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American Journal of Respiratory and... Jan 2024Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines...
Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in patients with systemic sclerosis (SSc). To date, clinical practice guidelines regarding treatment for patients with SSc-ILD are primarily consensus based. An international expert guideline committee composed of 24 individuals with expertise in rheumatology, SSc, pulmonology, ILD, or methodology, and with personal experience with SSc-ILD, discussed systematic reviews of the published evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Predetermined conflict-of-interest management strategies were applied, and recommendations were made for or against specific treatment interventions exclusively by the nonconflicted panelists. The confidence in effect estimates, importance of outcomes studied, balance of desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications for health equity were all considered in making the recommendations. This was in accordance with the American Thoracic Society guideline development process, which is in compliance with the Institute of Medicine standards for trustworthy guidelines. For treatment of patients with SSc-ILD, the committee: ) recommends the use of mycophenolate; ) recommends further research into the safety and efficacy of () pirfenidone and () the combination of pirfenidone plus mycophenolate; and ) suggests the use of () cyclophosphamide, () rituximab, () tocilizumab, () nintedanib, and () the combination of nintedanib plus mycophenolate. The recommendations herein provide an evidence-based clinical practice guideline for the treatment of patients with SSc-ILD and are intended to serve as the basis for informed and shared decision making by clinicians and patients.
Topics: Humans; United States; Immunosuppressive Agents; Lung Diseases, Interstitial; Cyclophosphamide; Rituximab; Scleroderma, Systemic; Lung
PubMed: 37772985
DOI: 10.1164/rccm.202306-1113ST -
Frontiers in Immunology 2023Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast.... (Review)
Review
Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast. While Pirfenidone and Nintedanib are FDA-approved drugs that can slow down the progression of pulmonary fibrosis, they are unable to reverse the disease. Therefore, there is an urgent demand to develop more efficient therapeutic approaches for pulmonary fibrosis. The intracellular DNA sensor called cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) plays a crucial role in detecting DNA and generating cGAMP, a second messenger. Subsequently, cGAMP triggers the activation of stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other signaling molecules involved in immune responses. Recent studies have highlighted the involvement of aberrant activation of cGAS-STING contributes to fibrotic lung diseases. This review aims to provide a comprehensive summary of the current knowledge regarding the role of cGAS-STING pathway in pulmonary fibrosis. Moreover, we discuss the potential therapeutic implications of targeting the cGAS-STING pathway, including the utilization of inhibitors of cGAS and STING.
Topics: Humans; Chromogranin A; DNA; Nucleotidyltransferases; Pulmonary Fibrosis; Second Messenger Systems; Signal Transduction
PubMed: 37965345
DOI: 10.3389/fimmu.2023.1273248 -
Drugs Nov 2023Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Pyridones; Phenotype
PubMed: 37882943
DOI: 10.1007/s40265-023-01950-0 -
Thorax Sep 2023Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Oral pirfenidone reduces lung function decline and mortality in patients with idiopathic pulmonary fibrosis (IPF). Systemic exposure can have significant side effects, including nausea, rash, photosensitivity, weight loss and fatigue. Reduced doses may be suboptimal in slowing disease progression.
METHODS
This phase 1b, randomised, open-label, dose-response trial at 25 sites in six countries (Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12618001838202) assessed safety, tolerability and efficacy of inhaled pirfenidone (AP01) in IPF. Patients diagnosed within 5 years, with forced vital capacity (FVC) 40%-90% predicted, and intolerant, unwilling or ineligible for oral pirfenidone or nintedanib were randomly assigned 1:1 to nebulised AP01 50 mg once per day or 100 mg two times per day for up to 72 weeks.
RESULTS
We present results for week 24, the primary endpoint and week 48 for comparability with published trials of antifibrotics. Week 72 data will be reported as a separate analysis pooled with the ongoing open-label extension study. Ninety-one patients (50 mg once per day: n=46, 100 mg two times per day: n=45) were enrolled from May 2019 to April 2020. The most common treatment-related adverse events (frequency, % of patients) were all mild or moderate and included cough (14, 15.4%), rash (11, 12.1%), nausea (8, 8.8%), throat irritation (5, 5.5%), fatigue (4, 4.4%) and taste disorder, dizziness and dyspnoea (three each, 3.3%). Changes in FVC % predicted over 24 and 48 weeks, respectively, were -2.5 (95% CI -5.3 to 0.4, -88 mL) and -4.9 (-7.5 to -2.3,-188 mL) in the 50 mg once per day and 0.6 (-2.2 to 3.4, 10 mL) and -0.4 (-3.2 to 2.3, -34 mL) in the 100 mg two times per day group.
