Background: Cardiovascular diseases are frequent in idiopathic pulmonary fibrosis (IPF) and impact on survival. We investigated the association of coronary artery calcium (CAC) score at IPF diagnosis and during mid-term follow-up, with adverse cardiovascular events and all-cause mortality.

Methods: Consecutive patients with IPF were retrospectively analyzed. Demographic data, smoking history, comorbidities and pulmonary function tests (PFTs) were recorded. All patients had at least two chest high resolution computed tomography (HRCT) performed 2 years apart. The total CAC score and visual fibrotic score were calculated and all clinically significant cardiovascular events and deaths were reported.

Results: The population consisted of 79 patients (57 male, mean age 74.4 ± 7.6 years); 67% of patients had a history of smoking, 48% of hypertension, 37% of dyslipidemia and 22.8% of diabetes. The visual score was 21.28 ± 7.99% at T0 and 26.54 ± 9.34% at T1, respectively (T1-T0 5.26 ± 6.13%, p< 0.001). CAC score at T0 and at T1 was 537.93 ± 839.94 and 759.98 ± 1027.6, respectively (T1-T0 224.66 ± 406.87, p< 0.001). Mean follow-up time was 2.47±1.1 years. On multivariate analysis, male sex (HR 3.58, 95% CI 1.14-11.2) and CAC score at T0 (HR 1.04, 95% CI 1.01-1.07) correlated with mortality and cardiovascular events. CAC score at T0 ≥405 showed 82% sensitivity and 100% specificity for predicting mortality and adverse cardiovascular events.

Conclusions: IPF patients with a CAC score at diagnosis ≥405 have a poor prognosis over a midterm follow-up. A higher CAC score is associated with mortality and cardiovascular events.

Idiopathic pulmonary fibrosis is a progressive disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is attracting considerable attention due to disease acceleration and substantial mortality. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. In this review pathways such as Wnt/β-catenin pathway, TGF-β/Smad signaling pathway and EMT in IPF, VEGF and its relation with PI3K–Akt signalling pathway, PI3-Akt pathway, PDGF Signalling Pathway, Hippo/YAP signalling, JAK/STAT pathway, Rnd3/p190/Rho-Gap pathway have been discussed. This review also covers current therapeutic strategies in relation to idiopathic pulmonary fibrosis.

Background: Patients with idiopathic pulmonary fibrosis (IPF) frequently have multiple comorbidities, which may influence survival but go under-recognised in clinical practice. We therefore report comorbidity, antifibrotic treatment use and survival of patients with IPF observed in the multi-national EMPIRE registry.

Methods: For this prospective IPF cohort, demographics, comorbidities, survival and causes of death were analysed. Comorbidities were noted by the treating physician based on the patient's past medical history or as reported during follow-up. Comorbidities were defined as prevalent when noted at enrolment, or as incident when recorded during follow-up. Survival was analysed by Kaplan-Meier estimates, log-rank test, and Cox proportional hazards models. Hazard ratios (HR) were adjusted for gender, age, smoking status and FVC at enrolment.

Results: A population of 3,580 patients with IPF from 11 Central and Eastern European countries was followed every 6 months for up to 6 years. At enrolment, 91.3% of patients reported at least one comorbidity, whereas more than one-third (37.8%) reported four or more comorbidities. Five-year survival was 53.7% in patients with no prevalent comorbidities, whereas it was 48.4%, 47.0%, 43.8% and 41.1% in patients with 1, 2, 3 and ≥ 4 comorbidities, respectively. The presence of multiple comorbidities at enrolment was associated with significantly worse survival (log-rank test P = 0.007). Adjusted HRs indicate that risk of death was increased by 44% in patients with IPF reporting ≥ 4 comorbidities at baseline compared with no comorbidity (P = 0.021). The relationship between number of comorbidities and decreased survival was also seen in patients receiving antifibrotic treatment (63% of all patients; log-rank test P < 0.001). Comorbidity as cause of death was identified in at least 26.1% of deaths.

Conclusions: The majority of patients with IPF demonstrate comorbidities, and many have comorbidity-related deaths. Increasing numbers of comorbidities are associated with worse survival; and this pattern is also present in patients receiving antifibrotic therapy.

Objective: To assess the prognostic performance of two quantitative CT (qCT) techniques in idiopathic pulmonary fibrosis (IPF) compared to established clinical measures of disease severity (GAP index).

