Prognostic Value of Human Epididymis Protein 4 in Connective Tissue Disease-Associated Interstitial Lung Disease with a Usual Interstitial Pneumonia Phenotype

Abstract

Background: Overexpression of human epididymis protein 4 (HE4) was previously described in idiopathic pulmonary fibrosis (IPF) and cystic fibrosis (CF), but whether serum HE4 concentrations can be considered a potential biomarker in connective tissue diseases (CTDs) with the usual interstitial pneumonia phenotype (UIP-CTDs) is still unknown.

Method: A total of 55 CTD patients with the UIP phenotype and 52 healthy controls were enrolled in this study. The serum levels of HE4 and Krebs von den Lungen-6 (KL-6) were evaluated in both cohorts. In addition, the pulmonary expression of HE4 was analyzed in 6 patients with rheumatoid arthritis-associated UIP (UIP-RA) using immunohistochemistry and 6 patients undergoing resection for early-stage lung cancer as normal control.

Results: The serum concentrations of both markers were higher in patients with UIP-CTD than in healthy controls (292.3 [196.6, 400.4] versus 79.5 [49.2, 101.4] pmol/L for HE4 and 1091.0 [779.0, 1654.0] versus 171.5 [77.0, 261.0] IU/ml for KL-6). Significant correlations with serum HE4 levels were observed for pulmonary function tests (PFTs), GAP index and C-reactive protein concentrations in patients with UIP-CTD. In immunohistochemistry analysis, elevated expression of HE4 in the bronchiolar epithelium and mesenchyme were observed in patients with UIP-RA compared with controls. The serum HE4 (> 277.5pmol/L) levels and GAP index were related to an increased risk of mortality (HR = 3.884, p = 0.034; HR = 1.480, p = 0.028, respectively).

Conclusion: Serum HE4 levels may be utilized as a biomarker in patients for evaluating the severity of disease and predicting the prognosis for UIP-CTD.

Note:
Funding Information: This study was supported by National Natural Science Foundation of China (Grant NO. 81400046, 82170077) and Key Project supported by Medical Science and Technology Development Foundation, Nanjing Department of Health (YKK20051).

Declaration of Interests: All authors have declared no conflicts of interest for this paper.

Ethics Approval Statement: Written informed consent to participate in this study and authorization to use the blood samples or lung specimens were obtained from all participants. This study protocol was approved by the ethics committee of Nanjing Drum Tower Hospital and conducted in accordance with the principles of the Declaration of Helsinki (1989).

Keywords: human epididymis protein 4, usual interstitial pneumonia, connective tissue disease-associated interstitial lung disease, Gender-Age-Physiology index