This study, for the first time, investigated the clinical value of Rcn3 in ILD patients. The primary findings in this study are as follows: the serum Rcn3 levels in CTD-ILD patients were significantly higher than that in IPF patients; the serum Rcn3 level may could be used as a biomarker to diagnose CTD-ILD from IPF; the severity of CTD-ILD represented by pulmonary function had a significantly positive correlation with serum Rcn3 level.
CTD-ILD is associated with significant morbidity and mortality due to sophisticated pathogenesis and limited treatment strategies and thus the early diagnosis and effective evaluation could be critical to improve the clinical outcome[20]. The diagnosis and prognostic prediction of CTD-ILD mainly depend on the clinical manifestations including the dyspnea score, pulmonary function degree and CT patterns, which are somewhat inconvenient for clinicians’ earlier decision making[21]. Therefore, the recent studies focused on looking for simple and effective biomarkers for diagnosis or to reflect the severity of ILD, such as Vitamin D, KL-6 and SP-D, although none of these biomarkers have been widely used in clinical practice[7]. Herein, we also indicated that the significant increase of serum Rcn3 level is a potential biomarker to diagnose CTD-ILD from IPF and is significant related with deleterious pulmonary function. Our data also indicated the diagnostic value of serum Rcn3 level: a cutoff of 2.73 ng/mL has a sensitivity of 69% and a specificity of 69% to diagnose CTD-ILD from IPF. The relatively low accuracy was likely due to the limited number of patients, it will shed additional light on the early diagnosis of CTD-ILD.
Both immune-inflammatory disorder and fibrogenesis are primary pathogenic mechanism of CTD-ILD, while the fibrogenesis caused by injury-repair deregulation account for the pathogenesis of IPF. Our previous study indicates the functions of Rcn3 in alveolar epithelium including the pro-inflammatory function during acute lung injury and the anti-fibrotic function during injury-repair process[12, 22]. Consistently, there was also a statistically significant difference in serum Rcn3 level between CTD-ILD and IPF patients, which is likely due to the different contributions of Rcn3 in these two diseases. In addition, CTD-ILD patients, but not IPF patients, exhibited significantly higher level of serum Rcn3 than controls, suggesting that Rcn3 could be more sensitive to immune-inflammatory interstitial changes. These findings indicated a significant clinical value in differential diagnosis of CTD-ILD from IPF.
In addition to the higher serum Rcn3 levels in CTD-ILD patients than IPF patients, our study also showed a significantly positive correlation between serum Rcn3 level and the severity of CTD-ILD represented by pulmonary function. This result suggest that Rcn3 could be more sensitive to immune-inflammatory deregulation-induced pulmonary interstitial remodeling compared to other markers, which could be explained by its critical role in fibrogenesis found in our previous studies on animal pulmonary fibrosis models[12]. Such hypothesis is in line with recent findings by other groups: Ding J et al[23] reported that Rcn3 showed a high expression in immune cells and fibroblast cells in Pan-cancer analysis; Park NR et al[24] showed that Rcn3 was a pivotal regulator of collagen fibrillogenesis during postnatal tendon development and Liu J et al[25] demonstrated that Rcn3 was significantly upregulated in keloids, in which abundant fibroblasts and collagen deposits involved. Together with these findings, our results showed that that serum Rcn3 levels could more sensitive and effective for prediction of CTD-ILD prognosis due to the involvements of Rcn3 both in immune-inflammatory response and fibrogenesis, both of which are primary pathogenic mechanism of CTD-ILD. However, a perspective study enrolling more subjects is worth to validate the clinical value of Rcn3 in ILD.
There were some limitations of our present study. First, this was a retrospective study that included data from a single-center cohort and enrolled a small number of patients. Second, although all diagnoses of ILD in our study were based on multidisciplinary discussion, IPF and CTD-ILD were not accurately diagnosed by histopathological examination in every patient. Third, whether the serum Rcn3 levels are different according to the types of CTD should be further investigated, giving that ILD is a common manifestation in CTD, such as rheumatoid arthritis, systemic sclerosis, and inflammatory myositis. However, this hypothesis requires analysis of a larger sample size to support.