Search Results (47)

Progressive fibrosing interstitial lung disease (PF-ILD) is a significant complication of connective tissue diseases (CTDs), particularly in systemic sclerosis (SSc), rheumatoid arthritis (RA), and idiopathic inflammatory myopathies (IIM). Despite clinical similarities with idiopathic pulmonary fibrosis (IPF), CTD-associated ILDs exhibit distinct pathogenetic and immunologic features. Objective: This review aims to summarize key predictive biomarkers and current treatment strategies associated with the progressive fibrosing phenotype in SSc-ILD, RA-ILD, and IIM-ILD. Methods: We conducted a focused literature search of PubMed and Scopus databases covering publications from January 2010 to February 2024. Included studies evaluated serum, cellular, or genetic biomarkers with predictive value for disease progression or treatment response. Only peer-reviewed English-language articles were included. Exclusion criteria encompassed single case reports and editorials. Results: Several biomarkers, including KL-6, SP-D, CXCL4, and anti-MDA5, demonstrate potential in predicting fibrotic progression in CTD-ILDs. However, variability in sensitivity and specificity across CTD subtypes limits broad clinical applicability. Therapeutic agents such as nintedanib and pirfenidone show efficacy in slowing lung function decline. Biologics including rituximab and tocilizumab offer additional options, particularly in immunologically active diseases. Conclusion: Although promising biomarkers and therapies are emerging, no single marker or intervention currently predicts or modifies PF-ILD outcomes across all CTD subsets. Prospective studies and integrative biomarker panels are needed to improve patient stratification and guide therapy. Full article

Background: Fibrosing interstitial lung diseases can evolve into acute exacerbations, which significantly impact morbidity and mortality. Currently, no routinely used clinical biomarkers can discern the potential progression in these patients. This study aims to analyze different biological markers used in routine clinical practice as possible predictive biomarkers for patients with acute fibrosing interstitial lung disease exacerbation. Methods: We conducted a retrospective, single-center study including patients diagnosed with acute exacerbation of fibrosing interstitial lung disease who required hospitalization between 2018 and 2019 at Vall d’Hebron Hospital, Spain. Patient demographics, clinical data, respiratory function, and comorbidities were collected at baseline. The primary outcome was survival at 30 days, 90 days, and 365 days, using Kaplan–Meier survival analysis and Cox regression. Results: Twenty-nine patients were included (mean age 70.4 years). At the 3-month follow-up, patients with ischemic heart disease showed higher survival rates (p = 0.02). Identifying an infection as the etiology of the exacerbation was associated with worse one-year survival rates compared to idiopathic cases (p = 0.03). Elevated levels of leukocytes (p < 0.01), neutrophils (p < 0.01), and fibrinogen (p = 0.03) were predictors of mortality. Additionally, patients who received a cumulative dose of corticosteroids between 501 and 1000 mg during the exacerbation showed higher one-year survival (p < 0.01). Conclusions: Routine clinical markers can help predict outcomes in AE-f-ILD. Further multicenter studies should validate these findings and assess the role of therapies in its management. Full article

