Seasonal fluctuation of serum Krebs von den Lungen-6 levels in systemic sclerosis-associated interstitial lung disease.

AIM: To evaluate whether seasonal changes influence fluctuations in serum Krebs von den Lungen-6 (KL-6) levels in systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: Summer was defined as the period between July and September, and winter as between December and February. The study was conducted between 2015 and 2016, with a focus on these two seasons. A diagnosis of ILD and ILD progression overtime were evaluated using chest computed tomography. Among patients with SSc-ILD, those with data on serum KL-6 and lactate dehydrogenase (LDH) levels in the 2015 winter, 2015 summer, and 2016 winter seasons were included. Patients with comorbidities that could affect serum KL-6 levels were excluded. RESULTS: Of 60 patients with SSc-ILD, 52 (86.7%) had stable ILD, 5 (8.3%) had worsened ILD, and 3 (5.0%) had improved ILD. Serum KL-6 levels were significantly higher during the winter than those during the summer (2015 winter vs. 2015 summer: 649 U/mL vs. 585 U/mL, p < .0001; 2016 winter vs. 2015 summer: 690 U/mL vs. 585 U/mL, p < .0001). No significant differences were observed between the winters of 2015 and 2016 (649 U/mL vs. 690 U/mL, p = .78). However, serum LDH levels did not exhibit seasonal fluctuations (2015 winter vs. 2015 summer: 203 U/L vs. 199 U/L, p = .3; 2016 winter vs. 2015 summer: 201 U/L vs. 199 U/L, p = .6; 2015 winter vs. 2016 winter: 203 U/L vs. 201 U/L, p = .24). CONCLUSION: Seasonal fluctuations in serum KL-6 levels were observed in patients with SSc-ILD.

Soluble CXCL16 is a prognostic biomarker associated with rapidly progressive interstitial lung disease complicated with dermatomyositis.

OBJECTIVES: Rapidly progressive interstitial lung disease (RPILD) in patients with dermatomyositis (DM) significantly impacts prognosis, leading to high mortality rates. Although several indicators have been demonstrated to strongly correlate with the risk of developing RPILD, their clinical utility still needs to be investigated. The objective of this study was to investigate the clinical significance of soluble CXCL16 (sCXCL16) in DM patients complicated with RPILD. METHODS: Serum sCXCL16 was measured by enzyme-linked immunosorbent assay in 96 patients with DM and 55 matching healthy donors. Correlations between sCXCL16 levels and clinical features, laboratory examinations and the predictive value of baseline sCXCL16 level for RPILD were analysed. RESULTS: The serum sCXCL16 levels were significantly higher in patients with DM (n = 96, 3.264 ± 1.516 ng/mL) compared with healthy donors (n = 55, 1.781 ± 0.318 ng/mL), especially in DM complicated with RPILD (n = 31, 4.441 ± 1.706 ng/mL). The sCXCL16 levels were positively correlated with levels of serum ferritin, C reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase, hydroxybutyrate dehydrogenase, and negatively correlated with peripheral lymphocytes percentage, but showed no correlation with levels of anti-melanoma differentiation-associated gene 5 antibody, Krebs von den Lungen-6 or creatine kinase. Multivariable analysis showed that elevated sCXCL16 was an independent prognostic factor for poor prognosis of RPILD in patients with DM. The 2-year survival rate was significantly lower in patients with high sCXCL16 level than in those with low sCXCL16 level. CONCLUSION: A higher serum sCXCL16 level was identified as a predictive biomarker of RPILD in patients with DM, and closely associated with poor prognosis.

SFTPB in serum extracellular vesicles as a biomarker of progressive pulmonary fibrosis.