Methods: Retrospective analysis of high-resolution CT scans for 59 patients (age 70.5 ± 8.8 years) with two qCT methods. Computer-aided lung informatics for pathology evaluation and ratings based analysis classified the lung parenchyma into six different patterns: normal, ground glass, reticulation, hyperlucent, honeycombing and pulmonary vessels. Filtration histogram-based texture analysis extracted texture features: mean intensity, standard deviation (SD), entropy, mean of positive pixels (MPPs), skewness and kurtosis at different spatial scale filters. Univariate Kaplan-Meier survival analysis assessed the different qCT parameters' performance to predict patient outcome and refine the standard GAP staging system. Multivariate cox regression analysis assessed the independence of the significant univariate predictors of patient outcome.

Results: The predominant parenchymal lung pattern was reticulation (16.6% ± 13.9), with pulmonary vessel percentage being the most predictive of worse patient outcome (p = 0.009). Higher SD, entropy and MPP, in addition to lower skewness and kurtosis at fine texture scale (SSF2), were the most significant predictors of worse outcome (p < 0.001). Multivariate cox regression analysis demonstrated that SD (SSF2) was the only independent predictor of survival (p < 0.001). Better patient outcome prediction was achieved after adding total vessel percentage and SD (SSF2) to the GAP staging system (p = 0.006).

Conclusion: Filtration-histogram texture analysis can be an independent predictor of patient mortality in IPF patients.

The revised definition of acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) was proposed in 2016, but changes in the incidence and impact on prognosis of the re-defined AE compared to those of the previous definition remain unclear. Clinical data of 445 patients with IPF (biopsy proven cases: 165) were retrospectively reviewed. The median follow-up period was 36.8 months and 17.5% (n = 78) experienced AE more than once. The 1- and 3-year incidence rates of AE were 6.7% and 16.6%, respectively, and idiopathic AE accounted for 82.1% of AE. Older age, lower diffusing capacity of the lung for carbon monoxide and 10% relative decline in forced vital capacity for 6 months were independently associated with AE. The in-hospital mortality rate following AE was 29.5%. In the multivariable analysis, AE was independently associated with poor prognosis in patients with IPF. Compared to the old definition, the revised definition relatively increased the incidence of AE by 20.4% and decreased the in-hospital mortality by 10.1%. Our results suggest that the revised definition affects approximately 20% increase in the incidences and 10% reduction in the in-hospital mortality of AE defined by the past definition.

Nintedanib is an oral small-molecule kinase inhibitor and first-line treatment for idiopathic pulmonary fibrosis. Nintedanib is a substrate of the drug efflux transporter ABCB1. Green tea flavonoids --especially epigallocatechin gallate (EGCG)-- are potent ABCB1 modulators. We investigated if concomitant administration of green tea extract (GTE) could result in a clinically relevant herb-drug interaction. Patients were randomized between A-B and B-A, with A being nintedanib alone and B nintedanib with GTE. Both periods lasted 7 days, in which nintedanib was administered twice daily directly after a meal. In period B, patients additionally received capsules with GTE (500 mg BID, >60% EGCG). Pharmacokinetic sampling for 12 h was performed at day 7 of each period. Primary endpoint was change in geometric mean for the area under the curve (AUC0-12 h). A linear mixed model was used to analyse AUCs and maximal concentration (Cmax). In 26 included patients, the nintedanib AUC0-12 h was 21% lower (95% CI -29% to -12%; P < 0.001) in period B (with GTE) compared to period A. Cmax did not differ significantly between periods; - 14% (95% CI -29% to +4%; P = 0.12). The detrimental effect was predominant in patients with the ABCB1 3435 C>T wild type variant. No differences in toxicities were observed. Exposure to nintedanib decreased with 21% when administered 60 min after GTC for only 7 days. This is a statistically significant interaction which could potentially impair treatment efficacy. Before patients and physicians should definitely be warned to avoid this combination, prospective clinical validation of an exposure-response relationship is necessary.

Background and objective: Rheumatoid arthritis (RA) is a frequent cause of interstitial lung disease (ILD); however, the impact of rheumatoid factor and anti-citrullinated peptide antibody seropositivity in ILD without connective tissue disease (CTD) is unclear. We examined the association of seropositivity with ILD progression, mortality and response to immunosuppression in non-CTD ILD.