Background/Objectives: Even today, interstitial lung disease (ILD) is diagnosed by chest high-resolution computed tomography (lung HR-CT). Large amounts of data are available about the usefulness of transthoracic lung ultrasound (LUS) in ILD. This study aimed to evaluate the transthoracic LUS capacity to discriminate different ILD patterns in systemic sclerosis (SSc) patients, such as usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP) with ground glass opacification/opacity (GGO), and NSIP with GGO and reticulations, as well as the possibility of identifying progressive fibrosing ILD. Methods: We enrolled SSc-patients attending the outpatient Clinic of the Rheumatology Unit of Policlinico of Foggia and the Rheumatology Unit of Policlinico of Bari who satisfied these inclusion criteria: age older than 18 years; the satisfaction of ACR/EULAR 2013 classification criteria for SSc; chest HR-CT scan within three months before or three months after transthoracic LUS evaluation; and availability of recent and complete pulmonary function test. The exclusion criteria were as follows: history or recent reactivation of chronic obstructive pulmonary disease, lung cancer, lung infection, heart failure, pulmonary oedema, pulmonary arterial hypertension, acute respiratory distress syndrome and diffuse alveolar haemorrhage and thoracic surgery. All enrolled SSc-patients underwent transthoracic LUS, performed by an experienced sonographer. The ILD diagnosis and the respective patterns were assessed by chest HR-CT, which still represents the best diagnostic tool. Results: ILD was observed in 99 (63.5%) patients. Of these, 25% had the UIP pattern and 75% the NSIP pattern (46 with GGO, 28 with GGO and reticulations). By receiver operating characteristic (ROC) curve analysis, higher values of accuracy, sensitivity, specificity, and negative clinical utility index (CUI) were found for pleural line irregularity (0.84 (95% CI: 0.75–0.91), 96%, and 73.6%, p = 0.0001; 0.72), and pleural line thickness (0.84 (95% CI: 0.74–0.91), 72%, and 96.4%, p = 0.0001; 0.85) for detecting the UIP pattern. The best performance among transthoracic LUS signs for NSIP with the GGO pattern was observed for B-lines (accuracy: 0.88 (95% CI: 0.80–0.93), sensitivity: 93.4% and specificity: 82.4, p = 0.0001; CUI+: 0.75, CUI−: 0.77). LUS signs with higher accuracy, sensitivity, and specificity for NSIP with GGO and reticulations were pleural line irregularity (0.89 (95% CI: 0.80–0.95), 96.4%, and 82.4%, p = 0.0001) with CUI−: 0.72, and B-lines (0.89 (95% CI: 0.80–0.95), 96.4%, 82.4%, p = 0.0001), with CUI+: 0.80 and CUI−: 0.70. Furthermore, a total number of B-lines > 10 maximises LUS performance with 92.3% sensitivity, and an accuracy of 0.83 (p = 0.0001) for detecting the NSIP pattern, particularly GGO. A sample-restricted analysis (66 SSc patients) evidenced the presence of progressive fibrosing ILD in 77% of these patients. By binary regression analysis, the unique LUS sign associated with progressive fibrosing ILD was the presence of pleural line irregularity (OR: 3.6; 95% CI 1.08–11.9; p = 0.036). Conclusions: Our study demonstrated that transthoracic LUS presented a high capacity to discriminate the different patterns of SSc-ILD. Therefore, the hypothesis that transthoracic LUS is an effective screening method for the evaluation of the presence of SSc-ILD and establishing the correct timing of chest HR-CT, in order to avoid patients receiving excessive exposure to ionising radiation, is supported. Full article

Background: The degree of exercise-induced oxygen desaturation and outcomes following antifibrotic drug therapy in asymptomatic patients with fibrosing interstitial lung disease (FILD) remain unclear. Methods: We compared clinical data, incidence of annual FILD progression, overall survival, and tolerability after initiating nintedanib between 58 patients with dyspnea and 18 patients without. Annual FILD progression was defined as >10% decrease in forced vital capacity (FVC), >15% decrease in diffusing capacity of the lungs for carbon monoxide (D_LCO), developing acute exacerbations, or FILD-related death within 1 year of starting nintedanib. Outcomes between the two groups were adjusted for covariates, including age, gender, FVC, D_LCO, and diagnosis of idiopathic pulmonary fibrosis, all known prognostic factors for FILD. Results: In 6-min walk test, incidence of decrease to <90% of SpO₂ was significantly lower in non-dyspnea group than in dyspnea group (24% vs. 55%, p = 0.028), but incidence of >4% decreases showed no significant difference (71% vs. 89%, p = 0.11) The incidence of annual progression was significantly lower in non-dyspnea than in dyspnea group (17% vs. 53%, adjusted p = 0.026). The relative change in D_LCO was significantly slower in non-dyspnea group (adjusted p = 0.036), but FVC was not (adjusted p = 0.067). Overall survival was longer in non-dyspnea group (adjusted p = 0.0089). The discontinuation rate and therapeutic period of nintedanib were not significantly different between the groups. Conclusions: Asymptomatic patients with FILD have severe exercise-induced oxygen desaturation and better outcomes after nintedanib therapy than symptomatic patients. Antifibrotic drug therapy should not be avoided solely because of a lack of symptoms. Full article

