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Chronic lung allograft dysfunction (CLAD) is the leading long-term cause of poor outcomes after transplant and manifests by fibrotic remodeling of small airways and/or pleuroparenchymal fibroelastosis. This study evaluated the effect of pirfenidone on quantitative radiographic and pulmonary function assessment in patients with CLAD. We performed a single-center, 6-month, randomized, placebo-controlled trial of pirfenidone in patients with CLAD. Randomization was stratified by CLAD phenotype. The primary outcome for this study was change in radiographic assessment of small airways disease, quantified as percentage of lung volume using parametric response mapping analysis of computed tomography scans (PRMfSAD); secondary outcomes included change in forced expiratory volume in 1 second (FEV 1), change in forced vital capacity (FVC), and change in radiographic quantification of parenchymal disease (PRMPD). Linear mixed models were used to evaluate the treatment effect on outcome measures. The goal enrollment of 60 patients was not met due to the coronavirus disease of 2019 pandemic, with 23 patients included in the analysis. There was no significant difference over the study period between the pirfenidone vs placebo groups with regards to the observed change in PRMfSAD (+4.2% vs −0.4%; p = 0.22), FEV 1 (−3.5% vs −3.6%; p = 0.97), FVC (−1.9% vs −4.6%; p = 0.41), or PRMPD (−0.6% vs −2.5%; p = 0.30). The study treatment tolerance and adverse events were generally similar between the pirfenidone and placebo groups. Pirfenidone had no apparent impact on radiographic evidence of allograft dysfunction or pulmonary function decline in a single-center randomized trial of CLAD patients that did not meet enrollment goals but had an acceptable tolerance and side-effect profile. [ABSTRACT FROM AUTHOR]

Background: Anxiety and depression are common comorbidities in idiopathic pulmonary fibrosis (IPF) that impair health-related quality of life. However, there is a lack of studies focusing on the mental disorder of IPF after antifibrotic treatment and their related predictive factors. Methods: Patients with an initial diagnosis of IPF were enrolled. Data on demographics, lung function, Generalized Anxiety Disorder-7 (GAD-7) Scale, Patient Health Questionnaire 9 (PHQ-9), Patient Health Questionnaire-15 (PHQ-15), and St. George's Respiratory Questionnaire total score(SGRQ-T) were collected. Changes in anxiety, depression, somatic symptoms, and quality of life scores before and after nintedanib treatment were compared, and the related predictive factors were analyzed. Results: A total of 56 patients with a first diagnosis of IPF were enrolled, with 42 and 35 patients suffering from anxiety and depression, respectively. The GAD-7, PHQ-9, PHQ-15, and SGRQ scores were higher in the anxiety and depression groups. SGRQ total score (SGRQ-T) [OR = 1.075, 95%CI = (1.011, 1.142)] was an independent predictor of IPF combined with anxiety (p < 0.05); SGRQ-T [OR = 1.080, 95%CI= (1.001, 1.167)] was also an independent predictor of IPF combined with depression (p < 0.05). After treatment, GAD-7, PHQ-9, PHQ-15, and SGRQ scores decreased (p < 0.05). ΔSGRQ-T significantly affected ΔGAD-7 (β = 0.376, p = 0.009) and ΔPHQ-9 (β = 0.329, p = 0.022). Conclusion: Anxiety and depression in IPF patients are closely related to somatic symptoms, pulmonary function, and quality of life. The SGRQ-T score is of great value for assessing anxiety and depression in patients with IPF. Short-term treatment with nintedanib antifibrotic therapy can alleviate anxiety and depression in IPF patients. [ABSTRACT FROM AUTHOR]

Abstract Background In 2020, Nintedanib (NTB), a tyrosine kinase inhibitor, was the first drug approved worldwide for treating progressive fibrosing interstitial lung disease (PF-ILD). This study evaluated the efficacy and safety of NTB in Japanese patients with CTD-associated PF-ILD in a real-world setting, as there are few reports on this topic. We also evaluated the efficacy and safety of combination therapy with NTB and immunosuppressive agents (IS). Methods CTD-associated PF-ILD patients receiving NTB at our institution were included in this retrospective study. To evaluate the efficacy and safety of NTB, we investigated changes in forced vital capacity (FVC) (%), diffusing capacity for carbon monoxide (DLCO) (%), monthly change in FVC (%/month), serum Krebs von den Lungen-6 (KL-6) levels (U/mL) before and after NTB treatment, and adverse events (AEs) during NTB treatment. Moreover, to evaluate the efficacy of the NTB + IS combination therapy, we divided the patients into two groups: one received only NTB (NTB group), and the other received both NTB and IS (NTB + IS group) following the diagnosis of CTD-associated PF-ILD. We analyzed the differences in the changes of these variables between the two groups. Results Twenty-six patients with CTD-associated PF-ILD were included. After NTB treatment, there were no significant deteriorations in FVC (%) and DLCO (%), while the monthly change in FVC (%/month) significantly increased (p

Idiopathic pulmonary fibrosis (IPF) is a severe and currently incurable disease that is associated with irreversible fibrotic remodeling of the lung parenchyma. Pathological remodeling of the lung leads to damage of the alveolo-capillary barrier. There is a reduction in the diffusing capacity of the lungs for respiratory gases. Later, changes in the mechanical properties of lung tissue occur - their compliance decreases and respiratory work increases. Impaired respiratory gases exchange with restrictive ventilatory failure lead to tissue hypoxia and muscle weakness. Progressive respiratory insufficiency develops. The triggers of fibrotic remodeling of the lung are currently unknown, as are the pathomechanisms that keep this process active. IPF can only be slowed pharmacologically, not reversed. It is therefore very important to start its treatment as soon as possible. Early detection of IPF patients requires a multidisciplinary approach. Diagnosis, treatment initiation, and monitoring in specialized centers offer the best chance of slowing disease progression, enhancing quality of life, and extending patient survival. In addition to antifibrotic therapy, good lifestyle management, maintenance of physical fitness and treatment of associated chronic diseases such as diabetes and cardiac comorbidities are important. Lung transplantation is an option for some patients with IPF. This is a challenging treatment modality, requiring close collaboration with transplant centers and expert selection of suitable candidates, influenced, among other things, by the availability of suitable donor lungs. Our article aims to provide current information about IPF, focusing on its functional consequences and clinical manifestation. We discuss the molecular and cellular mechanisms potentially involved in IPF development, as well as the morphological changes observed in lung biopsies and high-resolution computed tomography (HRCT) images. Finally, we summarize the existing treatment options. [ABSTRACT FROM AUTHOR]

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Abstract There is an unmet need for antifibrotic therapies to prevent the progression of liver cirrhosis. Previously, we conducted an exploratory trial to assess the safety and antifibrotic efficacy of PRI-724, a selective CBP/β-catenin inhibitor, in patients with liver cirrhosis. PRI-724 was well tolerated and exerted a potential antifibrotic effect. Here, we investigated whether the profiles of circulating microRNAs packaged in extracellular vesicles (EV-miRNAs) are associated with responses to liver fibrosis treatments. Eighteen patients who received PRI-724 for 12 weeks in a phase 1/2a study were classified as responders (n = 10) or non-responders (n = 8) based on changes in liver stiffness. Plasma samples were obtained before and after PRI-724 administration and the levels of EV-miRNAs were analyzed. Three miRNAs (miR-6510-5p, miR-6772-5p, and miR-4261) were identified as predictors of response or non-response to PRI-724, and the levels of three other miRNAs (miR-939-3p, miR-887-3p, and miR-7112-5p) correlated with the efficacy of treatment. Expression of miR-887-3p was detected in hepatocytes and was decreased significantly in liver tissue following PRI-724 treatment. In addition, transfection of a miR-887-3p mimic activated hepatic stellate cells. Thus, decreases in the miR-887-3p level in blood may reflect recovery from liver fibroses in patients with liver cirrhosis treated with PRI-724, although further validation studies are warranted to confirm this.

