CTD-ILD Group Research Articles

Relationship between nailfold capillaroscopy findings and the etiology and prognosis of interstitial lung disease

ObjectivesConnective tissue-associated interstitial lung diseases (CTD-ILD) are believed to be caused by microvascular damage. The objective of this study was to assess the nailfold capillaroscopy (NFC) pattern in patients diagnosed with both CTD-ILD and non-CTD-ILD to identify microvascular changes and determine the relation between capillaroscopic parameters, clinical variables, and disease-related measurements.Patients and methodsThis cross-sectional study included 95 patients with interstitial lung disease who applied to our Rheumatology and Chest Clinics between September 2021 and July 2023. The patients were divided into two groups based on their diagnosis: non-CTD-ILD (group 1) and CTD-ILD (group 2). Nailfold capillaroscopy was performed.ResultsNinety-five patients, 49 (51% female, mean age 62.31 ± 11.027 years) in group 1 and 46 (69.6% female, mean age 62.09 ± 10.887 years) in group 2, were included in the study. Abnormal capillary morphologies were both detected in the CTD-ILD group and the non-CTD-ILD groups. In patients with a usual interstitial pneumonia (UIP) pattern on chest computed tomography (CT), tortuosity was higher than in patients with non-specific interstitial pneumonia (NSIP) (P = 0.041), and the proportion of tortuosity increased significantly as the duration of the disease increased (P = 0.016).ConclusionOur study highlights capillaroscopic abnormalities alone may not be sufficient to differentiate CTD-ILD (other than systemic sclerosis) from non-CTD-ILD. The presence of NFC abnormalities in non-CTD-ILD may suggest that fibrotic lung disease could potentially play a role in the deterioration of the microvascular structure or abnormal angiogenesis. Our study demonstrated that a multidisciplinary approach, incorporating clinical, morphological, pathological, and serological evaluations, is necessary for interpreting ILD.Key Points• Capillaroscopic abnormalities can also be seen in non-CTD-ILD.• Capillaroscopy findings do not distinguish the non-Ssc etiology of ILD.• Nailfold capillaroscopy may have the potential to serve as a useful tool in predicting prognosis and monitoring the disease progression in patients with idiopathic pulmonary fibrosis (IPF).

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

Backgroundsphingosine-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.MethodsThis 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.ResultsSerum 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.ConclusionsSerum S1P level might be a clinically useful biomarker in evaluating the severity of CTD-ILD patients rather than IPF patients.

Anti-carbamylated protein antibodies drive AEC II toward a profibrotic phenotype by interacting with carbamylated TLR5.

This study looked at the role of anti-carbamylated protein (anti-CarP) antibodies in contributing to lung fibrosis in CTD-associated interstitial lung disease (ILD) in an autoantigen-dependent manner. ELISA was used to test serum samples, including 89 from the CTD-ILD group and 170 from the non-CTD-ILD group, for anti-CarP levels. Male C57BL/6 mice were used for the pulmonary fibrosis model and anti-CarP treatment in vivo (n = 5) and patient serum-derived or commercialized anti-CarP was used for cell treatment. We identified the carbamylated membrane protein via immunofluorescence (IF) and co-immunoprecipitation followed by mass spectrometry (MS) analysis. Quantitative RT-PCR, IF and western blot were performed to explore the antigen-dependent role of anti-CarP. A native electrophoretic mobility shift assay and MS analysis were used to verify direct interaction and carbamylation sites. A significantly higher serum anti-CarP level was observed in CTD with ILD than without ILD. In vivo, intrapulmonary delivery of anti-CarP induces epithelial-mesenchymal transition (EMT) and microfibrotic foci. Carbamylation was enriched in type II alveolar epithelial cells (AEC II). A novel carbamylated membrane receptor, specifically recognized by anti-CarP, was identified as toll-like receptor 5 (TLR5). We found anti-CarP induces the nuclear translocation of NF-κB and downstream events, including EMT and expression of inflammatory cytokines in AEC II, which were reversed by TLR5 blocking or TLR5 knockdown. Moreover, up to 12 lysine carbamylation sites were found in TLR5 ectodomain, allowing the interaction of anti-CarP with carbamylated TLR5. Overall, we found anti-CarP drives aberrant AEC II activation by interacting with carbamylated TLR5 to promote ILD progression.