Progressive pulmonary fibrosis (PPF), defined as the worsening of various interstitial lung diseases (ILDs), currently lacks useful biomarkers. To identify novel biomarkers for early detection of patients at risk of PPF, we performed a proteomic analysis of serum extracellular vesicles (EVs). Notably, the identified candidate biomarkers were enriched for lung-derived proteins participating in fibrosis-related pathways. Among them, pulmonary surfactant-associated protein B (SFTPB) in serum EVs could predict ILD progression better than the known biomarkers, serum KL-6 and SP-D, and it was identified as an independent prognostic factor from ILD-gender-age-physiology index. Subsequently, the utility of SFTPB for predicting ILD progression was evaluated further in 2 cohorts using serum EVs and serum, respectively, suggesting that SFTPB in serum EVs but not in serum was helpful. Among SFTPB forms, pro-SFTPB levels were increased in both serum EVs and lungs of patients with PPF compared with those of the control. Consistently, in a mouse model, the levels of pro-SFTPB, primarily originating from alveolar epithelial type 2 cells, were increased similarly in serum EVs and lungs, reflecting pro-fibrotic changes in the lungs, as supported by single-cell RNA sequencing. SFTPB, especially its pro-form, in serum EVs could serve as a biomarker for predicting ILD progression.

Elevated peripheral blood monocyte count is associated with prolonged postoperative hospitalization and functional decline in patients with interstitial lung diseases undergoing surgical lung biopsy.

OBJECTIVE: Monocyte count and red cell distribution width (RDW) have shown prognostic potential in patients with fibrotic lung diseases. Their kinetics and prognostic usefulness of peripheral blood indices in patients with interstitial lung diseases (ILDs) undergoing surgical lung biopsy for diagnostic reasons have not been studied. PATIENTS AND METHODS: We retrospectively included consecutive patients with ILD who underwent surgical lung biopsy for diagnostic purposes Between 07/11/2019 and 11/10/2022. RESULTS: Fifty-five (n=55) patients were included in the study. Median age was 65.0 years (95% CI: 63.0 to 66.0). Postoperative peripheral blood monocyte count on Day 1 was significantly higher compared to preoperative, perioperative, and postoperative values on Day 90 (repeated measures ANOVA, p<0.0001). Patients in the high postoperative monocyte count group had significantly increased length of postoperative hospital stay [Mann-Whitney test, p=0.007] and significantly lower Forced Vital Capacity (FVC)% predicted 3 months after surgery [Mann-Whitney test, p=0.029] compared to patients in the low postoperative monocyte count group. Postoperative RDW on Day 90 was significantly higher compared to preoperative, perioperative and postoperative-Day 1 RDW (repeated measures ANOVA, p=0.008, p=0.006, p<0.0001, respectively). Patients in the high postoperative RDW group did not have increased hospital stay (Mann-Whitney test, p=0.49) or decreased FVC% predicted at 3 months compared to patients in the low postoperative RDW group (Mann-Whitney test, p=0.91). CONCLUSIONS: Peripheral blood monocyte count could be a prognostic biomarker for patients with ILDs undergoing diagnostic surgical lung biopsies. RDW does not seem to represent an acute phase biomarker but seems to increase over time following disease progression. Larger studies are urgently required.

Serum S1P level in interstitial lung disease (ILD) is a potential biomarker reflecting the severity of pulmonary function.

BACKGROUND: sphingosine-1-phosphate (S1P), a naturally occurring sphingolipid, has been involved in pulmonary interstitial remodeling signaling. However, no study has examined its clinical merits for interstitial lung disease (ILD). This study aimed to investigate the serum level of S1P in ILD patients and its clinical correlation with the severity of disease in the two main types of ILDs: the IPF and the CTD-ILD patients. METHODS: This retrospective observational pilot study included 67 ILD patients and 26 healthy controls. These patients were stratified into the IPF group (35) and the CTD-ILD group (32). The severity of ILD was evaluated through pulmonary function indicators and the length of hospital stay. RESULTS: Serum S1P level was statistically higher in ILD patients than in health control (p = 0.002), while the Serum S1P levels in CTD-ILD and IPF patients were comparable. Serum S1P level further showed statistically negative correlation with pulmonary function indexes (TLC% pred, FVC% pred and FEV1% pred) and positive correlation with length of hospital stay (r = -0.38, p = 0.04; r = -0.41, p = 0.02, r = -0.37, p = 0.04; r = 0.42, p = 0.02, respectively) in CTD-ILD patients, although serum S1P level was not significantly correlated with inflammatory indexes. The IPF patients failed to exhibit a significant correlation of serum S1P level with pulmonary function and length of hospital stay. CONCLUSIONS: Serum S1P level might be a clinically useful biomarker in evaluating the severity of CTD-ILD patients rather than IPF patients.

