Últimas publicaciones sobre EPID en noviembre y diciembre

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Fibrosis Pulmonar Progresiva (FPP)

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Wang Y, et al. Cluster features in fibrosing interstitial lung disease and associations with prognosis. BMC Pulm Med. 2023

Background: Clustering is helpful in identifying subtypes in complex fibrosing interstitial lung disease (F-ILD) and associating them with prognosis at an early stage of the disease to improve treatment management. We aimed to identify associations between clinical characteristics and outcomes in patients with F-ILD. Methods: Retrospectively, 575 out of 926 patients with F-ILD were eligible for analysis. Four clusters were identified based on baseline data using cluster analysis. The clinical characteristics and outcomes were compared among the groups. Results: Cluster 1 was characterized by a high prevalence of comorbidities and hypoxemia at rest, with the worst lung function at baseline; Cluster 2 by young female patients with less or no smoking history; Cluster 3 by male patients with highest smoking history, the most noticeable signs of velcro crackles and clubbing of fingers, and the severe lung involvement on chest image; Cluster 4 by male patients with a high percentage of occupational or environmental exposure. Clusters 1 (median overall survival [OS] = 7.0 years) and 3 (OS = 5.9 years) had shorter OS than Clusters 2 (OS = not reached, Cluster 1: p < 0.001, Cluster 3: p < 0.001) and 4 (OS = not reached, Cluster 1: p = 0.004, Cluster 3: p < 0.001). Clusters 1 and 3 had a higher cumulative incidence of acute exacerbation than Clusters 2 (Cluster 1: p < 0.001, Cluster 3: p = 0.014) and 4 (Cluster 1: p < 0.001, Cluster 3: p = 0.006). Stratification by using clusters also independently predicted acute exacerbation (p < 0.001) and overall survival (p < 0.001). Conclusions: The high degree of disease heterogeneity of F-ILD can be underscored by four clusters based on clinical characteristics, which may be helpful in predicting the risk of fibrosis progression, acute exacerbation and overall survival.
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Ito T, et al. Safety and tolerability of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: first interim report of a 2-year post-marketing surveillance. Ther Res. 2023

Objective: To assess the safety of nintedanib in the treatment of patients with progressive fibrosing interstitial lung diseases (PF-ILDs) in real-world clinical settings in Japan. Methods: A non-interventional, prospective, observational 2-year post-marketing surveillance was undertaken of Japanese patients treated with nintedanib for PF-ILD (other than idiopathic pulmonary fibrosis) who were under routine clinical care between October 1, 2020 and October 15, 2022. Nintedanib 150 mg bid or 100 mg bid was administered; dose increase or decrease was allowed. Patients starting treatment with nintedanib were registered using case report forms (CRFs). An interim safety analysis was performed using the data snapshot taken on October 15, 2022. The primary outcome was the incidence of adverse drug reactions (ADRs). In general, the safety analyses were descriptive, focusing on hepatic function disorders, ADRs, serious adverse events (SAEs), and adverse events (AEs) leading to treatment discontinuation or death. Results: As of October 15, 2022, 425 patients had been enrolled; 250 12-week CRFs had been collected and, of these, 207 CRFs were cleaned; 207 patients were included in the safety analysis. ADRs occurred in 108/207 patients (52.17%). The most common ADRs were diarrhea (n= 49 [23.67%]) and hepatic function abnormal (n= 19 [9.18%]). Treatment was discontinued in 52/207 (25.12%) patients, mainly for AEs. AEs leading to discontinuation occurred in 34/207 patients (16.43%). The most common was diarrhea (n= 8 [3.86%]). Conclusions: The safety profile of nintedanib in Japanese patients with PF-ILDs in clinical practice is consistent with previous reports. No new safety concerns were observed.
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Kim K, et al. Factors for progressive pulmonary fibrosis in connective tissue disease-related interstitial lung disease. Ther Adv Respir Dis. 2023