Methods: A total of 1570 non-CTD patients (with idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, interstitial pneumonia with autoimmune features or unclassifiable ILD) and 181 RA-ILD patients were included from a prospective registry. Longitudinal forced vital capacity (FVC), transplant-free survival and incidence of progressive fibrosing-ILD (PF-ILD) were compared between seronegative non-CTD ILD (reference group), seropositive non-CTD ILD and RA-ILD using linear mixed-effect and Cox proportional hazards models adjusted for age, sex, smoking pack-years and baseline FVC. Interaction between seropositivity and immunosuppression on FVC decline was assessed in patients with ≥6 months of follow-up before and after the treatment.

Results: Two hundred and seventeen (13.8%) patients with seropositive non-CTD ILD had similar rates of FVC decline and transplant-free survival compared to seronegative non-CTD ILD, but more frequently met the criteria for PF-ILD (hazard ratio [HR] = 1.35, p = 0.004). RA-ILD had slower FVC decline (p = 0.03), less PF-ILD (HR = 0.75, p = 0.03) and lower likelihood of lung transplant or death (HR = 0.66, p = 0.01) compared to seronegative non-CTD ILD. No interaction was found between seropositivity and treatment on FVC decline in non-CTD ILD.

Conclusion: Seropositivity in non-CTD ILD was not associated with improved outcomes or treatment response, highlighting the importance of other disease features in determining prognosis and predicting response to immunosuppression..

Background: Silicosis is associated with an increased risk of developing systemic autoimmune rheumatic disease (SARD). The prognostic implications of this association are poorly characterized. The aim of this study was to determine the prevalence of SARD and autoimmune markers in a cohort of patients with exposure to silica and assess their impact on prognosis.

Method: We performed a prospective observational study of all patients attending the dedicated silicosis clinic of our pulmonology unit between 2009 and December 2017. Diagnosis was confirmed by a rheumatologist according to Spanish Rheumatology Society criteria. Autoimmune markers, pulmonary function tests, radiological progression, visits to the emergency department and primary care center, and hospital admissions for respiratory causes, and mortality were analyzed.

Results: Overall, 489 cases of silicosis and 95 cases of exposure were studied. In total, 54 (11.0%) patients with silicosis had SARD: 12 (2.4%) rheumatoid arthritis, 10 (2.0%) systemic lupus erythematosus, 10 (2.0%) systemic sclerosis, 3 (0.6%) Sjögren syndrome, 2 (0.4%) vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA +), 6 (1.2%) psoriatic arthritis, 3 (0.6%) ankylosing spondylitis, and 8 (1.6%) other autoimmune diseases with no special features. The patients with SARD visited the emergency room more often (63.0% vs. 42.5%; p = 0.004), and progressed more rapidly (22.2 vs. 11.7%; p = 0.030).

Conclusions: The presence of systemic rheumatic autoimmune diseases involves radiological progression and a higher clinical impact.

Aim: Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and is associated with high mortality, especially in progressive ILD. We aimed to identify predictors of disease progression in the early stages of ILD in a large sample of patients with RA.

Method: The medical records of 201 RA-ILD patients were retrospectively analyzed. According to changes in their pulmonary function tests, patients were divided into progressive disease and stable disease groups. Data were collected on clinical characteristics, laboratory findings, chest high-resolution computed tomography, and therapeutic agents. Univariate and multivariate analyses were performed to identify predictors of ILD progression.

Results: During a median follow up of 38 months, 105 (52.5%) patients were diagnosed with progressive ILD. These patients were mostly male, past or present smokers (P = 0.028, P = 0.021, respectively). Higher Health Assessment Questionnaire-Disability Index score and higher Disease Activity Score in 28 joints with erythrocyte sedimentation rate (DAS28-ESR) were observed in the ILD progression group (P = 0.003, P < 0.001, respectively). There were no significant differences in baseline respiratory symptoms, pulmonary function, or laboratory features. Multivariate analysis indicated that high DAS28-ESR, definite usual interstitial pneumonia pattern, fibrosis score, and less use of cyclophosphamide were independent risk factors for RA-ILD progression. Fifteen (7.46%) patients died during the follow up, and the most frequent cause of death was lung infection.

Conclusion: Our results suggested that high disease activity, definite usual interstitial pneumonia pattern, fibrosis score, and less use of cyclophosphamide at the onset of ILD may indicate the progression of ILD in RA patients.

Cross-analysis of clinical and pollution factors could help calculate the risk of fibrotic interstitial lung disease (ILD) development and progression. The intent of this study is to build a body of knowledge around early detection and diagnosis of lung disease, harnessing new data sets generated for other purposes. We cross-referenced exposure levels to particulate matter 2.5 (PM2.5) with telomere length of a cohort of 280 patients with fibrotic ILD to weigh impact and associations. There was no linear correlation between PM2.5 and telomere length in our data sets, as the value of the correlation coefficient was 0.08. This exploratory study offers additional insights into methodologies for investigating the development and prognosis of pulmonary fibrosis.

