Am J Manag Care. 2024 Oct;30(7 Suppl):S107-S113. doi: 10.37765/ajmc.2024.89632.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by a progressive decline in lung function, worsening quality of life, and high mortality. However, the rate and pattern of progression of IPF are variable. Real-world studies, which include a broader population of patients than clinical trials and collect data over longer periods, have provided important information on the clinical course of IPF and further insights into the efficacy and safety of antifibrotic therapies. They also highlight the worsening of patients' quality of life as lung function is lost, the high frequency of hospitalizations, and the impact of acute exacerbations on mortality in patients with IPF. Data from patient registries and analyses of claims data suggest that antifibrotic therapy is more likely to be used in patients who have worse lung function and that its use is associated with an improvement in life expectancy. The safety profile of antifibrotic therapies in real-world populations is consistent with that observed in clinical trials. Further real-world studies are needed to improve understanding of the course and impact of IPF in specific groups of patients and how the care provided to these patients might be improved.

PMID:39495030 | DOI:10.37765/ajmc.2024.89632

Sci Rep. 2024 Nov 2;14(1):26470. doi: 10.1038/s41598-024-77469-5.

ABSTRACT

Fibrosing interstitial lung diseases (ILDs) encompass a diverse range of scarring disorders that lead to progressive lung failure. Previous gene expression profiling studies focused on idiopathic pulmonary fibrosis (IPF) and bulk tissue samples. We employed digital spatial profiling to gain new insights into the spatial resolution of gene expression across distinct lung microenvironments (LMEs) in IPF, chronic hypersensitivity pneumonitis (CHP) and non-specific interstitial pneumonia (NSIP). We identified differentially expressed genes between LMEs within each condition, and across histologically similar regions between conditions. Uninvolved regions in IPF and CHP were distinct from normal controls, and displayed potential therapeutic targets. Hallmark LMEs of each condition retained distinct gene signatures, but these could not be reproduced in matched lung tissue samples. Based on these profiles and unsupervised clustering, we grouped previously unclassified ILD cases into NSIP or CHP. Overall, our work uniquely dissects gene expression profiles between LMEs within and across different types of fibrosing ILDs.

PMID:39488596 | DOI:10.1038/s41598-024-77469-5

medRxiv [Preprint]. 2024 Oct 15:2024.10.12.24315151. doi: 10.1101/2024.10.12.24315151.

ABSTRACT

BACKGROUND: The clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in individuals carrying these QVs.

METHODS: We identified QVs in telomere and non-telomere genes linked to monogenic PF forms using whole-genome sequences (WGS) from 888 Pulmonary Fibrosis Foundation Patient Registry (PFFPR) individuals. We also derived a PRS for IPF (PRS-IPF) from 19 previously published common sentinel IPF variants. Using regression models, we then examined the mutual relationships of QVs and PRS-IPF and their association with survival. Validation of results was sought in WGS from an independent IPF study (PROFILE, n=472), and results from the two cohorts were meta-analyzed.

RESULTS: Carriers of QVs in monogenic adult-onset PF genes, representing nearly 1 out of 6 IPF patients, were associated with lower PRS-IPF (Odds Ratio [OR]: 1.79; 95% Confidence Interval [CI]: 1.15-2.81; p=0.010) and shorter survival (Hazard Ratio [HR]: 1.53; 95% CI: 1.12-2.10; p=7.3×10 -3 ). Notably, carriers of pathogenic variants at telomere genes showed the strongest association with survival (HR: 1.76; 95% CI: 1.13-2.76; p=0.013). The meta-analysis of the results showed a consistent direction of effect across both cohorts.

CONCLUSIONS: We revealed the opposite effects of QVs and PRS-IPF on IPF survival. Thus, a distinct IPF molecular subtype might be defined by QVs in monogenic adult-onset PF genes. Assessing the carrier status for QVs and modelling PRS-IPF promises to further contribute to predicting disease progression among IPF patients.