Background: Progressive fibrosis can occur in connective tissue disease (CTD)-related interstitial lung disease (ILD) and make the prognosis worse. Objectives: This study aimed to investigate factors related to progressive pulmonary fibrosis (PPF) phenotype in CTD-ILDs. Design: Medical records of patients diagnosed as CTD and ILD at a single, tertiary hospital in South Korea were retrospectively reviewed. Methods: Patients whose lung functions were followed up for more than a year were included in analysis. PPF was defined as forced vital capacity (FVC) declined 10% or diffusion capacity of carbon monoxide (DLco) 15%. Results: Of 110 patients with CTD-ILD, 24.5% progressed into PPF. Rheumatoid arthritis (RA) and Sjogren's disease accounted for more than 63% of PPF. Compositions of CTD type were similar between PPF and non-PPF. Clinical characteristics and proportion of usual interstitial pneumonia (UIP) pattern on chest images were also similar between PPF and non-PPF. Approximately 10% of patients in both groups were treated with anti-fibrotic agents. Use of systemic steroids and/or other immunomodulating agents lowered the risk of developing PPF in CTD-ILD patients after adjusting for gender-age-physiology score and smoking status (adjusted odds ratio: 0.25, 95% confidence interval: 0.07-0.85). Conclusion: About a quarter of CTD-ILD progressed into PPF. The use of immunomodulating agents lowered the risk of developing PPF. To improve outcomes of patients, future studies need to detect patients at higher risk for PPF earlier and set up clinical guidelines for treatment strategies in the process of PPF.
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Case AH, et al. Defining the pathway to timely diagnosis and treatment of interstitial lung disease: a US Delphi survey. BMJ Open Respir Res. 2023

Introduction: Timely diagnosis of interstitial lung disease (ILD) is limited by obstacles in the current patient pathway. Misdiagnosis and delays are common and may lead to a significant burden of diagnostic procedures and worse outcomes. This Delphi survey aimed to identify consensus on the key steps that facilitate the patient journey to an accurate ILD diagnosis and appropriate management in the US. Methods: A modified Delphi analysis was conducted, comprising three online surveys based on a comprehensive literature search. The surveys spanned five domains (guidelines, community screening, diagnosis, management and specialist referral) and were completed by a panel of US physicians, including primary care physicians and pulmonologists practising in community or academic settings. A priori definitions of consensus agreement were median scores of 2-3 (agree strongly/agree), with an IQR of 0-1 for questions on a 7-point Likert scale from -3 to 3, or ≥80% agreement for binary questions. Results: Forty-nine panellists completed the surveys and 62 statements reached consensus agreement. There was consensus agreement on what should be included in the primary care evaluation of patients with suspected ILD and the next steps following workup. Regarding diagnosis in community pulmonology care, consensus agreement was reached on the requisition and reporting of high-resolution CT scans and the appropriate circumstances for holding multidisciplinary discussions. Additionally, there was consensus agreement on which symptoms and comorbidities should be monitored, the frequency of consultations and the assessment of disease progression. Regarding specialist referral, consensus agreement was reached on which patients should receive priority access to ILD centres and the contents of the referral package. Conclusions: These findings clarify the most common issues that should merit further evaluation for ILD and help define the steps for timely, accurate diagnosis and appropriate collaborative specialty management of patients with ILD.
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Koh SY, et al. Value of CT quantification in progressive fibrosing interstitial lung disease: a deep learning approach. Eur Radiol. 2023

