Connective Tissue Disease-related Interstitial Lung Research Articles

Health-related quality of life in a multiracial Asian interstitial lung disease cohort.

Understanding health-related quality of life (HRQL) in patients with interstitial lung disease (ILD) provides insight into disease burden and treatment effects on patients' well-being. We examined HRQL in a multiracial Asian ILD cohort using the King's brief ILD (K-BILD) and EuroQol 5-dimension-3-level (EQ5D-3L) questionnaires and their associations with several clinical variables. This was a single-centre cross-sectional study of ILD patients in a university-affiliated tertiary public hospital in Singapore. All patients completed two self-administered HRQL questionnaires upon study entry, and their clinical information was retrieved from electronic medical records. Ninety-nine patients (56% male, 75% Chinese) were included. The median (interquartile range) age was 63 (54-72) years. The most common ILD diagnosis was connective tissue disease-related ILD (n=51, 52%), followed by idiopathic pulmonary fibrosis (n=27, 27%). The mean (standard deviation) scores for the EQ5D-3L utility value, EQ5D Visual Analogue Scale (VAS) and K-BILD total were 0.806 (0.284), 75.1 (12.8) and 63.9 (14.3), respectively. A moderate correlation was found between the EQ5D-3L and K-BILD total and domain scores. The HRQL scores also correlate moderately with the modified Medical Research Council dyspnoea scale (mMRC) scores. There was a weak-to-moderate correlation between HRQL and forced vital capacity (FVC), carbon monoxide diffusing capacity (DLCO) and Charlson comorbidity index. Multiple linear regression showed a significant association of K-BILD total [beta coefficient 0.244, 95% confidence interval (CI): 0.075-0.414; P=0.005], K-BILD 'breathlessness and activities' (beta coefficient 0.448, 95% CI: 0.192-0.703; P=0.001), and the 'psychological' domain (beta coefficient 0.256, 95% CI: 0.024-0.488; P=0.031) with DLCO %pred after adjustment for age, sex, BMI, race, smoking history, comorbidities, FVC %pred and ILD diagnosis. Non-Chinese race was a predictor of better K-BILD 'psychological' domain (beta coefficient 8.680, 95% CI: 0.656-16.704; P=0.034) after adjustment. HRQL is significantly impaired in ILD patients, and low DLCO is a strong predictor of this impairment.

Connective tissue disease-related interstitial lung disease is alleviated by tripterine through inhibition of the PI3K/Akt, apoptosis, and TNF-α signalling pathways.

Background: Interstitial lung disease (ILD) is the major cause of morbidity and mortality in patients with various rheumatic diseases. However, more interventions need to be sought. Tripterine, an extract of Tripterygium wilfordii Hook. F, has been widely studied for its powerful anti-inflammatory effect. However, its mechanism of action in treating connective tissue disease-related (CTD)-ILD remains unclear. Purpose: To investigate the mechanism of tripterine in CTD-ILD treatment by combining network pharmacology and an in vivo experiment. Methods: The related targets of tripterine were obtained after searching the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform, Comparative Toxicogenomics Database, GeneCards, Search Tool for Interacting Chemicals database, and SymMap database. Following this, Online Mendelian Inheritance in Man, GeneCards, Genebank, and DrugBank were used to screen the targets of CTD-ILD. A target-signalling pathway network was constructed using Cytoscape. Additionally, topological analysis was performed. Protein interaction analysis was performed using the STRING online analysis platform. Following this, Gene Ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) signalling pathway enrichment analyses were performed. Subsequently, the molecular docking between tripterine and the core targets was verified. Finally, experimental verification was performed in bleomycin-induced model mice. Results: A total of 134 common targets and 10 core targets of tripterine, including signal transducer and activator of transcription 3, tumour necrosis factor (TNF), v-rel avian reticuloendotheliosis viral oncogene homolog A, protein kinase B (Akt) α (Akt1), mitogen-activated protein kinase (MAPK) 1, Jun transcription factor family, tumour protein 53, MAPK3, nuclear factor kappa B subunit 1, and caspase 8, were obtained. GO enrichment analysis revealed that, while treating CTD-ILD, tripterine was mainly involved in cytokine receptor binding, receptor-ligand activity, signal receptor activation, cytokine activity, protein ubiquitination, deoxyribonucleic acid transcriptase activity, etc. The KEGG pathway enrichment analysis revealed that the most significant signalling pathways were multiple viral infections and the phosphatidylinositol-3-kinase (PI3K)/Akt, TNF, and apoptosis signalling pathways. Molecular docking results revealed that tripterine had good docking activity with the core targets. Experimental studies also demonstrated that tripterine could inhibit the activation of PI3K/Akt, apoptosis, and TNF-α signalling pathways in lung tissue and significantly improve lung pathology and collagen deposition in the model mice. Conclusions: This study preliminarily revealed the potential molecular biological mechanism of tripterine while treating CTD-ILD might be related to inhibiting the PI3K/Akt, apoptosis, and TNF-α signalling pathways. Tripterygium wilfordii Hook. F. and its extract could be used clinically for treating CTD-ILD.

