[Dupilumab : a new treatment for severe T2 high asthma]. / Dupilumab, Dupixent® :un nouveau traitement pour l'asthme sévère avec un profil «T2 high¼.

Severe asthma often features a T2 high profile regulated by cytokines such as interleukins IL-4, IL-5 and IL-13. Dupilumab (Dupixent®) is humanized monoclonal antibody directed against the α subunit of the receptor for IL-4 and IL-13. Here we summarise the immunogical background of severe asthma which supports the use of dupilumab and the pivotal randomised controlled trials which have established the efficacy of dupilumab in treating people with severe asthma. Dupilumab reduces the exacerbation rate, has corticosteroids sparing effect, provides sustained improvement in expiratory flow rates and improved asthma control and quality of life with a reassuring safety profile. Dupilumab reduces the levels of FeNO values and of serum IgE but not those of circulating eosinophils. We also report on a few real life data with dupilumab supporting its clinical effectiveness.

L'asthme sévère est souvent caractérisé par un profil immunologique dit «T2 high¼ régulé par des cytokines telles que les interleukines IL-4, IL-5 et IL-13. Le dupilumab (Dupixent®) est un anticorps monoclonal humanisé dirigé contre la sous-unité α du récepteur à l'IL-4 et à l'IL-13. Nous présentons ici les bases immunologiques qui annoncent son efficacité dans le traitement de l'asthme sévère et les grandes études contrôlées qui ont validé son efficacité. Le dupilumab réduit la fréquence des exacerbations, permet une épargne en corticoïdes systémiques, améliore les débits expiratoires, le contrôle de la maladie et la qualité de vie des personnes asthmatiques, sans donner lieu à des effets secondaires notables. Il réduit le taux de FeNO et des IgE sériques, mais pas celui des éosinophiles circulants. Nous donnons également un aperçu de quelques données obtenues en vie réelle pour souligner son utilité en clinique.

Evidence for 2 clusters among patients with noneosinophilic asthma.

BACKGROUND: Although asthma is often seen as an eosinophilic disease associated with atopy, patients with noneosinophilic asthma represent a substantial part of the population with asthma. OBJECTIVE: To apply an unsupervised clustering method in a cohort of 588 patients with noneosinophilic asthma (sputum eosinophils < 3%) recruited from an asthma clinic of a secondary care center. METHODS: Our cluster analysis of the whole cohort identified 2 subgroups as cluster 1 (n = 417) and cluster 2 (n = 171). RESULTS: Cluster 1 comprised a predominantly female group with late disease onset, a low proportion of atopy (24%), and a substantial smoking history (53%). In this cluster, treatment burden was low (<50% of inhaled corticosteroid users); asthma control and quality of life were poor, with median Asthma Control Test, Asthma Control Questionnaire, and Asthma Quality of Life scores of 16, 1.7, and 4.5, respectively, whereas lung function was preserved with a median postbronchodilation forced expiratory volume in 1 second of 93% predicted. Cluster 2 was a predominantly male group, almost exclusively comprising patients with atopy (99%) with early disease onset and a moderate treatment burden (median inhaled corticosteroids dose 800 µg/d equivalent beclomethasone). In cluster 2, asthma was partially controlled, with median Asthma Control Test and Asthma Control Questionnaire scores reaching 18 and 1.3, respectively, and lung function well preserved with a median postbronchodilation of 95% predicted. Although systemic and airway neutrophilic inflammation was the dominant pattern in cluster 1, cluster 2 essentially comprised paucigranulocytic asthma with moderately elevated fraction exhaled nitric oxide. CONCLUSION: Noneosinophilic asthma splits into 2 clusters distinguishing by disease onset, atopic status, smoking history, systemic and airway inflammation, and disease control and quality of life.

[Tezepelumab (Tezspire®) : new biological treatment of severe asthma]. / Le médicament du mois. Tézépélumab (Tezspire®) : nouveau traitement biologique de l'asthme sévère.

Here we present pharmacological and clinical properties of a new biological targeting TSLP (Thymic Stromal LymphoPoietin). Tezspire® is the name of this targeted treatment which contains 210 mg tezepelumab administered subcutaneously once a month. As compared to placebo, tezepelumab reduced exacerbations whatever the baseline blood eosinophil counts, exhaled nitric oxide (FeNO) level and atopic status. The response was higher in patients exhibiting the highest levels of blood eosinophils and FeNO. Tezepelumab also improved pre- bronchodilatation forced expiratory volume in one second, symptomatic control of asthma and quality of life. Tezepelumab proved a broad anti-inflammatory effect by blocking IL-4, IL-13 and IL-5 pathways, inducing a significant reduction in serum total IgE levels, FeNO, blood and sub-mucosal eosinophils, without affecting neutrophil level. Tezepelumab also reduced bronchial hyperresponsiveness and mucus plugs.

Cet article présente les propriétés pharmacologiques et cliniques d'un nouveau traitement biologique ciblant TSLP («Thymic Stromal LymphoPoietin¼). Ce nouveau traitement ciblé porte le nom de Tezspire® et contient 210 mg de tézélépumab qui doit être administré par voie sous-cutanée une fois par mois. Comparé au placebo, le tézélépumab réduit les exacerbations quels que soient le taux d'éosinophiles systémiques, le taux de monoxyde d'azote (FeNO) dans l'air expiré ou le statut atopique. La réponse au traitement est plus importante chez les patients présentant les taux les plus élevés d'éosinophiles sanguins et de FeNO. Le tézélépumab améliore également les valeurs de volume expiré maximal par seconde avant bronchodilatation, le contrôle symptomatique de l'asthme et la qualité de vie. Le tézélépumab a démontré un effet anti-inflammatoire élargi en bloquant les voies IL-4, IL-13 et IL-5, induisant de ce fait une réduction significative des taux d'IgE sériques, de FeNO, d'éosinophiles sanguins et sous-muqueux, sans impact sur le taux de neutrophiles. Le tézélépumab réduit également l'hyperréactivité bronchique.

Cytokine-targeted therapies for asthma and COPD.

Asthma affects over 300 million people worldwide and its prevalence is increasing. COPD is the third leading cause of death globally. Asthma and COPD are complex inflammatory diseases of the airways in which impaired host defences lead to increased susceptibility to pathogens, pollutants and allergens. There is a constant interplay between host and the environment. Environmental exposures can alter the lung microbiome and influence the development of sensitisation by disrupting normal immunoregulation. The underlying airway inflammation in severe asthma is heterogeneous, with upregulation of type 2 cytokines in most cases but increased neutrophilic inflammation and activated T-helper 17 mediated immunity in others. COPD may also comprise several different phentoypes that are driven by different molecular mechanisms or endotypes. This disease heterogeneity is affected by comorbidities, treatments and environmental exposures. Recent intervention trials have shed light on the pathways beyond type 2 inflammation that can lead to beneficial outcomes versus potentially deleterious effects. We have made a great deal of progress over the last 10 years in terms of immunology and the pathophysiology of asthma and this has led to the development of novel treatments and major improvements in severe asthma outcomes. In COPD, however, no targeted treatments have demonstrated great improvements. This article reviews the mechanism of action and efficacy of the available biologics in asthma and COPD.