Glucocorticoid Treatment in Severe Asthma

Severe asthma affects approximately 3% to 10% of the asthmatic population and is characterized by persistent symptoms and frequent exacerbations despite high-intensity therapy. Historically, glucocorticoids (GCs) have been the mainstay of treatment due to their broad anti-inflammatory effects. However, long-term systemic GC use is associated with substantial toxicity and heterogeneous clinical response, largely influenced by underlying inflammatory endotypes. Type 2 (T2) asthma, marked by eosinophilia and cytokines such as IL-4, IL-5, and IL-13, generally responds well to GCs. In contrast, non-T2 phenotypes, often associated with neutrophilic inflammation, obesity, or smoking, exhibit GC resistance. Molecular mechanisms underlying GC resistance include GRβ overexpression, impaired GRα nuclear translocation via mitogen-activated protein kinase (MAPK) activation, and histone deacetylase-2 (HDAC2) inactivation by oxidative stress. Therapeutic strategies for severe asthma involve maximizing inhaled corticosteroids (ICSs) and adding long-acting bronchodilators or biologics before considering maintenance oral corticosteroids (OCSs). Despite these guidelines, OCS overuse remains common, with many patients exposed to cumulative doses associated with severe adverse effects. These include osteoporosis, diabetes, infections, neuropsychiatric symptoms, and adrenal suppression. Therefore, reducing systemic GC exposure is a key objective in modern asthma management. Biologic therapies targeting IgE (omalizumab), IL-5 (mepolizumab, reslizumab), IL-5Rα (benralizumab), IL-4Rα (dupilumab), and thymic stromal lymphopoietin (tezepelumab) have shown substantial OCS-sparing effects in clinical trials, enabling dose reduction or discontinuation in many patients with steroid-dependent asthma. These agents, aligned with precision medicine principles, allow for phenotype-specific treatment and improved safety profiles. Future efforts should focus on improving biomarker-driven treatment selection, expanding non-T2 therapeutic options, and implementing steroid stewardship protocols. In conclusion, while GCs remain essential for acute exacerbations and as bridging therapy, their chronic use should be minimized. Biologic therapies offer a transformative opportunity to reduce GC burden, improving long-term outcomes and quality of life in patients with severe asthma.