Scorpion venom polypeptide governs alveolar macrophage M1/M2 polarization to alleviate pulmonary fibrosis

The onset of connective tissue disease-related interstitial lung disease (CTD-ILD) is generally insidious and progressive, with pulmonary fibrosis in the middle stage, and eventually respiratory failure and death. This study aimed to explore the role of scorpion venom polypeptide (SVP), the primary active constituent of the entire scorpion, in alveolar macrophages and pulmonary fibrosis. Pulmonary fibrosis mouse models were established, and then SVP and JAK inhibitor (tofacitinib) was used to treat models. Alveolar macrophages were isolated and the impacts of SVP on M1/M2 polarization and the JAK/STAT6 pathway in vitro were assessed. H&E and Masson staining revealed that SVP and tofacitinib treatment alleviated lung damage and fibrosis. They also hindered the M2-polarization of macrophages in lung tissue and declined cytokine levels associated with M2 polarization (IL-4, IL-13) and fibrosis drivers (TGF-β, VEGF) in mice. Consistent with the trend presented by tofacitinib treatment, SVP suppressed the phosphorylation of proteins in the JAK/STAT6 pathway. In addition, the in vitro treatment of SVP on the isolated macrophages represented consistent results with in vivo experiments. The findings of the present study indicated that SVP suppressed the JAK/STAT6 signaling pathway, hindered alveolar macrophage M2-type polarization, and possessed the potential to ameliorate pulmonary fibrosis.

Is conventional transbronchial lung biopsy out: The evaluation of clinical value in diffuse parenchymal lung disease

IntroductionTransbronchial lung biopsy (TBLB) is a relatively safe technique routinely employed by pulmonologists for the diagnosis of diffuse parenchymal lung disease (DPLD). Cryobiopsy is associated with higher diagnostic yield and a favorable risk/benefit ratio. Nevertheless, TBLB remains the representative method for definite diagnosis in developing countries.ObjectivesThis study aimed to evaluate whether the results obtained from TBLB had clinical value to pulmonologists in the management of DPLD.MethodsWe performed a retrospective analysis of patients who underwent conventional TBLB for the diagnosis of DPLD from May 1, 2017, to April 30, 2019, at the Beijing Chao‐yang Hospital, Capital Medical University. The clinical value of TBLB was defined as leading to a specific histopathological diagnosis or being consistent with the clinical and radiological data.ResultsSeven hundred and forty‐three patients with suspected DPLD were recruited. Conventional TBLB was considered clinically valuable in 439 procedures (59.1%), including 360 cases provided with definitive histopathological diagnoses, and 79 cases that were consistent with the working diagnoses. Among the 439 cases of clinically valuable TBLBs, 88 (20.0%), 37, 77 (10.7%), and 61 (13.9%) cases were diagnosed as connective tissue disease‐related interstitial lung disease, definite histopathological diagnoses, malignancies, and nonspecific interstitial pneumonia, respectively.ConclusionsConventional TBLB served as a key determinant or provided supplementary information in the final diagnosis of non‐infectious DPLDs. TBLB decision‐making should therefore be based on clinical and radiological data.

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.

