The development of monoclonal antibody therapies targeting specific components of the pathways relevant to asthma pathophysiology has revolutionized treatment of severe asthma both in adults and children and helped to further unravel the heterogeneity of this disease. However, the availability of multiple agents, often with overlapping eligibility criteria, creates a need for pragmatic guidance for specialists undertaking care of patients with severe asthma. In this review, we provide an overview of the data supporting the clinical efficacy of biologics in distinct asthma phenotypes/endotypes. We also focus on the role of biomarkers and treatable traits, including comorbidities, in the choice of asthma biologics, highlight which treatments have been demonstrated to be steroid sparing in corticosteroid dependent asthma, and provide practical guidance that can drive shared decision making on treatment choice with patients. In addition, we summarize what is known to date regarding long-term safety of these drugs, and lastly, discuss future directions in biologics research.
- MeSH
- antiastmatika * terapeutické užití MeSH
- biologické markery MeSH
- biologické přípravky * terapeutické užití MeSH
- bronchiální astma * MeSH
- dítě MeSH
- dospělí MeSH
- fenotyp MeSH
- individualizovaná medicína MeSH
- lidé MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Since its global invasion in 2019, COVID-19 has affected several aspects of patients' lives and posed a significant impact on the health care system. Several patient populations were identified to be at high risk of contracting SARS-CoV-2 infection and/or developing severe COVID-19-related sequelae. Conversely, anyone who has contracted SARS-CoV-2 is at risk to experience symptoms and signs consistent with post-COVID manifestations. Patients with asthma were initially thought to be at increased risk and severity for SARS-CoV-2 infection. However, accumulating evidence demonstrates that asthma endotypes/phenotypes and comorbidities influence the risk stratification in this population. Furthermore, initial concerns about the potentially increased risk of poor outcomes with asthma treatments such as inhaled corticosteroids and biologics have not been substantiated. In this review, we provide an update on COVID-19 and asthma, including risk of susceptibility, clinical manifestations and course in this population as well as discuss recommendations for management.
- MeSH
- bronchiální astma * diagnóza MeSH
- COVID-19 * epidemiologie komplikace MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- komorbidita MeSH
- lidé MeSH
- SARS-CoV-2 MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- bronchiální astma * diagnóza terapie MeSH
- lidé MeSH
- pacienti MeSH
- praktičtí lékaři * MeSH
- stupeň vzdělání MeSH
- zdravotničtí záchranáři MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) or without (CRSsNP) are chronic respiratory diseases. These two disorders often co-exist based on common anatomical, immunological, histopathological, and pathophysiological basis. Usually, asthma with comorbid CRSwNP is driven by type 2 (T2) inflammation which predisposes to more severe, often intractable, disease. In the past two decades, innovative technologies and detection techniques in combination with newly introduced targeted therapies helped shape our understanding of the immunological pathways underlying inflammatory airway diseases and to further identify several distinct clinical and inflammatory subsets to enhance the development of more effective personalized treatments. Presently, a number of targeted biologics has shown clinical efficacy in patients with refractory T2 airway inflammation, including anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab)/anti-IL5R (benralizumab), anti-IL-4R-α (anti-IL-4/IL-13, dupilumab), and anti-TSLP (tezepelumab). In non-type-2 endotypes, no targeted biologics have consistently shown clinical efficacy so far. Presently, multiple therapeutical targets are being explored including cytokines, membrane molecules and intracellular signalling pathways to further expand current treatment options for severe asthma with and without comorbid CRSwNP. In this review, we discuss existing biologics, those under development and share some views on new horizons.
- MeSH
- biologické přípravky * terapeutické užití MeSH
- bronchiální astma * komplikace farmakoterapie epidemiologie MeSH
- chronická nemoc MeSH
- komorbidita MeSH
- lidé MeSH
- nosní polypy * komplikace farmakoterapie MeSH
- rinitida * komplikace farmakoterapie MeSH
- sinusitida * komplikace farmakoterapie MeSH
- zánět farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- biomedicínský výzkum MeSH
- bronchiální astma * terapie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- úvodní články MeSH
- úvodníky MeSH
PURPOSE OF REVIEW: Although respiratory viruses are common triggers of asthma exacerbation, it is unknown whether this also applies to infection with SARS-CoV-2. Indeed, patients with asthma and allergy appear underrepresented in large reports of COVID-19 cases worldwide. In this review, we evaluate existing literature on this topic and potential underlying mechanisms for any interrelationship between asthma and COVID-19. RECENT FINDINGS: Data from several preclinical and clinical reports suggest a lower susceptibility for COVID-19 in patients with underlying type 2 airway inflammation including asthma that may be related to a reduced expression of ACE2 and TMPRSS2 receptors for SARS-CoV-2. Corticosteroids further decrease expression of the ACE2 and TMPRSS2 receptors, hence may also have a protective effect against infection with SARS-CoV-2. In addition, some studies suggest that the reported improvement in asthma control and a reduction in asthma exacerbations during the COVID-19 pandemic may be related to improvement in adherence to controller therapy and reduced exposure to triggers, such as other respiratory viruses and air pollutants. Recent data point towards differential susceptibility for COVID-19 among asthma patients based on their phenotype and/or endotype. On the basis of existing evidence, continuation with controller therapies is recommended for all patients with asthma. For patients with severe uncontrolled asthma infected by SARS-CoV-2, adjustment of controllers and biologics should be based on a multidisciplinary decision. SUMMARY: Underrepresentation of SARS-CoV-2-infected patients with asthma and related allergic diseases may be based on potentially protective underlying mechanisms, such as type 2 airway inflammation, downregulation of ACE2/TMPRSS2 receptors, reduced exposures to triggers and improved adherence to controller medications. Although it is imperative that control should be maintained and asthma medications be continued in all patients, management of patients with severe uncontrolled asthma infected by SARS-CoV-2 including adjustment of controllers and biologics should be discussed on an individual basis.
