Mechanisms underlying corticosteroid resistance in patients with asthma: a review of current knowledge

ABSTRACT

Introduction

Corticosteroids are the most cost-effective anti-inflammatory drugs available for the treatment of asthma. Despite their effectiveness, several asthmatic patients have corticosteroid resistance or insensitivity and exhibit a poor response. Corticosteroid insensitivity implies a poor prognosis due to challenges in finding alternative therapeutic options for asthma.

Areas covered

In this review, we describe asthma phenotypes and endotypes, as well as their differential responsiveness to corticosteroids. In addition, we describe the mechanism of action of corticosteroids underlying their regulation of the expression of glucocorticoid receptors (GRs) and their anti-inflammatory effects. Furthermore, we summarize the mechanistic evidence underlying corticosteroid-insensitive asthma, which is mainly related to changes in GR gene expression, structure, and post-transcriptional modifications. Finally, various pharmacological strategies designed to reverse corticosteroid insensitivity are discussed.

Expert opinion

Corticosteroid insensitivity is influenced by the asthma phenotype, endotype, and severity, and serves as an indication for biological therapy. The molecular mechanisms underlying corticosteroid-insensitive asthma have been used to develop targeted therapeutic strategies. However, the lack of clinical trials prevents the clinical application of these treatments.

KEYWORDS:

• Corticosteroids
• corticosteroid resistance
• asthma
• chronic rhinosinusitis with nasal polyposis
• glucocorticoid receptor

Article highlights

• Asthma is a heterogenous disease with multiple phenotypes and endotypes that have varying degrees of corticosteroid responsiveness.

• Non-T2 inflammation, late-onset eosinophilic severe asthma, granulocytic (neutrophilic) asthma, late-onset asthma in smokers, and obesity-related asthma are particularly insensitive to the anti-inflammatory effects of corticosteroids.

• The severity of asthma is correlated with corticosteroid insensitivity, and severe asthma is characterized by corticosteroid insensitivity.

• The most extensively studied mechanisms involved in corticosteroid-insensitive asthma include Toll-like receptor overactivation, PI3K-δ/HDAC2 axis, low GRα/GRβ ratio, and GRser226 hyperphosphorylation.

• Preclinical evidence suggests the effectiveness of drug combinations in treating corticosteroid-insensitive asthma, although clinical evidence is needed to confirm the preclinical findings.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the grants PID2020-114871RB-I00 (J Cortijo), Fondo Europeo de Desarrollo Regional (FEDER) and Instituto de salud Carlos III, PI20/01363 (J Milara), CIBERES (CB06/06/0027) from the Spanish Government and by research grants from the Regional Government Prometeo 2017/023/UV (J Cortijo), from “Generalitat Valenciana”. Funding entities did not contribute to the study design or data collection, analysis and interpretation nor to the writing of the manuscript.