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.

Unclassifiable interstitial lung disease and autoimmunity: Towards IPAF in children?

Interstitial pneumonia with autoimmune features (IPAF) has been defined for adults with interstitial lung disease (ILD) and autoimmunity who do not meet the criteria for a specific connective tissue disease (CTD). We aimed to determine whether IPAF criteria could apply to children. We retrospectively studied patients with ILD and autoimmunity followed at Necker Hospital between 2008 and 2019. Children were classified according to specific CTD and IPAF criteria. The epidemiology and course of the disease were studied according to the final diagnosis. Among 27 patients, 6 fulfilled the criteria for IPAF and represented 4.5% of all patients with ILD during the study period. Other diagnoses included juvenile dermatomyositis (30%), overlap syndromes (19%), systemic lupus erythematosus (15%), systemic sclerosis (7%), mixed CTD (4%), and rheumatoid arthritis (4%). IPAF patients were more frequently boys versus CTD-ILD patients (67% vs. 14%, p = .02). Two patients had severe respiratory distress that led to death for one of them. The course was favorable for the others, with a good response to steroids. The course tended to be more favorable for IPAF patients than for those with CTD-ILD (0% lung fibrosis in the IPAF group vs. 43% in the CTD-ILD group, p = .07). We confirmed the existence of IPAF in children. Its prevalence was lower than in adults but comparable to that found for other pediatric series. Boys were more highly represented than in CTD-ILD. The course was favorable for most cases. Larger and more prospective studies are needed to confirm these results.

Prevalence of diaphragm dysfunction in patients with interstitial lung disease (ILD): The role of diaphragmatic ultrasound

BackgroundDiaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We hypothesized that diaphragm function, assessed by ultrasound, could be impaired in patients with ILD, considering both Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease (CTD-ILD), compared to healthy subjects. Moreover, this impairment could impact clinical and functional parameters. MethodsAll consecutive CTD-ILD and IPF patients followed in our center (March–October 2020) were screened. Diaphragm displacement (DD), inspiratory thickness (Ti), expiratory thickness (Te), thickening fraction (TF), and respiratory functional parameters were collected. The prevalence of diaphragmatic dysfunction (TF <30%) was then recorded. ResultsEighty-two consecutive patients (41 CTD-ILD, 41 IPF) and 15 age- and sex-matched controls were enrolled. In the overall population, 24 out of 82 (29%) presented diaphragmatic dysfunction. In CTD-ILD, DD and Ti were lower as compared to IPF (p = 0.021 and p = 0.036, respectively); while diaphragmatic dysfunction was more prevalent compared to controls (37% vs 7%, p = 0.043). TF positively correlated to patients’ functional parameters in the CTD-ILD group (FVC%pred: p = 0.003; r = 0.45), while not in the IPF group. Diaphragmatic dysfunction was associated with moderate/severe dyspnea in both CTD-ILD and IPF (p = 0.021). ConclusionThe prevalence of diaphragmatic dysfunction was 29% in patients with ILD and was associated with moderate/severe dyspnea. CTD-ILD presented lower DD compared with IPF and a higher prevalence of diaphragmatic dysfunction (TF<30%) compared with controls. TF was associated with lung function only in CTD-ILD patients, suggesting its potential role in the comprehensive patient assessment.

