Complication Of Connective Tissue Diseases Research Articles

Immunological characteristics of bronchoalveolar lavage fluid and blood across connective tissue disease-associated interstitial lung diseases.

Interstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). The heterogeneity of ILDs reflects differences in pathogenesis among diseases. This study aimed to clarify the characteristics of CTD-ILDs via a detailed analysis of the bronchoalveolar lavage fluid (BALF) and blood immune cells. BALF and blood samples were collected from 39 Japanese patients with newly diagnosed ILD: five patients with Sjögren's syndrome (SS), eight patients with dermatomyositis (DM), six patients with rheumatoid arthritis (RA), six patients with systemic sclerosis, four patients with anti-neutrophil cytoplasmic antibody-associated vasculitis, and 10 patients with idiopathic interstitial pneumonia. We performed single-cell RNA sequencing to analyze the gene expression profiles in these patients' immune cells. In patients with SS, B cells in the BALF were increased and genes associated with the innate and acquired immunity were enriched in both the BALF and blood. In contrast, patients with DM showed an upregulation of genes associated with viral infection in both the BALF and blood. In patients with RA, neutrophils in the BALF tended to increase, and their gene expression patterns changed towards inflammation. These disease-specific characteristics may help us understand the pathogenesis for each disease and discover potential biomarkers.

The impact of Marfan syndrome and Ehlers-Danlos syndrome on the risk of penile fracture in patients between 18 and 45 years.

Despite knowledge of the pathophysiology and clinical complications of connective tissue diseases (CTD), little is known regarding their impact on men's sexual health disorders. To investigate the prevalence of penile fracture (PF) in patients with Ehlers-Danlos Syndrome (EDS) and Marfan syndrome (MFS) in comparison with disease-free controls between 18 and 45years of age. A multicenter, international, electronic health record network (TriNetX) was queried to identify adult male patients (between 18 and 45years) with or without EDS and MFS between 1993 and 2023 using ICD-10 codes. The prevalence of PF was compared between patients with and without the diseases of interest. Prevalence ratios (PR) were generated with 95% confidence intervals. Prevalence of PF in patients with EDS and MFS when compared to disease-free controls. The number of patients with EDS, MFS, and control groups was 8060, 8642, and 20 184 547, respectively, with a mean age of 27.8 ± 7.58, 28.6 ± 7.4, and 31.6 ± 8.04years. Men with EDS had a higher prevalence of PF (PR 30.18, 95% CI [17.08-53.19]; P < 0.0001). Similarly, men with MFS had a higher prevalence of PF (PR 23.4, 95% CI [12.6-43.7]; P < 0.0001). This study demonstrates an association between CTD and men's sexual health disorders. It may be important to counsel such men about the risks of PF. This is the largest study to date to demonstrate an association between CTD and men's sexual health disorders. While the large sample sizes in this study contribute to the robustness of the findings, the study is limited by the use of a claims-based dataset, which does not provide further details about disease course and complications, and the use of a univariate analysis only. Patients with EDS and MFS are possibly at an elevated risk for PF. Due to the limitations of the TriNetX database, the analysis was limited to a univariate one, thus limiting the ability to control for confounders and limiting the generalizability of these findings. Further prospective research is needed to corroborate these findings.

The role of immune cells in the pathogenesis of connective tissue diseases-associated pulmonary arterial hypertension.

Connective tissue diseases-related pulmonary arterial hypertension (CTD-PAH) is a disease characterized by an elevated pulmonary artery pressure that arises as a complication of connective tissue diseases. The number of patients with CTD-PAH accounts for 25.3% of all PAH patients. The main pathological features of CTD-PAH are thickening of intima, media and adventitia of pulmonary arterioles, increased pulmonary vascular resistance, autoimmune activation and inflammatory reaction. It is worth noting that abnormal immune activation will produce autoantibodies and release cytokines, and abnormal immune cell recruitment will promote inflammatory environment and vascular remodeling. Therefore, almost all forms of connective tissue diseases are related to PAH. In addition to general therapy and targeted drug therapy for PAH, high-dose glucocorticoid combined with immunosuppressant can quickly alleviate and stabilize the basic CTD-PAH disease. Given this, the development of therapeutic approaches targeting immune dysregulation and heightened inflammation is recognized as a promising strategy to prevent or reverse the progression of CTD-PAH. This review explores the potential mechanisms by which immune cells contribute to the development of CTD-PAH and examines the clinical application of immunosuppressive therapies in managing CTD-PAH.