Effect size of rituximab on pulmonary function in the treatment of connective-tissue disease-related interstitial lung disease: a systematic review and meta-analysis

BackgroundRituximab (RTX) has been previously reported as directed treatment in patients with connective-tissue disease-related interstitial lung diseases (CTD-ILD). A systematic assessment of treatment effect size on pulmonary function outcomes and related adverse effects in patients with CTD-ILD has not been previously reported.MethodsWe performed a systematic review and meta-analysis of published reports from PubMed, Embase, and Cochrane Libraries. Randomized and non-randomized controlled trials, case–control, cohort, and case series (with five or more cases) containing individual pulmonary function data and adverse effects were included. Study endpoints were pre- and post-treatment change in percent predicted forced vital capacity (FVC %) and diffusion capacity for carbon monoxide (DLCO%), along with reported drug-related adverse events.ResultsTwenty studies totaling 411 patients were identified with 14 included in the meta-analysis of pulmonary function and six in the descriptive review. Random effects meta-analysis of pre- and post-treatment pulmonary function findings demonstrated increases in FVC% (n = 296) (mean difference (MD) 4.57%, [95% CI 2.63–6.51]) and DLCO% (n = 246) (MD 5.0% [95% CI 2.71–7.29]) after RTX treatment. RTX treatment-related adverse effects were reported in 13.6% of the pooled cohort.ConclusionsA systematic assessment of post-treatment effect size suggests a potential role for RTX in stabilizing or improving lung function in patients with CTD-ILD, with a modest but not insignificant adverse effect profile.

Study on short term treatment response of connective tissue disease related interstitial lung disease

Background: Interstitial lung disease is a major cause of morbidity and mortality in patients suffering from connective tissue diseases. Early detection and prompt recognition of symptoms with appropriate treatment is necessary for effective control of the disease and for better prognosis and long-term survival. Aim: To study the short-term treatment response of patients with connective tissue disease-related interstitial lung disease. Objectives: The purpose of this study was to evaluate the treatment response of connective tissue disease-related interstitial lung disease patients treated with intravenous pulses of cyclophosphamide (CYP) based on improvements in lung function: forced vital capacity (FVC)% predicted, forced expiratory volume in the first second (FEV1)% predicted, dyspnea Borg scale and 6-minute walk test. To determine the factors affecting the treatment outcomes like age, sex, duration of the connective tissue disease, type of connective tissue disease, HRCT type, and presence of PAH. Methods: A cohort study was conducted in the Department of General Medicine, Rheumatology, and Pulmonology at the Amala Institute of Medical Sciences, Thrissur, and Kerala from November 2015 to June 2017 that evaluated 74 patients having connective tissue disease-related ILD. A detailed history and a thorough clinical examination were done.

OA12 Autoantibodies are common in patients labelled as “idiopathic” interstitial lung disease suggesting a high prevalence of undiagnosed autoimmune connective tissue disease

Abstract Background/Aims In some patients, interstitial lung disease (ILD) may be the dominant or even sole clinically overt manifestation of an otherwise unrecognised autoimmune connective tissue disease (CTD). Accurate diagnosis can be challenging given considerable overlap of the clinical, radiological and histological disease features. Distinguishing CTD-related ILD (CTD-ILD) from idiopathic ILD can avoid a lung biopsy, enables appropriate immunosuppressive treatment, informs prognosis and facilitates monitoring for other CTD-associated complications. Autoantibodies are a hallmark feature of CTD, are highly disease-specific and their presence is strongly suggestive of covert CTD-ILD. We investigated patients who had been labelled with “idiopathic” ILD by their local hospital teams for the presence of autoantibodies that may suggest misdiagnosis. Methods Serum from two groups of patients recruited to UK Biomarkers of Interstitial Lung Disease (BILD) were analysed: 183 with a local diagnosis of idiopathic non-specific interstitial pneumonia (iNSIP) and 34 with a local diagnosis of idiopathic or Cryptogenic Organising Pneumonia (COP). Autoantibody status was determined by radio-immunoprecipitation. Results Overall, CTD-autoantibodies were identified in 15% of patients with a prior label of “idiopathic” ILD. CTD autoantibodies were more common in those with a prior diagnosis of COP, where more than 1 in 5 patient samples contained a potentially relevant autoantibody, see table. The autoantibodies identified included those readily detectable e.g. anti-Jo1, in addition to rarer antibodies not included in standard assays e.g. anti-EIF2B. Nearly half of all autoantibodies detected were anti-synthetase autoantibodies. Conclusion Covert CTD-ILD is potentially being missed as a diagnosis in patients who have been labelled by local teams as having idiopathic forms of inflammatory ILD (COP or iNSIP). More specific guidance on autoantibody testing and the interpretation of these test results could improve diagnosis and ensure patients receive more appropriate management. Disclosure S.L. Tansley: None. C.V. Cotton: None. F.K. McMorrow: None. H. Lu: None. Z.E. Betteridge: None. R.P. New: None. L.G. Spencer: None. N.J. McHugh: None. R.G. Cooper: None.