Clinical and prognostic associations of anti-Jo-1 antibody levels in patients with antisynthetase syndrome.

OBJECTIVE: To investigate the association of serum anti-Jo-1 antibody levels with the disease activity and prognosis in anti-Jo-1-positive patients with antisynthetase syndrome (ASS). METHODS: This study included 115 anti-Jo-1-positive patients with ASS who were admitted to China-Japan Friendship Hospital between 2009 and 2019. Anti-Jo-1 antibody serum levels at initial admission and follow-up were determined by enzyme-linked immunosorbent assay (ELISA). Global and organ disease activity was assessed at baseline and follow-up according to the International Myositis Assessment and Clinical Studies guidelines. RESULTS: Among enrolled patients, 70 (60.9%) patients initially presented with interstitial lung disease (ILD), and 46 (40%) patients presented with with muscle weakness at initial admission. At baseline, patients with ILD had lower levels of anti-Jo-1 antibodies than those without ILD (p = 0.012). Baseline anti-Jo-1 antibody levels were higher in patients with muscle weakness, skin involvement, and arthritis (all p < 0.05) compared to those without these manifestations. Baseline anti-Jo-1 antibody levels were positively correlated with skin visual analogue scale (VAS) scores (r = 0.25, p = 0.006), but not with disease activity in other organs. However, changes in anti-Jo-1 antibody levels were significantly positively correlated with the changes in PGA (ß = 0.002, p = 0.001), muscle (ß = 0.003, p < 0.0001), and pulmonary (ß = 0.002, p = 0.013) VAS scores, but not with skin and joint VAS scores. Older age of onset (hazard ratio [HR] 1.069, 95% confidence interval [CI]:1.010-1.133, p = 0.022) and higher C-reactive protein (CRP) levels (HR 1.333, 95% CI: 1.035-1.717, p = 0.026) were risk factors for death. CONCLUSION: Anti-Jo-1 titers appear to correlate more with disease activity changes over time rather than with organ involvement at baseline, which provides better clinical guidance for assessing the disease course using anti-Jo-1 levels.

Myositis Autoantibody Profiles and Clinical Significance in Patients with Inflammatory Myopathies in Southwest China.

BACKGROUND: The purpose of this study is to analyze the distribution of myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs) in patients with idiopathic inflammatory myopathies (IIMs) in southwest China and to explore the relevance between each subtype, each clinical feature, and to explore the relevance between the laboratory indexes. METHODS: For this study, 200 patients with IIMs were tested for myositis autoantibodies. Clinical manifestations and laboratory metrics were collected and the correlations between autoantibodies and clinical phenotypes were analyzed. RESULTS: MSAs were found in 73.5% of the patients. The most frequently MSAs were anti-MDA5 (26.8%), followed by anti-ARS (18.5%). Anti-Ro52 was the most prevalent in MAAs (46.2%). Interstitial lung disease (ILD) and arthralgia were more frequent in anti-MDA5 and anti-Jo-1 positive groups (each p < 0.05). Anti-TIF1-γ and anti-NXP2 were associated with dysphagia (each p < 0.05). Different antibody subtypes were associated with laboratory indicators of response to muscle damage and immune status. Logistic regression showed that anti-MDA5 and anti-Jo-1 were independent risk factors for ILD (OR = 4.542, p = 0.004; OR = 4.290, p = 0.018, respectively) and arthralgia (OR = 7.856, p = 0.000; OR = 5.731, p = 0.004, respectively), whereas anti-TIF1-γ and anti-NXP2 were independent risk factors for dysphagia (OR = 4.521, p = 0.009; OR = 6.889, p = 0.017, respectively). CONCLUSIONS: Different antibody subtypes were associated with specific clinical features. Anti-MDA5 and anti-Jo-1 were independent risk factors for ILD and arthralgia. Anti-TIF1-γ and anti-NXP2 were independent risk factors for dysphagia.

Prognostic value of serum oncomarkers for patients hospitalized with acute exacerbation of interstitial lung disease.