DISCUSSION
Side effects commonly associated with oral pirfenidone in other clinical trials were less frequent with AP01. Mean FVC % predicted remained stable in the 100 mg two times per day group. Further study of AP01 is warranted.
TRIAL REGISTRATION NUMBER
ACTRN12618001838202 Australian New Zealand Clinical Trials Registry.
Topics: Humans; Anti-Inflammatory Agents, Non-Steroidal; Australia; Idiopathic Pulmonary Fibrosis; Pyridones; Treatment Outcome; Vital Capacity; Male; Female; Middle Aged; Aged; Aged, 80 and over
PubMed: 36948586
DOI: 10.1136/thorax-2022-219391 -
Presse Medicale (Paris, France : 1983) Sep 2023Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of life. If left untreated, IPF has a median survival of 3 years. IPF affects ∼3 million people worldwide, with increasing incidence in older patients. The current concept of pathogenesis is that pulmonary fibrosis results from repetitive injury to the lung epithelium, with fibroblast accumulation, myofibroblast activation, and deposition of matrix. These injuries, in combination with innate and adaptive immune responses, dysregulated wound repair and fibroblast dysfunction, lead to recurring tissue remodeling and self-perpetuating fibrosis as seen in IPF. The diagnostic approach includes the exclusion of other interstitial lung diseases or underlying conditions and depends on a multidisciplinary team-based discussion combining radiological and clinical features and well as in some cases histology. In the last decade, considerable progress has been made in the understanding of IPF clinical management, with the availability of two drugs, pirfenidone and nintedanib, that decrease pulmonary lung function decline. However, current IPF therapies only slow disease progression and prognosis remains poor. Fortunately, there are multiple clinical trials ongoing with potential new therapies targeting different disease pathways. This review provides an overview of IPF epidemiology, current insights in pathophysiology, diagnostic and therapeutic management approaches. Finally, a detailed description of current and evolving therapeutic approaches is also provided.
Topics: Idiopathic Pulmonary Fibrosis; Humans; Pyridones; Indoles; Disease Progression
PubMed: 37156412
DOI: 10.1016/j.lpm.2023.104166 -
Respiratory Medicine Sep 2023The clinical spectrum of connective tissue disease-associated interstitial lung disease (CTD-ILD) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD)... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The clinical spectrum of connective tissue disease-associated interstitial lung disease (CTD-ILD) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) ranges from asymptomatic findings on radiographic imaging to a rapidly progressive illness leading to respiratory failure and death. The treatment is always challenging due to the paucity of proven effective treatments. Nintedanib and pirfenidone are recently approved antifibrotics in idiopathic pulmonary fibrosis. This study aimed to investigate the efficacy and safety of antifibrotic agents in the treatment of CTD-ILD and RA-ILD.
METHODS
Relevant databases were searched for randomized controlled trials that compared pirfenidone or nintedanib with placebo in patients with CTD-ILD and RA-ILD. The primary outcome was the change in forced vital capacity (FVC). The odds ratio or risk ratio with 95% confidence interval (CI) was estimated for categorical data, and the mean difference with 95% CI was estimated for continuous data. The I statistic was used to assess heterogeneity, and meta-analysis was performed when possible.
RESULTS
Ten studies with a total of 880 participants met the inclusion criteria. Of these, four studies were included in the meta-analysis. According to the pooled result, the annual decline of FVC was significantly decreased in the antifibrotic agent arm compared to that in the placebo arm (MD 70.58 mL/yr, 95% CI 40.55 to 100.61).
CONCLUSION
This review suggests a potential benefit and safety of antifibrotic treatment in slowing the decline of FVC in patients with CTD-ILD and RA-ILD. Further large-sample, random-controlled, high-quality trials are needed to provide more evidence in the decision-making regarding the use of antifibrotics in this group of patients.
CLINICAL TRIAL REGISTRATION
PROSPERO; No: CRD42022369112; URL: https://www.crd.york.ac.uk/prospero/.