P221 Autoantibodies are common in patients with idiopathic interstitial lung disease, suggesting a high prevalence of undiagnosed autoimmune connective tissue disease

Abstract Background/Aims In some patients, interstitial lung disease (ILD) may be the dominant or even sole manifestation of an otherwise unrecognised autoimmune connective tissue disease (CTD). Accurate diagnosis can be challenging given considerable overlap of the clinical, radiological and histological disease features. Distinguishing CTD related ILD (CTD-ILD) from idiopathic ILD, enables appropriate immunosuppressive treatment, informs prognosis and facilitates monitoring for other CTD associated complications. Occasionally a lung biopsy may be necessary to ensure accurate diagnosis. Autoantibodies are a hallmark feature of CTD, are highly disease specific and their presence is strongly suggestive of covert CTD-ILD. We investigated patients with idiopathic ILD for the presence of autoantibodies that may suggest misdiagnosis. Methods The serum from three subgroups of patients recruited to UK Biomarkers of Interstitial Lung Disease (BILD) were analysed: 171 with a diagnosis of idiopathic ILD and non-specific organising pneumonia on HRCT and 27 with a diagnosis of idiopathic ILD and cryptogenic organising pneumonia on HRCT. Autoantibody status was determined by radio-immunoprecipitation. Results Results are summarised in Table 1. Overall CTD-autoantibodies were identified in 15.6% of patients with idiopathic ILD, and were more common in those with NSIP, see table. Autoantibodies identified included those readily detectable e.g. anti-Jo1, in addition to rarer antibodies not included in standard assays e.g. anti-EIF3. Nearly half of all autoantibodies detected were anti-synthetase autoantibodies. Conclusion Covert-CTD is likely to be common amongst patients diagnosed with idiopathic ILD, particularly idiopathic NSIP. More specific guidance on autoantibody testing could improve diagnosis and ensure patients receive appropriate immunosuppressive treatment. Disclosure S. Tansley: None. C. Cotton: None. F.K. McMorrow: None. H. Lu: None. R.P. New: None. L.G. Spencer: None. N.J. McHugh: None. R.G. Cooper: None.

The mechanism of triptolide in the treatment of connective tissue disease-related interstitial lung disease based on network pharmacology and molecular docking

Background Interstitial lung disease (ILD) is associated with substantial morbidity and mortality, which is one of the key systematic manifestations of connective tissue disease (CTD). Tripterygium wilfordii, known as Leigongteng in Chinese, has been applied to treat connective tissue disease-related interstitial lung disease (CTD-ILD) for many years. Triptolide is a key effective component from Tripterygium wilfordii. But the molecular mechanism of Triptolide for treating CTD-ILD is not yet clear. Methods Gaining insight into the molecular mechanism of Triptolide intervention CTD-ILD, we used the method of network pharmacology. And then we conducted drug-target networks to analyse the potential protein targets between Triptolide and CTD-ILD. Finally, AutoDock Vina was selected for molecular docking. Results By analysing the interaction genes between Triptolide and CTD-ILD, 242 genes were obtained. The top 10 targets of the highest enrichment scores were STAT3, AKT1, MAPK1, IL6, TP53, MAPK3, RELA, TNF, JUN, JAK2. GO and KEGG enrichment analysis exhibited that multiple signalling pathways were involved. PI3K-Akt, multiple virus infections, cancer signalling, chemokine, and apoptosis signalling pathway are the main pathways for Triptolide intervention CTD-ILD. And it is related to various biological processes such as inflammation, infection, cell apoptosis, and cancer. Molecular docking shows Triptolide can bind with its target protein in a good bond by intermolecular force. Conclusions This study preliminarily reveals the internal molecular mechanism of Triptolide interfere with CTD-ILD through multiple targets, multiple access, validated through molecular docking. KEY MESSAGES Triptolide intervention CTD-ILD, which are related to various biological processes such as inflammation, infection, cell apoptosis, and cancer. PI3K-Akt, multiple virus infections, and apoptosis signalling pathway are the main pathways for Triptolide intervention CTD-ILD. Triptolide can bind with related target protein in a good bond by Intermolecular force, exhibiting a good docking activity.

