Increased levels of HE4 (WFDC2) in systemic sclerosis: a novel biomarker reflecting interstitial lung disease severity?

Human epididymis protein 4 (HE4, also known as WFDC-2) has been implicated in fibrotic disorders pathobiology. We tested the hypothesis that HE4 may be used as a candidate biomarker for systemic sclerosis (SSc)-related interstitial lung disease (SSc-ILD). A total of 169 consecutive SSc patients and 169 age-and sex-matched healthy controls were enrolled and blood samples were collected. Pulmonary function tests (PFTs) and paired lavage was performed on 169 patients and 37 healthy controls. All patients were classified as having SSc-no ILD or SSc-ILD, based on high-resolution computed tomography (CT) scans of the chest, and a semiquantitative grade of ILD extent was evaluated through CT scans (grade 1, 0-25%; grade 2, 26-50%; grade 3, 51-75%; grade 4, 76-100%). Serum and bronchoalveolar lavage fluid (BALF) HE4 levels were measured by enzyme-linked immunosorbent assay. Serum HE4 levels were higher in SSc patients [median (interquartile range), 139.4 (85.9-181.8) pmol/l] compared with healthy controls [39.5 (24.3-54.2) pmol/l, p < 0.001] and were higher in patients with SSc-ILD [172.1 (94.8-263.3) pmol/l] than in those with SSc-no ILD [97.4 (85.5-156.5) pmol/l, p < 0.001]. This observation was replicated in the BALF samples. Corresponding values were 510.8 (144.6-1013.8) pmol/l for SSc cohort, 754.4 (299-1060) pmol/l for SSc-ILD, 555.1 (203.7-776.2) pmol/l for SSc-no ILD, and 238.7 (97.7-397.6) pmol/l for controls. The semiquantitative grade of ILD on CT scan was significantly proportional to the HE4 levels and the lung function parameter (i.e., FVC) had a negative correlation with the HE4 levels. This is the first study to demonstrate the potential clinical utility of blood and BALF HE4 as a biomarker for SSc-ILD. Future prospective validation studies are warranted.

Zhang M ，Zhang L ，E L ，Xu K ，Wang XF ，Zhang B ，Su J ，Meng Z ... -  《-》

Human epididymis protein 4 as a new diagnostic biomarker for rheumatoid arthritis-associated interstitial lung disease.

Lin T ，Xu S ，Wang Y ，Nian X ，Shan X ，Jiang T ，Qiu M ... -  《CLINICAL AND EXPERIMENTAL RHEUMATOLOGY》

Association of elevated α-defensin levels with interstitial pneumonia in patients with systemic sclerosis.

Sakamoto N ，Kakugawa T ，Hara A ，Nakashima S ，Yura H ，Harada T ，Ishimoto H ，Yatera K ，Kuwatsuka Y ，Hara T ，Ichinose K ，Obase Y ，Ishimatsu Y ，Kohno S ，Mukae H ... -  《RESPIRATORY RESEARCH》

Human epididymis protein 4 is a new biomarker to predict the prognosis of progressive fibrosing interstitial lung disease.

The clinical course and prognosis of progressive fibrosing interstitial lung diseases (PF-ILDs) vary between individuals. Notably, predictive serum biomarkers for disease management are needed. Serum human epididymis protein 4 (HE4) is reportedly elevated in patients with idiopathic pulmonary fibrosis (IPF); however, its clinical utility remains unknown. We evaluated the potential of serum HE4 as a biomarker for patients with PF-ILD. Serum HE4 was measured in a retrospective study consisting of 34 patients with PF-ILD and 40 healthy volunteers. The relationship between serum HE4 levels and clinical parameters or prognosis was investigated. To validate the significance of results obtained, a prospective observational study was performed in 37 patients presenting PF-ILD and 40 control patients without PF-ILD. Serum HE4 levels were higher in patients with PF-ILD than in healthy volunteers (P < 0.01). Moreover, serum HE4 levels correlated with the extent of honeycombing on chest high-resolution computed tomography (r = 0.41, P = 0.015). In multivariate analysis using the Cox proportional hazard model, higher HE4 levels (>238 pmol/L) were associated with an elevated mortality risk; hazard ratio (HR) 7.27, 95% CI 1.56-34.0, P = 0.01 in the derivation cohort; HR 44.3, 95% CI 4.19-468, P < 0.01 in validation cohort. Serum HE4 levels may serve as a new diagnostic and prognostic biomarker for patients with PF-ILD.

Nishiyama N ，Masuo M ，Nukui Y ，Tateishi T ，Kishino M ，Tateishi U ，Morota K ，Ohbo K ，Miyazaki Y ... -  《-》

Human epididymis protein 4 as a clinical biomarker in identifying interstitial lung disease in patients with idiopathic inflammatory myopathies.

Human epididymis protein 4 (HE4) can differentiate interstitial lung disease from patients with some rheumatic diseases. However, the clinical utility of HE4 in idiopathic inflammatory myopathies (IIM) remains unclear. 80 IIM patients and 91 age and gender-matched healthy controls (HCs) were recruited. Clinical and laboratory data were recorded at baseline and 12 weeks. HE4 was tested by the method of electrochemical luminescence. Compared to HCs, the levels of HE4 significantly elevated in IIM patients. Patients with elevated HE4 had a higher interstitial lung disease (ILD) prevalence. Among patients with ILD, histological patterns of organizing pneumonia had higher HE4 levels than non-specific interstitial pneumonia. Further, there was a positive correlation between HE4 and the semi-quantitative CT grade (r = 0.778, p < 0.001) and a negative relation between HE4 and the percentage of forced vital capacity (p < 0.001) and diffusing capacity of the lung for carbon monoxide (DLco) (p = 0.001). An optimal cut-off value of HE4 (79.6 pmol/L) for distinguishing IIM-ILD was analyzed by ROC analysis with an AUC of 0.733 (p = 0.002). Regression analysis revealed that elevated HE4 independently identified IIM-related ILD (OR 34.8, 95 %CI, 3.58-338.14, p = 0.002). With the improvement after treatment, serum HE4 levels were significantly decreased (p = 0.006), accompanied by improved DLco% (p = 0.012). Serum HE4 was significantly elevated in patients with IIM and may be utilized as a serum biomarker to evaluate the disease severity and prognosis of IIM-related ILD.

Sun F ，Zhao J ，Li Y ，Wang H ，Cao X ，Cheng W ，Chen J ... -  《-》