- MeSH
- antiastmatika terapeutické užití MeSH
- bronchiální astma farmakoterapie imunologie patofyziologie virologie MeSH
- COVID-19 komplikace imunologie patofyziologie prevence a kontrola MeSH
- lidé MeSH
- ochranné faktory MeSH
- progrese nemoci MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
PURPOSE OF REVIEW: To provide an update on the implementation of precision medicine, based on treatable traits and mechanisms, in the daily clinical management of chronic airways diseases. RECENT FINDINGS: Recent insights into the complex and heterogeneous nature of chronic airway diseases including chronic obstructive pulmonary disease (COPD) and asthma identified several clinical and inflammatory phenotypes. This shifted the management focus of these diseases away from the prototypic disease labels and paved the way for developing novel targeted therapies.The concept of precision medicine aims to link the right patient to the right treatment, while minimizing the risk of adverse effects. Several treatable features ('treatable traits') have now been identified for these chronic airway diseases, including pulmonary, extra-pulmonary, and psychological/lifestyle/environmental traits. As the next step, innovative detection techniques should clarify underlying mechanisms and molecular pathways of these treatable traits and novel reliable point-of-care (composite) biomarkers to help predict responders to targeted therapies must be developed. SUMMARY: Precision medicine links the right patient to the right treatment. Identification of treatable traits in asthma and COPD will help optimize the treatment approach in these heterogeneous diseases. Furthermore, in-depth identification of underlying molecular pathways and reliable biomarkers in chronic airways diseases to guide targeted treatment in individual patients is in progress.
BACKGROUND: In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication. METHODS: Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40-80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice-web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061. FINDINGS: 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34-0·69], p<0·0001) and in the 125 mg dose group (RR 0·70 [0·51-0·95], p=0·0232) versus placebo in LAVOLTA I. Exacerbation rates were also reduced in biomarker-high patients in both dose groups versus placebo in LAVOLTA II (37·5 mg: RR 0·74 [95% CI 0·54-1·01], p=0·0609; 125 mg: RR 0·74 [0·54-1·02], p=0·0626). Pooling both studies, the proportion of patients who experienced treatment-emergent adverse events (79% [1125 of 1432 patients] for both lebrikizumab doses vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group. INTERPRETATION: Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out. FUNDING: F Hoffmann-La Roche.
- MeSH
- antiastmatika aplikace a dávkování MeSH
- biologické markery krev MeSH
- bronchiální astma krev farmakoterapie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- eozinofily účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- molekuly buněčné adheze krev MeSH
- monoklonální protilátky aplikace a dávkování MeSH
- počet leukocytů MeSH
- progrese nemoci MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Účel přehledu: Výsledné ukazatele týkající se astmatu jsou základním kamenem klinického výzkumu tohoto onemocnění. Ačkoli je známo, jak jsou důležité, pro výzkumníky je stále obtížné tyto ukazatele standardizovat, což je z velké části dáno různorodostí astmatu. Cílem tohoto článku je poskytnout přehled o nových doporučeních pro standardizaci výsledných ukazatelů týkajících se astmatu v klinických studiích a zmínit se o oblastech, jež by měly být zkoumány v budoucnu. Nové poznatky: Pro klinické studie zaměřené na astma se doporučuje uplatňovat několik výsledných ukazatelů, přičemž tyto ukazatele se v daných studiích využívají k posuzování různých intervencí. K těmto výsledným ukazatelům patří plicní funkce, ukazatele kontroly astmatu, příznaky, exacerbace, kvalita života, biomarkery, míra využívání zdravotní péče a náklady na zdravotní péči. Nověji byla v USA na semináři Asthma Outcomes Workshop (Seminář pro výsledné ukazatele týkající se astmatu), podporovaném Národními zdravotními instituty (National Institutes of Health, NIH) a Agenturou pro výzkum a kvalitu zdravotní péče (Agency for Healthcare Research and Quality, AHRQ), vydána doporučení ohledně klíčových ukazatelů, doplňkových ukazatelů a budoucích oblastí zájmu. Souhrn: Standardizace výsledných ukazatelů týkajících se astmatu umožňuje porovnávání výsledků napříč mnoha studiemi a pracovišti. Doporučení, která vyplynula ze semináře Asthma Outcomes Workshop, představují vynikající první krok ke standardizaci způsobu, jakým jsou výsledné ukazatele vztahující se k astmatu hodnoceny. Komunita vědců zabývajících se výzkumem astmatu nyní stojí před úkolem uvést tato doporučení do praxe, dále na nich stavět a rozvíjet je.