Immunomodulatory treatment of interstitial lung disease.

Interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) have an array of immunomodulatory treatment options compared with IPF, due to their inflammatory component. However, there is a relative paucity of guidance on the management of this heterogeneous group of diseases. In ILDs other than IPF, immunosuppression is the cornerstone of therapy, with varying levels of evidence for different immunomodulatory agents and for each specific ILD. Classification of ILDs is important for guiding treatment decisions. Immunomodulatory agents mainly include corticosteroids, mycophenolate mofetil (MMF), azathioprine, methotrexate, cyclophosphamide and rituximab. In this review, the available evidence for single agents in the most common ILDs is first discussed. We then reviewed practical therapeutic approaches in connective tissue disease–related ILD and interstitial pneumonia with autoimmune features, scleroderma-related ILD, vasculitis and dermatomyositis with hypoxemic respiratory failure, idiopathic non-specific interstitial pneumonia, hypersensitivity pneumonitis sarcoidosis, fibrosing organizing pneumonia and eosinophilic pneumonia. The treatment of acute exacerbations of ILD is also discussed. Therapy augmentation in ILD is dictated by the recognition of progression of disease. Criteria for the evaluation of progression of disease are then discussed. Finally, specific protocol and measures to increase patients’ safety are reviewed as well, including general monitoring and serologic surveillance, Pneumocystis jirovecii prophylaxis, patients’ education, genetic testing for azathioprine, MMF serum levels and cyclophosphamide administration protocols. Immunomodulatory therapies are largely successful in the management of ILDs and can be safely managed with the application of specific protocols, precautions and monitoring.

Management of Connective Tissue Disease-related Interstitial Lung Disease.

Purpose of ReviewThis review aims to collate current evidence on the screening, diagnosis, and treatment of various connective tissue disease (CTD)–associated interstitial lung diseases (CTD-ILD) and present a contemporary framework for the management of such patients. It also seeks to summarize treatment outcomes including efficacy and safety of immunosuppressants, anti-fibrotics, and stem cell transplantation in CTD-ILD.Recent FindingsScreening for ILD has been augmented by the use of artificial intelligence, ultra-low dose computerized tomography (CT) of the chest, and the use of chest ultrasound. Serum biomarkers have not found their way into clinical practice as yet. Identifying patients who need treatment and choosing the appropriate therapy is important to minimize the risk of therapy-related toxicity. The first-line drugs for systemic sclerosis (SSc) ILD include mycophenolate and cyclophosphamide. Nintedanib, an anti-fibrotic tyrosine kinase inhibitor, is approved for use in SSc-ILD. The US Food and Drug Administration (FDA) has recently approved tocilizumab subcutaneous injection for slowing the rate of decline in pulmonary function in adult patients with SSc-ILD. Autologous stem cell transplantation may have a role in select cases of SSc-ILD.SummaryCTD-ILD is a challenging area with diverse entities and variable outcomes. High-resolution CT is the investigative modality of choice. Treatment decisions need to be individualized and are based on patient symptoms, lung function, radiologic abnormalities, and the risk of disease progression. Precision medicine may play an important role in determining the optimal therapy for an individual patient in the future.