Lunch Symposium

Pulmonary arterial hypertension (PAH), defined as the presence of artery pulmonary artery pressure &gt; 20 mmHg, pulmonary artery wedge pressure [Formula: see text]15 mmHg, and pulmonary vascular resistance (PVR) &gt; 2Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjögren’s syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of CTD-PAH proposed worldwide. This symposium would highlight the most updated 2022 ESC/ERS guideline in the disease management of PAH, including latest haemodynmaic definitions of PAH, new risk stratification approach at reassessment and updated PAH treatment recommendations. In addition to the guideline update, important discussion would cover the important diagnostic, and screening algorithm for early detection of CTD-PAH and clinical experiences in managing difficult CTD-PAH cases.

Clinical significance of interleukin-6, total bilirubin, CD3 + CD4 + T cells counts in the acute exacerbation of connective tissue disease-associated interstitial lung disease: a cross-sectional study

ObjectiveInterstitial lung disease (ILD) is a severe complication of connective tissue disease (CTD) that can significantly impact patients' prognosis and quality of life. However, the current diagnostic arena lacks reliable biomarkers for detecting and monitoring the progression and exacerbation of CTD-ILD. This study aimed to investigate the clinical value of 12 serum cytokines in the diagnosis of CTD-ILD and prediction of the risk of acute exacerbation (AE) in this disease.MethodsThis study was a cross-sectional investigation. Ninety-one hospitalized CTD patients were allocated into two groups: CTD-ILD group (n = 61) and CTD-non-ILD group (n = 30), and 30 sex-age matched healthy volunteers were enrolled as controls. The serum concentrations of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, and IL-1β were measured by Luminex suspension arrays. Logistic regression was employed to determine the significance of variables in the occurrence of AE-CTD-ILD. A nomogram was constructed to visualize the independent variables.ResultsElevated levels of IL-6, IL-8, and TNF-α were observed and compared in the CTD-ILD group with CTD-non-ILD (all P < 0.05). Similarly, the levels of IL-6, IL-8 and TNF-α were higher in the acute exacerbation (AE-CTD-ILD) group compared with stable CTD-ILD (S-CTD-ILD) (P < 0.001, P < 0.001, and P = 0.022). Significant correlations between serum IL-6 and PaO2/FiO2 ratio (r = − 0.463, P < 0.001), percent predicted forced vital capacity (FVC%; r = − 0.362, P < 0.05), and total ground-glass opacity (GGO) score (r = 0.439, P < 0.001) were observed in CTD-ILD patients. Multivariate logistic regression analysis revealed that elevated IL-6 levels, total bilirubin (TBil), and decreased CD3 + CD4 + T cells counts were independent risk factors for the occurrence of AE-CTD-ILD (OR = 1.121, P = 0.024; OR = 1.865, P = 0.047; OR = 0.983, P = 0.037, respectively). Furthermore, by employing these three variables in combination for the prediction of AE status, their collective impact surpasses the independent effects of any single biomarker.ConclusionsElevated levels of serum IL-6, IL-8, and TNF-α were associated with the complication of ILD in CTD patients and the occurrence of AE in CTD-ILD patients. IL-6 could be a promising serum biomarker of severity and the occurrence of AE in CTD-ILD patients. The combination of the three variables (IL-6 level, TBil and CD3 + CD4 + T cells) predicted the AE-CTD-ILD better.

Recent Advances in the Treatment of Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases.