Objectives: To evaluate the relationship of changes in the deep learning-based CT quantification of interstitial lung disease (ILD) with changes in forced vital capacity (FVC) and visual assessments of ILD progression, and to investigate their prognostic implications. Methods: This study included ILD patients with CT scans at intervals of over 2 years between January 2015 and June 2021. Deep learning-based texture analysis software was used to segment ILD findings on CT images (fibrosis: reticular opacity + honeycombing cysts; total ILD extent: ground-glass opacity + fibrosis). Patients were grouped according to the absolute decline of predicted FVC (< 5%, 5-10%, and ≥ 10%) and ILD progression assessed by thoracic radiologists, and their quantification results were compared among these groups. The associations between quantification results and survival were evaluated using multivariable Cox regression analysis. Results: In total, 468 patients (239 men; 64 ± 9.5 years) were included. Fibrosis and total ILD extents more increased in patients with larger FVC decline (p < .001 in both). Patients with ILD progression had higher fibrosis and total ILD extent increases than those without ILD progression (p < .001 in both). Increases in fibrosis and total ILD extent were significant prognostic factors when adjusted for absolute FVC declines of ≥ 5% (hazard ratio [HR] 1.844, p = .01 for fibrosis; HR 2.484, p < .001 for total ILD extent) and ≥ 10% (HR 2.918, p < .001 for fibrosis; HR 3.125, p < .001 for total ILD extent). Conclusion: Changes in ILD CT quantification correlated with changes in FVC and visual assessment of ILD progression, and they were independent prognostic factors in ILD patients. Clinical relevance statement: Quantifying the CT features of interstitial lung disease using deep learning techniques could play a key role in defining and predicting the prognosis of progressive fibrosing interstitial lung disease.
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EPI asociada a Esclerosis Sistémica (EPI-ES)

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Di Battista M, et al. Lung ultrasound and high-resolution computed tomography quantitative variations during nintedanib treatment for systemic sclerosis-associated interstitial lung disease. Rheumatology (Oxford). 2023

Objectives: Lung ultrasound (LUS) and high-resolution computed tomography (HRCT) are commonly used for the evaluation of interstitial lung disease (ILD). Nintedanib (NIN) is an antifibrotic therapy approved for systemic sclerosis-associated ILD (SSc-ILD). We assessed LUS and quantitative HRCT changes in SSc-ILD patients treated with NIN during a one-year follow-up, evaluating relationships between imaging variations and functional or quality-of-life outcomes. Methods: SSc-ILD patients who started NIN were enrolled and followed for twelve months. Pulmonary function tests and patient-reported outcome measures (PROMs) were assessed half-yearly and quarterly, respectively. LUS was performed quarterly evaluating the presence of B-lines (BL) and pleural line irregularities (PLI). HRCT was repeated after one year and quantitatively analysed with CALIPER software. Results: Ten patients (70% female, mean age 62 years) were enrolled. The mean total number of both BL and PLI was constantly decreased during NIN treatment, being significantly reduced after twelve months (from 175.1 ± 66.7-120.8 ± 70.3 for BL, p= 0.005 and from 50.6 ± 32.5-37.2 ± 22.4 for PLI, p= 0.05). Male gender, smoking habit and baseline forced vital capacity <70% predicted were associated with worse LUS outcomes. A greater reduction of both BL and PLI was observed in those who improved in PROMs, especially modified Medical Research Council dyspnoea scale (p= 0.016 and p= 0.04, respectively) and Saint George's Respiratory Questionnaire (p= 0.006 and p= 0.026, respectively). No significant changes in the CALIPER percentages of normal parenchyma or ILD elements were observed after twelve months of NIN, thus paralleling the stabilization obtained at pulmonary function tests. Conclusions: We present preliminary results on NIN effects on SSc-ILD as assessed by LUS, a useful method for frequently repeated monitoring, and CALIPER, a valid implementation whenever a HRCT is performed.
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Philip SS, et al. Exploratory clinical subgroup clustering in systemic sclerosis Results from the Indian Progressive Systemic Sclerosis Registry. J Scleroderma Relat. 2023

