Biological Anti-IL-5/IL-5R Therapeutics for Chronic Obstructive Pulmonary Disease (COPD) with Specific Treatable Traits: A Real-World Retrospective Analysis.

Introduction: We describe the use of anti-IL-5 monoclonal antibodies from a COPD clinic, a source other than traditional clinical trials. The objectives were to characterize the patient subgroup prescribed anti-IL-5 monoclonal antibodies and to report potential benefits. Methods: This is a retrospective case series study of 17 patients treated in a COPD subspecialty clinic. All patients had a diagnosis of COPD (post-bronchodilator FEV1/FVC <0.7) and had been prescribed an anti-IL-5 biologic for at least 8 months. Acute exacerbations of COPD (AECOPDs) were collected as reported in electronic medical records. Results: All patients (17) enrolled were treated with biologics for ≥8 months, and 13 (76%) for ≥1 year. Patients were characterized by severe disease traits, FEV1 <50% predicted, recurrent exacerbations (3.5 moderate-to-severe AECOPDs in the year before treatment), high peripheral blood eosinophil counts (≥250 cells/µL in the previous year), all on inhaled triple therapy, and only 1 patient with a diagnosis of asthma prior to smoking. There was a statistically significant decrease in the exacerbation rate compared with baseline after 8 and 12 months of anti-IL-5 treatment, respectively, yielding the equivalent of a 2-3x reduction in exacerbation rate. Absolute FEV1 decreased, and the decline in FEV1 % of predicted reached statistical significance (p<0.05); CAT score improved (p<0.05). Discussion: This real-world evidence data aligns with existing studies suggesting the potential benefit of anti-IL-5 treatment for specific patients with COPD and therefore advocates for further investigation of RCTs on the use of anti-IL-5 biologics for well-characterized patients with COPD.

Mortality in individuals with COPD on long-term home non-invasive ventilation.

BACKGROUND: Real-world evidence regarding survival of patients with chronic obstructive pulmonary disease (COPD) using chronic non-invasive ventilation (NIV) is scarce. RESEARCH QUESTION: How do obesity and other factors relate to mortality in patients with COPD on chronic NIV? STUDY DESIGN: and Methods: We retrospectively analyzed data from COPD patients enrolled in a home ventilation program between 2014 and 2018. Survival was compared between obese and non-obese groups using the Kaplan-Meier method. Factors associated with mortality were identified using multivariable Cox proportional regression analyses with Least Absolute Selection and Shrinkage Operator (LASSO) regularization. Univariable analyses were also done stratified by obesity. RESULTS: Median survival was 80.0 (95% CI: 71.0-NA) months among obese (n = 205) and 30.0 (95%CI: 19.0-42.0) months in non-obese (n = 61) patients. NIV adherence was high in both groups. Mortality was associated with male gender [HR 1.44], chronic opioids or benzodiazepines use [HR 1.07], home oxygen use [HR 1.82], fixed pressure mode of ventilation [HR 1.55], NIV inspiratory pressure [HR 1.05], and thoracic cancer [HR 1.27]; obesity [HR: 0.43], age [HR 0.99] and NIV expiratory pressure [HR 0.94] were associated with decreased mortality. In the obese, univariable analyses revealed that chest wall disease, thoracic cancer, home oxygen use, FEV1% predicted, and ventilation parameters were associated with mortality. In the non-obese, male gender and respiratory comorbidities were related to mortality. INTERPRETATION: Obesity is associated with improved survival in COPD patients highly adherent to NIV. Other factors associated with mortality reflect disease severity and ventilator parameters, with differences between obese and non-obese patients.

Bromfenac ophthalmic solution for the treatment of postoperative ocular pain and inflammation: safety, efficacy, and patient adherence.

Ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used by clinicians to manage ocular inflammation and pain following cataract surgery. Over the past decade, the US Food and Drug Administration has approved multiple topical NSAIDs for these purposes, including several reformulated products. One of these medications, bromfenac ophthalmic solution, has a long and extensive history, with proven efficacy and safety in patients following cataract surgery. The evolution of bromfenac ophthalmic solution over the years has involved either lowering the concentration of the active ingredient or extending the dosing interval to improve patient adherence/compliance. This review will focus on the history and progression of bromfenac ophthalmic solution and report the available patient preference and adherence data regarding this ocular NSAID throughout its evolution.