PMID:39484282 | PMC:PMC11527076 | DOI:10.1101/2024.10.12.24315151

Monaldi Arch Chest Dis. 2024 Oct 29. doi: 10.4081/monaldi.2024.2952. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has been widely hypothesized to occur as a result of an interplay between a nexus of environmental and genetic risk factors. However, not much is known about the genetic aspect of this disease. The objective of this review was to identify the genetic polymorphisms associated with the risk of developing IPF. We searched PubMed, EBSCO CINAHL Plus, Web of Science, and Wiley Cochrane Library databases for studies on risk factors of IPF published between March 2000 and November 2023. Studies with an IPF diagnosis based only on the American Thoracic Society and the European Respiratory Society guidelines were included. Thirty-one case-control studies were included with 3997 IPF and 20,925 non-IPF subjects. Two of the studies enrolled biopsy-proven IPF patients; 13 studies diagnosed IPF on the basis of clinical and high-resolution computed tomography (HRCT) findings; and 14 studies diagnosed based on both biopsy and clinical and HRCT findings. 16 studies with MUC5B rs35705950, IL-4 rs2243250, IL-4 rs2070874, and tumor necrosis factor α (TNFα)-308 were eligible for meta-analysis. The allele contrast model (T versus G) for MUC5B rs35705950 revealed statistically significant association of T allele with the risk of IPF [odds ratio (OR) 3.84, 95% confidence interval (CI) 3.20 to 4.61, adjusted p<0.0001), as was the allele contrast model for Asian (OR 2.83, 95% CI 1.51 to 5.32, adjusted p=0.009) and Caucasian (OR 4.11, 95% CI 3.56 to 4.75, adjusted p<0.0001). The allele contrast models for IL-4 rs2243250, IL-4 rs2070874, and TNFα-308 did not demonstrate any significant association with IPF. This review suggests an association of MUC5B rs35705950 T allele with the risk of developing IPF. To our knowledge, this study is the first to aggregate several genetic polymorphisms associated with IPF.

PMID:39480160 | DOI:10.4081/monaldi.2024.2952

Front Cell Dev Biol. 2024 Oct 16;12:1470875. doi: 10.3389/fcell.2024.1470875. eCollection 2024.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a prevalent chronic pulmonary fibrosis disease characterized by alveolar epithelial cell damage, fibroblast proliferation and activation, excessive extracellular matrix deposition, and abnormal epithelial-mesenchymal transition (EMT), resulting in tissue remodeling and irreversible structural distortion. The mortality rate of IPF is very high, with a median survival time of 2-3 years after diagnosis. The exact cause of IPF remains unknown, but increasing evidence supports the central role of epigenetic changes, particularly microRNA (miRNA), in IPF. Approximately 10% of miRNAs in IPF lung tissue exhibit differential expression compared to normal lung tissue. Diverse miRNA phenotypes exert either a pro-fibrotic or anti-fibrotic influence on the progression of IPF. In the context of IPF, epigenetic factors such as DNA methylation and long non-coding RNAs (lncRNAs) regulate differentially expressed miRNAs, which in turn modulate various signaling pathways implicated in this process, including transforming growth factor-β1 (TGF-β1)/Smad, mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathways. Therefore, this review presents the epidemiology of IPF, discusses the multifaceted regulatory roles of miRNAs in IPF, and explores the impact of miRNAs on IPF through various pathways, particularly the TGF-β1/Smad pathway and its constituent structures. Consequently, we investigate the potential for targeting miRNAs as a treatment for IPF, thereby contributing to advancements in IPF research.

PMID:39479511 | PMC:PMC11521927 | DOI:10.3389/fcell.2024.1470875

Cureus. 2024 Sep 30;16(9):e70497. doi: 10.7759/cureus.70497. eCollection 2024 Sep.

ABSTRACT

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.

PMID:39479105 | PMC:PMC11524648 | DOI:10.7759/cureus.70497

Front Med (Lausanne). 2024 Oct 16;11:1503195. doi: 10.3389/fmed.2024.1503195. eCollection 2024.

ABSTRACT

[This corrects the article DOI: 10.3389/fmed.2024.1356825.].

PMID:39478828 | PMC:PMC11523292 | DOI:10.3389/fmed.2024.1503195

Respir Res. 2024 Oct 30;25(1):393. doi: 10.1186/s12931-024-03006-7.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.