There is an unmet need for antifibrotic therapies to prevent the progression of liver cirrhosis. Previously, we conducted an exploratory trial to assess the safety and antifibrotic efficacy of PRI-724, a selective CBP/β-catenin inhibitor, in patients with liver cirrhosis. PRI-724 was well tolerated and exerted a potential antifibrotic effect. Here, we investigated whether the profiles of circulating microRNAs packaged in extracellular vesicles (EV-miRNAs) are associated with responses to liver fibrosis treatments. Eighteen patients who received PRI-724 for 12 weeks in a phase 1/2a study were classified as responders (n = 10) or non-responders (n = 8) based on changes in liver stiffness. Plasma samples were obtained before and after PRI-724 administration and the levels of EV-miRNAs were analyzed. Three miRNAs (miR-6510-5p, miR-6772-5p, and miR-4261) were identified as predictors of response or non-response to PRI-724, and the levels of three other miRNAs (miR-939-3p, miR-887-3p, and miR-7112-5p) correlated with the efficacy of treatment. Expression of miR-887-3p was detected in hepatocytes and was decreased significantly in liver tissue following PRI-724 treatment. In addition, transfection of a miR-887-3p mimic activated hepatic stellate cells. Thus, decreases in the miR-887-3p level in blood may reflect recovery from liver fibroses in patients with liver cirrhosis treated with PRI-724, although further validation studies are warranted to confirm this. [ABSTRACT FROM AUTHOR]

Background: Nintedanib and pirfenidone are preferred pharmacological therapies for patients with idiopathic pulmonary fibrosis (IPF). However, evidence favoring antifibrotic therapy in patients with non-IPF fibrosing interstitial lung diseases (ILD) is limited. Objective: To investigate the effects of antifibrotic therapy on disease progression, all-cause mortality, and acute exacerbation (AE) risk in patients with non-IPF fibrosing ILDs. Design: Meta-analysis. Data sources and methods: Electronic databases were searched for articles published before 28 February 2023. Studies that evaluated the efficacy of antifibrotic agents in patients with fibrosing ILDs were selected. The primary outcome was the disease progression risk, and the secondary outcomes included all-cause mortality and AE risk. The GRADE criteria were used for the certainty of evidence assessment. Results: Nine studies with 1990 participants were included. Antifibrotic therapy reduced the rate of patients with disease progression (five trials with 1741 subjects; relative risk (RR), 0.56; 95% CI, 0.42–0.75; p < 0.0001; I 2 = 0; high-certainty evidence). Antifibrotic therapy did not significantly decrease all-cause mortality (nine trials with 1990 subjects; RR, 0.76; 95% CI, 0.55–1.03; p = 0.08; I 2 = 0; low-certainty evidence). However, in patients with progressive fibrosing ILDs (PF-ILD), antifibrotic therapy decreased all-cause mortality (four trials with 1100 subjects; RR, 0.69; 95% CI, 0.48–0.98; p = 0.04; I 2 = 0; low-certainty evidence). Conclusion: Our study supports the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Trial registration: This study protocol was registered with PROSPERO (registration number: CRD42023411272). [ABSTRACT FROM AUTHOR]

Background: Antifibrotic agents (AFAs) are now standard‐of‐care for idiopathic pulmonary fibrosis (IPF). Concerns have arisen about the safety of these drugs in patients undergoing lung transplantation (LTx). Methods: We performed a multi‐centre, nationwide, retrospective, observational study of French IPF patients undergoing LTx between 2011 and 2018 to determine whether maintaining AFAs in the peri‐operative period leads to increased bronchial anastomoses issues, delay in skin healing and haemorrhagic complications. We compared the incidence of post‐operative complications and the survival of patients according to AFA exposure. Results: Among 205 patients who underwent LTx for IPF during the study period, 58 (28%) had received AFAs within 4 weeks before LTx (AFA group): pirfenidone in 37 (18.0%) and nintedanib in 21 (10.2%). The median duration of AFA treatment before LTx was 13.8 (5.6–24) months. The AFA and control groups did not significantly differ in airway, bleeding or skin healing complications (p = 0.91, p = 0.12 and p = 0.70, respectively). Primary graft dysfunction was less frequent in the AFA than control group (26% vs. 43%, p = 0.02), and the 90‐day mortality was lower (7% vs. 18%, p = 0.046). Conclusions: AFA therapy did not increase airway, bleeding or wound post‐operative complications after LTx and could be associated with reduced rates of primary graft dysfunction and 90‐day mortality. [ABSTRACT FROM AUTHOR]

Progressive pulmonary fibrosis (PPF) can be fatal in non-idiopathic interstitial lung diseases. We report a descriptive series of 13 patients with PPF who received treatment with nintedanib, a multitargeted tyrosine kinase inhibitor with antifibrotic effect. Although the reduced number of patients and the observational nature of a case series prevent us from providing strong evidence, our results suggest that nintedanib could be effective in PPF of various etiologies. Nintedanib could also be useful in specific populations such as patients awaiting lung transplant and elderly patients.

According to recent WHO estimates, chronic HBV infection is one of the leading causes of death and disability in patients with infectious diseases. From 780 thousand to 1 million deaths are annually recorded in the world as a result of cirrhosis of the liver and hepatocellular carcinoma. Pathogenetic features of the course and outcomes of chronic hepatitis B are determined by the immunological, genetic factors of the host, as well as the molecular biological structure of the virus. The aim of the work was to study the interaction of polymorphic loci of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620), IL-10 (rs1800896), IL-4 (rs2243250) and the degree of structural changes in the liver based on the non-invasive Fibrotest technique in patients with chronic hepatitis B as part of a search for possible predictors of predisposition to the rapid progression of liver fibrosis. The study included 82 patients with chronic hepatitis B. Assessment of morphological changes (stage of fibrosis) was carried out by the method of non-invasive diagnosis of FibroScan, which is an alternative to puncture biopsy of the liver. It has been suggested that homozygous alleles СС IL-4 (rs2243250), GG TNFα (rs1800620), СС SMAD family member 7 (rs4939827) have a protective effect on the course of chronic hepatitis B, as these variants of allelic polymorphism of cytokine genes were found mainly in patients with CHB with a degree of fibrosis F0-F1. The heterozygous genotypes СТ IL-4 (rs2243250) and GA TNFα (rs1800620), the mutant homozygous ТТ SMAD family member 7 (rs4939827) have a profibrotic effect on the course of chronic hepatitis B, as they are found mainly in patients with chronic hepatitis B with degree of fibrosis F3. The established relationship between the liver fibrosis stage according to the METAVIR scale and the polymorphism of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620) and IL-4 (rs2243250) made it possible to create a prognostic scale for assessing the individual risk of rapid progression of liver fibrosis. The proposed scale, due to a comprehensive assessment of the polymorphism of cytokine gene alleles and the stage of liver fibrosis using the METAVIR scale, makes it possible to carry out an individual assessment of the risk of progression of chronic hepatitis and, possibly, draw up a personalized treatment plan for the patient. Coding of the studied polymorphisms and subsequent counting can be automated, which does not require significant financial investments. The possibilities of the prognostic scale are proven on the example of a group of patients who received the antifibrotic agent bicyclol in comparison with the control group.

