Human epididymis protein 4 is associated with severity and poor prognosis of connective tissue disease-associated interstitial lung disease with usual interstitial pneumonia pattern.

Overexpression of human epididymis protein 4 (HE4) was previously described in idiopathic pulmonary fibrosis (IPF), but whether serum HE4 can be considered as a potential biomarker in connective tissue disease-associated interstitial lung disease (CTD-ILD) with usual interstitial pneumonia (UIP) pattern was still unknown. A total of 55 CTD-ILD patients with UIP pattern (UIP-CTD) 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, immunohistochemistry analysis for HE4 was performed on the lung sections of 6 patients with rheumatoid arthritis-associated UIP (UIP-RA) and 6 patients with early-stage lung cancer as normal control. The levels of serum HE4 and KL-6 were higher in patients with UIP-CTD than in healthy controls (292.3 pmol/L versus 79.5 pmol/L for HE4, p < 0.001; 1091.0 IU/mL versus 171.5 IU/mL for KL-6, p < 0.001). Significant correlations between serum HE4 levels and percentpredicted forced vital capacity (FVC%) (r = -0.425, p = 0.004), percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r = -0.447, p = 0.003), and Gender-Age-Physiology (GAP) index (r = 0.494, p < 0.001) were observed in UIP-CTD patients. In immunohistochemistry analysis, elevated expression of HE4 in bronchiolar epithelium and mesenchyme was observed in patients with UIP-RA compared with controls. The serum levels of HE4 (≥277.5 pmol/L) and GAP index were related to an increased risk of mortality (HR = 3.884, p = 0.034; HR = 1.480, p = 0.028, respectively). The expression of HE4 in serum and lung specimens was significantly elevated in UIP-CTD patients. Moreover, serum HE4 may be utilized as a biomarker to evaluate the severity of disease and predict the prognosis of UIP-CTD patients.

Meng K ，Tian M ，Gui X ，Xie M ，Gao Y ，Shi S ，Zhao T ，Xiao Y ，Cai H ，Ding J ... -  《-》

Elevated serum human epididymis protein 4 is associated with disease severity and worse survival in idiopathic pulmonary fibrosis: a cohort study.

Elevated expression of human epididymis protein 4 (HE4) was previously described in connective tissue disease-associated interstitial lung diseases (CTD-ILDs) and cystic fibrosis (CF), but the clinical significance of HE4 has remained unknown in idiopathic pulmonary fibrosis (IPF), which is a progressive fibrosing ILD with a heterogeneous course that is in urgent need of reliable biomarkers in its clinical practice. A total of 27 IPF patients with acute exacerbation status (AE-IPF), 32 IPF patients with stable status (S-IPF), and 29 sex-age matched healthy controls were retrospectively included. The levels of serum HE4 and Krebs von den Lungen-6 (KL-6) of the 3 cohorts were measured. In addition, the pulmonary expression of HE4 was evaluated in lung transplant specimens of IPF using immunohistochemistry and Western blot, and noncancerous lung tissue resected from early-stage lung cancer patients as controls. The endpoint of follow-up was March 1st, 2022, and the Cox regression model was used to analyze the prognostic value of HE4. The levels of HE4 and KL-6 were obviously elevated in AE-IPF patients compared to S-IPF (296.4 vs. 178.1 pmol/L for HE4, P<0.001; 2,007.0 vs. 990.5 IU/mL for KL-6, P<0.001) or healthy controls (296.4 vs. 51.8 pmol/L for HE4, P<0.001; 2,007.0 vs. 181.0 IU/mL for KL-6, P<0.001). Significant correlations were observed between serum HE4 levels and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r=-0.526, P<0.001), percent predicted forced vital capacity (FVC%) (r=-0.344, P=0.024), gender-age-physiology (GAP) index (r=0.535, P<0.001), and oxygenation index (r=-0.550, P<0.001) in IPF patients. In histological analysis, overexpression of HE4 in mucosal epithelium of dilated bronchi was observed in IPF patients compared with controls. Multivariate cox regression revealed that serum levels of HE4 [hazard ratio (HR) =1.004, P=0.042] and GAP index (HR =1.374, P=0.010) were associated with worse survival in IPF patients. The expression of serum HE4 was obviously elevated in IPF patients, especially in AE-IPF patients. In addition, serum HE4 could be utilized as a biomarker of disease severity and poor prognosis of IPF patients. These findings warrant further validation in larger, multi-center, and longitudinal cohorts.