Introduction: Rheumatoid arthritis (RA) is the most common inflammatory autoimmune disease, characterised by symmetric destructive arthritis and synovitis. Lung involvement is frequent, including in the form of interstitial lung disease (ILD). RA-ILD often presents with a radiologic and pathologic pattern of usual interstitial pneumonia, similar to idiopathic pulmonary fibrosis, highlighting the similarities between the two diseases, but other patterns and pathological associations are described.

Areas covered: This article reviews the pathogenesis of pulmonary fibrosis in the setting of rheumatoid arthritis as well as the current and future therapeutic options.

Expert opinion: Pulmonary fibrosis in the setting of RA-ILD is an example of genotype-environment interaction and involves multiple mechanisms including autoimmunity, inflammation and fibrogenesis. Despite that ILD conveys most of the exceeding mortality in RA patients, there are no official guidelines for the management of RA-ILD. Attention should be paid to potential lung toxicity of RA treatment even though some of them might help stabilise the ILD. Current standard of care is often composed of glucocorticoids that may be associated with immunosuppressive therapy. Following the approval of antifibrotic therapy for ILDs with a progressive fibrosing phenotype, current works are evaluating the benefit of such treatment in RA-ILD.

Nintedanib is a multi-tyrosine kinase inhibitor widely used to treat progressive fibrosing interstitial lung diseases because it slows the reduction in forced vital capacity. However, the prognosis for patients treated with nintedanib remains poor. To improve nintedanib treatment, we examined the effects of nintedanib on gene expression in the lungs of induced-rheumatoid arthritis-associated interstitial lung disease model mice, which develop rheumatoid arthritis and subsequent pulmonary fibrosis. Using next-generation sequencing, we identified 27 upregulated and 130 downregulated genes in the lungs of these mice after treatment with nintedanib. The differentially expressed genes included mucin 5B and heat shock protein 70 family genes, which are related to interstitial lung diseases, as well as genes associated with extracellular components, particularly the myocardial architecture, suggesting unanticipated effects of nintedanib. Of the genes upregulated in the nintedanib-treated lung, expression of regulatory factor X2, which is suspected to be involved in cilia movement, and bone morphogenetic protein receptor type 2, which is involved in the pathology of pulmonary hypertension, was detected by immunohistochemistry and RNA in situ hybridization in peripheral airway epithelium and alveolar cells. Thus, the present findings indicate a set of genes whose expression alteration potentially underlies the effects of nintedanib on pulmonary fibrosis. It is expected that these findings will contribute to the development of improved nintedanib strategies for the treatment of progressive fibrosing interstitial lung diseases.

Objective: The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken.

Methods: Patient-reported outcome (PRO) measures (St. George's Respiratory Questionnaire [SGRQ], Functional Assessment of Chronic Illness Therapy [FACIT]-Dyspnoea, and Health Assessment Questionnaire-Disability Index [HAQ-DI], incorporating the Scleroderma Health Assessment Questionnaire visual analogue scale [SHAQ VAS]) at baseline and week 52 were assessed for associations to SSc-ILD severity.

Results: At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted (week 52: SGRQ 45.1 vs 34.0 [p< 0.0001]; FACIT-Dyspnoea 48.9 vs 44.5 [p< 0.0001]; HAQ-DI 0.7 vs 0.6 [p< 0.0228]; SHAQ VAS breathing problems 3.6 vs 2.6 [p< 0.0001]). Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (p< 0.001).

Conclusion: Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL.

Objective: To investigate the correlation of HRCT findings with pulmonary metabolic activity in the corresponding regions using 18F-FDG PET/CT and inflammatory markers in patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD).

Methods: This was a cross-sectional study involving 23 adult patients with SSc-associated ILD without other connective tissue diseases. The study also involved 18F-FDG PET/CT, HRCT, determination of serum chemokine levels, clinical data, and pulmonary function testing.