BACKGROUND: Different types of inflammatory processes and fibrosis have been implicated in the pathogenesis of interstitial lung disease (ILD), a heterogeneous, diffuse, parenchymal lung disease. Acute exacerbation (AE) of ILD is characterized by significant respiratory deterioration and is associated with high mortality rates. Several serum oncomarkers have been used to determine the prognosis of ILD; however, the prognostic value of serum oncomarker levels in patients with AE-ILD remains unclear. OBJECTIVE: To evaluate the prognostic value of serum oncomarker levels in patients with AE-ILD and its main subtypes. DESIGN: Retrospective study. METHODS: The serum levels of 8 oncomarkers in 281 patients hospitalized with AE-ILD at our institution between 2017 and 2022 were retrospectively reviewed. The baseline characteristics and serum oncomarker levels were compared between the survival and non-survival groups of AE-ILD and its main subtypes. Multivariate logistic regression analysis was performed to identify independent prognosis-related markers, and the best prognostic predictor was analyzed using receiver operating characteristic curve (ROC) analysis. RESULT: Idiopathic pulmonary fibrosis (IPF; n = 65), idiopathic nonspecific interstitial pneumonia (iNSIP; n = 26), and connective tissue disease-associated interstitial lung disease (CTD-ILD; n = 161) were the three main subtypes of ILD. The in-hospital mortality rate among patients with AE-ILD was 21%. The serum oncomarker levels of most patients with AE-ILD and its main subtypes in the non-survival group were higher than those in the survival group. Multivariate analysis revealed that ferritin and cytokeratin 19 fragments (CYFRA21-1) were independent prognostic risk factors for patients hospitalized with AE-ILD or AE-CTD-ILD. CYFRA21-1 was identified as an independent prognostic risk factor for patients hospitalized with AE-IPF or AE-iNSIP. CONCLUSION: CYFRA21-1 may be a viable biomarker for predicting the prognosis of patients with AE-ILD, regardless of the underlying subtype of ILD. Ferritin has a prognostic value in patients with AE-ILD or AE-CTD-ILD.

Multidimensional biomarker approach integrating tumor markers, inflammatory indicators, and disease activity indicators may improve prediction of rheumatoid arthritis-associated interstitial lung disease.

INTRODUCTION: Rheumatoid arthritis (RA) often leads to interstitial lung disease (ILD), significantly affecting patient outcomes. This study explored the diagnostic accuracy of a multi-biomarker approach to offer a more efficient and accessible diagnostic strategy for RA-associated ILD (RA-ILD). METHODS: Patients diagnosed with RA, with or without ILD, at Beijing Tiantan Hospital from October 2019 to October 2023 were analyzed. A total of 125 RA patients were included, with 76 diagnosed with RA-ILD. The study focused on three categories of indicators: tumor markers, inflammatory indicators, and disease activity measures. The heatmap correlation analysis was employed to analyze the correlation among these indicators. Logistic regression was used to determine odds ratios (OR) for indicators linked to RA-ILD risk. Receiver-operating characteristic (ROC) curve analysis was employed to evaluate the diagnostic potential of these indicators for RA-ILD. RESULTS: The results of logistic regression analysis showed that tumor markers (carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and cytokeratin 19 fragment (CYFRA21-1)), as well as inflammatory indicators (neutrophil, neutrophil-to-lymphocyte ratio (NLR), platelet, C-reactive protein (CRP)) and disease activity measures (disease activity score-28-CRP (DAS28-CRP), rheumatoid factor (RF), and anti-cyclic peptide containing citrulline (anti-CCP)), were significantly associated with RA-ILD. The correlation coefficients among these indicators were relatively low. Notably, the combination indicator 4, which integrated the aforementioned three categories of biomarkers, demonstrated improved diagnostic accuracy with an AUC of 0.857. CONCLUSION: The study demonstrated that combining tumor markers, inflammatory indicators, and disease activity measures significantly enhanced the prediction of RA-ILD. Key Points • Multidimensional strategy: Integrated tumor markers, inflammatory indicators, and disease activity measures to enhance early detection of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). • Diagnostic accuracy: Employed heatmap correlation and logistic regression, identifying significant associations and improving diagnostic accuracy with a multidimensional biomarker combination. • Superior performance: The combined multidimensional biomarker strategy demonstrated higher diagnostic precision compared to individual or dual-category indicators. • Clinical relevance: Offers a promising, accessible approach for early detection of RA-ILD in clinical settings, potentially improving patient outcomes.