Interstitial pneumonia with autoimmune features: monocentric prospective study

To study demographic, clinical, serological and morphological features of interstitial pneumonia with autoimmune features (IPAF), compare survival in IPAF and interstitial lung disease in connective tissue diseases (CTD-ILD), and identify predictors of mortality and transformation to CTD in the IPAF group. The IPAF group included 48 patients (75.0% women, median age 57.5 years), CTD-ILD - 49 patients (79.6% women, median age 60.0 years). The analysis of demographic, clinical, laboratory and instrumental data was performed, as well as comparison of survival with the Kaplan-Meier method and the log-rank test in the IPAF and CTD-ILD groups. In the IPAF group, predictors of mortality and the development of CTD were studied with multivariate regression analysis. Duration of observation period did not differ significantly in the IPAF and CTD-ILD groups (40.0 and 37.0 months, respectively). Clinical criteria of IPAF were observed in 25 (52.1%) patients, serological - in 44 (91.7%), morphological - in 44 (91.7%). Mortality in the IPAF group was significantly higher than in the CTD-ILD group (29.2 and 6.1%, respectively; p=0.023). The presence of diabetes mellitus, CT-pattern of usual interstitial pneumonia, and an initial low forced vital capacity value were independent predictors of mortality in the IPAF group. During the observation period, the development of CTD was noted in 4 (8.3%) patients with IPAF. The independent predictor of the CTD development was the increased C-reactive protein level. IPAF is characterized by a lower survival rate compared to CTD-ILD, and a relatively low risk of CTD transformation.

Clinical association study on the matrix metalloproteinase expression in the serum of patients with connective tissue disease complicated with interstitial lung disease.

This study was implemented to reveal the expression and the clinical correlation of matrix metalloproteinases (MPSs) with connective tissue disease (CTD) complicated with interstitial lung disease (ILD). This clinical study was conducted with 260 patients (151 males, 109 females; mean age: 47.3±12.5 years; range, 29 to 67 years) between October 2019 and October 2020. Among the subjects, 100 were CTD patients (CTD group), 80 were CTD patients with ILD (CTD-ILD group) and 80 were healthy individuals (control group). The MMP-2, -3, -7, and -9 levels in the serum of the three groups were detected by enzyme-linked immunosorbent assay. Serum levels of MMP-3, -7, and -9 in the CTD-ILD group were higher, while the MMP-2 level was lower than those in the CTD group and the control group. The MMP-7 level in the serum of the CTD-ILD group was positively related to C-reactive protein, erythrocyte sedimentation rate, and rheumatoid factor and negatively correlated with immunoglobulin G and complement 3. The MMP-7 expression in the serum was positively correlated with forced expiratory volume in one second (FEV1%), FEV1/forced expiratory volume (FVC), and FVC in CTD-ILD patients. Pearson statistical analysis revealed that there was a significant positive correlation between the MMP-7 expression and the percentage of B cells in the serum of CTD-ILD patients. Expressions of MMP-3, -7, and -9 are significantly increased in the serum of patients with CTD and related interstitial lung lesions, and the high expression of MMP-7 indicates dynamic lung lesions, which is possible to be used as a possible biomarker for early diagnosis and assessment of disease progression.

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.

Evaluation of rheumatoid arthritis and connective tissue disease-related interstitial lung disease with pulmonary physiologic test, HRCT, and patient-based measures of dyspnea and functional disability.