Objective: To conduct an exploratory cluster analysis of systemic sclerosis patients from the baseline data of the Indian systemic sclerosis registry. Methods: Patients satisfying American College of Rheumatology-European League Against Rheumatism classification criteria for systemic sclerosis were included. The clusters formed using clinical and immunological parameters were compared. Results: Of the 564 systemic sclerosis registry participants, 404 patients were included. We derived four clusters of which three were anti-topoisomerase I predominant and one was anti-centromere antibody 2 dominant. Cluster 1 (n-82 (20.3%)) had diffuse cutaneous systemic sclerosis patients with the most severe skin disease, anti-topoisomerase I positivity, males, younger age of onset and high prevalence of musculoskeletal, vasculopathic and gastrointestinal features. Cluster 2 (n-141 (34.9%)) was also diffuse cutaneous systemic sclerosis and anti-topoisomerase I predominant but with less severe skin phenotype than cluster 1 and a lesser prevalence of musculoskeletal, vasculopathic and gastrointestinal features. Cluster 3 (n-119 (29.5%)) had limited cutaneous systemic sclerosis patients with anti-topoisomerase I positivity along with other antibodies. The proximal muscle weakness was higher and digital pitting scars were lower, while other organ involvement was similar between clusters 2 and 3. Cluster 4 (n-62 (15.30%)) was the least severe group with limited cutaneous systemic sclerosis and anti-centromere antibody predominance. Age of onset was higher with low musculoskeletal disease and a higher presence of upper gastrointestinal features. The prevalence of interstitial lung disease was similar in the three anti-topoisomerase I predominant clusters. Conclusion: With exploratory cluster analysis, we confirmed the possibility of subclassification of systemic sclerosis along a spectrum based on clinical and immunological characteristics. We also corroborated the presence of anti-topoisomerase I in limited cutaneous systemic sclerosis and the association of interstitial lung disease with anti-topoisomerase I.
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Investigación básica - Biomarcadores

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Joannes A, et al. Anti-fibrotic effects of nintedanib on lung fibroblasts derived from patients with Progressive Fibrosing Interstitial Lung Diseases (PF-ILDs). Pulm Pharmacol Ther. 2023

The tyrosine kinase inhibitor nintedanib has been recently approved for the treatment of Interstitial Lung Diseases (ILDs) that manifest a progressive fibrosis phenotype other than Idiopathic pulmonary Fibrosis (IPF). Nintedanib reduces the development of lung fibrosis in various animal models resembling features of PF-ILD and in vitro, it inhibits the fibrosing phenotype of human lung fibroblasts (HLFs) isolated from patients with IPF. To get insight on the cellular and molecular mechanisms that drive the clinical efficiency of nintedanib in patients with non-IPF PF-ILD, we investigated its effects on the fibrosing functions of HLFs derived from patients with PF-hypersensitivity pneumonitis (PF-HP, n = 7), PF-sarcoidosis (n = 5) and pleuroparenchymal fibroelastosis (PPFE, n = 4). HLFs were treated with nintedanib (10 nM-1 μM) and then stimulated with PDGF-BB (25-50 ng/ml) or TGF-β1 (1 ng/ml) for 24-72 h to assess proliferation and migration or differentiation. At nanomolar concentrations, nintedanib reduced the levels of PDGF receptor and ERK1/2 phosphorylation, the proliferation and the migration of PF-HP, PF-sarcoidosis and PPFE HLFs stimulated with PDGF-BB. Moreover, nintedanib also attenuates the myofibroblastic differentiation driven by TGF-β1 but only when it is used at 1 μM. The drug reduced the phosphorylation of SMAD2/3 and decreased the induction of collagen, fibronectin and α-smooth muscle actin expression induced by TGF-β1. In conclusion, our results demonstrate that nintedanib counteracts fundamental fibrosing functions of lung fibroblasts derived from patients with PF-HP, PF-sarcoidosis and PPFE, at concentrations previously reported to inhibit control and IPF HLFs. Such effects may contribute to its clinical benefit in patients suffering from these irreversible ILDs.
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Zhong B, et al. Identifying the link between serum VEGF and KL-6 concentrations: a correlation analysis for idiopathic pulmonary fibrosis interstitial lung disease progression. Front Med (Lausanne). 2023