METHODS: A double bleomycin dose was administered to 18-24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8-12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.

RESULTS: Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.

CONCLUSIONS: Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.

PMID:39478545 | DOI:10.1186/s12931-024-03006-7

Respir Investig. 2024 Oct 29;62(6):1204-1208. doi: 10.1016/j.resinv.2024.10.010. Online ahead of print.

ABSTRACT

BACKGROUND: Constipation is associated with the prognosis of several chronic diseases. However, the effect of constipation on the prognosis of idiopathic interstitial pneumonias (IIPs) remains unclear. This study aimed to investigate the association between constipation and the prognosis of patients with IIPs.

METHODS: In this single-center, observational study, the association between constipation and survival of patients with IIPs was retrospectively investigated using a marginal structural model (MSM) analysis with weighting of age, sex, body mass index, treatment (corticosteroids, immunosuppressants, and antifibrotic agents), and pulmonary function (percent predicted forced vital capacity and diffusing capacity of the lungs for carbon monoxide).

RESULTS: A total of 433 patients with IIPs (148 and 285 patients with idiopathic pulmonary fibrosis [IPF] and those without IPF) were included in the study. During the observation period, 238 patients developed constipation. The MSM analysis showed that constipation was significantly associated with shorter overall survival (hazard ratio [HR], 2.374; 95% confidence interval, 1.924-2.928, p < 0.001). When the use of antifibrotic agents was weighted separately as nintedanib or pirfenidone, constipation was significantly associated with shorter survival (HR, 2.427; 95% CI, 1.972-2.988, p < 0.001; and HR, 2.395; 95% CI, 1.940-2.957, p < 0.001, respectively). Furthermore, a subgroup analysis showed that constipation was associated with worse survival in patients with IPF and in those without IPF, regardless of the disease severity.

CONCLUSIONS: This study shows that constipation is an independent prognostic factor for patients with IIPs, suggesting its potential clinical utility.

PMID:39476439 | DOI:10.1016/j.resinv.2024.10.010

Br J Hosp Med (Lond). 2024 Oct 30;85(10):1-7. doi: 10.12968/hmed.2024.0180. Epub 2024 Oct 27.

ABSTRACT

A 26-year-old female presented with a 3-month history of dry cough, unintentional weight loss, night sweats and fatigue. Her background history was significant for ulcerative colitis, managed with Adalimumab for almost 2 years. Clinical examination was unremarkable, apart from some mild pallor. Abnormal chest x-ray findings prompted a computerised tomography (CT) thorax which demonstrated multifocal peri-bronchial consolidation. The differential diagnosis was multifocal organising pneumonia and tuberculosis (TB). Extensive investigations, including invasive bronchial imaging and biopsy, ultimately ruled out TB. This paper reports a case of Adalimumab-induced organising pneumonia and discusses its clinical implications.

PMID:39475044 | DOI:10.12968/hmed.2024.0180

Adv Sci (Weinh). 2024 Oct 30:e2405406. doi: 10.1002/advs.202405406. Online ahead of print.

ABSTRACT

Mitochondrial permeability transition pore (mPTP) opening is a key hallmark of injured type II alveolar epithelial cells (AECIIs) in idiopathic pulmonary fibrosis (IPF). Inhibiting mPTP opening in AECIIs is considered a potential IPF treatment. Herein, a "double braking" strategy on mPTP by cyclosporin A (CsA) derived ionizable lipid with 3D structure (3D-lipid) binding cyclophilin D (CypD) and siRNA downregulating mitochondrial calcium uniporter (MCU) expression is proposed for treating IPF. 3D-lipid and MCU targeting siRNA (siMCU) are co-assembled to form stable 3D-LNP/siMCU nanoparticles (NPs), along with helper lipids. In vitro results demonstrated that these NPs effectively inhibit mPTP opening by 3D-lipid binding with CypD and siRNA downregulating MCU expression, thereby decreasing damage-associated molecular patterns (DAMPs) release and suppressing epithelial-to-mesenchymal transition (EMT) process in bleomycin-induced A549 cells. In vivo results revealed that 3D-LNP/siMCU NPs effectively ameliorated collagen deposition, pro-fibrotic factors secretion, and fibroblast activation in bleomycin-induced pulmonary fibrosis (PF) mouse models. Moreover, compared to the commercial MC3-based formulation, optimized Opt-MC3/siRNA NPs with incorporating 3D-lipid as the fifth component, showed superior therapeutic efficacy against PF due to their enhanced stability and higher gene silencing efficiency. Overall, the nanomedicine containing 3D-lipid and siMCU will be a promising and potential approach for IPF treatment.