We aim to investigate the relationship between pulmonary function and imaging parameters with symptom-related patient-reported outcome measures (PROs). We included 65 patients of rheumatoid arthritis (RA) and connective tissue disease (CTD) with and without interstitial lung disease (ILD) into this cross-sectional study. We evaluated the relationship between FVC, DLco, and PROs and compared to HRCT findings. PROs included visual analogue scale for breathing, modified Borg scale, medical research council dyspnea scale, St. George's respiratory questionnaire (SGRQ), Leicester cough questionnaire, and Short Form 36 quality of life (SF-36 QoL). The mean age was 57.4 ± 9.7 and 61.9% (39/65) of patients had an established ILD. In RA-ILD group, SGRQ score was higher (p < 0.001) and SF-36 physical functioning score was lower (p = 0.02) than CTD-ILD group. In RA group, there was a significant correlation between FVC and SF-36 role functioning/physical score (r = 0.724, p = 0.012). In CTD group, SF-36 general health score was correlated with both FVC (r = 0.441, p = 0.045) and DLco (r = 0.485, p = 0.035), and also SF-36 physical functioning score was correlated with FVC (r = 0.441, p = 0.040). PROs were found to be similar between ILD and non-ILD patients. SF-36 QoL total and SGRQ outcomes were worse in non-ILD group. We concluded that PROs could be used to evaluate health-related quality of life (HRQoL) in RA- or CTD-related ILD. The physical health determinants of HRQoL are measurably worse in RA-ILD patients than in CTD patients. But, PROs may not be very helpful in differentiating patients with cough and/or shortness of breath due to ILD or non-ILD causes in RA/CTD. • HRQoL may be affected differently among specific subtypes of ILD. • PROs can be used to evaluate dyspnea and function of patients with RA- or CTD-related ILD but are not distinguished from patients with cough and/or shortness of breath due to non-ILD causes in RA/CTD.

Neutrophil-To-Lymphocyte Ratio and Systemic Immune-Inflammation Index-Biomarkers in Interstitial Lung Disease.

Background and objectives: The aims of the study were to evaluate the utility of neutrophil-to-lymphocyte ratio (NLR) and the systemic immune-inflammation index (SII) as inflammation markers and prognostic factors in patients with known interstitial lung disease secondary to connective tissue diseases (CTD-ILD) compared with idiopathic pulmonary fibrosis (IPF). Materials and Methods: Forty-two patients with known interstitial lung disease (21 with IPF and 21 with CTD-ILD) and 42 control matched healthy patients were included. The NLR was calculated as the absolute neutrophil count divided by the absolute lymphocyte count, and the SII was calculated as follows: SII = platelets × neutrophils/lymphocytes, with the data being obtained from the patients data charts at admission, before any treatment. Results: our hypothesis was that in patients with interstitial lung disease NLR and SII would have higher values compared with patients with CTD-ILD or control healthy patients. The mean NLR value was 3.01 (±1.35) among patients with idiopathic pulmonary fibrosis, and 2.38 (±1.08) among patients with CTD-ILD without significant statistical difference (p = 0.92). There was however a clinically significant statistical difference when compared with the control group, where NLR was 2.00 (±1.05) (p = 0.003). SII values were 619.37 (±329.51) in patients with IPF, 671.55 (±365.73) in CTD-ILD group and 569.73 (±326.67) in healthy subjects (p = 0.13) Conclusions: A mean NLR value of 2.8 and a SII value over 500 in patients with connective diseases can become a marker of pulmonary interstitial involvement. In the context of non-exacerbated interstitial lung disease, NLR and SII have reduced numerical values, without being statistically correlated with prognosis when we compared with patients with connective tissue diseases without exacerbation or with healthy people, the cut off being of 2.4. However subsequent studies in larger patient samples might provide changes in these cut-off values.

Acute exacerbations of fibrosing interstitial lung disease associated with connective tissue diseases: a population-based study