Abstract Background Currently, two disease-modifying antifibrotic drugs are indicated for the treatment of idiopathic pulmonary fibrosis. The objective of this study was to analyse antifibrotic and overall prescription medication use of IPF patients in the real world. Methods Data was collected from the FinnishIPF registry and the Registry of the Social Insurance Institution of Finland (SII). Purchases of all prescription medicines were assessed. The frequency, the initiation interval, the duration, and the breaks of the antifibrotic treatments were defined. The association between the prescription of antifibrotic therapy and different patient-related clinical parameters was studied. Accordingly, the relationships between the delay in starting therapy and patient-related variables were analysed. Results Of the 263 IPF patients, 132 (50.2%) had started antifibrotic treatment during the study period 2011–2018. The mean interval from the diagnosis to the first purchase was 367 (SD 429) days. The antifibrotic drug was switched in 14% of patients. Discontinuation of therapy occurred most commonly during the first year of the treatment. The one-year persistence was 77.1% for pirfenidone and 78.9% for nintedanib. A tendency of treating patients under 75 years was noticed. Low forced vital capacity predicted earlier initiation of medication. Conclusions The initiation of antifibrotics after diagnosis was slow, probably due to reimbursement limitations. Younger age at diagnosis affected treatment initiation although it is unknown which patients benefit most from these medications. The reasons for discontinuation of the antifibrotic therapy during the first year should be a focus in clinical work and further studies.

Modern antiviral therapy regimens for patients with chronic viral hepatitis aim to achieve either long-term suppression of pathogen replication (e.g., nucleoside analogs in chronic hepatitis B) or complete elimination of the virus (such as direct-acting antiviral drugs in chronic hepatitis C). However, antiviral agents do not have a significant impact on the complete restoration of biochemical processes or the prevention of further progression of morphological changes in the liver. These limitations emphasize the ongoing need for new therapeutic strategies that target the processes of fibrogenesis. The aim of the work is to assess the possibility of the effect of the drug "Bicyclol" on fibrotic changes in patients with chronic hepatitis B+C using a non-invasive scale of the rate of fibrosis. Materials and methods An analysis of the dynamics of 62 patients with chronic hepatitis B and C (HCV+C) was conducted. All patients received long-term antiviral therapy consisting of pegylated interferon for 48 weeks. In the main group (Group I), patients with chronic hepatitis B and C were prescribed the drug "Bicyclol" after completing antiviral treatment with interferon. The control group (Group II) followed the principles of proper nutrition and took traditional hepatoprotectors. Based on the identified correlations, a non-invasive scale was proposed to assess the individual risk of liver fibrosis progression. Research results Against the background of the use of an antiviral treatment regimen, the normalization of cytolysis indicators was observed in most patients with CHB+C, but in some patients it was short-lived. Treatment with the drug "Bicyclol" contributed to a further decrease in cytolysis indicators, in the vast majority of patients with CHB+C, the activity of ALT and AST reached the upper limit of the norm. In patients with CHB+C who received only basic treatment without an antifibrotic component, a tendency to maintain an elevated level of transaminases was observed. Conclusions. Thus, the use of the hepatoprotector "Bicyclol" for 12 months ensures a decrease in cytolysis in the liver, is accompanied by a decrease in the severity of fibrosis, and in some patients - its reverse development. The use of the proposed prognostic scale makes it possible to assess the need for early appointment of antifibrotic therapy.

Background: Currently, two disease-modifying antifibrotic drugs are indicated for the treatment of idiopathic pulmonary fibrosis. The objective of this study was to analyse antifibrotic and overall prescription medication use of IPF patients in the real world. Methods: Data was collected from the FinnishIPF registry and the Registry of the Social Insurance Institution of Finland (SII). Purchases of all prescription medicines were assessed. The frequency, the initiation interval, the duration, and the breaks of the antifibrotic treatments were defined. The association between the prescription of antifibrotic therapy and different patient-related clinical parameters was studied. Accordingly, the relationships between the delay in starting therapy and patient-related variables were analysed. Results: Of the 263 IPF patients, 132 (50.2%) had started antifibrotic treatment during the study period 2011–2018. The mean interval from the diagnosis to the first purchase was 367 (SD 429) days. The antifibrotic drug was switched in 14% of patients. Discontinuation of therapy occurred most commonly during the first year of the treatment. The one-year persistence was 77.1% for pirfenidone and 78.9% for nintedanib. A tendency of treating patients under 75 years was noticed. Low forced vital capacity predicted earlier initiation of medication. Conclusions: The initiation of antifibrotics after diagnosis was slow, probably due to reimbursement limitations. Younger age at diagnosis affected treatment initiation although it is unknown which patients benefit most from these medications. The reasons for discontinuation of the antifibrotic therapy during the first year should be a focus in clinical work and further studies. [ABSTRACT FROM AUTHOR]

(1) The role of the immune response in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. We hypothesized that peripheral blood immune phenotypes will be different in IPF patients and may relate to the disease severity and progression. (2) Whole blood flow cytometry staining was performed at diagnosis in 32 IPF patients, and in 32 age- and smoking-matched healthy controls. Thirty-one IPF patients were followed up for one year and categorized as stable or progressors based on lung function, deterioration and/or death. At 18–60 months, immunophenotypes were characterized again. (3) The main results showed that: (1) compared to matched controls, at diagnosis, patients with IPF showed more neutrophils, CD8+HLA-DR+ and CD8+CD28− T cells, and fewer B lymphocytes and naïve T cells; (2) in IPF, circulating neutrophils, eosinophils and naïve T cells were associated with lung function abnormalities; (3) patients whose disease progressed during the 12 months of follow-up showed evidence of cytotoxic dysregulation, with increased CD8+CD28− T cells, decreased naïve T cells and an inverted CD4/CD8 ratio at baseline; and (4) blood cell alterations were stable over time in survivors. (4) IPF is associated with abnormalities in circulating immune cells, particularly in the cytotoxic cell domain. Patients with progressive IPF, despite antifibrotic therapy, present an over-activated and exhausted immunophenotype at diagnosis, which is maintained over time. [ABSTRACT FROM AUTHOR]

Background and Objective: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung fibrosis of unknown aetiology. Epidemiological studies have suggested that IPF progression may negatively affect nutritional status. Weight loss during antifibrotic therapy is also frequently encountered. The association of nutritional status and outcome has not been fully evaluated in IPF patients. Methods: This retrospective multicohort study assessed nutritional status of 301 IPF patients receiving antifibrotic therapy (Hamamatsu cohort, n = 151; Seirei cohort, n = 150). Nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI). The GNRI was calculated based on body mass index and serum albumin. The relationship between nutritional status and tolerability of antifibrotic therapy as well as mortality was explored. Results: Of 301 patients, 113 (37.5%) had malnutrition‐related risk (GNRI < 98). Patients with malnutrition‐related risk were older, had increased exacerbations and worse pulmonary function than those without a GNRI status <98. Malnutrition‐related risk was associated with a higher incidence of discontinuation of antifibrotic therapy, particulary due to gastrointestinal disturbances. IPF patients with malnutrition‐related risk (GNRI < 98) had shorter survival than those without such risk (median survival: 25.9 vs. 41.1 months, p < 0.001). In multivariate analysis, malnutrition‐related risk was a prognostic indicator of antifibrotic therapy discontinuation and mortality, independent of age, sex, forced vital capacity, or gender–age–physiology index. Conclusion: Nutritional status has significant effects on the treatment and outcome in patients with IPF. Assessment of nutritional status may provide important information for managing patients with IPF. [ABSTRACT FROM AUTHOR]