Background/Objectives: Interstitial lung disease (ILD) is one of the most severe complications of rheumatoid arthritis (RA). Real-world data on antifibrotic treatment are needed. Our objective was to evaluate the real-world effectiveness and tolerability of antifibrotic agents in patients with progressive fibrosing RA-ILD. Methods: A longitudinal, retrospective, observational study was conducted on a cohort of RA-ILD patients treated with either nintedanib or pirfenidone. The data collected included pulmonary function test (PFT) results, adverse events (AEs), tolerability, and drug retention. Results: Twenty-seven patients were included; 25 (92.5%) initiated nintedanib, while two initiated pirfenidone. The median follow-up duration was 25 months (IQR 7–27). The mean decline in %pFVC and %pDLCO from ILD diagnosis to the initiation of antifibrotic therapy were −8.9% and −14.8%, respectively. After 6 months of treatment, most patients achieved stabilization in PFT: a ∆%pFVC of +1.2% (p = 0.611 compared with baseline) and a ∆%pDLCO of +3.9% (p = 0.400). Eighteen patients completed one year of therapy, with a modest improvement in %pFVC (+4.7%; p = 0.023) and stabilization in %pDLCO (−3.8%; p = 0.175). This trend persisted among the nine patients who completed 2 years of treatment (%pFVC +7.7%; p = 0.037 and %pDLCO −2.2%; p = 0.621). During the follow-up period, 15% of patients died, and 4% underwent lung transplantation. Adverse events occurred in 81% of patients, leading to discontinuation in 18.5% of cases. The most frequent adverse events were gastrointestinal events and hepatitis, leading to a permanent dose reduction of 40% for nintedanib and 14% for pirfenidone. A second antifibrotic agent was prescribed for 18.5% of the patients. At the end of the follow-up period, 63% of the total cohort remained on antifibrotic therapy. Conclusions: According to our results, antifibrotic initiation was associated with a modest improvement in the trajectory of %pFVC and stabilization in %pDLCO. The discontinuation rate in our cohort (37%) was higher than that reported in clinical trials but similar to that reported in previously published real-world studies. Full article

A 66-year-old man, a 40-year smoker, was diagnosed with rheumatoid arthritis in 2018. He was treated for one year with methotrexate, and, later in 2020, he was diagnosed with interstitial pulmonary fibrosis. In 2022, treatment with nintedanib was initiated, with clinical improvement being indicated but without showing a functional or imaging benefit. The evolution of the disease was rapidly progressive and unfavorable, with death occurring due to pulmonary thromboembolism. Following the autopsy, triple lesions of the RA at the lung level were confirmed: interstitial, of the NSIP type with a fibrosing character at the level of the lower airways of the bilateral bronchiectasis type, and vascular damage due to pulmonary thromboembolism secondary to chronic inflammation. Full article