BackgroundAcute exacerbation (AE) is the major cause of morbidity and mortality in patients with idiopathic pulmonary fibrosis (IPF). AEs also occur in other forms of fibrosing interstitial lung disease (fILD). The clinical features and prognosis of AE patients with connective tissue diseases (CTDs) associated-ILD has not been fully described.MethodsWe retrospectively reviewed 177 patients with either IPF or a characterized CTD-ILD admitted to Nanjing Drum Tower Hospital with an AE from January 2010 to December 2016.ResultsThe study cohort included 107 subjects with AE-IPF and 70 cases with AE-CTD-ILD. Female gender, prior use of corticosteroid and immunosupressants, lower serum albumin, higher D-dimer level, TLC% pred, survival, and treatment with immunosupressants and caspofungin were more common in the CTD-ILD group (all p<0.05). The incidences of AE-CTD-ILD and AE-IPF were similar in our single center (p = 0.526). TLC% pred was the risk factor for AE after ILD diagnosis for 1 year in CTD patients (p = 0.018). Log-rank tests showed patients with CTD-ILD had a significantly lower mortality rate compared with IPF patients after AEs (p = 0.029). No significant difference in survival was noted among CTD subgroups (p = 0.353). The survival was negatively correlated with WBC count, LDH and CT score, (p = 0.006, p = 0.013 and p = 0.035, respectively), and positively correlated with PaO2/FiO2 ratio (p<0.001) in the CTD-ILD group. WBC count and PO2/FiO2 ratio were the independent predictors for survival in AE-CTD-ILD after adjusting for other clinical variates in Cox regression Models (p = 0.038 and p < 0.001, respectively).ConclusionsThe clinical characteristics of patients with AE-CTD-ILD differed from those with AE-IPF, while AE incidences were similar between the two groups. Subjects with AE-CTD-fILD tended to have a better prognosis, and WBC count and PO2/FiO2 ratio were the independent survival predictors for these patients.

The diagnostic value of serum KL-6 in connective tissue disease associated interstitial lung disease

Objective: To evaluate the diagnostic value of the serum Krebs von den Lungen-6 (KL-6) for the interstitial lung disease associated with connective tissue diseases (CTD-ILD). Methods: 84 patients with CTD-ILD (CTD-ILD group) and 91 patients with connective tissue disease (CTD group) who visited the department of rheumatology and immunology of People's Hospital of Xinjiang Uygur Autonomous Region between January, 2016 and December, 2017 were included. Serum KL-6 levels were measured by commercially available enzyme linked immunosorbent assay (ELISA) kits. Results: The significantly higher levels of KL-6 were determined in the CTD-ILD group than CTD group [1 239 (577, 2 094) vs 152 (89, 280) U/ml] (P<0.001). The optimal cutoff value of serum KL-6 for diagnosis of CTD-ILD was 402 U/ml, and the sensitivity and specificity were 82.1% and 86.8%, respectively. Area Under the Curve (AUC) was 0.905. Logistic regression analysis revealed that elevated KL-6 and decreased Carbon monoxide diffusion capacity were independently correlated with the occurrence of CTD-ILD, the decreased of DLcoSB% (OR=0.928, 95%CI: 0.891-0.968) and increase of KL-6 level (OR=1.005, 95%CI: 1.003-1.007) was the independent risk factor for the occurrence of ILD. Conclusion: The serum KL-6 is an important biomarker for the diagnosis of CTD-ILD and when the level of KL-6 is increased, the ILD should be alert.

Long-term clinical course and outcome of interstitial pneumonia with autoimmune features.

Idiopathic interstitial pneumonia (IIP) with autoimmune features that does not fulfil connective tissue disease (CTD) criteria has been recently defined as interstitial pneumonia with autoimmune features (IPAF). However, its long-term clinical course and outcome are poorly understood. We included consecutive patients diagnosed with IIP (n = 586) or CTD-related interstitial lung disease (CTD-ILD, n = 149). Some patients with IIP were reclassified as IPAF based on recent guidelines. The median follow-up period was 45 months. Among the IIP patients, 109 (18.6%) were reclassified as IPAF. Compared to the non-IPAF-IIP group, the IPAF group had slower diffusing capacity of the lung for carbon monoxide (DLCO ) and total lung capacity declines, and more frequent CTD development during follow-up periods. The prognosis of the IPAF was better than that of the non-IPAF-IIP and similar to that of the CTD-ILD. IPAF was associated with better prognosis in the IIP cohort on univariate but not on multivariate analysis. Usual interstitial pneumonia (UIP) pattern, old age and low DLCO independently predicted mortality in the IPAF group. Compared to the non-IPAF-IIP group, the IPAF group had slower lung function declines and more frequent CTD development during follow-up. Although the prognosis of IPAF group was better than that of non-IPAF-IIP group and similar to that of CTD-ILD group, it showed poor prognosis in patients with old age, UIP pattern, and low DLCO .

