Serum Uric Acid as a Diagnostic Biomarker for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

Previous studies have suggested a correlation between uric acid (UA) and lung lesion in some diseases. However, it remains unknown whether UA contributes to the lung injury in rheumatoid arthritis (RA). Our study aimed to investigate the clinical value of the UA level in the severity of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We measured UA in serum and bronchoalveolar lavage fluid (BALF), and UA levels of subjects were compared. As for the role of UA on ILD, we incubated A549 cells with UA and the expression of EMT markers was measured by immunofluorescence staining. The concentrations and messenger RNA expression of IL-1, IL-6, and transforming growth factor-β (TGF-β) were measured by ELISA and RT-PCR, respectively. We observed that serum UA levels in RA were significantly higher than those in controls. And, higher UA was measured in both serum and BALF of patients with RA-ILD, particularly those with interstitial pneumonia (UIP) pattern. Additionally, the correlation of the serum and BALF UA levels with serum KL-6, a biomarker of ILDs, in RA was significant (r = 0.44, p < 0.01; r = 0.43, p < 0.01). And, the negative correlations of UA, in both serum and BALF, with forced vital capacity (r =  -0.61, p < 0.01; r =  -0.34, p < 0.01) and diffusing capacity for carbon monoxide (r =  -0.43, p < 0.01; r =  -0.30, p < 0.01) were measured in patients. In the ROC curve analysis, the AUC value of UA for RA-ILD was 0.744 (95% CI: 0.69-0.80; p < 0.01), and the AUC of serum UA for predicting UIP pattern of patients with RA-ILD was 0.845 (95% CI: 0.78-0.91; p < 0.01), which showed the significance of the UA in clinical settings. Also, the in vitro experiment showed that UA induced epithelial-to-mesenchymal transition (EMT) and production of IL-1, IL-6, and TGF-β in A549 cells. Therefore, the elevated UA levels may be a diagnostic marker in RA-ILD, particularly RA-UIP.

Wang Z ，Wang W ，Xiang T ，Gong B ，Xie J ... -  《-》

Plasma IL-36α and IL-36γ as Potential Biomarkers in Interstitial Lung Disease Associated with Rheumatoid Arthritis: a Pilot Study in the Chinese Population.

Interstitial lung disease (ILD) is a frequent extra-articular manifestation of rheumatoid arthritis (RA) and increases mortality in patients with RA. Early identification of ILD, especially the usual interstitial pneumonia (UIP) pattern with a poor prognosis, is important for guiding treatment of RA-ILD and preventing damage resulting from a delay in diagnosis. Interleukin-36 (IL-36) cytokines are involved in connective tissue diseases. However, IL-36 expression in RA-ILD is unknown. In this study, the clinical relevance of plasma IL-36 cytokines was evaluated in 39 patients with RA-ILD and three other groups (30 healthy controls [HCs], 35 RA patients without ILD, and 27 patients with idiopathic pulmonary fibrosis [IPF]) in the Chinese population. Plasma IL-36α and IL-36γ concentrations were elevated in patients with RA-ILD compared with those in HCs and patients with RA. RA-ILD patients with UIP pattern had higher plasma IL-36γ concentrations than those with RA-ILD without UIP, but these were lower than those in patients with IPF. Receiver operating curve analysis suggested that IL-36α and IL-36γ were potential biomarkers for identifying ILD in patients with RA. Additionally, the optimal cutoff value of IL-36γ for distinguishing RA-ILD with the UIP pattern from RA-ILD without UIP was 555.40 pg/mL and that for distinguishing RA-ILD from IPF was 655.10 pg/mL. No significant difference in plasma IL-36β or IL-36Ra concentrations was found between patients with RA-ILD and the three other groups. We also found that the lungs originating from different types of patients with PF, including RA-ILD and IPF, and those from mice following bleomycin-induced PF were characterized by increased IL-36γ expression. Our findings suggest that using IL-36 cytokines to identify patients with RA for further ILD workups may provide additional diagnostic value to the current clinically available assays. Moreover, IL-36γ may help to identify the presence of the UIP pattern in patients with RA-ILD and to discriminate RA-ILD from IPF.