Pulmonary hypertension (PH) is a severe vascular complication of connective tissue diseases (CTD). Patients with CTD may develop PH belonging to diverse groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) secondary PH due to lung disease and/or hypoxia and (4) chronic thromboembolic pulmonary hypertension (CTEPH). PAH most often develops in systemic scleroderma (SSc), mostly in its limited variant. PAH-CTD is a progressive disease characterized by poor prognosis. Therefore, early diagnosis should be established. A specific treatment for PAH-CTD is currently available and recommended: prostacyclin derivative (treprostinil, epoprostenol, iloprost, selexipag), nitric oxide and natriuretic pathway: stimulators of soluble guanylate cyclase (sGC: riociguat) and phosphodiesterase-five inhibitors (PDE5i: sildenafil, tadalafil), endothelin receptor antagonists (ERA: bosentan, macitentan, ambrisentan). Moreover, novel drugs, e.g., sotatercept, have been intensively investigated in clinical trials. We aim to review the literature on recent advances in the treatment strategy and prognosis of patients with PAH-CTD. In this manuscript, we discuss the mechanism of action of PAH-specific drugs and new agents and the latest research conducted on PAH-CTD patients.

Long-Term Survival of Patients with Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: A Single-Center Cohort.

Pulmonary arterial hypertension (PAH) is a rare but severe complication of connective tissue disease (CTD). CTD-associated PAH (CTD-PAH) is the most common subgroup of PAH in East Asia. We prospectively collected 41 patients with CTD-PAH and followed them for a mean period of 43 ± 36 months. The long-term survival rates of the CTD-PAH patients at 1, 2, 3 and 5 years were 90%, 80%, 77%, and 60%, respectively. The non-survivors had more dilated main pulmonary arteries, higher pulmonary artery pressure and pulmonary vascular resistance (PVR). PAH-specific therapy resulted in improvements in functional class, 6-minute walk distance, serum uric acid, right ventricular function and PVR. Increased C-reactive protein during follow-up, indicating inflammatory processes, was also crucial for the management of CTD-PAH. Therefore targeting both PAH and inflammation is important in this specific subgroup of PAH. The results of this study may help develop treatment strategies for CTD-PAH patients.

Proteomics: Potential techniques for discovering the pathogenesis of connective tissue diseases-interstitial lung disease.

Interstitial lung disease (ILD) is one of the most serious lung complications of connective tissue disease (CTD). The application of proteomics in the past decade has revealed that various proteins are involved in the pathogenesis of each subtype of CTD-ILD through different pathways, providing novel ideas to study pathological mechanisms and clinical biomarkers. On this basis, a multidimensional diagnosis or prediction model is established. This paper reviews the results of proteomic detection of different subtypes of CTD-ILD and discusses the role of some differentially expressed proteins in the development of pulmonary fibrosis and their potential clinical applications.

2023 Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) Joint Consensus on Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.

Serum Biomarkers in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening complication of connective tissue diseases (CTDs) characterised by increased pulmonary arterial pressure and pulmonary vascular resistance. CTD-PAH is the result of a complex interplay among endothelial dysfunction and vascular remodelling, autoimmunity and inflammatory changes, ultimately leading to right heart dysfunction and failure. Due to the non-specific nature of the early symptoms and the lack of consensus on screening strategies-except for systemic sclerosis, with a yearly transthoracic echocardiography as recommended-CTD-PAH is often diagnosed at an advanced stage, when the pulmonary vessels are irreversibly damaged. According to the current guidelines, right heart catheterisation is the gold standard for the diagnosis of PAH; however, this technique is invasive, and may not be available in non-referral centres. Hence, there is a need for non-invasive tools to improve the early diagnosis and disease monitoring of CTD-PAH. Novel serum biomarkers may be an effective solution to this issue, as their detection is non-invasive, has a low cost and is reproducible. Our review aims to describe some of the most promising circulating biomarkers of CTD-PAH, classified according to their role in the pathophysiology of the disease.

A study of the diagnostic value of a modified transthoracic lung ultrasound scoring method in interstitial lung disease.