According to recent WHO estimates, chronic HBV infection is one of the leading causes of death and disability in patients with infectious diseases. From 780 thousand to 1 million deaths are annually recorded in the world as a result of cirrhosis of the liver and hepatocellular carcinoma. Pathogenetic features of the course and outcomes of chronic hepatitis B are determined by the immunological, genetic factors of the host, as well as the molecular biological structure of the virus. The aim of the work was to study the interaction of polymorphic loci of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620), IL-10 (rs1800896), IL-4 (rs2243250) and the degree of structural changes in the liver based on the non-invasive Fibrotest technique in patients with chronic hepatitis B as part of a search for possible predictors of predisposition to the rapid progression of liver fibrosis. The study included 82 patients with chronic hepatitis B. Assessment of morphological changes (stage of fibrosis) was carried out by the method of non-invasive diagnosis of FibroScan, which is an alternative to puncture biopsy of the liver. It has been suggested that homozygous alleles СС IL-4 (rs2243250), GG TNFα (rs1800620), СС SMAD family member 7 (rs4939827) have a protective effect on the course of chronic hepatitis B, as these variants of allelic polymorphism of cytokine genes were found mainly in patients with CHB with a degree of fibrosis F0-F1. The heterozygous genotypes СТ IL-4 (rs2243250) and GA TNFα (rs1800620), the mutant homozygous ТТ SMAD family member 7 (rs4939827) have a profibrotic effect on the course of chronic hepatitis B, as they are found mainly in patients with chronic hepatitis B with degree of fibrosis F3. The established relationship between the liver fibrosis stage according to the METAVIR scale and the polymorphism of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620) and IL-4 (rs2243250) made it possible to create a prognostic scale for assessing the individual risk of rapid progression of liver fibrosis. The proposed scale, due to a comprehensive assessment of the polymorphism of cytokine gene alleles and the stage of liver fibrosis using the METAVIR scale, makes it possible to carry out an individual assessment of the risk of progression of chronic hepatitis and, possibly, draw up a personalized treatment plan for the patient. Coding of the studied polymorphisms and subsequent counting can be automated, which does not require significant financial investments. The possibilities of the prognostic scale are proven on the example of a group of patients who received the antifibrotic agent bicyclol in comparison with the control group. [ABSTRACT FROM AUTHOR]

Background & Aims: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. Methods: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2−/−). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. Results: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. Conclusions: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

The viral infectious disease pandemic caused by SARS-CoV-2 has affected over 500 million people and killed over 6 million. This is the official data provided by the WHO as of the end of May 2022. Among people who have recovered from COVID-19, post-COVID syndrome is quite common. Scattered epidemiological studies on post-COVID syndrome, however, indicate its high relevance. One of the manifestations of post-COVID syndrome is the development of pulmonary fibrosis (PF). This article is devoted to the analysis of literature data on epidemiology, immunomorphology, as well as X-ray morphological and functional characteristics of PF in patients with post-COVID syndrome. Attention is drawn to the various phenotypes of the post-COVID syndrome and the incidence of PF, which, as clinical practice shows, is most common in people who have had severe COVID-19. This article discusses in detail the molecular biological and immunological mechanisms of PF development. The fibrotic process of the lung parenchyma is not an early manifestation of the disease; as a rule, radiomorphological signs of this pathological process develop after four weeks from the onset of acute manifestations of a viral infection. The characteristic signs of PF include those that indicate the process of remodulation of the lung tissue: volumetric decrease in the lungs, cellular degeneration of the lung parenchyma, bronchiectasis and traction bronchiolectasis. The process of remodulating the lung tissue, in the process of fibrosis, is accompanied by a violation of the lung function; a particularly sensitive test of functional disorders is a decrease in the diffusion capacity of the lung tissue. Therefore, in the process of monitoring patients with post-COVID syndrome, a dynamic study of the ventilation function of the lungs is recommended. The main clinical manifestation of PF is dyspnea that occurs with minimal exertion. Shortness of breath also reflects another important aspect of fibrous remodulation of the lung parenchyma oxygen dissociation is disturbed, which reflects a violation of the gas exchange function of the lungs. There are no generally accepted treatments for PF in post-COVID syndrome. The literature considers such approaches as the possibility of prescribing antifibrotic therapy, hyaluronidase, and medical gases: thermal helium, nitric oxide, and atomic hydrogen. The article draws attention to the unresolved issues of post-covid PF in people who have had COVID-19.

Idiopathic pulmonary fibrosis is a specific form of chronic progressive fibrotic interstitial pneumonia of unknown etiology. Over the past decade, significant progress has been made in developing and utilizing a diagnostic algorithm for patients with idiopathic pulmonary fibrosis, involving analysis of clinical, laboratory, and instrumental data, primarily the results of high-resolution chest computed tomography. Early antifibrotic therapy can alter the disease course, slow its progression, and improve the prognosis.

BACKGROUND: The prognosis of idiopathic pulmonary fibrosis (IPF) can be predicted by the gender, age, and physiology (GAP) index. However, antifibrotic therapy (i.e., nintedanib and pirfenidone) may improve survival. AIMS: This study aimed to compare the outcomes of antifibrotic-treated IPF with the survival predicted by the GAP index. METHODS: A retrospective cohort study was conducted from March 2014 to January 2020. The electronic health-care records of all IPF patients treated with nintedanib or pirfenidone were reviewed. Besides standard demographic and mortality data, the variables required to calculate the GAP index were also extracted. RESULTS: Eighty-one patients (male 55, 68%; age 71.4 ± 10.2 years) with IPF received antifibrotic therapy (nintedanib 44.4%; pirfenidone 55.6%; mean follow-up 35 ± 16.5 months). Cumulative mortality (whole cohort 3 years 12%; 4 years 26%; 5 years 33%) was significantly less than predicted by the GAP index. CONCLUSIONS: The survival of antifibrotic-treated IPF is better than predicted by the GAP index. Novel systems for prognostication are required. The survival benefit from pirfenidone and nintedanib seem similar overall. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis plays an indispensable role in cardiac tissue homeostasis and repair after myocardial infarction (MI). The cardiac fibroblast-to-myofibroblast differentiation and extracellular matrix collagen deposition are the hallmarks of cardiac fibrosis, which are modulated by multiple signaling pathways and various types of cells in time-dependent manners. Our understanding of the development of cardiac fibrosis after MI has evolved in basic and clinical researches, and the regulation of fibrotic remodeling may facilitate novel diagnostic and therapeutic strategies, and finally improve outcomes. Here, we aim to elaborate pathophysiology, examination and intervention of cardiac fibrosis after MI. [ABSTRACT FROM AUTHOR]

Abstract Background Aberrant extracellular matrix (ECM) deposition and remodelling is important in the disease pathogenesis of pulmonary fibrosis (PF). We characterised neoepitope biomarkers released by ECM turnover in lung tissue from bleomycin-treated rats and patients with PF and analysed the effects of two antifibrotic drugs: nintedanib and pirfenidone. Methods Precision-cut lung slices (PCLS) were prepared from bleomycin-treated rats or patients with PF. PCLS were incubated with nintedanib or pirfenidone for 48 h, and levels of neoepitope biomarkers of type I, III and VI collagen formation or degradation (PRO-C1, PRO-C3, PRO-C6 and C3M) as well as fibronectin (FBN-C) were assessed in the culture supernatants. Results In rat PCLS, incubation with nintedanib led to a reduction in C3M, reflecting type III collagen degradation. In patient PCLS, incubation with nintedanib reduced the levels of PRO-C3 and C3M, thus showing effects on both formation and degradation of type III collagen. Incubation with pirfenidone had a marginal effect on PRO-C3. There were no other notable effects of either nintedanib or pirfenidone on the other neoepitope biomarkers studied. Conclusions This study demonstrated that nintedanib modulates neoepitope biomarkers of type III collagen turnover and indicated that C3M is a promising translational neoepitope biomarker of PF in terms of therapy assessment.