Lung Cancer development and mortality in interstitial lung disease with and without connective tissue diseases: a five-year Nationwide population-based study

BackgroundConnective tissue disease associated with interstitial lung disease (CTD-ILD) and interstitial lung disease (ILD) alone have same pathological and imaging backgrounds. However, the differences between lung cancer development and the mortality risk between these two conditions are unclear. Incidence of primary lung cancer and all-cause mortality were studied between interstitial lung disease patients with and without connective tissue disease.MethodsData were extracted from the Korean National Health Insurance Research Database in 2009. A total of 12,787 cases of ILD without idiopathic pulmonary fibrosis and 2491 cases of CTD-ILD were diagnosed in 2009. The cohort was followed up until June 30, 2014. Incident lung cancers and all-cause mortality were ascertained.ResultsThe overall incidence of lung cancer was 165.7 and 161.8 per 10,000 person-years in the CTD-ILD and ILD-only, respectively (rate ratio, 1.08; 95% confidence interval, 0.89–1.30). CTD-ILD patients in the 40–49 and 50–59 years old age groups had lung cancer incidence rates of 92.5 and 139.2, which were 2.0 and 1.7 times higher than those in the ILD-only, respectively. All-cause mortality was significantly higher in the CTD-ILD group compared to ILD-only group in patients aged 50–79 years. All-cause mortality of women in the 50–59, 60–69 and 70–79 age groups was 2.0, 1.8, and 1.4 times higher in the CTD-ILD group than in the ILD-only group, respectively.ConclusionsCTD-ILD patients aged < 60 years had a higher lung cancer incidence than ILD-only patients in the same age group. Furthermore, CTD-ILD patients aged 50–79 years had higher all-cause mortality than ILD-only patients in the same age group.

The Differences of Interstitial Lung Diseases in High-Resolution Computerized Tomography and Pulmonary Function Test among Different Connective Tissue Diseases, and the Correlated Factors

Objective. To study the difference of interstitial lung diseases (ILDs) in high-resolution computerized tomography and pulmonary function test among different connective tissue diseases (CTDs). Methods. 209 patients with different CTDs were recruited and underwent lung HRCT and PFT. Eerythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum ferritin (SF), anti-SSA, and so on were tested. Based on HRCT, a patient was classified into ILD group (CTD+ILD) or non-ILD group (CTD-ILD). HRCT, PFT, and laboratory markers were compared according to CTDs and CTD-associated ILDs. Results. The incidences of ILD were 79.6%, 82.0%, 89.7%, and 97.1% respectively for Rheumatoid arthritis (RA), primary Sjogren’s symptom (pSS), dermatomyositis/polymyositis (DM/PM), and systemic sclerosis (SSc) groups. RA and pSS patients exhibited more nodules, patching, ground-glass opacity, and cord shadow foci in HRCT, DM/PM and SSc patients exhibited more reticular opacity and honeycombing foci. RA and pSS patients exhibited more obstructive ventilatory disorder, small airway dysfunction and emphysema in PFT, and DM/PM and SSc patients exhibited more restrictive ventilatory disorder, mixed ventilatory disorder. ESR, CRP and SF were significantly higher in total CTD+ILD group than in total CTD-ILD group (P = 0.047, 0.006, 0.004, respectively), and higher in different CTD+ ILD groups than in comparable CTD-ILD groups (P = 0.049, 0.048, and 0.023, pSS+ILD, SSc+ILD and RA+ILD compared to pSS-ILD, SSc-ILD and RA-ILD, respectively for ESR, CRP, SF). The positive rate of anti-SSA was significantly higher in DM/PM+ILD group than in DM/PM-ILD group (P = 0.025). Conclusions. The manifestations and incidences of ILDs differ among different CTDs in HRCT and PFT, and inflammation and anti-SSA are positively correlated with ILDs in different CTDs, which provide important evidences for judging disease condition and prognosis.