PMID:39475000 | DOI:10.1002/advs.202405406

Turk J Med Sci. 2024 May 27;54(5):900-907. doi: 10.55730/1300-0144.5866. eCollection 2024.

ABSTRACT

BACKGROUND/AIM: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are two entities categorized as fibrotic lung diseases. With a similar clinical presentation and treatment modalities in many cases, the line differentiating these two diseases may not be evident. Hence, it was aimed herein to evaluate the effectiveness of antifibrotic treatment and the course of fibrotic lung diseases.

MATERIALS AND METHODS: The study included patients diagnosed with IPF and PPF who were given antifibrotic treatment and followed-up for 12 months at our clinic. At the final follow-up, treatment response and radiological evaluation were investigated via high-resolution computed tomography.

RESULTS: Eighty-seven patients were included in the study (57 with IPF and 30 with PPF). Under antifibrotic treatment, there were no statistically significant decreases in the six-minute walking test, forced vital capacity, and diffusing capacity of the lungs for carbon monoxide values at 6 and 12 months posttreatment. The most common side effects were photosensitivity for patients under the pirfenidone regimen, while diarrhea was predominantly observed in the PPF group. Radiological progression was observed in 22.9% of the patients at 12 months posttreatment. Hospitalization requirements were more evident in the PPF group, with at least one hospitalization history present in 60% (n = 18) of the PPF patients compared to 12.3% (n = 7) of the IPF patients.

CONCLUSION: A personalized approach is preferred with similar clinical profiles for both treatment modalities, with specific side effects considered.

PMID:39473748 | PMC:PMC11518374 | DOI:10.55730/1300-0144.5866

Sci Rep. 2024 Oct 30;14(1):26044. doi: 10.1038/s41598-024-74570-7.

ABSTRACT

The role and detailed mechanisms of lncRNAs in idiopathic pulmonary fibrosis (IPF) are not fully understood. qPCR was conducted to verify lncRNA FEZF1-AS1 expression in the transforming growth factor-beta 1 (TGF-β1)-stimulated human lung fibroblasts (HLF) and A549. The EMT-related proteins were performed by western blotting. Cell proliferation, migration, and transition were detected by CCK-8, colony formation, wound-healing and transwell assays. A dual-luciferase reporter assay was conducted to validate the target relationship of FEZF1-AS1 and miR-200c-3p. FEZF1-AS1 is highly expressed in the fibrotic A549 and HLF. in vitro experiments revealed that FEZF1-AS1 facilitates cell proliferation, migration and invasion. Knockdown of FEZF1-AS1 attenuated TGF-b1-induced fibrogenesis both in vitro. Moreover, silencing FEZF1-AS1 inhibited fibrogenesis through modulation of miR-200c-3p. In addition, inhibition of miR-200c-3p promoted fibrogenesis by regulation of Zinc finger E-box binding homeobox 1 (ZEB1). Mechanistically, FEZF1-AS1 promoted lung fibrosis by acting as a competing endogenous RNA (ceRNA) for miR-200c-3p. FEZF1-AS1 silencing increased the expression and activity of miR-200c-3p to inhibit ZEB1 and alleviate lung fibrogenesis in A549 and HLF. In addition, our study showed that FEZF1-AS1 can regulate enhancer of zeste homolog2 (EZH2) to upregulate fibrosis-related proteins and promote lung fibrosis. In summary, the results of our study revealed the pulmonary fibrogenic effect of FEZF1-AS1 in cellular experiments, demonstrating the potential roles and mechanisms of the FEZF1-AS1/miR-200c-3p/ZEB1 and FEZF1-AS1/EZH2 pathways, which provides a novel and potential therapeutic target to lung fibrosis.

