Loss of mucosal tolerance to glycoprotein 2 isoform 1 is a potential novel diagnostic biomarker for cholangiocarcinoma.

BACKGROUND: Anti-glycoprotein 2 (anti-GP2) IgA and antineutrophil-cytoplasmic antibodies to proteinase 3 (PR3-ANCA) have been reported as predictive markers of cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC), but their prevalence in CCA patients without PSC remains unclear. METHODS: This study involved Asian discovery (n = 118) and European validation (n = 38) cohorts of CCA patients without PSC, alongside 49 Asian and 82 European pancreatic ductal adenocarcinoma (PDAC) patients, 21 with benign pancreatic neoplasms (BPN) and 45 with hepatocellular carcinoma (HCC), and 157 healthy controls (HC) from Asia and Europe. We analyzed the prevalence of PR3-ANCA, IgA and IgG against GP21 and GP24, and the CA19-9 levels. RESULTS: Anti-GP21 IgA was the most prevalent in both CCA cohorts (discovery: 55.1 %; validation: 42.1 %) and significantly higher than in other groups except PDAC (all p < 0.05). It demonstrated the best diagnostic performance in distinguishing CCA from disease controls and HC, outperforming tumor markers. No significant correlation was found between anti-GP21 IgA levels and CA19-9 levels. CONCLUSION: Our findings show that anti-GP21 IgA revealing the loss of mucosal tolerance is a potential novel diagnostic biomarker for CCA.

Antibodies against neutrophil extracellular traps (NETs) potentiate clinical performance of anti-double-stranded DNA antibodies in systemic lupus erythematosus.

Autoantibodies against NETs (ANETA) are present in SLE patients. We aimed to determine the clinical relevance of ANETA in SLE. Serum from 129 SLE patients, 161 patients with various rheumatoid diseases (DC), and 53 healthy controls (HC) were tested by a home-made ANETA ELISA platform. ANETA showed a sensitivity of 35.7% and a specificity of 92.5%, respectively, in the diagnosis of SLE. The combination of ANETA with anti-dsDNA antibody increased the diagnostic sensitivity from 49.6% to 62.8% for SLE. The presence of ANETA potentiates the clinical utility of anti-dsDNA antibodies in identifying a subset of SLE patients with higher disease activity and hematological abnormalities. The binding of ANETA to NETs did not inhibit the immunostimulatory effect of NETs. Our findings suggested that ANETA have potential as clinically relevant biomarkers that potentiate the clinical performance of anti-dsDNA antibodies in the diagnosis, risk stratification and subtyping of patients with SLE.

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

Objective: Human epididymis protein 4 (HE4) have been implicated in the pulmonary involvements. We aimed to investigate the clinical utility of HE4 in clinical stratification in patients with rheumatoid arthritis (RA). Methods: This study included a discovery cohort comprising 70 RA patients and 64 healthy controls (HCs), and a validation cohort comprising 98 RA patients and 75 HCs. Human epididymis protein 4 were determined by electrochemical luminescence analyzer. Results: The levels of HE4 were significantly elevated in patients with RA compared to HCs. The positive rates of HE4 in patients with RA and HCs were 50.0% and 0, respectively, in the discovery cohort and 53.1 and 1.3%, respectively, in the validation cohort. When RA patients were subgrouped according to HE4 status, HE4-positive group displayed higher prevalence of interstitial lung disease (ILD) compared to HE4-negative group (28.6 vs. 11.4% in discovery cohort and 57.7 vs. 8.7% in the validation cohort). A positive correlation between the levels of HE4 with the degree of lung impairment was identified. Receiver operating curve (ROC) analysis revealed an optimal cut-off value of 104.3 pmol/L in HE4 for distinguishing RA-ILD from RA-non ILD with the areas under the curve (AUC) of 0.790. Multivariate logistic regression analysis illustrated that high levels of HE4 independently identified patients with RA-ILD (OR, 9.080, p < 0.001). Conclusion: Our findings showed a novel role of HE4 in RA risk stratification, suggest that introducing HE4 to the current RA test panel may serve as an indicator in identifying RA patients for further RA-ILD workups, such as high-resolution computed tomography (HRCT).

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

Background: We 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). Methods: A 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. Findings: The 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). Conclusions: Our 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.

Elevated Serum Small Dense Low-Density Lipoprotein Cholesterol May Increase the Risk and Severity of Coronary Heart Disease and Predict Cardiovascular Events in Patients with Type 2 Diabetes Mellitus.