Interstitial lung disease (ILD) is a serious complication of connective tissue disease (CTD) with significant morbidity and mortality. Lung ultrasound (LUS) has been widely used in the diagnosis of a variety of lung diseases. However, there is no standard ultrasound scanning method or scoring method for connective tissue disease associated with interstitial lung disease (CTD-ILD); therefore, it is necessary to establish a set of standard evaluation methods. A total of 60 consecutive patients with clinically confirmed CTD and suspected ILD were prospectively included in this study. LUS and high-resolution computed tomography (HRCT) were used to examine all patients. The time between HRCT and LUS examinations was less than 2 weeks. The ultrasonographic results were evaluated with the modified scoring method and the Buda scoring method. The imaging results were evaluated with the HRCT Warrick scoring method. The primary aim was to evaluate the diagnostic value of a modified ultrasound scoring method in CTD-ILD. The results of the Youden index for the diagnosis of CTD-ILD by the modified method, the Buda method, and the HRCT method were 0.845, 0.711, and 0.911, respectively, with areas under the receiver operating characteristic (ROC) curve (AUC) of 0.982 [95% confidence interval (CI): 0.945-1.000], 0.950 (95% CI: 0.851-0.990), and 0.985 (95% CI: 0.949-1.000), respectively. With a clinical diagnosis as the gold standard, the consistency of the modified method and the HRCT method for CTD-ILD was high (Kappa values =0.872 and 0.913, respectively). The values of the modified method and the Buda method consistently and significantly increased with the increasing severity of CTD-ILD. For the former, there were significant differences between the mild, moderate, and severe groups (P<0.05). The ROC curve used to calculate the modified ultrasound score predicted the critical values of mild and severe pulmonary fibrotic lesions at 34 points (sensitivity, 100%; specificity, 92.9%; AUC =0.933; 95% CI: 0.807-1.000) and 64.5 points (sensitivity, 92.0%; specificity, 85.3%; AUC =0.972; 95% CI: 0.929-1.000). The modified ultrasound method has a higher diagnostic value than the Buda method for CTD-ILD.

Identification and management of connective tissue disease-associated interstitial lung disease: evidence-based Japanese consensus statements

ABSTRACT Background Interstitial lung disease (ILD) is a common complication of connective tissue diseases (CTD), but there are few clinical trials to guide disease management. We aimed to develop expert consensus statements and an algorithm for CTD-ILD management. Research design and methods Based on a targeted literature review, we developed 109 statements on managing CTD-ILD across six domains. We used a modified Delphi process to survey 22 physicians in Japan involved in managing CTD-ILD (specialists in pulmonology, rheumatology, pathology, and radiology). These panelists participated in two rounds of web-based survey to establish consensus statements, which were used to define an algorithm. Consensus was defined as a mean value ≥70 on a scale of 0 (strong disagreement) to 100 (strong agreement). Results Between May–August 2022, consensus was reached on 93 statements on CTD-ILD management. The most important consensus statements included screening CTD patients for ILD (typically with high-resolution computed tomography), using imaging, pulmonary function testing and serum biomarkers for diagnosis and severity assessment, regularly following up patients, and multidisciplinary management of CTD-ILD. Consensus statements were interpreted into an algorithm for clinical guidance. Conclusions Using the Delphi process, we have developed consensus statements and an algorithm to guide clinical decision-making for CTD-ILD.

IL-22 inhibits bleomycin-induced pulmonary fibrosis in association with inhibition of IL-17A in mice

BackgroundInterstitial lung disease, a common extra-articular complication of connective tissue disease, is characterized by progressive and irreversible pulmonary inflammation and fibrosis, which causes significant mortality. IL-22 shows a potential in regulating chronic inflammation and possibly plays an anti-fibrotic role by protecting epithelial cells. However, the detailed effects and underlying mechanisms are still unclear. In this study, we explored the impact of IL-22 on pulmonary fibrosis both in vivo and in vitro.MethodsTo induce pulmonary fibrosis, wild-type mice and IL-22 knockout mice were intratracheally injected with bleomycin followed by treatments with recombinant IL-22 or IL-17A neutralizing antibody. We investigated the role of IL-22 on bleomycin-induced pulmonary fibrosis and the mechanism in the possible interaction between IL-22 and IL-17A. Fibrosis-related genes were detected using RT-qPCR, western blot, and immunofluorescence. Inflammatory and fibrotic changes were assessed based on histological features. We also used A549 human alveolar epithelial cells, NIH/3T3 mouse fibroblast cells, and primary mouse lung fibroblasts to study the impact of IL-22 on fibrosis in vitro.ResultsIL-22 knockout mice showed aggravated pulmonary fibrosis compared with wild-type mice, and injection of recombinant IL-22 decreased the severe fibrotic manifestations in IL-22 knockout mice. In cell culture assays, IL-22 decreased protein levels of Collagen I in A549 cells, NIH/3T3 cells, and primary mouse lung fibroblasts. IL-22 also reduced the protein level of Collagen I in NIH/3T3 cells which were co-cultured with T cells. Mechanistically, IL-22 reduced the Th17 cell proportion and IL-17A mRNA level in lung tissues, and treatment with an IL-17A neutralizing antibody alleviated the severe pulmonary fibrosis in IL-22 knockout mice. The IL-17A neutralizing antibody also reduced Collagen I expression in NIH/3T3 cells in vitro. Knockdown of IL-17A with siRNAs or administration of IL-22 in NIH/3T3 cells and MLFs decreased expression of Collagen I, an effect blocked by concurrent use of recombinant IL-17A.ConclusionsIL-22 mediated an anti-fibrogenesis effect in the bleomycin-induced pulmonary fibrosis model and this effect was associated with inhibition of IL-17A.