Usual interstitial pneumonia is the most common type of microscopic polyangiitis (MPA)-associated interstitial lung disease, and patients may initially present with isolated pulmonary fibrosis, which often leads to a misdiagnosis of idiopathic pulmonary fibrosis (IPF). Here, we describe a patient who developed fever of unknown origin, microscopic hematuria and renal insufficiency, who then tested positive for antineutrophil cytoplasmic antibody (ANCA) and was diagnosed with MPA after receiving antifibrotic medication for IPF (original diagnosis) for almost 10 years. The patient's symptoms were ameliorated after administration of additional glucocorticoids and immunosuppressants.

Background: Idiopathic pulmonary fibrosis (IPF) primarily affects old patients. Old age is a predictor of mortality. Nintedanib, the only antifibrotic drug approved in Italy for patients aged >80 years, can slow the progression of IPF by reducing the rate of decline in forced vital capacity (FVC) and the risk of exacerbations. Objectives: The primary aim of the study was to compare the decline of FVC after 12 months of nintedanib in patients aged >80 years versus younger patients. Differences related to other functional data, safety, tolerability, hospitalizations, exacerbations, and mortality were evaluated. Methods: An observational, retrospective, multicenter study was carried out in Italy. Results: 159 (122 [76.7%] males) patients were recruited: 106 (66.7%) aged ≤80 years and 53 (33.3%) aged >80 years. FVC decline after 12 months of therapy was not significantly different (−45 mL [−170; 75] vs. −20 mL [−138; 110] mL; p: 0.51). No differences were found for other functional data. Diarrhea was the most frequent adverse event (AE). Rate and type of any AEs, permanent/temporary dose reduction, or drug discontinuation were not significantly different between patients aged ≤80 vs. >80 years. Furthermore, acute exacerbations, hospitalization, and mortality were not significantly different. Conclusions: Nintedanib is effective and safe in patients with IPF aged >80 years, and no significant differences were found when clinical outcomes were compared with those of younger patients. Thus, older age should not be a barrier for the early prescription of antifibrotic treatment in IPF patients. [ABSTRACT FROM AUTHOR]

Alcohol-related liver diseases are one of the leading causes of death worldwide, primarily due to complications of liver cirrhosis (LC). Early detection of alcohol-induced liver fibrosis (LF) is a difficult task, since often alcoholic liver disease (ALD) is clinically manifested only at late stages. Given that not all alcoholic suffer from ALD, the widespread use of liver biopsy to verify the diagnosis is not advisable. Despite the variety of proposed non-invasive methods for assessing the severity of LF in patients with ALD, none of them has sufficient validation and therefore cannot be recommended for widespread use in clinical practice. The most well-studied transient elastography, due to its suboptimal specificity, can be effectively used only to exclude clinically significant LF or LC. The only proven approach to treat ALD is persistent and total alcohol abstinence. While the therapeutic options for patients with severe forms of acute hepatitis remain unchanged since the 70s of the last century and are based mainly on the use of corticosteroids, currently, there are no approaches to antifibrotic therapy of ALD approved by the guidelines. At the same time, modern achievements in understanding the pathophysiological mechanisms of this disease have served as an impetus for the development of ways to solve the problem. In particular, providing intestinal eubiosis may be an important goal for the prevention and treatment of alcohol-induced LF. Randomized controlled multicenter trials involving a large number of patients are needed to confirm this and other hypotheses related to antifibrotic therapy of ALD and to accept them as a standard of medical care.

(1) The role of the immune response in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. We hypothesized that peripheral blood immune phenotypes will be different in IPF patients and may relate to the disease severity and progression. (2) Whole blood flow cytometry staining was performed at diagnosis in 32 IPF patients, and in 32 age- and smoking-matched healthy controls. Thirty-one IPF patients were followed up for one year and categorized as stable or progressors based on lung function, deterioration and/or death. At 18–60 months, immunophenotypes were characterized again. (3) The main results showed that: (1) compared to matched controls, at diagnosis, patients with IPF showed more neutrophils, CD8+HLA-DR+ and CD8+CD28− T cells, and fewer B lymphocytes and naïve T cells; (2) in IPF, circulating neutrophils, eosinophils and naïve T cells were associated with lung function abnormalities; (3) patients whose disease progressed during the 12 months of follow-up showed evidence of cytotoxic dysregulation, with increased CD8+CD28− T cells, decreased naïve T cells and an inverted CD4/CD8 ratio at baseline; and (4) blood cell alterations were stable over time in survivors. (4) IPF is associated with abnormalities in circulating immune cells, particularly in the cytotoxic cell domain. Patients with progressive IPF, despite antifibrotic therapy, present an over-activated and exhausted immunophenotype at diagnosis, which is maintained over time.

Post-COVID lung impairment and diseases are major public health concern in the pandemic of COVID-19. Multiple etiological factors can lead to post-COVID respiratory symptoms, with post COVID fibrosis or diffuse parenchymal lung disease being the major concern. We searched PubMed database for English literature related to post-COVID lung disease and we summarized the existing evidence on radiological, physiological, and histopathological aspects of post-COVID lung diseases. We suggest a guidance on the evaluation of these patients and highlight management considerations including general care, pulmonary rehabilitation, and lung transplantation. We also explain gaps in knowledge and awaited ongoing research results, especially in the field of drug therapies including corticosteroids and antifibrotics.

Background: The efficacy of antifibrotic agents in idiopathic pulmonary fibrosis (IPF) has been demonstrated and early introduction is recommended, especially in patients with preserved performance status (PS). We aimed to determine the proportion of untreated IPF cases using real-world data and to assess the factors associated with non-intervention., Methods: A prospective observational study using questionnaires was performed on 518 patients with interstitial lung disease (ILD) and their attending physicians who visited a clinic, general hospital, or tertiary respiratory center between December 2019 and October 2020. Patients responded with subjective symptoms and PS, whereas physicians responded with diagnosis, treatment, and reasons for their treatment choices. Principal component analysis (PCA) was performed using age, sex, BMI, medical facility, specialized tests, and symptom severity., Results: We included 207 patients with IPF. Among them, 168 has a good PS (≤2), which could be indicative of treatment; 130 (77.4%) were not treated with antifibrotic agents. The PCA revealed a trend consistent with that of antifibrotic agent therapy and the distribution of medical facilities, with a treatment intervention rate of 16% in general hospitals and 62% in tertiary respiratory centers. In general hospitals, low symptom severity (PS, mMRC, and no use of long-term oxygen therapy) was a relevant factor for non-intervention with antifibrotic agents (p < 0.001)., Conclusion: Antifibrotic treatment interventions varied by facility in cases with good PS. Patients with milder symptoms are not being treated early in general hospitals and more collaboration between general hospitals and specialized facilities is necessary., Competing Interests: Declaration of competing interest M.A. (Maki Asami-Noyama) received subsidies from Nippon Boehringer Ingelheim Co., Ltd. The other authors have no conflicts of interests., (Copyright © 2024 The Author. Published by Elsevier B.V. All rights reserved.)