PMID:39472569 | DOI:10.1038/s41598-024-74570-7

Drug Metab Dispos. 2024 Oct 29:DMD-AR-2024-001917. doi: 10.1124/dmd.124.001917. Online ahead of print.

ABSTRACT

Pirfenidone (PIR) is used to treatment of idiopathic pulmonary fibrosis. After oral administration, it is metabolized by cytochrome P450 1A2 to 5-hydroxylpirfenidone (5-OH PIR) and further oxidized to 5-carboxylpirfenidone (5-COOH PIR), a major metabolite excreted in the urine (90% of the dose). This study aimed to identify enzymes that catalyze the formation of 5-COOH PIR from 5-OH PIR in the human liver. 5-COOH PIR was formed from 5-OH PIR in the presence of NAD+ by human liver microsomes (HLM) more than by human liver cytosol (HLC), with the concomitant formation of the aldehyde form (5-CHO PIR) as an intermediate metabolite. By purifying enzymes from HLM, alcohol dehydrogenases (ADHs) were identified as candidate enzymes catalyzing 5-CHO PIR formation, although ADHs are localized in the cytoplasm. Among constructed recombinant ADH1-5 expressed in HEK293T cells, only ADH4 efficiently catalyzed 5-CHO PIR formation from 5-OH PIR with a K m value (29.0 {plus minus} 4.9 µM), which was close to that by HLM (59.1 {plus minus} 4.6 µM). In contrast to commercially available HLC, in-house prepared HLC clearly showed substantial 5-CHO PIR formation, and ADH4 protein levels were significantly (rs = 0.772, P < 0.0001) correlated with 5-CHO PIR formation in 25 in-house prepared HLC samples. Some components of the commercially available HLC may inhibit ADH4 activity. Disulfiram, an inhibitor of aldehyde dehydrogenases (ALDH), decreased 5-COOH PIR formation and increased 5-CHO PIR formation from 5-OH PIR in HLM. ALDH2 knockdown in HepG2 cells by siRNA decreased 5-COOH PIR formation by 61%. Significance Statement This study clarified that 5-COOH PIR formation from 5-OH PIR proceeds via a two-step oxidation reaction catalyzed by ADH4 and disulfiram-sensitive enzymes, including ALDH2. Inter-individual differences in the expression levels or functions of these enzymes could cause variations in the pharmacokinetics of PIR.

PMID:39472076 | DOI:10.1124/dmd.124.001917

Bioorg Med Chem. 2024 Sep 5;115:117908. doi: 10.1016/j.bmc.2024.117908. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease characterized by irreversible tissue scarring, leading to severe respiratory dysfunction. Despite current treatments with the drugs Pirfenidone and Nintedanib, effective management of IPF remains inadequate due to limited therapeutic benefits and significant side effects. This review focuses on the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway, a critical regulator of cellular processes linked to fibrosis, such as fibroblast proliferation, inflammation, and epithelial-mesenchymal transition (EMT). We discuss recent advances in understanding the role of the PI3K/mTOR pathway in IPF pathogenesis and highlight emerging therapies targeting this pathway. The review compiles evidence from both preclinical and clinical studies, suggesting that PI3K/mTOR inhibitors may offer new hope for IPF treatment by modulating fibrosis and improving patient outcomes. Moreover, it outlines the potential for these inhibitors to be developed into effective, personalized treatment options, underscoring the importance of further research to explore their efficacy and safety profiles comprehensively.

PMID:39471771 | DOI:10.1016/j.bmc.2024.117908

Biomater Adv. 2024 Oct 28;166:214084. doi: 10.1016/j.bioadv.2024.214084. Online ahead of print.