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs. Full article

Background: Interstitial lung disease (ILD) represents a frequent cause of morbidity and mortality in primary Sjogren syndrome (pSS). However, the prevalence and behavior of pSS-ILD remains incomplete, largely based on retrospective heterogeneous studies. Aim of the study: To investigate the prevalence of progressive pulmonary fibrosis (PPF) in a multicentric cohort of patients with pSS-ILD. Additionally, this study explored possible correlations between PPF and clinical, demographic, and serological features of pSS. Methods: All consecutive patients with pSS-ILD were enrolled in a 6-month period. Clinical, demographic, and serological features of pSS, other than functional and radiological lung features, were collected. Clinical behaviors of ILD other than PPF were also investigated. Results: Seventy-two patients were enrolled. A fibrosing ILD pattern was observed in 65.3% of patients with pSS-ILD; among them, 55.3% showed a PPF. The radiologic pattern (NSIP, UIP, or others) was not associated with PPF; in particular, patients with PFF had UIP in 42.3% of cases and NSIP in 57.7%, without a significant difference with respect to the non-PPF group (p = 0.29). Shorter pSS disease duration, higher age at pSS diagnosis, and lower frequency of antinuclear antibodies were correlated with the PPF subgroup. However, multivariate analysis did not confirm these associations. Discussion: This study provides valuable insights into the prevalence and characteristics of PPF in pSS-ILD. In particular, UIP and NSIP showed a similar evolution towards PPF in patients with pSS; for NSIP, this behavior was more frequent than for other rheumatic diseases. Our results emphasize the importance of early recognition of PPF for timely intervention and careful follow-up. Conclusions: This study provides valuable insights into the prevalence and characteristics of PPF in pSS-ILD. In particular, UIP and NSIP showed a similar evolution towards PPF in patients with pSS; for NSIP, this behavior was more frequent than for other rheumatic diseases. Our results emphasize the importance of early recognition of PPF for timely intervention and careful follow-up. Full article

Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases (ILD). Both drugs have side effects that affect patients in different ways and have different levels of severity, making treatment even more challenging for patients and clinicians. The present review aims to assess the effectiveness and potential complications of Pirfenidone and Nintedanib treatment regimens across various ILD diseases. A detailed search was performed in relevant articles published between 2018 and 2023 listed in PubMed, UpToDate, Google Scholar, and ResearchGate, supplemented with manual research. The following keywords were searched in the databases in all possible combinations: Nintedanib; Pirfenidone, interstitial lung disease, and idiopathic pulmonary fibrosis. The most widely accepted method for evaluating the progression of ILD is through the decline in forced vital capacity (FVC), as determined by respiratory function tests. Specifically, a decrease in FVC over a 6–12-month period correlates directly with increased mortality rates. Antifibrotic drugs Pirfenidone and Nintedanib have been extensively validated; however, some patients reported several side effects, predominantly gastrointestinal symptoms (such as diarrhea, dyspepsia, and vomiting), as well as photosensitivity and skin rashes, particularly associated with Pirfenidone. In cases where the side effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. However, further research is needed to optimize the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Finally, other studies are requested to establish the treatments that can stop ILD progression. Full article

Fibrosing interstitial lung diseases (FILDs), e.g., due to idiopathic pulmonary fibrosis (IPF), are chronic progressive diseases with a poor prognosis. The management of these diseases is challenging and focuses mainly on the suppression of progression with anti-fibrotic drugs. Therefore, novel FILD treatments are needed. In recent years, cell-based therapy with various stem cells has been investigated for FILD, and the use of mesenchymal stem cells (MSCs) has been widely reported and clinical studies are also ongoing. Induced pluripotent stem cells (iPSCs) have also been reported to have an anti-fibrotic effect in FILD; however, these have not been as well studied as MSCs in terms of the mechanisms and side effects. While MSCs show a potent anti-fibrotic effect, the possibility of quality differences between donors and a stable supply in the case of donor shortage or reduced proliferative capacity after cell passaging needs to be considered. The application of iPSC-derived cells has the potential to overcome these problems and may lead to consistent quality of the cell product and stable product supply. This review provides an overview of iPSCs and FILD, followed by the current status of cell-based therapy for FILD, and then discusses the possibilities and perspectives of FILD therapy with iPSC-derived cells. Full article