Diagnostic Value of Krebs von den Lungen (KL-6) for Interstitial Lung Disease: A European Prospective Cohort.

INTRODUCTION: Krebs von den Lungen 6 (KL-6) is a mucin-1 glycoprotein produced by type II pneumocytes. High levels of KL-6 in blood may be found in patients with lung fibrosis. In Asia this biomarker is used for diagnosis and prognosis in interstitial lung diseases (ILD). There is a lack of information regarding KL-6 cut-off point for diagnosis and prognosis in European population. The aim of this study was to establish the cut-off point for serum KL-6 associated with the presence of ILD in the Spanish population. METHODS: Prospective study including subjects who underwent chest HRCT, PFTs and autoimmune blood analysis. Two groups were created: non-ILD subjects and ILD patients. Serum KL-6 concentrations were measured using a Lumipulse KL-6 reagent assay and the optimal cut-off value was evaluated by a ROC analysis. Data on demographics and smoking history was also collected. RESULTS: One hundred seventy-nine patients were included, 102 with ILD. Median serum KL-6 values overall were 762U/mL, 1080 (±787)U/mL for the ILD group vs 340 (±152)U/mL for the non-ILD group (p<0.0001). The main radiological pattern was NSIP (43%). ROC analysis showed greater specificity (86%) and sensitivity (82%) for KL-6 465U/mL for detecting ILD patients. The multivariate logistic regression model pointed to the male sex, higher KL-6 values, lower FVC and low DLCO values as independent factors associated with ILD. CONCLUSION: Serum KL-6 values greater than 465U/mL have excellent sensitivity and specificity for detecting ILD in our Spanish cohort. Multicentre studies are needed to validate our results.

Serum netrin-1 levels are high in Rheumatoid arthritis associated interstitial lung disease.

BACKGROUND: Recent data show that netrin-1 has a role in development of pulmonary fibrosis. This study was aimed to investigate serum netrin-1 level and its relation to interstitial lung disease(ILD) in patients with rheumatoid arthritis (RA). METHOD: 42 RA patients with RA-ILD, 58 RA patients without RA-ILD (RA non-ILD group), and 61 healthy volunteers were included in this study. The modified DAS28-ESR score was used to calculate disease activity in RA patients. Using the quantitative immunoassay method, Serum netrin-1 levels were measured with an ELISA kit (Catalog number: E-EL-H2328; lab science, lot number: GZWTKZ5SWK, Texas, USA). RESULTS: The median value of netrin-1 was found to be significantly higher in the RA-ILD group (82.9 [59.9-124]) compared to both the RA non-ILD group(52.9 [49.5-73.1])(B = -0.006, OR = 0.994, CI 95 %=0.989-0.999, P = 0.018) and the control group(53.5 [49.5-87.5]) (B: -0.005, OR: 0.994, CI 95 %: 0.990-0.999, p: 0.022). A cut-off value of 61.78 for netrin-1 was found to have a sensitivity of 73.8 % and a specificity of 69 % for the diagnosis of RA-ILD (AUC [95 %Cl] = 0.771 [0.679-0.862], p < 0.0001).It was found that high serum netrin-1 level was strongly associated with the RA-usual interstitial pneumonia(UIP) pattern and poorly related to the RA-nonspecific interstitial pneumonia(NSIP) pattern compared to the RA non-ILD group. CONCLUSIONS: Netrin-1 is elevated in the serum of patients with RA-ILD, especially in the UIP pattern. Netrin-1 may be a potential candidate for predicting the development of RA-ILD that should be investigated in the pathophysiological and therapeutic fields..

Forensic application of three interstitial pneumonia markers: search for new pneumonia markers in dead bodies.