Topics: Humans; Antifibrotic Agents; Lung Diseases, Interstitial; Connective Tissue Diseases; Idiopathic Pulmonary Fibrosis; Vital Capacity
PubMed: 37315742
DOI: 10.1016/j.rmed.2023.107329 -
Arthritis Research & Therapy Jul 2023Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease... (Review)
Review
Many clinical trial results are available to inform best practices in the treatment of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD).Herein, we summarize the results of clinical trials, including patient-reported outcome instruments, for the treatment of patients with ILD associated with systemic sclerosis (SSc/scleroderma), rheumatoid arthritis, and idiopathic inflammatory myositis, the diseases with the most available data. For SSc-ILD, the US Food and Drug Administration approved nintedanib (a tyrosine kinase inhibitor) in 2020 and subcutaneous tocilizumab (an IL-6 receptor monoclonal antibody) in 2021. Rituximab was recently shown to have similar efficacy but better tolerability than intravenous cyclophosphamide (CYC) for CTD-ILD therapy. Scleroderma Lung Study II, conducted in patients with SSc-ILD, showed that oral CYC and mycophenolate mofetil (MMF) were comparable in their effects on lung function, but MMF was better tolerated. The increasing treatment armamentarium for patients with CTD-ILD offers physicians new opportunities to improve patient outcomes.
Topics: Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Connective Tissue Diseases; Cyclophosphamide; Mycophenolic Acid; Scleroderma, Systemic; Scleroderma, Localized; Lung
PubMed: 37422652
DOI: 10.1186/s13075-023-03090-y -
Sarcoidosis, Vasculitis, and Diffuse... Sep 2023Sarcoidosis may progress to pulmonary fibrosis in 5% of patients with significantly increased mortality. Histopathology shows fibrosis in a lymphangitic pattern...
Sarcoidosis may progress to pulmonary fibrosis in 5% of patients with significantly increased mortality. Histopathology shows fibrosis in a lymphangitic pattern surrounding the granulomas. Th1 to Th2 shift in environment along with angiogenesis is implicated in exuberant fibrosis. Clinical features include dyspnea, cough, and frequently with pulmonary function tests showing a mixed ventilatory defect with severely decreased diffusion capacity of carbon monoxide. Serologic markers including soluble interleukin 2 receptor, chitotriosidase and kern von den lunges 6, and chemokine ligand 18 are elevated and implicated in progression of disease. CT imaging shows fibrosis along bronchovascular bundles with reticulations, traction bronchiectasis and honeycombing predominantly in the upper and central distribution. Complications include sarcoidosis-associated pulmonary hypertension (SAPH) and chronic pulmonary aspergillosis. Treatment involves glucocorticoids and steroid-sparing agents in the presence of active granulomas. Anti-fibrotic agents such as pirfenidone and nintedanib have been shown to slow down pulmonary function decline in randomized clinical trials involving sarcoidosis-associated pulmonary fibrosis. Transplant workup is indicated in New York Heart Association class III or IV with similar success rates as in other lung transplant patients.
PubMed: 37712364
DOI: 10.36141/svdld.v40i3.14830 -
Journal of Personalized Medicine Dec 2023Pulmonary fibrosis, a critical outcome of chronic inflammatory diseases, has gained prominence in the context of post-coronavirus (post-COVID-19) complications. This... (Review)
Review
Pulmonary fibrosis, a critical outcome of chronic inflammatory diseases, has gained prominence in the context of post-coronavirus (post-COVID-19) complications. This review delves into the multifaceted landscape of post-COVID-19 pulmonary fibrosis, elucidating the intricate molecular mechanisms underlying its pathogenesis and highlighting promising therapeutic avenues. Examining the aftermath of severe acute respiratory syndrome-2 (SARS-CoV-2) infection, the review reveals key signaling pathways implicated in the fibrotic cascade. Drawing parallels with previous coronavirus outbreaks enhances our understanding of the distinctive features of post-COVID-19 fibrosis. Antifibrotic drugs, like pirfenidone and nintedanib, take center stage; their mechanisms of action and potential applications in post-COVID-19 cases are thoroughly explored. Beyond the established treatments, this review investigates emerging therapeutic modalities, including anti-interleukin agents, immunosuppressants, and experimental compounds, like buloxybutide, saracatinib, sirolimus, and resveratrol. Emphasizing the critical importance of early intervention, this review highlights the dynamic nature of post-COVID-19 pulmonary fibrosis research. In conclusion, the synthesis of current knowledge offers a foundation for advancing our approaches to the prevention and treatment of these consequential sequelae of COVID-19.
PubMed: 38248752
DOI: 10.3390/jpm14010051 -
Advanced Science (Weinheim,... Apr 2024Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process...
Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3β (p-GSK-3β), thereby promoting β-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic β-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.
Topics: Animals; Mice; beta Catenin; Fibrosis; Glycogen Synthase Kinase 3 beta; Kidney; Kidney Diseases; Wikstroemia; Diterpenes; cdc42 GTP-Binding Protein
PubMed: 38240457
DOI: 10.1002/advs.202307850