SP-D and CCL18, have also demonstrated promise. 47,48 Predicting Prognosis in SSc-ILD While there are limitations to the use of pulmonary function tests and HRCT in the screening of SSc patients for ILD, their use in guiding prognostication and treatment decisions is well established.…”

“…[45][46][47] Other biomarkers, including SP-D and CCL18, have also demonstrated promise. 47,48 Predicting Prognosis in SSc-ILD While there are limitations to the use of pulmonary function tests and HRCT in the screening of SSc patients for ILD, their use in guiding prognostication and treatment decisions is well established. Severe ILD is in itself predictive of likelihood of progression.…”

Prospects for Stratified and Precision Medicine in Systemic Sclerosis Treatment

“…Three promising molecular markers in SSc-ILD highlighted in a recent study include SP-D (surfactant protein), KL-6 (Krebs von den Lungen-6), and CCL19. SP-D was the superior biomarker for diagnosis, KL-6 levels correlated with severity of SSc-ILD, while CCL19 was a predictive biomarker of SSc-ILD progression [9]. Other molecular markers are mentioned later in the text, but those under current investigation include mucin-1 (MUC-1), and CA15-3 which seem to be reliable predictors for cases of more than 20% fibrosis, where specific immunosuppressive therapy is considered to be indicated [10].…”

Progression of Interstitial Lung Disease in Systemic Sclerosis: The Importance of Pneumoproteins Krebs von den Lungen 6 and CCL18

“…Furthermore, KL‐6 correlates with disease severity in different SSc‐related ILD populations . Two observational studies have shown that high KL‐6 levels predict worse outcomes in SSc‐related ILD.…”