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【 2019-02-12 发布 】 临床报道
该图发表于Journal of Allergy and Clinical Immunology，Volume 142，Stanley J. Szefler，Asthma in the lifespan：Time for a paradigm shift，Pages 773-780，Copyright Elsevier（2018）。
药物当然在哮喘管理中发挥作用。近年来引入了几种，包括长效抗胆碱能药噻托溴铵; mepolizumab和reslizumab，抗白细胞介素（IL）5单克隆抗体; 贝那利珠单抗，一种针对嗜酸性粒细胞受体的抗体; 最近，dupilumab是一种针对IL4受体α亚基的人单克隆抗体。本综述简要总结了可用于批准的omalizumab，mepolizumab，reslizumab，benralizumab和dupilumab生物制剂的信息，以及一些正在评估的新药物。
Omalizumab是一种人源化抗免疫球蛋白（Ig）E单克隆抗体，可结合循环IgE，导致IgE水平降低; 抑制IgE与其受体的结合; 和下调肥大细胞，嗜碱性粒细胞和树突细胞上的IgE受体。 Omalizumab结合游离IgE，但不结合与肥大细胞结合的IgE，导致与过敏反应相关的炎症介质释放减少。
目前在临床试验中，fevipiprant是Th2细胞（CRTh2）上表达的化学引诱物受体 - 同源分子的竞争性拮抗剂。 CRTh2是一种前列腺素D2受体，主要通过过敏细胞（如肥大细胞）的产生来介导炎症反应。使用fevipiprant的结果不一致，仅限于2期研究。
Tezepelumab仍在进行临床试验。虽然没有对儿科人群进行过研究，但是尽管中度至高度ICS和长效β受体激动剂治疗，对未成年人哮喘的成人中的tezepelumab进行的2期研究表明，恶化率显着降低。[ 6 ]最可能有反应的患者的生物标志物谱仍然未知。
Review of Biologics in Children With Severe Asthma Shifts in Management
We have a unique opportunity to significantly reduce the worldwide burden of asthma in children and thus affect respiratory disease in adults. This will require a paradigm shift that is directed at altering the natural history of asthma, reducing asthma exacerbations, and preventing long-term adverse outcomes of childhood asthma.
For the past 50 years, we have seen paradigm shifts in asthma management about every 10 years (Figure). With the latest update of the asthma guidelines in 2007, this paradigm shift focused on achieving asthma control defined within two domains: impairment and risk. Impairment consists of day and night symptoms, rescue medication use, pulmonary function, and questionnaires to assess these measures over a short-term period. Risk directs attention to the assessment of the potential for exacerbations, adverse responses to medications, and progression of the disease.
Asthma treatment is organized into a step-care fashion to decrease impairment, minimize risk, and provide a decision path to achieve control. As part of this decision path, it is important to follow spirometry over time to define trajectories of lung growth, measure asthma burden, use biomarkers to select and monitor therapy, carefully evaluate adherence to the current management plan, and address social determinants of health in making decisions to step up therapy. In addition, as part of the current update to the asthma guidelines, six key questions are being addressed, including the intermittent use of inhaled corticosteroids (ICSs) and long-acting muscarinic antagonists, the safety and effectiveness of bronchial thermoplasty, the clinical utility of fraction of exhaled nitric oxide, the effectiveness of indoor allergen reduction, and the role of immunotherapy.
Medications certainly play a role in asthma management. Several have been introduced in recent years, including tiotropium, a long-acting anticholinergic; mepolizumab and reslizumab, anti-interleukin (IL) 5 monoclonal antibodies; benralizumab, an antibody that is directed toward eosinophil receptors; and most recently dupilumab, a human monoclonal antibody to the alpha subunit of the IL4 receptor. This review briefly summarizes the information available for the approved biologics of omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab, in addition to a few new medications that are being evaluated.