Background: Idiopathic pulmonary fibrosis interstitial lung disease (IPF-ILD) is a progressive lung disease characterized by excessive collagen deposition and fibrotic changes in the lungs. Identifying reliable serum markers that correlate with disease progression is crucial for diagnosis and prognosis. Objective: This study aimed to explore the association between serum markers KL-6 and VEGF and IPF-ILD. Specifically, it assessed their correlation with PaO2, a measure of pulmonary gas function, to provide diagnostic and prognostic indicators. Methods: Patients with IPF-ILD were included, and their serum levels of KL-6 and VEGF were measured. Correlations with fibrotic damage and PaO2 were analyzed using statistical methods. Results: The analysis confirmed a positive correlation between the serum marker KL-6 and the degree of fibrotic damage in IPF-ILD. On the other hand, the serum marker VEGF was found to promote disease progression. In terms of correlation with PaO2, both KL-6 and VEGF demonstrated high sensitivity and specificity. Specifically, the correlation between KL-6 and PaO2 suggests that it can be used as a reliable indicator to assess the status of pulmonary oxygenation function in patients with ILD. The correlation between VEGF and PaO2 helps to understand its role in the progression of IPF-ILD and provides an important basis for predicting patient prognosis. Conclusion: This study confirmed the correlation between KL-6 and VEGF with IPF-ILD and their association with PaO2. KL-6 and VEGF demonstrated high specificity and sensitivity in diagnosing, monitoring, and predicting prognosis in IPF-ILD. These findings contribute to our understanding of the disease and have clinical implications for diagnosis and prognostication.
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Revisiones

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Liakouli V, et al. Systemic sclerosis interstitial lung disease: unmet needs and potential solutions. Nat Rev Rheumatol. 2024

Systemic sclerosis (SSc), or scleroderma, is a rare, complex, systemic autoimmune disease of unknown aetiology, characterized by high morbidity and mortality often resulting from cardiopulmonary complications such as interstitial lung disease and pulmonary arterial hypertension. Despite substantial progress in unravelling the pathways involved in the pathogenesis of SSc and the increasing number of therapeutic targets tested in clinical trials, there is still no cure for this disease, although several proposed treatments might limit the involvement of specific organs, thereby slowing the natural history of the disease. A specific focus of recent research has been to address the plethora of unmet needs regarding the global management of SSc-related interstitial lung disease, including its pathogenesis, early diagnosis, risk stratification of patients, appropriate treatment regimens and monitoring of treatment response, as well as the definition of progression and predictors of progression and mortality. More refined stratification of patients on the basis of clinical features, molecular signatures, identification of subpopulations with distinct clinical trajectories and implementation of outcome measures for future clinical trials could also improve therapeutic management strategies, helping to avoid poor outcomes related to lung involvement.
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Walsh SLF, et al. Imaging Features of Autoimmune Disease-Related Interstitial Lung Diseases. J Thorac Imaging. 2023

Interstitial lung diseases (ILDs) associated with autoimmune diseases show characteristic signs of imaging. Radiologic signs are also used in the identification of ILDs with features suggestive of autoimmune disease that do not meet the criteria for a specific autoimmune disease. Radiologists play a key role in identifying these signs and assessing their relevance as part of multidisciplinary team discussions. A radiologist may be the first health care professional to pick up signs of autoimmune disease in a patient referred for assessment of ILD or with suspicion for ILD. Multidisciplinary team discussion of imaging findings observed during follow-up may inform a change in diagnosis or identify progression, with implications for a patient's treatment regimen. This article describes the imaging features of autoimmune disease-related ILDs and the role of radiologists in assessing their relevance.
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Bernardinello N, et al. Emerging Treatments for Childhood Interstitial Lung Disease. Paediatr Drugs. 2024