Results: In this cohort of patients with long-term disease (disease duration, 11.8 ± 8.7 years), a nonspecific interstitial pneumonia pattern was found in 19 (82.6%). Honeycombing areas had higher median standardized uptake values (1.95; p = 0.85). Serum levels of soluble tumor necrosis factor receptor 1, soluble tumor necrosis factor receptor 2, C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 10 were higher in SSc patients than in controls. Serum levels of CCL2-a marker of fibroblast activity-were correlated with pure ground-glass opacity (GGO) areas on HRCT scans (p = 0.007). 18F-FDG PET/CT showed significant metabolic activity for all HRCT patterns. The correlation between serum CCL2 levels and GGO on HRCT scans suggests a central role of fibroblasts in these areas, adding new information towards the understanding of the mechanisms surrounding cellular and molecular elements and their expression on HRCT scans in patients with SSc-associated ILD.

Conclusions: 18F-FDG PET/CT appears to be unable to differentiate the intensity of metabolic activity across HRCT patterns in chronic SSc patients. The association between CCL2 and GGO might be related to fibroblast activity in these areas; however, upregulated CCL2 expression in the lung tissue of SSc patients should be investigated in order to gain a better understanding of this association.

Systemic sclerosis (SSc) is a rare connective tissue disease characterised by immune dysfunction, vascular damage and fibrosis affecting the skin and multiple internal organs. The clinical spectrum of SSc is wide and its manifestations may lead to severe morbidity and mortality, in addition to a great impact on patients' quality of life. Due to the multifaceted clinical manifestations of SSc, its management requires a combined expertise of different medical specialists to guarantee an adequate disease control and prevent organ complications. Multi-disciplinary teams (MDT), which are composed by physicians and other specialized health professionals, represent therefore a key element for the comprehensive management of SSc patients. Moreover, MTD can improve communication and patients' empowerment while the presence of dedicated nurses can help patients to ask questions about their condition. The scope of this narrative review is to analyse the available evidences regarding the role of MDT in the management of SSc patients, and how this holistic approach may improve different disease domains and the overall prognosis. MDT regarding the cardiovascular and lung complication are the more represented in literature, given the great impact in prognosis. Nonetheless, MDT have been shown to be fundamental also in other disease domains as they can intercept early manifestations, thus stratifying patients based on the individual risks in order to personalize patients' follow-up. MDTs may also minimize the treatment delay, enabling fast-track specialist referral. On the other hand, there are few trials specifically studying MDT in SSc and several authors have highlight the lack of standardization.

Idiopathic pulmonary fibrosis is defined as a chronic progressive fibrosing interstitial pneumonia of unknown etiology. There are intrinsic and extrinsic risk factors that could favor the development of the disease in individuals with a genetic predisposition. The diagnosis is made by characteristic radiological and/or histological findings on high-resolution computed tomography and lung biopsy, respectively, in the absence of a specific identifiable cause. The median survival of the disease for patients without treatment is 3-5years from the onset of symptoms, although its natural history is variable and unpredictable. Currently, there are two antifibrotic drugs that reduce disease progression. The multidisciplinary approach will consider the nutritional and emotional status, physical conditioning, and treatment of comorbidities, as well as lung transplantation and palliative care in advanced stages. The following article reviews the fundamental aspects for the diagnosis and treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a progressive disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is attracting considerable attention due to disease acceleration and substantial mortality. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. In this review pathways such as Wnt/β-catenin pathway, TGF-β/Smad signaling pathway and EMT in IPF, VEGF and its relation with PI3K–Akt signalling pathway, PI3-Akt pathway, PDGF Signalling Pathway, Hippo/YAP signalling, JAK/STAT pathway, Rnd3/p190/Rho-Gap pathway have been discussed. This review also covers current therapeutic strategies in relation to idiopathic pulmonary fibrosis.

Objective: Detect the expression of Interleukin-6 (IL-6) in the serum of patients with systemic sclerosis (SSc) and assess its association with clinical and laboratory features of the disease.

Methods: The clinical data from 50 patients with SSc in the affiliated hospital of Xuzhou Medical University, China were retrospectively analyzed. The level of IL-6 in peripheral blood of systemic sclerosis patients was compared between the different clinical phenotypes groups. Spearman correlation test was used to analyze the correlation of the IL-6 with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), creatinine, and cystatin C.

Results: Interleukin-6 increased in the disease course ≥5 years, systemic sclerosis-Interstitial lung disease (SSc-ILD), pulmonary arterial hypertension (PAH), gastrointestinal involvement, and cardiac involvement group compared with the group with disease course <5 years, no SSc-ILD, PAH, gastrointestinal involvement, and no cardiac involvement group. The differences were statistically significant (p < 0.05). Correlation analysis showed that IL-6 in the group with disease course ≥5 years had a positive correlation with ESR (Rs = 0.438, p = 0.022) and CRP (Rs = 0.825, P < 0.001), whereas it was negatively correlated with creatinine (Rs = -0.481, p = 0.011). Nevertheless, when it came to disease course <5 years, the figures had no statistically significant difference.