Zheng W ，Hu X ，Zou M ，Hu N ，Song W ，Wang R ，Liu Y ，Hou Q ，Liu Y ，Chen X ，Cheng Z ... -  《-》

Soluble programmed death molecule 1 (sPD-1) as a predictor of interstitial lung disease in rheumatoid arthritis.

Previous studies have indicated that the programmed death molecule 1 (PD-1) signaling pathway may play a key role in rheumatoid arthritis (RA). However, the pathogenesis of rheumatoid arthritis-related interstitial lung disease (RA-ILD) is not clear. We examined the serum levels of soluble PD-1 in patients with RA and its relationship with RA-ILD. Blood samples were obtained from 87 patients with RA (58 with ILD and 29 without ILD) and 45 healthy controls. Serum sPD-1 was measured by Enzyme-Linked Immunosorbent Assay. The pulmonary interstitial disease score was completed by a pulmonary physician and a radiologist through chest high-resolution computed tomography. Patients with RA-ILD were tested for lung function [e.g., forced vital capacity (FVC%), diffusing capacity of lungs for carbon monoxide (DLCO%)]. Associations between ILD and various markers, including sPD-1 and confounding factors, were investigated by logistic regression analysis. Diagnostic values of sPD-1 for the presence of ILD were investigated using receiver operating characteristic curve analysis. Serum sPD-1 levels were higher in RA patients with ILD than in RA patients without ILD and healthy controls (185.1 ± 109.0 pg/ml vs. 119.1 ± 77.5 pg/ml vs. 52.1 ± 21.7 pg/ml, P < 0.05). Serum sPD-1 levels were positively correlated with RF titer (P = 0.02, r = 0.249), anti-cyclic citrullinated peptide antibody status (P = 0.02, r = 0.243), and serum IgG levels (P < 0.001, r = 0.368), negatively associated with FVC% (P = 0.02, r = - 0.344), forced expiratory volume (FEV1%) (P  = 0.01, r = - 0.354), total lung capacity (TLC%) (P = 0.046, r = - 0.302), and was independently associated with the presence of ILD in RA patients by multivariate logistic regression analysis. The sensitivity and specificity of sPD-1 levels for the detection of ILD in RA patients were 58.6% and 75.9%, respectively. The area under the curve was 0.689. Serum sPD-1 levels were increased in RA patients with ILD. Increased sPD-1 may be a valuable biomarker to predict the presence of ILD in patients with RA.

Xu L ，Jiang L ，Nie L ，Zhang S ，Liu L ，Du Y ，Xue J ... -  《BMC IMMUNOLOGY》

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》

Fragmented gelsolins are increased in rheumatoid arthritis-associated interstitial lung disease with usual interstitial pneumonia pattern.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) occurs in 10%-30% of patients with RA, and interstitial lung disease (ILD) is associated with increased mortality in up to 10% of patients with RA. The pathogenesis of RA-ILD is virtually unknown. The aim of this study is to investigate the proteins related to UIP pattern by comparing to OP pattern in RA-ILD using proteome analysis of bronchoalveolar lavage fluid (BALF). Proteomic differences in BALF were compared between the UIP pattern and OP pattern by examining BALF from 5 patients with the UIP pattern and 7 patients with the OP pattern by two-dimensional gel electrophoresis and mass spectrometry. In individual comparisons of BALF samples, the levels of the protein gelsolin and Ig kappa chain C region were significantly higher in the UIP pattern than in the OP pattern. In contrast, the levels of α-1 antitrypsin, CRP, haptoglobin β, and surfactant protein A (isoform number 5) were all significantly higher in the OP pattern than in the UIP pattern. Gelsolin was cleaved into two fragments, a C-terminal half and N-terminal half, and the levels of both were significantly higher in the UIP pattern than in the OP pattern. Fragmented gelsolins may be associated with the pathogenesis of fibrosis in RA-ILD.

Suhara K ，Miyazaki Y ，Okamoto T ，Ishizuka M ，Tsuchiya K ，Inase N ... -  《-》