ABSTRACT

Pulmonary delivery of nintedanib has noticeable advantages over the current oral administration in managing idiopathic pulmonary fibrosis (IPF). However, it remains a challenge to construct an efficient lung delivery system for insoluble nintedanib to resist nebulization instabilities and alveolar macrophage clearance. Herein, we attempted to develop nintedanib as inhalable nanocrystals stabilized with polysorbates. Different types of polysorbates (polysorbate 20, 40, 60, 80) and various drug-surfactant molar ratios (DSR = 10, 30, 60) were screened to determine the optimal nintedanib nanocrystal formulation. Most formulations (except those stabilized by polysorbate 40) could tailor nintedanib nanocrystals with sizes around 600 nm, and the nebulization-caused drug loss could be significantly reduced when DSR increased to 60. Meanwhile, all nanocrystals boosted the in vitro drug dissolution rate and improved the aerosol performance of nintedanib. Although nebulization-caused particle aggregation was found in most formulations, the nanocrystal stabilized with polysorbate 80 at DSR 60 presented no apparent size change after nebulization. This formulation exhibited superior alveolar macrophage evasion, enhanced fibroblast cluster infiltration, and improved fibroblast cluster inhibition compared with other formulations, indicating its significant potential for pulmonary nintedanib delivery. Overall, this study explored the potential of polysorbates in stabilizing nintedanib nanocrystals for nebulization and proposed practical solutions to transfer nintedanib from oral to lung delivery.

PMID:39471574 | DOI:10.1016/j.bioadv.2024.214084

Adv Ther. 2024 Oct 28. doi: 10.1007/s12325-024-03023-4. Online ahead of print.

ABSTRACT

INTRODUCTION: Nintedanib is approved for the treatment of idiopathic pulmonary fibrosis (IPF), other forms of progressive pulmonary fibrosis (PPF), and systemic sclerosis-associated interstitial lung disease (ILD). We present global post-marketing safety data for nintedanib in these fibrosing ILDs.

METHODS: Data on adverse events in patients with fibrosing ILDs who were treated with nintedanib were collected via spontaneous reporting and solicited reporting in various studies (excluding clinical trials). Data were collected from 15 October 2014 (first regulatory approval) to 15 October 2023. Adverse events were coded using the Medical Dictionary for Regulatory Activities. Cumulative exposure to nintedanib was estimated using sales data.

RESULTS: Cumulative exposure to nintedanib was 380,557 patient-years. Diarrhoea was reported at a rate of 227.5 per 1000 patient-years. Only 2.6% of diarrhoea events were reported as serious. Of 39,788 (33.6%) diarrhoea events with a known time to onset, almost 60% occurred within the first 3 months of treatment. The rate of serious liver enzyme and bilirubin elevations (including drug-induced liver injury) was 4.0 per 1000 patient-years. Bleeding was reported at a rate of 24.2 per 1000 patient-years. Most (81.3%) bleeding events were non-serious. The rates of myocardial infarction, ischaemic stroke, and venous thromboembolism were 3.3, 3.3, and 2.0 per 1000 patient-years, respectively. Gastrointestinal perforation was reported at a rate of 0.9 per 1000 patient-years.

CONCLUSION: Post-marketing safety data on established and potential adverse events associated with nintedanib in patients with fibrosing ILDs, collected over 9 years, demonstrated a safety profile that was similar to that established in clinical trials and provided in the product labels. Education of patients about the adverse events that may be associated with nintedanib, and the effective management of adverse events when they occur, is important to minimise the impact of adverse events and help patients remain on treatment.

PMID:39466587 | DOI:10.1007/s12325-024-03023-4

Front Immunol. 2024 Oct 11;15:1437767. doi: 10.3389/fimmu.2024.1437767. eCollection 2024.

ABSTRACT

BACKGROUND: Recent literature has shown the presence of B cells and autoantibodies in idiopathic pulmonary fibrosis (IPF) which would imply the presence of tertiary lymphoid structures (TLS, sites where the immune response is triggered), yet TLS are not considered features of the histological characteristics of IPF.

AIM: This study aims to quantify the presence, size, and degree of activation of TLS in biopsied and explanted lungs from patients with early- and late-IPF, never treated with antifibrotics, and relate their presence and activity to the clinical course, disease progression, and lung inflammation.