874 A NOT-SO-RARE COMPLICATION OF CONNECTIVE TISSUE DISEASE

Abstract Pulmonary hypertension is a not-so-rare complication of connective tissue diseases and is usually related with an inauspicious prognosis. We present the case of a 67-years-old woman hospitalized for progressive dyspnea. Two-dimensional echocardiography showed numerous features related to pulmonary hypertension (PH) with moderate Mitral Regurgitation. The right cardiac catheterization confirmed mixed PH (pre and post capillary) without chest angio-TC evidence of pulmonary thromboembolism. Thanks to optimized medical therapy (B-Blocker, ACE-i and diuretics), there was a significant clinical improvement documented at discharge. After 1 year, due to recurrence of dyspnea, she was admitted to our medical unit. Her clinical examination showed some of the characteristics of a connective tissue disease. Compared to previous echocardiography, a moderate to mild reduction of MR was documented. Chest CT scan revealed interstitial lung disease likely related to patient's underlying pathology. Immunological screening tests detected the presence of antinuclear (ANA) and anti-topoisomerase (ATA) antibodies. Right heart catheterization documented a worsening of PH with only pre-capillary component. On the basis of the above findings, a diagnosis of CREST syndrome complicated with PH was made, and the patient was started on oral combination of macitentan and riociguat. The frequency of this complication in connective tissue disease, the need for screening tests and different treatment approaches of pre and post capillary pulmonary hypertension is discussed.

Rituximab for connective tissue disease-associated interstitial lung disease

Interstitial lung disease (ILD) is one of the most frequent and severe visceral complications of connective tissue diseases (CTDs).1 Despite the recent approval of nintedanib for the treatment of fibrosing progressive ILDs other than idiopathic pulmonary fibrosis,2 management of CTD-ILDs remains challenging. While fibrosing ILD represents at least 50% of ILD cases in patients with rheumatoid arthritis, the frequency of fibrosing subsets in CTDs is significantly lower.1,3 Therefore, immunosuppressants continue to be the most commonly adopted therapy for CTD-ILDs.

Recommendations for the diagnosis and treatment of connective tissue disease associated pulmonary arterial hypertension in China

Pulmonary arterial hypertension (PAH) is a clinicopathological syndrome caused by the increase of pulmonary artery, and it is the most serious complication of connective tissue disease (CTD). In recent years, a lot of progress has been made in the diagnosis, treatment and evaluation of PAH. Chinese Rheumatology Association formulated this recommendation on the basis of current experience and guidelines, in order to promote early screening, early diagnosis and early intervention of CTD-PAH, as well as patient follow-up and management, to improve the prognosis of CTD-PAH patients.