Pirfenidone is a groundbreaking antifibrotic agent that has become a cornerstone in managing fibrotic interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF). This review comprehensively analyzes pirfenidone's mechanisms of action, clinical efficacy, safety profile, and emerging applications beyond IPF. Pirfenidone exerts its therapeutic effects by inhibiting key pathways involved in fibrosis, including transforming growth factor-beta (TGF-β) and other pro-fibrotic cytokines. It also reduces oxidative stress and inflammation. Clinical trials have consistently demonstrated pirfenidone's ability to slow the decline in lung function, reduce disease progression, and improve survival rates in IPF patients. Furthermore, emerging evidence supports its potential use in other fibrotic ILDs and non-pulmonary fibrotic conditions, such as liver and kidney fibrosis. Despite its proven benefits, pirfenidone's safety and tolerability profiles require careful monitoring, with gastrointestinal and photosensitivity reactions being the most common adverse effects. Future research is poised to explore combination therapies, personalized treatment approaches, and novel applications of pirfenidone in a broader range of fibrotic disorders. As the field of antifibrotic therapy advances, pirfenidone remains a pivotal agent with the potential to significantly impact the management of fibrotic diseases across multiple organ systems. This review aims to provide clinicians and researchers with a detailed understanding of pirfenidone's current role and prospects in treating fibrosis., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Babariya et al.)

Idiopathic pulmonary fibrosis (IPF) is the archetypal interstitial lung disease. It is a chronic progressive condition that is challenging to manage as the clinical course of the disease is often difficult to predict. The prevalence of IPF is rising globally and in Japan, where it is estimated to affect 27 individuals per 100,000 of the population. Greater patient numbers and the poor prognosis associated with IPF diagnosis mean that there is a growing need for disease management approaches that can slow or even reverse disease progression and improve survival. Considerable progress has been made in recent years, with the approval of two antifibrotic therapies for IPF (pirfenidone and nintedanib), the availability of Japanese treatment guidelines, and the creation of global and Japanese disease registries. Despite this, significant unmet needs remain with respect to the diagnosis, treatment, and management of this complex disease. Each of these challenges will be discussed in this review, including making a timely and differential diagnosis of IPF, uptake and adherence to antifibrotic therapy, patient access to pulmonary rehabilitation, lung transplantation and palliative care, and optimal strategies for monitoring and staging disease progression, with a particular focus on the status in Japan. In addition, the review will reflect upon how ongoing research, clinical trials of novel therapies, and technologic advancements (including artificial intelligence, biomarkers, and genomic classification) may help address these challenges in the future., Competing Interests: Declaration of competing interest Masashi Bando has received honoraria from AstraZeneca and Nippon Boehringer Ingelheim; Hirofumi Chiba has received honoraria and research funding from Nippon Boehringer Ingelheim; Yasunari Miyazaki has received honoraria and research funding from Nippon Boehringer Ingelheim; Takafumi Suda has received honoraria from AstraZeneca and Nippon Boehringer Ingelheim and research funding from Chugai Pharmaceutical and Nippon Boehringer Ingelheim.The authors did not receive payment related to the development of this manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations., (Copyright © 2024. Published by Elsevier B.V.)

One of the most likely and serious complications of the novel coronavirus infection (COVID-19) is pneumofibrosis, which can negatively affect the duration and quality of life of patients who have suffered from this disease. The appearance of fibrotic changes in COVID-19 is due to a number of pathological processes that occur in the lungs after the pathogen, the SARS- CoV-2 virus, enters there. First of all, an inflammatory response is triggered, which is mediated by macrophages and granulocytes, due to which the synthesis of pro-inflammatory cytokines, incl. IL-1, TNF, which are potent inducers of hyaluronic acid synthetase. There is a decrease in the content of fibrinolysis activators in the pulmonary endothelium, which contributes to the accumulation of fibrin in the vessels of the lungs. Fibrin can escape into the interstitial space and cause the formation of sclerosing alveolitis. The increasing defeat of pneumocytes favors the release of fibrin into the lumen of the alveoli, which causes the formation of hyaline membranes. The regulation of the fibrotic process involves immunocompetent cells, primarily CD4 + T-lymphocytes, which are capable of producing cytokines, chemokines and growth factors, and these, in turn, stimulate the proliferation and differentiation of fibroblasts, as well as their production of collagen. The more severe forms of infectious process can lead to the greater risk of developing fibrotic changes. Risk factors are a large area of lung damage, the use of artificial pulmonary ventilation, ARDS, fibrosis in anamnesis. An additional role in the pathomorphogenesis of pneumofibrosis is played by smoking, external inhalation effects (inhalation of organic and inorganic dust), gastroesophageal reflux, type II diabetes mellitus, genetic factors (familial idiopathic pulmonary fibrosis). The pathogenetic features of COVID-19 require administration of anti-fibrotic treatment. Bovhyaluronidazum azoximerum, a drug that is a conjugate of the proteolytic enzyme hyaluronidase, is considered as an antifibrotic agent. The treatment regimens with this drug recommended in the period of convalescence for patients who have undergone COVID-19 are given.

Cardiac fibrosis occurs ubiquitously in ischemic heart failure, genetic cardiomyopathies, diabetes mellitus, and aging. It triggers myocardial stiffness, which impairs cardiac function, ultimately progressing to end-stage heart failure and increased mortality. Although several targets for anti-fibrotic therapies have been identified, including TGF-β and receptor tyrosine kinase, there is currently no FDA-approved drug specifically targeting cardiac fibrosis. G protein-coupled receptors (GPCRs) are integral, multipass membrane-bound receptors that exhibit diverse and cell-specific expression, offering novel and unrealized therapeutic targets for cardiac fibrosis. This review highlights the emerging roles of several GPCRs and briefly explores their downstream pathways that are crucial in cardiac fibrosis. We will not only provide an overview of the GPCRs expressed on cardiac fibroblasts that are directly involved in myofibroblast activation but also describe those GPCRs which contribute to cardiac fibrosis via indirect crosstalk mechanisms. We also discuss the challenges of identifying novel effective therapies for cardiac fibrosis and offer strategies to circumvent these challenges.

Background: Aberrant extracellular matrix (ECM) deposition and remodelling is important in the disease pathogenesis of pulmonary fibrosis (PF). We characterised neoepitope biomarkers released by ECM turnover in lung tissue from bleomycin-treated rats and patients with PF and analysed the effects of two antifibrotic drugs: nintedanib and pirfenidone.Methods: Precision-cut lung slices (PCLS) were prepared from bleomycin-treated rats or patients with PF. PCLS were incubated with nintedanib or pirfenidone for 48 h, and levels of neoepitope biomarkers of type I, III and VI collagen formation or degradation (PRO-C1, PRO-C3, PRO-C6 and C3M) as well as fibronectin (FBN-C) were assessed in the culture supernatants.Results: In rat PCLS, incubation with nintedanib led to a reduction in C3M, reflecting type III collagen degradation. In patient PCLS, incubation with nintedanib reduced the levels of PRO-C3 and C3M, thus showing effects on both formation and degradation of type III collagen. Incubation with pirfenidone had a marginal effect on PRO-C3. There were no other notable effects of either nintedanib or pirfenidone on the other neoepitope biomarkers studied.Conclusions: This study demonstrated that nintedanib modulates neoepitope biomarkers of type III collagen turnover and indicated that C3M is a promising translational neoepitope biomarker of PF in terms of therapy assessment. [ABSTRACT FROM AUTHOR]