Conclusion: Serum IL-6 in patients with systemic sclerosis is related to different clinical phenotypes. IL-6 helps to diagnose various phases of diseases, monitor severities of diseases, and predict the prognosis of patients.

Objectives: To compare the lung CT volume (CTvol) and pulmonary function tests in an interstitial lung disease (ILD) population. Then to evaluate the CTvol loss between idiopathic pulmonary fibrosis (IPF) and non-IPF and explore a prognostic value of annual CTvol loss in IPF.

Methods: We conducted in an expert center a retrospective study between 2005 and 2018 on consecutive patients with ILD. CTvol was measured automatically using commercial software based on a deep learning algorithm. In the first group, Spearman correlation coefficients (r) between forced vital capacity (FVC), total lung capacity (TLC), and CTvol were calculated. In a second group, annual CTvol loss was calculated using linear regression analysis and compared with the Mann-Whitney test. In a last group of IPF patients, annual CTvol loss was calculated between baseline and 1-year CTs for investigating with the Youden index a prognostic value of major adverse event at 3 years. Univariate and log-rank tests were calculated.

Results: In total, 560 patients (4610 CTs) were analyzed. For 1171 CTs, CTvol was correlated with FVC (r: 0.86) and TLC (r: 0.84) (p < 0.0001). In 408 patients (3332 CT), median annual CTvol loss was 155.7 mL in IPF versus 50.7 mL in non-IPF (p < 0.0001) over 5.03 years. In 73 IPF patients, a relative annual CTvol loss of 7.9% was associated with major adverse events (log-rank, p < 0.0001) in univariate analysis (p < 0.001).

Conclusions: Automated lung CT volume may be an alternative or a complementary biomarker to pulmonary function tests for the assessment of lung volume loss in ILD.

Disease progression (DP) is an important parameter for the prognosis of idiopathic pulmonary fibrosis (IPF). This study aimed to evaluate the baseline serum biomarkers for predicting the DP in IPF. Seventy-four patients who were diagnosed with IPF and had their serum Krebs von den Lungen-6 (KL-6) and monocyte count, which might be associated with prognosis of IPF, checked more than twice were included. KL-6 ≥ 1000 U/mL and monocyte ≥ 600/μL were arbitrarily set as the cut-off values for DP. The DP was defined as a 10% reduction in forced vital capacity, a 15% reduction in diffusing capacity of the lung for carbon monoxide relative to the baseline, or disease-related mortality. Of the 74 patients, 18 (24.3%) were defined as having DP. The baseline KL-6 level was significantly increased in the DP group compared to the stable disease group (median, 1228.0 U/mL vs. 605.5 U/mL, P = 0.019). Multivariate Cox analyses demonstrated that a high KL-6 level (KL-6 ≥ 1000 U/mL; hazard ratio, 2.761 or 2.845; P = 0.040 or 0.045) was independently associated with DP in each model. The baseline serum KL-6 level might be a useful biomarker for DP in IPF.

Introduction: Pulmonary fibrosis is an age-related, progressive, and fatal disease with a median survival of 3-5 years after diagnosis; idiopathic pulmonary fibrosis (IPF) is the most common type. It is characterized by fibroblast proliferation and accumulation of excessive extracellular matrix. Patients with IPF are at increased risk for lung cancer. Epigenetic mechanisms are involved in lung fibrosis and cancer, and DNA methylation is critical in disease pathogenesis and progression. Therefore, studies of DNA methylation contribute to better understanding of the underlying mechanisms of these two respiratory diseases, and can offer novel diagnostic and treatment options.

Areas covered: This review discusses the latest advances in our understanding of epigenetic factors related to DNA methylation that impact development of lung cancer and pulmonary fibrosis, discusses the role of DNA methylation in promoting or inhibiting these diseases, and proposes its potential clinical significance in disease diagnosis and treatment.

Expert opinion: DNA methylation plays a critical role in lung cancer and fibrosis pathogenesis. DNA methylation offers a new biomarker for disease diagnosis or monitoring, and provides a new therapeutic target for treatment.

Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad's phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of "seronegative" SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2-7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients' stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns' interpretation. The gold-standard technique for autoantibodies' identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients.