Publications by authors named "Michael E Wechsler"

Article Synopsis
  • - The development of the CompOsite iNdexes For Response in asthMa (CONFiRM) aimed to create patient-centered tools that measure responses to biologics for severe asthma in both adults and children, integrating clinical data and quality of life (QoL) indicators.
  • - Experts and patients collaborated to identify significant outcome changes and devised CONFiRM scores, which demonstrated high levels of agreement on key factors, with patients emphasizing the importance of quality of life more than healthcare professionals did.
  • - The CONFiRM scores effectively measure treatment response, with strong validity metrics indicating their reliability, and they facilitate a comprehensive assessment of biologics’ effectiveness; further studies are required for prospective validation.
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Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis associated with varying clinical presentations and overlapping multiorgan involvement. Asthma is a predominant feature of EGPA, typically in its prodromal phase, often severe, and precedes vasculitic complications. However, there is paucity of studies describing the prevalence and characteristics of EGPA in the asthma population.

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  • * Interleukin-5 (IL-5) is crucial in the activation and survival of eosinophils, making it an essential target for treatments aimed at severe asthma, with therapies like mepolizumab and reslizumab blocking IL-5, while benralizumab targets its receptor for enhanced efficacy.
  • * Despite the lack of direct comparative trials for these therapies, research continues to explore the differences between partial and complete eosinophil depletion, highlighting the ongoing debate about their clinical significance in treating eosinophilic asthma. *
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  • The management of severe asthma has evolved to focus on targeted therapies, particularly monoclonal antibodies (mAbs) that target specific molecular pathways, leading to improved care since the introduction of IgE-targeting biologics in 2003.
  • New mAbs targeting interleukin pathways and other molecules have been approved, successfully improving patient symptoms and reducing the need for oral corticosteroids, but many patients still struggle with exacerbations and achieving remission.
  • Ongoing research is exploring innovative therapies and molecular targets aimed at personalizing treatment for asthma, despite some experimental therapies not getting approval due to effectiveness issues, with the future looking hopeful for better patient outcomes.
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In the United States, Black and Latino children with asthma are more likely than White children with asthma to require emergency department visits or hospitalizations because of an asthma exacerbation. Although many cite patient-level socioeconomic status and access to health care as primary drivers of disparities, there is an emerging focus on a major root cause of disparities-systemic racism. Current conceptual models of asthma disparities depict the historical and current effects of systemic racism as the foundation for unequal exposures to social determinants of health, environmental exposures, epigenetic factors, and differential healthcare access and quality.

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Article Synopsis
  • The studies NAVIGATOR and DESTINATION evaluated the effectiveness of tezepelumab in treating severe, uncontrolled asthma.
  • Results showed that a higher percentage of patients receiving tezepelumab experienced a complete clinical response and on-treatment clinical remission compared to those on placebo.
  • Conclusion suggests that tezepelumab significantly improves patient outcomes, leading to better lung function and fewer asthma exacerbations over time.
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  • - Inflammation is a key factor in the development and worsening of Chronic Obstructive Pulmonary Disease (COPD), with ongoing research revealing complex cellular interactions and differences in individual inflammatory responses.
  • - Understanding these nuances helps researchers and clinicians tailor treatments to individual patients, advancing the concept of precision medicine in COPD care.
  • - This review discusses the role of inflammation in COPD, its effects on health, and highlights current and new anti-inflammatory treatment options, including biological therapies and phosphodiesterase (PDE) inhibitors.
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Background: Depemokimab is an ultra-long-acting biologic therapy with enhanced binding affinity for interleukin-5 that may enable effective 6-month dosing intervals.

Methods: In these phase 3A, randomized, placebo-controlled replicate trials, we evaluated the efficacy and safety of depemokimab in patients with severe asthma and an eosinophilic phenotype characterized by a high eosinophil count (≥300 cells per microliter in the previous 12 months or ≥150 cells per microliter at screening) and a history of exacerbations despite the receipt of medium- or high-dose inhaled glucocorticoids. Patients were randomly assigned in a 2:1 ratio to receive either depemokimab (at a dose of 100 mg subcutaneously) or placebo at weeks 0 and 26, plus standard care.