Serum MMP-9, SP-D, and VEGF levels reflect the severity of connective tissue disease-associated interstitial lung diseases

BackgroundInterstitial lung disease (ILD) is a common pulmonary complication of connective tissue disease (CTD). This study aims to evaluate the clinical diagnostic value of matrix metalloproteinase-9 (MMP-9), surfactant protein-D (SP-D), and vascular endothelial growth factor (VEGF) as potential biomarkers for CTD-ILD.MethodsThis research included 33 CTD-ILD patients, 31 CTD patients without ILD, and 24 healthy control subjects. Then, the value of biomarkers for the diagnosis and evaluation of CTD-ILD was assessed through high-resolution computed tomography (HRCT) findings and pulmonary function test (PFT) parameters.ResultsThe serum MMP-9, SP-D, and VEGF levels in the CTD-ILD group were higher than those in the CTD-NILD group and healthy group. The ROC curve indicates that VEGF has good to excellent diagnostic performance in diagnosing CTD-ILD, the cut-off that best optimizes sensitivity and specificity in diagnosing CTD-ILD is 277.60 pg/ml (sensitivity, 87.9%; specificity, 83.6%), with an area under the curve (AUC) of 0.905 (95% confidence interval (CI) 0.842–0.968); The ROC curve for MMP-9 suggests this biomarker is fair for diagnosis of CTD-ILD(sensitivity, 81.8%; specificity, 81.8%), with an AUC of 0.867 (95% CI 0.784–0.950), but SP-D only provided lower specificity with higher sensitivity in diagnosing CTD-ILD(sensitivity, 90.9%; specificity, 40.0%). The different serum biomarkers are more specific and sensitive when combined to diagnose ILD. The semiquantitative score for the degree of ILD severity on HRCT was positively correlated with SP-D and VEGF levels (r = 0.461, P = 0.007; r = 0.362, P = 0.039), and serum MMP-9 levels were elevated in the UIP subgroup compared to the non-UIP subgroup. The percentage of diffusing capacity of the lung for carbon monoxide (DLco) (% predicted) had a negative correlation with the SP-D level (r = − 0.407, P = 0.044) and a statistically negative correlation between MMP-9 and the forced vital capacity (FVC) (r = − 0.451, P = 0.024).ConclusionsSerum MMP-9, SP-D, and VEGF levels may have clinical value in screening and evaluating the severity of CTD-ILD.

Screening value of lung ultrasound in connective tissue disease related interstitial lung disease

BackgroundInterstitial lung disease (ILD) is a common pulmonary complication of connective tissue disease (CTD) that can lead to poor quality of life and prognosis. ObjectivesTo explore the screening value of lung ultrasound (LUS) for connective tissue disease-associated interstitial lung disease (CTD-ILD). MethodsData of patients with CTD were collected, and each patient underwent LUS, high-resolution computed tomography (HRCT), and pulmonary function tests. Considering HRCT is the gold standard for diagnosing CTD-ILD, patients were divided into CTD-ILD and CTD-non-ILD groups. The LUS and HRCT results were assessed using semiquantitative and Warrick scores, respectively. Pulmonary function results were also collected. Receiver operating characteristic (ROC) curves were used to evaluate the accuracy of LUS diagnosis. Spearman correlation analysis was used to analyze the correlation between LUS, HRCT, and lung function indices. ResultsA total of 88 patients (65 with CTD-ILD and 23 with CTD-non-ILD) were included in this study. The sensitivity and specificity of LUS for the diagnosis of CTD-ILD were 86.60% and 82.60%, respectively, which was consistent with the HRCT results (P < 0.05). The LUS results (total number of B-lines, frequency of B-line, pleural thickness, and pleural-line irregularity) were positively correlated with the HRCT Warrick score (r = 0.77, 0.76, 0.65 and 0.71, P < 0.05). ConclusionsLUS may be a promising tool for screening patients with CTD-ILD.

Effect of Baricitinib on the epithelial-mesenchymal transition of alveolar epithelial cells induced by IL-6