Tian M ，Meng K ，Gao Y ，Zhang J ，Xie M ，Tian Y ，Liu X ，Ma M ，Cai Y ，Wu H ，Ding J ，Chen J ，Cai H ... -  《-》

Comparison of clinical courses and mortality of connective tissue disease-associated interstitial pneumonias and chronic fibrosing idiopathic interstitial pneumonias.

Interstitial lung disease (ILD) is a common pulmonary manifestation of connective tissue diseases (CTD). Prognostic effect of radiological usual interstitial pneumonia (UIP) pattern in CTD-associated interstitial lung disease (CTD-ILD) is unknown. This study aimed to investigate the disease progression and mortality of patients with CTD-ILD and idiopathic interstitial pneumonias (IIP) including idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia and the prognostic impact of the radiological UIP pattern on both disease groups. The medical records of 91 patients (55 with CTD-ILD and 36 with IIP) diagnosed with ILD at pulmonary medicine department, Faculty of Medicine, Gazi University from 2004 to 2014 were retrospectively reviewed. Patients included whose baseline high-resolution computed tomography (HRCT) scans showed either a UIP or non-UIP pattern. While 67.3% (n = 37) of CTD-ILD patients possessed UIP pattern, 38.9% (n = 14) of IIP patients had UIP pattern in HRCT. Respiratory functions including the forced expiratory volume in the first second (FEV1 ), functional vital capacity (FVC), and transfer coefficient for carbon monoxide (diffusing capacity of the lung for carbon monoxide [DLCO]) of IIP group at the time of diagnosis were significantly lower than CTD-ILD group (P = .007, P = .002, and P = .019, respectively). There was no significant survival difference between CTD-ILD and IIP by using the log-rank test (P = .76). Multivariate analysis revealed that UIP pattern in HRCT (Hazard ratio: 1.85; 95% Confidence interval = 1.14-3; P = .013), annual FVC (Hazard ratio: 0.521; 95% Confidence interval = 0.32-0.84; P = .007), and annual DLCO declines (Hazard ratio: 0.943; 95% Confidence interval = 0.897-0.991; P = .02) were independent risk factors for mortality in both CTD-ILD and IIP groups. We found that UIP pattern in HRCT and annual losses in respiratory functions were the main determinants of prognosis of ILDs either idiopathic or CTD-associated.

Yıldırım F ，Türk M ，Bitik B ，Erbaş G ，Köktürk N ，Haznedaroğlu Ş ，Türktaş H ... -  《-》

Plasma LTBP2 as a potential biomarker in differential diagnosis of connective tissue disease-associated interstitial lung disease and idiopathic pulmonary fibrosis: a pilot study.

Few biomarkers distinguish connective tissue disease-associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF). Latent transforming growth factor-β binding protein-2 (LTBP2), a secreted extracellular matrix protein, is involved in pulmonary fibrosis. However, the role of LTBP2 in differentially diagnosing CTD-ILD and IPF is unclear. In this study, enzyme-linked immunosorbent assays quantified plasma LTBP2 concentrations in 200 individuals (35 healthy controls, 42 CTD patients without ILD, 89 CTD-ILD patients, and 34 IPF patients). CTD-ILD and IPF were further classified based on chest imaging pattern and pulmonary function test results. Plasma LTBP2 levels were significantly elevated in the IPF group compared with the CTD-ILD group. ROC analysis further suggested the possible value of LTBP2 in differentially diagnosing CTD-ILD and IPF. Additionally, CTD-ILD patients with progressive lung fibrosis had higher plasma LTBP2 concentrations than those who did not. Similarly, patients with IPF developing acute exacerbation showed higher plasma LTBP2 levels than those with stable IPF. This is the first study showing that LTBP2 was closely associated with the usual interstitial pneumonia (UIP) pattern in rheumatoid arthritis-associated ILD (RA-ILD). Moreover, the optimal cutoff values of LTBP2 for distinguishing IPF from CTD-UIP/RA-UIP were 33.75 and 38.33 ng/mL with an AUC of 0.682 and 0.681, respectively. Our findings suggest that plasma LTBP2 levels may differentially diagnose CTD-ILD and IPF, and assess their fibrotic activity. Additionally, clinical LTBP2 evaluation may be a great aid to identifying the presence of the UIP pattern in RA-ILD and to discriminating IPF from CTD-UIP, particularly RA-UIP.

Zou M ，Hu X ，Song W ，Gao H ，Wu C ，Zheng W ，Cheng Z ... -  《-》

Serum KL-6 levels reflect the severity of interstitial lung disease associated with connective tissue disease.

Lee JS ，Lee EY ，Ha YJ ，Kang EH ，Lee YJ ，Song YW ... -  《-》