Covid-19 Course in Connective Tissue Disease-Related Interstitial Lung Disease Patients

Covid-19 Course in Connective Tissue Disease-Related Interstitial Lung Disease Patients

Medication-induced Pulmonary Injury: A Scenario- and Pattern-based Approach to a Perplexing Problem.

Medication-induced pulmonary injury (MIPI) is a complex medical condition that has become increasingly common yet remains stubbornly difficult to diagnose. Diagnosis can be aided by combining knowledge of the most common imaging patterns caused by MIPI with awareness of which medications a patient may be exposed to in specific clinical settings. The authors describe six imaging patterns commonly associated with MIPI: sarcoidosis-like, diffuse ground-glass opacities, organizing pneumonia, centrilobular ground-glass nodules, linear-septal, and fibrotic. Subsequently, the occurrence of these patterns is discussed in the context of five different clinical scenarios and the medications and medication classes typically used in those scenarios. These scenarios and medication classes include the rheumatology or gastrointestinal clinic (disease-modifying antirheumatic agents), cardiology clinic (antiarrhythmics), hematology clinic (cytotoxic agents, tyrosine kinase inhibitors, retinoids), oncology clinic (immune modulators, tyrosine kinase inhibitors, monoclonal antibodies), and inpatient service (antibiotics, blood products). Additionally, the article draws comparisons between the appearance of MIPI and the alternative causes of lung disease typically seen in those clinical scenarios (eg, connective tissue disease-related interstitial lung disease in the rheumatology clinic and hydrostatic pulmonary edema in the cardiology clinic). Familiarity with the most common imaging patterns associated with frequently administered medications can help insert MIPI into the differential diagnosis of acquired lung disease in these scenarios. However, confident diagnosis is often thwarted by absence of specific diagnostic tests for MIPI. Instead, a working diagnosis typically relies on multidisciplinary consensus. ©RSNA, 2021.

Assessing the role for nailfold videocapillaroscopy in interstitial lung disease classfication: a systematic review and meta-analysis.

The nailfold videocapillaroscopy (NVC) has been known to assist with interstitial lung disease (ILD) classification. However, evidence on its diagnostic efficacy is limited, particularly in some connective tissue disease-related interstitial lung diseases (CTD-ILD), and in interstitial pneumonia with autoimmune features (IPAF). This study aimed to address this limitation by conducting a meta-analysis on the efficacy of the NVC in ILD subgroups of CTD-ILD, IPAF and idiopathic pulmonary fibrosis (IPF). MEDLINE, EMBASE, CENTRAL were screened from inception to December 2020 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies that report prevalence of nailfold abnormalities (NVC+) in CTD-ILD, IPAF and IPF cohorts were included. Data were presented as prevalence ratio (PR) with 95% CI using a random-effects model. Quality of evidence was assessed using GRADE criteria. Twenty-one studies were eligible. Prevalence of NVC+ was highest in CTD-ILD; PR (95 CI%) 80.4% (74.3%, 85.3%), followed by IPAF; 27.4% (10.9%, 53.7%), and IPF; 13.8% (5.7%, 29.9%). Late scleroderma pattern was the most prevalent nailfold pattern; 40.4% (28.1%, 54.1%) in our CTD-ILD cohort. Quality of evidence was low for CTD-ILD, IPAF and IPF cohorts, moderate for the late scleroderma pattern cohort. NVC can increase the diagnostic accuracy of ILD when used in a multi-disciplinary setting, and appears to have greatest utility in CTD-ILD, followed by IPAF and IPF. The Late Scleroderma Pattern was the most frequent nailfold capillary pattern in SSc-ILD. Future research will allow for greater understanding of the prognostic value of the NVC in ILD.

Predictive Factors for Pneumomediastinum During Management of Connective Tissue Disease-related Interstitial Lung Disease: A Retrospective Study.