Post-COVID lung impairment and diseases are major public health concern in the pandemic of COVID-19. Multiple etiological factors can lead to post-COVID respiratory symptoms, with post COVID fibrosis or diffuse parenchymal lung disease being the major concern. We searched PubMed database for English literature related to post-COVID lung disease and we summarized the existing evidence on radiological, physiological, and histopathological aspects of post-COVID lung diseases. We suggest a guidance on the evaluation of these patients and highlight management considerations including general care, pulmonary rehabilitation, and lung transplantation. We also explain gaps in knowledge and awaited ongoing research results, especially in the field of drug therapies including corticosteroids and antifibrotics. [ABSTRACT FROM AUTHOR]

Rationale: The diagnosis of idiopathic pulmonary fibrosis (IPF) remains challenging and can result in delayed or misdiagnosis. IPF diagnosis is based on the presence of either a radiographic or histologic usual interstitial pneumonia (UIP) pattern in the absence of an identifiable etiology. The Envisia Genomic Classifier is a clinically validated molecular diagnostic test that identifies UIP in transbronchial biopsies. Objectives: To determine the impact of the Envisia Genomic Classifier on physicians' clinical decision-making in the diagnosis and management of IPF. Methods: This prospective randomized decision impact survey was designed to test the hypothesis that including an Envisia UIP-positive result will increase IPF diagnoses, diagnostic confidence, and the recommendation for antifibrotic therapy. The survey included patients from the BRAVE (Bronchial Sample Collection for a Novel Genomic Test) study who had a high-resolution computed tomographic scan without a typical UIP pattern, an Envisia UIP-positive result, and a final diagnosis of IPF by multidisciplinary team discussion. Each case was presented in three different formats: a pre-post cohort, where each case is presented initially without and then with Envisia, and two independent cohorts, where each case is presented without and with Envisia, respectively. Results: U.S.-based pulmonologists from community and academic centers in geographically diverse practices were approached for inclusion in this study. 103 (65%) U.S.-based pulmonologists met the inclusion criteria and provided 605 case reviews of 11 patient cases. The number of IPF diagnoses increased with Envisia by an absolute difference of 39% from 47 (30%) before Envisia to 107 (69%) after Envisia in the pre-post cohort and by 13% in the independent cohorts. High confidence (⩾90%) of interstitial lung disease diagnoses was more commonly seen with Envisia in both the pre-post cohort and in the independent cohorts. Recommendation for antifibrotic treatment increased with Envisia by an absolute difference of 36% from 15 (10%) before Envisia to 72 (46.4%) after Envisia in the pre-post cohort and by 11% in the independent cohorts. Conclusions: This decision impact survey suggests the clinical utility of the Envisia Classifier by demonstrating a significant increase in IPF diagnoses, diagnostic confidence, and recommendation for antifibrotic therapies to assist physicians in effectively managing patients to improve outcomes of patients with IPF. [ABSTRACT FROM AUTHOR]

Rationale: Multimorbidity is common and leads to substantial concomitant medication burden in patients with interstitial lung disease (ILD), which may affect tolerability of ILD-targeted medications and health outcomes. Objectives: To determine the associations of concomitant medication burden with tolerability of ILD-targeted medications and survival in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF ILD. Methods: Patients with IPF receiving nintedanib or pirfenidone and patients with non-IPF ILD receiving azathioprine or mycophenolate were identified from two Australian and Canadian registries. Baseline concomitant medication burden was evaluated using three measures: medication count, polypharmacy (⩾5 medications), and the medication regimen complexity index (MRCI). Medication intolerance and discontinuation were evaluated at 6 months and 1 year after initiation of ILD-targeted medications, respectively. Cox regression models and likelihood ratio tests were used to determine the prognostic significance of medication burden on transplant-free survival. Results: In 645 treated patients with IPF, 43% experienced adverse reactions leading to intolerance (defined as dose reduction, temporary dose interruption, or permanent drug discontinuation) of antifibrotic medications within 6 months of initiation, with high baseline concomitant medication burden being consistently associated with intolerance (medication count: P = 0.005; polypharmacy: P = 0.006; MRCI: P = 0.004). This association was not observed for immunosuppressive medications in 1,255 treated patients with non-IPF ILD, who also had a lower intolerance (18%). Baseline concomitant medication burden was not independently associated with permanent discontinuation of antifibrotic (29%) and immunosuppressive medications (20%) at 1 year. The MRCI was the only measure of concomitant medication burden associated with transplant-free survival in both cohorts (P < 0.01 for both), which improved prognostication beyond common clinical factors and the ILD-GAP index (P < 0.001 for both). Conclusions: Concomitant medication burden is associated with intolerance of antifibrotic medications in patients with IPF. Medication regimen complexity is superior to simpler evaluation of concomitant medication burden for predicting prognosis in ILD. [ABSTRACT FROM AUTHOR]

Abstract Background Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated. Methods This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses. Results The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7–35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p

Tsipora M Huisman, Douglas T Dieterich, Scott L Friedman Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: Scott L FriedmanIcahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Ave, Room 1170C, New York, NY, 10025, USAEmail Scott.friedman@mssm.eduAbstract: There have been major advances in the treatment of HBV and HCV with anti-viral treatments, which is reducing the prevalence of fibrosis due to these viruses and obviating the need for anti-fibrotic therapies in these diseases. At the same time, however, the prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing, of which a substantial fraction of patients have non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis. Accordingly, NASH is emerging as the leading indication for liver transplantation in North America and Europe. Progress in uncovering pathogenic determinants of fibrosis in NASH include metabolic dysregulation in hepatocytes that induce inflammation and cytokine secretion leading to cell injury and apoptosis, among others. These pathogenic events converge upon hepatic stellate cells, which are the primary fibrogenic cell in liver, and represent a target of new therapeutic candidates that are currently being evaluated in animal models and clinical trials. This review highlights key experimental and investigational therapies for NASH fibrosis, whose evaluation will be accelerated as new non-invasive markers of fibrosis are established. While no drugs are approved yet for NASH fibrosis, there is growing optimism that new pharmacotherapies are likely to emerge within the next 3 years that will favorably alter the natural history of disease.Keywords: liver fibrosis, novel treatments, NASH, pharmacotherapies, antifibrotic therapy, cirrhosis, hepatic stellate cell

In last 2 years the infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in infection of million people around the world. Because of the lack of definitive treatment, it is reported a huge risk of mortality. The post-Covid interstitial lung fibrosis is one of the most severe consequences of associated with COVID-19 pneumonia. The persistent respiratory complications may cause substantial population morbidity, long term disability, deterioration of quality of life and even death. [ABSTRACT FROM AUTHOR]

Abstract Background FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF). Methods Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted). Results 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study. Conclusions FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF. Trial registration: NCT02803580

The problem of fibrosing interstitial lung diseases (ILDs) unites specialists from different areas: pulmonologists, radiologists, therapists, rheumatologists, occupational doctors and others. Actual achievements in studying fibrosing ILDs which are connected with development of immunology and molecular biological methods for the determination of biomarkers, new principles of image-diagnostics of lung pathology, search of new therapeutic “targets”, dictate the necessity of integration of knowledge by specialists from different areas of medicine for improvement pharmacotherapy algorithms. These algorithms directed to decrease fibrosis progression in ILDs, improve quality and increase lifespan of the patients.