Childhood interstitial lung disease (chILD) is a large and heterogeneous group of disorders characterized by diffuse lung parenchymal markings on chest imaging and clinical signs such as dyspnea and hypoxemia from functional impairment. While some children already present in the neonatal period with interstitial lung disease (ILD), others develop ILD during their childhood and adolescence. A timely and accurate diagnosis is essential to gauge treatment and improve prognosis. Supportive care can reduce symptoms and positively influence patients' quality of life; however, there is no cure for many of the chILDs. Current therapeutic options include anti-inflammatory or immunosuppressive drugs. Due to the rarity of the conditions and paucity of research in this field, most treatments are empirical and based on case series, and less than a handful of small, randomized trials have been conducted thus far. A trial on hydroxychloroquine yielded good safety but a much smaller effect size than anticipated. A trial in fibrotic disease with the multitargeted tyrosine kinase inhibitor nintedanib showed similar pharmacokinetics and safety as in adults. The unmet need for the treatment of chILDs remains high. This article summarizes current treatments and explores potential therapeutic options for patients suffering from chILD.
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Akiyama M, et al. Does a window of opportunity for rheumatoid arthritis-associated interstitial lung disease exist? Autoimmun Rev. 2023

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis, eventually leading to joint destruction. Remarkable advancements in the emergence of molecular targeted therapies and the treatment strategy based on treat-to-target have made it possible for patients to lead their daily lives without disabilities. Specifically, early diagnosis and appropriate treatment without missing a 'window of opportunity' are crucial for improving joint outcomes. On the other hand, interstitial lung disease (ILD) is an extra-articular complication of RA and has an impact on life prognosis. Importantly, it has become evident that achieving remission of arthritis is critical not only for joint outcomes but also to prevent the irreversible progression of pulmonary fibrosis in RA-ILD. Therefore, a 'window of opportunity' may exist not only for joints but also for RA-ILD. However, within RA-ILD, there are cases that progress from an NSIP pattern or airway involvement to a UIP pattern, while there are cases without progression, suggesting that their disease behavior may be diverse. Thus, accumulating evidence is necessary to accurately determine the disease behavior of RA-ILD. This review provides an overview of clinical and radiological features and treatment strategies for RA-ILD, incorporating the latest findings.
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Ferrari HM, et al. Systemic-Sclerosis-Related Interstitial Lung Disease: A Review of the Literature and Recommended Approach for Clinical Pharmacists. Ann Pharmacother. 2023.

Objective: To describe the efficacy, safety, and clinical utility of pharmacologic agents in the treatment of systemic sclerosis-related interstitial lung disease (SSc-ILD). Data sources: A review of the literature was performed using the terms lung diseases, (interstitial/therapy) AND (scleroderma, systemic/therapy) OR (scleroderma, systemic) AND (lung diseases, interstitial/therapy) in PubMed, Ovid MEDLINE, CINAHL, and Web of Science. ClinicalTrials.gov was also searched to identify ongoing studies. The initial search was performed in October 2022, with follow-up searches performed in October 2023. Study selection and data abstraction: Articles reviewed were limited to those written in the English language, human studies, and adult populations. Data synthesis: A variety of therapeutic agents, including mycophenolate, azathioprine, cyclophosphamide (CYC), rituximab (RTX), nintedanib, and tocilizumab (TCZ) have slowed the rate of decline in forced vital capacity (FVC) and disease progression. Only nintedanib and TCZ have a labeled indication for SSc-ILD. Two agents, belimumab and pirfenidone, have shown encouraging results in smaller phase II and phase III studies, but have yet to be approved by the Food and Drug Administration. Relevance to patient care and clinical practice: Patients with pulmonary manifestations of SSc-ILD have worse outcomes and lower survival rates compared with those without. It is imperative that disease management be individualized to achieve optimal patient-centered care. Pharmacists are uniquely suited to support this individualized management. Conclusion: Numerous pharmacologic agents have been studied and repurposed in the treatment of SSc-ILD, with nintedanib and TCZ gaining approval to slow the rate of decline in pulmonary function in SSc-ILD. Other agents, including belimumab and pirfenidone, are on the horizon as potential treatment options; but further studies are needed to compare their efficacy and safety with the current standard of care.


PC-ES-112261

 

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