Objective To identify factors associated with pneumomediastinum during management of connective tissue disease (CTD)-related interstitial lung disease (ILD). Methods Patients diagnosed with pneumomediastinum after the initiation of corticosteroid therapy for their CTD-ILD were enrolled. The baseline characteristics of patients who developed pneumomediastinum after the initiation of corticosteroid therapy (n=13, all occurring within 120 days) were compared to those of patients who did not develop pneumomediastinum (n=49). A multivariate logistic regression analysis was performed to identify factors associated with pneumomediastinum. A receiver operating characteristic (ROC) curve analysis was also performed to assess the predictive performance. Results The body mass index (BMI) [odds ratio (OR) (95% confidence interval (CI)) 0.482 (0.272-0.853)] and serum lactate dehydrogenase (LDH) [OR (95% CI) 1.013 (1-1.025)] levels at baseline were identified as independent factors associated with pneumomediastinum after corticosteroid initiation. The optimal cut-off points of the BMI and LDH levels for predicting pneumomediastinum development, as estimated by the Youden index, were 20.2 kg/m2 and 378 U/L, respectively. LDH showed a sensitivity of 61.5% and the highest specificity of 87.8%. Importantly, combining these markers resulted in the highest sensitivity of 100% and a specificity of 71.4%. Conclusion A low BMI and high serum LDH levels at baseline are useful predictive factors for pneumomediastinum development in CTD-ILD patients.

Computed Tomography Findings Suggestive of Connective Tissue Disease in the Setting of Usual Interstitial Pneumonia.

A usual interstitial pneumonia (UIP) pattern is common in idiopathic pulmonary fibrosis (IPF) and connective tissue disease-related interstitial lung disease (CTD-ILD). The purpose of the study was to validate imaging findings differentiating CTD-ILD from IPF in UIP. Patients with a multidisciplinary diagnosis of CTD-ILD or IPF and a UIP pattern on computed tomography and/or pathology were included in this study. Prevalence of 3 computed tomography findings shown to be associated with CTD-ILD (the straight edge sign [SES], the exuberant honeycombing sign, and the anterior upper lobe sign [AULS]) were tabulated in CTD-ILD and IPF subjects. The ability of each of these signs to discriminate between CTD-ILD and IPF was evaluated. Survival analysis was also performed using log-rank analysis. The study cohort included 50 CTD-ILD and 100 IPF subjects with UIP. The SES and the AULS were more common in CTD-ILD than IPF (prevalence, 36.0% and 34.9% in CTD-ILD vs 8.3% and 17.2% in IPF, respectively [P = 0.0105 - <0.001]). The highest specificity (95.7%) of CTD-ILD diagnosis was seen with bilateral SES. Moreover, the SES was associated with improved survival (P = 0.0383), which appeared to be largely because of improvement in survival in IPF subjects. The presence of AULS was associated with pulmonary functional abnormalities. A radiographic UIP pattern with evidence of SES or the AULS should raise suspicion for CTD-ILD rather than IPF. Patients with IPF and SES have an attenuated disease course and might represent a different phenotype than those without the SES.

Differentiation of Idiopathic Pulmonary Fibrosis from Connective Tissue Disease-Related Interstitial Lung Disease Using Quantitative Imaging.

A usual interstitial pneumonia (UIP) imaging pattern can be seen in both idiopathic pulmonary fibrosis (IPF) and connective tissue disease-related interstitial lung disease (CTD-ILD). The purpose of this multicenter study was to assess whether quantitative imaging data differ between IPF and CTD-ILD in the setting of UIP. Patients evaluated at two medical centers with CTD-ILD or IPF and a UIP pattern on CT or pathology served as derivation and validation cohorts. Chest CT data were quantitatively analyzed including total volumes of honeycombing, reticulation, ground-glass opacity, normal lung, and vessel related structures (VRS). VRS was compared with forced vital capacity percent predicted (FVC%) and percent predicted diffusing capacity of the lungs for carbon monoxide (DLCO%). There were 296 subjects in total, with 40 CTD-ILD and 85 IPF subjects in the derivation cohort, and 62 CTD-ILD and 109 IPF subjects in the validation cohort. VRS was greater in IPF across the cohorts on univariate (p < 0.001) and multivariable (p < 0.001–0.047) analyses. VRS was inversely correlated with DLCO% in both cohorts on univariate (p < 0.001) and in the derivation cohort on multivariable analysis (p = 0.003) but not FVC%. Total volume of normal lung was associated with DLCO% (p < 0.001) and FVC% (p < 0.001–0.009) on multivariable analysis in both cohorts. VRS appears to have promise in differentiating CTD-ILD from IPF. The underlying pathophysiological relationship between VRS and ILD is complex and is likely not explained solely by lung fibrosis.

