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BACKGROUND: Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations. OBJECTIVE: Our study aimed to explore the corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway. METHOD: The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for SEA. We analysed paired sputum (n=16) and plasma (n=25) samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed additional sputum proteins using ELISA. RESULTS: In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. CONCLUSION: At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.
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OBJECTIVE: To explore the evidence for adopting a "treatable traits" approach to asthma management. DATA SOURCES: PubMed, Medline, and Google Scholar. STUDY SELECTIONS: The above-mentioned databases were searched for randomized, controlled phase III or IV trials of adults containing the word "asthma" in the title published in the previous 10 years and for all articles containing the title words "treatable AND trait(s)," "asthma AND biomarker(s) OR smoking OR obesity OR laryngeal OR management" published within the previous 5 years. Articles were excluded if they were not published in English. Our search identified 257 articles for consideration. We also manually searched the reference lists of studies identified and searched the websites of the British Thoracic Society, European Respiratory Society, National Institute for Health and Care Excellence, and Global Initiative for Asthma for specific guidance related to asthma management. RESULTS: The "treatable traits" are described within 3 domains of pulmonary, extrapulmonary, or behavioral and lifestyle traits. We consider whether treatment should be targeted toward these traits where they are present in asthma patients, based on currently available evidence, rather than increasing treatment in response to symptoms in line with current step-up, step-down asthma management guidelines. CONCLUSION: We advocate that a treatable traits approach should be applied more broadly to the assessment and management of inadequately controlled asthma, rather than a step-up, step-down approach based on patient symptoms. This approach should be focused on the 2 treatable pulmonary traits of TH2 inflammation and airflow obstruction along with smoking cessation, in the first instance.
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Asma , Adulto , Asma/diagnóstico , Asma/terapia , Humanos , Pulmão , FenótipoRESUMO
Background: Asthma attacks are a common problem for people with asthma and are responsible for significant healthcare costs. There is interest in a precision medicine approach to treatment. However, the choice of trial outcome measures for asthma attack treatment is hampered by the absence of a consensus on suitability. We carried out a systematic review to understand the characteristics of outcome measures used in randomised controlled trials of asthma attack treatment. Have randomised controlled trials of asthma attack treatment measured outcomes that are useful to patients and healthcare providers? Methods: The protocol was registered on PROSPERO (CRD42022311479). We searched for randomised controlled trials comparing treatments for adults with asthma attacks, published in English between 1972 and 2022 on MEDLINE, Embase and Cochrane Library databases. We recorded the outcome measures and study characteristics. Results: We identified 208 eligible randomised controlled trials from 35 countries. Trials ranged from 12 to 1109 participants, with a median of 60. The most common settings were the emergency department (n=165) and hospital admission (n=33). Only 128 studies had primary and secondary outcomes defined clearly. In those that did, 73% of primary outcomes measured change in lung function or other physiological parameters over a short period (usually <24â h). Patient-reported and healthcare utilisation outcomes were the primary outcome in 27%. Conclusions: Outcomes in randomised controlled trials of asthma attack treatment focus on short-term changes in lung function and may not capture patient-centred and economically important longer-term measures. More work is needed to investigate patient and other stakeholder preferences on core outcome sets.
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Asthma exacerbations in people treated with mepolizumab result in less peak expiratory flow reduction than placebo but similar symptom scores. Symptoms recover slower, indicating these exacerbations may be less prednisolone responsive. https://bit.ly/3xQsFRB.
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The field of asthma has undergone a dramatic change in recent years. Advances in our understanding of type 2 airway inflammation have driven the discovery of monoclonal antibodies targeting specific aspects of the immune pathway. In landmark trials, these drugs have shown efficacy in reducing asthma attacks and exposure to oral corticosteroids, important causes of morbidity in people with asthma. Our review explores the key features of type 2 inflammation in asthma and summarizes the clinical trial evidence of the novel monoclonal antibody treatments and future avenues for treatment.
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Asma , Humanos , Anticorpos Monoclonais/uso terapêutico , Inflamação/complicações , Terapia Biológica/efeitos adversosRESUMO
BACKGROUND: Asthma attacks are a common and important problem. Someone experiences an asthma attack in the United Kingdom every 10 seconds. Asthma attacks cause coughing, wheezing, breathlessness, and chest tightness and are highly stressful for patients. They result in reduced quality of life, with days lost from work or school. Asthma attacks are treated with oral corticosteroids (OCSs), but these have many short- and long-term side effects. Asthma monoclonal antibodies (mAbs) have revolutionized the treatment of severe asthma by reducing asthma attacks and OCS burden by over 50%, but some people still experience attacks while on mAbs. The MEX study showed that residual asthma attacks are broadly eosinophilic (high fractional exhaled nitric oxide [FeNO]) or noneosinophilic (low FeNO), but it did not measure response to OCS treatment. There is an evidence gap in understanding the clinical and inflammatory responses that occur when using OCSs to treat residual asthma attacks in patients taking asthma mAbs. OBJECTIVE: The primary objective is to compare the clinical recovery between high-FeNO and low-FeNO attacks after acute treatment with oral prednisolone among people established on long-term asthma mAb treatment. The exploratory objective is to compare the inflammatory response to acute treatment with oral prednisolone between high-FeNO and low-FeNO attacks. METHODS: BOOST (Breakthrough Asthma Attacks Treated With Oral Steroids) is a single-center, prospective observational study of 60 adults established on long-term asthma mAb treatment who receive acute treatment with oral prednisolone (usual care) for an asthma attack. The primary outcome will be the proportion of treatment failure (the need to start oral prednisolone or antibiotics or an unscheduled health care visit for asthma, following an attack) at day 28. The secondary outcomes will be the change in forced expiratory volume in 1 second and the change in visual analogue scale symptom score between the stable state, attack, day 7, and day 28 visits. The exploratory outcomes include the changes in sputum, nasal, and blood inflammometry between the stable state, attack, day 7, and day 28 visits. RESULTS: The last asthma attack visit is anticipated to occur in December 2023. Data analysis and publication will take place in 2024. CONCLUSIONS: We will test the hypothesis that there is a difference in the rate of recovery of clinical and inflammatory measures between high-FeNO and low-FeNO asthma attacks that occur in patients on mAb therapy. The study data will help power a future randomized placebo-controlled trial of prednisolone treatment for nonsevere attacks in patients treated with asthma mAbs and will provide important information on whether corticosteroid treatment should be FeNO-directed. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46741.