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In this instalment of the How I Do It series on severe asthma, we tackle the clinical conundrum of choosing the right biologic for the right patient with severe asthma. With 6 biologics now approved for use in this area comprising 4 different targeting strategies (anti-Ig E: omalizumab; anti-IL-5 and anti-IL-5-receptor: mepolizumab, reslizumab, and benralizumab; anti-IL-4-receptor: dupilumab; anti-thymic stromal lymphopoietin: tezepelumab), this question is increasingly complex. Recognizing that no head-to-head trial has compared biologics, we based our review on the expected effects of inhibiting different aspects of type 2 airway inflammation, supported whenever possible by clinical trial and real-world data.

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Background: Biologic asthma therapies reduce exacerbations and long-term oral corticosteroids (LTOCS) use in randomized controlled trials (RCTs); however, there are limited data on outcomes among patients ineligible for RCTs. Hence, we investigated responsiveness to biologics in a real-world population of adults with severe asthma.

Methods: Adults in the International Severe Asthma Registry (ISAR) with ≥24 weeks of follow-up were grouped into those who did, or did not, initiate biologics (anti-IgE, anti-IL5/IL5R, anti-IL4/13).

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Introduction: Many patients with severe asthma continue to experience symptoms and exacerbations despite treatment with standard-of-care therapy. In the phase 3 NAVIGATOR study, tezepelumab significantly reduced exacerbations over 52 weeks compared with placebo in patients with severe, uncontrolled asthma. This analysis assessed the efficacy of tezepelumab in reducing asthma exacerbations in various clinically relevant subgroups of patients in NAVIGATOR.

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Background: Biologic effectiveness is often assessed as response, a term that eludes consistent definition. Identifying those most likely to respond in real-life has proven challenging.

Objective: To explore definitions of biologic responders in adults with severe asthma and investigate patient characteristics associated with biologic response.

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Article Synopsis
  • - The study investigates the link between eosinophilia and ocular vascular issues, highlighting the procoagulant effects of eosinophils, which can lead to various cardiovascular problems and eye conditions.
  • - A retrospective, multicenter analysis of 57 patients revealed that the majority experienced eye issues as the first sign of eosinophil-related diseases, with specific conditions like central retinal artery occlusion being common among them.
  • - The findings indicate a poor visual prognosis for these patients, with only 10% achieving full recovery, suggesting the need for urgent treatment and further research on eosinophilia's impacts.
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  • The study investigates how pre-biologic biomarker levels, specifically immunoglobulin E (IgE), blood eosinophil count (BEC), and fractional exhaled nitric oxide (FeNO), influence asthma treatment outcomes when patients start biologic therapy.
  • Conducted across 23 countries with over 3750 patients, the research focused on changes in exacerbation rates, symptom control, and lung function about a year after starting treatment.
  • Results showed that higher levels of BEC and FeNO were linked to significant improvements in lung function for specific biologic therapies, while IgE was not a strong predictor of treatment effectiveness.
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Article Synopsis
  • There is currently no agreed-upon definition for asthma remission in real life, and the factors that help patients achieve it after starting biologics are not well understood.
  • A study analyzed data from 23 countries to see how many adults with severe asthma reached multidomain-defined remission after beginning biologic treatment, using specific criteria for remission.
  • Results showed that less than a quarter of participants achieved full remission, with higher chances for those with fewer exacerbations, lower corticosteroid use, and better control and lung function before treatment, suggesting that early intervention is crucial for better outcomes.
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Background: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma.

Objective: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment.

Methods: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma.

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Background: Poor sleep quality is often reported by individuals with asthma, particularly by those who have poor asthma control overall. However, there is little understanding of how underlying sleep disorders such as insomnia may impact asthma control. Furthermore, given the frequent overlap of depression and insomnia, the incremental impact of mood disorders and insomnia on asthma control remains unclear.

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Rare eosinophil-associated disorders (EADs), including hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis, and eosinophilic gastrointestinal disorders, are a heterogeneous group of conditions characterized by blood and/or tissue hypereosinophilia and eosinophil-related clinical manifestations. Although the recent availability of biologic therapies that directly and indirectly target eosinophils has the potential to dramatically improve treatment options for all EADs, clinical trials addressing their safety and efficacy in rare EADs have been relatively few. Consequently, patient access to therapy is limited for many biologics, and the establishment of evidence-based treatment guidelines has been extremely difficult.

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Background: Exacerbation frequency strongly influences treatment choices in patients with severe asthma.

Research Question: What is the extent of the variability of exacerbation rate across countries and its implications in disease management?

Study Design And Methods: We retrieved data from the International Severe Asthma Registry, an international observational cohort of patients with a clinical diagnosis of severe asthma. We identified patients aged ≥ 18 years who did not initiate any biologics prior to baseline visit.

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