Multiple Mechanisms Contribute To Telomere Maintenance.

The unlimited growth potential of tumors depends on telomere maintenance and typically depends on telomerase, an RNA-dependent DNA polymerase, which reverse transcribes the telomerase RNA template, synthesizing telomere repeats at the ends of chromosomes. Studies in various model organisms genetically deleted for telomerase indicate that several recombination-based mechanisms also contribute to telomere maintenance. Understanding the molecular basis of these mechanisms is critical since some human tumors form without telomerase, yet the sequence is maintained at the telomeres. Recombination-based mechanisms also likely contribute at some frequency to telomere maintenance in tumors expressing telomerase. Preventing telomere maintenance is predicted to impact tumor growth, yet inhibiting telomerase may select for the recombination-based mechanisms. Telomere recombination mechanisms likely involve altered or unregulated pathways of DNA repair. The use of some DNA damaging agents may encourage the use of these unregulated pathways of DNA repair to be utilized and may allow some tumors to generate resistance to these agents depending on which repair pathways are altered in the tumors. This review will discuss the various telomere recombination mechanisms and will provide rationale regarding the possibility that L1 retrotransposition may contribute to telomere maintenance in tumors lacking telomerase.

Role of urotensin II in health and disease.

Urotensin II (UII) is an 11 amino acid cyclic peptide originally isolated from the goby fish. The amino acid sequence of UII is exceptionally conserved across most vertebrate taxa, sharing structural similarity to somatostatin. UII binds to a class of G protein-coupled receptor known as GPR14 or the urotensin receptor (UT). UII and its receptor, UT, are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal, and metabolic systems. UII is generally agreed to be the most potent endogenous vasoconstrictor discovered to date. Its physiological mechanisms are similar in some ways to other potent mediators, such as endothelin-1. For example, both compounds elicit a strong vascular smooth muscle-dependent vasoconstriction via Ca(2+) release. UII also exerts a wide range of actions in other systems, such as proliferation of vascular smooth muscle cells, fibroblasts, and cancer cells. It also 1) enhances foam cell formation, chemotaxis of inflammatory cells, and inotropic and hypertrophic effects on heart muscle; 2) inhibits insulin release, modulates glomerular filtration, and release of catecholamines; and 3) may help regulate food intake and the sleep cycle. Elevated plasma levels of UII and increased levels of UII and UT expression have been demonstrated in numerous diseased conditions, including hypertension, atherosclerosis, heart failure, pulmonary hypertension, diabetes, renal failure, and the metabolic syndrome. Indeed, some of these reports suggest that UII is a marker of disease activity. As such, the UT receptor is emerging as a promising target for therapeutic intervention. Here, a concise review is given on the vast physiologic and pathologic roles of UII.

Potential role of endothelin-1 in pulmonary fibrosis: from the bench to the clinic.

Endothelin-1 (ET-1) plays a central role in lung fibrosis. It is released in the lung at low concentrations from the endothelium, epithelium, and vascular smooth muscle cells and orchestrates a variety of effects. In the context of wound healing, ET-1 acts with other profibrotic mediators to recruit fibroblasts and allow for their differentiation to contractile myofibroblasts. These specialized cells in turn lay down fibrotic tissue and contract at the site of lesions to restore tissue integrity. Apoptosis and reversion to quiescence ensues. However, in diseases of the lung such as idiopathic pulmonary fibrosis (IPF), the fibrotic response is uncontrolled. Progressive injury to lung tissue, isolated both temporally and geographically, is uncontrolled and eventually causes enough tissue damage to alter pulmonary architecture and compromise function. The initiating mechanisms are as of yet largely unknown; however, ET-1 has clearly emerged as a key mediator of this disease. Here, a comprehensive overview of the role of ET-1 in fibrosis is given. A guided perspective begins from the scope of its various molecular interactions to its many cellular processes, and finally to the implications of these functions in IPF.