ObjectiveInterstitial lung disease (ILD) is one of the common complications of Connective tissue disease (CTD). Epithelial-mesenchymal transition (EMT) is one of the main pathological mechanisms of ILD. IL-6 may induce ILD through the JAK/STAT pathway. Therefore, exploring the mechanism of IL-6 on the EMT of alveolar epithelial cells and inhibition JAK/STAT pathway with Baricitinib on the EMT of alveolar epithelial cells is helpful in revealing the pathogenesis of CTD-ILD and guiding treatment. MethodsElectrochemiluminescence was applied to detect the changes in serum IL-6 levels before and after treatment in 37 patients with anti-synthetase syndrome-associated ILD; A549 cells (a human AEC cell line) were incubated with IL-6, Baricitinib, or both IL-6 and Baricitinib, and changes in EMT-related markers levels were measured using real-time PCR, western blotting and fluorescence microscopy. The related proteins in the JAK/STAT signaling pathways were examined by western blot. The level of Connective tissue growth factor (CTGF) and Hydroxyproline (Hyp) in cell supernatants was measured by ELISA. ResultsSerum IL-6 level in patients with anti-synthetase syndrome-associated ILD was significantly higher than that in health (6.78(4.19, 16.14)pg/ml vs. 2.10(1.43, 5.18)pg/ml, p < 0.01). The level of IL-6 in the improvement group of ASS-ILD was considerably decreased than that before treatment(before(7.48(4.54, 22.76) pg/mL vs. 5.00(3.46, 11.32)pg/mL, p < 0.01), p < 0.01), and the level of IL-6 in the progressive group of ASS-ILD was significantly higher than that before treatment(before(7.49(6.77, 35.80) pg/mL vs. 30.02(8.01, 82.98) pg/mL, p < 0.05). IL-6 increased the expression of epithelial phenotypic marker E-cadherin and inhibited mesenchymal phenotypic markers, including vimentin and N-cadherin in A549 cells. Moreover, IL-6-induced EMT was attenuated by Baricitinib. Furthermore, we found that IL-6 activated the phosphorylation of JAK1/2, STAT3, and Baricitinib, partially inhibiting these changes in this process. Baricitinib reduced the secretion of CTGF and Hyp in A549 cells. ConclusionThe significant higher level of IL-6 in patients with anti-synthase syndrome-associated ILD may be related to disease activity and recurrence. Our results suggest that Baricitinib attenuates epithelial-mesenchymal transition in alveolar epithelial cells in the presence of IL-6 through the JAK/STAT signaling pathway.

Evaluation of connective tissue disease-related interstitial lung disease using ultrasound elastography: a preliminary study.

Interstitial lung disease (ILD) is a common pulmonary complication of connective tissue disease (CTD), which can lead to shortened survival. This article explores the ability of shear wave elastography (SWE) to assess lung surface elastic properties and to distinguish healthy lungs from diseased lungs with connective tissue disease-related interstitial lung disease (CTD-ILD). We aimed to determine whether SWE can be used to assess the severity of CTD-ILD. A total of 65 CTD-ILD patients and 60 healthy volunteers were included for the case group and the control group, respectively. All participants underwent lung ultrasound (count of B-line and measurement of pleural line thickness) and SWE [measurement of Young's modulus (Emean) and shear wave velocity (SMV) (Cmean)] examinations at 50 lung sites. All participants also underwent an examination with high-resolution computed tomography (HRCT) and a pulmonary function test (PFT). For SWE assessment, the Q-box was set to its minimum size (1 mm) and manually placed on the pleural line, rather than inside the lung, to measure the stiffness of the lung surface. The intra- and inter-reliability of SWE measurements of healthy controls (HC), the receiver operating characteristic (ROC) curve for SWE for CTD-ILD, and correlations between different assessment methods were analyzed. Excellent intra- and inter-reliability of SWE measurements on the mid-anterior lung site of HCs (correlation coefficient >0.97; P<0.01) were found. The results of the lung ultrasound of case group participants were significantly higher than those of HCs at each site (P<0.001). The SWE results revealed a significant increase in both Emean and Cmean in CTD-ILD patients (P<0.001) compared with HCs at certain sites (P<0.001). The areas under the curve (AUC) of Emean and Cmean for CTD-ILD were 0.646 and 0.647 (P<0.05), respectively, and the cutoff values for Emean and Cmean to distinguish CTD-ILD from healthy lungs were 15.81 kPa and 2.31 m/s, respectively. There was no significant correlation between the SWE measured values and the number of B-lines, or the HRCT and PFT results, respectively (P>0.05). As a noninvasive ultrasound elastography (UE) technique, SWE may provide a novel method to differentiate CTD-ILD-affected lungs and healthy lungs. It is a reliable way to measure the stiffness of a healthy lung surface in the supine position. However, the ability of SWE to evaluate the severity of CTD-ILD may be limited.