METHODS: Immunohistochestry for B cells and CD4, CD8, and CD45 cells was performed in lung tissue from IPF patients: 18 at diagnosis (early), 39 explanted (end-stage), and 12 smoking controls. TLS activation was assessed by CD40 expression. Spirometry along 31 (12-72) months of follow-up was used to characterize end-stage IPF as slow progressors or rapid progressors.

RESULTS: B cells, along with other inflammatory cells, were higher in early- and end-stage IPF than in controls (p < 0.001). In rapid progressors, all inflammatory cells were higher than in slow progressors (p < 0.05). TLS were present in 100% of early- and end-stage IPF and in 50% of controls. In end-stage IPF, the TLS area and activation score were higher than in early IPF (p < 0.0001; p = 0.005) and controls (p < 0.04; p < 0.002). TLS activation score correlated with FVC decline during follow-up in rapid progressors (r = 0.73; p = 0.007) but not in slow progressors.

CONCLUSIONS: A prominent B-cell infiltration, along with the presence of TLS, the activity of which correlates with FVC decline, is an important component of IPF from the beginning of the disease, likely playing an important role on its mechanism and progression.

PMID:39464888 | PMC:PMC11502372 | DOI:10.3389/fimmu.2024.1437767

BMJ Case Rep. 2024 Oct 26;17(10):e259153. doi: 10.1136/bcr-2023-259153.

ABSTRACT

A male patient in his 70s with a history of tobacco use, organising pneumonia and rheumatoid arthritis that had been treated for several years with rituximab currently being treated with tocilizumab, presented with progressively worsening shortness of breath, increasing oxygen requirements and weakness. He had a history of COVID-19 infection 6 months prior to presentation. Initial COVID-19 PCR testing at presentation was negative. Bronchoalveolar lavage was positive for COVID-19 but negative for spike antibodies. It was thought that he did not clear his prior COVID-19 infection due to his immunocompromised state while taking rituximab. On recommendation of infectious disease, he was treated with a prolonged course of nirmatrelvir/ritonavir, remdesivir and corticosteroids with significant symptom improvement.

PMID:39461843 | DOI:10.1136/bcr-2023-259153

Medicina (Kaunas). 2024 Oct 16;60(10):1702. doi: 10.3390/medicina60101702.

ABSTRACT

Background and Objectives: Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and secondary pulmonary fibrosis (SPF), is a progressive lung disease that significantly impairs respiratory function. Accurate differentiation between IPF and SPF is crucial for effective management. This study explores the association between pulmonary fibrosis and hepatic conditions, evaluating the utility of various hemogram-derived ratios and hepatic fibrosis scores in distinguishing between IPF and SPF. Materials and Methods: We conducted a retrospective study involving patients diagnosed with IPF or SPF at the "Leon Daniello" Clinical Hospital of Pneumology in Cluj-Napoca, Romania. Pulmonary fibrosis was confirmed via imaging techniques, and hepatic steatosis and fibrosis were assessed using non-invasive scores. We analyzed clinical, laboratory, and pulmonary function data, focusing on hemogram-derived ratios and hepatic scores. Statistical analyses, including ROC curves, were used to evaluate the effectiveness of these biomarkers in differentiating IPF from SPF. Results: We included a total of 38 patients with IPF and 28 patients with SPF. Our findings revealed that IPF patients had a significantly higher FIB-4 score compared to SPF patients, suggesting increased hepatic fibrosis risk in IPF, as well as an increased RDW/PLT ratio. Conversely, SPF patients exhibited elevated PLR, PNR, and SII, reflecting a more pronounced inflammatory profile. PLR and PNR demonstrated the highest discriminatory ability between IPF and SPF, while traditional hepatic fibrosis scores showed limited differentiation capabilities. No significant differences in pulmonary function tests were observed across hepatic fibrosis risk categories. Conclusions: The study highlights the value of biomarkers like PLR and PNR in differentiating between IPF and SPF, offering additional diagnostic insights beyond traditional imaging. Integrating hepatic assessments into the management of pulmonary fibrosis could improve diagnostic accuracy and patient care.

PMID:39459489 | DOI:10.3390/medicina60101702