Current and Future Biologics
Biologic therapies, in particular those targeting the "allergic" or T-helper 2 (Th2) pathway, are being considered for children with severe asthma. However, a great deal of variability exists in the extent to which these biologic therapies have been studied in children.
Omalizumab is a humanized anti-immunoglobulin (Ig) E monoclonal antibody that binds circulating IgE, causing a decrease in IgE levels; inhibition of IgE binding with its receptors; and downregulation of IgE receptors on mast cells, basophils, and dendritic cells. Omalizumab binds to free IgE, but not to IgE bound to mast cells, resulting in a decreased release of inflammatory mediators related to the allergic response.
Omalizumab use in both adults and children with asthma reduced exacerbations and hospitalizations and increased the likelihood of withdrawing ICS therapy.
Omalizumab is approved by the US Food and Drug Administration for moderate to severe asthma in patients aged 6 years or older with environmental allergies. Studies are ongoing with omalizumab, including the Preventing Asthma in High Risk Kids (PARK) study, to determine whether 2 years of omalizumab in children aged 2-3 years will prevent progression to persistent asthma.
Mepolizumab, Reslizumab, and Benralizumab
IL5 is a cytokine that recruits eosinophils from the bone marrow and promotes both the activation and longevity of these cells. Three anti-IL5 biologic therapies have been approved: mepolizumab, reslizumab, and benralizumab. Mepolizumab and reslizumab are humanized monoclonal antibodies against IL5, whereas benralizumab is a humanized monoclonal antibody against the IL5 receptor.
The IL4 cytokine is an essential cytokine to Th2 cell polarization, whereas the IL13 cytokine is associated with periostin production in the bronchial epithelial cells, ultimately resulting in smooth-muscle contraction, mucus production, airway remodeling and hyperresponsiveness, and goblet cell hyperplasia. IL13 also works with IL4 to result in IgE production. The IL4 receptor (alpha subunit) is critical for both IL4 and IL13 signal transduction.
Dupilumab is a human monoclonal antibody to the alpha subunit of the IL4 receptor, thereby blocking the activity of IL4 and IL13, and has been shown to not only reduce asthma exacerbations but also improve pulmonary function.
Dupilumab was recently approved for the treatment of moderate to severe asthma in patients aged 12 years or older with an eosinophilic phenotype or oral corticosteroid- dependent asthma. A study is ongoing with dupilumab in children aged 6 years to younger than 12 years with uncontrolled persistent asthma.
Currently in clinical trials, fevipiprant is a competitive antagonist to chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2). CRTh2 is a prostaglandin D2 receptor that mediates inflammatory effects largely through its production by allergic cells, such as mast cells. Results with fevipiprant have been inconsistent and limited to phase 2 studies.[4,5]
Tezepelumab is a human anti-thymic stromal lymphopoietin (TSLP) monoclonal immunoglobulin that prevents binding of TSLP with its receptor, preventing TSLP-initiated inflammatory responses through activation of dendritic cells and mast cells.
Tezepelumab is still undergoing clinical trials. Although no studies have been conducted in the pediatric population, a phase 2 study of tezepelumab in adults with uncontrolled asthma despite medium to high ICS and long-acting beta-agonist therapy noted significant reductions in exacerbation rates. The biomarker profile of patients most likely to respond also remains unknown.
What Still Lies Ahead
The Global Initiative for Asthma recently published a pocket guide that includes recommendations for the diagnosis and management of difficult-to-control asthma in adolescents and adults. This resource should be useful in the consideration of biologic treatments for patients; however, little information is currently available to differentiate the comparative efficacy of the various biologics. Defining predictive and monitoring biomarkers to assess the likelihood of patients responding to these medications will be important. Until then, cost, convenience, available patient profiles, and family burden should be part of the decision-making process. Long-term studies will also be needed to determine whether these new treatments can prevent disease progression as well as further prevent or even reverse airway damage that has already occurred. New medications are being introduced that may significantly affect the disease, but the risk versus benefit must be carefully assessed, especially in children, to determine which patients are most likely to show a favorable response.
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