In forensic cases, detailed identification of pneumonia is important. Our objective was to statistically determine the applicability of three interstitial lung disease (ILD) markers for forensic diagnosis using serum collected from dead bodies with various postmortem intervals (PMIs). We retrospectively analyzed the levels of postmortem serum Krebs von den Lungen-6 (KL-6) and pulmonary surfactant-associated proteins A and D (SP-A and SP-D) using 221 samples obtained during forensic autopsy at our facility from 2019 to 2023. We evaluated the diagnostic efficacy of ILD markers for various pneumonias against the pathological diagnosis, and examined the assessment of the severity of ILD. When comparing the ILD group with bacterial pneumonia (BP) versus the control group, there was a significant increase in KL-6 in the ILD group. When comparing the severe ILD (SILD) group with the mild ILD (MILD) group, there was a significant increase in KL-6 and SP-D in the SILD group. The optimal cutoff values for differentiating SILD were 607.0 U/mL for KL-6, 55.5 ng/mL for SP-A, and 160.0 ng/mL for SP-D, and the sensitivity/specificity (%) of KL-6, SP-A, and SP-D for SILD were 84.1/95.2, 55.6/85.7, and 66.7/74.6, respectively. This is the first study to examine KL-6 in postmortem serum in forensic medicine. By analyzing dead bodies with various PMIs, our results confirmed statistically that postmortem serum KL-6 specifically detects ILD, postmortem serum SP-A has high sensitivity to lung injury, and postmortem serum SP-D is potentially useful in assessing the severity of ILD.

Plasma Matrix Metalloproteinase Concentrations and Risk of Interstitial Lung Disease in a Prospective Rheumatoid Arthritis Cohort.

OBJECTIVE: To evaluate the associations of plasma matrix metalloproteinases (MMPs) with prevalent and incident interstitial lung disease (ILD) in people with rheumatoid arthritis (RA). METHODS: Within a multicenter, prospective cohort of US veterans with RA, we performed a cross-sectional study of prevalent ILD and cohort study of incident ILD. ILD diagnoses were validated by medical record review of provider diagnoses and chest imaging and/or pathology reports. MMP-1, 3, 7, and 9 concentrations were measured in plasma samples, then standardized and categorized into quartiles. The associations of MMPs with prevalent and incident ILD were assessed with logistic (prevalent) and Cox (incident) regression models adjusted for RA-ILD risk factors. RESULTS: Among 2,312 participants (88.9% male; mean age 63.8 years), 96 had prevalent ILD. Incident ILD developed in 130 participants over 17,378 person-years of follow-up (crude incidence rate 7.5/1,000 person-years). Participants with the highest quartile of MMP-7 concentrations had a nearly four-fold increased odds of prevalent ILD (adjusted odds ratio 3.78 [95% confidence interval (95% CI) 1.86-7.65]) and over two-fold increased risk of incident ILD (adjusted hazard ratio 2.33 [95% CI 1.35-4.02]). Higher MMP-9 concentrations were also associated with prevalent and incident ILD, as well as negatively correlated with forced vital capacity among those with prevalent ILD (r = -0.30, P = 0.005). CONCLUSION: MMP-7 and MMP-9 were strongly associated with both prevalent and incident ILD in this large, multicenter RA cohort after adjustment for other RA-ILD risk factors. These population-level findings further support a potential pathogenic role for MMPs in RA-ILD and suggest that their measurement could facilitate RA-ILD risk stratification.

Serum heme oxygenase-1 as a prognostic biomarker in patients with acute exacerbation of interstitial lung disease.

Serum heme oxygenase (HO)-1 level has been reported as a clinically reliable diagnostic biomarker for acute exacerbation of interstitial lung disease (ILD); however, its utility for predicting mortality among these patients is unclear. Serum HO-1 levels of patients newly diagnosed with acute exacerbation of ILD were measured at the time of initiating steroid pulse therapy. The relationship between serum HO-1 and various other serum biomarkers, change in HRCT findings, and disease prognosis at 12 weeks after diagnosis of acute exacerbation was evaluated in 51 patients, of whom 17 (33%) had idiopathic pulmonary fibrosis (IPF). Serum HO-1 was higher in patients with acute exacerbation of IPF than in patients with acute exacerbation of other ILDs. Serum HO-1 levels were higher in patients who died within these 12 weeks than in survivors. Among age, sex, comorbidities, IPF diagnosis, HRCT findings, and blood biomarkers, serum HO-1 was a primary predictor of 12-week mortality. In 41 patients who underwent repeat HRCT, serum HO-1 was higher in patients with honeycomb progression than in those without. Serum HO-1 measurement could be useful for evaluating disease mortality and morbidity of patients with acute exacerbation of ILDs.