Background: Anxiety and depression are common comorbidities in idiopathic pulmonary fibrosis (IPF) that impair health-related quality of life. However, there is a lack of studies focusing on the mental disorder of IPF after antifibrotic treatment and their related predictive factors., Methods: Patients with an initial diagnosis of IPF were enrolled. Data on demographics, lung function, Generalized Anxiety Disorder-7 (GAD-7) Scale, Patient Health Questionnaire 9 (PHQ-9), Patient Health Questionnaire-15 (PHQ-15), and St. George's Respiratory Questionnaire total score(SGRQ-T) were collected. Changes in anxiety, depression, somatic symptoms, and quality of life scores before and after nintedanib treatment were compared, and the related predictive factors were analyzed., Results: A total of 56 patients with a first diagnosis of IPF were enrolled, with 42 and 35 patients suffering from anxiety and depression, respectively. The GAD-7, PHQ-9, PHQ-15, and SGRQ scores were higher in the anxiety and depression groups. SGRQ total score (SGRQ-T) [OR = 1.075, 95%CI= (1.011, 1.142)] was an independent predictor of IPF combined with anxiety ( p  < 0.05); SGRQ-T [OR = 1.080, 95%CI= (1.001, 1.167)] was also an independent predictor of IPF combined with depression ( p  < 0.05). After treatment, GAD-7, PHQ-9, PHQ-15, and SGRQ scores decreased ( p  < 0.05). ΔSGRQ-T significantly affected ΔGAD-7 (β = 0.376, p  = 0.009) and ΔPHQ-9 (β = 0.329, p  = 0.022)., Conclusion: Anxiety and depression in IPF patients are closely related to somatic symptoms, pulmonary function, and quality of life. The SGRQ-T score is of great value for assessing anxiety and depression in patients with IPF. Short-term treatment with nintedanib antifibrotic therapy can alleviate anxiety and depression in IPF patients.

Background: The incidence of acute exacerbation (AE) 31 days after surgery in lung cancer (LC) patients with interstitial lung disease (ILD) has not yet been elucidated. This study aimed to identify the AE incidence rate, mortality rate, and risk factors in patients with late-stage LC with ILD. Methods: We conducted a retrospective study on 410 patients with ILD on preoperative computed tomography among 3939 patients with LC who underwent their first surgery between August 2008 and July 2019. We divided the patients into Group A (early AE; 18cases), Group B (late AE; 40 cases), and Group C (no AE; 352 cases). Results: There were no significant differences in the clinical background between Groups A and B. The AE incidence rates were 0.56 case per person-years at ≤ 30 days, 0.24 at 90 days, 0.14 at 180 days, 0.10 at 1 year, 0.078 at 2 years, 0.086 at 3 years, 0.064 at 4 years, and 0.059 at 5 years after surgery. The mortality rates of the first AE were 10/18 (56%), 3/5 (60%), 7/13 (54%), and 7/22 (32%) at onset ≤ 30 days, 31–90 days, 91–365 days, and 366–1825 days after surgery, respectively. Multivariate Cox proportional analysis showed that adjuvant chemotherapy and a usual IP (UIP) pattern on CT + KL-6 ≥ 1000 (hazard ratio 3.647, 2.631) were predictors of late AEs. Conclusions: Patients with adjuvant chemotherapy and a usual IP (UIP) pattern on CT + KL-6 ≥ 1000 are likely to develop later AEs. Therefore, early intervention with antifibrotic therapy is recommended. [ABSTRACT FROM AUTHOR]

A number of patients with interstitial lung diseases (ILD) of various etiologies, including hypersensitive pneumonitis, diffuse connective tissue diseases (rheumatoid arthritis, systemic scleroderma, dermatomyositis), sarcoidosis, idiopathic non-specific interstitial pneumonia (NSIP) and unclassified ILD develop rapid deterioration of lung ventilation function due to the progression of fibrotic changes, accompanied by a decrease in physical performance and quality of life. It is proposed to distinguish a progressive fibrotic phenotype from those with similar pathogenetic mechanisms, radiologic pattern, clinical course, and prognosis. The progressive course of the fibrotic process is assessed by reducing the forced vital capacity of the lungs (FVC), increasing the severity of signs of pulmonary fibrosis according to computed tomography (CT) and worsening respiratory symptoms. There are several risk factors for the progression of ILD, such as male gender, older age, lower initial pulmonary function, and radiological or pathological picture of usual interstitial pneumonia (UIP). Currently, the role of antifibrotic drugs in the treatment of this pathology is being actively studied. Previously, the common approach was to use this group of drugs in patients with idiopathic pulmonary fibrosis (IPF) and immunosuppressive drugs in patients with other fibrotic subtypes of IL. However, the results of clinical studies have shown a favorable response to antifibrotic therapy for a wider range of fibrotic ILD, manifested in a decrease in the annual rate of FVC reduction. And in 2020, the use of the first anti-fibrotic drug was approved for the treatment of patients with advanced pulmonary fibrosis, NOT related to idiopathic pulmonary fibrosis (IPF).

Maria Paula Diaz Soto,1 Joseph K Lim2 1Department of Medicine, Yale School of Medicine, New Haven, CT, USA; 2Yale Liver Center and Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USACorrespondence: Joseph K LimProfessor of Medicine, Yale Liver Center and Section of Digestive Diseases, Yale School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520-8019, USATel +1 (203) 737-6063Fax +1 (203) 785-7273Email joseph.lim@yale.eduAbstract: Non-alcoholic steatohepatitis (NASH) is associated with significant morbidity and mortality due to liver cirrhosis, liver failure, and hepatocellular carcinoma, and represents a leading indication for liver transplantation in the United States (U.S.). A growing spectrum of novel therapies are currently in clinical development and target several mechanisms of action which address hepatic steatosis, steatohepatitis, and hepatic fibrosis. Cenicriviroc (Allergan, Dublin, Ireland) is a novel oral antagonist of CC-motif chemokine receptors 2 and 5 (CCR2/5) which have demonstrated expression on circulating monocytes and Kupffer cells. Preclinical models have confirmed that CCR2/5 antagonism may block fat accumulation and Kupffer cell activation and disrupt monocyte/macrophage recruitment and hepatic stellate cell activation responsible for fibrogenesis. Herein we review results from the phase 2b CENTAUR trial and study designs for the phase 2b TANDEM and phase 3 AURORA trials and discuss the potential role of cenicriviroc in future pharmacotherapy for NASH fibrosis.Keywords: cenicriviroc, fatty liver, non-alcoholic steatohepatitis, liver fibrosis, antifibrotic therapy, clinical trials

Abstract Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components—the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established.

With the increasing burden of liver cirrhosis, the most advanced stage of hepatic fibrosis, there is a need to better understand the pathological processes and mechanisms to target specific treatments to reverse or cease fibrosis progression. Antiviral therapy for hepatitis B and C has effectively treated underlying causes of chronic liver disease and has induced fibrosis reversal in some; however, this has not been targeted for the majority of aetiologies for cirrhosis including alcohol or nonalcoholic steatohepatitis. Fibrosis, characterised by the accumulation of extracellular matrix proteins, is caused by chronic injury from toxic, infectious, or metabolic causes. The primary event of fibrogenesis is increased matrix production and scar formation mediated by the hepatic stellate cell, which is the principal cell type involved. Experimental models using rodent and human cell lines of liver injury have assisted in better understanding of fibrogenesis, especially in recognising the role of procoagulant factors. This has led to interventional studies using anticoagulants in animal models with reversal of fibrosis as the primary endpoint. Though these trials have been encouraging, no antifibrotic therapies are currently licenced for human use. This literature review discusses current knowledge in the pathophysiology of hepatic fibrosis, including characteristics of the extracellular matrix, signalling pathways, and hepatic stellate cells. Current types of experimental models used to induce fibrosis, as well as up-to-date anticoagulant therapies and agents targeting the hepatic stellate cell that have been trialled in animal and human studies with antifibrotic properties, are also reviewed.