The Application of Transbronchial Lung Cryobiopsy and Uniportal and Tubeless Video-Assisted Thoracic Surgery in the Multidisciplinary Diagnosis of Interstitial Lung disease-A Real-World Prospective Study.

The application of transbronchial lung cryobiopsy (TBLC) and uniportal and tubeless video-assisted thoracic surgery (UT-VATS) in the multidisciplinary diagnosis of interstitial lung disease (ILD) has not been demonstrated in real-world clinical practice. This prospective study included 137 patients with no definitive diagnosis who were the subject of two multidisciplinary discussion (MDD) sessions. As indicated in the first MDD, 67 patients underwent UT-VATS and 70 underwent TBLC. The specificity of biopsy information and its contribution to final MDD diagnosis were evaluated in the second MDD. The post-operative complications and hospitalization costs associated with the two biopsy methods were compared. UT-VATS was favored for patients initially diagnosed with idiopathic pulmonary fibrosis (IPF), bronchiolitis-associated interstitial lung disease (RB-ILD)/desquamative interstitial pneumonia (DIP) and undefined idiopathic interstitial pneumonia (UIIP), while TBLC was preferred for pulmonary lymphangioleiomyomatosis (PLAM) and pulmonary alveolar proteinosis (PAP). The spirometry parameters were better in patients who underwent UT-VATS than those who underwent TBLC. UT-VATS provided more specific pathological results than TBLC (85.7 vs 73.7%, p = 0.06). In patients initially diagnosed with UIIP, pathological information from UT-VATS was more clinically useful than that obtained from TBLC, although both tests contributed similarly to cases initially diagnosed as interstitial pneumonia with auto-immune features (IPAF)/connective tissue disease-related ILD (CTD-ILD). The safety of UT-VATS was comparable with TBLC although TBLC was cheaper during hospitalization (US$4,855.7 vs US$3,590.9, p < 0.001). multidisciplinary discussion decisions about biopsies were driven by current knowledge of sampling and diagnosis capacity as well as potential risks of different biopsy methods. The current MDD considered UT-VATS more informative than TBLC in cases initially diagnosed as UIIP although they were equally valuable in patients initially diagnosed with IPAF/CTD-ILD.

Interstitial Lung Disease in Connective Tissue Disease: A Common Lesion With Heterogeneous Mechanisms and Treatment Considerations.

Connective tissue disease (CTD) related interstitial lung disease (CTD-ILD) is one of the leading causes of morbidity and mortality of CTD. Clinically, CTD-ILD is highly heterogenous and involves rheumatic immunity and multiple manifestations of respiratory complications affecting the airways, vessels, lung parenchyma, pleura, and respiratory muscles. The major pathological features of CTD are chronic inflammation of blood vessels and connective tissues, which can affect any organ leading to multi-system damage. The human lung is particularly vulnerable to such damage because anatomically it is abundant with collagen and blood vessels. The complex etiology of CTD-ILD includes genetic risks, epigenetic changes, and dysregulated immunity, which interact leading to disease under various ill-defined environmental triggers. CTD-ILD exhibits a broad spectra of clinical manifestations: from asymptomatic to severe dyspnea; from single-organ respiratory system involvement to multi-organ involvement. The disease course is also featured by remissions and relapses. It can range from stability or slow progression over several years to rapid deterioration. It can also present clinically as highly progressive from the initial onset of disease. Currently, the diagnosis of CTD-ILD is primarily based on distinct pathology subtype(s), imaging, as well as related CTD and autoantibodies profiles. Meticulous comprehensive clinical and laboratory assessment to improve the diagnostic process and management strategies are much needed. In this review, we focus on examining the pathogenesis of CTD-ILD with respect to genetics, environmental factors, and immunological factors. We also discuss the current state of knowledge and elaborate on the clinical characteristics of CTD-ILD, distinct pathohistological subtypes, imaging features, and related autoantibodies. Furthermore, we comment on the identification of high-risk patients and address how to stratify patients for precision medicine management approaches.