High-titer rheumatoid factor seropositivity predicts mediastinal lymphadenopathy and mortality in rheumatoid arthritis-related interstitial lung disease.

Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a common connective tissue disease-related ILD (CTD-ILD) associated with high morbidity and mortality. Although rheumatoid factor (RF) seropositivity is a risk factor for developing RA-ILD, the relationship between RF seropositivity, mediastinal lymph node (MLN) features, and disease progression is unknown. We aimed to determine if high-titer RF seropositivity predicted MLN features, lung function impairment, and mortality in RA-ILD. In this retrospective cohort study, we identified patients in the University of Chicago ILD registry with RA-ILD. We compared demographic characteristics, serologic data, MLN size, count and location, and pulmonary function over 36 months among patients who had high-titer RF seropositivity (≥ 60 IU/ml) and those who did not. Survival analysis was performed using Cox regression modeling. Amongst 294 patients with CTD-ILD, available chest computed tomography (CT) imaging and serologic data, we identified 70 patients with RA-ILD. Compared to RA-ILD patients with low-titer RF, RA-ILD patients with high-titer RF had lower baseline forced vital capacity (71% vs. 63%; P = 0.045), elevated anti-cyclic citrullinated peptide titer (122 vs. 201; P = 0.001), CT honeycombing (50% vs. 80%; P = 0.008), and higher number of MLN ≥ 10 mm (36% vs. 76%; P = 0.005). Lung function decline over 36 months did not differ between groups. Primary outcomes of death or lung transplant occurred more frequently in the high-titer RF group (HR 2.8; 95% CI 1.1-6.8; P = 0.028). High-titer RF seropositivity was associated with MLN enlargement, CT honeycombing, and decreased transplant-free survival. RF titer may be a useful prognostic marker for stratifying patients by pulmonary disease activity and mortality risk.

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome.

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

Metabolic characteristics in patients with COVID-19 and no-COVID-19 interstitial pneumonia with mild-to-moderate symptoms and similar radiological severity.

BACKGROUND AND AIMS: It is known that the highest COVID-19 mortality rates are among patients who develop severe COVID-19 pneumonia. However, despite the high sensitivity of chest CT scans for diagnosing COVID-19 in a screening population, the appearance of a chest CT is thought to have low diagnostic specificity. The aim of this retrospective case-control study is based on evaluation of clinical and radiological characteristics in patients with COVID-19 (n = 41) and no-COVID-19 interstitial pneumonia (n = 48) with mild-to-moderate symptoms. METHODS AND RESULTS: To this purpose we compared radiological, clinical, biochemical, inflammatory, and metabolic characteristics, as well as clinical outcomes, between the two groups. Notably, we found similar radiological severity of pneumonia, which we quantified using a disease score based on a high-resolution computed tomography scan (COVID-19 = 18.6 ± 14.5 vs n-COVID-19 = 23.2 ± 15.2, p = 0.289), and comparable biochemical and inflammatory characteristics. However, among patients without diabetes, we observed that COVID-19 patients had significantly higher levels of HbA1c than n-COVID-19 patients (COVID-19 = 41.5 ± 2.6 vs n-COVID-19 = 38.4 ± 5.1, p = 0.012). After adjusting for age, sex, and BMI, we found that HbA1c levels were significantly associated with the risk of COVID-19 pneumonia (odds ratio = 1.234 [95%CI = 1.051-1.449], p = 0.010). CONCLUSIONS: In this retrospective case-control study, we found similar radiological and clinical characteristics in patients with COVID-19 and n-COVID-19 pneumonia with mild-to-moderate symptoms. However, among patients without diabetes HbA1c levels were higher in COVID-19 patients than in no-COVID-19 individuals. Future studies should assess whether reducing transient hyperglycemia in individuals without overt diabetes may lower the risk of SARS-CoV-2 infection.

sFlt-1 and CA 15.3 are indicators of endothelial damage and pulmonary fibrosis in SARS-CoV-2 infection.