BACKGROUND: Coronary heart disease (CHD) is a common and severe complication in type 2 diabetes mellitus (T2DM) patients. Increased amount of circulatory small dense low-density lipoprotein cholesterol (sdLDL-C) particles is known to be a sign of dyslipidemia and can result in atherosclerosis. However, the association between serum sdLDL-C levels and CHD in T2DM patients remains unclear. METHODS: A total of 3684 T2DM patients who received selective coronary angiography (CAG) were selected. For analyzing the association between sdLDL-C and CHD severity in T2DM, the patients with CHD were further divided into four subgroups according to the quartiles of sdLDL-C. A multivariate logistic regression was used for analyzing the risks and severity of CHD. A total of 3427 patients with continuous stable CHD were recruited and followed up for 5 years. RESULTS: Serum sdLDL-C levels in the CHD group were significantly increased compared with those in the non-CHD group [0.80 (0.49) mmol/L vs. 0.70 (0.30) mmol/L, p < 0.001]. The results from CHD subgroup analysis indicated that the sdLDL-C levels in patients with multiple-vessel disease and high Gensini score (GS) were significantly increased. By adjusting the confounding factors and analyzing with multiple logistic regression, we found that sdLDL-C independently correlated with the presence and severity of CHD (CHD: OR = 2.257; multiple-vessel disease: OR = 3.288; high GS: OR = 2.554). A total of 484 major cardiovascular events (MACEs) were documented. After Kaplan-Meier analysis and chi-squared analysis, the incidence of MACEs in the high sdLDL-C group was higher than that in the low sdLDL-C group (16.04% vs. 12.25%, p = 0.002). CONCLUSION: In T2DM patients, elevated serum sdLDL-C may increase the severity of CHD and predict cardiovascular events in the future. Therefore, serum sdLDL-C may be a potential biomarker for the surveillance of CHD in T2DM patients.

Use of the Nuclear Matrix Protein 22 BladderChek Test for the Detection of Primary and Recurrent Urothelial Carcinoma.

OBJECTIVE: To evaluate the performance of the nuclear matrix protein 22 (NMP22) BladderChek test in urothelial carcinoma (UC). METHODS: We retrospectively analyzed 1318 patients who performed the NMP22 BladderChek tests. Of them, 103 were primary UC patients, 90 were surgical treatment UC patients, and 1125 were benign disease patients. The performance of the NMP22 BladderChek test for the diagnosis of primary and recurrent UC was evaluated. Moreover, the performance of urine cytology and the NMP22 BladderChek test for the diagnosis of primary UC was compared in 90 available subjects including 48 primary UC patients and 42 benign disease patients. RESULTS: The sensitivity and specificity of the NMP22 BladderChek test were 37.9% and 95.8%, respectively, for the diagnosis of primary UC (n = 1228). The corresponding parameters of the NMP22 BladderChek test were 31.0% and 88.5%, respectively, for the diagnosis of recurrent UC (n = 90). The sensitivity and specificity of urine cytology were 54.2% and 97.6%, respectively, for the diagnosis of primary UC (n = 90); the corresponding parameters of the NMP22 BladderChek test were 41.7% and 83.3%, respectively; the corresponding parameters of the two tests combination were 64.6% and 83.3%, respectively. There was a significant difference in the performance between the NMP22 BladderChek test and urine cytology or the combination of two tests (P = 0.017 and 0.001, respectively). CONCLUSIONS: The NMP22 BladderChek test has a low sensitivity for detecting primary and recurrent UC. Urine cytology is superior to the NMP22 BladderChek test, and combined use of the two tests improves the sensitivity in the detection of primary UC.

The Imbalance of Circulating Follicular Helper T Cells and Follicular Regulatory T Cells Is Associated With Disease Activity in Patients With Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the colon and rectum, in which the abnormality of B cells is involved in both its pathogenesis and progression. Follicular helper T cells (TFH) play an important role in assisting the immune function of human B cells in germinal centers, and follicular regulatory T cells (TFR) have the function of inhibiting TFH and germinal center B cell responses. The significance of circulating TFH and TFR in ulcerative colitis (UC) remains unclear. We analyzed peripheral blood of active and stable remission UC patients and found that circulating TFR was significantly decreased while TFH was increased in active UC patients. As to TFH subsets, TFH2 was elevated while TFH17 was decreased in active UC, with IL-4/IL-17A secretion enhanced. Helios+ and CD45RA-FoxP3high TFR cells were decreased while CD226+ and CD45RA+FoxP3int TFR cells were increased in active UC patients. The levels of new memory B cells, plasmablasts and serum IgG were significantly increased in active UC patients, and were positively correlated with TFH and TFH2, and negatively correlated with TFR. Serum CRP and Mayo Clinic scores were positively correlated with TFH and TFH2 but negatively correlated with TFR. Serum IL-12 and IL-21 were up-regulated while IL-10 was down-regulated in active UC. To conclude, an imbalance of circulating TFH and TFR cells is associated with disease activity in UC patients. Our results suggest a new mechanism for TFH and TFR imbalance in the pathogenesis of UC, providing a new perspective for theoretical research and therapeutic strategies for UC.