The expression and clinical role of KL-6 in serum and BALF of patients with different diffuse interstitial lung diseases

To detect the levels of KL-6 in the serum and the bronchoalveolar lavage fluid (BALF) of patients with different type of diffuse interstitial lung diseases(DILD), and to analyze its correlation with pulmonary function, pulmonary HRCT scores and other parameters. Seventy-three patients with DILD were enrolled, including 34 patients with idiopathic pulmonary fibrosis (IPF), 10 patients with stage Ⅰ sarcoidosis(SAR Ⅰ), 15 patients with hypersensitivity pneumonia (HP), 14 patients with connective tissue diseases (CTD). Enzyme-linked immune sorbent assay (ELISA) was used to detect the levels of KL-6 in the serum and the BALF of these patients. In the IPF group, FVC predicted percentage and DLCO predicted percentage were significantly lower than those of the SAR Ⅰ group[(70±14)% vs (82±6)%, (49±13)% vs(81±6)%, P<0.05], but were no different compared to the CTD-ILD group(P>0.05). In the IPF group, the percentage of neutrophils in BALF was higher than that of the SAR Ⅰ group[(9±7)% vs (6±4)%, P<0.05]], and the percentage of lymphocytes and CD4/CD8 ratio in BALF were lower than those of the SAR Ⅰ group[(12±7)% vs (23±13)%, (1.5±0.8) vs(4.0±5.1), P<0.05]. In the IPF group, the level of KL-6 in serum was higher than that of the SAR Ⅰ and the HP group[(858±516)U/ml vs (339±168)U/ml, (553±287)U/ml, P<0.05], but was no different compared to the CTD-ILD group (P>0.05). In the CTD-ILD group, the level of KL-6 in serum was higher than that of the SAR Ⅰ [(687±350) U/ml vs (339±168)U/ml, P<0.05]]. In the IPF group, the level of KL-6 in BALF was (437±252)U/ml, and was higher than that of other 3 groups(P<0.05). In the IPF group, the level of serum KL-6 was negatively correlated with FVC and DLCO(r=-0.46, -0.58, P<0.01), the level of serum KL-6 was positively correlated with pulmonary HRCT reticular pattern and honeycombing scores(r=0.62, 0.41, P<0.05). In patients with IPF, the levels of KL-6 in serum and BALF were increased and the level of KL-6 in serum was correlated with FVC, DLCO and pulmonary HRCT reticular pattern and honeycombing scores.KL-6 may be a marker for the diagnosis of IPF.

Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study.

It was aimed to evaluate KL-6 glycoprotein levels to determine if it may be a diagnostic marker for the connective tissue diseases (CTDs) predicting CTD-related interstitial lung diseases (ILDs) (CTD-ILD) development and to examine if there was a difference between patients and healthy controls. The study included 113 patients with CTD (45 CTD without lung involvement, 68 CTD-ILD) and 45 healthy control subjects. KL-6 glycoprotein levels were analyzed with ELISA in patients and the control group. The relationship between KL-6 glycoprotein levels and CTD-ILD was assessed. In the comparison of all the groups in the study, significantly higher levels of KL-6 were determined in the CTD-ILD group than in either the CTD without pulmonary involvement group or the healthy control group (p < 0.008 and p < 0.001, respectively). There was no statistically significant difference between the KL-6 levels in the healthy control group and the CTD without pulmonary involvement group (p = 0.289). The KL-6 levels did not differ significantly according to the connective tissue diseases in the diagnostic groups (systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, mixed connective tissue disease, scleroderma, polymyositis/ dermatomyositis). In the healthy control group, there was a statistically significant difference between KL-6 levels in smokers and non-smokers. Smokers had significantly higher serum KL-6 levels compared with non-smokers (p < 0.05). There was no statistically significant difference between smoking status (pack-year) and serum KL-6 levels. There was no statistically significant correlation between serum KL-6 levels and time since diagnosis of CTD and CTD-ILD. The level of KL-6 as a predictive factor could be used to identify the clinical development of ILD before it is detected on imaging modality. Further prospective clinical studies are needed to define whether levels of KL-6 might have prognostic value or might predict progressive ILD.