Introduction: Pulmonary fibrosis is an irreversible condition that may be caused by known (including viral triggers such as SARS-CoV-2) and unknown insults. The latter group includes idiopathic pulmonary fibrosis (IPF), which is a chronic, progressive fibrosing interstitial pneumonia of unknown cause. The longer the insult acts on lung tissue, the lower the probability of a complete resolution of the damage. An emerging clinical entity post-COVID-19 is pulmonary fibrosis (PCPF), which shares many pathological, clinical, and immunological features with IPF. The fibrotic response in both diseases—IPF and PCPF—is orchestrated in part by the immune system. An important role regarding the inhibitory or stimulatory effects on immune responses is exerted by the immune checkpoints (ICs). The aim of the present study was to analyse the similarities and differences between CD4+, CD8+, and NK cells in the peripheral blood of patients affected by fibrotic disease, IPF, and PCPF compared with sarcoidosis patients and healthy controls. The second aim was to evaluate the expression and co-expression of PD-1 and TIGIT on CD4, CD8, and NK cells from our patient cohort. Methods: One hundred and fifteen patients affected by IPF, PCPF, and sarcoidosis at the rare pulmonary disease centre of the University of Siena were enrolled. Forty-eight patients had an IPF diagnosis, 55 had PCPF, and 12 had sarcoidosis. Further, ten healthy controls were enrolled. PCPF patients were included between 6 and 9 months following hospital discharge for COVID-19. The peripheral blood samples were collected, and through flow cytometric analysis, we analysed the expression of CD4, CD8, NK cells, PD-1, and TIGIT. Results: The results show a greater depletion of CD4 and NK cells in IPF patients compared to other groups (p = 0.003), in contrast with CD8 cells (p < 001). Correlation analysis demonstrated an indirect correlation between CD4 and CD8 cells in IPF and sarcoidosis patients (p < 0.001 = −0.87 and p = 0.042; r = −0.6, respectively). Conversely, PCPF patients revealed a direct correlation between CD4 and CD8 cells (p < 0.001; r = 0.90) accentuating an immune response restoration. The expression of PD-1 and TIGIT was abundant on T and NK cell subsets of the two lung fibrotic groups, IPF and PCPF. Analogously, the co-expression of PD-1 and TIGIT on the surfaces of CD4 and CD8 were increased in such diseases. Conclusions: Our study shines a spotlight on the immune responses involved in the development of pulmonary fibrosis, idiopathic and secondary to SARS-CoV-2 infection. We observed a significant imbalance not only in CD4, CD8, and NK blood percentages in IPF and PCPF patients but also in their functional phenotypes evaluated through the expression of ICs. Full article

Interstitial Lung Disease (ILD) involves lung disorders marked by chronic inflammation and fibrosis. ILDs include pathologies like idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD (CTD-ILD), hypersensitivity pneumonitis (HP) or sarcoidosis. Existing data covers pathogenesis, diagnosis (especially using high-resolution computed tomography), and treatments like antifibrotic agents. Despite progress, ILD diagnosis and management remains challenging with significant morbidity and mortality. Recent focus is on Progressive Fibrosing ILD (PF-ILD), characterized by worsening symptoms and fibrosis on HRCT. Prevalence is around 30%, excluding IPF, with a poor prognosis. Early diagnosis is crucial for optimizing outcomes in PF-ILD individuals. The lung microbiome comprises all the microorganisms that are in the respiratory tract. Relatively recent research try to evaluate its role in respiratory disease. Healthy lungs have a diverse microbial community. An imbalance in bacterial composition, changes in bacterial metabolic activities, or changes in bacterial distribution within the lung termed dysbiosis is linked to conditions like COPD, asthma and ILDs. We conducted a systematic review of three important scientific data base using a focused search strategy to see how the lung microbiome is involved in the progression of ILDs. Results showed that some differences in the composition and quality of the lung microbiome exist in ILDs that show progressive fibrosing phenotype. The results seem to suggest that the lung microbiota could be involved in ILD progression, but more studies showing its exact pathophysiological mechanisms are needed. Full article

