Elevated Serum Human Epididymis Protein 4 Is Associated With Disease Activity and Systemic Involvements in Primary Sjögren’s Syndrome

Abstract

BackgroundWe aimed to investigate the clinical utility of human epididymis protein 4, a tumor biomarker being widely utilized in clinical practice in the diagnosis of ovarian cancer, in primary Sjögren’s Syndrome (pSS).MethodsA total of 109 pSS patients and 113 healthy controls (HCs) were included in the study. HE4 were determined by Roche Cobas E601 electrochemical luminescence analyzer. Clinical and laboratory findings were reviewed, and the relationships between HE4 and clinical parameters were determined by Spearman’s correlation test. The European league against rheumatism Sjögren’s syndrome disease activity index (ESSDAI) was utilized to evaluate disease activity.FindingsThe levels of HE4 were significantly elevated in patients with pSS compared to HCs (103.65 pmol/L vs. 46.52 pmol/L, p<0.001). The levels of HE4 were positively correlated with ESSDAI scores (r=0.462, p<0.001). Significant positive correlations between the levels of HE4 with pulmonary involvements (r=0.442, p<0.001) and renal involvements (r=0.320, p=0.001) were observed. Receiver operating curve (ROC) analysis revealed an optimal cut-off value of 104.90 pmol/L and 128.05 pmol/L for distinguishing patients with pulmonary and renal involvements, with the areas under the ROC curve (AUCs) of 0.778 (95%CI 0.685-0.870, p<0.001) and 0.768 (95%CI 0.646-0.891, p=0.001), respectively. Among patients with pulmonary involvement, the levels of HE4 were positively correlated with the semiquantitative HRCT grade (r=0.417, p=0.016), and negatively correlated with the percentage of forced vital capacity (FVC) (r= -0.460, p=0.047) and diffusing capacity of the lung for carbon monoxide (DLco) (r= -0.623, p=0.004). For patients with renal involvement, HE4 was positively correlated with creatinine (r=0.588, p=0.021) and negatively correlated with estimated glomerular filtration rate (r= -0.599, p=0.030).ConclusionsOur findings demonstrated a novel role of HE4 in clinical stratification of pSS, suggesting that introducing HE4 to the current pSS test panel may provide additional diagnostic value, particularly in evaluating disease activity and pulmonary/renal involvements.

Serum Human Epididymis Protein 4 as a Novel Biomarker in Identifying Patients With Interstitial Lung Disease in Rheumatoid Arthritis

“…Further, high levels of HE4 can stratify patients into SSc-ILD subsets (10). We also showed that HE4 can identify primary Sjögren's syndrome (pSS) patients at risk of pulmonary/renal involvements (11). Taken together, these…”

“…Human epididymis protein 4 has been widely utilized as an effective biomarker in the diagnosis and follow-up of patients with ovarian cancer. Of interest, accumulating evidence suggest that HE4 may also has diagnostic potential in other clinical settings, including lung adenocarcinomas ( 17 ), renal fibrosis ( 18 ), cystic fibrosis ( 19 ), as well as autoimmune-related organ involvements, such as SSc-ILD ( 10 ) and pSS-related pulmonary/renal involvements ( 11 ). In this study, we extended the clinical application of HE4 into the diagnosis of RA.…”

“…Further, high levels of HE4 can stratify patients into SSc-ILD subsets ( 10 ). We also showed that HE4 can identify primary Sjögren's syndrome (pSS) patients at risk of pulmonary/renal involvements ( 11 ). Taken together, these findings suggest that HE4 may have a diagnostic potential in disease stratification in patients with autoimmune diseases.…”

Human epididymis protein 4 (HE4) is a novel biomarker for fibrosis in IgG4-related disease and can predict poor prognosis

“…HE4 is a widely used and high-value biomarker for diverse neoplastic diseases, and recent reports indicate that elevated HE4 levels occur in a variety of autoimmune diseases, including SLE, 11 RA 13 and pSS. 12 Available evidence also indicates that it is closely related to concurrent interstitial lung disease and renal involvement. As IgG4-RD is an immune-mediated fibroinflammatory disease, 21 we hypothesised that HE4 might be a potential biomarker for IgG4-RD and evaluated its utility.…”

“…Congruently, HE4 was found to be elevated in some autoimmune diseases, including systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and rheumatoid arthritis (RA), and notably, this increase was greater in patients with SLE with lupus nephritis 11 patients with pSS and patients with RA with interstitial lung disease. 12 13 HE4 has also been recently recognised as a biomarker for fibrotic disease and is reportedly involved in the aetiopathology of fibrotic diseases because fibroblast-derived HE4 has protease inhibitor activity that can promote the aggregation of collagen and cause fibrosis. 14 15 Based on these observations, and the fact that IgG4-RD is a recognised immune-mediated fibroinflammatory disease, we hypothesised that HE4 may play a role in IgG4-RD fibrosis and that it may be a potential biomarker for this disease.…”