Aberrant expression of cytokine interleukin 9 along with interleukin 4 and interferon γ in connective tissue disease-associated interstitial lung disease: association with severity of pulmonary fibrosis.

IntroductionConnective tissues diseases (CTDs) are a heterogeneous group of disorders that share certain clinical characteristics and disturbed immunoregulation. Interstitial lung diseases (ILDs), also known as diffuse parenchymal lung diseases, are among the most serious pulmonary complications associated with CTDs. Interleukin 9 (IL-9), IL-4 and interferon γ (IFN-γ) – cytokines with important roles in autoimmune disease – were studied in CTD patients and CTD-ILD patients.Material and methodsSixty-one hospitalized untreated CTD patients were recruited, and 20 healthy volunteers were enrolled as controls. The 61 CTD patients were divided into a simple CTD group and a CTD-ILD group, and the plasma protein IL-9, IL-4 and IFN-γ levels were measured by enzyme-linked immunosorbent assay (ELISA).ResultsThe results indicate that the serum IL-9 levels were significantly higher in CTD-ILD and simple CTD patients than they were in healthy controls (each p < 0.05) and that the levels were elevated in CTD-ILD patients compared with simple CTD patients (p < 0.05). The IL-4 levels were higher in CTD-ILD patients than they were in the simple CTD patients (p < 0.05) and healthy controls (p < 0.01). In addition, the serum IL-9 levels were negatively correlated with the level of IFN-γ (r2 = 0.34, p = 0.01), the estimated percentage of predicted forced vital capacity (FVC%) (r2 = 0.36, p = 0.00) and the estimated percentage of predicted diffusing capacity (DLCO%) (r2 = 0.27, p = 0.04) and were positively correlated with the IL-4 level (r2 = 0.31, p = 0.01).ConclusionsInterleukin-9 may play an important role in the pathogenesis of CTD and may contribute to the progression of interstitial lung injury in CTD patients.

Comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia

To compare disease progression and mortality between idiopathic interstitial pneumonia (IIP) and interstitial lung disease (ILD) due to connective tissue diseases (CTD) including scleroderma, rheumatoid arthritis, systemic lupus, polymyositis, dermatomyositis, Sjögren's syndrome, and mixed CTD. A case-control study of patients with CTD-ILD (n = 46) and IIP controls (n = 51), seen at the University of Michigan between July 1,1998 and June 30,1999 and followed until March 30, 2002, was conducted. Survival analysis and Cox regression were performed to estimate survival, accounting for demographic and clinical parameters, including pulmonary function tests and high resolution computed tomography (HRCT) diagnosis and scoring. Median followup time was 4.4 person-years. Five-year survival in the IIP group was 51.9% (95% confidence interval [95% CI] 30.8-69.4) versus 43.4% (95% CI 21.1-63.9) in the CTD-ILD group. There were no significant differences among HRCT diagnostic categories between IIP and CTD-ILD. A fibrotic score > or = 2 was associated with decreased survival among the entire group. Age at diagnosis and most recent forced vital capacity were significant predictors of mortality when adjusted for IIP versus CTD-ILD diagnosis, sex, and interstitial score. Contrary to expectation, CTD-ILD compared with IIP appears to be associated with a worse prognosis when adjusted for age. A higher fibrotic score is suggestive of decreased survival.