COVID-19 pandemic led to a worldwide increase of hospitalizations for interstitial pneumonia with thrombosis complications, endothelial injury and multiorgan disease. Common CT findings include lung bilateral infiltrates, bilateral ground-glass opacities and/or consolidation whilst no current laboratory parameter consents rapidly evaluation of COVID-19 risk and disease severity. In the present work we investigated the association of sFLT-1 and CA 15.3 with endothelial damage and pulmonary fibrosis. Serum sFlt-1 has been associated with endothelial injury and sepsis severity, CA 15.3 seems an alternative marker for KL-6 for fibrotic lung diseases and pulmonary interstitial damage. We analysed 262 SARS-CoV-2 patients with differing levels of clinical severity; we found an association of serum sFlt-1 (ROC AUC 0.902, decision threshold > 90.3 pg/mL, p < 0.001 Sens. 83.9% and Spec. 86.7%) with presence, extent and severity of the disease. Moreover, CA 15.3 appeared significantly increased in COVID-19 severe lung fibrosis (ICU vs NON-ICU patients 42.6 ± 3.3 vs 25.7 ± 1.5 U/mL, p < 0.0001) and was associated with lung damage severity grade (ROC AUC 0.958, decision threshold > 24.8 U/mL, p < 0.0001, Sens. 88.4% and Spec. 91.8%). In conclusion, serum levels of sFlt-1 and CA 15.3 appeared useful tools for categorizing COVID-19 clinical stage and may represent a valid aid for clinicians to better personalise treatment.

Circulating bioactive bacterial DNA is associated with immune activation and complications in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by profound primary antibody defects and frequent infections, yet autoimmune/inflammatory complications of unclear origin occur in 50% of individuals and lead to increased mortality. Here, we show that circulating bacterial 16S rDNA belonging to gut commensals was significantly increased in CVID serum (P < 0.0001), especially in patients with inflammatory manifestations (P = 0.0007). Levels of serum bacterial DNA were associated with parameters of systemic immune activation, increased serum IFN-γ, and the lowest numbers of isotype-switched memory B cells. Bacterial DNA was bioactive in vitro and induced robust host IFN-γ responses, especially among patients with CVID with inflammatory manifestations. Patients with X-linked agammaglobulinemia (Bruton tyrosine kinase [BTK] deficiency) also had increased circulating bacterial 16S rDNA but did not exhibit prominent immune activation, suggesting that BTK may be a host modifier, dampening immune responses to microbial translocation. These data reveal a mechanism for chronic immune activation in CVID and potential therapeutic strategies to modify the clinical outcomes of this disease.

Association of Red Blood Cell Distribution Width Levels with Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD).

OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic value of red blood cell distribution width (RDW) in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). METHODS: We retrospectively reviewed 213 CTD-ILD patients and 97 CTD patients without ILD from February 2017 to February 2020. Hospital and office records were used as data sources. CTD-ILD patients were followed up. RESULTS: Patients with CTD-ILD had significantly higher RDW than those with CTD without ILD (p < 0.001). The area under the receiver operating characteristic curve (AUROC) of RDW for discriminating CTD-ILD from CTD without ILD was 0.64 (95% CI: 0.57-0.70, p < 0.001). The cutoff value of RDW for discriminating CTD-ILD from CTD without ILD was 13.95% with their corresponding specificity (55.9%) and sensitivity (70.1%). Correlation analyses showed that the increased RDW was significantly correlated with decreased DLCO%predicted (r = -0.211, p = 0.002). Cox multiple regression analysis indicated that RDW (HR = 1.495, p < 0.001) was an independent factor in the survival of CTD-ILD. The best cutoff value of RDW to predict the survival of patients with CTD-ILD was 14.05% (AUC = 0.78, 95% CI: 0.72-0.84, p < 0.001). The log-rank test showed a significant difference in survival between the two groups (RDW > 14.05% and RDW < 14.05%). CONCLUSION: RDW was higher in CTD-ILD patients and had a negative correlation with DLCO%predicted. RDW may be an important serum biomarker for severity and prognosis of patients with CTD-ILD.