Interstitial lung diseases comprise a heterogenous range of diffuse lung disorders, potentially resulting in pulmonary fibrosis. While idiopathic pulmonary fibrosis has been recognized as the paradigm of a progressive fibrosing interstitial lung disease, other conditions with a progressive fibrosing phenotype characterized by a significant deterioration of the lung function may lead to a burden of significant symptoms, a reduced quality of life, and increased mortality, despite treatment. There is now evidence indicating that some common underlying biological mechanisms can be shared among different chronic fibrosing disorders; therefore, different biomarkers for disease-activity monitoring and prognostic assessment are under evaluation. Thus, understanding the common pathways that induce the progression of pulmonary fibrosis, comprehending the diversity of these diseases, and identifying new molecular markers and potential therapeutic targets remain highly crucial assignments. The purpose of this review is to examine the main pathological mechanisms regulating the progression of fibrosis in interstitial lung diseases and to provide an overview of potential biomarker and therapeutic options for patients with progressive pulmonary fibrosis. Full article

Background: Interstitial lung diseases (ILDs) encompass a diverse group of disorders affecting the lung interstitium, leading to inflammation, fibrosis, and impaired respiratory function. Currently, the identification of new diagnostic and prognostic biomarkers for ILDs turns out to be necessary. Several studies show the role of KL-6 in various types of interstitial lung disease and suggest that serum KL-6 levels can be used as a prognostic marker of disease. The aim of this study was to analyze KL-6 expression either in serum or bronchoalveolar lavage samples in order to: (i) make a serum vs. BAL comparison; (ii) better understand the local behavior of fibrosis vs. the systemic one; and (iii) evaluate any differences in patients with progressive fibrosis (PPF) versus patients with non-progressive fibrosis (nPPF). Methods: We used qRT-PCR to detect KL-6 expression both in serum and BAL samples. Mann–Whitney’s U test was used to compare the differential expression between groups. Results: In serum, KL-6 is more highly expressed in PPF than in non-progressive fibrosis (p = 0.0295). This difference is even more significant in BAL (p < 0.001). Therefore, it is clear that KL-6 values are related to disease progression. Significant differences were found by making a comparison between BAL and serum. KL-6 was markedly higher in serum than BAL (p = 0.0146). Conclusions: This study identifies KL-6 as a promising biomarker for the severity of the fibrosing process and disease progression in ILDs, with significantly higher levels observed in PPF compared to nPPF. Moreover, the marked difference in KL-6 levels between serum and BAL emphasizes its potential diagnostic and prognostic relevance, providing enlightening insights into both the local and systemic aspects of ILDs. Full article

Background: The INBUILD study demonstrated the efficacy of nintedanib in the treatment of progressive fibrosing interstitial lung disease different to idiopathic pulmonary fibrosis, including rheumatoid arthritis (RA)-related ILD. Nevertheless, the prevalence of RA-ILD patients that may potentially benefit from nintedanib remains unknown. Objectives and methods: The aim of the present multicentre study was to investigate the prevalence and possible associated factors of fibrosing progressive patterns in a cross-sectional cohort of RA-ILD patients. Results: One hundred and thirty-four RA-ILD patients with a diagnosis of RA-ILD, who were confirmed at high-resolution computed tomography and with a follow-up of at least 24 months, were enrolled. The patients were defined as having a progressive fibrosing ILD in case of a relative decline in forced vital capacity > 10% predicted and/or an increased extent of fibrotic changes on chest imaging in a 24-month period. Respiratory symptoms were excluded to reduce possible bias due to the retrospective interpretation of cough and dyspnea. According to radiologic features, ILD was classified as usual interstitial pneumonia (UIP) in 50.7% of patients, nonspecific interstitial pneumonia in 19.4%, and other patterns in 29.8%. Globally, a fibrosing progressive pattern was recorded in 36.6% of patients (48.5% of patients with a fibrosing pattern) with a significant association to the UIP pattern. Conclusion: We observed that more than a third of RA-ILD patients showed a fibrosing progressive pattern and might benefit from antifibrotic treatment. This study shows some limitations, such as the retrospective design. The exclusion of respiratory symptoms’ evaluation might underestimate the prevalence of progressive lung disease but increases the value of results. Full article